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Novel molecule prolongs half-life of bleeding disorder treatments
A novel therapeutic approach using aptamers – short single strands of DNA or RNA designed to selectively bind to a target – shows promise for treating von Willebrand Disease (VWD), and other congenital bleed disorders such as hemophilia A, investigators say.
In a proof-of-concept study using healthy volunteers, the experimental anti–von Willebrand factor (VWF) molecule BT200 appeared to decrease clearance of VWF and resulted in a twofold increase in endogenous levels of VWF and factor VIII at low doses.
BT200 is currently being explored in a phase 2 trial in patients with hemophilia A and VWD type 2B, Katarina Kovacevic, MPharm, from the Medical University of Vienna, reported at the European Hematology Association annual congress.
“We expect to see a half-life increase of 2 to 4 times of factor VIII products, which will allow us to have a longer time between treatments,” she said in an oral abstract presentation (Abstract S302).
Lab-made nucleotide strings
Aptamers are sometimes call “chemical antibodies” because of their high affinity and high specificity for extracellular targets, Dr. Kovacevic said. Unlike conventional humanized or human-derived antibodies, however, they are nonimmunogenic and are less costly to manufacture.
In a previous study from her center, a different anti-VWF aptamer labeled ARC1779 increased plasma levels of VWF, factor VIII, and platelet counts in patients with VWD type 2B.
However, the drug was inconvenient to use, requiring 72-hour infusions, she noted.
In a study published in Feb. 4, 2021 in Scientific Reports, Dr. Kovacevic and colleagues reported that BT200 blocks VWF and platelet function in patients with ischemic strokes, even in the presence of high levels of VWF in patients with left carotid artery atherosclerotic strokes.
The ability of the molecule to block VWF platelet binding may explain how the anti-VWF agent actually results in higher circulating levels of VWF, which also carries factor VIII, said Veronica H. Flood, MD, a VWD specialist at Children’s Hospital of Wisconsin and associate professor at the Medical College of Wisconsin in Milwaukee.
“It might inhibit clearance of the von Willebrand factor, so it’s almost like this was an incidental side effect,” she said in an interview. “Incidentally, this happens to also give you higher levels of the von Willebrand factor and the factor VIII, and with a longer half-life than anything we currently have, so it’s a super-creative strategy,” she said.
Dr. Flood was not involved in the study.
Long half-life
BT200 is a third-generation peglyated anti-VWF aptamer that has been shown in preclinical studies to have a long half-life in nonhuman primates. It inhibits the A1 domain of VWF to prevent it from binding to platelet glycoprotein 1b (GP1b).
In the randomized, double-blind, placebo-controlled trial reported at the EHA congress, 88 healthy volunteers received single doses of BT200 ranging from 0.l8 mg to 48 mg by subcutaneous injection or intravenous infusion, 8 received multiple doses, 8 were evaluated for possible interactions with desmopressin, and 8 were evaluated for bioavailability of the aptamer.
The investigators observed a dose-related increase in BT200 concentrations, with a mean plasma terminal elimination half life of between 118 and 284 hours (about 5-12 days). There was also a dose-dependent increase in bioavailability of the agents, reaching 90% at the highest dose level.
The ability of BT200 to inhibit the A1 domains of VWF also was dose dependent, with the largest effect seen with doses of 12 mg and higher. The molecule decreased VWF activity and ristocetin-induced platelet aggregation, and prolonged collagen adenosine diphosphate closure time.
At the highest doses, BT200 caused complete inhibition of VWF (P < .001), and volunteers developed clinical signs of mild mucosal bleeding.
But the aptamer also increased in a dose-dependent fashion VWF antigen levels and factor VIII clotting activity more than fourfold (P <.001).
“This resulted in increased thrombogenicity as measured by thrombin generation and enhanced clotting. In the absence of an increase in VWF propeptide levels, this effect is considered due to decreased clearance of VWF,” the investigators wrote in the study abstract.
They noted that they saw a clinically meaningful twofold increase in both VWF and factor VIII at doses lower than 6 mg.
‘Super-exciting strategy’
“This trial identified a novel mechanism of action for BT200: It decreases the clearance of VWF/FVIII, which can be exploited for congenital bleeding disorders. This built a solid foundation for an ongoing basket trial in patients with von Willebrand disease or hemophilia A, which already confirms the expected effect sizes,” Dr. Kovacevic and colleagues wrote.
“I will be interested to see what the clinical side effects are, because there may be some off-target effects, but in reality it is a super-exciting strategy, and there is really a dire need for longer half-life products for these patients,” Dr. Flood said.
The study was sponsored by Band Therapeutics, a division of Guardian Therapeutics. Dr. Kovacevic and Dr. Flood reported having no conflicts of interest to disclose.
A novel therapeutic approach using aptamers – short single strands of DNA or RNA designed to selectively bind to a target – shows promise for treating von Willebrand Disease (VWD), and other congenital bleed disorders such as hemophilia A, investigators say.
In a proof-of-concept study using healthy volunteers, the experimental anti–von Willebrand factor (VWF) molecule BT200 appeared to decrease clearance of VWF and resulted in a twofold increase in endogenous levels of VWF and factor VIII at low doses.
BT200 is currently being explored in a phase 2 trial in patients with hemophilia A and VWD type 2B, Katarina Kovacevic, MPharm, from the Medical University of Vienna, reported at the European Hematology Association annual congress.
“We expect to see a half-life increase of 2 to 4 times of factor VIII products, which will allow us to have a longer time between treatments,” she said in an oral abstract presentation (Abstract S302).
Lab-made nucleotide strings
Aptamers are sometimes call “chemical antibodies” because of their high affinity and high specificity for extracellular targets, Dr. Kovacevic said. Unlike conventional humanized or human-derived antibodies, however, they are nonimmunogenic and are less costly to manufacture.
In a previous study from her center, a different anti-VWF aptamer labeled ARC1779 increased plasma levels of VWF, factor VIII, and platelet counts in patients with VWD type 2B.
However, the drug was inconvenient to use, requiring 72-hour infusions, she noted.
In a study published in Feb. 4, 2021 in Scientific Reports, Dr. Kovacevic and colleagues reported that BT200 blocks VWF and platelet function in patients with ischemic strokes, even in the presence of high levels of VWF in patients with left carotid artery atherosclerotic strokes.
The ability of the molecule to block VWF platelet binding may explain how the anti-VWF agent actually results in higher circulating levels of VWF, which also carries factor VIII, said Veronica H. Flood, MD, a VWD specialist at Children’s Hospital of Wisconsin and associate professor at the Medical College of Wisconsin in Milwaukee.
“It might inhibit clearance of the von Willebrand factor, so it’s almost like this was an incidental side effect,” she said in an interview. “Incidentally, this happens to also give you higher levels of the von Willebrand factor and the factor VIII, and with a longer half-life than anything we currently have, so it’s a super-creative strategy,” she said.
Dr. Flood was not involved in the study.
Long half-life
BT200 is a third-generation peglyated anti-VWF aptamer that has been shown in preclinical studies to have a long half-life in nonhuman primates. It inhibits the A1 domain of VWF to prevent it from binding to platelet glycoprotein 1b (GP1b).
In the randomized, double-blind, placebo-controlled trial reported at the EHA congress, 88 healthy volunteers received single doses of BT200 ranging from 0.l8 mg to 48 mg by subcutaneous injection or intravenous infusion, 8 received multiple doses, 8 were evaluated for possible interactions with desmopressin, and 8 were evaluated for bioavailability of the aptamer.
The investigators observed a dose-related increase in BT200 concentrations, with a mean plasma terminal elimination half life of between 118 and 284 hours (about 5-12 days). There was also a dose-dependent increase in bioavailability of the agents, reaching 90% at the highest dose level.
The ability of BT200 to inhibit the A1 domains of VWF also was dose dependent, with the largest effect seen with doses of 12 mg and higher. The molecule decreased VWF activity and ristocetin-induced platelet aggregation, and prolonged collagen adenosine diphosphate closure time.
At the highest doses, BT200 caused complete inhibition of VWF (P < .001), and volunteers developed clinical signs of mild mucosal bleeding.
But the aptamer also increased in a dose-dependent fashion VWF antigen levels and factor VIII clotting activity more than fourfold (P <.001).
“This resulted in increased thrombogenicity as measured by thrombin generation and enhanced clotting. In the absence of an increase in VWF propeptide levels, this effect is considered due to decreased clearance of VWF,” the investigators wrote in the study abstract.
They noted that they saw a clinically meaningful twofold increase in both VWF and factor VIII at doses lower than 6 mg.
‘Super-exciting strategy’
“This trial identified a novel mechanism of action for BT200: It decreases the clearance of VWF/FVIII, which can be exploited for congenital bleeding disorders. This built a solid foundation for an ongoing basket trial in patients with von Willebrand disease or hemophilia A, which already confirms the expected effect sizes,” Dr. Kovacevic and colleagues wrote.
