Elisabeth M. Battinelli, MD, PhD

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Decision Making in Venous Thromboembolism

Author(s)

Ariela L. Marshall, MD

Elisabeth M. Battinelli, MD, PhD

Jean M. Connors, MD

From the Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA.

Abstract

Objective: To review the diagnosis and management of venous thromboembolism (VTE).
Methods: Review of the literature.
Results: VTE and its associated complications account for significant morbidity and mortality. Various imaging modalities can be employed to support a diagnosis of a VTE and are used based on clinical suspicion arising from the presence of signs and symptoms. Clinical decision rules have been developed that can help determine which patients warrant further testing. Anticoagulation, the mainstay of VTE treatment, increases bleeding risk, necessitating tailored treatment strategies that must incorporate etiology, risk, benefit, cost, and patient preference.
Conclusion: Further study is needed to understand individual patient risks and to identify treatments that will lead to improved patient outcomes.

Venous thromboembolism (VTE) and its associated complications account for significant morbidity and mortality. Each year between 100 and 180 persons per 100,000 in Western countries develop VTE. The majority of VTEs are classified as either pulmonary embolism (PE), which accounts for one third of the events, or deep vein thrombosis (DVT), which is responsible for the remaining two thirds. Between 20% and 30% of those patients diagnosed with thrombotic events will die within the first month after diagnosis [1].PE is a common consequence of DVT; 40% of patients who are diagnosed with DVT will be subsequently found to have PE upon further imaging. This high rate of association is also seen in those who present with PE, 70% of whom will also be found to have concomitant DVT [2,3].

There are many risk factors for VTE, including patient-specific demographic factors, environmental factors, and pharmacologic factors (Table 1). One of the main demographic factors associated with development of VTE is age. It is rare for children to suffer a thrombotic event, whereas older persons have a risk of 450 to 600 events per 100,000 [1]. Other demographic risk factors, both inherited and acquired, have been associated with increased risk of VTE. Inherited risk factors include factor V leiden mutation, prothrombin gene mutation, protein C and protein S deficiencies, antithrombin deficiency, and dysfibrinogenemia. The prevalence of these inherited thrombophilias in patients with VTE is about 25% to 35% compared to 10% in controls without VTE [4,5].Acquired risk factors include prior VTE, malignancy, surgery, trauma, obesity, smoking, pregnancy, and immobilization [6–9].Additionally, multiple medical conditions, including the antiphospholipid antibody syndrome, myeloproliferative neoplasms, paroxysmal nocturnal hemoglobinuria, renal disease (particularly nephritic syndrome), liver disease, and inflammatory bowel disease have been shown to increase risk of VTE [10–13].

Anatomic risk factors include Paget-Schroetter syndrome (compression of upper extremity veins due to abnormalities at the thoracic outlet), May-Thurner syndrome (significant compression of the left common iliac vein by the right common iliac artery), and abnormalities of the inferior vena cava [14–16].Medications that are associated with increased risk of VTE include but are not limited to estrogen (both in oral contraceptives as well as hormone replacement therapy) [17,18],the selective estrogen receptor modulator tamoxifen [19],testosterone [20],and glucocorticoids [21].It is important to note that many patients with VTE have more than one acquired risk factor for thrombosis [22],and also that acquired risk factors are more likely to lead to VTE in the setting of underlying inherited thrombophilic conditions [23].

Pathogenesis

Abnormalities in both coagulation factors and the vascular bed are at the core of the pathogenesis of VTE. The multifaceted etiology of thrombosis was first described in 1856 by Virchow, who defined a triad of defects in the vessel wall, platelets, and coagulation proteins [24].Usually the vessel wall is lined with endothelial cells that provide a nonthrombotic surface and limit platelet aggregation through release of prostacyclins and nitric oxide. When the endothelial lining is compromised, the homeostatic surveillance system is disturbed and platelet activation and the coagulation system are initiated. Tissue factor exposure in the damaged area of the vessel leads to activation of the coagulation cascade. Collagen that is present in the area of the wound is also exposed and can activate platelets, which provide the phospholipid surface upon which the coagulation cascade occurs. Platelets initially tether to the exposed collagen through binding of glycoprotein Ib-V-IX in association with von Willebrand factor [25].The thrombus is initiated as more platelets are recruited to exposed collagen of the injured endothelium through aggregation in response to the binding of GPIIIb/IIa with fibrinogen. This process is self-perpetuating as these activated platelets release additional proteins such as adenosine diphosphate (ADP), serotonin, and thromboxane A2, all of which fuel the recruitment and activation of additional platelets [26].

Diagnosis

The key to decreasing the morbidity and mortality associated with VTE is timely diagnosis and early initiation of therapy. Various imaging modalities can be employed to support a diagnosis of a VTE and are used based on clinical suspicion arising from the presence of signs and symptoms. DVT is usually associated with pain in calf or thigh, unilateral swelling, tenderness, and redness. PE can present as chest pain, shortness of breath, syncope, hemoptysis, and/or cardiac palpitations.

Decision Rules

Clinical decision rules based on signs, symptoms, and risk factors have been developed to estimate the pretest probability of PE or DVT and to help determine which patients warrant further testing. These clinical decision rules include the Wells criteria (separate rules for DVT and PE) [27,28],as well as the Geneva score [29],which is focused on identifying patients with a likelihood of having a PE. In general, these clinical rules are applied at presentation to predict the risk of VTE, and patients who score high are evaluated by imaging modalities, while those with lower scores should be considered for further stratification based on D-dimer testing. The goal of clinical assessment and use of a decision rule is to identify patients at low risk of VTE to reduce the number of imaging studies performed. Most of the decision rules focus on the use of noninvasive evaluations that are easily implemented, including clinical history and presentation, abnormalities in oxygen saturation, chest radiography findings, and electro-cardiography.

