Vascular

Ischemic colitis is one of the diagnoses that should be considered when patients present with abdominal pain, diarrhea, and intestinal bleeding (others are infectious colitis, inflammatory bowel disease, diverticulitis, and colon cancer). Its incidence is difficult to determine, as many mild cases are transient and are either not reported or misdiagnosed. However, it is the most common type of intestinal ischemia¹ and is responsible for an estimated 1 in 2,000 hospital admissions.²

In this review, we review the main causes of and risk factors for colonic ischemia and discuss how to diagnose and treat it.

BLOOD SUPPLY IS TENUOUS IN ‘WATERSHED’ AREAS

The superior and inferior mesenteric arteries have an extensive network of collateral blood vessels at both the base and border of the mesentery, called the arch of Riolan and the marginal artery of Drummond, respectively.

From Baixauli J, et al. Investigation and management of ischemic colitis. Cleve Clin J Med 2003; 70:920–934.

MANY POSSIBLE CAUSES AND FACTORS

Age. Ischemic colitis most often occurs in elderly people; the average age is 70 years.⁶ Binns and Isaacson⁷ suggest that age-related tortuosity of the colonic arteries increases vascular resistance and contributes to colonic ischemia in elderly patients.

Hypotension and hypovolemia are the most common mechanisms of colonic ischemia. Hypotension can be due to sepsis or impaired left ventricular function, and hypovolemia can be caused by dehydration or bleeding. These result in systemic hypoperfusion, triggering a mesenteric vasoconstrictive reflex. Once the hypoperfusion resolves and blood flow to the ulcerated portions resumes, bleeding develops from reperfusion injury.⁸

Cardiac thromboembolism can also contribute to colonic ischemia. Hourmand-Ollivier et al⁹ found a cardiac source of embolism in almost one-third of patients who had ischemic colitis, suggesting the need for routine screening with electrocardiography, Holter monitoring, and transthoracic echocardiography.

Myocardial infarction. Cappell¹⁰ found, upon colonoscopic examination, that about 14% of patients who developed hematochezia after a myocardial infarction had ischemic colitis. These patients had more complications and a worse in-hospital prognosis than did patients who had ischemic colitis due to other causes.¹¹

Major vascular surgical procedures can disrupt the colonic blood supply, and in two case series,^12,13 up to 7% of patients who underwent endoscopy after open aortoiliac reconstructive surgery had evidence of ischemic colitis. In other series,^14,15 the segment most often affected was the distal left colon, and the cause was iatrogenic ligation of the inferior mesenteric artery or intraoperative hypoperfusion in patients with chronic occlusion of this artery. Endovascular repair of aortoiliac aneurysm also carries a risk of ischemic colitis, though this risk is smaller (< 2%).¹⁶

Hypercoagulable states. The role of acquired or hereditary hypercoagulable states in colonic ischemia has not been extensively investigated and remains poorly understood.

Conditions that increase clotting can cause thrombotic occlusion of small vessels that supply the colon, leading to ischemia. In small retrospective studies and case reports,^17–26 28% to 74% of patients who had ischemic colitis had abnormal results on tests for protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, the factor V Leiden mutation, and the prothrombin G20210A mutation. However, in what percentage of cases the abnormality actually caused the ischemic colitis remains unknown.

Arnott et al²⁷ reported that 9 of 24 patients with ischemic colitis had abnormal results on testing for hypercoagulable conditions. Three patients had mildly persistent elevation in anticardiolipin antibodies, but none had the factor V Leiden mutation or a deficiency of protein C, protein S, or antithrombin.

Koutroubakis et al²⁰ reported significantly higher prevalences of antiphospholipid antibodies and heterogeneity for the factor V Leiden mutation in 35 patients with a history of ischemic colitis than in 18 patients with diverticulitis and 52 healthy controls (19.4% vs 0 and 1.9%, 22.2% vs 0 and 3.8%, respectively). Overall, 26 (72%) of 36 patients had at least one abnormal hypercoagulable test result.

Most patients with ischemic colitis are relatively old (over 60 years), and many have multiple concomitant vascular risk factors, suggesting that many factors contribute to ischemic colitis and that thrombophilia is not necessarily the direct cause. Hypercoagulable states may play a more important role in young, healthy patients who present with chronic or recurrent colonic ischemia.

Because no large clinical trials have been done and data are scarce and limited to case reports and small retrospective studies, a hypercoagulable evaluation is reserved for younger patients and those with recurrent, unexplained ischemic colitis.

Even if we detect thrombophilia, nobody yet knows what the appropriate medical treatment should be. Although some cases of ischemic colitis with associated thrombophilia have been successfully treated with anticoagulants,^28,29 the benefit of diagnosing and treating a hypercoagulable state in ischemic colitis is still unproven. Therefore, oral anticoagulation should be used only in those in whom a hypercoagulable state is the most likely cause of severe or recurrent colonic ischemia.

There are no official guidelines on the duration of anticoagulation in such patients, but we treat for 6 months and consider indefinite treatment if the ischemic colitis recurs.

Medications that should always be considered as possible culprits include:

• Alosetron (Lotronex), which was temporarily withdrawn by the US Food and Drug Administration because of its association with ischemic colitis when prescribed to treat diarrhea-predominant irritable bowel syndrome.³⁰ It was later reinstated, with some restrictions.
• Digitalis
• Diuretics
• Estrogens
• Danazol (Danocrine)
• Nonsteroidal anti-inflammatory drugs
• Tegaserod (Zelnorm)
• Paclitaxel (Abraxane)
• Carboplatin (Paraplatin)
• Sumatriptan (Imitrex)
• Simvastatin (Zocor)
• Interferon-ribavirin³¹
• Pseudoephedrine (eg, Sudafed).³²

Endoscopic retrograde cholangiopancreatography can cause ischemic colitis if the rare life-threatening complication of mesenteric hematoma occurs.³³

Chronic constipation can lead to colonic ischemia by increasing intraluminal pressure, which hinders blood flow and reduces the arteriovenous oxygen gradient in the colonic wall.^34,35

Long-distance running can cause sustained bouts of ischemia, likely due to shunting of blood away from the splanchnic circulation, along with dehydration and electrolyte abnormalities. Affected runners present with lower abdominal pain and hematochezia. The colitis usually resolves without sequelae with rehydration and electrolyte correction.³⁶

Vasospasm has been described as a cause of ischemia. During systemic hypoperfusion, vasoactive substances shunt blood from the gut to the brain through mesenteric vasoconstriction.³⁷ This phenomenon can occur in dehydration-induced hypotension, heart failure, septic shock, or exposure to drugs such as antihypertensive medications, digoxin, or cocaine. Necrosis of the villous layer and transmural infarctions can occur with uninterrupted ischemia lasting more than 8 hours.³⁸

Snake venom. The bite of Agkistrodon blomhoffii brevicaudus, a pit viper found in China and Korea, was recently reported to cause transient ischemic colitis due to disseminated intravascular coagulation. The condition resolved in about 10 days after treatment with polyvalent antivenom solution, transfusion of platelets and fresh frozen plasma, and empirically chosen antibiotics, ie, ampicillin-sulbactam (Unasyn) and metronidazole (Flagyl).³⁹

CLINICAL MANIFESTATIONS

As stated above, ischemic colitis should be included in the differential diagnosis when assessing patients with abdominal pain, diarrhea, or bloody stools.

Typical presentation

The typical presentation of acute colonic ischemia includes:

• Rapid onset of mild abdominal pain
• Tenderness over the affected bowel area, usually on the left side near the splenic flexure or the rectosigmoid junction
• Mild to moderate hematochezia beginning within 1 day of the onset of abdominal pain. The bleeding is often not profuse and does not cause hemodynamic instability or require transfusion.⁴⁰

Differentiate from mesenteric ischemia

It is important to differentiate between ischemic colitis and mesenteric ischemia, which is more serious and affects the small bowel.

Most patients with acute mesenteric ischemia complain of sudden onset of severe abdominal pain out of proportion to the tenderness on physical examination, they appear profoundly ill, and they do not have bloody stools until the late stages. They need urgent mesenteric angiography or another fast imaging test.⁴

In contrast, many patients with chronic mesenteric ischemia (or “abdominal angina”) report recurrent severe postprandial abdominal pain, leading to fear of food and weight loss.

Varies in severity

The severity of ischemic colitis varies widely, with hypoperfusion affecting as little as a single segment or as much as the entire colon. Over three-fourths of cases are the milder, nongangrenous form, which is temporary and rarely causes long-term complications such as persistent segmental colitis or strictures.⁴¹ In contrast, gangrenous colonic ischemia, which accounts for about 15% of cases, can be life-threatening.

Colonic ischemia can be categorized according to its severity and clinical presentation⁴²:

• Reversible colonopathy (submucosal or intramural hemorrhage)
• Transient colitis (45% of cases were reversible or transient in a 1978 report by Boley et al⁴³)
• Chronic colitis (19% of cases)
• Stricture (13%)
• Gangrene (19%)
• Fulminant universal colitis.

The resulting ischemic injury can range from superficial mucosal damage to mural or even full-thickness transmural infarction.⁴⁴

Although most cases involve the left colon, about one-fourth involve the right. Right-sided colonic ischemia tends to be more severe: about 60% of patients require surgery (five times more than with colitis of other regions), and the death rate is twice as high (close to 23%).⁴⁵

DIAGNOSIS DEPENDS ON SUSPICION

The diagnosis of colonic ischemia largely depends on clinical suspicion, especially since many other conditions (eg, infectious colitis, inflammatory bowel disease, diverticulitis, colon cancer) present with abdominal pain, diarrhea, and hematochezia. One study showed that a clinical presentation of lower abdominal pain or bleeding, or both, was 100% predictive of ischemic colitis when accompanied by four or more of the following risk factors: age over 60, hemodialysis, hypertension, hypoalbuminemia, diabetes mellitus, or drug-induced constipation. ⁴⁶

Stool studies can identify organisms

Invasive infections with Salmonella, Shigella, and Campylobacter species and Eschericia coli O157:H7 should be identified early with stool studies if the patient presents as an outpatient or has been hospitalized less than 72 hours. Parasites such as Entamoeba histolytica and Angiostrongylus costaricensis and viruses such as cytomegalovirus should be considered in the differential diagnosis, as they can cause ischemic colitis.^41,47Clostridium difficile should be excluded in those exposed to antibiotics.

Blood tests may indicate tissue injury

Although no laboratory marker is specific for ischemic colitis, elevated serum levels of lactate, lactate dehydrogenase, creatine kinase, or amylase may indicate tissue injury. The combination of abdominal pain, a white blood cell count greater than 20 × 10⁹/L, and metabolic acidosis suggests intestinal ischemia and infarction.

Endoscopy is the test of choice

Endoscopy has become the diagnostic test of choice in establishing the diagnosis of ischemic colitis, although computed tomography (CT) can provide suggestive findings and exclude other illnesses. Colonoscopy has almost completely replaced radiography with bariumenema contrast as a diagnostic tool because it is more sensitive for detecting mucosal changes, it directly visualizes the mucosa, and it can be used to obtain biopsy specimens.⁴⁸

Colonoscopy is performed without bowel preparation to prevent hypoperfusion caused by dehydrating cathartics. In addition, the scope should not be advanced beyond the affected area, and minimal air insufflation should be used to prevent perforation.

Endoscopic findings can help differentiate ischemic colitis from other, clinically similar diseases. For instance, unlike irritable bowel disease, ischemic colitis tends to affect a discrete segment with a clear delineation between affected and normal mucosa, it spares the rectum, the mucosa heals rapidly as seen on serial colonoscopic examinations, and a single linear ulcer, termed the “single-stripe” sign, runs along the longitudinal axis of the colon.^49,50

Biopsy features are not specific, as findings of hemorrhage, capillary thrombosis, granulation tissue with crypt abscesses, and pseudopolyps can also be seen in other conditions, such as Crohn disease.^54,55

Imaging studies are often used, but the findings lack specificity.

Plain abdominal radiography can help only in advanced ischemia, in which distention or pneumatosis can be seen.

CT with contrast can reveal thickening of the colon wall in a segmental pattern in ischemic colitis, but this finding also can be present in infectious and Crohn colitis. CT findings of colonic ischemia also include pericolic streakiness and free fluid. Pneumatosis coli often signifies infarcted bowel.⁵⁶ However, CT findings can be completely normal in mild cases or if done early in the course.

Angiography in severe cases

Since colonic ischemia is most often transient, mesenteric angiography is not indicated in mild cases. Angiography is only considered in more severe cases, especially when only the right colon is involved, the diagnosis of colonic ischemia has not yet been determined, and acute mesenteric ischemia needs to be excluded. A focal lesion is often seen in mesenteric ischemia, but not often in colonic ischemia.

Looking for the underlying cause

Once the diagnosis of ischemic colitis is made, an effort should be made to identify the cause (Table 1). The initial step can be to remove or treat reversible causes such as medications or infections. As mentioned earlier, electrocardiography, Holter monitoring, and transthoracic echocardiography should be considered in patients with ischemic colitis to rule out cardiac embolic sources.⁹ A hypercoagulable workup can be done, but only in young patients without other clear causes or patients with recurrent events.

CONSERVATIVE TREATMENT IS ENOUGH FOR MOST

Based on Brandt LS, et al. AGA technical review on intestinal ischemic. American Gastroenterological Association. Gastroenterology 2000; 118:954–968.

Empirically chosen broad-spectrum antibiotics that cover both aerobic and anaerobic coliform bacteria are reserved for patients with moderate to severe colitis to minimize bacterial translocation and sepsis.

Whenever symptomatic ileus is present, a nasogastric tube should be placed to alleviate vomiting and abdominal discomfort.

Antiplatelet agents have not been evaluated in treating ischemic colitis and are generally not used. As mentioned earlier, anticoagulation has been used in patients who have been proven to have hypercoagulable conditions,^28,29 but its benefit is not yet proven. Currently, if the coagulation profile is abnormal, anticoagulation should be used only in cases of recurrent colonic ischemia or in young patients with severe cases in the absence of a clear cause. Anticoagulation should also be used in confirmed cases of cardiac embolization.

Surgery for some

Exploratory laparotomy with possible subtotal or segmental colectomy may be needed in acute, subacute, or chronic settings.⁴² Acute indications include peritoneal signs, massive bleeding, and fulminant ischemic colitis. Subacute indications are lack of resolution, with symptoms that persist for more than 2 or 3 weeks, or malnutrition or hypoalbuminemia due to protein-losing colonopathy. Colon stricture can be chronic and becomes an indication for surgery only when symptomatic, as some strictures resolve with time (months to years).

Right hemicolectomy and primary anastomosis of viable remaining colon is performed for right-sided colonic ischemia and necrosis, while left-sided colonic ischemia is managed with a proximal stoma and distal mucous fistula, or Hartmann procedure. Re-anastomosis and ostomy closure are usually done after 4 to 6 months.⁵⁷ However, resection and primary anastomosis can also be an option for patients with isolated ischemia of the sigmoid colon.⁵⁸ Transendoscopic dilation or stenting of short strictures can be an alternative to surgery, although experience with this is limited.^59,60

THE PROGNOSIS IS USUALLY GOOD

The prognosis depends on the extent of injury and comorbidities. Transient, self-limited ischemia involving the mucosa and submucosa has a good prognosis, while fulminant ischemia with transmural infarction carries a poor one, as it can progress to necrosis and death.

Although up to 85% of cases of ischemic colitis managed conservatively improve within 1 or 2 days and resolve completely within 1 or 2 weeks, close to one-fifth of patients develop peritonitis or deteriorate clinically and require surgery.^61,62 Surgical resection is required when irreversible ischemic injury and chronic colitis develop, as both can lead to bacteremia and sepsis, colonic stricture, persistent abdominal pain and bloody diarrhea, and protein-losing enteropathy.⁴⁰

Ischemic colitis is one of the diagnoses that should be considered when patients present with abdominal pain, diarrhea, and intestinal bleeding (others are infectious colitis, inflammatory bowel disease, diverticulitis, and colon cancer). Its incidence is difficult to determine, as many mild cases are transient and are either not reported or misdiagnosed. However, it is the most common type of intestinal ischemia¹ and is responsible for an estimated 1 in 2,000 hospital admissions.²

In this review, we review the main causes of and risk factors for colonic ischemia and discuss how to diagnose and treat it.

BLOOD SUPPLY IS TENUOUS IN ‘WATERSHED’ AREAS

The superior and inferior mesenteric arteries have an extensive network of collateral blood vessels at both the base and border of the mesentery, called the arch of Riolan and the marginal artery of Drummond, respectively.

From Baixauli J, et al. Investigation and management of ischemic colitis. Cleve Clin J Med 2003; 70:920–934.

MANY POSSIBLE CAUSES AND FACTORS

Age. Ischemic colitis most often occurs in elderly people; the average age is 70 years.⁶ Binns and Isaacson⁷ suggest that age-related tortuosity of the colonic arteries increases vascular resistance and contributes to colonic ischemia in elderly patients.

Hypotension and hypovolemia are the most common mechanisms of colonic ischemia. Hypotension can be due to sepsis or impaired left ventricular function, and hypovolemia can be caused by dehydration or bleeding. These result in systemic hypoperfusion, triggering a mesenteric vasoconstrictive reflex. Once the hypoperfusion resolves and blood flow to the ulcerated portions resumes, bleeding develops from reperfusion injury.⁸

Cardiac thromboembolism can also contribute to colonic ischemia. Hourmand-Ollivier et al⁹ found a cardiac source of embolism in almost one-third of patients who had ischemic colitis, suggesting the need for routine screening with electrocardiography, Holter monitoring, and transthoracic echocardiography.

Myocardial infarction. Cappell¹⁰ found, upon colonoscopic examination, that about 14% of patients who developed hematochezia after a myocardial infarction had ischemic colitis. These patients had more complications and a worse in-hospital prognosis than did patients who had ischemic colitis due to other causes.¹¹

Major vascular surgical procedures can disrupt the colonic blood supply, and in two case series,^12,13 up to 7% of patients who underwent endoscopy after open aortoiliac reconstructive surgery had evidence of ischemic colitis. In other series,^14,15 the segment most often affected was the distal left colon, and the cause was iatrogenic ligation of the inferior mesenteric artery or intraoperative hypoperfusion in patients with chronic occlusion of this artery. Endovascular repair of aortoiliac aneurysm also carries a risk of ischemic colitis, though this risk is smaller (< 2%).¹⁶

Hypercoagulable states. The role of acquired or hereditary hypercoagulable states in colonic ischemia has not been extensively investigated and remains poorly understood.

Conditions that increase clotting can cause thrombotic occlusion of small vessels that supply the colon, leading to ischemia. In small retrospective studies and case reports,^17–26 28% to 74% of patients who had ischemic colitis had abnormal results on tests for protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, the factor V Leiden mutation, and the prothrombin G20210A mutation. However, in what percentage of cases the abnormality actually caused the ischemic colitis remains unknown.

Arnott et al²⁷ reported that 9 of 24 patients with ischemic colitis had abnormal results on testing for hypercoagulable conditions. Three patients had mildly persistent elevation in anticardiolipin antibodies, but none had the factor V Leiden mutation or a deficiency of protein C, protein S, or antithrombin.

Koutroubakis et al²⁰ reported significantly higher prevalences of antiphospholipid antibodies and heterogeneity for the factor V Leiden mutation in 35 patients with a history of ischemic colitis than in 18 patients with diverticulitis and 52 healthy controls (19.4% vs 0 and 1.9%, 22.2% vs 0 and 3.8%, respectively). Overall, 26 (72%) of 36 patients had at least one abnormal hypercoagulable test result.

Most patients with ischemic colitis are relatively old (over 60 years), and many have multiple concomitant vascular risk factors, suggesting that many factors contribute to ischemic colitis and that thrombophilia is not necessarily the direct cause. Hypercoagulable states may play a more important role in young, healthy patients who present with chronic or recurrent colonic ischemia.

Because no large clinical trials have been done and data are scarce and limited to case reports and small retrospective studies, a hypercoagulable evaluation is reserved for younger patients and those with recurrent, unexplained ischemic colitis.

Even if we detect thrombophilia, nobody yet knows what the appropriate medical treatment should be. Although some cases of ischemic colitis with associated thrombophilia have been successfully treated with anticoagulants,^28,29 the benefit of diagnosing and treating a hypercoagulable state in ischemic colitis is still unproven. Therefore, oral anticoagulation should be used only in those in whom a hypercoagulable state is the most likely cause of severe or recurrent colonic ischemia.

There are no official guidelines on the duration of anticoagulation in such patients, but we treat for 6 months and consider indefinite treatment if the ischemic colitis recurs.

Medications that should always be considered as possible culprits include:

• Alosetron (Lotronex), which was temporarily withdrawn by the US Food and Drug Administration because of its association with ischemic colitis when prescribed to treat diarrhea-predominant irritable bowel syndrome.³⁰ It was later reinstated, with some restrictions.
• Digitalis
• Diuretics
• Estrogens
• Danazol (Danocrine)
• Nonsteroidal anti-inflammatory drugs
• Tegaserod (Zelnorm)
• Paclitaxel (Abraxane)
• Carboplatin (Paraplatin)
• Sumatriptan (Imitrex)
• Simvastatin (Zocor)
• Interferon-ribavirin³¹
• Pseudoephedrine (eg, Sudafed).³²

Endoscopic retrograde cholangiopancreatography can cause ischemic colitis if the rare life-threatening complication of mesenteric hematoma occurs.³³

Chronic constipation can lead to colonic ischemia by increasing intraluminal pressure, which hinders blood flow and reduces the arteriovenous oxygen gradient in the colonic wall.^34,35

Long-distance running can cause sustained bouts of ischemia, likely due to shunting of blood away from the splanchnic circulation, along with dehydration and electrolyte abnormalities. Affected runners present with lower abdominal pain and hematochezia. The colitis usually resolves without sequelae with rehydration and electrolyte correction.³⁶

Vasospasm has been described as a cause of ischemia. During systemic hypoperfusion, vasoactive substances shunt blood from the gut to the brain through mesenteric vasoconstriction.³⁷ This phenomenon can occur in dehydration-induced hypotension, heart failure, septic shock, or exposure to drugs such as antihypertensive medications, digoxin, or cocaine. Necrosis of the villous layer and transmural infarctions can occur with uninterrupted ischemia lasting more than 8 hours.³⁸

Snake venom. The bite of Agkistrodon blomhoffii brevicaudus, a pit viper found in China and Korea, was recently reported to cause transient ischemic colitis due to disseminated intravascular coagulation. The condition resolved in about 10 days after treatment with polyvalent antivenom solution, transfusion of platelets and fresh frozen plasma, and empirically chosen antibiotics, ie, ampicillin-sulbactam (Unasyn) and metronidazole (Flagyl).³⁹

CLINICAL MANIFESTATIONS

As stated above, ischemic colitis should be included in the differential diagnosis when assessing patients with abdominal pain, diarrhea, or bloody stools.

Typical presentation

The typical presentation of acute colonic ischemia includes:

• Rapid onset of mild abdominal pain
• Tenderness over the affected bowel area, usually on the left side near the splenic flexure or the rectosigmoid junction
• Mild to moderate hematochezia beginning within 1 day of the onset of abdominal pain. The bleeding is often not profuse and does not cause hemodynamic instability or require transfusion.⁴⁰

Differentiate from mesenteric ischemia

It is important to differentiate between ischemic colitis and mesenteric ischemia, which is more serious and affects the small bowel.

Most patients with acute mesenteric ischemia complain of sudden onset of severe abdominal pain out of proportion to the tenderness on physical examination, they appear profoundly ill, and they do not have bloody stools until the late stages. They need urgent mesenteric angiography or another fast imaging test.⁴

In contrast, many patients with chronic mesenteric ischemia (or “abdominal angina”) report recurrent severe postprandial abdominal pain, leading to fear of food and weight loss.

Varies in severity

The severity of ischemic colitis varies widely, with hypoperfusion affecting as little as a single segment or as much as the entire colon. Over three-fourths of cases are the milder, nongangrenous form, which is temporary and rarely causes long-term complications such as persistent segmental colitis or strictures.⁴¹ In contrast, gangrenous colonic ischemia, which accounts for about 15% of cases, can be life-threatening.

Colonic ischemia can be categorized according to its severity and clinical presentation⁴²:

• Reversible colonopathy (submucosal or intramural hemorrhage)
• Transient colitis (45% of cases were reversible or transient in a 1978 report by Boley et al⁴³)
• Chronic colitis (19% of cases)
• Stricture (13%)
• Gangrene (19%)
• Fulminant universal colitis.