“I will be interested to see what the clinical side effects are, because there may be some off-target effects, but in reality it is a super-exciting strategy, and there is really a dire need for longer half-life products for these patients,” Dr. Flood said.
The study was sponsored by Band Therapeutics, a division of Guardian Therapeutics. Dr. Kovacevic and Dr. Flood reported having no conflicts of interest to disclose.
A novel therapeutic approach using aptamers – short single strands of DNA or RNA designed to selectively bind to a target – shows promise for treating von Willebrand Disease (VWD), and other congenital bleed disorders such as hemophilia A, investigators say.
In a proof-of-concept study using healthy volunteers, the experimental anti–von Willebrand factor (VWF) molecule BT200 appeared to decrease clearance of VWF and resulted in a twofold increase in endogenous levels of VWF and factor VIII at low doses.
BT200 is currently being explored in a phase 2 trial in patients with hemophilia A and VWD type 2B, Katarina Kovacevic, MPharm, from the Medical University of Vienna, reported at the European Hematology Association annual congress.
“We expect to see a half-life increase of 2 to 4 times of factor VIII products, which will allow us to have a longer time between treatments,” she said in an oral abstract presentation (Abstract S302).
Lab-made nucleotide strings
Aptamers are sometimes call “chemical antibodies” because of their high affinity and high specificity for extracellular targets, Dr. Kovacevic said. Unlike conventional humanized or human-derived antibodies, however, they are nonimmunogenic and are less costly to manufacture.
In a previous study from her center, a different anti-VWF aptamer labeled ARC1779 increased plasma levels of VWF, factor VIII, and platelet counts in patients with VWD type 2B.
However, the drug was inconvenient to use, requiring 72-hour infusions, she noted.
In a study published in Feb. 4, 2021 in Scientific Reports, Dr. Kovacevic and colleagues reported that BT200 blocks VWF and platelet function in patients with ischemic strokes, even in the presence of high levels of VWF in patients with left carotid artery atherosclerotic strokes.
The ability of the molecule to block VWF platelet binding may explain how the anti-VWF agent actually results in higher circulating levels of VWF, which also carries factor VIII, said Veronica H. Flood, MD, a VWD specialist at Children’s Hospital of Wisconsin and associate professor at the Medical College of Wisconsin in Milwaukee.
“It might inhibit clearance of the von Willebrand factor, so it’s almost like this was an incidental side effect,” she said in an interview. “Incidentally, this happens to also give you higher levels of the von Willebrand factor and the factor VIII, and with a longer half-life than anything we currently have, so it’s a super-creative strategy,” she said.
Dr. Flood was not involved in the study.
Long half-life
BT200 is a third-generation peglyated anti-VWF aptamer that has been shown in preclinical studies to have a long half-life in nonhuman primates. It inhibits the A1 domain of VWF to prevent it from binding to platelet glycoprotein 1b (GP1b).
In the randomized, double-blind, placebo-controlled trial reported at the EHA congress, 88 healthy volunteers received single doses of BT200 ranging from 0.l8 mg to 48 mg by subcutaneous injection or intravenous infusion, 8 received multiple doses, 8 were evaluated for possible interactions with desmopressin, and 8 were evaluated for bioavailability of the aptamer.
The investigators observed a dose-related increase in BT200 concentrations, with a mean plasma terminal elimination half life of between 118 and 284 hours (about 5-12 days). There was also a dose-dependent increase in bioavailability of the agents, reaching 90% at the highest dose level.
The ability of BT200 to inhibit the A1 domains of VWF also was dose dependent, with the largest effect seen with doses of 12 mg and higher. The molecule decreased VWF activity and ristocetin-induced platelet aggregation, and prolonged collagen adenosine diphosphate closure time.
At the highest doses, BT200 caused complete inhibition of VWF (P < .001), and volunteers developed clinical signs of mild mucosal bleeding.
But the aptamer also increased in a dose-dependent fashion VWF antigen levels and factor VIII clotting activity more than fourfold (P <.001).
“This resulted in increased thrombogenicity as measured by thrombin generation and enhanced clotting. In the absence of an increase in VWF propeptide levels, this effect is considered due to decreased clearance of VWF,” the investigators wrote in the study abstract.
They noted that they saw a clinically meaningful twofold increase in both VWF and factor VIII at doses lower than 6 mg.
‘Super-exciting strategy’
“This trial identified a novel mechanism of action for BT200: It decreases the clearance of VWF/FVIII, which can be exploited for congenital bleeding disorders. This built a solid foundation for an ongoing basket trial in patients with von Willebrand disease or hemophilia A, which already confirms the expected effect sizes,” Dr. Kovacevic and colleagues wrote.
“I will be interested to see what the clinical side effects are, because there may be some off-target effects, but in reality it is a super-exciting strategy, and there is really a dire need for longer half-life products for these patients,” Dr. Flood said.
The study was sponsored by Band Therapeutics, a division of Guardian Therapeutics. Dr. Kovacevic and Dr. Flood reported having no conflicts of interest to disclose.
FROM EHA 2021
First year of life sees initial bleeding episodes in children with von Willebrand disease
To remedy a lack of data on infants and toddlers with von Willebrand disease (VWD), researchers examined data on patients collected from the U.S. Hemophilia Treatment Center Network. They examined birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were younger than 2 years of age.
For these patients, the mean age of diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history of VWD were diagnosed approximately 4 months earlier than those with none (P < .001), according to the report by Brandi Dupervil, DHSC, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, and colleagues.
Approximately 14% of the patients were born preterm and 13% had low birth weight, proportions that were higher than national preterm birth rates (approximately 12% and 8%, respectively). There was no way of knowing from the data whether this was due to the presence of VWD or other factors, according to the report (Blood Adv. 2021;5[8]:2079-86).
Specialized care
The study found that initial bleeding episodes were most commonly oropharyngeal, related to circumcision, or intracranial or extracranial, and that most initial bleeding episodes occurred within the first year of life, according to the researchers.
Overall, there were 274 bleeding episodes among 73 children, including oral/nasal episodes (38 patients experienced 166 episodes), soft tissue hematomas (15 patients experienced 57 episodes), and head injuries, including skull fractures (13 patients experienced 19 episodes), according to the report.
In terms of treatment, among the two-thirds of the patients who had intervention to prevent or treat bleeding, most received either plasma-derived VW factor/factor VIII concentrates or antifibrinolytics.
Overall, the researchers advocated a team approach to treating these children “including genetic counselors throughout the prepartum period who work to increase expectant mothers’ understanding of the risks associated with having a child with VWD.”
They also recommended the input of “adult and pediatric hematologists, obstetrician gynecologists, genetic counselors, nurses, and social workers throughout the pre- and postpartum period who seek to optimize outcomes and disease management.”
The authors reported that they had no competing interests.
To remedy a lack of data on infants and toddlers with von Willebrand disease (VWD), researchers examined data on patients collected from the U.S. Hemophilia Treatment Center Network. They examined birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were younger than 2 years of age.
For these patients, the mean age of diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history of VWD were diagnosed approximately 4 months earlier than those with none (P < .001), according to the report by Brandi Dupervil, DHSC, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, and colleagues.
Approximately 14% of the patients were born preterm and 13% had low birth weight, proportions that were higher than national preterm birth rates (approximately 12% and 8%, respectively). There was no way of knowing from the data whether this was due to the presence of VWD or other factors, according to the report (Blood Adv. 2021;5[8]:2079-86).
Specialized care
The study found that initial bleeding episodes were most commonly oropharyngeal, related to circumcision, or intracranial or extracranial, and that most initial bleeding episodes occurred within the first year of life, according to the researchers.
Overall, there were 274 bleeding episodes among 73 children, including oral/nasal episodes (38 patients experienced 166 episodes), soft tissue hematomas (15 patients experienced 57 episodes), and head injuries, including skull fractures (13 patients experienced 19 episodes), according to the report.
In terms of treatment, among the two-thirds of the patients who had intervention to prevent or treat bleeding, most received either plasma-derived VW factor/factor VIII concentrates or antifibrinolytics.
Overall, the researchers advocated a team approach to treating these children “including genetic counselors throughout the prepartum period who work to increase expectant mothers’ understanding of the risks associated with having a child with VWD.”
They also recommended the input of “adult and pediatric hematologists, obstetrician gynecologists, genetic counselors, nurses, and social workers throughout the pre- and postpartum period who seek to optimize outcomes and disease management.”
The authors reported that they had no competing interests.
To remedy a lack of data on infants and toddlers with von Willebrand disease (VWD), researchers examined data on patients collected from the U.S. Hemophilia Treatment Center Network. They examined birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were younger than 2 years of age.
For these patients, the mean age of diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history of VWD were diagnosed approximately 4 months earlier than those with none (P < .001), according to the report by Brandi Dupervil, DHSC, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, and colleagues.
Approximately 14% of the patients were born preterm and 13% had low birth weight, proportions that were higher than national preterm birth rates (approximately 12% and 8%, respectively). There was no way of knowing from the data whether this was due to the presence of VWD or other factors, according to the report (Blood Adv. 2021;5[8]:2079-86).