D-Dimer Testing

D-dimer testing is at the core of all predictive models for VTE. D-dimer is a fibrin degradation product that is detectable in the blood during active fibrinolysis and occurs after clot formation. The concentration of D-dimer increases in patients with active clot. D-dimer testing is usually performed as a quantitative ELISA or automated turbidometric assay and is highly sensitive (> 95%) in excluding a diagnosis of VTE if results are in the normal range [30].The presence of a normal D-dimer and a low probability based on clinical assessment criteria can be integrated to determine which patients have a low (generally < 99%) likelihood of having VTE [31].It should be noted that other factors can lead to an increased D-dimer, including malignancy, trauma, critical illness, disseminated intravascular coagulation, pregnancy, infection, and postoperative status, which can produce false-positive results and cloud the utility of the test in excluding those at low risk of VTE from undergoing imaging [32–34].Additionally, D-dimer values naturally increase with age and recent work has shown utility of an age-adjusted D-dimer threshold, though this method is not yet widespread in clinical practice [35,36].

Imaging

After application of a clinical prediction rule, the mainstay of diagnosis of VTE is imaging. For DVT the use of ultrasonography is considered the gold standard, with both high sensitivity (89–100%) and specificity (86–100%), especially when the DVT is located proximally [37–39].We generally recommend compression ultrasound starting with the proximal veins but expanding to include the whole leg if the proximal studies are negative [40–42].Other diagnostic options include computed tomography (CT) venography, which is not first line as it is highly invasive and exposes the patient to iodine-based contrast dyes, and magnetic resonance venography (MRV), which offers superb visualization for diagnosis of pelvic vein thrombosis but is limited because of availability and cost issues.

Helical CT pulmonary angiography (CTPA) is the diagnostic test of choice in PE, with high sensitivity (96%) and specificity (95%), and has replaced conventional ventilation perfusion (VQ) scanning or other methods such as magnetic resonance pulmonary angiography in most settings [43,44].CTPA should be avoided in patients who have severe chronic kidney disease or a contrast allergy, and is often avoided in patients who are pregnant due to potential risk of radiation exposure, and in such situations VQ scanning may be employed.

Algorithmic Approach to Workup

Our general practice is to apply the Wells clinical prediction rule (Table 2 for DVT and Table 3 for PE), as this system is likely the most familiar to a large number of clinicians and a score can be obtained promptly but accurately based on easily accessible data from history and exam. We generally use the simplified modified criteria presented in the Tables. Once the clinical prediction rule has been applied, we use 2 risk-based algorithms for further evaluation (Figure 1 and Figure 2) [45,46]. In general, we initially perform a D-dimer test for low-risk patients, while we advocate for prompt imaging in high-risk patients to avoid delays in treatment should VTE be diagnosed. Once a diagnosis of VTE is established, treatment should be started promptly. One exception may be isolated

distal DVT, where it is reasonable to defer treatment in favor of serial ultrasound testing to rule to rule out proximal extension unless the patient is significantly symptomatic with the distal DVT alone [40].

Of note, there are multiple clinical situations in which the application of a clinical prediction rule followed by D-dimer testing and/or imaging cannot be “standardized” with such algorithms. These include situations where D-dimer may be falsely positive (as above), situations in which alternative imaging strategies should be used to avoid contrast exposure in workup of PE (as above), and workup of suspected upper extremity DVT. Upper extremity ultrasound comprises about 10% of all DVT and frequently occurs in the setting of risk factors such as central venous catheters or pacemakers; specific upper-extremity risk-assessment rules have been developed [47,48].

D-dimer is generally not as useful in workup of upper extremity DVT (given high prevalence of factors that lead to false-positive DVT) and we generally perform compression ultrasonography up front in patients in whom we have high clinical suspicion for upper extremity DVT. In all such clinical situations above, workup should be individualized in accordance with patient factors and careful physician assessment.

Acute Treatment Options

The first step in treatment is identification of patients who are at high risk of

VTE-related mortality, especially those with PE and hemodynamic instability (defined as systolic blood pressure < 90 mm Hg or a drop in pressure more than 40 mm Hg for more than 15 minutes in the absence of new-onset arrhythmia, hypovolemia, and sepsis). This patient population should be considered for emergent management with thrombolytic therapy, typically recombinant tissue plasminogen activator (t-PA, alteplase). Thrombolysis should be reserved for those who have not had any surgical procedures in the last 2 weeks, have no evidence of neurosurgical bleeding, and are not at risk of a bleeding diathesis. Patients who present without frank hemodynamic instability but have evidence of right ventricular dysfunction (by echocardiography or biomarkers such as troponin elevation) may be at “intermediate risk” for adverse outcomes and the role of thrombolytics in this population is an area of active investigation [49,50].

In standard cases of DVT and PE without hemodynamic compromise, the current standard of care is to initiate parenteral anticoagulation. The immediate goal of therapy is to treat rapidly with anticoagulants to prevent the thrombus from propagating further and to prevent DVT from embolization to the lungs or other vascular beds. The initial treatment of VTE has been extensively discussed and guidelines have been established with recommendations for initiation of anticoagulation; the American College of Chest Physicians (ACCP) released the 9th edition of their guidelines in 2012 based on consensus agreements derived from primary data [51].

Heparin-based drugs are the mainstay of initial treatment. These drugs act by potentiating antithrombin and therefore inactivating thrombin and other coagulation factors such as Xa. Unfractionated heparin (UFH) can be administered as an initial bolus followed by a continuous infusion with dosing being based on weight and titrated to activated partial thromboplastin time (aPTT) or the anti-factor Xa level. Alternatively, patients may be treated with a low molecular weight heparin (LMWH) administered subcutaneously in fixed weight-adjusted doses, which obviates the need for monitoring in most cases [52].LMWHs work in a similar manner to UFH but have more anti-Xa activity in comparison to anti-thrombin activity. LMWH appears to be more effective than UFH for initial treatment of VTE and has been associated with lower risk of major hemorrhage [53].The options for treatment of VTE have expanded in recent years with the approval of fondparinux, a pentasaccharide specifically targeted to inhibit factor Xa. Fondaparinux has been shown to have similar efficacy to LMWH in patients with DVT [54],and while it has not been evaluated directly against LMWH for initial treatment of PE it has been shown to be at least as effective and safe as UFH [55].