The resulting ischemic injury can range from superficial mucosal damage to mural or even full-thickness transmural infarction.⁴⁴

Although most cases involve the left colon, about one-fourth involve the right. Right-sided colonic ischemia tends to be more severe: about 60% of patients require surgery (five times more than with colitis of other regions), and the death rate is twice as high (close to 23%).⁴⁵

DIAGNOSIS DEPENDS ON SUSPICION

The diagnosis of colonic ischemia largely depends on clinical suspicion, especially since many other conditions (eg, infectious colitis, inflammatory bowel disease, diverticulitis, colon cancer) present with abdominal pain, diarrhea, and hematochezia. One study showed that a clinical presentation of lower abdominal pain or bleeding, or both, was 100% predictive of ischemic colitis when accompanied by four or more of the following risk factors: age over 60, hemodialysis, hypertension, hypoalbuminemia, diabetes mellitus, or drug-induced constipation. ⁴⁶

Stool studies can identify organisms

Invasive infections with Salmonella, Shigella, and Campylobacter species and Eschericia coli O157:H7 should be identified early with stool studies if the patient presents as an outpatient or has been hospitalized less than 72 hours. Parasites such as Entamoeba histolytica and Angiostrongylus costaricensis and viruses such as cytomegalovirus should be considered in the differential diagnosis, as they can cause ischemic colitis.^41,47Clostridium difficile should be excluded in those exposed to antibiotics.

Blood tests may indicate tissue injury

Although no laboratory marker is specific for ischemic colitis, elevated serum levels of lactate, lactate dehydrogenase, creatine kinase, or amylase may indicate tissue injury. The combination of abdominal pain, a white blood cell count greater than 20 × 10⁹/L, and metabolic acidosis suggests intestinal ischemia and infarction.

Endoscopy is the test of choice

Endoscopy has become the diagnostic test of choice in establishing the diagnosis of ischemic colitis, although computed tomography (CT) can provide suggestive findings and exclude other illnesses. Colonoscopy has almost completely replaced radiography with bariumenema contrast as a diagnostic tool because it is more sensitive for detecting mucosal changes, it directly visualizes the mucosa, and it can be used to obtain biopsy specimens.⁴⁸

Colonoscopy is performed without bowel preparation to prevent hypoperfusion caused by dehydrating cathartics. In addition, the scope should not be advanced beyond the affected area, and minimal air insufflation should be used to prevent perforation.

Endoscopic findings can help differentiate ischemic colitis from other, clinically similar diseases. For instance, unlike irritable bowel disease, ischemic colitis tends to affect a discrete segment with a clear delineation between affected and normal mucosa, it spares the rectum, the mucosa heals rapidly as seen on serial colonoscopic examinations, and a single linear ulcer, termed the “single-stripe” sign, runs along the longitudinal axis of the colon.^49,50

Biopsy features are not specific, as findings of hemorrhage, capillary thrombosis, granulation tissue with crypt abscesses, and pseudopolyps can also be seen in other conditions, such as Crohn disease.^54,55

Imaging studies are often used, but the findings lack specificity.

Plain abdominal radiography can help only in advanced ischemia, in which distention or pneumatosis can be seen.

CT with contrast can reveal thickening of the colon wall in a segmental pattern in ischemic colitis, but this finding also can be present in infectious and Crohn colitis. CT findings of colonic ischemia also include pericolic streakiness and free fluid. Pneumatosis coli often signifies infarcted bowel.⁵⁶ However, CT findings can be completely normal in mild cases or if done early in the course.

Angiography in severe cases

Since colonic ischemia is most often transient, mesenteric angiography is not indicated in mild cases. Angiography is only considered in more severe cases, especially when only the right colon is involved, the diagnosis of colonic ischemia has not yet been determined, and acute mesenteric ischemia needs to be excluded. A focal lesion is often seen in mesenteric ischemia, but not often in colonic ischemia.

Looking for the underlying cause

Once the diagnosis of ischemic colitis is made, an effort should be made to identify the cause (Table 1). The initial step can be to remove or treat reversible causes such as medications or infections. As mentioned earlier, electrocardiography, Holter monitoring, and transthoracic echocardiography should be considered in patients with ischemic colitis to rule out cardiac embolic sources.⁹ A hypercoagulable workup can be done, but only in young patients without other clear causes or patients with recurrent events.

CONSERVATIVE TREATMENT IS ENOUGH FOR MOST

Based on Brandt LS, et al. AGA technical review on intestinal ischemic. American Gastroenterological Association. Gastroenterology 2000; 118:954–968.

Empirically chosen broad-spectrum antibiotics that cover both aerobic and anaerobic coliform bacteria are reserved for patients with moderate to severe colitis to minimize bacterial translocation and sepsis.

Whenever symptomatic ileus is present, a nasogastric tube should be placed to alleviate vomiting and abdominal discomfort.

Antiplatelet agents have not been evaluated in treating ischemic colitis and are generally not used. As mentioned earlier, anticoagulation has been used in patients who have been proven to have hypercoagulable conditions,^28,29 but its benefit is not yet proven. Currently, if the coagulation profile is abnormal, anticoagulation should be used only in cases of recurrent colonic ischemia or in young patients with severe cases in the absence of a clear cause. Anticoagulation should also be used in confirmed cases of cardiac embolization.

Surgery for some

Exploratory laparotomy with possible subtotal or segmental colectomy may be needed in acute, subacute, or chronic settings.⁴² Acute indications include peritoneal signs, massive bleeding, and fulminant ischemic colitis. Subacute indications are lack of resolution, with symptoms that persist for more than 2 or 3 weeks, or malnutrition or hypoalbuminemia due to protein-losing colonopathy. Colon stricture can be chronic and becomes an indication for surgery only when symptomatic, as some strictures resolve with time (months to years).

Right hemicolectomy and primary anastomosis of viable remaining colon is performed for right-sided colonic ischemia and necrosis, while left-sided colonic ischemia is managed with a proximal stoma and distal mucous fistula, or Hartmann procedure. Re-anastomosis and ostomy closure are usually done after 4 to 6 months.⁵⁷ However, resection and primary anastomosis can also be an option for patients with isolated ischemia of the sigmoid colon.⁵⁸ Transendoscopic dilation or stenting of short strictures can be an alternative to surgery, although experience with this is limited.^59,60

THE PROGNOSIS IS USUALLY GOOD

The prognosis depends on the extent of injury and comorbidities. Transient, self-limited ischemia involving the mucosa and submucosa has a good prognosis, while fulminant ischemia with transmural infarction carries a poor one, as it can progress to necrosis and death.

Although up to 85% of cases of ischemic colitis managed conservatively improve within 1 or 2 days and resolve completely within 1 or 2 weeks, close to one-fifth of patients develop peritonitis or deteriorate clinically and require surgery.^61,62 Surgical resection is required when irreversible ischemic injury and chronic colitis develop, as both can lead to bacteremia and sepsis, colonic stricture, persistent abdominal pain and bloody diarrhea, and protein-losing enteropathy.⁴⁰

Ischemic colitis is one of the diagnoses that should be considered when patients present with abdominal pain, diarrhea, and intestinal bleeding (others are infectious colitis, inflammatory bowel disease, diverticulitis, and colon cancer). Its incidence is difficult to determine, as many mild cases are transient and are either not reported or misdiagnosed. However, it is the most common type of intestinal ischemia¹ and is responsible for an estimated 1 in 2,000 hospital admissions.²

In this review, we review the main causes of and risk factors for colonic ischemia and discuss how to diagnose and treat it.

BLOOD SUPPLY IS TENUOUS IN ‘WATERSHED’ AREAS

The superior and inferior mesenteric arteries have an extensive network of collateral blood vessels at both the base and border of the mesentery, called the arch of Riolan and the marginal artery of Drummond, respectively.

From Baixauli J, et al. Investigation and management of ischemic colitis. Cleve Clin J Med 2003; 70:920–934.

MANY POSSIBLE CAUSES AND FACTORS

Age. Ischemic colitis most often occurs in elderly people; the average age is 70 years.⁶ Binns and Isaacson⁷ suggest that age-related tortuosity of the colonic arteries increases vascular resistance and contributes to colonic ischemia in elderly patients.

Hypotension and hypovolemia are the most common mechanisms of colonic ischemia. Hypotension can be due to sepsis or impaired left ventricular function, and hypovolemia can be caused by dehydration or bleeding. These result in systemic hypoperfusion, triggering a mesenteric vasoconstrictive reflex. Once the hypoperfusion resolves and blood flow to the ulcerated portions resumes, bleeding develops from reperfusion injury.⁸

Cardiac thromboembolism can also contribute to colonic ischemia. Hourmand-Ollivier et al⁹ found a cardiac source of embolism in almost one-third of patients who had ischemic colitis, suggesting the need for routine screening with electrocardiography, Holter monitoring, and transthoracic echocardiography.

Myocardial infarction. Cappell¹⁰ found, upon colonoscopic examination, that about 14% of patients who developed hematochezia after a myocardial infarction had ischemic colitis. These patients had more complications and a worse in-hospital prognosis than did patients who had ischemic colitis due to other causes.¹¹

Major vascular surgical procedures can disrupt the colonic blood supply, and in two case series,^12,13 up to 7% of patients who underwent endoscopy after open aortoiliac reconstructive surgery had evidence of ischemic colitis. In other series,^14,15 the segment most often affected was the distal left colon, and the cause was iatrogenic ligation of the inferior mesenteric artery or intraoperative hypoperfusion in patients with chronic occlusion of this artery. Endovascular repair of aortoiliac aneurysm also carries a risk of ischemic colitis, though this risk is smaller (< 2%).¹⁶

Hypercoagulable states. The role of acquired or hereditary hypercoagulable states in colonic ischemia has not been extensively investigated and remains poorly understood.

Conditions that increase clotting can cause thrombotic occlusion of small vessels that supply the colon, leading to ischemia. In small retrospective studies and case reports,^17–26 28% to 74% of patients who had ischemic colitis had abnormal results on tests for protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, the factor V Leiden mutation, and the prothrombin G20210A mutation. However, in what percentage of cases the abnormality actually caused the ischemic colitis remains unknown.

Arnott et al²⁷ reported that 9 of 24 patients with ischemic colitis had abnormal results on testing for hypercoagulable conditions. Three patients had mildly persistent elevation in anticardiolipin antibodies, but none had the factor V Leiden mutation or a deficiency of protein C, protein S, or antithrombin.

Koutroubakis et al²⁰ reported significantly higher prevalences of antiphospholipid antibodies and heterogeneity for the factor V Leiden mutation in 35 patients with a history of ischemic colitis than in 18 patients with diverticulitis and 52 healthy controls (19.4% vs 0 and 1.9%, 22.2% vs 0 and 3.8%, respectively). Overall, 26 (72%) of 36 patients had at least one abnormal hypercoagulable test result.

Most patients with ischemic colitis are relatively old (over 60 years), and many have multiple concomitant vascular risk factors, suggesting that many factors contribute to ischemic colitis and that thrombophilia is not necessarily the direct cause. Hypercoagulable states may play a more important role in young, healthy patients who present with chronic or recurrent colonic ischemia.

Because no large clinical trials have been done and data are scarce and limited to case reports and small retrospective studies, a hypercoagulable evaluation is reserved for younger patients and those with recurrent, unexplained ischemic colitis.

Even if we detect thrombophilia, nobody yet knows what the appropriate medical treatment should be. Although some cases of ischemic colitis with associated thrombophilia have been successfully treated with anticoagulants,^28,29 the benefit of diagnosing and treating a hypercoagulable state in ischemic colitis is still unproven. Therefore, oral anticoagulation should be used only in those in whom a hypercoagulable state is the most likely cause of severe or recurrent colonic ischemia.

There are no official guidelines on the duration of anticoagulation in such patients, but we treat for 6 months and consider indefinite treatment if the ischemic colitis recurs.

Medications that should always be considered as possible culprits include:

• Alosetron (Lotronex), which was temporarily withdrawn by the US Food and Drug Administration because of its association with ischemic colitis when prescribed to treat diarrhea-predominant irritable bowel syndrome.³⁰ It was later reinstated, with some restrictions.
• Digitalis
• Diuretics
• Estrogens
• Danazol (Danocrine)
• Nonsteroidal anti-inflammatory drugs
• Tegaserod (Zelnorm)
• Paclitaxel (Abraxane)
• Carboplatin (Paraplatin)
• Sumatriptan (Imitrex)
• Simvastatin (Zocor)
• Interferon-ribavirin³¹
• Pseudoephedrine (eg, Sudafed).³²

Endoscopic retrograde cholangiopancreatography can cause ischemic colitis if the rare life-threatening complication of mesenteric hematoma occurs.³³

Chronic constipation can lead to colonic ischemia by increasing intraluminal pressure, which hinders blood flow and reduces the arteriovenous oxygen gradient in the colonic wall.^34,35

Long-distance running can cause sustained bouts of ischemia, likely due to shunting of blood away from the splanchnic circulation, along with dehydration and electrolyte abnormalities. Affected runners present with lower abdominal pain and hematochezia. The colitis usually resolves without sequelae with rehydration and electrolyte correction.³⁶

Vasospasm has been described as a cause of ischemia. During systemic hypoperfusion, vasoactive substances shunt blood from the gut to the brain through mesenteric vasoconstriction.³⁷ This phenomenon can occur in dehydration-induced hypotension, heart failure, septic shock, or exposure to drugs such as antihypertensive medications, digoxin, or cocaine. Necrosis of the villous layer and transmural infarctions can occur with uninterrupted ischemia lasting more than 8 hours.³⁸

Snake venom. The bite of Agkistrodon blomhoffii brevicaudus, a pit viper found in China and Korea, was recently reported to cause transient ischemic colitis due to disseminated intravascular coagulation. The condition resolved in about 10 days after treatment with polyvalent antivenom solution, transfusion of platelets and fresh frozen plasma, and empirically chosen antibiotics, ie, ampicillin-sulbactam (Unasyn) and metronidazole (Flagyl).³⁹

CLINICAL MANIFESTATIONS

As stated above, ischemic colitis should be included in the differential diagnosis when assessing patients with abdominal pain, diarrhea, or bloody stools.

Typical presentation

The typical presentation of acute colonic ischemia includes:

• Rapid onset of mild abdominal pain
• Tenderness over the affected bowel area, usually on the left side near the splenic flexure or the rectosigmoid junction
• Mild to moderate hematochezia beginning within 1 day of the onset of abdominal pain. The bleeding is often not profuse and does not cause hemodynamic instability or require transfusion.⁴⁰

Differentiate from mesenteric ischemia

It is important to differentiate between ischemic colitis and mesenteric ischemia, which is more serious and affects the small bowel.

Most patients with acute mesenteric ischemia complain of sudden onset of severe abdominal pain out of proportion to the tenderness on physical examination, they appear profoundly ill, and they do not have bloody stools until the late stages. They need urgent mesenteric angiography or another fast imaging test.⁴

In contrast, many patients with chronic mesenteric ischemia (or “abdominal angina”) report recurrent severe postprandial abdominal pain, leading to fear of food and weight loss.

Varies in severity

The severity of ischemic colitis varies widely, with hypoperfusion affecting as little as a single segment or as much as the entire colon. Over three-fourths of cases are the milder, nongangrenous form, which is temporary and rarely causes long-term complications such as persistent segmental colitis or strictures.⁴¹ In contrast, gangrenous colonic ischemia, which accounts for about 15% of cases, can be life-threatening.

Colonic ischemia can be categorized according to its severity and clinical presentation⁴²:

• Reversible colonopathy (submucosal or intramural hemorrhage)
• Transient colitis (45% of cases were reversible or transient in a 1978 report by Boley et al⁴³)
• Chronic colitis (19% of cases)
• Stricture (13%)
• Gangrene (19%)
• Fulminant universal colitis.

The resulting ischemic injury can range from superficial mucosal damage to mural or even full-thickness transmural infarction.⁴⁴

Although most cases involve the left colon, about one-fourth involve the right. Right-sided colonic ischemia tends to be more severe: about 60% of patients require surgery (five times more than with colitis of other regions), and the death rate is twice as high (close to 23%).⁴⁵

DIAGNOSIS DEPENDS ON SUSPICION

The diagnosis of colonic ischemia largely depends on clinical suspicion, especially since many other conditions (eg, infectious colitis, inflammatory bowel disease, diverticulitis, colon cancer) present with abdominal pain, diarrhea, and hematochezia. One study showed that a clinical presentation of lower abdominal pain or bleeding, or both, was 100% predictive of ischemic colitis when accompanied by four or more of the following risk factors: age over 60, hemodialysis, hypertension, hypoalbuminemia, diabetes mellitus, or drug-induced constipation. ⁴⁶

Stool studies can identify organisms

Invasive infections with Salmonella, Shigella, and Campylobacter species and Eschericia coli O157:H7 should be identified early with stool studies if the patient presents as an outpatient or has been hospitalized less than 72 hours. Parasites such as Entamoeba histolytica and Angiostrongylus costaricensis and viruses such as cytomegalovirus should be considered in the differential diagnosis, as they can cause ischemic colitis.^41,47Clostridium difficile should be excluded in those exposed to antibiotics.

Blood tests may indicate tissue injury

Although no laboratory marker is specific for ischemic colitis, elevated serum levels of lactate, lactate dehydrogenase, creatine kinase, or amylase may indicate tissue injury. The combination of abdominal pain, a white blood cell count greater than 20 × 10⁹/L, and metabolic acidosis suggests intestinal ischemia and infarction.

Endoscopy is the test of choice

Endoscopy has become the diagnostic test of choice in establishing the diagnosis of ischemic colitis, although computed tomography (CT) can provide suggestive findings and exclude other illnesses. Colonoscopy has almost completely replaced radiography with bariumenema contrast as a diagnostic tool because it is more sensitive for detecting mucosal changes, it directly visualizes the mucosa, and it can be used to obtain biopsy specimens.⁴⁸

Colonoscopy is performed without bowel preparation to prevent hypoperfusion caused by dehydrating cathartics. In addition, the scope should not be advanced beyond the affected area, and minimal air insufflation should be used to prevent perforation.

Endoscopic findings can help differentiate ischemic colitis from other, clinically similar diseases. For instance, unlike irritable bowel disease, ischemic colitis tends to affect a discrete segment with a clear delineation between affected and normal mucosa, it spares the rectum, the mucosa heals rapidly as seen on serial colonoscopic examinations, and a single linear ulcer, termed the “single-stripe” sign, runs along the longitudinal axis of the colon.^49,50

Biopsy features are not specific, as findings of hemorrhage, capillary thrombosis, granulation tissue with crypt abscesses, and pseudopolyps can also be seen in other conditions, such as Crohn disease.^54,55

Imaging studies are often used, but the findings lack specificity.

Plain abdominal radiography can help only in advanced ischemia, in which distention or pneumatosis can be seen.

CT with contrast can reveal thickening of the colon wall in a segmental pattern in ischemic colitis, but this finding also can be present in infectious and Crohn colitis. CT findings of colonic ischemia also include pericolic streakiness and free fluid. Pneumatosis coli often signifies infarcted bowel.⁵⁶ However, CT findings can be completely normal in mild cases or if done early in the course.

Angiography in severe cases

Since colonic ischemia is most often transient, mesenteric angiography is not indicated in mild cases. Angiography is only considered in more severe cases, especially when only the right colon is involved, the diagnosis of colonic ischemia has not yet been determined, and acute mesenteric ischemia needs to be excluded. A focal lesion is often seen in mesenteric ischemia, but not often in colonic ischemia.

Looking for the underlying cause

Once the diagnosis of ischemic colitis is made, an effort should be made to identify the cause (Table 1). The initial step can be to remove or treat reversible causes such as medications or infections. As mentioned earlier, electrocardiography, Holter monitoring, and transthoracic echocardiography should be considered in patients with ischemic colitis to rule out cardiac embolic sources.⁹ A hypercoagulable workup can be done, but only in young patients without other clear causes or patients with recurrent events.

CONSERVATIVE TREATMENT IS ENOUGH FOR MOST

Based on Brandt LS, et al. AGA technical review on intestinal ischemic. American Gastroenterological Association. Gastroenterology 2000; 118:954–968.

Empirically chosen broad-spectrum antibiotics that cover both aerobic and anaerobic coliform bacteria are reserved for patients with moderate to severe colitis to minimize bacterial translocation and sepsis.

Whenever symptomatic ileus is present, a nasogastric tube should be placed to alleviate vomiting and abdominal discomfort.

Antiplatelet agents have not been evaluated in treating ischemic colitis and are generally not used. As mentioned earlier, anticoagulation has been used in patients who have been proven to have hypercoagulable conditions,^28,29 but its benefit is not yet proven. Currently, if the coagulation profile is abnormal, anticoagulation should be used only in cases of recurrent colonic ischemia or in young patients with severe cases in the absence of a clear cause. Anticoagulation should also be used in confirmed cases of cardiac embolization.

Surgery for some

Exploratory laparotomy with possible subtotal or segmental colectomy may be needed in acute, subacute, or chronic settings.⁴² Acute indications include peritoneal signs, massive bleeding, and fulminant ischemic colitis. Subacute indications are lack of resolution, with symptoms that persist for more than 2 or 3 weeks, or malnutrition or hypoalbuminemia due to protein-losing colonopathy. Colon stricture can be chronic and becomes an indication for surgery only when symptomatic, as some strictures resolve with time (months to years).

Right hemicolectomy and primary anastomosis of viable remaining colon is performed for right-sided colonic ischemia and necrosis, while left-sided colonic ischemia is managed with a proximal stoma and distal mucous fistula, or Hartmann procedure. Re-anastomosis and ostomy closure are usually done after 4 to 6 months.⁵⁷ However, resection and primary anastomosis can also be an option for patients with isolated ischemia of the sigmoid colon.⁵⁸ Transendoscopic dilation or stenting of short strictures can be an alternative to surgery, although experience with this is limited.^59,60

THE PROGNOSIS IS USUALLY GOOD

The prognosis depends on the extent of injury and comorbidities. Transient, self-limited ischemia involving the mucosa and submucosa has a good prognosis, while fulminant ischemia with transmural infarction carries a poor one, as it can progress to necrosis and death.

Although up to 85% of cases of ischemic colitis managed conservatively improve within 1 or 2 days and resolve completely within 1 or 2 weeks, close to one-fifth of patients develop peritonitis or deteriorate clinically and require surgery.^61,62 Surgical resection is required when irreversible ischemic injury and chronic colitis develop, as both can lead to bacteremia and sepsis, colonic stricture, persistent abdominal pain and bloody diarrhea, and protein-losing enteropathy.⁴⁰

A 72-year-old man whose medical history includes diabetes mellitus, hypertension, coronary artery disease, aortic valve replacement, atrial fibrillation, and chronic obstructive pulmonary disease was in his usual state of health until 2 weeks ago, when he developed a purpuric rash on his legs. His physician started him on prednisone 40 mg daily for the rash; however, 1 week later he presented to a hospital emergency room when his family found him confused and diaphoretic.

In the emergency room, he was found to be hypoglycemic, with a serum glucose level of 40 mg/dL, which was promptly treated. His mental status improved partially. In the hospital, the rash worsened and progressed upwards to his trunk and upper extremities. He was transferred to our institution for further workup and management.

A review of systems reveals occasional epistaxis in the summer, recent fatigue, cough, and shortness of breath on exertion. His medications at the time of transfer include warfarin (Coumadin), amlodipine (Norvasc), insulin, ipratropium and albuterol (Combivent) inhalers, and prednisone 40 mg daily. He has not undergone surgery recently.

PHYSICAL EXAMINATION

He is alert and oriented to person but not to time and place.

Vital signs. Oral temperature 101.1°F (38.4°C), pulse rate 108, blood pressure 108/79 mm/Hg, respiratory rate 22, oxygen saturation 93% by pulse oximetry on room air, weight 94 kg (207 lb).

Head, eyes, ears, nose, and throat. No pallor or icterus, pupils are equally reactive, nasal mucosa not inflamed or ulcerated, mucous membranes moist, no sinus tenderness.

Neck. No jugular venous distention and no cervical lymphadenopathy.

Cardiovascular. Tachycardia, irregularly irregular rhythm, prosthetic valve sounds, no murmurs, rubs, or gallops.

Respiratory. Bibasal crackles (right side more than the left). No wheezing.

Abdomen. Soft, nontender, nondistended, no palpable organomegaly, bowel sounds normal.

Extremities. No edema, good peripheral pulses.

Neurologic. No focal deficits noted.

Lymphatic. No enlarged lymph nodes.

Musculoskeletal. Traumatic right second distal interphalangeal amputation. Otherwise, no joint abnormality or restriction of movement.

Initial laboratory values:

• White blood cell count 15.78 × 10⁹/L (normal 4.5–11.0)
• Absolute neutrophil count 13.3 × 10⁹/L (4.0–11.0)
• Hemoglobin 13.3 g/dL (13.5–17.5)
• Platelet count 133 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.8
• Sodium 136 mmol/L (135–146)
• Potassium 4.6 mmol/L (3.5–5.0)
• Blood urea nitrogen 31 mg/dL (10–25)
• Creatinine 1.6 mg/dL (0.70–1.40)
• Glucose 62 mg/dL (65–100)
• Bicarbonate 23 mmol/L (23–32)
• Albumin 2.5 g/dL (3.5–5.0)
• Total protein 4.6 g/dL (6.0–8.4)
• Bilirubin 1.2 mg/dL (0.0–1.5)
• Aspartate aminotransferase 41 U/L (7–40)
• Alanine aminotransferase 74 U/L (5–50)
• Alkaline phosphatase 55 U/L (40–150)
• C-reactive protein 9.9 mg/dL (0.0–1.0).

Other studies

Electrocardiography shows atrial fibrillation and left ventricular hypertrophy, but no acute changes.

Computed tomography (CT) of the head shows no evidence of hemorrhage or infarction.