Specialized care
The study found that initial bleeding episodes were most commonly oropharyngeal, related to circumcision, or intracranial or extracranial, and that most initial bleeding episodes occurred within the first year of life, according to the researchers.
Overall, there were 274 bleeding episodes among 73 children, including oral/nasal episodes (38 patients experienced 166 episodes), soft tissue hematomas (15 patients experienced 57 episodes), and head injuries, including skull fractures (13 patients experienced 19 episodes), according to the report.
In terms of treatment, among the two-thirds of the patients who had intervention to prevent or treat bleeding, most received either plasma-derived VW factor/factor VIII concentrates or antifibrinolytics.
Overall, the researchers advocated a team approach to treating these children “including genetic counselors throughout the prepartum period who work to increase expectant mothers’ understanding of the risks associated with having a child with VWD.”
They also recommended the input of “adult and pediatric hematologists, obstetrician gynecologists, genetic counselors, nurses, and social workers throughout the pre- and postpartum period who seek to optimize outcomes and disease management.”
The authors reported that they had no competing interests.
FROM BLOOD ADVANCES
Elevated factor VIII troughs can lead to a higher proportion of zero bleeds in hemophilia
Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).
Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.
The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.
The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
Promising results
In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.
“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
Problems remain
In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.
“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.
The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.
Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).
Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.
The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.
The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
Promising results
In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.
“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
Problems remain
In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.
“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.
The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.
Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).
Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.
The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.
The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
Promising results
In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.
“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
Problems remain
In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.
“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.
The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.
FROM BLOOD
Medical homes a boon to patients with bleeding disorders
As bleeding disorders are increasingly recognized as a national health priority, hematologists are focusing on how the patient-centered medical home – a widely accepted concept in primary care and in some specialties – can improve outcomes and quality life for their patients.
The patient-centered medical home is a model of health care delivery in which patients receive comprehensive, accessible care that is fully integrated across all providers and elements of a healthcare system.1 The concept emerged in the 1960s among pediatricians seeking to better coordinate care for children with complex medical needs. Since then, the patient-centered medical home has become a globally recognized standard – not only in primary care, but also in specialties such as endocrinology, oncology, and geriatric medicine. The movement to establish medical homes for patients with bleeding disorders is more recent and is receiving national attention.
Why a medical home?
The advent of prophylactic therapies for bleeding disorders has vastly improved the outlook for many patients compared to just a few decades ago. However, treatment options remain limited, and patients who have severe disease or complications – such as an inadequate treatment response or the development of inhibitory antibodies to replacement clotting factors – are at risk for recurrent breakthrough bleeding that can lead to synovitis and ultimately culminate in progressive, irreversible joint damage. The resulting pain and limitation of motion greatly compromises patients’ quality of life across physical, psychological, and social domains, undermines their ability to live and work independently, and greatly increases treatment costs.2-4 Family members, too, face high stress and lower quality of life when they struggle to obtain and manage treatment while caring for loved ones with bleeding disorders.5
For patients with bleeding disorders, a patient-centered medical home can help address or surmount these challenges, said Amy Shapiro, MD, medical director of the Indiana Hemophilia and Thrombosis Center in Indianapolis, Ind., which was the first hemophilia treatment center in the country to be formally certified as a medical home.
Dr. Shapiro explained that a patient-centered medical home leverages the care of an integrated multidisciplinary team to help optimize therapies and patient outcomes across all domains of life. She sees the medical home concept as a natural fit for patients with bleeding disorders, given the complexity of their needs and the number of specialties involved. “When you have hemophilia, you don’t just need a hematologist to manage your care. You need nurses, physical therapists, and social workers. You need coordinated care for genetic counseling. You also need to coordinate dental hygiene and surgical interventions, if these are required. Patients need nutrition counseling, and they may need assistance with education or career options if too many days are missed from work or school. Patients or their families may need counseling on choosing the right insurance program so they don’t choose a plan that may create more hardships for them because of their chronic disorder.”
Meeting these needs requires the help of an integrated care team, which many individuals with bleeding disorders lack. “If you are just out there in the community and you have medical issues that need to be dealt with, often the individuals themselves have to coordinate their own care, including their medications and their appointments with different specialists,” said Dr. Shapiro. “For example, a care provider may tell a patient that they need a physical therapist and give them some names, and then the patient has to take it from there and not only find the provider, but also determine if their insurance provides coverage.”
A medical home takes a completely different approach, she explained. “At my center, when we say you need a physical therapist, we have a physical therapist on staff. Our therapist provides an assessment and determines the need for ongoing PT and whether that can be done at home with a plan and intermittent oversight, or whether the patient needs a referral, and whether the person the patient is referred to needs education on how to provide PT for someone with hemophilia. A medical home provides all this in one place. It is a place where patients know they will receive either direct services, or support to shepherd their care and outcomes, and oversight of that support as well.”
Few studies have directly assessed the medical home model in the setting of bleeding disorders, but a number have evaluated the impact of integrated care, a more general term for the practice of coordinating multidisciplinary care to improve access and outcomes while eliminating redundancies and unnecessary costs. In a recent systematic review and meta-analysis of 27 nonrandomized studies of patients with hemophilia, integrated care was linked to lower mortality, fewer emergency room visits and hospitalizations, shorter lengths of stay in the hospital, and fewer missed days of school and work.6 Such findings, combined with promising outcomes data from studies of patient-centered medical homes in other disease settings, suggest that the patient-centered medical home can significantly benefit patients with bleeding disorders and their families and caregivers.
Creating a medical home
Establishing a patient-centered medical home can be challenging, involving a plethora of stakeholders and a considerable investment of time, energy, and resources. Organizations such as the National Committee for Quality Assurance and the Accreditation Association for Ambulatory Health Care have formal certification programs to help ensure that an inpatient or outpatient center that calls itself a medical home truly is one.7-8
The certification process requires centers to document activities in areas such as patients’ rights and responsibilities, administration and governance, patient and care team relationships, clinical records and other health information, and quality, comprehensiveness, continuity, and accessibility.7 Achieving certification is rigorous, often requiring centers to document compliance with more than 100 policies, procedures, and standards.
For the Indiana Hemophilia and Thrombosis Center, becoming certified as a medical home “was a multiyear process and an ongoing process,” said Dr. Shapiro. “It involves documentation of quality improvement initiatives, obtaining input from patients to document their satisfaction, and looking at all types of systems within our center and how we integrate care so that all those systems function together. It’s a difficult process, but treatment centers are a medical home for patients with bleeding disorders, and this is an effort to provide some documentation on a national level of how we’re doing everything that we are doing.”
She noted that the process of obtaining medical home certification may require an even higher level of commitment if a bleeding disorder (hemophilia) treatment center is embedded in a university or academic medical center. In this case, more stakeholders are involved, and more hoops may need to be jumped through to implement processes that meet medical home standards while still adhering to any requirements at the organizational level.
Certification programs for patient-centered medical homes are not designed around specific disorders or diseases, but a closer look at their compliance metrics underscores how medical homes can benefit patients with bleeding disorders. For example, to receive medical home certification from the Accreditation Association for Ambulatory Health Care, a center needs to be able to document that patients’ care is not transferred without first making arrangements with a receiving health care provider, that the quality improvement programs are peer-led, and that these programs assess and address diverse measures of clinical performance, cost-effectiveness, and administrative functioning.7-9
Medical homes, the NHPCC, and Healthy People 2030
Creating patient-centered medical homes for patients with bleeding disorders is now a quality improvement objective of the National Hemophilia Program Coordinating Center, or NHPCC. Established in 2012 and funded by the federal Health Resources and Services Administration, the NHPCC partners with the eight regional hemophilia networks and more than 140 federally funded hemophilia treatment centers across the United States to identify gaps, standardize and improve access to care, and share and promote best practices for the treatment and management of blood disorders.10
In the United States, receiving care in a hemophilia treatment center (which, despite its name, typically offers care for other disorders such as von Willebrand disease) has been linked to lower mortality and fewer hospitalizations related to bleeding complications.11 To continue to improve on these outcomes, the NHPCC, regional networks, and hemophilia treatment centers are prioritizing medical homes and ranking their establishments alongside core objectives such as bettering patient and family engagement and improving the transition from pediatric to adult care.12
As part of this quality improvement work, the NHPCC, regional leadership, and hemophilia treatment centers meet regularly to identify needs and priorities, plan programs, and ensure that each center is meeting the goals and objectives set out by its federal grant.13 Such partnerships help improve and integrate care within a coordinated national framework, Dr. Shapiro said. “We all are charged with this same mission,” she added. “That doesn’t mean that every treatment center looks exactly the same, has the same number of staff, or does everything the same way, but we all have the same mission, and we know what that is. That is the work of the NHPCC, to determine and document that and help level and improve care throughout the country.”