Both LMWH and fondaparinux are cleared renally and therefore have increased bleeding risk in patients with renal impairment. In patients with creatinine clearance of less than 30 mL/min, dose reduction or lengthening of dosing interval may be appropriate. Anti-factor Xa activity can be used as a functional assay to monitor and titrate the level of anticoagulation in patients treated with UFH, LMWH, and fondaparinux. Monitoring is useful in the setting of impaired renal function (as above) in addition to extremes of body weight and pregnancy. When used for monitoring of UFH, the anti-factor Xa activity can be measured at any time during administration with a therapeutic goal range of 0.3–0.7 international units (IU)/mL. When used for LMWH, a “peak” anti-factor Xa should be measured approximately 4 hours after dosing, with therapeutic goals depending on preparation and schedule of treatment but generally between 0.6 to 1.0 IU/mL for twice daily and around 1.0 -2.0 IU/mL for once-daily [56].For patients on dialysis, we generally use intravenous UFH for acute treatment of VTE, though recent work has shown that enoxaparin (doses of 0.4 to 1 mg/kg/day) was as safe as UFH with respect to bleeding and was associated with shorter hospital length of stay [57].For long-term treatment of VTE, warfarin is generally preferred based on clinical experience with this agent, though small studies have suggested that parenteral agents may be useful alternatives to warfarin [58].

In many patients who are clinically stable without significant medical comorbidities, outpatient administration of these medications without hospitalization is considered safe. Patients with DVT are often safe to manage as outpatients unless significant clot burden is present and thrombolysis is being considered. For PE, the pulmonary embolism severity index (PESI) and simplified index (sPESI) may be useful to risk-stratify patients and identify those at low risk of complications who may be suitable for outpatient treatment [59,60].Studies have shown that hemodynamically stable patients who did not require supplemental oxygenation or have contraindications to LMWH therapy were safely managed as outpatients with low risk of recurrent VTE and bleeding [61,62].One exception may be patients with intermediate risk PE, who are hemodynamically stable but have evidence of right ventricular dysfunction and may be better served by an initial in-hospital observation period, especially if thrombolysis is being considered.

Most patients who present with VTE are transitioned to warfarin for long-term therapy. Warfarin can be started on the same day as parenteral anticoagulation. Both drugs are overlapped for at least 5 days, with a target INR of 2.0–3.0. Patients may achieve the target INR level quickly because factor VII has a short half-life and the level drops quickly; however, the overlap of 5 days is essential even when the INR is in the target range because a full anticoagulant affect is not achieved until prothrombin levels decline, and this is a slow process due to the long half-life of prothrombin. Warfarin also causes rapid decrease in levels of natural anticoagulants such as protein C and protein S, which further exacerbates the net hypercoagulable state in the short-term. Warfarin without a bridging parenteral agent carries a risk of warfarin-induced skin necrosis [63]and is not effective as an initial anticoagulant treatment in acute VTE as there is a relatively high risk of symptomatic clot extension or recurrent VTE compared to warfarin with use of a bridging agent [64].In specific cases such as cancer-associated VTE (see discussion below), LMWH is preferred to warfarin for long-term active therapy.

Long-Term Active Therapy After Acute Treatment

Duration of Anticoagulation

Recommended duration of anticoagulation depends on a myriad of factors including severity of VTE, risk of recurrence, bleeding risk, and lifestyle modification issues, as well as on the safety and availability of alternative therapies such as low-intensity warfarin, aspirin, or the new oral anticoagulants. The decision tree for length of treatment starts with whether the VTE was a provoked or a spontaneous event. Provoked events occur when the event is associated with an identifiable risk factor, such as immobilization from prolonged medical illness or surgical intervention, pregnancy or oral contraceptive use, and prolonged air travel.

Consensus guidelines suggest that 3 months of anti-coagulation are generally sufficient treatment for a provoked VTE [51,65,66]. Data from multiple studies and a meta-analysis suggests that less than 3 months of anticoagulation (4 to 6 weeks in most trials) is associated with an approximately 1.5-fold higher risk of recurrent VTE than 3 months [67,68].However, data from this meta-analysis also suggests that anticoagulation for longer than 3 months (6 to 12 months in most trials) is not associated with higher rates of recurrent VTE. We generally anticoagulate for 3 months in patients with provoked VTE.

Determining the duration of anticoagulation is more complex in patients with idiopathic/unprovoked VTE. Kearon and colleagues found that in patients with first idiopathic VTE, patients who were anticoagulated for 24 months versus 3 months had lower risk of recurrent VTE (1.3% per patient-year with 24 months versus 27.4% per patient-year with 3 months) [69].Similar studies and meta-analyses have demonstrated decreased recurrence rates in patients anticoagulated for a prolonged period of time. However, one study of prolonged anticoagulation revealed that at 3 years there was no difference in recurrence rate in patients with PE who were anticoagulated for 6 months versus 1 year [70].The likelihood of recurrent DVT in patients with first episode of idiopathic proximal DVT treated with either 3 months or 12 months of warfarin was similar after treatment was discontinued [71].Prolonged periods of anticoagulation do not directly influence risk of recurrence but instead may only delay occurrence of a second event [72].For that reason, the decision is essentially whether to anticoagulate for 3 months or to continue therapy indefinitely [73]. Current guidelines recommend continuing anticoagulation for 3 months in those at high risk of bleeding, and continuing for an extended duration in those at low or moderate bleeding risk [51]. Patients' values and perferences should be entertained and decisions made on a patient-by-patient basis.