Blood cultures are sent at the time of hospital admission.

WHICH TEST IS NEXT?

1. Which is the most appropriate next step for this patient?

• Urinalysis
• CT of the chest
• Echocardiography
• Skin biopsy

The rash in Figure 1 is palpable purpura, which strongly suggests small-vessel cutaneous vasculitis, a condition that can occur in a broad range of settings. An underlying cause is identified in over 70% of cases. Cutaneous vasculitis may herald a primary small-vessel systemic vasculitis such as Wegener granulomatosis, microscopic polyangiitis, or Henoch-Schönlein purpura. It can also be secondary to a spectrum of underlying triggers or diseases that include medications, infections, malignancies such as lymphoproliferative disorders, cryoglobulinemia secondary to hepatitis C viral infection, and connective tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus.

Infective endocarditis is associated with a secondary form of vasculitis and is a strong possibility in this patient, who has a prosthetic aortic valve, fever, and a high white blood cell count.

Thrombocytopenia should also prompt an assessment for any drugs the patient is taking that affect platelet function. However, thrombocytopenia typically results in nonpalpable purpura.

Idiopathic isolated cutaneous vasculitis, in which no underlying cause for the cutaneous vasculitis can be identified, is the diagnosis in less than 30% of cases.

A vasculitic disease process can involve multiple sites, which may be asymptomatic on presentation. Identifying these sites is important, not only to establish the diagnosis, but also to detect potentially life-threatening complications early.

Thus, in this patient, urinalysis should be done promptly to check for active sediment consisting of red cell casts, which would suggest renal involvement (glomerulonephritis). Also, a rising blood pressure and creatinine would point to renal involvement and warrant more aggressive initial therapy.

Chest radiography should be done to rule out pulmonary infiltrates, septic emboli, nodules, or cavities that could represent vasculitic or infectious involvement of the lungs. CT of the chest may be needed to further characterize abnormalities on chest radiography.

Echocardiography should certainly be pursued as part of the workup for endocarditis, but urinalysis is of the utmost importance in this patient at this point.

More diagnostic information is needed before considering skin biopsy.

Our patient’s sedimentation rate is 24 mm/hour. The urinalysis is strongly positive for blood and a moderate amount of protein but negative for leukocyte esterase and nitrite. The urine sediment contains numerous red blood cell casts and 6 to 10 white blood cells per high-power field.

Pending return of blood cultures, ceftriaxone (Rocephin) and azithromycin (Zithromax) are started to treat possible community-acquired pneumonia. Vancomycin (Vancocin) is empirically added, given the possibility of prosthetic valve endocarditis. Gram stain on blood cultures shows gram-positive cocci.

Ground-glass attenuation implies focal or diffuse opacification of the lung that does not obscure the vascular structures, is not associated with air bronchograms, and appears as a “veil” across the lung parenchyma.¹ It can be seen in acute diseases such as infection (including pneumonia from atypical bacteria, viruses, acid-fast bacilli, and Pneumocystis jiroveci), pulmonary hemorrhage of any cause, acute viral, eosinophilic, and interstitial pneumonias, and hypersensitivity pneumonitis. It can also be seen in chronic disease states such as interstitial lung disease, bronchoalveolar carcinoma, alveolar proteinosis, and sarcoidosis.

WHICH TEST WOULD NOT HELP?

2. Which of the following tests is least likely to help in the diagnostic evaluation at this point?

• Transthoracic echocardiography
• Transesophageal echocardiography
• Bronchoscopy
• Cystoscopy

In this case, the least likely to help is cystoscopy.

This patient’s vasculitic-appearing rash, ground-glass pulmonary infiltrates, and impaired renal function with red cell casts suggest a pulmonary-renal syndrome, and with this constellation of features, a systemic vasculitis is very likely. Therefore, the focus of the evaluation should be on any evidence to support a diagnosis of vasculitis, as well as other possible causes.

In a patient with diabetes, an artificial heart valve, and fever, the possibility of infection, especially endocarditis, remains high. Transthoracic echocardiography is warranted, and if it is negative for vegetations, transesophageal echocardiography would be a reasonable next option.

Bronchoscopy is warranted to determine if the infiltrates represent pulmonary hemorrhage, which can be seen in certain types of vasculitic and systemic disorders.

The finding of red cell casts in the urine indicates glomerulonephritis, and therefore the kidneys are the likely source of the urinary red blood cells, making cystoscopy of no utility in this current, acute setting.

Case continued: His condition worsens

Transthoracic echocardiography reveals a well-seated mechanical prosthetic aortic valve, trivial aortic regurgitation, a peak gradient of 23 mm Hg and a mean gradient of 12 mm Hg (normal values for his prosthetic valve), and no valvular vegetations. Transesophageal echocardiography confirms the absence of vegetations.

His oxygen requirement increases, and analysis of arterial blood gases reveals a pH of 7.37, Pco₂ 49 mm Hg (normal range 35–45), Po₂ 102 mm Hg (normal 80–100), and bicarbonate 28 mmol/L while breathing 100% supplemental oxygen by a nonrebreather face mask. He is taken to the medical intensive care unit for intubation and mechanical ventilation. Bronchoscopy performed while he is intubated confirms diffuse alveolar hemorrhage. Pulse intravenous methylprednisolone (Solu-Medrol) therapy is started.

DIFFUSE ALVEOLAR HEMORRHAGE

3. Which of the following is not true about diffuse alveolar hemorrhage?

• Its onset is usually abrupt or of short duration
• It is always associated with hemoptysis
• Radiography most commonly shows new patchy or diffuse alveolar opacities
• Pulmonary function testing shows increased diffusing capacity of the lung for carbon monoxide (Dlco)

Hemoptysis is absent at presentation in as many as 33% of patients.

The onset of diffuse alveolar hemorrhage is usually abrupt or of short duration, with initial symptoms of cough, fever, and dyspnea. Some patients, such as ours, can present with severe acute respiratory distress syndrome requiring mechanical ventilation. Radiography most often shows new patchy alveolar opacities, and CT may reveal a ground-glass appearance. On pulmonary function testing, the Dlco is high, owing to the hemoglobin within the alveoli.

ACUTE GLOMERULONEPHRITIS PLUS PULMONARY HEMORRHAGE EQUALS…?

4. Which disease could have manifestations consistent with acute glomerulonephritis and pulmonary hemorrhage?

• Antiglomerular basement membrane disease
• Wegener granulomatosis
• Microscopic polyangiitis
• Systemic lupus erythematosus

All of these are possible.

The combined presentation of acute glomerulonephritis and pulmonary hemorrhage (also called pulmonary-renal syndrome) is usually seen in antiglomerular basement membrane disease (Goodpasture syndrome) and small-vessel systemic vasculitides such as Wegener granulomatosis and microscopic polyangiitis.^2,3 It can also be seen in patients with systemic lupus erythematosus.

Antiglomerular basement membrane disease

In antiglomerular basement membrane disease, circulating antibodies are directed towards an antigen intrinsic to the glomerular basement membrane, typically leading to acute glomerulonephritis associated with crescent formation. It may present as acute renal failure in which urinalysis shows proteinuria with sediment characterized by red cell casts. Pulmonary involvement, usually alveolar hemorrhage, is present in approximately 60% to 70% of cases.

The diagnosis requires demonstration of antiglomerular basement membrane antibodies in either the serum or the kidney. Renal biopsy is usually recommended because the accuracy of serum assays is variable.

A key histologic feature of the renal lesion in antiglomerular basement membrane disease is crescentic glomerulonephritis in which immunofluorescence microscopy demonstrates the virtually pathognomonic finding of linear deposition of immunoglobulin G along the glomerular capillaries.

The treatment of choice for antiglomerular basement membrane disease is plasmapheresis and immunosuppression with a combination of glucocorticoids and cyclophosphamide (Cytoxan). If the disease is high on the differential diagnosis, empiric plasmapheresis should be started while waiting for diagnostic studies, because the prognosis of untreated glomerulonephritis is poor.

Wegener granulomatosis

Wegener granulomatosis is a systemic vasculitis of the medium and small arteries, arterioles, and venules that classically involves the upper and lower respiratory tracts and the kidneys. Patients may present with persistent rhinorrhea and epistaxis, cough with chest radiographs showing nodules, fixed infiltrates, or cavities, and abnormal urinary sediment with microscopic hematuria with or without red cell casts.

From 75% to 90% of patients with active Wegener granulomatosis are positive for antineutrophil cytoplasmic antibody (ANCA). In 60% to 80% of cases, ANCA is directed against proteinase 3 (PR3), which produces a cytoplasmic standing pattern by immunofluorescence (cANCA), while 5% to 20% have ANCA directed against myeloper-oxidase, which produces a perinuclear staining pattern (pANCA). A small number of patients with Wegener granulomatosis are ANCA-negative.

The diagnosis is usually confirmed by tissue biopsy at the site of active disease, which shows necrotizing vasculitis with granulomatous inflammation. The renal lesion is typically that of a focal, segmental, necrotizing glomerulonephritis that has few to no immune complexes (pauci-immune glomerulonephritis).

The treatment of severe disease involves a combination of cyclophosphamide and glucocorticoids initially to achieve remission followed by maintenance therapy with methotrexate or azathioprine (Imuran).

Microscopic polyangiitis

Microscopic polyangiitis is a systemic vasculitis of the capillaries, venules, and arterioles, with little or no immune complex deposition. Nearly all patients have renal involvement, and 10% to 30% have lung involvement. In those with lung involvement, diffuse alveolar hemorrhage is the most common manifestation.

On histopathologic study, microscopic polyangiitis differs from Wegener granulomatosis in that it does not have granuloma formation. However, the renal lesion is that of a pauci-immune glomerulonephritis and is identical to that seen in Wegener granulomatosis. From 70% to 85% of patients with microscopic polyangiitis are ANCA-positive, and most of these have pANCA.

The management of active severe microscopic polyangiitis is identical to that of Wegener granulomatosis.

Systemic lupus erythematosus

Systemic lupus erythematosus is an autoimmune disease characterized by tissue-binding autoantibody and immune-complex-mediated organ damage. It can involve multiple organ systems, and the diagnosis is based on characteristic clinical features and autoantibodies. The sensitivity of antinuclear antibody for lupus is close to 100%, which makes it a good screening tool. Antibodies to dsDNA and Smith antigen have high specificity for lupus.

About 75% of patients have renal involvement at some point in their disease course. The different types of renal disease in systemic lupus are usually differentiated with a renal biopsy, with immune-complex-mediated glomerular diseases being the most common.

The most common pulmonary manifestation is pleuritis with or without pleural effusion. Life-threatening pulmonary manifestations include pulmonary hemorrhage and interstitial inflammation leading to fibrosis.

Lupus has great clinical variability and the treatment approach is based on the organ manifestations, disease activity, and severity.

CASE CONTINUED: ARRIVING AT THE DIAGNOSIS

We start our patient on cyclophosphamide 175 mg daily in view of possible Wegener granulomatosis.

Even though purpura is extremely rare in primary antiglomerular basement membrane disease, this patient has life-threatening pulmonary hemorrhage, a complication seen in over 50% of these patients. Therefore, plasmapheresis is started empirically.

On the second day of cyclophosphamide treatment, tests for ANCA, glomerular basement membrane antibody, and antinuclear antibody are reported as negative, and complement levels are normal. Bronchoalveolar lavage shows no infection. Follow-up blood cultures are negative.

To summarize the findings so far, this patient has a purpuric skin rash, active urine sediment with red cell casts indicating glomerulonephritis, acute renal failure, and severe pulmonary hemorrhage requiring mechanical ventilation. Although one set of blood cultures showed gram-positive cocci, no source of infection, particularly endocarditis, could be identified.

Antiglomerular basement membrane disease would still be high on the list of suspected diagnoses, given his diffuse alveolar hemorrhage. As mentioned earlier, renal biopsy is imperative to making a diagnosis, because serologic tests have variable accuracy. And making the correct diagnosis has therapeutic implications.

Renal biopsy is performed and shows immune-complex mesangiopathic glomerulonephritis with positive immunofluorescent staining in the mesangium for IgA. Only one glomerulus shows fibrinoid necrosis.

Skin biopsy results obtained earlier showed positive direct immunofluorescence for IgA. Both renal and skin biopsies suggested Henoch-Schönlein purpura.

IgA deposition in the kidney and skin has been associated with liver cirrhosis, celiac disease, and infections with agents such as human immunodeficiency virus, cytomegalovirus, Haemophilus parainfluenzae, and Staphylococcus aureus. In a Japanese study,⁴ renal biopsy specimens from 116 patients with IgA nephropathy and from 122 patients with other types of kidney disease were examined for the presence of S aureus antigen in the glomeruli. Although antigen was not detected in non-IgA disease, 68% of specimens from patients with IgA nephropathy had S aureus cell envelope antigen together with IgA antibody in the glomeruli. However, no single antigen has been consistently identified, so it seems more probable that the development of IgA deposition in kidneys is a consequence of aberrant IgA immune response rather than the antigen itself.

HENOCH-SCHÖNLEIN PURPURA

Henoch-Schönlein purpura is a systemic vasculitis with a prominent cutaneous component. It is characterized by the tissue deposition of IgA-containing immune complexes. It is predominantly a disease of children but it can be seen in adults. A UK study found the prevalence to be 20 per 100,000 children, with the highest prevalence between ages 4 and 7 (70 per 100,000).⁵

The four cardinal clinical features of Henoch-Schönlein purpura are purpuric rash, abdominal pain, arthralgia, and renal involvement. Almost all patients have purpuric rash at some point in their disease course. Arthralgia with or without arthritis is typically migratory, oligoarticular, and nondeforming, usually affecting the large joints of the lower extremities; involvement of the upper extremities is less common.

Skin biopsy typically shows leukocytoclastic vasculitis in postcapillary venules with IgA deposition, and these findings are pathognomonic of Henoch-Schönlein purpura.

Gastrointestinal involvement can range from mild symptoms such as nausea, vomiting, abdominal pain, and paralytic ileus to severe disease such as gastrointestinal hemorrhage, bowel infarction, bowel perforation, and intussusception.

Renal involvement is common and is important, as it can in rare cases progress to end-stage renal disease. The urinalysis usually shows mild proteinuria with active sediment with red cell casts. Most patients have relatively mild disease, characterized by asymptomatic hematuria with a normal or slightly elevated creatinine. However, severe involvement may occur, with nephrotic syndrome, hypertension, and acute renal failure.

Different presentation in adults vs children

Adults with Henoch-Schönlein purpura only rarely present with bowel intussusception, whereas some studies have found that adults are more likely than children to develop significant renal involvement, including end-stage renal disease.^6,7

There is a general but not absolute correlation between the severity of clinical manifestations and the findings on renal biopsy. A poor prognosis (significant proteinuria, hypertension, renal insufficiency, or end-stage renal disease) is associated with crescent formation involving more than 50% of the glomeruli.⁸

Our current understanding of the longterm outcome of the renal disease in Henoch-Schönlein purpura is primarily derived from studies in children. In one study, complete recovery occurred in 94% of children and 89% of adults.⁷ A long-term study of 250 adults with Henoch-Schönlein purpura and renal involvement of sufficient severity to require biopsy reported that, at a median follow up of 15 years, 11% had become dialysis-dependent and 13% had severe renal failure (creatinine clearance < 30 mL/min).⁶ Recurrence is common, occurring in approximately one-third of patients, more likely in those with nephritis.⁸

The diagnosis of Henoch-Schönlein purpura is typically made on the basis of key clinical features. In patients such as ours who have an atypical presentation, biopsy of affected skin and renal biopsy can be essential in the diagnosis. Diffuse alveolar hemorrhage is exceedingly rare in Henoch-Schönlein purpura but can be seen, as in our patient.^9,10 In this setting, the findings of IgA deposits in skin and renal biopsy specimens, together with the absence of other clinical, serologic, or histologic features of other more-common potential causes, secured the diagnosis in this patient.

Henoch-Schönlein purpura is usually self-limited and requires no specific therapy. Evidence suggests that glucocorticoids enhance the rate of resolution of the arthritis and abdominal pain but do not appear to prevent recurrent disease or lessen the likelihood of progression of renal disease.⁸ Patients with severe renal involvement with renal function impairment may benefit from pulse intravenous corticosteroid therapy (methylprednisolone 250–1,000 mg per day for 3 days), followed by oral steroids for 3 months.¹¹

In anecdotal reports, renal function improved in 19 of 21 children with Henoch-Schönlein purpura and severe crescentic nephritis.¹² Studies have evaluated cyclophosphamide¹³ and plasmapheresis,¹⁴ but their role remains uncertain. Renal transplantation is an option in patients who progress to end-stage renal disease.

OUR CASE CONTINUED

In our patient, plasmapheresis was discontinued. As the pulmonary hemorrhage had developed during treatment with prednisone, we decided to continue cyclophosphamide, given the life-threatening nature of his disease. His pulmonary status improved and he was extubated.

During his initial hospital stay, he was taking heparin for anticoagulation therapy. However, given the life-threatening diffuse alveolar hemorrhage, heparin was stopped during the course of his stay in the intensive care unit. Once he was stable and was transferred out of the intensive care unit, heparin was resumed, and his anticoagulation therapy was bridged to warfarin just before discharge. He was eventually discharged on a tapering dose of oral prednisone and cyclophosphamide for 3 months, after which he was switched to azathioprine for maintenance therapy. He was doing well 6 months later, with a serum creatinine level of 1.6 mg/dL, no red cell casts in the urine, and no rash.

TAKE-HOME POINT

In any case of suspected vasculitis that presents with skin disease, it is essential to look for other sites with potentially life-threatening involvement. Henoch-Schönlein purpura is a systemic vasculitis with a prominent cutaneous component. It is not always benign and can be associated with serious complications such as renal failure, gastrointestinal events, and, very rarely, diffuse alveolar hemorrhage.

A 72-year-old man whose medical history includes diabetes mellitus, hypertension, coronary artery disease, aortic valve replacement, atrial fibrillation, and chronic obstructive pulmonary disease was in his usual state of health until 2 weeks ago, when he developed a purpuric rash on his legs. His physician started him on prednisone 40 mg daily for the rash; however, 1 week later he presented to a hospital emergency room when his family found him confused and diaphoretic.

In the emergency room, he was found to be hypoglycemic, with a serum glucose level of 40 mg/dL, which was promptly treated. His mental status improved partially. In the hospital, the rash worsened and progressed upwards to his trunk and upper extremities. He was transferred to our institution for further workup and management.

A review of systems reveals occasional epistaxis in the summer, recent fatigue, cough, and shortness of breath on exertion. His medications at the time of transfer include warfarin (Coumadin), amlodipine (Norvasc), insulin, ipratropium and albuterol (Combivent) inhalers, and prednisone 40 mg daily. He has not undergone surgery recently.

PHYSICAL EXAMINATION

He is alert and oriented to person but not to time and place.

Vital signs. Oral temperature 101.1°F (38.4°C), pulse rate 108, blood pressure 108/79 mm/Hg, respiratory rate 22, oxygen saturation 93% by pulse oximetry on room air, weight 94 kg (207 lb).

Head, eyes, ears, nose, and throat. No pallor or icterus, pupils are equally reactive, nasal mucosa not inflamed or ulcerated, mucous membranes moist, no sinus tenderness.

Neck. No jugular venous distention and no cervical lymphadenopathy.

Cardiovascular. Tachycardia, irregularly irregular rhythm, prosthetic valve sounds, no murmurs, rubs, or gallops.

Respiratory. Bibasal crackles (right side more than the left). No wheezing.

Abdomen. Soft, nontender, nondistended, no palpable organomegaly, bowel sounds normal.

Extremities. No edema, good peripheral pulses.

Neurologic. No focal deficits noted.

Lymphatic. No enlarged lymph nodes.

Musculoskeletal. Traumatic right second distal interphalangeal amputation. Otherwise, no joint abnormality or restriction of movement.

Initial laboratory values:

• White blood cell count 15.78 × 10⁹/L (normal 4.5–11.0)
• Absolute neutrophil count 13.3 × 10⁹/L (4.0–11.0)
• Hemoglobin 13.3 g/dL (13.5–17.5)
• Platelet count 133 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.8
• Sodium 136 mmol/L (135–146)
• Potassium 4.6 mmol/L (3.5–5.0)
• Blood urea nitrogen 31 mg/dL (10–25)
• Creatinine 1.6 mg/dL (0.70–1.40)
• Glucose 62 mg/dL (65–100)
• Bicarbonate 23 mmol/L (23–32)
• Albumin 2.5 g/dL (3.5–5.0)
• Total protein 4.6 g/dL (6.0–8.4)
• Bilirubin 1.2 mg/dL (0.0–1.5)
• Aspartate aminotransferase 41 U/L (7–40)
• Alanine aminotransferase 74 U/L (5–50)
• Alkaline phosphatase 55 U/L (40–150)
• C-reactive protein 9.9 mg/dL (0.0–1.0).

Other studies

Electrocardiography shows atrial fibrillation and left ventricular hypertrophy, but no acute changes.

Computed tomography (CT) of the head shows no evidence of hemorrhage or infarction.

Blood cultures are sent at the time of hospital admission.

WHICH TEST IS NEXT?

1. Which is the most appropriate next step for this patient?

• Urinalysis
• CT of the chest
• Echocardiography
• Skin biopsy

The rash in Figure 1 is palpable purpura, which strongly suggests small-vessel cutaneous vasculitis, a condition that can occur in a broad range of settings. An underlying cause is identified in over 70% of cases. Cutaneous vasculitis may herald a primary small-vessel systemic vasculitis such as Wegener granulomatosis, microscopic polyangiitis, or Henoch-Schönlein purpura. It can also be secondary to a spectrum of underlying triggers or diseases that include medications, infections, malignancies such as lymphoproliferative disorders, cryoglobulinemia secondary to hepatitis C viral infection, and connective tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus.

Infective endocarditis is associated with a secondary form of vasculitis and is a strong possibility in this patient, who has a prosthetic aortic valve, fever, and a high white blood cell count.

Thrombocytopenia should also prompt an assessment for any drugs the patient is taking that affect platelet function. However, thrombocytopenia typically results in nonpalpable purpura.

Idiopathic isolated cutaneous vasculitis, in which no underlying cause for the cutaneous vasculitis can be identified, is the diagnosis in less than 30% of cases.

A vasculitic disease process can involve multiple sites, which may be asymptomatic on presentation. Identifying these sites is important, not only to establish the diagnosis, but also to detect potentially life-threatening complications early.

Thus, in this patient, urinalysis should be done promptly to check for active sediment consisting of red cell casts, which would suggest renal involvement (glomerulonephritis). Also, a rising blood pressure and creatinine would point to renal involvement and warrant more aggressive initial therapy.

Chest radiography should be done to rule out pulmonary infiltrates, septic emboli, nodules, or cavities that could represent vasculitic or infectious involvement of the lungs. CT of the chest may be needed to further characterize abnormalities on chest radiography.

Echocardiography should certainly be pursued as part of the workup for endocarditis, but urinalysis is of the utmost importance in this patient at this point.

More diagnostic information is needed before considering skin biopsy.

Our patient’s sedimentation rate is 24 mm/hour. The urinalysis is strongly positive for blood and a moderate amount of protein but negative for leukocyte esterase and nitrite. The urine sediment contains numerous red blood cell casts and 6 to 10 white blood cells per high-power field.

Pending return of blood cultures, ceftriaxone (Rocephin) and azithromycin (Zithromax) are started to treat possible community-acquired pneumonia. Vancomycin (Vancocin) is empirically added, given the possibility of prosthetic valve endocarditis. Gram stain on blood cultures shows gram-positive cocci.

Ground-glass attenuation implies focal or diffuse opacification of the lung that does not obscure the vascular structures, is not associated with air bronchograms, and appears as a “veil” across the lung parenchyma.¹ It can be seen in acute diseases such as infection (including pneumonia from atypical bacteria, viruses, acid-fast bacilli, and Pneumocystis jiroveci), pulmonary hemorrhage of any cause, acute viral, eosinophilic, and interstitial pneumonias, and hypersensitivity pneumonitis. It can also be seen in chronic disease states such as interstitial lung disease, bronchoalveolar carcinoma, alveolar proteinosis, and sarcoidosis.

WHICH TEST WOULD NOT HELP?

2. Which of the following tests is least likely to help in the diagnostic evaluation at this point?

• Transthoracic echocardiography
• Transesophageal echocardiography
• Bronchoscopy
• Cystoscopy

In this case, the least likely to help is cystoscopy.

This patient’s vasculitic-appearing rash, ground-glass pulmonary infiltrates, and impaired renal function with red cell casts suggest a pulmonary-renal syndrome, and with this constellation of features, a systemic vasculitis is very likely. Therefore, the focus of the evaluation should be on any evidence to support a diagnosis of vasculitis, as well as other possible causes.

In a patient with diabetes, an artificial heart valve, and fever, the possibility of infection, especially endocarditis, remains high. Transthoracic echocardiography is warranted, and if it is negative for vegetations, transesophageal echocardiography would be a reasonable next option.

Bronchoscopy is warranted to determine if the infiltrates represent pulmonary hemorrhage, which can be seen in certain types of vasculitic and systemic disorders.