The NHPCC also engages other stakeholders, including consumer agencies and professional organizations. Recent achievements have included a first-ever national patient needs assessment, a tandem technical needs assessment of hemophilia treatment centers, an educational outreach program for genetic counselors, a webinar on transitioning care for adolescents, a national survey of the federal 340B Drug Pricing Program, and a survey of minority patients to identify and characterize problems such as language and insurance barriers, the lack of culturally appropriate educational materials on blood disorders, and difficulties getting transportation to treatment centers or educational programs.14
In part because of this advocacy work, the U.S. Department of Health and Human Services recently included hemophilia for the first time in Healthy People, its evidence-based set of decade-long objectives aimed at improving the health of all Americans. In Healthy People 2030, the specific objective for hemophilia is to reduce the proportion of patients with severe disease who experience more than four joint bleeds per year to 13.3% (the current estimate is 16.9%).15
For Healthy People to prioritize hemophilia for the first time alongside much more common conditions such as diabetes and heart disease reflects the challenges of managing bleeding disorders and the efforts by the NHPCC and other stakeholders to raise awareness about current needs. To track progress in meeting the Healthy People 2030 objective, the NHPCC will work with federal partners to analyze patient-level data gathered through the Centers for Disease Control’s Community Counts Registry for Bleeding Disorders Surveillance program, which collects data from hemophilia treatment centers across the United States and includes patients with all levels of disease severity.
“The inclusion of bleeding disorders in Healthy People 2030 is really very significant,” said Dr. Shapiro. “These are disorders that affect less than 200,000 Americans, which is the definition of a rare disease in this context. To have hemophilia considered as a national priority is very important, not only for hemophilia, but also for other rare diseases that may in the future also be considered as being as of national importance in this way.”
References
1. Rodriguez-Saldana J. 2019. The Patient-Centered Medical Home, Primary Care, and Diabetes. In: Rodriguez-Saldana J. (eds) The Diabetes Textbook. Springer, Cham.
2. J Comorb. 2011;1:51-59.
3. Eur J Haematol. 2018 Apr;100 Suppl 1:5-13.
4. Blood. 2003;102(7):2358-63.
5. Haemophilia. 2014 Jul;20(4):541-9.
6. Haemophilia. 2016;22(Suppl 3):31-40.
7. AAAHC. Medical Home.
8. NCQA. Patient-centered medical home (PCMH).
9. AAAHC, 2013. Medical Home On-Site Certification Handbook.
10. Centers for Disease Control and Prevention. HTC Population Profile.
11. Blood Transfus. 2014;12 Suppl 3(Suppl 3):e542-e548.
12. American Thrombosis and Hemostasis Network.
13. The Great Lakes Regional Hemophilia Network.
14. American Thrombosis and Hemostasis Network. What the NHPCC does.
15. U.S. Department of Health and Human Services. Healthy People 2030: Blood Disorders.
As bleeding disorders are increasingly recognized as a national health priority, hematologists are focusing on how the patient-centered medical home – a widely accepted concept in primary care and in some specialties – can improve outcomes and quality life for their patients.
The patient-centered medical home is a model of health care delivery in which patients receive comprehensive, accessible care that is fully integrated across all providers and elements of a healthcare system.1 The concept emerged in the 1960s among pediatricians seeking to better coordinate care for children with complex medical needs. Since then, the patient-centered medical home has become a globally recognized standard – not only in primary care, but also in specialties such as endocrinology, oncology, and geriatric medicine. The movement to establish medical homes for patients with bleeding disorders is more recent and is receiving national attention.
Why a medical home?
The advent of prophylactic therapies for bleeding disorders has vastly improved the outlook for many patients compared to just a few decades ago. However, treatment options remain limited, and patients who have severe disease or complications – such as an inadequate treatment response or the development of inhibitory antibodies to replacement clotting factors – are at risk for recurrent breakthrough bleeding that can lead to synovitis and ultimately culminate in progressive, irreversible joint damage. The resulting pain and limitation of motion greatly compromises patients’ quality of life across physical, psychological, and social domains, undermines their ability to live and work independently, and greatly increases treatment costs.2-4 Family members, too, face high stress and lower quality of life when they struggle to obtain and manage treatment while caring for loved ones with bleeding disorders.5
For patients with bleeding disorders, a patient-centered medical home can help address or surmount these challenges, said Amy Shapiro, MD, medical director of the Indiana Hemophilia and Thrombosis Center in Indianapolis, Ind., which was the first hemophilia treatment center in the country to be formally certified as a medical home.
Dr. Shapiro explained that a patient-centered medical home leverages the care of an integrated multidisciplinary team to help optimize therapies and patient outcomes across all domains of life. She sees the medical home concept as a natural fit for patients with bleeding disorders, given the complexity of their needs and the number of specialties involved. “When you have hemophilia, you don’t just need a hematologist to manage your care. You need nurses, physical therapists, and social workers. You need coordinated care for genetic counseling. You also need to coordinate dental hygiene and surgical interventions, if these are required. Patients need nutrition counseling, and they may need assistance with education or career options if too many days are missed from work or school. Patients or their families may need counseling on choosing the right insurance program so they don’t choose a plan that may create more hardships for them because of their chronic disorder.”
Meeting these needs requires the help of an integrated care team, which many individuals with bleeding disorders lack. “If you are just out there in the community and you have medical issues that need to be dealt with, often the individuals themselves have to coordinate their own care, including their medications and their appointments with different specialists,” said Dr. Shapiro. “For example, a care provider may tell a patient that they need a physical therapist and give them some names, and then the patient has to take it from there and not only find the provider, but also determine if their insurance provides coverage.”
A medical home takes a completely different approach, she explained. “At my center, when we say you need a physical therapist, we have a physical therapist on staff. Our therapist provides an assessment and determines the need for ongoing PT and whether that can be done at home with a plan and intermittent oversight, or whether the patient needs a referral, and whether the person the patient is referred to needs education on how to provide PT for someone with hemophilia. A medical home provides all this in one place. It is a place where patients know they will receive either direct services, or support to shepherd their care and outcomes, and oversight of that support as well.”
Few studies have directly assessed the medical home model in the setting of bleeding disorders, but a number have evaluated the impact of integrated care, a more general term for the practice of coordinating multidisciplinary care to improve access and outcomes while eliminating redundancies and unnecessary costs. In a recent systematic review and meta-analysis of 27 nonrandomized studies of patients with hemophilia, integrated care was linked to lower mortality, fewer emergency room visits and hospitalizations, shorter lengths of stay in the hospital, and fewer missed days of school and work.6 Such findings, combined with promising outcomes data from studies of patient-centered medical homes in other disease settings, suggest that the patient-centered medical home can significantly benefit patients with bleeding disorders and their families and caregivers.
Creating a medical home
Establishing a patient-centered medical home can be challenging, involving a plethora of stakeholders and a considerable investment of time, energy, and resources. Organizations such as the National Committee for Quality Assurance and the Accreditation Association for Ambulatory Health Care have formal certification programs to help ensure that an inpatient or outpatient center that calls itself a medical home truly is one.7-8
The certification process requires centers to document activities in areas such as patients’ rights and responsibilities, administration and governance, patient and care team relationships, clinical records and other health information, and quality, comprehensiveness, continuity, and accessibility.7 Achieving certification is rigorous, often requiring centers to document compliance with more than 100 policies, procedures, and standards.
For the Indiana Hemophilia and Thrombosis Center, becoming certified as a medical home “was a multiyear process and an ongoing process,” said Dr. Shapiro. “It involves documentation of quality improvement initiatives, obtaining input from patients to document their satisfaction, and looking at all types of systems within our center and how we integrate care so that all those systems function together. It’s a difficult process, but treatment centers are a medical home for patients with bleeding disorders, and this is an effort to provide some documentation on a national level of how we’re doing everything that we are doing.”
She noted that the process of obtaining medical home certification may require an even higher level of commitment if a bleeding disorder (hemophilia) treatment center is embedded in a university or academic medical center. In this case, more stakeholders are involved, and more hoops may need to be jumped through to implement processes that meet medical home standards while still adhering to any requirements at the organizational level.
Certification programs for patient-centered medical homes are not designed around specific disorders or diseases, but a closer look at their compliance metrics underscores how medical homes can benefit patients with bleeding disorders. For example, to receive medical home certification from the Accreditation Association for Ambulatory Health Care, a center needs to be able to document that patients’ care is not transferred without first making arrangements with a receiving health care provider, that the quality improvement programs are peer-led, and that these programs assess and address diverse measures of clinical performance, cost-effectiveness, and administrative functioning.7-9
Medical homes, the NHPCC, and Healthy People 2030
Creating patient-centered medical homes for patients with bleeding disorders is now a quality improvement objective of the National Hemophilia Program Coordinating Center, or NHPCC. Established in 2012 and funded by the federal Health Resources and Services Administration, the NHPCC partners with the eight regional hemophilia networks and more than 140 federally funded hemophilia treatment centers across the United States to identify gaps, standardize and improve access to care, and share and promote best practices for the treatment and management of blood disorders.10
In the United States, receiving care in a hemophilia treatment center (which, despite its name, typically offers care for other disorders such as von Willebrand disease) has been linked to lower mortality and fewer hospitalizations related to bleeding complications.11 To continue to improve on these outcomes, the NHPCC, regional networks, and hemophilia treatment centers are prioritizing medical homes and ranking their establishments alongside core objectives such as bettering patient and family engagement and improving the transition from pediatric to adult care.12
As part of this quality improvement work, the NHPCC, regional leadership, and hemophilia treatment centers meet regularly to identify needs and priorities, plan programs, and ensure that each center is meeting the goals and objectives set out by its federal grant.13 Such partnerships help improve and integrate care within a coordinated national framework, Dr. Shapiro said. “We all are charged with this same mission,” she added. “That doesn’t mean that every treatment center looks exactly the same, has the same number of staff, or does everything the same way, but we all have the same mission, and we know what that is. That is the work of the NHPCC, to determine and document that and help level and improve care throughout the country.”