For patients at high risk of recurrent VTE, we generally recommend indefinite anticoagulation unless the patient has a significantly elevated bleeding risk or strongly prefers to discontinue anticoagulation and compliance concerns are evident. High-risk patients are those who have suffered from multiple episodes of recurrent VTE, those who have clotted while being anticoagulated, and those with acquired risk factors, such as antiphospholipid antibodies and malignancy. Other high-risk groups are those with high-risk thrombophilias such as deficiency of protein S, protein C, or antithrombin, homozygous factor V Leiden or prothrombin gene mutations, and compound heterozygous factor V Leiden/prothrombin gene mutation in the setting of an unprovoked event. Further discussion of models for risk assessment of recurrence is provided below.

Assessment of Bleeding Risk

The bleeding risk associated with the use of anticoagulation must be weighed against the risk of clotting events when determining duration of anticoagulation, especially in those patients for whom indefinite anticoagulation is a consideration. Risk of bleeding while on anticoagulation is approximately 1–3% per 100 patient-years [74],but concomitant medical conditions such as renal failure, diabetes-related cerebrovascular disease, malignancy, advanced age, and use of antiplatelet agents all increase the risk of bleeding. Bleeding risk is highest when patients first initiate anticoagulation and is approximately 10 times the risk in the first month of therapy than after the first year of therapy [75].

Risk assessment models such as the RIETE score may be helpful when indefinite anticoagulation is a possibility [76].The RIETE score encompasses 6 risk factors (age > 75 years, recent bleeding, cancer, creatinine level > 1.2 mg/dL, anemia, or PE at baseline) to categorize patients into low risk (0 points, 0.3% risk of bleeding), intermediate risk (1–4 points, 2.6% risk of bleeding) and high risk (> 4 points, 6.2% risk of bleeding) within 3 months of anticoagulant therapy. The ACCP has developed a more extensive list of 17 potential risk factors for bleeding to categorize patients into low risk (no risk factors, 0.8%/year risk of bleeding), intermediate risk (1 risk factor, 1.6%/year risk of bleeding) and high risk (2 or more risk factors, >6.5%/year risk of bleeding) categories [77].The RIETE score is simpler to use but was not developed for assessing risk of bleeding during indefinite therapy, while the ACCP risk categorization predicts a yearly risk and is therefore applicable for long-term risk assessment but is more cumbersome to use. In practice, we generally use a clinical gestalt of a patient’s clinical risk factors (particularly age, renal or hepatic dysfunction, and frequent falls) to assess if they may be at high risk of bleeding and if the risk of indefinite anticoagulation may thus outweigh the potential benefit.

We also note that several scoring systems (HAS-BLED, HEMORR2HAGES, and ATRIA scores) have been developed to predict those at high risk of bleeding on anticoagulation for atrial fibrillation [78–80].These scores generally include similar clinical risk factors to those in the RIETE and ACCP scoring systems. Several studies have compared the HAS-BLED, HEMORR2HAGES, and ATRIA scores and a systematic review and meta-analysis concluded that the HAS-BLED score is recommended, due to increased sensitivity and ease of application [81].However, as these scores have not been validated for anticoagulation in the setting of VTE, we do not use them in this capacity.

Risk Stratification for Recurrent VTE

When predicting risk of recurrent VTE, clinical risk factors including obesity, male gender, and underlying thrombophilia (including the “high risk” inherited thrombophilias identified above) must taken into consideration. Location of the thrombus must also be considered; it has also been demonstrated that patients with DVT involving the iliofemoral veins are at higher risk of recurrence than those without iliac involvement [82].Other factors that may be useful in risk stratification include D-dimer level and ultrasound to search for residual venous thrombosis.

D-dimer Levels

D-dimer levels are one of the more promising methods for assessing the risk of recurrent VTE after cessation of anticoagulation, especially in the case of idiopathic VTE where indefinite anticoagulation should be considered but may pose either risk of bleeding or significant inconvenience to patients. A normal D-dimer measured 1 month after cessation of anticoagulation offers a high negative predictive value for risk of recurrence [83].A number of studies have demonstrated that patients with elevated D-dimer 1 month after anticoagulation cessation are at increased risk for a recurrent event [84–86].Two predictive models that have been developed incorporate D-dimer testing into decision making [87,88].The DASH predictive model relies on the D-dimer result in addition to age, male sex, and use of hormone therapy as a method of risk stratification for recurrent VTE in patients with a first unprovoked event. Using this scoring system, patients with a score of 0 or 1 had a recurrence rate of 3.1%, those with a score of 2 a recurrence rate of 6.4%, and those with a score of 3 or greater a recurrence rate of 12.3%. The authors postulate that by using this assessment scheme they can avoid lifelong anticoagulation in 51% of patients. The Vienna prediction model uses male sex, location of VTE (proximal DVT and PE are at higher risk), and D-dimer level to predict risk of recurrent VTE. This model has recently been updated to include a “dynamic” component to predict risk of recurrence of VTE from multiple random time points [89].

Overall, D-dimer may be useful for risk stratification. We often employ the method of stopping anticoagulation in patients with unprovoked VTE after 3 months (if the patient has no identifiable clinical risk factors that place them at high risk of recurrence) and testing D-dimer 1 month after cessation of anticoagulation. An elevated D-dimer is a solid reason to restart anticoagulation (potentially on an indefinite basis), while a negative D-dimer provides support for withholding further anticoagulation in the absence of other significant risk factors for recurrence. However, lack of agreement regarding assay cut-points as well as multiple reasons other than VTE for D-dimer elevation may limit widespread use of this method. We generally use a cutpoint of 250 ug/L as “negative,” though at least one study showed that cut-points of 250 ug/L versus 500 ug/L did not change the utility of this method [90].In our practice, risk prediction models are most useful to provide patients with additional information and a visual presentation to support our recommendation. This is particularly true of the Vienna prediction rule, which is available in a printable nomogram which can be distributed to patients and completed together during the clinic visit.