The finding of red cell casts in the urine indicates glomerulonephritis, and therefore the kidneys are the likely source of the urinary red blood cells, making cystoscopy of no utility in this current, acute setting.

Case continued: His condition worsens

Transthoracic echocardiography reveals a well-seated mechanical prosthetic aortic valve, trivial aortic regurgitation, a peak gradient of 23 mm Hg and a mean gradient of 12 mm Hg (normal values for his prosthetic valve), and no valvular vegetations. Transesophageal echocardiography confirms the absence of vegetations.

His oxygen requirement increases, and analysis of arterial blood gases reveals a pH of 7.37, Pco₂ 49 mm Hg (normal range 35–45), Po₂ 102 mm Hg (normal 80–100), and bicarbonate 28 mmol/L while breathing 100% supplemental oxygen by a nonrebreather face mask. He is taken to the medical intensive care unit for intubation and mechanical ventilation. Bronchoscopy performed while he is intubated confirms diffuse alveolar hemorrhage. Pulse intravenous methylprednisolone (Solu-Medrol) therapy is started.

DIFFUSE ALVEOLAR HEMORRHAGE

3. Which of the following is not true about diffuse alveolar hemorrhage?

• Its onset is usually abrupt or of short duration
• It is always associated with hemoptysis
• Radiography most commonly shows new patchy or diffuse alveolar opacities
• Pulmonary function testing shows increased diffusing capacity of the lung for carbon monoxide (Dlco)

Hemoptysis is absent at presentation in as many as 33% of patients.

The onset of diffuse alveolar hemorrhage is usually abrupt or of short duration, with initial symptoms of cough, fever, and dyspnea. Some patients, such as ours, can present with severe acute respiratory distress syndrome requiring mechanical ventilation. Radiography most often shows new patchy alveolar opacities, and CT may reveal a ground-glass appearance. On pulmonary function testing, the Dlco is high, owing to the hemoglobin within the alveoli.

ACUTE GLOMERULONEPHRITIS PLUS PULMONARY HEMORRHAGE EQUALS…?

4. Which disease could have manifestations consistent with acute glomerulonephritis and pulmonary hemorrhage?

• Antiglomerular basement membrane disease
• Wegener granulomatosis
• Microscopic polyangiitis
• Systemic lupus erythematosus

All of these are possible.

The combined presentation of acute glomerulonephritis and pulmonary hemorrhage (also called pulmonary-renal syndrome) is usually seen in antiglomerular basement membrane disease (Goodpasture syndrome) and small-vessel systemic vasculitides such as Wegener granulomatosis and microscopic polyangiitis.^2,3 It can also be seen in patients with systemic lupus erythematosus.

Antiglomerular basement membrane disease

In antiglomerular basement membrane disease, circulating antibodies are directed towards an antigen intrinsic to the glomerular basement membrane, typically leading to acute glomerulonephritis associated with crescent formation. It may present as acute renal failure in which urinalysis shows proteinuria with sediment characterized by red cell casts. Pulmonary involvement, usually alveolar hemorrhage, is present in approximately 60% to 70% of cases.

The diagnosis requires demonstration of antiglomerular basement membrane antibodies in either the serum or the kidney. Renal biopsy is usually recommended because the accuracy of serum assays is variable.

A key histologic feature of the renal lesion in antiglomerular basement membrane disease is crescentic glomerulonephritis in which immunofluorescence microscopy demonstrates the virtually pathognomonic finding of linear deposition of immunoglobulin G along the glomerular capillaries.

The treatment of choice for antiglomerular basement membrane disease is plasmapheresis and immunosuppression with a combination of glucocorticoids and cyclophosphamide (Cytoxan). If the disease is high on the differential diagnosis, empiric plasmapheresis should be started while waiting for diagnostic studies, because the prognosis of untreated glomerulonephritis is poor.

Wegener granulomatosis

Wegener granulomatosis is a systemic vasculitis of the medium and small arteries, arterioles, and venules that classically involves the upper and lower respiratory tracts and the kidneys. Patients may present with persistent rhinorrhea and epistaxis, cough with chest radiographs showing nodules, fixed infiltrates, or cavities, and abnormal urinary sediment with microscopic hematuria with or without red cell casts.

From 75% to 90% of patients with active Wegener granulomatosis are positive for antineutrophil cytoplasmic antibody (ANCA). In 60% to 80% of cases, ANCA is directed against proteinase 3 (PR3), which produces a cytoplasmic standing pattern by immunofluorescence (cANCA), while 5% to 20% have ANCA directed against myeloper-oxidase, which produces a perinuclear staining pattern (pANCA). A small number of patients with Wegener granulomatosis are ANCA-negative.

The diagnosis is usually confirmed by tissue biopsy at the site of active disease, which shows necrotizing vasculitis with granulomatous inflammation. The renal lesion is typically that of a focal, segmental, necrotizing glomerulonephritis that has few to no immune complexes (pauci-immune glomerulonephritis).

The treatment of severe disease involves a combination of cyclophosphamide and glucocorticoids initially to achieve remission followed by maintenance therapy with methotrexate or azathioprine (Imuran).

Microscopic polyangiitis

Microscopic polyangiitis is a systemic vasculitis of the capillaries, venules, and arterioles, with little or no immune complex deposition. Nearly all patients have renal involvement, and 10% to 30% have lung involvement. In those with lung involvement, diffuse alveolar hemorrhage is the most common manifestation.

On histopathologic study, microscopic polyangiitis differs from Wegener granulomatosis in that it does not have granuloma formation. However, the renal lesion is that of a pauci-immune glomerulonephritis and is identical to that seen in Wegener granulomatosis. From 70% to 85% of patients with microscopic polyangiitis are ANCA-positive, and most of these have pANCA.

The management of active severe microscopic polyangiitis is identical to that of Wegener granulomatosis.

Systemic lupus erythematosus

Systemic lupus erythematosus is an autoimmune disease characterized by tissue-binding autoantibody and immune-complex-mediated organ damage. It can involve multiple organ systems, and the diagnosis is based on characteristic clinical features and autoantibodies. The sensitivity of antinuclear antibody for lupus is close to 100%, which makes it a good screening tool. Antibodies to dsDNA and Smith antigen have high specificity for lupus.

About 75% of patients have renal involvement at some point in their disease course. The different types of renal disease in systemic lupus are usually differentiated with a renal biopsy, with immune-complex-mediated glomerular diseases being the most common.

The most common pulmonary manifestation is pleuritis with or without pleural effusion. Life-threatening pulmonary manifestations include pulmonary hemorrhage and interstitial inflammation leading to fibrosis.

Lupus has great clinical variability and the treatment approach is based on the organ manifestations, disease activity, and severity.

CASE CONTINUED: ARRIVING AT THE DIAGNOSIS

We start our patient on cyclophosphamide 175 mg daily in view of possible Wegener granulomatosis.

Even though purpura is extremely rare in primary antiglomerular basement membrane disease, this patient has life-threatening pulmonary hemorrhage, a complication seen in over 50% of these patients. Therefore, plasmapheresis is started empirically.

On the second day of cyclophosphamide treatment, tests for ANCA, glomerular basement membrane antibody, and antinuclear antibody are reported as negative, and complement levels are normal. Bronchoalveolar lavage shows no infection. Follow-up blood cultures are negative.

To summarize the findings so far, this patient has a purpuric skin rash, active urine sediment with red cell casts indicating glomerulonephritis, acute renal failure, and severe pulmonary hemorrhage requiring mechanical ventilation. Although one set of blood cultures showed gram-positive cocci, no source of infection, particularly endocarditis, could be identified.

Antiglomerular basement membrane disease would still be high on the list of suspected diagnoses, given his diffuse alveolar hemorrhage. As mentioned earlier, renal biopsy is imperative to making a diagnosis, because serologic tests have variable accuracy. And making the correct diagnosis has therapeutic implications.

Renal biopsy is performed and shows immune-complex mesangiopathic glomerulonephritis with positive immunofluorescent staining in the mesangium for IgA. Only one glomerulus shows fibrinoid necrosis.

Skin biopsy results obtained earlier showed positive direct immunofluorescence for IgA. Both renal and skin biopsies suggested Henoch-Schönlein purpura.

IgA deposition in the kidney and skin has been associated with liver cirrhosis, celiac disease, and infections with agents such as human immunodeficiency virus, cytomegalovirus, Haemophilus parainfluenzae, and Staphylococcus aureus. In a Japanese study,⁴ renal biopsy specimens from 116 patients with IgA nephropathy and from 122 patients with other types of kidney disease were examined for the presence of S aureus antigen in the glomeruli. Although antigen was not detected in non-IgA disease, 68% of specimens from patients with IgA nephropathy had S aureus cell envelope antigen together with IgA antibody in the glomeruli. However, no single antigen has been consistently identified, so it seems more probable that the development of IgA deposition in kidneys is a consequence of aberrant IgA immune response rather than the antigen itself.

HENOCH-SCHÖNLEIN PURPURA

Henoch-Schönlein purpura is a systemic vasculitis with a prominent cutaneous component. It is characterized by the tissue deposition of IgA-containing immune complexes. It is predominantly a disease of children but it can be seen in adults. A UK study found the prevalence to be 20 per 100,000 children, with the highest prevalence between ages 4 and 7 (70 per 100,000).⁵

The four cardinal clinical features of Henoch-Schönlein purpura are purpuric rash, abdominal pain, arthralgia, and renal involvement. Almost all patients have purpuric rash at some point in their disease course. Arthralgia with or without arthritis is typically migratory, oligoarticular, and nondeforming, usually affecting the large joints of the lower extremities; involvement of the upper extremities is less common.

Skin biopsy typically shows leukocytoclastic vasculitis in postcapillary venules with IgA deposition, and these findings are pathognomonic of Henoch-Schönlein purpura.

Gastrointestinal involvement can range from mild symptoms such as nausea, vomiting, abdominal pain, and paralytic ileus to severe disease such as gastrointestinal hemorrhage, bowel infarction, bowel perforation, and intussusception.

Renal involvement is common and is important, as it can in rare cases progress to end-stage renal disease. The urinalysis usually shows mild proteinuria with active sediment with red cell casts. Most patients have relatively mild disease, characterized by asymptomatic hematuria with a normal or slightly elevated creatinine. However, severe involvement may occur, with nephrotic syndrome, hypertension, and acute renal failure.

Different presentation in adults vs children

Adults with Henoch-Schönlein purpura only rarely present with bowel intussusception, whereas some studies have found that adults are more likely than children to develop significant renal involvement, including end-stage renal disease.^6,7

There is a general but not absolute correlation between the severity of clinical manifestations and the findings on renal biopsy. A poor prognosis (significant proteinuria, hypertension, renal insufficiency, or end-stage renal disease) is associated with crescent formation involving more than 50% of the glomeruli.⁸

Our current understanding of the longterm outcome of the renal disease in Henoch-Schönlein purpura is primarily derived from studies in children. In one study, complete recovery occurred in 94% of children and 89% of adults.⁷ A long-term study of 250 adults with Henoch-Schönlein purpura and renal involvement of sufficient severity to require biopsy reported that, at a median follow up of 15 years, 11% had become dialysis-dependent and 13% had severe renal failure (creatinine clearance < 30 mL/min).⁶ Recurrence is common, occurring in approximately one-third of patients, more likely in those with nephritis.⁸

The diagnosis of Henoch-Schönlein purpura is typically made on the basis of key clinical features. In patients such as ours who have an atypical presentation, biopsy of affected skin and renal biopsy can be essential in the diagnosis. Diffuse alveolar hemorrhage is exceedingly rare in Henoch-Schönlein purpura but can be seen, as in our patient.^9,10 In this setting, the findings of IgA deposits in skin and renal biopsy specimens, together with the absence of other clinical, serologic, or histologic features of other more-common potential causes, secured the diagnosis in this patient.

Henoch-Schönlein purpura is usually self-limited and requires no specific therapy. Evidence suggests that glucocorticoids enhance the rate of resolution of the arthritis and abdominal pain but do not appear to prevent recurrent disease or lessen the likelihood of progression of renal disease.⁸ Patients with severe renal involvement with renal function impairment may benefit from pulse intravenous corticosteroid therapy (methylprednisolone 250–1,000 mg per day for 3 days), followed by oral steroids for 3 months.¹¹

In anecdotal reports, renal function improved in 19 of 21 children with Henoch-Schönlein purpura and severe crescentic nephritis.¹² Studies have evaluated cyclophosphamide¹³ and plasmapheresis,¹⁴ but their role remains uncertain. Renal transplantation is an option in patients who progress to end-stage renal disease.

OUR CASE CONTINUED

In our patient, plasmapheresis was discontinued. As the pulmonary hemorrhage had developed during treatment with prednisone, we decided to continue cyclophosphamide, given the life-threatening nature of his disease. His pulmonary status improved and he was extubated.

During his initial hospital stay, he was taking heparin for anticoagulation therapy. However, given the life-threatening diffuse alveolar hemorrhage, heparin was stopped during the course of his stay in the intensive care unit. Once he was stable and was transferred out of the intensive care unit, heparin was resumed, and his anticoagulation therapy was bridged to warfarin just before discharge. He was eventually discharged on a tapering dose of oral prednisone and cyclophosphamide for 3 months, after which he was switched to azathioprine for maintenance therapy. He was doing well 6 months later, with a serum creatinine level of 1.6 mg/dL, no red cell casts in the urine, and no rash.

TAKE-HOME POINT

In any case of suspected vasculitis that presents with skin disease, it is essential to look for other sites with potentially life-threatening involvement. Henoch-Schönlein purpura is a systemic vasculitis with a prominent cutaneous component. It is not always benign and can be associated with serious complications such as renal failure, gastrointestinal events, and, very rarely, diffuse alveolar hemorrhage.

A 72-year-old man whose medical history includes diabetes mellitus, hypertension, coronary artery disease, aortic valve replacement, atrial fibrillation, and chronic obstructive pulmonary disease was in his usual state of health until 2 weeks ago, when he developed a purpuric rash on his legs. His physician started him on prednisone 40 mg daily for the rash; however, 1 week later he presented to a hospital emergency room when his family found him confused and diaphoretic.

In the emergency room, he was found to be hypoglycemic, with a serum glucose level of 40 mg/dL, which was promptly treated. His mental status improved partially. In the hospital, the rash worsened and progressed upwards to his trunk and upper extremities. He was transferred to our institution for further workup and management.

A review of systems reveals occasional epistaxis in the summer, recent fatigue, cough, and shortness of breath on exertion. His medications at the time of transfer include warfarin (Coumadin), amlodipine (Norvasc), insulin, ipratropium and albuterol (Combivent) inhalers, and prednisone 40 mg daily. He has not undergone surgery recently.

PHYSICAL EXAMINATION

He is alert and oriented to person but not to time and place.

Vital signs. Oral temperature 101.1°F (38.4°C), pulse rate 108, blood pressure 108/79 mm/Hg, respiratory rate 22, oxygen saturation 93% by pulse oximetry on room air, weight 94 kg (207 lb).

Head, eyes, ears, nose, and throat. No pallor or icterus, pupils are equally reactive, nasal mucosa not inflamed or ulcerated, mucous membranes moist, no sinus tenderness.

Neck. No jugular venous distention and no cervical lymphadenopathy.

Cardiovascular. Tachycardia, irregularly irregular rhythm, prosthetic valve sounds, no murmurs, rubs, or gallops.

Respiratory. Bibasal crackles (right side more than the left). No wheezing.

Abdomen. Soft, nontender, nondistended, no palpable organomegaly, bowel sounds normal.

Extremities. No edema, good peripheral pulses.

Neurologic. No focal deficits noted.

Lymphatic. No enlarged lymph nodes.

Musculoskeletal. Traumatic right second distal interphalangeal amputation. Otherwise, no joint abnormality or restriction of movement.

Initial laboratory values:

• White blood cell count 15.78 × 10⁹/L (normal 4.5–11.0)
• Absolute neutrophil count 13.3 × 10⁹/L (4.0–11.0)
• Hemoglobin 13.3 g/dL (13.5–17.5)
• Platelet count 133 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.8
• Sodium 136 mmol/L (135–146)
• Potassium 4.6 mmol/L (3.5–5.0)
• Blood urea nitrogen 31 mg/dL (10–25)
• Creatinine 1.6 mg/dL (0.70–1.40)
• Glucose 62 mg/dL (65–100)
• Bicarbonate 23 mmol/L (23–32)
• Albumin 2.5 g/dL (3.5–5.0)
• Total protein 4.6 g/dL (6.0–8.4)
• Bilirubin 1.2 mg/dL (0.0–1.5)
• Aspartate aminotransferase 41 U/L (7–40)
• Alanine aminotransferase 74 U/L (5–50)
• Alkaline phosphatase 55 U/L (40–150)
• C-reactive protein 9.9 mg/dL (0.0–1.0).

Other studies

Electrocardiography shows atrial fibrillation and left ventricular hypertrophy, but no acute changes.

Computed tomography (CT) of the head shows no evidence of hemorrhage or infarction.

Blood cultures are sent at the time of hospital admission.

WHICH TEST IS NEXT?

1. Which is the most appropriate next step for this patient?

• Urinalysis
• CT of the chest
• Echocardiography
• Skin biopsy

The rash in Figure 1 is palpable purpura, which strongly suggests small-vessel cutaneous vasculitis, a condition that can occur in a broad range of settings. An underlying cause is identified in over 70% of cases. Cutaneous vasculitis may herald a primary small-vessel systemic vasculitis such as Wegener granulomatosis, microscopic polyangiitis, or Henoch-Schönlein purpura. It can also be secondary to a spectrum of underlying triggers or diseases that include medications, infections, malignancies such as lymphoproliferative disorders, cryoglobulinemia secondary to hepatitis C viral infection, and connective tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus.

Infective endocarditis is associated with a secondary form of vasculitis and is a strong possibility in this patient, who has a prosthetic aortic valve, fever, and a high white blood cell count.

Thrombocytopenia should also prompt an assessment for any drugs the patient is taking that affect platelet function. However, thrombocytopenia typically results in nonpalpable purpura.

Idiopathic isolated cutaneous vasculitis, in which no underlying cause for the cutaneous vasculitis can be identified, is the diagnosis in less than 30% of cases.

A vasculitic disease process can involve multiple sites, which may be asymptomatic on presentation. Identifying these sites is important, not only to establish the diagnosis, but also to detect potentially life-threatening complications early.

Thus, in this patient, urinalysis should be done promptly to check for active sediment consisting of red cell casts, which would suggest renal involvement (glomerulonephritis). Also, a rising blood pressure and creatinine would point to renal involvement and warrant more aggressive initial therapy.

Chest radiography should be done to rule out pulmonary infiltrates, septic emboli, nodules, or cavities that could represent vasculitic or infectious involvement of the lungs. CT of the chest may be needed to further characterize abnormalities on chest radiography.

Echocardiography should certainly be pursued as part of the workup for endocarditis, but urinalysis is of the utmost importance in this patient at this point.

More diagnostic information is needed before considering skin biopsy.

Our patient’s sedimentation rate is 24 mm/hour. The urinalysis is strongly positive for blood and a moderate amount of protein but negative for leukocyte esterase and nitrite. The urine sediment contains numerous red blood cell casts and 6 to 10 white blood cells per high-power field.

Pending return of blood cultures, ceftriaxone (Rocephin) and azithromycin (Zithromax) are started to treat possible community-acquired pneumonia. Vancomycin (Vancocin) is empirically added, given the possibility of prosthetic valve endocarditis. Gram stain on blood cultures shows gram-positive cocci.

Ground-glass attenuation implies focal or diffuse opacification of the lung that does not obscure the vascular structures, is not associated with air bronchograms, and appears as a “veil” across the lung parenchyma.¹ It can be seen in acute diseases such as infection (including pneumonia from atypical bacteria, viruses, acid-fast bacilli, and Pneumocystis jiroveci), pulmonary hemorrhage of any cause, acute viral, eosinophilic, and interstitial pneumonias, and hypersensitivity pneumonitis. It can also be seen in chronic disease states such as interstitial lung disease, bronchoalveolar carcinoma, alveolar proteinosis, and sarcoidosis.

WHICH TEST WOULD NOT HELP?

2. Which of the following tests is least likely to help in the diagnostic evaluation at this point?

• Transthoracic echocardiography
• Transesophageal echocardiography
• Bronchoscopy
• Cystoscopy

In this case, the least likely to help is cystoscopy.

This patient’s vasculitic-appearing rash, ground-glass pulmonary infiltrates, and impaired renal function with red cell casts suggest a pulmonary-renal syndrome, and with this constellation of features, a systemic vasculitis is very likely. Therefore, the focus of the evaluation should be on any evidence to support a diagnosis of vasculitis, as well as other possible causes.

In a patient with diabetes, an artificial heart valve, and fever, the possibility of infection, especially endocarditis, remains high. Transthoracic echocardiography is warranted, and if it is negative for vegetations, transesophageal echocardiography would be a reasonable next option.

Bronchoscopy is warranted to determine if the infiltrates represent pulmonary hemorrhage, which can be seen in certain types of vasculitic and systemic disorders.

The finding of red cell casts in the urine indicates glomerulonephritis, and therefore the kidneys are the likely source of the urinary red blood cells, making cystoscopy of no utility in this current, acute setting.

Case continued: His condition worsens

Transthoracic echocardiography reveals a well-seated mechanical prosthetic aortic valve, trivial aortic regurgitation, a peak gradient of 23 mm Hg and a mean gradient of 12 mm Hg (normal values for his prosthetic valve), and no valvular vegetations. Transesophageal echocardiography confirms the absence of vegetations.

His oxygen requirement increases, and analysis of arterial blood gases reveals a pH of 7.37, Pco₂ 49 mm Hg (normal range 35–45), Po₂ 102 mm Hg (normal 80–100), and bicarbonate 28 mmol/L while breathing 100% supplemental oxygen by a nonrebreather face mask. He is taken to the medical intensive care unit for intubation and mechanical ventilation. Bronchoscopy performed while he is intubated confirms diffuse alveolar hemorrhage. Pulse intravenous methylprednisolone (Solu-Medrol) therapy is started.

DIFFUSE ALVEOLAR HEMORRHAGE

3. Which of the following is not true about diffuse alveolar hemorrhage?

• Its onset is usually abrupt or of short duration
• It is always associated with hemoptysis
• Radiography most commonly shows new patchy or diffuse alveolar opacities
• Pulmonary function testing shows increased diffusing capacity of the lung for carbon monoxide (Dlco)

Hemoptysis is absent at presentation in as many as 33% of patients.

The onset of diffuse alveolar hemorrhage is usually abrupt or of short duration, with initial symptoms of cough, fever, and dyspnea. Some patients, such as ours, can present with severe acute respiratory distress syndrome requiring mechanical ventilation. Radiography most often shows new patchy alveolar opacities, and CT may reveal a ground-glass appearance. On pulmonary function testing, the Dlco is high, owing to the hemoglobin within the alveoli.

ACUTE GLOMERULONEPHRITIS PLUS PULMONARY HEMORRHAGE EQUALS…?

4. Which disease could have manifestations consistent with acute glomerulonephritis and pulmonary hemorrhage?

• Antiglomerular basement membrane disease
• Wegener granulomatosis
• Microscopic polyangiitis
• Systemic lupus erythematosus

All of these are possible.

The combined presentation of acute glomerulonephritis and pulmonary hemorrhage (also called pulmonary-renal syndrome) is usually seen in antiglomerular basement membrane disease (Goodpasture syndrome) and small-vessel systemic vasculitides such as Wegener granulomatosis and microscopic polyangiitis.^2,3 It can also be seen in patients with systemic lupus erythematosus.

Antiglomerular basement membrane disease

In antiglomerular basement membrane disease, circulating antibodies are directed towards an antigen intrinsic to the glomerular basement membrane, typically leading to acute glomerulonephritis associated with crescent formation. It may present as acute renal failure in which urinalysis shows proteinuria with sediment characterized by red cell casts. Pulmonary involvement, usually alveolar hemorrhage, is present in approximately 60% to 70% of cases.

The diagnosis requires demonstration of antiglomerular basement membrane antibodies in either the serum or the kidney. Renal biopsy is usually recommended because the accuracy of serum assays is variable.

A key histologic feature of the renal lesion in antiglomerular basement membrane disease is crescentic glomerulonephritis in which immunofluorescence microscopy demonstrates the virtually pathognomonic finding of linear deposition of immunoglobulin G along the glomerular capillaries.

The treatment of choice for antiglomerular basement membrane disease is plasmapheresis and immunosuppression with a combination of glucocorticoids and cyclophosphamide (Cytoxan). If the disease is high on the differential diagnosis, empiric plasmapheresis should be started while waiting for diagnostic studies, because the prognosis of untreated glomerulonephritis is poor.

Wegener granulomatosis

Wegener granulomatosis is a systemic vasculitis of the medium and small arteries, arterioles, and venules that classically involves the upper and lower respiratory tracts and the kidneys. Patients may present with persistent rhinorrhea and epistaxis, cough with chest radiographs showing nodules, fixed infiltrates, or cavities, and abnormal urinary sediment with microscopic hematuria with or without red cell casts.