The NHPCC also engages other stakeholders, including consumer agencies and professional organizations. Recent achievements have included a first-ever national patient needs assessment, a tandem technical needs assessment of hemophilia treatment centers, an educational outreach program for genetic counselors, a webinar on transitioning care for adolescents, a national survey of the federal 340B Drug Pricing Program, and a survey of minority patients to identify and characterize problems such as language and insurance barriers, the lack of culturally appropriate educational materials on blood disorders, and difficulties getting transportation to treatment centers or educational programs.14
In part because of this advocacy work, the U.S. Department of Health and Human Services recently included hemophilia for the first time in Healthy People, its evidence-based set of decade-long objectives aimed at improving the health of all Americans. In Healthy People 2030, the specific objective for hemophilia is to reduce the proportion of patients with severe disease who experience more than four joint bleeds per year to 13.3% (the current estimate is 16.9%).15
For Healthy People to prioritize hemophilia for the first time alongside much more common conditions such as diabetes and heart disease reflects the challenges of managing bleeding disorders and the efforts by the NHPCC and other stakeholders to raise awareness about current needs. To track progress in meeting the Healthy People 2030 objective, the NHPCC will work with federal partners to analyze patient-level data gathered through the Centers for Disease Control’s Community Counts Registry for Bleeding Disorders Surveillance program, which collects data from hemophilia treatment centers across the United States and includes patients with all levels of disease severity.
“The inclusion of bleeding disorders in Healthy People 2030 is really very significant,” said Dr. Shapiro. “These are disorders that affect less than 200,000 Americans, which is the definition of a rare disease in this context. To have hemophilia considered as a national priority is very important, not only for hemophilia, but also for other rare diseases that may in the future also be considered as being as of national importance in this way.”
References
1. Rodriguez-Saldana J. 2019. The Patient-Centered Medical Home, Primary Care, and Diabetes. In: Rodriguez-Saldana J. (eds) The Diabetes Textbook. Springer, Cham.
2. J Comorb. 2011;1:51-59.
3. Eur J Haematol. 2018 Apr;100 Suppl 1:5-13.
4. Blood. 2003;102(7):2358-63.
5. Haemophilia. 2014 Jul;20(4):541-9.
6. Haemophilia. 2016;22(Suppl 3):31-40.
7. AAAHC. Medical Home.
8. NCQA. Patient-centered medical home (PCMH).
9. AAAHC, 2013. Medical Home On-Site Certification Handbook.
10. Centers for Disease Control and Prevention. HTC Population Profile.
11. Blood Transfus. 2014;12 Suppl 3(Suppl 3):e542-e548.
12. American Thrombosis and Hemostasis Network.
13. The Great Lakes Regional Hemophilia Network.
14. American Thrombosis and Hemostasis Network. What the NHPCC does.
15. U.S. Department of Health and Human Services. Healthy People 2030: Blood Disorders.
As bleeding disorders are increasingly recognized as a national health priority, hematologists are focusing on how the patient-centered medical home – a widely accepted concept in primary care and in some specialties – can improve outcomes and quality life for their patients.
The patient-centered medical home is a model of health care delivery in which patients receive comprehensive, accessible care that is fully integrated across all providers and elements of a healthcare system.1 The concept emerged in the 1960s among pediatricians seeking to better coordinate care for children with complex medical needs. Since then, the patient-centered medical home has become a globally recognized standard – not only in primary care, but also in specialties such as endocrinology, oncology, and geriatric medicine. The movement to establish medical homes for patients with bleeding disorders is more recent and is receiving national attention.
Why a medical home?
The advent of prophylactic therapies for bleeding disorders has vastly improved the outlook for many patients compared to just a few decades ago. However, treatment options remain limited, and patients who have severe disease or complications – such as an inadequate treatment response or the development of inhibitory antibodies to replacement clotting factors – are at risk for recurrent breakthrough bleeding that can lead to synovitis and ultimately culminate in progressive, irreversible joint damage. The resulting pain and limitation of motion greatly compromises patients’ quality of life across physical, psychological, and social domains, undermines their ability to live and work independently, and greatly increases treatment costs.2-4 Family members, too, face high stress and lower quality of life when they struggle to obtain and manage treatment while caring for loved ones with bleeding disorders.5
For patients with bleeding disorders, a patient-centered medical home can help address or surmount these challenges, said Amy Shapiro, MD, medical director of the Indiana Hemophilia and Thrombosis Center in Indianapolis, Ind., which was the first hemophilia treatment center in the country to be formally certified as a medical home.
Dr. Shapiro explained that a patient-centered medical home leverages the care of an integrated multidisciplinary team to help optimize therapies and patient outcomes across all domains of life. She sees the medical home concept as a natural fit for patients with bleeding disorders, given the complexity of their needs and the number of specialties involved. “When you have hemophilia, you don’t just need a hematologist to manage your care. You need nurses, physical therapists, and social workers. You need coordinated care for genetic counseling. You also need to coordinate dental hygiene and surgical interventions, if these are required. Patients need nutrition counseling, and they may need assistance with education or career options if too many days are missed from work or school. Patients or their families may need counseling on choosing the right insurance program so they don’t choose a plan that may create more hardships for them because of their chronic disorder.”
Meeting these needs requires the help of an integrated care team, which many individuals with bleeding disorders lack. “If you are just out there in the community and you have medical issues that need to be dealt with, often the individuals themselves have to coordinate their own care, including their medications and their appointments with different specialists,” said Dr. Shapiro. “For example, a care provider may tell a patient that they need a physical therapist and give them some names, and then the patient has to take it from there and not only find the provider, but also determine if their insurance provides coverage.”
A medical home takes a completely different approach, she explained. “At my center, when we say you need a physical therapist, we have a physical therapist on staff. Our therapist provides an assessment and determines the need for ongoing PT and whether that can be done at home with a plan and intermittent oversight, or whether the patient needs a referral, and whether the person the patient is referred to needs education on how to provide PT for someone with hemophilia. A medical home provides all this in one place. It is a place where patients know they will receive either direct services, or support to shepherd their care and outcomes, and oversight of that support as well.”
Few studies have directly assessed the medical home model in the setting of bleeding disorders, but a number have evaluated the impact of integrated care, a more general term for the practice of coordinating multidisciplinary care to improve access and outcomes while eliminating redundancies and unnecessary costs. In a recent systematic review and meta-analysis of 27 nonrandomized studies of patients with hemophilia, integrated care was linked to lower mortality, fewer emergency room visits and hospitalizations, shorter lengths of stay in the hospital, and fewer missed days of school and work.6 Such findings, combined with promising outcomes data from studies of patient-centered medical homes in other disease settings, suggest that the patient-centered medical home can significantly benefit patients with bleeding disorders and their families and caregivers.
Creating a medical home
Establishing a patient-centered medical home can be challenging, involving a plethora of stakeholders and a considerable investment of time, energy, and resources. Organizations such as the National Committee for Quality Assurance and the Accreditation Association for Ambulatory Health Care have formal certification programs to help ensure that an inpatient or outpatient center that calls itself a medical home truly is one.7-8
The certification process requires centers to document activities in areas such as patients’ rights and responsibilities, administration and governance, patient and care team relationships, clinical records and other health information, and quality, comprehensiveness, continuity, and accessibility.7 Achieving certification is rigorous, often requiring centers to document compliance with more than 100 policies, procedures, and standards.
For the Indiana Hemophilia and Thrombosis Center, becoming certified as a medical home “was a multiyear process and an ongoing process,” said Dr. Shapiro. “It involves documentation of quality improvement initiatives, obtaining input from patients to document their satisfaction, and looking at all types of systems within our center and how we integrate care so that all those systems function together. It’s a difficult process, but treatment centers are a medical home for patients with bleeding disorders, and this is an effort to provide some documentation on a national level of how we’re doing everything that we are doing.”
She noted that the process of obtaining medical home certification may require an even higher level of commitment if a bleeding disorder (hemophilia) treatment center is embedded in a university or academic medical center. In this case, more stakeholders are involved, and more hoops may need to be jumped through to implement processes that meet medical home standards while still adhering to any requirements at the organizational level.