Imaging Analysis

Imaging analysis may also assist with risk stratification. Clinical assessment modules have been developed that incorporate repeat imaging studies for assessment of recannulization of affected veins. In patients with residual vein thrombosis (RVT) at the time anticoagulation was stopped, the hazard ratio for recurrence was 2.4 compared to those without RVT [91].There are a number of ways RVT could impact recurrence, including inpaired venous flow leading to stasis and activation of the coagulation cascade. Subsequent studies used serial ultrasound to determine when to stop anticoagulation. In one study, patients were anticoagulated for 3 months and for those that had RVT, anticoagulation was continued for up to 9 months for provoked and 21 months for unprovoked VTE. In comparison to fixed dosing of 6 months of anti-coagulation, those who had their length of anticoagulation tailored to ultrasonography findings had a lower rate of recurrent VTE [92].Limitations to using RVT in clinical decision-making include lack of a standard definition of RVT and variability in both timing of ultrasound (operator variability) and interpretation of results [93].

Other Options

Another option in patients who are being considered for indefinite anticoagulation is to decrease the intensity of anticoagulation. Since this would theoretically lower the risk of bleeding, the perceived benefit of long-term, low-intensity anticoagulation would be reduction in both bleeding and clotting risk. The PREVENT trial randomized patients who had received full-dose anticoagulation for a median of 6.5 months to either low-intensity warfarin (INR goal of 1.5-2.0 instead of 2.0-3.0) or placebo. In the anticoagulation group, there was a 64% risk reduction in recurrent VTE (hazard ratio 0.36, 95% CI 0.19 to 0.67) but an increased risk of bleeding (hazard ratio 1.92, 95% CI 1.26 to 2.93) [94].The ELATE study randomized patients with unprovoked VTE who had completed 3 or more months of full-intensity warfarin therapy (target INR 2.0–3.0) to continue therapy with either low-intensity warfarin (target INR 1.5–2.0) or full-intensity warfarin (target INR 2.0-3.0). Compared to the low-intensity group, the conventional-intensity group had lower rates of recurrent VTE and no increased rates of major bleeding [95].This study, however, has been criticized because of its overall low bleeding rate in both treatment groups.

Aspirin is an option in patients in whom long-term anticoagulation is untenable. The ASPIRE trial demonstrated that in patients with unprovoked VTE who had completed a course of initial anticoagulation, aspirin 100 mg daily reduced the risk of major vascular events compared to placebo with no increase in bleeding [96].However, aspirin was not associated with a significant reduction in risk of VTE alone (only the composite vascular event endpoint). The WARFASA trial, however, demonstrated that aspirin 100 mg daily was associated with a significant reduction in recurrent VTE compared to placebo after 6 to 18 months of anticoagulation without an increase in major bleeding [97].The absolute risk of recurrence was 11% in the placebo group and 5.9% in the aspirin group. More recently, the INSPIRE collaboration analyzed data from both trials and found that aspirin after initial anticoagulation reduced the risk of recurrent VTE by approximately 42% with a low rate of major bleeding [98].The absolute risk reduction was even larger in men and older patients. For this reason, we recommend aspirin to those patients in whom indefinite anticoagulation may be warranted from the standpoint of reducing risk of recurrent VTE but in whom the risk of bleeding precludes its use.

Hypercoagulable States In Specific Populations

Inherited Thrombophilias

Patients with a hereditary thrombophilia are at increased risk for incident VTE [99].These inherited mutations result in either a loss of normal anticoagulant function or gain of a prothrombotic state. Hereditary disorders associated with VTE include deficiency of antithrombin, protein C, or protein S, or the presence of factor V Leiden and/or prothrombin G20210A mutations. Although deficiency of protein C, protein S, or antithrombin is uncommon and affects only 0.5% of the population, these states have been associated with a 10-fold increased risk of thrombosis in comparison to the general population. Factor V Leiden and prothrombin gene mutation are less likely to be associated with incident thrombosis (2 to 5-fold increased risk of VTE) and are more prevalent in the Caucasian population [100].Though these hereditary thrombophilias increase risk of VTE, prophylactic anti-coagulation prior to a first VTE is not generally indicated.

Data regarding the impact of the inherited thrombophilias on risk of recurrent VTE is less well defined. While some data suggest that inherited thrombophilias are associated with increased risk of recurrent VTE, the degree of impact may be clinically modest especially in those with heterozygous factor V Leiden or prothrombin gene mutations [101].Ideally, a clinical trial would be designed to assess whether hereditary thrombophilia testing is beneficial for patients with VTE in decision-making regarding length of anticoagulation, type of anticoagulation, and risk of recurrence. If a patient with a low-risk inherited thrombophilia has a DVT in the setting of an additional provoking risk factor (surgery, pregnancy, etc), a 3-month course of anticoagulation followed by D-dimer assessment as above is reasonable. If a patient with an inherited thrombophilia experiences an idiopathic VTE, or if a patient with a “high-risk” thrombophilia as described above experiences any type of VTE, we generally recommend indefinite anticoagulation in the absence of high bleeding risk, though again this is a very patient-dependent choice.

Acquired Thrombophilias

Antiphospholipid Syndrome

Antibodies directed against proteins that bind phospho-lipids are associated with an acquired hypercoagulable state. The autoantibodies are categorized as antiphospho-lipid antibodies (APLAs), which include anticardiolipin antibodies (IgG and IgM), beta-2 glycoprotein 1 antibodies (anti-B2 GP), and lupus anticoagulant. These antibodies can form autonomously, as seen in primary disorders, or in association with autoimmune disease as a secondary disorder.