From 75% to 90% of patients with active Wegener granulomatosis are positive for antineutrophil cytoplasmic antibody (ANCA). In 60% to 80% of cases, ANCA is directed against proteinase 3 (PR3), which produces a cytoplasmic standing pattern by immunofluorescence (cANCA), while 5% to 20% have ANCA directed against myeloper-oxidase, which produces a perinuclear staining pattern (pANCA). A small number of patients with Wegener granulomatosis are ANCA-negative.

The diagnosis is usually confirmed by tissue biopsy at the site of active disease, which shows necrotizing vasculitis with granulomatous inflammation. The renal lesion is typically that of a focal, segmental, necrotizing glomerulonephritis that has few to no immune complexes (pauci-immune glomerulonephritis).

The treatment of severe disease involves a combination of cyclophosphamide and glucocorticoids initially to achieve remission followed by maintenance therapy with methotrexate or azathioprine (Imuran).

Microscopic polyangiitis

Microscopic polyangiitis is a systemic vasculitis of the capillaries, venules, and arterioles, with little or no immune complex deposition. Nearly all patients have renal involvement, and 10% to 30% have lung involvement. In those with lung involvement, diffuse alveolar hemorrhage is the most common manifestation.

On histopathologic study, microscopic polyangiitis differs from Wegener granulomatosis in that it does not have granuloma formation. However, the renal lesion is that of a pauci-immune glomerulonephritis and is identical to that seen in Wegener granulomatosis. From 70% to 85% of patients with microscopic polyangiitis are ANCA-positive, and most of these have pANCA.

The management of active severe microscopic polyangiitis is identical to that of Wegener granulomatosis.

Systemic lupus erythematosus

Systemic lupus erythematosus is an autoimmune disease characterized by tissue-binding autoantibody and immune-complex-mediated organ damage. It can involve multiple organ systems, and the diagnosis is based on characteristic clinical features and autoantibodies. The sensitivity of antinuclear antibody for lupus is close to 100%, which makes it a good screening tool. Antibodies to dsDNA and Smith antigen have high specificity for lupus.

About 75% of patients have renal involvement at some point in their disease course. The different types of renal disease in systemic lupus are usually differentiated with a renal biopsy, with immune-complex-mediated glomerular diseases being the most common.

The most common pulmonary manifestation is pleuritis with or without pleural effusion. Life-threatening pulmonary manifestations include pulmonary hemorrhage and interstitial inflammation leading to fibrosis.

Lupus has great clinical variability and the treatment approach is based on the organ manifestations, disease activity, and severity.

CASE CONTINUED: ARRIVING AT THE DIAGNOSIS

We start our patient on cyclophosphamide 175 mg daily in view of possible Wegener granulomatosis.

Even though purpura is extremely rare in primary antiglomerular basement membrane disease, this patient has life-threatening pulmonary hemorrhage, a complication seen in over 50% of these patients. Therefore, plasmapheresis is started empirically.

On the second day of cyclophosphamide treatment, tests for ANCA, glomerular basement membrane antibody, and antinuclear antibody are reported as negative, and complement levels are normal. Bronchoalveolar lavage shows no infection. Follow-up blood cultures are negative.

To summarize the findings so far, this patient has a purpuric skin rash, active urine sediment with red cell casts indicating glomerulonephritis, acute renal failure, and severe pulmonary hemorrhage requiring mechanical ventilation. Although one set of blood cultures showed gram-positive cocci, no source of infection, particularly endocarditis, could be identified.

Antiglomerular basement membrane disease would still be high on the list of suspected diagnoses, given his diffuse alveolar hemorrhage. As mentioned earlier, renal biopsy is imperative to making a diagnosis, because serologic tests have variable accuracy. And making the correct diagnosis has therapeutic implications.

Renal biopsy is performed and shows immune-complex mesangiopathic glomerulonephritis with positive immunofluorescent staining in the mesangium for IgA. Only one glomerulus shows fibrinoid necrosis.

Skin biopsy results obtained earlier showed positive direct immunofluorescence for IgA. Both renal and skin biopsies suggested Henoch-Schönlein purpura.

IgA deposition in the kidney and skin has been associated with liver cirrhosis, celiac disease, and infections with agents such as human immunodeficiency virus, cytomegalovirus, Haemophilus parainfluenzae, and Staphylococcus aureus. In a Japanese study,⁴ renal biopsy specimens from 116 patients with IgA nephropathy and from 122 patients with other types of kidney disease were examined for the presence of S aureus antigen in the glomeruli. Although antigen was not detected in non-IgA disease, 68% of specimens from patients with IgA nephropathy had S aureus cell envelope antigen together with IgA antibody in the glomeruli. However, no single antigen has been consistently identified, so it seems more probable that the development of IgA deposition in kidneys is a consequence of aberrant IgA immune response rather than the antigen itself.

HENOCH-SCHÖNLEIN PURPURA

Henoch-Schönlein purpura is a systemic vasculitis with a prominent cutaneous component. It is characterized by the tissue deposition of IgA-containing immune complexes. It is predominantly a disease of children but it can be seen in adults. A UK study found the prevalence to be 20 per 100,000 children, with the highest prevalence between ages 4 and 7 (70 per 100,000).⁵

The four cardinal clinical features of Henoch-Schönlein purpura are purpuric rash, abdominal pain, arthralgia, and renal involvement. Almost all patients have purpuric rash at some point in their disease course. Arthralgia with or without arthritis is typically migratory, oligoarticular, and nondeforming, usually affecting the large joints of the lower extremities; involvement of the upper extremities is less common.

Skin biopsy typically shows leukocytoclastic vasculitis in postcapillary venules with IgA deposition, and these findings are pathognomonic of Henoch-Schönlein purpura.

Gastrointestinal involvement can range from mild symptoms such as nausea, vomiting, abdominal pain, and paralytic ileus to severe disease such as gastrointestinal hemorrhage, bowel infarction, bowel perforation, and intussusception.

Renal involvement is common and is important, as it can in rare cases progress to end-stage renal disease. The urinalysis usually shows mild proteinuria with active sediment with red cell casts. Most patients have relatively mild disease, characterized by asymptomatic hematuria with a normal or slightly elevated creatinine. However, severe involvement may occur, with nephrotic syndrome, hypertension, and acute renal failure.

Different presentation in adults vs children

Adults with Henoch-Schönlein purpura only rarely present with bowel intussusception, whereas some studies have found that adults are more likely than children to develop significant renal involvement, including end-stage renal disease.^6,7

There is a general but not absolute correlation between the severity of clinical manifestations and the findings on renal biopsy. A poor prognosis (significant proteinuria, hypertension, renal insufficiency, or end-stage renal disease) is associated with crescent formation involving more than 50% of the glomeruli.⁸

Our current understanding of the longterm outcome of the renal disease in Henoch-Schönlein purpura is primarily derived from studies in children. In one study, complete recovery occurred in 94% of children and 89% of adults.⁷ A long-term study of 250 adults with Henoch-Schönlein purpura and renal involvement of sufficient severity to require biopsy reported that, at a median follow up of 15 years, 11% had become dialysis-dependent and 13% had severe renal failure (creatinine clearance < 30 mL/min).⁶ Recurrence is common, occurring in approximately one-third of patients, more likely in those with nephritis.⁸

The diagnosis of Henoch-Schönlein purpura is typically made on the basis of key clinical features. In patients such as ours who have an atypical presentation, biopsy of affected skin and renal biopsy can be essential in the diagnosis. Diffuse alveolar hemorrhage is exceedingly rare in Henoch-Schönlein purpura but can be seen, as in our patient.^9,10 In this setting, the findings of IgA deposits in skin and renal biopsy specimens, together with the absence of other clinical, serologic, or histologic features of other more-common potential causes, secured the diagnosis in this patient.

Henoch-Schönlein purpura is usually self-limited and requires no specific therapy. Evidence suggests that glucocorticoids enhance the rate of resolution of the arthritis and abdominal pain but do not appear to prevent recurrent disease or lessen the likelihood of progression of renal disease.⁸ Patients with severe renal involvement with renal function impairment may benefit from pulse intravenous corticosteroid therapy (methylprednisolone 250–1,000 mg per day for 3 days), followed by oral steroids for 3 months.¹¹

In anecdotal reports, renal function improved in 19 of 21 children with Henoch-Schönlein purpura and severe crescentic nephritis.¹² Studies have evaluated cyclophosphamide¹³ and plasmapheresis,¹⁴ but their role remains uncertain. Renal transplantation is an option in patients who progress to end-stage renal disease.

OUR CASE CONTINUED

In our patient, plasmapheresis was discontinued. As the pulmonary hemorrhage had developed during treatment with prednisone, we decided to continue cyclophosphamide, given the life-threatening nature of his disease. His pulmonary status improved and he was extubated.

During his initial hospital stay, he was taking heparin for anticoagulation therapy. However, given the life-threatening diffuse alveolar hemorrhage, heparin was stopped during the course of his stay in the intensive care unit. Once he was stable and was transferred out of the intensive care unit, heparin was resumed, and his anticoagulation therapy was bridged to warfarin just before discharge. He was eventually discharged on a tapering dose of oral prednisone and cyclophosphamide for 3 months, after which he was switched to azathioprine for maintenance therapy. He was doing well 6 months later, with a serum creatinine level of 1.6 mg/dL, no red cell casts in the urine, and no rash.

TAKE-HOME POINT

In any case of suspected vasculitis that presents with skin disease, it is essential to look for other sites with potentially life-threatening involvement. Henoch-Schönlein purpura is a systemic vasculitis with a prominent cutaneous component. It is not always benign and can be associated with serious complications such as renal failure, gastrointestinal events, and, very rarely, diffuse alveolar hemorrhage.

A 74-year-old man is admitted to the hospital with a 7-day history of fever, rigors, chest pain, and general weakness. He underwent coronary artery bypass surgery 10 years ago.

After 2 weeks of intravenous ceftriaxone 2 g/day, the patient undergoes excision of the mycotic pseudoaneurysm of the descending aorta, with placement of an aortic homograft. Biopsy of the excised aortic segment shows calcified fibroatheromatous plaques with no evidence of cystic medial degeneration or granulomas.

DISCUSSION

Mycotic aneurysm is a localized and irreversible dilatation of an artery due to destruction of the vessel wall by an infection. The dilatation is at least one and one-half times the normal diameter of the affected artery. It may be a true aneurysm or a pseudoaneurysm, involving all or some layers of the arterial wall. It is a rare but life-threatening condition.

A mycotic aneurysm can develop from septic embolization to the vasa vasorum, hematogenous seeding of an existing aneurysm, or extension from a contiguous site of infection.^1,2 Mycotic infections of the aorta show a preference for male patients already infected with S enteritidis or S typhimurium. ³ Predisposing factors include rheumatic deformity of the valves, a bicuspid valve, impaired immunity,⁴ self-induced or iatrogenic arterial trauma,^5,6 atherosclerotic deposits and calcification of the endovascular structure,⁷ and, in elderly patients, Salmonella septicemia.^8,9 Computed tomography is the most useful imaging modality.^10,11 Surgical interventions, in addition to parenteral antibiotic therapy for at least 6 weeks,^11,12 are required to:

• Confirm the diagnosis
• Reconstruct the arterial vasculature
• Manage the complications of sepsis
• Start preventive measures (ie, cholecystectomy).²

A 74-year-old man is admitted to the hospital with a 7-day history of fever, rigors, chest pain, and general weakness. He underwent coronary artery bypass surgery 10 years ago.

After 2 weeks of intravenous ceftriaxone 2 g/day, the patient undergoes excision of the mycotic pseudoaneurysm of the descending aorta, with placement of an aortic homograft. Biopsy of the excised aortic segment shows calcified fibroatheromatous plaques with no evidence of cystic medial degeneration or granulomas.

DISCUSSION

Mycotic aneurysm is a localized and irreversible dilatation of an artery due to destruction of the vessel wall by an infection. The dilatation is at least one and one-half times the normal diameter of the affected artery. It may be a true aneurysm or a pseudoaneurysm, involving all or some layers of the arterial wall. It is a rare but life-threatening condition.

A mycotic aneurysm can develop from septic embolization to the vasa vasorum, hematogenous seeding of an existing aneurysm, or extension from a contiguous site of infection.^1,2 Mycotic infections of the aorta show a preference for male patients already infected with S enteritidis or S typhimurium. ³ Predisposing factors include rheumatic deformity of the valves, a bicuspid valve, impaired immunity,⁴ self-induced or iatrogenic arterial trauma,^5,6 atherosclerotic deposits and calcification of the endovascular structure,⁷ and, in elderly patients, Salmonella septicemia.^8,9 Computed tomography is the most useful imaging modality.^10,11 Surgical interventions, in addition to parenteral antibiotic therapy for at least 6 weeks,^11,12 are required to:

• Confirm the diagnosis
• Reconstruct the arterial vasculature
• Manage the complications of sepsis
• Start preventive measures (ie, cholecystectomy).²

A 74-year-old man is admitted to the hospital with a 7-day history of fever, rigors, chest pain, and general weakness. He underwent coronary artery bypass surgery 10 years ago.

After 2 weeks of intravenous ceftriaxone 2 g/day, the patient undergoes excision of the mycotic pseudoaneurysm of the descending aorta, with placement of an aortic homograft. Biopsy of the excised aortic segment shows calcified fibroatheromatous plaques with no evidence of cystic medial degeneration or granulomas.

DISCUSSION

Mycotic aneurysm is a localized and irreversible dilatation of an artery due to destruction of the vessel wall by an infection. The dilatation is at least one and one-half times the normal diameter of the affected artery. It may be a true aneurysm or a pseudoaneurysm, involving all or some layers of the arterial wall. It is a rare but life-threatening condition.

A mycotic aneurysm can develop from septic embolization to the vasa vasorum, hematogenous seeding of an existing aneurysm, or extension from a contiguous site of infection.^1,2 Mycotic infections of the aorta show a preference for male patients already infected with S enteritidis or S typhimurium. ³ Predisposing factors include rheumatic deformity of the valves, a bicuspid valve, impaired immunity,⁴ self-induced or iatrogenic arterial trauma,^5,6 atherosclerotic deposits and calcification of the endovascular structure,⁷ and, in elderly patients, Salmonella septicemia.^8,9 Computed tomography is the most useful imaging modality.^10,11 Surgical interventions, in addition to parenteral antibiotic therapy for at least 6 weeks,^11,12 are required to:

• Confirm the diagnosis
• Reconstruct the arterial vasculature
• Manage the complications of sepsis
• Start preventive measures (ie, cholecystectomy).²

A 43-year-old woman presents to the emergency department with substernal chest pressure of moderate intensity that started approximately 6 hours ago. The pressure radiates to both arms and is accompanied by nausea. She says she has had no emesis, diaphoresis, fevers, chills, shortness of breath, abdominal pain, melena, dysuria, weight loss, headaches, change in vision, seizures, joint pain, or skin rashes. She also says she has had no prior similar episodes and has no history of myocardial infarction (MI) or stroke.

The patient has a history of gastroesophageal reflux disease and uterine fibroids. She has had three pregnancies, one ending in spontaneous abortion at 12 weeks and two ending with healthy children delivered by cesarean section. She does not take any daily medications. She has smoked one pack per day over the last 25 years. She denies using alcohol or illicit drugs.

The patient’s mother had idiopathic deep vein thrombosis (DVT) at age 46, her father had an MI at age 65, and her sister had an MI at age 43.

On examination, she is in mild distress but is alert and oriented. Her temperature is 99.0°F (37.2°C), blood pressure 98/66 mm Hg, heart rate 65 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 99% on room air. Her body mass index is 19.5 (normal range 18.5–24.9). Her skin appears normal. Her head and neck show no obvious abnormalities, lymphadenopathy, thyromegaly, or bruits. Her heart, lungs, and abdomen are normal, as are her strength, sensation, reflexes, and gait.

Laboratory values at the time of admission:

• White blood cell count 12.58 × 10⁹/L (reference range 4.0–11.0)
• Hemoglobin 15.4 g/dL (12.0–16.0)
• Platelet count 122 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.1 (0.9–1.1)
• Activated partial thromboplastin time 29.1 seconds (24.6–34).

A heart attack, and then a stroke

An initial electrocardiogram shows normal sinus rhythm, left anterior hemiblock, and nonspecific T-wave abnormalities. Cardiac enzymes are measured at intervals: her troponin T level is less than 0.01 ng/mL at the time of admission but rises to 0.75 ng/mL 3 hours later (normal range 0.0–0.1 ng/mL). Similarly, her creatine kinase-MB level is 3.3 ng/mL at admission but rises to 71.9 ng/mL 3 hours later (normal range 0.0–8.0 ng/mL).

The patient is diagnosed with non-ST-elevation MI. An intravenous heparin drip is started, and she is sent for urgent cardiac catheterization, which shows a total occlusion in a lateral obtuse marginal branch of the left circumflex artery due to a thrombus in the vessel. Otherwise, her coronary arteries are angiographically free of disease. The heparin drip is continued, and treatment is started with abciximab (ReoPro) and tissue plasminogen activator (Alteplase). She is sent to the cardiac intensive care unit for recovery, where she is placed on continuous cardiac monitoring, with no evidence of arrhythmia.

One day later, the left side of her face is drooping, her left arm is weak, and her speech is slurred. Magnetic resonance imaging of the brain shows an acute ischemic infarct in the right temporoparietal area and multiple areas of subacute to chronic ischemia. Magnetic resonance angiography of the brain indicates patent vessels. Both transthoracic and transesophageal echocardiography are performed and indicate normal left ventricular size, ejection fraction of 55%, valves without thrombus or vegetations, aorta with mild atheroma, and no patent foramen ovale by Doppler flow or agitated saline contrast study. Carotid artery Doppler ultrasonography shows 40% to 59% stenosis bilaterally.

ARTERIAL THROMBOSIS

1. Which of the following is a risk factor for arterial thrombosis?

• Atherosclerosis
• Protein C deficiency
• Use of oral contraceptive pills
• The factor V Leiden mutation

Protein C deficiency, the use of oral contraceptives, and the factor V Leiden mutation are typically associated with venous thrombosis¹; they have been documented as a cause of arterial thrombosis only in some case reports. In contrast, atherosclerosis is a well-established risk factor for arterial thrombosis.

Arterial occlusion can be due to thrombosis, embolism, or trauma

The causes of arterial occlusion can be categorized as thrombotic, embolic, or traumatic (Table 1).

Atherosclerosis is a risk factor for thrombosis and can be a source of emboli. Atherosclerotic plaque rupture may release inflammatory mediators, which also predispose to thrombosis.² This patient’s coronary arteries are essentially free of atherosclerotic disease per angiography. However, studies of intravascular ultrasonography have shown that coronary angiography may not detect all atherosclerotic plaques, as angiography can show only the lumen of the artery and not the plaque itself.³ For that reason, atherosclerosis has not been ruled out completely, and further workup is needed to evaluate other possible causes of her thrombotic events.

Embolism is the most likely cause of her stroke, however. Cases of arterial embolism can be classified on the basis of the origin of the thrombus, ie, the heart, an artery, or the venous system via a patent foramen ovale (paradoxical embolism). This patient’s echocardiogram reveals mild aortic atheroma, which can be a source of emboli, especially soon after intervention.

Case continues: Acute and recurrent DVT

While recovering from her MI and stroke, the patient develops edema and pain in both legs. Doppler ultrasonography is performed, which reveals acute DVT in the right gastrocnemius and posterior tibial veins and left soleal vein, despite her continued heparin therapy.

Her platelet count is 189 × 10⁹/L, so heparin-induced thrombocytopenia is not suspected; the new DVT is thought to be due to her hospitalization. Several days later, oral warfarin (Coumadin) is started and titrated to an INR of 2.0 to 3.0, the heparin is phased out, and the patient is sent home.

In the first few months after discharge, the patient presents to the emergency department three times with severe leg pain, and each time she is found to have extensive DVT in various leg veins even though she is complying with her warfarin therapy. At each visit, her INR is in the range of 2.5 to 3.1.

Comment. Her recurrent DVT warrants further evaluation for risk factors for venous thrombosis, which can be divided into hereditary and acquired factors.

Hereditary risk factors include the factor V Leiden mutation, the prothrombin gene mutation, hyperhomocysteinemia, dysfibrinogenemia, and deficiencies of protein C, protein S, and antithrombin.

Acquired risk factors include the antiphospholipid antibody syndrome, cancer, immobilization, surgery, congestive heart failure, pregnancy, use of hormonal contraceptives, hormone replacement therapy, nephrotic syndrome, trauma, and infection.^1,4

TESTING FOR HYPERCOAGULABLE STATES

2. In view of our patient’s recurrent thrombotic episodes, should she be tested for hypercoagulable states?

• Yes
• No

Testing for hypercoagulable conditions is warranted if it will affect the patient’s management or outcome. Some authorities recommend testing patients who are clinically characterized as “strongly” thrombophilic,⁵ ie, those who present with DVT and are younger than age 50, have recurrent thrombotic episodes, have a first-degree relative with documented thromboembolism before age 50, or have thrombotic episodes despite warfarin therapy.

This patient should be tested for hypercoagulable conditions because her initial DVT occurred before age 50 (at age 43), she has had recurrent, apparently idiopathic thrombotic episodes, she has a family history of thromboembolism, and she had clots while on therapeutic warfarin therapy, all of which suggest a hypercoagulable state. Furthermore, the confirmation of her diagnosis may affect her medical management, as it may determine if further testing and therapies are needed.

Case continues: Tests are negative

Laboratory tests for hypercoagulable conditions are performed and are negative for the factor V Leiden mutation, the prothrombin gene mutation, antithrombin deficiency, and protein C and S deficiencies. A screen for antiphospholipid antibodies is indeterminate.

TREATMENT AFFECTS TEST RESULTS

3. If a patient is on warfarin therapy, which test results may be affected?

• Antithrombin levels
• Protein C and S levels
• Factor V Leiden mutation

Warfarin decreases the levels of proteins C and S; therefore, the levels of these substances cannot be accurately interpreted in a patient taking warfarin.

All anticoagulants prolong the clotting time and may affect the results of assays based on the clotting time, such as the prothrombin time, the partial thromboplastin time, the dilute Russell’s viper venom time (DRVVT), the hexagonal phase phospholipid neutralization assay, the thrombin time, and clottable protein C and protein S. Heparin reduces the level of antithrombin; however, laboratories now have heparin-binding agents that reduce the effect of heparin in clotting studies.

Acute thrombotic states lower the levels of antithrombin and proteins C and S.

Assays not based on the clotting time (immunogenic or genetic tests such as those for anticardiolipin antibodies and the factor V Leiden and prothrombin gene mutations) are not affected by anticoagulant use.⁵

However, the presence or absence of a hypercoagulable state should not affect the treatment of acute DVT, and a full 6- to 12-month course of anticoagulation should be completed.^6,7 If possible, lupus anticoagulant testing should be repeated 2 weeks after anticoagulation is stopped.⁸

This patient needs lifelong anticoagulation because of her repeated thrombotic episodes. Stopping the medication for 2 weeks for testing would increase the risk of rethrombosis in this patient, and most experts would not advise it.

In summary, testing for hypercoagulable conditions is not recommended during an acute thrombotic episode and is preferably performed while the patient is not on anticoagulation therapy. If the patient is already on anticoagulation, the results of tests for hypercoagulable conditions should be interpreted with caution.

Case continues: Another stroke

During the subsequent year, the patient’s primary care physician monitors her warfarin use and sends her for age-appropriate cancer screening, including a breast examination, Papanicolaou smear, and mammography. Also, given her history of smoking, a chest radiograph is ordered. All of these studies are normal. In addition, evaluations for hematologic disorders such as myelodysplastic syndrome, polycythemia vera, and Waldenström macroglobulinema reveal normal complete blood counts and normal results on serum and urine protein electrophoresis.

Later that year, she returns to the emergency department with complete aphasia and total right-sided paralysis. Magnetic resonance imaging shows an acute infarct in the left frontal operculum, a subacute infarct in the right cerebellum, and multiple chronic cortical and subcortical infarcts throughout the brain. Ultrasonography shows an extensive new DVT in her right leg. Her INR at this time is 3.1.

WHAT CONDITIONS CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

4. Given that the patient has evidence of both recurrent arterial and venous thromboses, which of the following conditions is likely?

• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia
• Malignancy
• All of the above

Conditions associated with both arterial and venous thrombosis include antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, malignancy, paradoxical embolism, hyperhomocysteinemia, myeloproliferative disorders, myelodysplastic disorder, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.^1,4

At present, the exact mechanism that causes Trousseau syndrome is unknown. Some hypotheses implicate mucin (produced by the cancer),¹⁰ tissue factor,¹¹ tumor-associated cysteine proteinase,¹² tumor hypoxia,¹³ and oncogene activation as plausible triggers for this syndrome.

DOES SHE HAVE ANTIPHOSPHOLIPID ANTIBODY SYNDROME?

5. The patient is positive for lupus anticoagulant. Does she have antiphospholipid antibody syndrome?

• Yes
• No
• Repeat testing is needed to meet the diagnostic criteria

The Sapporo criteria¹⁵ indicate that antiphospholipid antibody syndrome is present if at least one clinical criterion and one laboratory criterion are met. The clinical criteria are one or more episodes of arterial or venous thrombosis or pregnancy-related morbidity, ie:

• Unexplained intrauterine fetal death at 10 weeks gestation or later with no apparent fetal abnormality
• Premature births of a morphologically normal fetus at less than 34 weeks of gestation due to preeclampsia, eclampsia, or placental insufficiency
• Three or more spontaneous abortions at 10 weeks of gestation or earlier, with no known paternal chromosomal abnormalities or maternal hormonal abnormalities and normal maternal anatomy.