Certification programs for patient-centered medical homes are not designed around specific disorders or diseases, but a closer look at their compliance metrics underscores how medical homes can benefit patients with bleeding disorders. For example, to receive medical home certification from the Accreditation Association for Ambulatory Health Care, a center needs to be able to document that patients’ care is not transferred without first making arrangements with a receiving health care provider, that the quality improvement programs are peer-led, and that these programs assess and address diverse measures of clinical performance, cost-effectiveness, and administrative functioning.7-9
Medical homes, the NHPCC, and Healthy People 2030
Creating patient-centered medical homes for patients with bleeding disorders is now a quality improvement objective of the National Hemophilia Program Coordinating Center, or NHPCC. Established in 2012 and funded by the federal Health Resources and Services Administration, the NHPCC partners with the eight regional hemophilia networks and more than 140 federally funded hemophilia treatment centers across the United States to identify gaps, standardize and improve access to care, and share and promote best practices for the treatment and management of blood disorders.10
In the United States, receiving care in a hemophilia treatment center (which, despite its name, typically offers care for other disorders such as von Willebrand disease) has been linked to lower mortality and fewer hospitalizations related to bleeding complications.11 To continue to improve on these outcomes, the NHPCC, regional networks, and hemophilia treatment centers are prioritizing medical homes and ranking their establishments alongside core objectives such as bettering patient and family engagement and improving the transition from pediatric to adult care.12
As part of this quality improvement work, the NHPCC, regional leadership, and hemophilia treatment centers meet regularly to identify needs and priorities, plan programs, and ensure that each center is meeting the goals and objectives set out by its federal grant.13 Such partnerships help improve and integrate care within a coordinated national framework, Dr. Shapiro said. “We all are charged with this same mission,” she added. “That doesn’t mean that every treatment center looks exactly the same, has the same number of staff, or does everything the same way, but we all have the same mission, and we know what that is. That is the work of the NHPCC, to determine and document that and help level and improve care throughout the country.”
The NHPCC also engages other stakeholders, including consumer agencies and professional organizations. Recent achievements have included a first-ever national patient needs assessment, a tandem technical needs assessment of hemophilia treatment centers, an educational outreach program for genetic counselors, a webinar on transitioning care for adolescents, a national survey of the federal 340B Drug Pricing Program, and a survey of minority patients to identify and characterize problems such as language and insurance barriers, the lack of culturally appropriate educational materials on blood disorders, and difficulties getting transportation to treatment centers or educational programs.14
In part because of this advocacy work, the U.S. Department of Health and Human Services recently included hemophilia for the first time in Healthy People, its evidence-based set of decade-long objectives aimed at improving the health of all Americans. In Healthy People 2030, the specific objective for hemophilia is to reduce the proportion of patients with severe disease who experience more than four joint bleeds per year to 13.3% (the current estimate is 16.9%).15
For Healthy People to prioritize hemophilia for the first time alongside much more common conditions such as diabetes and heart disease reflects the challenges of managing bleeding disorders and the efforts by the NHPCC and other stakeholders to raise awareness about current needs. To track progress in meeting the Healthy People 2030 objective, the NHPCC will work with federal partners to analyze patient-level data gathered through the Centers for Disease Control’s Community Counts Registry for Bleeding Disorders Surveillance program, which collects data from hemophilia treatment centers across the United States and includes patients with all levels of disease severity.
“The inclusion of bleeding disorders in Healthy People 2030 is really very significant,” said Dr. Shapiro. “These are disorders that affect less than 200,000 Americans, which is the definition of a rare disease in this context. To have hemophilia considered as a national priority is very important, not only for hemophilia, but also for other rare diseases that may in the future also be considered as being as of national importance in this way.”
References
1. Rodriguez-Saldana J. 2019. The Patient-Centered Medical Home, Primary Care, and Diabetes. In: Rodriguez-Saldana J. (eds) The Diabetes Textbook. Springer, Cham.
2. J Comorb. 2011;1:51-59.
3. Eur J Haematol. 2018 Apr;100 Suppl 1:5-13.
4. Blood. 2003;102(7):2358-63.
5. Haemophilia. 2014 Jul;20(4):541-9.
6. Haemophilia. 2016;22(Suppl 3):31-40.
7. AAAHC. Medical Home.
8. NCQA. Patient-centered medical home (PCMH).
9. AAAHC, 2013. Medical Home On-Site Certification Handbook.
10. Centers for Disease Control and Prevention. HTC Population Profile.
11. Blood Transfus. 2014;12 Suppl 3(Suppl 3):e542-e548.
12. American Thrombosis and Hemostasis Network.
13. The Great Lakes Regional Hemophilia Network.
14. American Thrombosis and Hemostasis Network. What the NHPCC does.
15. U.S. Department of Health and Human Services. Healthy People 2030: Blood Disorders.
FDA approves new treatment option for rare anemia
A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.
Special concern
Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.
The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.
Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
About the disease
PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.
Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.
A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.
Special concern
Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.
The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.
Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
About the disease
PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.
Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.
A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.
Special concern
Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.
The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.
Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
About the disease
PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.
Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.
Health costs over 25 times higher for hemophilia B patients than controls
As the burden of hemophilia B in patients increases from mild to severe forms of the disease, the already high economic cost of treatment rises significantly, according to a large retrospective database study.
Researchers developed four profile categories (mild, moderate, moderate-severe, and severe) for men with hemophilia B on the basis of the frequency of hemorrhage events and factor IX replacement claims as identified from the IBM MarketScan database (June 2011–February 2019). The mean annual health care resource use (HRU) and costs were compared between 5,454 patients with hemophilia B and 1:1 demographically matched controls.
Economic burden
Total health care costs rose with increasingly severe clinical profiles, with hemophilia-related treatments being the primary cost driver, researchers led by Tyler W. Buckner, MD, of the University of Colorado at Denver, Aurora, wrote in Blood Advances.
This was particularly true among patients with more severe clinical profiles, who were more likely to be on prophylaxis with all of its associated costs.
The mean overall total costs incurred by patients with hemophilia B over the study period were $201,635 versus $7,879 for matched controls, a more than 25-fold difference (P < .001). In addition, across all four clinical profiles categories, all-cause total costs, medical costs, and pharmacy costs were significantly higher among patients with hemophilia B than matched controls (P < .001 for all), the researchers added.
Annual total health care costs also increased with increasing severity of hemophilia B clinical profiles, ranging from $80,811 and $137,455 in the mild and moderate groups to $251,619 and $632,088 in the moderate-severe and severe groups, respectively.
“Hemophilia-related treatments represented the primary cost driver. HRU was uniformly higher among patients with hemophilia B across clinical profiles, medical service types examined, and with respect to opioid use. The significant burden highlights that unmet needs remain in hemophilia B,” the researchers concluded.
This study was supported by uniQure. Dr. Buckner has received honoraria or fees for serving on advisory boards or as a consultant for uniQure. Several of the coauthors are employees of Analysis Group, which received consulting fees from uniQure to conduct this study, and two of the authors are employees of and own stock in uniQure.
As the burden of hemophilia B in patients increases from mild to severe forms of the disease, the already high economic cost of treatment rises significantly, according to a large retrospective database study.
Researchers developed four profile categories (mild, moderate, moderate-severe, and severe) for men with hemophilia B on the basis of the frequency of hemorrhage events and factor IX replacement claims as identified from the IBM MarketScan database (June 2011–February 2019). The mean annual health care resource use (HRU) and costs were compared between 5,454 patients with hemophilia B and 1:1 demographically matched controls.
Economic burden
Total health care costs rose with increasingly severe clinical profiles, with hemophilia-related treatments being the primary cost driver, researchers led by Tyler W. Buckner, MD, of the University of Colorado at Denver, Aurora, wrote in Blood Advances.
This was particularly true among patients with more severe clinical profiles, who were more likely to be on prophylaxis with all of its associated costs.
The mean overall total costs incurred by patients with hemophilia B over the study period were $201,635 versus $7,879 for matched controls, a more than 25-fold difference (P < .001). In addition, across all four clinical profiles categories, all-cause total costs, medical costs, and pharmacy costs were significantly higher among patients with hemophilia B than matched controls (P < .001 for all), the researchers added.
Annual total health care costs also increased with increasing severity of hemophilia B clinical profiles, ranging from $80,811 and $137,455 in the mild and moderate groups to $251,619 and $632,088 in the moderate-severe and severe groups, respectively.
“Hemophilia-related treatments represented the primary cost driver. HRU was uniformly higher among patients with hemophilia B across clinical profiles, medical service types examined, and with respect to opioid use. The significant burden highlights that unmet needs remain in hemophilia B,” the researchers concluded.
This study was supported by uniQure. Dr. Buckner has received honoraria or fees for serving on advisory boards or as a consultant for uniQure. Several of the coauthors are employees of Analysis Group, which received consulting fees from uniQure to conduct this study, and two of the authors are employees of and own stock in uniQure.
As the burden of hemophilia B in patients increases from mild to severe forms of the disease, the already high economic cost of treatment rises significantly, according to a large retrospective database study.