Criteria have been developed to distinguish antiphospholipid-associated clotting disorders from other forms of thrombophilia. The updated Sapporo criteria depend on both laboratory and clinical diagnostic criteria [102].The laboratory diagnosis of APLAs requires the presence of lupus anticoagulants, anticardiolipin antibodies, or anti-B2 GP on at least 2 assays at least 12 weeks apart with elevation above the 99th percentile of the testing laboratory’s normal distribution [103].Testing for lupus anticoagulant is based on 3 stages, the first of which is inhibition of phospholipid-dependent coagulation tests with prolonged clotting time (eg, aPTT or dilute Russell’s viper venom time). The diagnosis is confirmed by a secondary test in which excess hexagonal phase phospholipids are added to incubate with the patient’s plasma to absorb the APLA [104].The presence of anticardiolipin antibodies and anti beta-2 GP antibodies is determined using ELISA based immunoassays. Unlike most other thrombophilias, antiphospholipid syndrome is associated with both arterial and venous thromboembolic events and may be an indication for lifelong anticoagulation after a first thrombotic event. We generally recommend indefinite anticoagulation in the absence of significant bleeding risk.

Cancer-Associated Hypercoagulable State

Patients with cancer have a propensity for thromboembolic events. The underlying mechanisms responsible for cancer-associated clotting events are multifactorial and an area of intense research. Tumor cells can initiate activation of the clotting cascade through release of tissue factor and other pro-coagulant molecules [105].Type and stage of cancer impact risk of VTE, and the tumor itself can compress vasculature leading to venous stasis. Furthermore, chemotherapy, hormone therapy, antiangiogenic drugs, erythropoietin agents, and indwelling central venous catheters all are associated with increased risk of thrombotic events. Approximately 25% of all cancer patients will experience a thrombotic event during the course of their disease [106]. In fact, the presence of a spontaneous clot may be a harbinger of underlying malignancy [107].Approximately 10% of patients who present with an idiopathic VTE are diagnosed with cancer in the next 1 to 2 years.

The utility of extensive cancer screening in patients with spontaneous clotting events is often debated. The small studies that have addressed cancer associated clots have not demonstrated any mortality benefit with extensive screening. A prospective cohort study addressed the utility of limited versus extensive screening [108].In this study, all patients underwent a series of basic screening tests such as history taking, physical examination, chest radiograph, and basic laboratory parameters. Approximately half of the patients underwent additional testing (CT of chest and abdomen and mammography for women). Screening did not result in increased survival or fewer cancer-related deaths. 3.5 % of patients in the extensive screening group were diagnosed with malignancy in comparison to 2.4% in the limited screening group. During follow-up, cancer was diagnosed in 3.7% and 5.0% in the extensive and limited screening groups, respectively. The authors concluded that the low yield of extensive screening and lack of survival benefit did not warrant routinely ordering cancer screening tests above and beyond age-appropriate screening in patients with idiopathic VTE. However, it is known that identification of occult malignancy at an earlier stage of disease is beneficial, and cancer diagnosed within one year of an episode of VTE is generally more advanced and associated with a poorer prognosis [109].It is our practice to take a through history from patients with unprovoked clots particularly focusing on symptoms suggestive of an underlying cancer. We recommend that patients be up to date with all age-appropriate cancer screening.

Heparin-based products (rather than warfarin) are recommended for long-term treatment of cancer-associated DVT. Several trials, most prominently the CLOT trial, have demonstrated that LMWH is associated with reduced risk of recurrent VTE compared with warfarin in cancer patients [110].Fondaparinux may be a reasonable alternative if a patient is unable to tolerate a LMWH. In terms of treatment duration, patients with cancer-associated VTE should be anticoagulated indefinitely as long as they continue to have evidence of active malignancy and/or remain on antineoplastic treatment [111].

Heparin has potential anticancer effects beyond its anticoagulation properties. It is believed that heparin use in patients with cancer can influence cancer progression by acting as an antimetastatic agent. The molecular mechanisms underlying this significant observation are not completely understood, although the first documented benefit of these drugs dates back to the 1970s [112].Overall, LMWH have been associated with improved overall survival in cancer patients and this effect appears to be distinct from its ability to prevent life-threatening VTE episodes [113].

Estrogen-Related Thromboembolic Disease

Pregnancy is a well-established acquired hypercoagulable state, and thromboembolic disease accounts for significant morbidity and mortality in pregnancy and the postpartum period. Approximately 1 in 1000 women will suffer from a thrombotic event during pregnancy or shortly after delivery [8]. The etiology of the tendency to clot during pregnancy is multifactorial and mainly reflects venous stasis due to vasculature compression by the uterus, changes in coagulation factors as the pregnancy progresses, and endothelial damage during delivery, especially Cesarean section. Both factor VIII and von Willebrand factor levels increase, especially in the final months of pregnancy. Simultaneously, levels of the natural anticoagulant protein S diminish, leading to an acquired resistance to activated protein C which results in increased thrombin generation and therefore a hypercoagulable state [114].The risk of thrombosis in pregnancy is clearly heightened in women with inherited thrombophilias, especially in the postpartum period [115].

Similarly to pregnancy, hormone-based contraceptive agents and estrogen replacement therapies are also associated with increased thrombotic risk. Over the years, drug manufacturers have tried to mitigate the clotting risk associated with these drugs by reducing the amount of estrogen and altering the type of progesterone used, yet a risk still remains, resulting in a VTE incidence 2 to 7 times higher in this population [116].The risk is highest in the first 4 months of use and is unaffected by duration of use; risk extends for 3 months after cessation of estrogen-containing therapy. Patients who develop VTE while taking an oral contraceptive are generally instructed to stop the contraceptive and consider an alternative form of birth control. Although routine screening for thrombophilia is not offered to women before prescribing oral contraceptives, a thorough personal and family history regarding venous and arterial thrombotic events as well as recurrent pregnancy loss in women should be taken to evaluate thromboembolic risk factors. We generally avoid use of oral contraceptives in patients with a known hereditary thrombophilia, and consider screening prior to initiation of therapy in those with a strong family history of VTE.