The laboratory criteria are:

• Lupus anticoagulant present
• Anticardiolipin antibody (IgG or IgM) titer greater than 40 IgG antiphospholipid units (GPL) or IgM antiphospholipid units (MPL) or higher than the 99th percentile of the testing laboratory normal reference range
• Anti-beta-2 glycoprotein-I antibody (IgG or IgM) titer greater than 20 GPL or MPL or higher than the 99th percentile of the testing laboratory normal reference range.

The patient likely has antiphospholipid antibody syndrome because her lupus anticoagulant screen is positive and she meets the clinical criteria of thrombosis, and she should continue to be treated accordingly. However, to officially meet the revised Sapporo criteria, she would need to have laboratory tests that are positive on two or more occasions at least 12 weeks apart.

Case continues: Lung cancer is found

The patient reports that she has lost 10 pounds in 4 months. Since age-appropriate cancer testing was previously performed, a more extensive evaluation for weight loss is undertaken, with computed tomography of the chest, abdomen, and pelvis. These tests reveal a nodule in the right upper lobe of the lung, scarring in the right middle and left lower lung lobes, and hilar lymphadenopathy. Bronchoscopy with transbronchial biopsy confirms that she has adenocarcinoma of the lung.

6. What is suggested as a sufficient workup for malignancy in patients with idiopathic venous thromboembolism?

• Computed tomography of the chest, abdomen, and pelvis for every patient with idiopathic venous thromboembolism
• Positron emission tomography and tumor marker levels
• A comprehensive history and physical examination, routine laboratory tests, chest radiography, age- and sex-specific cancer screening, and patient-specific testing as indicated clinically

To date, there is no evidence to support a cancer evaluation beyond a comprehensive medical history and physical examination, routine laboratory testing, chest radiography, and age- and sex-specific cancer screening unless it is dictated by the patient’s clinical presentation. A study by Cornuz et al¹⁶ suggested that this approach is appropriate for detecting cancer in patients with idiopathic venous thromboembolism.

A 2004 study¹⁷ attempted to answer the question of what to do about patients who have idiopathic venous thromboembolism but no other signs or symptoms that raise any clinical suspicion of cancer. This study randomized patients with idiopathic venous thromboembolism to undergo either routine medical management or an extensive malignancy evaluation. The evaluation included ultrasonography of the abdomen and pelvis, computed tomography of the abdomen and pelvis, gastroscopy or a double-contrast barium swallow study, colonoscopy or sigmoidoscopy followed by a barium enema, stool occult blood testing, and sputum cytology. Women were also tested for the tumor markers carcinoembryonic antigen, alpha-fetoprotein, and CA-125, and they underwent mammography and Papanicolaou testing; men were tested for prostate-specific antigen and underwent ultrasonography of the prostate. The results of the study did not reveal a statistically significant survival benefit in the group that underwent extensive cancer evaluation.

These studies indicate that the decision to test for cancer should be guided by clinical suspicion. Our patient lost 10 pounds in 4 months, smokes, and has had recurrent venous thromboembolism, so testing was appropriate.

After her diagnosis with adenocarcinoma of the lung, the patient has yet another DVT despite an INR of 3.1 and treatment with warfarin and aspirin.

LOW-MOLECULAR-WEIGHT HEPARIN FOR PATIENTS WITH CANCER?

7. True or false? Low-molecular-weight heparin is more effective than warfarin in preventing DVT in cancer patients without increasing the bleeding risk.

• True
• False

This statement is true. The American College of Chest Physicians (ACCP) recommends immediate treatment of DVT with low-molecular-weight heparin for 6 to 12 months after a thrombotic event in a patient with malignancy.^6,18

Two major studies provide evidence for these recommendations: the Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT)¹⁹ and the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (LITE)²⁰ studies.

The CLOT¹⁹ study showed that dalteparin (Fragmin) 200 IU/kg subcutaneously once daily for l month and then 150 IU/kg once daily was more effective than oral warfarin titrated to an INR of 2.5 and did not increase the risk of bleeding.

The LITE trial²⁰ showed the efficacy of tinzaparin (Innohep) 175 IU/kg subcutaneously daily, which can be used as an alternative.

Enoxaparin sodium (Lovenox) 1.5 mg/kg once daily has also been used. However, if low-molecular-weight heparin is not available, warfarin titrated to an INR of 2 to 3 is also acceptable.¹⁸

The ACCP consensus panel recommends giving anticoagulation for an initial 6 to 12 months and continuing it as long as there is evidence of active malignancy.⁶ The American Society for Clinical Oncology also recommends placement of an inferior vena cava filter for patients who have contraindications to anticoagulation or for whom low-molecular-weight heparin fails.¹⁸

Case continues: Summing up

In conclusion, our patient had an underlying malignancy, causing Trousseau syndrome. Before her cancer was diagnosed, she also had test results that suggested antiphospholipid antibody syndrome. Both of these conditions likely contributed to her hypercoagulable state, increasing her propensity for clotting and causing her recurrent thrombosis. The patient is currently on low-molecular-weight heparin and is undergoing palliative chemotherapy for metastatic adenocarcinoma of the lung. To this date, she has not had any new thrombotic events.

TAKE-HOME POINTS

• Risk factors for arterial occlusion can be divided into thrombotic, embolic, and traumatic categories.
• Risk factors for venous thrombosis can be divided into hereditary and acquired categories.
• Evaluation for hypercoagulable conditions is recommended if it will affect patient management or outcome. Patients to be considered for testing include those with idiopathic DVT and who are under age 50, those with a history of recurrent thrombosis, and those with a first-degree relative with documented venous thromboembolism before age 50.
• Evaluation for hypercoagulable conditions should ideally be performed either before starting anticoagulation therapy or 2 weeks after completing it.
• Potential causes of both arterial and venous thrombosis include antiphospholipid antibody syndrome, cancer, hyperhomocysteinemia, heparin-induced thrombocytopenia, paradoxical emboli, myeloproliferative disorders, myelodysplastic syndrome, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.
• Current evidence does not support an extensive cancer evaluation in patients with idiopathic venous thromboembolism, unless dictated by the patient’s clinical condition.
• In patients with venous thromboembolism and active malignancy, anticoagulation is recommended for at least 6 to 12 months and as long as there is evidence of active malignancy.

A 43-year-old woman presents to the emergency department with substernal chest pressure of moderate intensity that started approximately 6 hours ago. The pressure radiates to both arms and is accompanied by nausea. She says she has had no emesis, diaphoresis, fevers, chills, shortness of breath, abdominal pain, melena, dysuria, weight loss, headaches, change in vision, seizures, joint pain, or skin rashes. She also says she has had no prior similar episodes and has no history of myocardial infarction (MI) or stroke.

The patient has a history of gastroesophageal reflux disease and uterine fibroids. She has had three pregnancies, one ending in spontaneous abortion at 12 weeks and two ending with healthy children delivered by cesarean section. She does not take any daily medications. She has smoked one pack per day over the last 25 years. She denies using alcohol or illicit drugs.

The patient’s mother had idiopathic deep vein thrombosis (DVT) at age 46, her father had an MI at age 65, and her sister had an MI at age 43.

On examination, she is in mild distress but is alert and oriented. Her temperature is 99.0°F (37.2°C), blood pressure 98/66 mm Hg, heart rate 65 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 99% on room air. Her body mass index is 19.5 (normal range 18.5–24.9). Her skin appears normal. Her head and neck show no obvious abnormalities, lymphadenopathy, thyromegaly, or bruits. Her heart, lungs, and abdomen are normal, as are her strength, sensation, reflexes, and gait.

Laboratory values at the time of admission:

• White blood cell count 12.58 × 10⁹/L (reference range 4.0–11.0)
• Hemoglobin 15.4 g/dL (12.0–16.0)
• Platelet count 122 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.1 (0.9–1.1)
• Activated partial thromboplastin time 29.1 seconds (24.6–34).

A heart attack, and then a stroke

An initial electrocardiogram shows normal sinus rhythm, left anterior hemiblock, and nonspecific T-wave abnormalities. Cardiac enzymes are measured at intervals: her troponin T level is less than 0.01 ng/mL at the time of admission but rises to 0.75 ng/mL 3 hours later (normal range 0.0–0.1 ng/mL). Similarly, her creatine kinase-MB level is 3.3 ng/mL at admission but rises to 71.9 ng/mL 3 hours later (normal range 0.0–8.0 ng/mL).

The patient is diagnosed with non-ST-elevation MI. An intravenous heparin drip is started, and she is sent for urgent cardiac catheterization, which shows a total occlusion in a lateral obtuse marginal branch of the left circumflex artery due to a thrombus in the vessel. Otherwise, her coronary arteries are angiographically free of disease. The heparin drip is continued, and treatment is started with abciximab (ReoPro) and tissue plasminogen activator (Alteplase). She is sent to the cardiac intensive care unit for recovery, where she is placed on continuous cardiac monitoring, with no evidence of arrhythmia.

One day later, the left side of her face is drooping, her left arm is weak, and her speech is slurred. Magnetic resonance imaging of the brain shows an acute ischemic infarct in the right temporoparietal area and multiple areas of subacute to chronic ischemia. Magnetic resonance angiography of the brain indicates patent vessels. Both transthoracic and transesophageal echocardiography are performed and indicate normal left ventricular size, ejection fraction of 55%, valves without thrombus or vegetations, aorta with mild atheroma, and no patent foramen ovale by Doppler flow or agitated saline contrast study. Carotid artery Doppler ultrasonography shows 40% to 59% stenosis bilaterally.

ARTERIAL THROMBOSIS

1. Which of the following is a risk factor for arterial thrombosis?

• Atherosclerosis
• Protein C deficiency
• Use of oral contraceptive pills
• The factor V Leiden mutation

Protein C deficiency, the use of oral contraceptives, and the factor V Leiden mutation are typically associated with venous thrombosis¹; they have been documented as a cause of arterial thrombosis only in some case reports. In contrast, atherosclerosis is a well-established risk factor for arterial thrombosis.

Arterial occlusion can be due to thrombosis, embolism, or trauma

The causes of arterial occlusion can be categorized as thrombotic, embolic, or traumatic (Table 1).

Atherosclerosis is a risk factor for thrombosis and can be a source of emboli. Atherosclerotic plaque rupture may release inflammatory mediators, which also predispose to thrombosis.² This patient’s coronary arteries are essentially free of atherosclerotic disease per angiography. However, studies of intravascular ultrasonography have shown that coronary angiography may not detect all atherosclerotic plaques, as angiography can show only the lumen of the artery and not the plaque itself.³ For that reason, atherosclerosis has not been ruled out completely, and further workup is needed to evaluate other possible causes of her thrombotic events.

Embolism is the most likely cause of her stroke, however. Cases of arterial embolism can be classified on the basis of the origin of the thrombus, ie, the heart, an artery, or the venous system via a patent foramen ovale (paradoxical embolism). This patient’s echocardiogram reveals mild aortic atheroma, which can be a source of emboli, especially soon after intervention.

Case continues: Acute and recurrent DVT

While recovering from her MI and stroke, the patient develops edema and pain in both legs. Doppler ultrasonography is performed, which reveals acute DVT in the right gastrocnemius and posterior tibial veins and left soleal vein, despite her continued heparin therapy.

Her platelet count is 189 × 10⁹/L, so heparin-induced thrombocytopenia is not suspected; the new DVT is thought to be due to her hospitalization. Several days later, oral warfarin (Coumadin) is started and titrated to an INR of 2.0 to 3.0, the heparin is phased out, and the patient is sent home.

In the first few months after discharge, the patient presents to the emergency department three times with severe leg pain, and each time she is found to have extensive DVT in various leg veins even though she is complying with her warfarin therapy. At each visit, her INR is in the range of 2.5 to 3.1.

Comment. Her recurrent DVT warrants further evaluation for risk factors for venous thrombosis, which can be divided into hereditary and acquired factors.

Hereditary risk factors include the factor V Leiden mutation, the prothrombin gene mutation, hyperhomocysteinemia, dysfibrinogenemia, and deficiencies of protein C, protein S, and antithrombin.

Acquired risk factors include the antiphospholipid antibody syndrome, cancer, immobilization, surgery, congestive heart failure, pregnancy, use of hormonal contraceptives, hormone replacement therapy, nephrotic syndrome, trauma, and infection.^1,4

TESTING FOR HYPERCOAGULABLE STATES

2. In view of our patient’s recurrent thrombotic episodes, should she be tested for hypercoagulable states?

• Yes
• No

Testing for hypercoagulable conditions is warranted if it will affect the patient’s management or outcome. Some authorities recommend testing patients who are clinically characterized as “strongly” thrombophilic,⁵ ie, those who present with DVT and are younger than age 50, have recurrent thrombotic episodes, have a first-degree relative with documented thromboembolism before age 50, or have thrombotic episodes despite warfarin therapy.

This patient should be tested for hypercoagulable conditions because her initial DVT occurred before age 50 (at age 43), she has had recurrent, apparently idiopathic thrombotic episodes, she has a family history of thromboembolism, and she had clots while on therapeutic warfarin therapy, all of which suggest a hypercoagulable state. Furthermore, the confirmation of her diagnosis may affect her medical management, as it may determine if further testing and therapies are needed.

Case continues: Tests are negative

Laboratory tests for hypercoagulable conditions are performed and are negative for the factor V Leiden mutation, the prothrombin gene mutation, antithrombin deficiency, and protein C and S deficiencies. A screen for antiphospholipid antibodies is indeterminate.

TREATMENT AFFECTS TEST RESULTS

3. If a patient is on warfarin therapy, which test results may be affected?

• Antithrombin levels
• Protein C and S levels
• Factor V Leiden mutation

Warfarin decreases the levels of proteins C and S; therefore, the levels of these substances cannot be accurately interpreted in a patient taking warfarin.

All anticoagulants prolong the clotting time and may affect the results of assays based on the clotting time, such as the prothrombin time, the partial thromboplastin time, the dilute Russell’s viper venom time (DRVVT), the hexagonal phase phospholipid neutralization assay, the thrombin time, and clottable protein C and protein S. Heparin reduces the level of antithrombin; however, laboratories now have heparin-binding agents that reduce the effect of heparin in clotting studies.

Acute thrombotic states lower the levels of antithrombin and proteins C and S.

Assays not based on the clotting time (immunogenic or genetic tests such as those for anticardiolipin antibodies and the factor V Leiden and prothrombin gene mutations) are not affected by anticoagulant use.⁵

However, the presence or absence of a hypercoagulable state should not affect the treatment of acute DVT, and a full 6- to 12-month course of anticoagulation should be completed.^6,7 If possible, lupus anticoagulant testing should be repeated 2 weeks after anticoagulation is stopped.⁸

This patient needs lifelong anticoagulation because of her repeated thrombotic episodes. Stopping the medication for 2 weeks for testing would increase the risk of rethrombosis in this patient, and most experts would not advise it.

In summary, testing for hypercoagulable conditions is not recommended during an acute thrombotic episode and is preferably performed while the patient is not on anticoagulation therapy. If the patient is already on anticoagulation, the results of tests for hypercoagulable conditions should be interpreted with caution.

Case continues: Another stroke

During the subsequent year, the patient’s primary care physician monitors her warfarin use and sends her for age-appropriate cancer screening, including a breast examination, Papanicolaou smear, and mammography. Also, given her history of smoking, a chest radiograph is ordered. All of these studies are normal. In addition, evaluations for hematologic disorders such as myelodysplastic syndrome, polycythemia vera, and Waldenström macroglobulinema reveal normal complete blood counts and normal results on serum and urine protein electrophoresis.

Later that year, she returns to the emergency department with complete aphasia and total right-sided paralysis. Magnetic resonance imaging shows an acute infarct in the left frontal operculum, a subacute infarct in the right cerebellum, and multiple chronic cortical and subcortical infarcts throughout the brain. Ultrasonography shows an extensive new DVT in her right leg. Her INR at this time is 3.1.

WHAT CONDITIONS CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

4. Given that the patient has evidence of both recurrent arterial and venous thromboses, which of the following conditions is likely?

• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia
• Malignancy
• All of the above

Conditions associated with both arterial and venous thrombosis include antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, malignancy, paradoxical embolism, hyperhomocysteinemia, myeloproliferative disorders, myelodysplastic disorder, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.^1,4

At present, the exact mechanism that causes Trousseau syndrome is unknown. Some hypotheses implicate mucin (produced by the cancer),¹⁰ tissue factor,¹¹ tumor-associated cysteine proteinase,¹² tumor hypoxia,¹³ and oncogene activation as plausible triggers for this syndrome.

DOES SHE HAVE ANTIPHOSPHOLIPID ANTIBODY SYNDROME?

5. The patient is positive for lupus anticoagulant. Does she have antiphospholipid antibody syndrome?

• Yes
• No
• Repeat testing is needed to meet the diagnostic criteria

The Sapporo criteria¹⁵ indicate that antiphospholipid antibody syndrome is present if at least one clinical criterion and one laboratory criterion are met. The clinical criteria are one or more episodes of arterial or venous thrombosis or pregnancy-related morbidity, ie:

• Unexplained intrauterine fetal death at 10 weeks gestation or later with no apparent fetal abnormality
• Premature births of a morphologically normal fetus at less than 34 weeks of gestation due to preeclampsia, eclampsia, or placental insufficiency
• Three or more spontaneous abortions at 10 weeks of gestation or earlier, with no known paternal chromosomal abnormalities or maternal hormonal abnormalities and normal maternal anatomy.

The laboratory criteria are:

• Lupus anticoagulant present
• Anticardiolipin antibody (IgG or IgM) titer greater than 40 IgG antiphospholipid units (GPL) or IgM antiphospholipid units (MPL) or higher than the 99th percentile of the testing laboratory normal reference range
• Anti-beta-2 glycoprotein-I antibody (IgG or IgM) titer greater than 20 GPL or MPL or higher than the 99th percentile of the testing laboratory normal reference range.

The patient likely has antiphospholipid antibody syndrome because her lupus anticoagulant screen is positive and she meets the clinical criteria of thrombosis, and she should continue to be treated accordingly. However, to officially meet the revised Sapporo criteria, she would need to have laboratory tests that are positive on two or more occasions at least 12 weeks apart.

Case continues: Lung cancer is found

The patient reports that she has lost 10 pounds in 4 months. Since age-appropriate cancer testing was previously performed, a more extensive evaluation for weight loss is undertaken, with computed tomography of the chest, abdomen, and pelvis. These tests reveal a nodule in the right upper lobe of the lung, scarring in the right middle and left lower lung lobes, and hilar lymphadenopathy. Bronchoscopy with transbronchial biopsy confirms that she has adenocarcinoma of the lung.

6. What is suggested as a sufficient workup for malignancy in patients with idiopathic venous thromboembolism?

• Computed tomography of the chest, abdomen, and pelvis for every patient with idiopathic venous thromboembolism
• Positron emission tomography and tumor marker levels
• A comprehensive history and physical examination, routine laboratory tests, chest radiography, age- and sex-specific cancer screening, and patient-specific testing as indicated clinically

To date, there is no evidence to support a cancer evaluation beyond a comprehensive medical history and physical examination, routine laboratory testing, chest radiography, and age- and sex-specific cancer screening unless it is dictated by the patient’s clinical presentation. A study by Cornuz et al¹⁶ suggested that this approach is appropriate for detecting cancer in patients with idiopathic venous thromboembolism.

A 2004 study¹⁷ attempted to answer the question of what to do about patients who have idiopathic venous thromboembolism but no other signs or symptoms that raise any clinical suspicion of cancer. This study randomized patients with idiopathic venous thromboembolism to undergo either routine medical management or an extensive malignancy evaluation. The evaluation included ultrasonography of the abdomen and pelvis, computed tomography of the abdomen and pelvis, gastroscopy or a double-contrast barium swallow study, colonoscopy or sigmoidoscopy followed by a barium enema, stool occult blood testing, and sputum cytology. Women were also tested for the tumor markers carcinoembryonic antigen, alpha-fetoprotein, and CA-125, and they underwent mammography and Papanicolaou testing; men were tested for prostate-specific antigen and underwent ultrasonography of the prostate. The results of the study did not reveal a statistically significant survival benefit in the group that underwent extensive cancer evaluation.

These studies indicate that the decision to test for cancer should be guided by clinical suspicion. Our patient lost 10 pounds in 4 months, smokes, and has had recurrent venous thromboembolism, so testing was appropriate.

After her diagnosis with adenocarcinoma of the lung, the patient has yet another DVT despite an INR of 3.1 and treatment with warfarin and aspirin.

LOW-MOLECULAR-WEIGHT HEPARIN FOR PATIENTS WITH CANCER?

7. True or false? Low-molecular-weight heparin is more effective than warfarin in preventing DVT in cancer patients without increasing the bleeding risk.

• True
• False

This statement is true. The American College of Chest Physicians (ACCP) recommends immediate treatment of DVT with low-molecular-weight heparin for 6 to 12 months after a thrombotic event in a patient with malignancy.^6,18

Two major studies provide evidence for these recommendations: the Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT)¹⁹ and the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (LITE)²⁰ studies.

The CLOT¹⁹ study showed that dalteparin (Fragmin) 200 IU/kg subcutaneously once daily for l month and then 150 IU/kg once daily was more effective than oral warfarin titrated to an INR of 2.5 and did not increase the risk of bleeding.

The LITE trial²⁰ showed the efficacy of tinzaparin (Innohep) 175 IU/kg subcutaneously daily, which can be used as an alternative.

Enoxaparin sodium (Lovenox) 1.5 mg/kg once daily has also been used. However, if low-molecular-weight heparin is not available, warfarin titrated to an INR of 2 to 3 is also acceptable.¹⁸

The ACCP consensus panel recommends giving anticoagulation for an initial 6 to 12 months and continuing it as long as there is evidence of active malignancy.⁶ The American Society for Clinical Oncology also recommends placement of an inferior vena cava filter for patients who have contraindications to anticoagulation or for whom low-molecular-weight heparin fails.¹⁸

Case continues: Summing up

In conclusion, our patient had an underlying malignancy, causing Trousseau syndrome. Before her cancer was diagnosed, she also had test results that suggested antiphospholipid antibody syndrome. Both of these conditions likely contributed to her hypercoagulable state, increasing her propensity for clotting and causing her recurrent thrombosis. The patient is currently on low-molecular-weight heparin and is undergoing palliative chemotherapy for metastatic adenocarcinoma of the lung. To this date, she has not had any new thrombotic events.

TAKE-HOME POINTS

• Risk factors for arterial occlusion can be divided into thrombotic, embolic, and traumatic categories.
• Risk factors for venous thrombosis can be divided into hereditary and acquired categories.
• Evaluation for hypercoagulable conditions is recommended if it will affect patient management or outcome. Patients to be considered for testing include those with idiopathic DVT and who are under age 50, those with a history of recurrent thrombosis, and those with a first-degree relative with documented venous thromboembolism before age 50.
• Evaluation for hypercoagulable conditions should ideally be performed either before starting anticoagulation therapy or 2 weeks after completing it.
• Potential causes of both arterial and venous thrombosis include antiphospholipid antibody syndrome, cancer, hyperhomocysteinemia, heparin-induced thrombocytopenia, paradoxical emboli, myeloproliferative disorders, myelodysplastic syndrome, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.
• Current evidence does not support an extensive cancer evaluation in patients with idiopathic venous thromboembolism, unless dictated by the patient’s clinical condition.
• In patients with venous thromboembolism and active malignancy, anticoagulation is recommended for at least 6 to 12 months and as long as there is evidence of active malignancy.

A 43-year-old woman presents to the emergency department with substernal chest pressure of moderate intensity that started approximately 6 hours ago. The pressure radiates to both arms and is accompanied by nausea. She says she has had no emesis, diaphoresis, fevers, chills, shortness of breath, abdominal pain, melena, dysuria, weight loss, headaches, change in vision, seizures, joint pain, or skin rashes. She also says she has had no prior similar episodes and has no history of myocardial infarction (MI) or stroke.

The patient has a history of gastroesophageal reflux disease and uterine fibroids. She has had three pregnancies, one ending in spontaneous abortion at 12 weeks and two ending with healthy children delivered by cesarean section. She does not take any daily medications. She has smoked one pack per day over the last 25 years. She denies using alcohol or illicit drugs.

The patient’s mother had idiopathic deep vein thrombosis (DVT) at age 46, her father had an MI at age 65, and her sister had an MI at age 43.

On examination, she is in mild distress but is alert and oriented. Her temperature is 99.0°F (37.2°C), blood pressure 98/66 mm Hg, heart rate 65 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 99% on room air. Her body mass index is 19.5 (normal range 18.5–24.9). Her skin appears normal. Her head and neck show no obvious abnormalities, lymphadenopathy, thyromegaly, or bruits. Her heart, lungs, and abdomen are normal, as are her strength, sensation, reflexes, and gait.