Researchers developed four profile categories (mild, moderate, moderate-severe, and severe) for men with hemophilia B on the basis of the frequency of hemorrhage events and factor IX replacement claims as identified from the IBM MarketScan database (June 2011–February 2019). The mean annual health care resource use (HRU) and costs were compared between 5,454 patients with hemophilia B and 1:1 demographically matched controls.
Economic burden
Total health care costs rose with increasingly severe clinical profiles, with hemophilia-related treatments being the primary cost driver, researchers led by Tyler W. Buckner, MD, of the University of Colorado at Denver, Aurora, wrote in Blood Advances.
This was particularly true among patients with more severe clinical profiles, who were more likely to be on prophylaxis with all of its associated costs.
The mean overall total costs incurred by patients with hemophilia B over the study period were $201,635 versus $7,879 for matched controls, a more than 25-fold difference (P < .001). In addition, across all four clinical profiles categories, all-cause total costs, medical costs, and pharmacy costs were significantly higher among patients with hemophilia B than matched controls (P < .001 for all), the researchers added.
Annual total health care costs also increased with increasing severity of hemophilia B clinical profiles, ranging from $80,811 and $137,455 in the mild and moderate groups to $251,619 and $632,088 in the moderate-severe and severe groups, respectively.
“Hemophilia-related treatments represented the primary cost driver. HRU was uniformly higher among patients with hemophilia B across clinical profiles, medical service types examined, and with respect to opioid use. The significant burden highlights that unmet needs remain in hemophilia B,” the researchers concluded.
This study was supported by uniQure. Dr. Buckner has received honoraria or fees for serving on advisory boards or as a consultant for uniQure. Several of the coauthors are employees of Analysis Group, which received consulting fees from uniQure to conduct this study, and two of the authors are employees of and own stock in uniQure.
FROM BLOOD ADVANCES
High variability found in studies assessing hemophilia-related pain
Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.
The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.
The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.
Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
Conflicting results
Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.
All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.
Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.
The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.
“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.
The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.
Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.
The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.
The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.
Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
Conflicting results
Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.
All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.
Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.
The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.
“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.
The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.
Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.
The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.
The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.
Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
Conflicting results
Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.
All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.
Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.
The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.
“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.
The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.
FROM THE JOURNAL OF PAIN
Real-world outcomes of caplacizumab for iTTP comparable to clinical trial results
Real-world data for caplacizumab outcomes matched those seen in randomized controlled trials (RCTs) for the treatment of immune-mediated thrombotic thrombocytopenic purpura (iTTP), according to the results of a retrospective study.
Data collected from 2018 to 2020 were assessed for 85 patients (4 of them children) receiving caplacizumab at 22 United Kingdom hospitals, according to a report published online in Blood.
Researchers Tina Dutt, PhD, from the Liverpool (England) University Hospitals NHS Foundation Trust, and her colleagues compared patient characteristics and outcomes in these real-world clinical settings to those of caplacizumab trial endpoint results and to historical outcomes in the precaplacizumab era.
Acquired thrombotic thrombocytopenic purpura is an immune-mediated deficiency of the von Willebrand factor–cleaving protease (ADAMTS13), which allows unrestrained adhesion of von Willebrand factor multimers to platelets, leading to thrombocytopenia, hemolytic anemia, and tissue ischemia.
Standard management of iTTP has focused on the replacement of ADAMTS13 and the removal of autoantibodies using plasma exchange and immunosuppression, an approach which has reduced the mortality of acute TTP from greater than 90% to between 10% and 20%, according to the report.
Caplacizumab is a novel anti–von Willebrand factor immunoglobulin fragment that inhibits this interaction between von Willebrand factor multimers and platelets and is now added to the standard treatment regimen. The drug has been assessed in two pivotal multicenter RCTs that led to European Union and U.S. Food and Drug Administration approval.
Benefits and risk
Eighty-four of 85 patients received steroid and rituximab as well as plasma exchange along with caplacizumab treatment. All patients had ADAMTS13 activity at presentation less than 20 IU/dL, with 99% of patients (84/85) having ADAMTS13 activity less than 10 IU/dL, confirming a clinical diagnosis of acute TTP, according to the researchers.
The median time to platelet count normalization (3 days), the median duration of plasma exchange (7 days), and the median hospital stay (12 days) were all comparable with the RCT data, according to the researchers. In addition, the median duration of plasma exchange and time from beginning plasma exchange to platelet count normalization were favorable, compared with historical outcomes (P < .05).
TTP recurred in 5 of the 85 patients, all of whom had persistent ADAMTS13 activity less than 5 IU/dL.
There were 31 adverse events reported in 26 patients, 17 of these (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab). The overall mortality was 6% (five patients), with no deaths attributed to caplacizumab. In four of the five deaths, caplacizumab was introduced more than 48 hours after plasma exchange initiation (range 3-21 days).
“This real-world evidence from the largest series of TTP patients receiving caplacizumab, outside of the pivotal studies, provides confirmation of the therapeutic benefits of caplacizumab and its inherent bleeding risk,” the researchers concluded.
Dr. Dutt and several of her colleagues reported receiving honoraria from Sanofi for serving on advisory boards, as well as speaker fees from Sanofi and Alexion.
Real-world data for caplacizumab outcomes matched those seen in randomized controlled trials (RCTs) for the treatment of immune-mediated thrombotic thrombocytopenic purpura (iTTP), according to the results of a retrospective study.
Data collected from 2018 to 2020 were assessed for 85 patients (4 of them children) receiving caplacizumab at 22 United Kingdom hospitals, according to a report published online in Blood.
Researchers Tina Dutt, PhD, from the Liverpool (England) University Hospitals NHS Foundation Trust, and her colleagues compared patient characteristics and outcomes in these real-world clinical settings to those of caplacizumab trial endpoint results and to historical outcomes in the precaplacizumab era.
Acquired thrombotic thrombocytopenic purpura is an immune-mediated deficiency of the von Willebrand factor–cleaving protease (ADAMTS13), which allows unrestrained adhesion of von Willebrand factor multimers to platelets, leading to thrombocytopenia, hemolytic anemia, and tissue ischemia.
Standard management of iTTP has focused on the replacement of ADAMTS13 and the removal of autoantibodies using plasma exchange and immunosuppression, an approach which has reduced the mortality of acute TTP from greater than 90% to between 10% and 20%, according to the report.
Caplacizumab is a novel anti–von Willebrand factor immunoglobulin fragment that inhibits this interaction between von Willebrand factor multimers and platelets and is now added to the standard treatment regimen. The drug has been assessed in two pivotal multicenter RCTs that led to European Union and U.S. Food and Drug Administration approval.
Benefits and risk
Eighty-four of 85 patients received steroid and rituximab as well as plasma exchange along with caplacizumab treatment. All patients had ADAMTS13 activity at presentation less than 20 IU/dL, with 99% of patients (84/85) having ADAMTS13 activity less than 10 IU/dL, confirming a clinical diagnosis of acute TTP, according to the researchers.
The median time to platelet count normalization (3 days), the median duration of plasma exchange (7 days), and the median hospital stay (12 days) were all comparable with the RCT data, according to the researchers. In addition, the median duration of plasma exchange and time from beginning plasma exchange to platelet count normalization were favorable, compared with historical outcomes (P < .05).
TTP recurred in 5 of the 85 patients, all of whom had persistent ADAMTS13 activity less than 5 IU/dL.
There were 31 adverse events reported in 26 patients, 17 of these (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab). The overall mortality was 6% (five patients), with no deaths attributed to caplacizumab. In four of the five deaths, caplacizumab was introduced more than 48 hours after plasma exchange initiation (range 3-21 days).
“This real-world evidence from the largest series of TTP patients receiving caplacizumab, outside of the pivotal studies, provides confirmation of the therapeutic benefits of caplacizumab and its inherent bleeding risk,” the researchers concluded.
Dr. Dutt and several of her colleagues reported receiving honoraria from Sanofi for serving on advisory boards, as well as speaker fees from Sanofi and Alexion.
Real-world data for caplacizumab outcomes matched those seen in randomized controlled trials (RCTs) for the treatment of immune-mediated thrombotic thrombocytopenic purpura (iTTP), according to the results of a retrospective study.
Data collected from 2018 to 2020 were assessed for 85 patients (4 of them children) receiving caplacizumab at 22 United Kingdom hospitals, according to a report published online in Blood.
Researchers Tina Dutt, PhD, from the Liverpool (England) University Hospitals NHS Foundation Trust, and her colleagues compared patient characteristics and outcomes in these real-world clinical settings to those of caplacizumab trial endpoint results and to historical outcomes in the precaplacizumab era.
Acquired thrombotic thrombocytopenic purpura is an immune-mediated deficiency of the von Willebrand factor–cleaving protease (ADAMTS13), which allows unrestrained adhesion of von Willebrand factor multimers to platelets, leading to thrombocytopenia, hemolytic anemia, and tissue ischemia.
Standard management of iTTP has focused on the replacement of ADAMTS13 and the removal of autoantibodies using plasma exchange and immunosuppression, an approach which has reduced the mortality of acute TTP from greater than 90% to between 10% and 20%, according to the report.