Superficial VTE

Although the main disorders that comprise VTE are DVT and PE, another common presentation is superficial venous thromboembolism (SVT). The risk factors for developing an SVT are similar to those for DVT. In addition, varicose veins also increase the incidence of developing SVT [117].SVT is not associated with excessive mortality, and the main concern with it is progression to DVT. About 25% of patients diagnosed with SVT may have DVT or PE at the time of diagnosis and about 3% without DVT or PE at time of diagnosis developed one of these complications over the following 3 months; clot propagation is another common complication [118].Ultrasound may be of utility in diagnosing occult DVT in patients who initially diagnosed with SVT [119].

For patients who have only SVT at baseline without concomitant DVT or PE, it is difficult to determine which patients are at risk for developing DVT. Some risk stratification models include clot location. Since SVT clots usually develop in the saphenous vein, the clot would need to either progress from the sapheno-femoral junction to the common femoral vein; thus, any clots located near the sapheno-femoral junction are at risk of progressing into the deep vasculature [120].Clots within 3 cm of the junction may be more likely to progress to DVT [121].Chengelis and colleagues feel that proximal saphenous vein thrombosis should likely be treated with anticoagulation [122].Others have taken a more general approach, stating that all clots above the knee or in the thigh area should be treated aggressively [123].

There are solid data for the use of anticoagulation in SVT. In the STEFLUX (Superficial ThromboEmbolism and Fluxum) study, participants received the LMWH parnaparin at one of 3 doses: 8500 IU once daily for 10 days followed by placebo for 20 days, 8500 IU once daily for 10 days and then 6400 IU once daily for 20 days, or 4250 IU once daily for 30 days. Those who received the intermediate dosing had lower rates of DVT, PE, and relapse/SVT recurrence in the first 33 days [124].In the CALISTO trial, fondaparinux 2.5mg per day for 45 days effectively reduced the risk of symptomatic DVT, PE, or SVT recurrence or extension and was not associated with any increased major bleeding compared to placebo [125].A Cochrane review included 30 studies involving over 6500 participants with SVT of the lower extremities. The treatments used in these studies included fondaparinux, LMWH, UFH, non-steriodal anti-inflammatory agents, topical treatment, and surgery. According to the findings, use of fondaparinux at prophylactic dosing for 6 weeks is considered a valid therapeutic option for SVT [126].It is our practice to consider the use of anticoagulants (generally LMWH or fondaparinux) as part of the treatment regimen for SVT.

Target-Specific Oral Anticoagulants And Treatment of VTE

Because of warfarin’s narrow therapeutic window, need for frequent monitoring, significant drug and food interactions, and unfavorable kinetics, the target-specific oral anticoagulants (TSOACs) have been developed with the aim of offering alternatives to warfarin therapy (Figure 3). These drugs have been developed to inhibit either thrombin or factor Xa to disrupt the coagulation cascade. Since these drugs bind directly to coagulation factor, they are associated with rapid onset of action, a wide therapeutic window, fewer drug interactions than warfarin, and predictable dose-response allowing for fixed dosing without lab monitoring.

The direct thrombin inhibitor dabigatran directly binds to thrombin in a concentration-dependent manner [127].Peak plasma concentration is achieved within 0.5 to 2.0 hours after ingestion, and its half-life is 12 to 17 hours. Use of dabigatran in both primary and secondary prevention of VTE has been extensively studied, especially in orthopedic surgery where there have been 4 main trials (RE-MOBILIZE, RE-MODEL, RE-NOVATE, and RE-NOVATE I and II). While RE-MOBILIZE showed that dabigatran 220 mg or 150 mg once daily was inferior to enoxaparin 30 mg twice daily in preventing VTE after total knee arthroplasty, RE-MODEL and RE-NOVATE I and II demonstrated that dabigatran 150 mg or 220 mg once daily was noninferior to enoxaparin 40 mg once daily for prevention of VTE in patients undergoing total knee replacement and hip replacement [128–131].The side effect profile was also promising, with no significant differences in the frequency of major bleeding between dabigatran and enoxaparin. Pooled data and meta-analyses from these trials have demonstrated that for prevention of VTE associated with hip or knee surgery, dabigatran 220 mg or 150 mg once daily is as effective as 40 mg of enoxaparin given daily or 30 mg given twice a day, with a similar bleeding profile [132,133].

More recently, dabigatran been used in the acute treatment and secondary prevention of VTE. In the RE-COVER trial, dabigatran 150 mg twice daily was compared to warfarin (INR 2–3) in the treatment of acute VTE for 6 months, after an initial treatment period of up to 9 days with LMWH or UFH. Dabigatran was noninferior to warfarin with respect to 6-month incidence of recurrent symptomatic objectively confirmed VTE and related deaths, and was not associated with increased bleeding [134].In the RE-MEDY and RE-SONATE trials of extended anticoagulation, dabigatran was as effective as warfarin for prevention of recurrent VTE when continued after 3 months of initial anticoagulation and associated with less bleeding, and was more effective than placebo in preventing recurrent VTE but associated with a higher risk of bleeding [135].Unexpectedly, the risk of acute coronary syndrome was slightly higher in the dabigatran group than the warfarin group, as seen in other studies.

Rivaroxaban, a TSOAC that targets factor Xa, has also shown efficacy in preventing VTE after knee or hip surgery. The RE-CORD 1-4 studies all focused on the use of rivaroxaban in comparison to enoxaparin and found that rivaroxaban 10 mg once daily was superior to enoxaparin 40 mg once daily in prevention of VTE in total knee and total hip arthroplasty [136–138].Meta-analysis of multiple rivaroxaban VTE prophylaxis trials also demonstrated that rivaroxaban significantly lowered the risk of VTE in these surgical patients in comparison to the use of enoxaparin [139].Prophylactic use of rivaroxaban was also studied in acutely ill hospitalized patients in the MAGELLAN trial. Rivaroxaban 10 mg daily for 35 days was compared to enoxaparin 40 mg daily for 10 days followed by placebo and was found to be noninferior to enoxaparin in reduction of VTE risk at day 10 and superior to placebo at day 35 [140].However, the rate of bleeding, although low in both arms, was higher in the rivaroxaban arm.