Laboratory values at the time of admission:

• White blood cell count 12.58 × 10⁹/L (reference range 4.0–11.0)
• Hemoglobin 15.4 g/dL (12.0–16.0)
• Platelet count 122 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.1 (0.9–1.1)
• Activated partial thromboplastin time 29.1 seconds (24.6–34).

A heart attack, and then a stroke

An initial electrocardiogram shows normal sinus rhythm, left anterior hemiblock, and nonspecific T-wave abnormalities. Cardiac enzymes are measured at intervals: her troponin T level is less than 0.01 ng/mL at the time of admission but rises to 0.75 ng/mL 3 hours later (normal range 0.0–0.1 ng/mL). Similarly, her creatine kinase-MB level is 3.3 ng/mL at admission but rises to 71.9 ng/mL 3 hours later (normal range 0.0–8.0 ng/mL).

The patient is diagnosed with non-ST-elevation MI. An intravenous heparin drip is started, and she is sent for urgent cardiac catheterization, which shows a total occlusion in a lateral obtuse marginal branch of the left circumflex artery due to a thrombus in the vessel. Otherwise, her coronary arteries are angiographically free of disease. The heparin drip is continued, and treatment is started with abciximab (ReoPro) and tissue plasminogen activator (Alteplase). She is sent to the cardiac intensive care unit for recovery, where she is placed on continuous cardiac monitoring, with no evidence of arrhythmia.

One day later, the left side of her face is drooping, her left arm is weak, and her speech is slurred. Magnetic resonance imaging of the brain shows an acute ischemic infarct in the right temporoparietal area and multiple areas of subacute to chronic ischemia. Magnetic resonance angiography of the brain indicates patent vessels. Both transthoracic and transesophageal echocardiography are performed and indicate normal left ventricular size, ejection fraction of 55%, valves without thrombus or vegetations, aorta with mild atheroma, and no patent foramen ovale by Doppler flow or agitated saline contrast study. Carotid artery Doppler ultrasonography shows 40% to 59% stenosis bilaterally.

ARTERIAL THROMBOSIS

1. Which of the following is a risk factor for arterial thrombosis?

• Atherosclerosis
• Protein C deficiency
• Use of oral contraceptive pills
• The factor V Leiden mutation

Protein C deficiency, the use of oral contraceptives, and the factor V Leiden mutation are typically associated with venous thrombosis¹; they have been documented as a cause of arterial thrombosis only in some case reports. In contrast, atherosclerosis is a well-established risk factor for arterial thrombosis.

Arterial occlusion can be due to thrombosis, embolism, or trauma

The causes of arterial occlusion can be categorized as thrombotic, embolic, or traumatic (Table 1).

Atherosclerosis is a risk factor for thrombosis and can be a source of emboli. Atherosclerotic plaque rupture may release inflammatory mediators, which also predispose to thrombosis.² This patient’s coronary arteries are essentially free of atherosclerotic disease per angiography. However, studies of intravascular ultrasonography have shown that coronary angiography may not detect all atherosclerotic plaques, as angiography can show only the lumen of the artery and not the plaque itself.³ For that reason, atherosclerosis has not been ruled out completely, and further workup is needed to evaluate other possible causes of her thrombotic events.

Embolism is the most likely cause of her stroke, however. Cases of arterial embolism can be classified on the basis of the origin of the thrombus, ie, the heart, an artery, or the venous system via a patent foramen ovale (paradoxical embolism). This patient’s echocardiogram reveals mild aortic atheroma, which can be a source of emboli, especially soon after intervention.

Case continues: Acute and recurrent DVT

While recovering from her MI and stroke, the patient develops edema and pain in both legs. Doppler ultrasonography is performed, which reveals acute DVT in the right gastrocnemius and posterior tibial veins and left soleal vein, despite her continued heparin therapy.

Her platelet count is 189 × 10⁹/L, so heparin-induced thrombocytopenia is not suspected; the new DVT is thought to be due to her hospitalization. Several days later, oral warfarin (Coumadin) is started and titrated to an INR of 2.0 to 3.0, the heparin is phased out, and the patient is sent home.

In the first few months after discharge, the patient presents to the emergency department three times with severe leg pain, and each time she is found to have extensive DVT in various leg veins even though she is complying with her warfarin therapy. At each visit, her INR is in the range of 2.5 to 3.1.

Comment. Her recurrent DVT warrants further evaluation for risk factors for venous thrombosis, which can be divided into hereditary and acquired factors.

Hereditary risk factors include the factor V Leiden mutation, the prothrombin gene mutation, hyperhomocysteinemia, dysfibrinogenemia, and deficiencies of protein C, protein S, and antithrombin.

Acquired risk factors include the antiphospholipid antibody syndrome, cancer, immobilization, surgery, congestive heart failure, pregnancy, use of hormonal contraceptives, hormone replacement therapy, nephrotic syndrome, trauma, and infection.^1,4

TESTING FOR HYPERCOAGULABLE STATES

2. In view of our patient’s recurrent thrombotic episodes, should she be tested for hypercoagulable states?

• Yes
• No

Testing for hypercoagulable conditions is warranted if it will affect the patient’s management or outcome. Some authorities recommend testing patients who are clinically characterized as “strongly” thrombophilic,⁵ ie, those who present with DVT and are younger than age 50, have recurrent thrombotic episodes, have a first-degree relative with documented thromboembolism before age 50, or have thrombotic episodes despite warfarin therapy.

This patient should be tested for hypercoagulable conditions because her initial DVT occurred before age 50 (at age 43), she has had recurrent, apparently idiopathic thrombotic episodes, she has a family history of thromboembolism, and she had clots while on therapeutic warfarin therapy, all of which suggest a hypercoagulable state. Furthermore, the confirmation of her diagnosis may affect her medical management, as it may determine if further testing and therapies are needed.

Case continues: Tests are negative

Laboratory tests for hypercoagulable conditions are performed and are negative for the factor V Leiden mutation, the prothrombin gene mutation, antithrombin deficiency, and protein C and S deficiencies. A screen for antiphospholipid antibodies is indeterminate.

TREATMENT AFFECTS TEST RESULTS

3. If a patient is on warfarin therapy, which test results may be affected?

• Antithrombin levels
• Protein C and S levels
• Factor V Leiden mutation

Warfarin decreases the levels of proteins C and S; therefore, the levels of these substances cannot be accurately interpreted in a patient taking warfarin.

All anticoagulants prolong the clotting time and may affect the results of assays based on the clotting time, such as the prothrombin time, the partial thromboplastin time, the dilute Russell’s viper venom time (DRVVT), the hexagonal phase phospholipid neutralization assay, the thrombin time, and clottable protein C and protein S. Heparin reduces the level of antithrombin; however, laboratories now have heparin-binding agents that reduce the effect of heparin in clotting studies.

Acute thrombotic states lower the levels of antithrombin and proteins C and S.

Assays not based on the clotting time (immunogenic or genetic tests such as those for anticardiolipin antibodies and the factor V Leiden and prothrombin gene mutations) are not affected by anticoagulant use.⁵

However, the presence or absence of a hypercoagulable state should not affect the treatment of acute DVT, and a full 6- to 12-month course of anticoagulation should be completed.^6,7 If possible, lupus anticoagulant testing should be repeated 2 weeks after anticoagulation is stopped.⁸

This patient needs lifelong anticoagulation because of her repeated thrombotic episodes. Stopping the medication for 2 weeks for testing would increase the risk of rethrombosis in this patient, and most experts would not advise it.

In summary, testing for hypercoagulable conditions is not recommended during an acute thrombotic episode and is preferably performed while the patient is not on anticoagulation therapy. If the patient is already on anticoagulation, the results of tests for hypercoagulable conditions should be interpreted with caution.

Case continues: Another stroke

During the subsequent year, the patient’s primary care physician monitors her warfarin use and sends her for age-appropriate cancer screening, including a breast examination, Papanicolaou smear, and mammography. Also, given her history of smoking, a chest radiograph is ordered. All of these studies are normal. In addition, evaluations for hematologic disorders such as myelodysplastic syndrome, polycythemia vera, and Waldenström macroglobulinema reveal normal complete blood counts and normal results on serum and urine protein electrophoresis.

Later that year, she returns to the emergency department with complete aphasia and total right-sided paralysis. Magnetic resonance imaging shows an acute infarct in the left frontal operculum, a subacute infarct in the right cerebellum, and multiple chronic cortical and subcortical infarcts throughout the brain. Ultrasonography shows an extensive new DVT in her right leg. Her INR at this time is 3.1.

WHAT CONDITIONS CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

4. Given that the patient has evidence of both recurrent arterial and venous thromboses, which of the following conditions is likely?

• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia
• Malignancy
• All of the above

Conditions associated with both arterial and venous thrombosis include antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, malignancy, paradoxical embolism, hyperhomocysteinemia, myeloproliferative disorders, myelodysplastic disorder, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.^1,4

At present, the exact mechanism that causes Trousseau syndrome is unknown. Some hypotheses implicate mucin (produced by the cancer),¹⁰ tissue factor,¹¹ tumor-associated cysteine proteinase,¹² tumor hypoxia,¹³ and oncogene activation as plausible triggers for this syndrome.

DOES SHE HAVE ANTIPHOSPHOLIPID ANTIBODY SYNDROME?

5. The patient is positive for lupus anticoagulant. Does she have antiphospholipid antibody syndrome?

• Yes
• No
• Repeat testing is needed to meet the diagnostic criteria

The Sapporo criteria¹⁵ indicate that antiphospholipid antibody syndrome is present if at least one clinical criterion and one laboratory criterion are met. The clinical criteria are one or more episodes of arterial or venous thrombosis or pregnancy-related morbidity, ie:

• Unexplained intrauterine fetal death at 10 weeks gestation or later with no apparent fetal abnormality
• Premature births of a morphologically normal fetus at less than 34 weeks of gestation due to preeclampsia, eclampsia, or placental insufficiency
• Three or more spontaneous abortions at 10 weeks of gestation or earlier, with no known paternal chromosomal abnormalities or maternal hormonal abnormalities and normal maternal anatomy.

The laboratory criteria are:

• Lupus anticoagulant present
• Anticardiolipin antibody (IgG or IgM) titer greater than 40 IgG antiphospholipid units (GPL) or IgM antiphospholipid units (MPL) or higher than the 99th percentile of the testing laboratory normal reference range
• Anti-beta-2 glycoprotein-I antibody (IgG or IgM) titer greater than 20 GPL or MPL or higher than the 99th percentile of the testing laboratory normal reference range.

The patient likely has antiphospholipid antibody syndrome because her lupus anticoagulant screen is positive and she meets the clinical criteria of thrombosis, and she should continue to be treated accordingly. However, to officially meet the revised Sapporo criteria, she would need to have laboratory tests that are positive on two or more occasions at least 12 weeks apart.

Case continues: Lung cancer is found

The patient reports that she has lost 10 pounds in 4 months. Since age-appropriate cancer testing was previously performed, a more extensive evaluation for weight loss is undertaken, with computed tomography of the chest, abdomen, and pelvis. These tests reveal a nodule in the right upper lobe of the lung, scarring in the right middle and left lower lung lobes, and hilar lymphadenopathy. Bronchoscopy with transbronchial biopsy confirms that she has adenocarcinoma of the lung.

6. What is suggested as a sufficient workup for malignancy in patients with idiopathic venous thromboembolism?

• Computed tomography of the chest, abdomen, and pelvis for every patient with idiopathic venous thromboembolism
• Positron emission tomography and tumor marker levels
• A comprehensive history and physical examination, routine laboratory tests, chest radiography, age- and sex-specific cancer screening, and patient-specific testing as indicated clinically

To date, there is no evidence to support a cancer evaluation beyond a comprehensive medical history and physical examination, routine laboratory testing, chest radiography, and age- and sex-specific cancer screening unless it is dictated by the patient’s clinical presentation. A study by Cornuz et al¹⁶ suggested that this approach is appropriate for detecting cancer in patients with idiopathic venous thromboembolism.

A 2004 study¹⁷ attempted to answer the question of what to do about patients who have idiopathic venous thromboembolism but no other signs or symptoms that raise any clinical suspicion of cancer. This study randomized patients with idiopathic venous thromboembolism to undergo either routine medical management or an extensive malignancy evaluation. The evaluation included ultrasonography of the abdomen and pelvis, computed tomography of the abdomen and pelvis, gastroscopy or a double-contrast barium swallow study, colonoscopy or sigmoidoscopy followed by a barium enema, stool occult blood testing, and sputum cytology. Women were also tested for the tumor markers carcinoembryonic antigen, alpha-fetoprotein, and CA-125, and they underwent mammography and Papanicolaou testing; men were tested for prostate-specific antigen and underwent ultrasonography of the prostate. The results of the study did not reveal a statistically significant survival benefit in the group that underwent extensive cancer evaluation.

These studies indicate that the decision to test for cancer should be guided by clinical suspicion. Our patient lost 10 pounds in 4 months, smokes, and has had recurrent venous thromboembolism, so testing was appropriate.

After her diagnosis with adenocarcinoma of the lung, the patient has yet another DVT despite an INR of 3.1 and treatment with warfarin and aspirin.

LOW-MOLECULAR-WEIGHT HEPARIN FOR PATIENTS WITH CANCER?

7. True or false? Low-molecular-weight heparin is more effective than warfarin in preventing DVT in cancer patients without increasing the bleeding risk.

• True
• False

This statement is true. The American College of Chest Physicians (ACCP) recommends immediate treatment of DVT with low-molecular-weight heparin for 6 to 12 months after a thrombotic event in a patient with malignancy.^6,18

Two major studies provide evidence for these recommendations: the Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT)¹⁹ and the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (LITE)²⁰ studies.

The CLOT¹⁹ study showed that dalteparin (Fragmin) 200 IU/kg subcutaneously once daily for l month and then 150 IU/kg once daily was more effective than oral warfarin titrated to an INR of 2.5 and did not increase the risk of bleeding.

The LITE trial²⁰ showed the efficacy of tinzaparin (Innohep) 175 IU/kg subcutaneously daily, which can be used as an alternative.

Enoxaparin sodium (Lovenox) 1.5 mg/kg once daily has also been used. However, if low-molecular-weight heparin is not available, warfarin titrated to an INR of 2 to 3 is also acceptable.¹⁸

The ACCP consensus panel recommends giving anticoagulation for an initial 6 to 12 months and continuing it as long as there is evidence of active malignancy.⁶ The American Society for Clinical Oncology also recommends placement of an inferior vena cava filter for patients who have contraindications to anticoagulation or for whom low-molecular-weight heparin fails.¹⁸

Case continues: Summing up

In conclusion, our patient had an underlying malignancy, causing Trousseau syndrome. Before her cancer was diagnosed, she also had test results that suggested antiphospholipid antibody syndrome. Both of these conditions likely contributed to her hypercoagulable state, increasing her propensity for clotting and causing her recurrent thrombosis. The patient is currently on low-molecular-weight heparin and is undergoing palliative chemotherapy for metastatic adenocarcinoma of the lung. To this date, she has not had any new thrombotic events.

TAKE-HOME POINTS

• Risk factors for arterial occlusion can be divided into thrombotic, embolic, and traumatic categories.
• Risk factors for venous thrombosis can be divided into hereditary and acquired categories.
• Evaluation for hypercoagulable conditions is recommended if it will affect patient management or outcome. Patients to be considered for testing include those with idiopathic DVT and who are under age 50, those with a history of recurrent thrombosis, and those with a first-degree relative with documented venous thromboembolism before age 50.
• Evaluation for hypercoagulable conditions should ideally be performed either before starting anticoagulation therapy or 2 weeks after completing it.
• Potential causes of both arterial and venous thrombosis include antiphospholipid antibody syndrome, cancer, hyperhomocysteinemia, heparin-induced thrombocytopenia, paradoxical emboli, myeloproliferative disorders, myelodysplastic syndrome, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.
• Current evidence does not support an extensive cancer evaluation in patients with idiopathic venous thromboembolism, unless dictated by the patient’s clinical condition.
• In patients with venous thromboembolism and active malignancy, anticoagulation is recommended for at least 6 to 12 months and as long as there is evidence of active malignancy.

A 54-year-old man presents with sudden visual loss in the left eye. The left eye and left periorbital area have been painful for the past 5 days.

Duplex ultrasonography of the carotid arteries shows total occlusion of the left internal carotid artery. Fluorescein angiography of the fundus reveals focal hyperfluorescence with delayed arteriovenous transit time in the left eye.

Q: Which of the following diagnoses is the most likely at this point in the evaluation?

• Hypertensive retinopathy
• Diabetic retinopathy
• Human immunodeficiency virus (HIV) retinopathy
• Retinal involvement of systemic autoimmune disease
• Ocular ischemic syndrome

A: The ocular symptoms of hypertension, diabetes mellitus, HIV infection, and other autoimmune diseases usually present bilaterally, and funduscopic examination often reveals other signs such as vessel tortuosity, venous dilation, microaneurysms, retinal hemorrhages, hard exudates, and new vessel formation, in addition to cotton wool spots. In this patient, the lack of these signs and the unilateral cotton wool spots combined with the delay in arteriovenous transit time on fluorescein angiography point to ocular ischemic syndrome.

Ocular ischemic syndrome is the result of hypoperfusion of the globe caused by obstruction of the carotid or the ophthalmic artery,¹ most commonly from atherosclerosis. Retinal hypoperfusion is also caused by arteritis, external compression, dissection of the artery,² and, rarely, cardiac failure.

USUAL SIGNS AND SYMPTOMS

Usually, the patient presents with visual loss that has progressed gradually over a period of weeks or months and is associated with dull aching in the eye or orbit (“ocular angina”).³ Cotton wool spots on funduscopic examination represent retinal nerve fiber layer infarcts, a sign of retinal hypoperfusion. Delays in the choroidal filling time and the arteriole-to-venule transit time on fluorescein angiography confirm the diagnosis.

Strong clue to underlying disease

Ocular ischemic syndrome is an important clue to underlying macrovascular atherosclerotic disease: 50% of patients with ocular ischemic syndrome have ischemic heart disease, 25% have a history of stroke, and 20% have severe peripheral vascular disease. Ocular complications of the syndrome are rubeosis iridis, neovascular glaucoma, and neovascularization of the optic disc and retina. Prompt diagnosis is very important because the death rate at 5 years is 40%.⁴

Recommended workup

The recommended workup is a thorough history and physical examination to identify underlying systemic disease such as diabetes, hypertension, or collagen vascular disease. When carotid artery disease is suspected, a noninvasive vascular workup with carotid duplex ultrasonography is mandatory to confirm carotid arterial disease, to establish its cause, and to assess the severity of the lesion.

CURRENT TREATMENT OPTIONS

Treatment focuses on the control of systemic risk factors and follow-up to monitor for systemic and ocular complications. The combination of aspirin and extended-release dipyridamole (Aggrenox) is currently considered the most effective antiplatelet strategy, as it reduces the risk of stroke by 37% compared with 25% with aspirin alone.⁵

Carotid endarterectomy has been shown to benefit symptomatic patients with nondisabling stroke, amaurosis fugax, and a hemispheric transient ischemic attack and who have carotid stenosis of 70% to 99%. The North American Symptomatic Carotid Endarterectomy Trial found a 2-year stroke rate of 9% in such patients who underwent endarterectomy vs 26% in those treated with antiplatelet therapy alone.^6,7 Some improvement in visual outcomes was also noted, but the data so far are not conclusive.⁶

Bypass procedures such as anastomosis of the superficial temporal artery to the middle cerebral artery have been tried in patients with 100% obstruction of the carotid artery in whom a thrombus has propagated distally, thus precluding endarterectomy.

We continue to monitor our patient for the development of ocular complications. The development of retinal neovascularization may warrant panretinal photocoagulation with or without anterior retinal cryoablation. Panretinal photocoagulation decreases the retinal demand for oxygen and decreases the release of angiogenic factors, thereby arresting the growth of neovascularization and preventing complications such as vitreous hemorrhage and tractional retinal detachment. Although no studies have analyzed the benefit of panretinal photocoagulation in patients with ocular ischemia, its long-term benefit has been well documented in diabetic patients.⁸

A 54-year-old man presents with sudden visual loss in the left eye. The left eye and left periorbital area have been painful for the past 5 days.

Duplex ultrasonography of the carotid arteries shows total occlusion of the left internal carotid artery. Fluorescein angiography of the fundus reveals focal hyperfluorescence with delayed arteriovenous transit time in the left eye.

Q: Which of the following diagnoses is the most likely at this point in the evaluation?

• Hypertensive retinopathy
• Diabetic retinopathy
• Human immunodeficiency virus (HIV) retinopathy
• Retinal involvement of systemic autoimmune disease
• Ocular ischemic syndrome

A: The ocular symptoms of hypertension, diabetes mellitus, HIV infection, and other autoimmune diseases usually present bilaterally, and funduscopic examination often reveals other signs such as vessel tortuosity, venous dilation, microaneurysms, retinal hemorrhages, hard exudates, and new vessel formation, in addition to cotton wool spots. In this patient, the lack of these signs and the unilateral cotton wool spots combined with the delay in arteriovenous transit time on fluorescein angiography point to ocular ischemic syndrome.

Ocular ischemic syndrome is the result of hypoperfusion of the globe caused by obstruction of the carotid or the ophthalmic artery,¹ most commonly from atherosclerosis. Retinal hypoperfusion is also caused by arteritis, external compression, dissection of the artery,² and, rarely, cardiac failure.

USUAL SIGNS AND SYMPTOMS

Usually, the patient presents with visual loss that has progressed gradually over a period of weeks or months and is associated with dull aching in the eye or orbit (“ocular angina”).³ Cotton wool spots on funduscopic examination represent retinal nerve fiber layer infarcts, a sign of retinal hypoperfusion. Delays in the choroidal filling time and the arteriole-to-venule transit time on fluorescein angiography confirm the diagnosis.

Strong clue to underlying disease

Ocular ischemic syndrome is an important clue to underlying macrovascular atherosclerotic disease: 50% of patients with ocular ischemic syndrome have ischemic heart disease, 25% have a history of stroke, and 20% have severe peripheral vascular disease. Ocular complications of the syndrome are rubeosis iridis, neovascular glaucoma, and neovascularization of the optic disc and retina. Prompt diagnosis is very important because the death rate at 5 years is 40%.⁴

Recommended workup

The recommended workup is a thorough history and physical examination to identify underlying systemic disease such as diabetes, hypertension, or collagen vascular disease. When carotid artery disease is suspected, a noninvasive vascular workup with carotid duplex ultrasonography is mandatory to confirm carotid arterial disease, to establish its cause, and to assess the severity of the lesion.

CURRENT TREATMENT OPTIONS

Treatment focuses on the control of systemic risk factors and follow-up to monitor for systemic and ocular complications. The combination of aspirin and extended-release dipyridamole (Aggrenox) is currently considered the most effective antiplatelet strategy, as it reduces the risk of stroke by 37% compared with 25% with aspirin alone.⁵

Carotid endarterectomy has been shown to benefit symptomatic patients with nondisabling stroke, amaurosis fugax, and a hemispheric transient ischemic attack and who have carotid stenosis of 70% to 99%. The North American Symptomatic Carotid Endarterectomy Trial found a 2-year stroke rate of 9% in such patients who underwent endarterectomy vs 26% in those treated with antiplatelet therapy alone.^6,7 Some improvement in visual outcomes was also noted, but the data so far are not conclusive.⁶

Bypass procedures such as anastomosis of the superficial temporal artery to the middle cerebral artery have been tried in patients with 100% obstruction of the carotid artery in whom a thrombus has propagated distally, thus precluding endarterectomy.

We continue to monitor our patient for the development of ocular complications. The development of retinal neovascularization may warrant panretinal photocoagulation with or without anterior retinal cryoablation. Panretinal photocoagulation decreases the retinal demand for oxygen and decreases the release of angiogenic factors, thereby arresting the growth of neovascularization and preventing complications such as vitreous hemorrhage and tractional retinal detachment. Although no studies have analyzed the benefit of panretinal photocoagulation in patients with ocular ischemia, its long-term benefit has been well documented in diabetic patients.⁸

A 54-year-old man presents with sudden visual loss in the left eye. The left eye and left periorbital area have been painful for the past 5 days.

Duplex ultrasonography of the carotid arteries shows total occlusion of the left internal carotid artery. Fluorescein angiography of the fundus reveals focal hyperfluorescence with delayed arteriovenous transit time in the left eye.

Q: Which of the following diagnoses is the most likely at this point in the evaluation?

• Hypertensive retinopathy
• Diabetic retinopathy
• Human immunodeficiency virus (HIV) retinopathy
• Retinal involvement of systemic autoimmune disease
• Ocular ischemic syndrome

A: The ocular symptoms of hypertension, diabetes mellitus, HIV infection, and other autoimmune diseases usually present bilaterally, and funduscopic examination often reveals other signs such as vessel tortuosity, venous dilation, microaneurysms, retinal hemorrhages, hard exudates, and new vessel formation, in addition to cotton wool spots. In this patient, the lack of these signs and the unilateral cotton wool spots combined with the delay in arteriovenous transit time on fluorescein angiography point to ocular ischemic syndrome.

Ocular ischemic syndrome is the result of hypoperfusion of the globe caused by obstruction of the carotid or the ophthalmic artery,¹ most commonly from atherosclerosis. Retinal hypoperfusion is also caused by arteritis, external compression, dissection of the artery,² and, rarely, cardiac failure.