Rivaroxaban has been studied in randomized clinical trials for acute treatment of DVT and PE and for extended prophylaxis for recurrent VTE (EINSTEIN-DVT, EINSTEIN-PE and EINSTEIN-Extension, respectively). The treatment strategy for use of rivaroxaban differed from that of dabigatran (in the RE-COVER trial), as rivaroxaban was used upfront as initial anticoagulation rather than after an initial period of parenteral therapy with LMWH or UFH. In both the DVT and PE trials, rivaroxaban was noninferior to standard treatment with enoxaparin followed by warfarin therapy, with no significant difference in major bleeding at 6 months of treatment [141,142].The extension trial also demonstrated that use of rivaroxaban in comparison to placebo for an additional 6 or 12 months after standard therapy was associated with significantly fewer recurrent VTE [141]. These studies led to FDA approval for rivaroxaban for primary prevention of VTE in patients undergoing elective total hip or knee repair surgery, for treatment of acute DVT or PE, and for extended prophylaxis in patients following initial treatment.

The anti-factor Xa TSOAC apixaban has been studied in similar fashion as rivaroxaban. In the AMPLIFY study, apixaban was given at a dose of 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months (as monotherapy, without initial parenteral agent) and compared to enoxaparin followed by warfarin for treatment of acute VTE. Apixaban was as effective as warfarin in terms of recurrent symptomatic VTE or VTE-related death, and was associated with significantly fewer bleeding events [143].Extended-duration apixaban given at treatment dose (5 mg twice daily) or at prophylactic dose (2.5 mg twice daily) for 12 months after completion of treatment-dose apixaban for VTE demonstrated superiority to placebo for extended prophylaxis in AMPLIFY-EXT, and there was no increase in major bleeding compared to placebo [144].Apixaban was recently approved by the FDA for both treatment and secondary prophylaxis of VTE.

More recently, a third anti-factor Xa TSOAC edoxaban demonstrated noninferiority to warfarin in prevention of recurrent symptomatic VTE when administered to patients with DVT or PE at 60 mg once daily for 3 to 12 months [145].Edoxaban also led to significantly less bleeding than warfarin. Edoxaban was recently approved by the FDA for treatment of VTE.

These TSOACs show promise in treatment and prevention of VTE but should be used in patients who meet appropriate criteria for renal function, age, and bleeding risk, as there are currently no available antidotes to reverse their effects. If significant bleeding occurs and cannot be controlled by usual maneuvers such as mechanical compression or surgical intervention, there is little data to guide the use of pharmacologic interventions. Plasma dabigatran levels can be reduced through the use of hemodialysis [146].Antibodies capable of neutralizing dabigatran have been developed, and one specific antibody, idarucizumab, was well-tolerated and showed immediate and complete reversal of dabigatran in subjects of different age and renal function [147,148].Andexanet, a modified recombinant derivative of factor Xa with no catalytic activty, acts as a “decoy receptor” with higher affinity to factor Xa inhibitors than natural factor Xa. Phase II studies in healthy volunteers demonstrated that andexanet immediately reversed the anticoagulation activity of apixaban, rivaroxaban, enoxaparin, and most recently edoxaban without thrombotic consequences [149].Two randomized, double-blind, placebo-controlled phase III studies (ANNEXA-A, looking at the reversal of apixaban, and ANNEXA-R, looking at reversal of rivaroxaban) are underway, and preliminary results show that a single intravenous bolus of andexanet demonstrated almost complete reversal [150].Finally, aripazine (PER977), a synthetic small molecule that binds to heparins as well as all TSOACs, was shown in a phase II trial to decrease blood clotting time to within 10% above baseline value in 10 minutes or less with an effect lasting for 24 hours [151].

Some have advocated for use of prothrombin complex concentrate (PCC) or recombinant factor VIIa for reversal of TSOAC-associated bleeding. Rivaroxaban was demonstrated to be partially reversible by PCC, whereas this approach was not as successful for dabigatran in healthy volunteers [152].In vitro evidence, however, showed that PCC did not significantly change aPTT [153].At present, the use of nonspecific hemostatic agents (including recombinant factor VIIa, 4-factor prothrombin complex concentrate, and activated prothrombin complex concentrates) is suggested for reversal of TSOACs in patients who present with life-threatening bleeding [154,155].

Conclusion

Patients with VTE present with a wide range of findings and factors that impact management. Decision making in VTE management is a fluid process that should be re-evaluated as new data emerge and individual circumstances change. There is more focus on VTE prevention and treatment today than there was even a decade ago. Diagnostic algorithms, identification of new risk factors, refinement in understanding of the pathogenesis of thrombosis, and identification of new anticoagulants with more favorable risk-benefit profiles will all ultimately contribute to improved patient care.

Corresponding author: Jean M. Connors, MD, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02215.

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Issue

Journal of Clinical Outcomes Management - May 2015, VOL. 22, NO. 5

Publications

Journal of Clinical Outcomes Management

Topics

Hematology

Vascular

Read more about Decision Making in Venous Thromboembolism

Sections

Clinical Review

Author(s)

Ariela L. Marshall, MD

Elisabeth M. Battinelli, MD, PhD

Jean M. Connors, MD

Author(s)

Ariela L. Marshall, MD

Elisabeth M. Battinelli, MD, PhD

Jean M. Connors, MD

From the Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA.

Abstract

Objective: To review the diagnosis and management of venous thromboembolism (VTE).
Methods: Review of the literature.
Results: VTE and its associated complications account for significant morbidity and mortality. Various imaging modalities can be employed to support a diagnosis of a VTE and are used based on clinical suspicion arising from the presence of signs and symptoms. Clinical decision rules have been developed that can help determine which patients warrant further testing. Anticoagulation, the mainstay of VTE treatment, increases bleeding risk, necessitating tailored treatment strategies that must incorporate etiology, risk, benefit, cost, and patient preference.
Conclusion: Further study is needed to understand individual patient risks and to identify treatments that will lead to improved patient outcomes.