USUAL SIGNS AND SYMPTOMS

Usually, the patient presents with visual loss that has progressed gradually over a period of weeks or months and is associated with dull aching in the eye or orbit (“ocular angina”).³ Cotton wool spots on funduscopic examination represent retinal nerve fiber layer infarcts, a sign of retinal hypoperfusion. Delays in the choroidal filling time and the arteriole-to-venule transit time on fluorescein angiography confirm the diagnosis.

Strong clue to underlying disease

Ocular ischemic syndrome is an important clue to underlying macrovascular atherosclerotic disease: 50% of patients with ocular ischemic syndrome have ischemic heart disease, 25% have a history of stroke, and 20% have severe peripheral vascular disease. Ocular complications of the syndrome are rubeosis iridis, neovascular glaucoma, and neovascularization of the optic disc and retina. Prompt diagnosis is very important because the death rate at 5 years is 40%.⁴

Recommended workup

The recommended workup is a thorough history and physical examination to identify underlying systemic disease such as diabetes, hypertension, or collagen vascular disease. When carotid artery disease is suspected, a noninvasive vascular workup with carotid duplex ultrasonography is mandatory to confirm carotid arterial disease, to establish its cause, and to assess the severity of the lesion.

CURRENT TREATMENT OPTIONS

Treatment focuses on the control of systemic risk factors and follow-up to monitor for systemic and ocular complications. The combination of aspirin and extended-release dipyridamole (Aggrenox) is currently considered the most effective antiplatelet strategy, as it reduces the risk of stroke by 37% compared with 25% with aspirin alone.⁵

Carotid endarterectomy has been shown to benefit symptomatic patients with nondisabling stroke, amaurosis fugax, and a hemispheric transient ischemic attack and who have carotid stenosis of 70% to 99%. The North American Symptomatic Carotid Endarterectomy Trial found a 2-year stroke rate of 9% in such patients who underwent endarterectomy vs 26% in those treated with antiplatelet therapy alone.^6,7 Some improvement in visual outcomes was also noted, but the data so far are not conclusive.⁶

Bypass procedures such as anastomosis of the superficial temporal artery to the middle cerebral artery have been tried in patients with 100% obstruction of the carotid artery in whom a thrombus has propagated distally, thus precluding endarterectomy.

We continue to monitor our patient for the development of ocular complications. The development of retinal neovascularization may warrant panretinal photocoagulation with or without anterior retinal cryoablation. Panretinal photocoagulation decreases the retinal demand for oxygen and decreases the release of angiogenic factors, thereby arresting the growth of neovascularization and preventing complications such as vitreous hemorrhage and tractional retinal detachment. Although no studies have analyzed the benefit of panretinal photocoagulation in patients with ocular ischemia, its long-term benefit has been well documented in diabetic patients.⁸

In this issue of the Journal we review two special situations in which low-molecular-weight heparins have special advantages. Babu and Carman discuss patients with cancer and thromboembolic disease. These patients are particularly difficult to manage since they tend to have recurrent thrombosis, sometimes even while on anticoagulant therapy, and they tend to have more bleeding complications from warfarin therapy. Inanition, drug interactions, and organ dysfunction make warfarin titration problematic, and the possibility of vascular metastases is always a concern. Low-molecular-weight heparins —which, unlike warfarin, work primarily by antagonizing factor Xa activity—have proven to be as effective as warfarin in reversing the many hypercoagulable effects of malignancy, although it wasn’t obvious at first that they would be.

Gibson and Powrie review the issues we face when pregnant patients need anticoagulation. While drug interactions and organ dysfunction are rarely problems in this setting, warfarin is teratogenic and is therefore strongly contraindicated early in pregnancy, and its peripartum use has been associated with bleeding complications. Furthermore, unfractionated heparin is associated with the development of osteoporosis, and it requires frequent injections. The low-molecular-weight heparins thus have a definite niche in the management of pregnant women, but with a caveat: dosing of these agents by weight alone in this setting is fraught with the potential for underdosing. Catastrophic outcomes have been reported in pregnant patients with older mechanical cardiac valves who were switched from warfarin to low-molecular-weight heparin therapy. Plus, if the patient is to receive neuraxial regional anesthesia, low-molecular-weight heparins should be discontinued at least 12 hours before catheter placement if prophylactic doses have been given, or 24 hours if therapeutic doses have been given.

Low-molecular-weight heparins have greatly enhanced our ability to treat thromboembolic disease. But, as the authors of these two papers discuss, many management nuances still must be noted.

In this issue of the Journal we review two special situations in which low-molecular-weight heparins have special advantages. Babu and Carman discuss patients with cancer and thromboembolic disease. These patients are particularly difficult to manage since they tend to have recurrent thrombosis, sometimes even while on anticoagulant therapy, and they tend to have more bleeding complications from warfarin therapy. Inanition, drug interactions, and organ dysfunction make warfarin titration problematic, and the possibility of vascular metastases is always a concern. Low-molecular-weight heparins —which, unlike warfarin, work primarily by antagonizing factor Xa activity—have proven to be as effective as warfarin in reversing the many hypercoagulable effects of malignancy, although it wasn’t obvious at first that they would be.

Gibson and Powrie review the issues we face when pregnant patients need anticoagulation. While drug interactions and organ dysfunction are rarely problems in this setting, warfarin is teratogenic and is therefore strongly contraindicated early in pregnancy, and its peripartum use has been associated with bleeding complications. Furthermore, unfractionated heparin is associated with the development of osteoporosis, and it requires frequent injections. The low-molecular-weight heparins thus have a definite niche in the management of pregnant women, but with a caveat: dosing of these agents by weight alone in this setting is fraught with the potential for underdosing. Catastrophic outcomes have been reported in pregnant patients with older mechanical cardiac valves who were switched from warfarin to low-molecular-weight heparin therapy. Plus, if the patient is to receive neuraxial regional anesthesia, low-molecular-weight heparins should be discontinued at least 12 hours before catheter placement if prophylactic doses have been given, or 24 hours if therapeutic doses have been given.

Low-molecular-weight heparins have greatly enhanced our ability to treat thromboembolic disease. But, as the authors of these two papers discuss, many management nuances still must be noted.

In this issue of the Journal we review two special situations in which low-molecular-weight heparins have special advantages. Babu and Carman discuss patients with cancer and thromboembolic disease. These patients are particularly difficult to manage since they tend to have recurrent thrombosis, sometimes even while on anticoagulant therapy, and they tend to have more bleeding complications from warfarin therapy. Inanition, drug interactions, and organ dysfunction make warfarin titration problematic, and the possibility of vascular metastases is always a concern. Low-molecular-weight heparins —which, unlike warfarin, work primarily by antagonizing factor Xa activity—have proven to be as effective as warfarin in reversing the many hypercoagulable effects of malignancy, although it wasn’t obvious at first that they would be.

Gibson and Powrie review the issues we face when pregnant patients need anticoagulation. While drug interactions and organ dysfunction are rarely problems in this setting, warfarin is teratogenic and is therefore strongly contraindicated early in pregnancy, and its peripartum use has been associated with bleeding complications. Furthermore, unfractionated heparin is associated with the development of osteoporosis, and it requires frequent injections. The low-molecular-weight heparins thus have a definite niche in the management of pregnant women, but with a caveat: dosing of these agents by weight alone in this setting is fraught with the potential for underdosing. Catastrophic outcomes have been reported in pregnant patients with older mechanical cardiac valves who were switched from warfarin to low-molecular-weight heparin therapy. Plus, if the patient is to receive neuraxial regional anesthesia, low-molecular-weight heparins should be discontinued at least 12 hours before catheter placement if prophylactic doses have been given, or 24 hours if therapeutic doses have been given.

Low-molecular-weight heparins have greatly enhanced our ability to treat thromboembolic disease. But, as the authors of these two papers discuss, many management nuances still must be noted.

Venous thromboembolism (VTE) has various differing causes, so its treatment is not necessarily the same in all cases. Most cases of VTE are related to an easily identified risk factor. In patients with an apparently idiopathic event, identifying an underlying cause may alter therapy. In particular, identification of a malignancy may affect the choice of therapy and the duration of treatment.

In this review, we explore the role of cancer screening in patients with idiopathic VTE, then highlight the treatment for VTE in patients with cancer.

‘IDIOPATHIC’ VTE CAN BE DUE TO CANCER

Most patients with venous thrombosis have one of the components of Virchow’s triad: a hypercoagulable state, venous injury, or venous stasis. Those without identifiable risk factors for VTE are considered to have idiopathic VTE. In these patients, a search for a contributing factor may be indicated.

In 1861, the astute clinician Dr. Armand Trousseau noted a link between deep venous thrombosis and pancreatic cancer, stating that if cancer of an internal organ is suspected but the diagnosis cannot be verified, the diagnosis may be confirmed by the sudden, spontaneous appearance of thrombophlebitis in a large vein.¹

Today, from 2% to 25% of patients with idiopathic VTE are found to have cancer within 24 months of the diagnosis of VTE.^2–11 The goals of cancer screening in idiopathic VTE are to detect cancer at an early, treatable stage and to optimize the VTE therapy to decrease the risks of recurrence and anticoagulation-associated complications in patients who are found to have cancer. However, several questions must be considered first:

• What are the risks and costs of the screening?
• Will discovering the cancer sooner benefit the patient in terms of survival?
• If cancer is found, what are the possible complications or risks of the additional procedures, interventions, or treatments required?
• What is the psychological impact of the screening?

EVIDENCE SUPPORTING CANCER SCREENING AFTER IDIOPATHIC VTE

Piccioli et al¹² recently performed a randomized, controlled trial comparing cancer-related death rates in 99 patients with idiopathic VTE screened for malignancy vs 102 patients with idiopathic VTE who were not screened.

The screened group underwent:

• Abdominal and pelvic ultrasonography and computed tomography (CT)
• Gastroscopy or double-contrast barium-swallow evaluation
• Colonoscopy or sigmoidoscopy followed by barium enema
• Testing for fecal occult blood
• Sputum cytology
• Measurement of carcinoembryonic antigen, alpha-fetoprotein, and cancer antigen 125.
• Mammography and Papanicolaou smears (women)
• Ultrasonography of the prostate and prostate-specific antigen testing (men).

Patients were followed for 2 years. The screening uncovered cancer in 13 patients. Cancer developed in one other patient in the screening group during follow-up; in the control group, 10 patients developed symptomatic cancer during follow-up. Overall, the time to cancer diagnosis was 11.6 months in the unscreened group vs 1 month in the screened group (P < .001). Nine of the 14 patients with cancer in the screened group had T1 or T2 disease without local or distant metastasis vs 2 of the 10 control patients with cancer (P = .047). Unfortunately, this study did not have adequate power to detect the effect of screening on survival.

Di Nisio et al¹³ used data from this trial to perform a decision analysis for cancer screening. They calculated that abdominal and pelvic CT, with or without mammography and with or without sputum cytologic testing, would cost the least per life-year gained and would harm the fewest number of patients. They also suggested that substituting CT of the chest for sputum cytology may provide additional diagnostic benefit.

However, this strategy has not been clinically tested. Given the limited number of patients and the short follow-up in this initial trial, larger trials are needed to look at the cost-effectiveness of this screening model and whether it increases survival.

Our recommendations

Because the data are limited, our approach to looking for an early, treatable malignancy in patients with idiopathic VTE follows the current consensus:

• A thorough history and physical, including an extensive review of systems
• Basic laboratory testing with a complete blood cell count, comprehensive metabolic profile, and urinalysis
• Chest radiography
• Other age- and sex-specific cancer screening tests.

Adding CT of the abdomen, pelvis, or chest to this evaluation may be considered. However, tumor marker testing, which typically has high false-positive rates, is not routinely warranted.¹³ Additional investigation should be considered if abnormalities are detected during the initial evaluation or in patients with recurrent VTE during therapy.

While this strategy may be most cost-effective, Monreal et al¹⁴ suggest that it may miss up to half of cancers ultimately discovered.

MANAGING VTE IN PATIENTS WITH KNOWN CANCER

Managing VTE is far more complex in cancer patients than in patients without cancer. Also, cancer patients with VTE have lower rates of survival than cancer patients without VTE and are at greater risk of adverse outcomes such as anticoagulant-associated bleeding and recurrent venous thrombotic events.^15–17

Up to 21.5% of patients with VTE have another event within 5 years,¹⁸ but the risk is two to three times higher if they also have cancer.^16,18 The risk of recurrence may be linked to the location of the thrombus and to the extent of the malignancy.

In one study, the 3-month rate of recurrence was up to 5.1% if the clot was in the popliteal vein, 5.3% if in the femoral vein, and 11.8% if in the iliac vein.¹⁹

Prandoni et al¹⁶ found that the risks of VTE recurrence and bleeding were higher in patients with extensive cancer than in those with less-extensive cancer. In this study, major bleeding was documented in 12.4% of patients with cancer vs 4.9% of patients without cancer. Compared with patients without cancer, the hazard ratio for a major bleeding event was 4.8 in patients with extensive cancer and 0.5 in patients with less-extensive cancer.

In addition, not all patients with bleeding had excessive levels of anticoagulation, and not all patients with recurrent events had subtherapeutic levels.^16,17 Therefore, treatment of venous thrombosis in cancer patients requires a careful, individualized risk-to-benefit decision analysis.

ACUTE THERAPY FOR VTE: PARENTERAL AGENTS

Treatment in the first several hours or days after a thromboembolic event is with short-acting parenteral agents: unfractionated heparin; one of the low-molecular-weight heparins (LMWHs), ie, dalteparin (Fragmin), enoxaparin (Lovenox), or tinzaparin (Innohep); or fondaparinux (Arixtra).

Before starting anticoagulation, consider:

• Does the patient have severe chronic kidney disease (ie, a creatinine clearance < 30 mL/min)? If so, unfractionated heparin may be better than an LMWH or fondaparinux, which are cleared by the kidney.
• Does he or she need inpatient care? If not, LMWH therapy at home may be appropriate.
• Are there concerns about the ease of anticoagulation administration (ie, whether the patient can give the injections or have a family member do it), the cost of the drugs, or the ability to reverse the anticoagulant effect, if necessary? If so, unfractionated heparin may be more appropriate.

For acute treatment, the 2008 guidelines of the American College of Chest Physicians²⁰ (ACCP) recommend using an LMWH in a weight-based dose; unfractionated heparin given intravenously; unfractionated heparin given subcutaneously with monitoring and dosing adjustments; unfractionated heparin given subcutaneously at a fixed dose; or fondaparinux (grade 1A recommendation). The 2007 National Comprehensive Cancer Network (NCCN) guidelines²¹ recommend an LMWH, fondaparinux, or unfractionated heparin. Treatment should start promptly after the diagnosis of VTE is confirmed. However, if VTE is strongly suspected and a delay in diagnostic testing is anticipated, therapy should be started while awaiting the test results.

LONG-TERM THERAPY: LMWH OR WARFARIN

The ACCP and the NCCN guidelines recommend LMWH monotherapy for extended treatment of VTE in patients with active malignancy, when appropriate.^20,21 However, if long-term LMWH is not appropriate, then oral anticoagulation with a vitamin K antagonist, such as the coumarin derivative warfarin (Coumadin), is an alternative and should be started on the same day as the heparin. The heparin and the warfarin therapy must overlap for a minimum of 4 or 5 days and until a stable, therapeutic level of anticoagulation is achieved, ie, an international normalized ratio (INR) of 2 to 3 for 2 consecutive days.²⁰

The duration of anticoagulant therapy depends on comorbidities and the patient’s underlying predisposition for VTE. In patients with limited disease, the guidelines recommend continuing anticoagulation for a minimum of 3 to 6 months for deep venous thrombosis and pulmonary embolism.^20–21 Patients with active malignancy, ongoing treatment for the cancer, or continued risk factors may need indefinite treatment. In some circumstances, such as catheter-associated deep venous thrombosis, anticoagulation should continue for as long as the catheter is in place and for 1 to 3 months after its removal.²¹

WARFARIN CAN BE DIFFICULT TO USE

In 1954, the US Food and Drug Administration (FDA) approved the vitamin K antagonist warfarin for medical use in humans. Experience has shown it to be effective in preventing and treating VTE. However, it can be somewhat difficult to use, for several reasons:

• A narrow therapeutic window
• Genetic polymorphisms and variability in dose response
• Drug interactions and dietary considerations
• The need for laboratory monitoring and dose adjustment
• Patient noncompliance or miscommunication between the patient and physician.²²

In cancer patients, the response to warfarin may be unpredictable because of poor nutrition, interactions with chemotherapy and antibiotics, and comorbid conditions.²² Furthermore, its onset of action can be delayed and its clearance may be prolonged, further increasing the risk of complications, especially in patients prone to developing chemotherapy-related anemia or thrombocytopenia.²² Bleeding risk is the highest in the first 3 months of therapy. In addition, the risk of bleeding is higher in older patients, women, and patients with a history of gastrointestinal bleeding, stroke, recent myocardial infarction, diabetes, renal insufficiency, malignancy, or anemia.^23,24

ADVANTAGES AND DISADVANTAGES OF LMWH

The advantages of the LMWHs over unfractionated heparin include a lower risk of heparin-induced thrombocytopenia, greater bioavailability when given subcutaneously (which also permits once-daily or twice-daily dosing), and no need for laboratory monitoring in most patients. LMWHs have a short half-life, so omitting one or two doses will adequately interrupt therapy. Also, LMWHs have been shown to be as safe and effective as unfractionated heparin in treating VTE. They can be given safely at home, thus enhancing quality of life.^25–31

On the other hand, these drugs cost more than unfractionated heparin or warfarin, their dosage must be adjusted in patients with renal insufficiency, their anticoagulant effect can be reversed only to a limited extent, and their dose must be adjusted according to weight in morbidly obese or in very thin patients.^32,33

LMWHs are expensive, but may be worth it

As initial therapy, the LMWHs are cost-effective compared with unfractionated heparin in patients with VTE.^34,35 However, they cost more with extended use. A cost-effectiveness analysis comparing 6 months of LMWH therapy to standard warfarin concluded that LMWH therapy was more costly.³⁵ However, the impact of fewer hospitalizations, probably fewer bleeding complications, and better quality of life are difficult to analyze in this decision model and should also be considered when deciding about therapy for an individual patient.³⁵

LMWHs are cleared by the kidney

All LMWHs are renally cleared, so patients with significant renal insufficiency (creatinine clearance < 30 mL/min) are at greater risk of bleeding complications. The rate below which clearance is impaired varies among the different LMWHs. Only enoxaparin has approved dosing regimens for use in patients with renal impairment.

If the patient has renal insufficiency, the ACCP guidelines suggest using unfractionated heparin, or if using LMWH, monitoring anti-factor Xa levels to avoid drug accumulation and increased bleeding risk.²⁵ If bleeding occurs, LMWHs have limited reversibility with protamine sulfate, which is estimated to neutralize about 60% of the anti-factor Xa activity of LMWHs.²⁵

Adjusting LMWHs for body weight

In the Registro Informatizado de la Enfermedad Tromboembólica (RIETE),³³ patients weighing less than 50 kg had a higher risk of bleeding than patients weighing 50 to 100 kg, so in thinner patients the risk of bleeding from LMWH vs oral anticoagulation must be considered carefully and monitored prudently.

Although there is little evidence to suggest a higher bleeding risk in morbidly obese patients (> 150 kg), they may be at risk of subtherapeutic treatment, and monitoring with anti-factor Xa assays is recommended.^25,32,33

LMWH VS WARFARIN FOR VTE IN CANCER PATIENTS

LMWHs are the first-line treatment for VTE in cancer patients.^20,21 Several randomized controlled trials compared the efficacy of LMWH vs warfarin in patients with cancer.

Meyer et al³⁶ randomized patients to receive either warfarin for 3 months at an INR between 2 and 3, or enoxaparin 1.5 mg/kg subcutaneously daily. Seventy-one patients received warfarin and 67 received enoxaparin. Fifteen (21%, 95% confidence interval [CI] 12%–32%) of the 71 patients assigned to warfarin experienced one major outcome event, defined as major bleeding or recurrent VTE, compared with 7 (10.5%) of the 67 patients assigned to receive enoxaparin (95% CI 4%–20%, P = .09). Six patients in the warfarin group died of bleeding vs none of the patients in the enoxaparin group. Overall, the warfarin group had a higher rate of bleeding, although this did not reach statistical significance. Despite weekly INR measurements, only 41% of the measured values were within the therapeutic range during the 3 months of treatment.³⁶

Lee et al³⁷ randomized cancer patients with deep venous thrombosis, pulmonary embolism, or both to receive 6 months of dalteparin alone, dosed at 200 IU/kg daily for 1 month, then decreased to 75% to 80% of the original dose (150 IU/kg) daily for the duration of therapy, or dalteparin followed by warfarin. During the 6-month follow-up, 17.4% of patients in the warfarin group had a recurrent thromboembolic event vs 8.8% in the dalteparin group (P = .0017). No statistically significant difference was noted in rates of major bleeding, minor bleeding, or death.³⁷

Hull et al³⁸ reported statistically significantly fewer episodes of recurrent VTE at 12 months in cancer patients treated with once-daily tinzaparin vs warfarin. In the tinzaparin group the recurrence rate was 7%, vs 16% in the warfarin group (P = .044). No difference in rates of bleeding or death were found.

Deitcher et al³⁹ compared enoxaparin with long-term warfarin in 102 patients. While this trial did not have the power to detect clinical differences in recurrent thromboembolic events or bleeding complications, at 180 days they noted 97% compliance with once-daily or twice-daily enoxaparin therapy.

Noble and Finlay,⁴⁰ in another small study, found LMWH therapy to be qualitatively more acceptable for palliative-care cancer patients than oral therapy.

In general, long-term therapy with once-daily or twice-daily LMWH is well tolerated. Currently, dalteparin is the only LMWH approved by the FDA for extended monotherapy in cancer-related VTE.

DO LMWHS AFFECT CANCER?

In vitro and animal studies indicate that LMWH may have antimetastatic and antiangiogenic properties.^41–44

Altinbas et al⁴⁵ reported significantly better chemotherapy-induced tumor response rates and survival rates in patients with small cell lung cancer randomized to receive combination chemotherapy plus prophylactic dalteparin 5,000 IU daily compared with combination chemotherapy alone. However, as provocative as these results may be, we need to test the effects of LWMHs on different cancer types in a prospective clinical trial. For now, this area remains controversial.

It has been suggested that anticoagulants may improve survival in patients with nonmetastatic cancer. Supporting this observation, a post hoc analysis of the trial by Lee et al³⁷ found a statistically significantly lower cancer-specific mortality rate in nonmetastatic cancer patients treated with dalteparin vs oral therapy with a coumarin derivative. In patients without metastatic disease, the death rate at 12 months was 36% in patients treated with oral therapy vs 20% in patients treated with dalteparin (P = .03).⁴⁶

These findings are consistent with those of the Fragmin Advanced Malignancy Outcome Study (FAMOUS),⁴⁷ the first randomized, placebo-controlled trial of dalteparin 5,000 IU daily in patients with advanced solid tumors and without evidence of underlying thrombosis. Overall, dalteparin prophylaxis did not increase survival. However, in a subgroup of patients with a better prognosis and who were alive 17 months after diagnosis, survival was statistically significantly longer in patients treated with dalteparin.

Another small trial showed similar survival benefits in cancer patients without VTE.⁴⁸ The results may suggest a long-term favorable effect of LMWH on tumor cell biology, which could translate into a favorable outcome in some patients. It is important to note, however, that not all trials have shown this same clinical benefit.⁴⁹

In general, the growing body of laboratory and clinical data indicates that LMWHs may suppress tumor growth and metastasis. However, definitive conclusions about these effects are not yet possible because of variations in study design, tumor type, and patient populations. Further investigations into the role of LMWHs in the treatment of VTE and in cancer progression are ongoing.

THE EVIDENCE IN PERSPECTIVE

Illness and the recurrence of VTE in patients with cancer depend on the location and extent of the underlying cancer. Rates of death are higher in VTE patients with cancer than in VTE patients without cancer. Patients with limited or localized disease may not die of the cancer itself but of complications of acute pulmonary embolism. Therefore, it is important to recognize the different options for and the potential side effects of treating VTE.

If patients are hospitalized for an acute thromboembolic event and unfractionated heparin is chosen as the initial anticoagulant, using a weight-based nomogram has been shown to achieve therapeutic levels within 24 hours and reduce the rates of recurrence of thromboembolic events.⁵⁰

Warfarin treatment may pose a particular challenge for both cancer patients and physicians, since multiple drug interactions, anorexia, and comorbid conditions contribute to an unpredictable response.

The risk of bleeding is higher in cancer patients than in the general population, and the decision to start anticoagulants should be based on an individualized risk-benefit profile. Several trials have shown LMWH to be more effective and safer than warfarin in cancer patients.

These considerations, along with the other advantages of LMWHs (ease of use, less need for laboratory monitoring, and better patient tolerance), make LMWHs a good choice for initial therapy. Extended LMWH therapy is currently favored for initial management in patients with cancer. Trials are under way to further assess the antitumor properties and potential survival benefit in patients with selected solid tumors.