Caplacizumab is a novel anti–von Willebrand factor immunoglobulin fragment that inhibits this interaction between von Willebrand factor multimers and platelets and is now added to the standard treatment regimen. The drug has been assessed in two pivotal multicenter RCTs that led to European Union and U.S. Food and Drug Administration approval.
Benefits and risk
Eighty-four of 85 patients received steroid and rituximab as well as plasma exchange along with caplacizumab treatment. All patients had ADAMTS13 activity at presentation less than 20 IU/dL, with 99% of patients (84/85) having ADAMTS13 activity less than 10 IU/dL, confirming a clinical diagnosis of acute TTP, according to the researchers.
The median time to platelet count normalization (3 days), the median duration of plasma exchange (7 days), and the median hospital stay (12 days) were all comparable with the RCT data, according to the researchers. In addition, the median duration of plasma exchange and time from beginning plasma exchange to platelet count normalization were favorable, compared with historical outcomes (P < .05).
TTP recurred in 5 of the 85 patients, all of whom had persistent ADAMTS13 activity less than 5 IU/dL.
There were 31 adverse events reported in 26 patients, 17 of these (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab). The overall mortality was 6% (five patients), with no deaths attributed to caplacizumab. In four of the five deaths, caplacizumab was introduced more than 48 hours after plasma exchange initiation (range 3-21 days).
“This real-world evidence from the largest series of TTP patients receiving caplacizumab, outside of the pivotal studies, provides confirmation of the therapeutic benefits of caplacizumab and its inherent bleeding risk,” the researchers concluded.
Dr. Dutt and several of her colleagues reported receiving honoraria from Sanofi for serving on advisory boards, as well as speaker fees from Sanofi and Alexion.
FROM BLOOD
Close joint health monitoring essential with new hemophilia therapies
Novel therapies have transformed the treatment of hemophilia in recent decades, but these new approaches also raise new challenges for clinicians who monitor joint health in persons with hemophilia, a specialist said.
“Patient-reported outcomes should be combined with other, more objective outcome measures for joint health monitoring, and joint ultrasound is a promising tool for objective joint health monitoring, although, due to its relatively recent introduction in clinical practice, we lack objective data and standardization,” said Roberta Gualtierotti, MD, PhD, from the Università Degli Studi of Milan.
She reviewed the challenges and approaches to monitoring joint health in persons with hemophilia during the annual congress of the European Association for Haemophilia and Allied Disorders.
Over the last decades the target of hemophilia treatment has shifted from prolonging survival to improving joint health and quality of life, and care has improved with the introduction of novel therapies such as extended half-life replacement products, nonreplacement therapies, and gene therapy, she noted.
However, “due to different pharmacodynamics and pharmacokinetics profiles, the currently available therapies cannot be compared to each other on several levels,” Dr. Gualtierotti said.
Laboratory monitoring of replacement therapies with standard coagulation assays may be unreliable, and depending on the mechanism of action and type of administration of nonreplacement agents, patients may experience breakthrough bleeding, especially after traumatic injury, she said.
Until the specific noncoagulatory effects of factor VIII on bone and joint health is better understood, close monitoring of patients will be required, she added.
Outcome measures
Subjective measures of joint health include patient-reported bleeding rates and health-related quality of life. These are practical for home management, but patients may not be able to distinguish symptoms of acute joint bleeding from chronic arthritis pain, with the potential for either under- or overtreatment, and subjective reporting is likely to miss subclinical bleeding that can occur even when patients are on prophylaxis.
Health-related quality of life tools, whether generic or specific for hemophilia, are not sensitive to small improvements, and they are not always used in routine clinical practice.
Objective measures include physical examination with scoring according to the World Federation of Hemophilia (Gilbert Scale) score or Hemophilia Joint Health Score, but these measures have limited ability to identify early or subclinical joint abnormalities.
“Therefore, joint physical examination on its own is not a sufficient measure of treatment efficacy, and it should be used in combination with other tools more objective, such as imaging,” Dr. Gualtierotti said.
Get the picture?
Imaging with x-rays, MRI, and, recently in some centers, point-of-care ultrasound can provide clinicians with important real-time information about the joint stability and health.
Point-of-care ultrasound in particular offers promise as a practical tool, with no ionizing radiation and high sensitivity for synovial hyperplasia subclinical joint effusion. It’s relatively inexpensive, can be used to image multiple joints, and allows for ease of follow-up, she said. The technique requires specialized training, however, and there is a lack of prospective data about its utility in hemophilia.
Various ultrasound scoring systems have been proposed, and home-based ultrasound is currently being explored in several clinical trials, Dr. Gualtierotti noted.
Other avenues for remote joint health monitoring under consideration are serum or synovial biomarkers for joint bleeding and arthropathy that could be employed at bedside or at home, smartphone apps for breakthrough bleeding and patient-reported outcomes, and sensors for detecting abnormalities in gait that may signal joint dysfunction, she said.
Best practice
In the question-and-answer session following the talk, Fernando Zikan, MD, from the Federal University of Rio de Janeiro noted that, “in underdeveloped countries, we still find it very difficult to guide good practices for joint health control by the patient and family members. Which strategy do you think is fundamental for the patient to feel safe to notice changes in his body?”
“It would be useful to educate patients to come to the center whenever the patient has trauma and whenever an increase in his physical activity occurs. If this is far, a bedside ultrasound evaluation by the general practitioner could help avoid joint damage. Finally, a correct rehabilitation is fundamental,” Dr. Gualtierotti replied.
Asked by several others whether she used ultrasound in her daily practice, Dr. Gualtierotti said that “we use joint ultrasound in our clinical practice in the regular annual check-up examination and whenever the patient suspects and reports hemarthrosis.”
Dr. Gualtierotti reported participation in advisory boards for Biomarin, Pfizer, Bayer, and Takeda, and in educational seminars sponsored by Pfizer, Sobi, and Roche. She has received support for congress travel and/or attendance by Bayer and Pfizer. Dr. Zikan reported no relevant disclosures.
Novel therapies have transformed the treatment of hemophilia in recent decades, but these new approaches also raise new challenges for clinicians who monitor joint health in persons with hemophilia, a specialist said.
“Patient-reported outcomes should be combined with other, more objective outcome measures for joint health monitoring, and joint ultrasound is a promising tool for objective joint health monitoring, although, due to its relatively recent introduction in clinical practice, we lack objective data and standardization,” said Roberta Gualtierotti, MD, PhD, from the Università Degli Studi of Milan.
She reviewed the challenges and approaches to monitoring joint health in persons with hemophilia during the annual congress of the European Association for Haemophilia and Allied Disorders.
Over the last decades the target of hemophilia treatment has shifted from prolonging survival to improving joint health and quality of life, and care has improved with the introduction of novel therapies such as extended half-life replacement products, nonreplacement therapies, and gene therapy, she noted.
However, “due to different pharmacodynamics and pharmacokinetics profiles, the currently available therapies cannot be compared to each other on several levels,” Dr. Gualtierotti said.
Laboratory monitoring of replacement therapies with standard coagulation assays may be unreliable, and depending on the mechanism of action and type of administration of nonreplacement agents, patients may experience breakthrough bleeding, especially after traumatic injury, she said.
Until the specific noncoagulatory effects of factor VIII on bone and joint health is better understood, close monitoring of patients will be required, she added.
Outcome measures
Subjective measures of joint health include patient-reported bleeding rates and health-related quality of life. These are practical for home management, but patients may not be able to distinguish symptoms of acute joint bleeding from chronic arthritis pain, with the potential for either under- or overtreatment, and subjective reporting is likely to miss subclinical bleeding that can occur even when patients are on prophylaxis.
Health-related quality of life tools, whether generic or specific for hemophilia, are not sensitive to small improvements, and they are not always used in routine clinical practice.
Objective measures include physical examination with scoring according to the World Federation of Hemophilia (Gilbert Scale) score or Hemophilia Joint Health Score, but these measures have limited ability to identify early or subclinical joint abnormalities.
“Therefore, joint physical examination on its own is not a sufficient measure of treatment efficacy, and it should be used in combination with other tools more objective, such as imaging,” Dr. Gualtierotti said.
Get the picture?
Imaging with x-rays, MRI, and, recently in some centers, point-of-care ultrasound can provide clinicians with important real-time information about the joint stability and health.
Point-of-care ultrasound in particular offers promise as a practical tool, with no ionizing radiation and high sensitivity for synovial hyperplasia subclinical joint effusion. It’s relatively inexpensive, can be used to image multiple joints, and allows for ease of follow-up, she said. The technique requires specialized training, however, and there is a lack of prospective data about its utility in hemophilia.
Various ultrasound scoring systems have been proposed, and home-based ultrasound is currently being explored in several clinical trials, Dr. Gualtierotti noted.
Other avenues for remote joint health monitoring under consideration are serum or synovial biomarkers for joint bleeding and arthropathy that could be employed at bedside or at home, smartphone apps for breakthrough bleeding and patient-reported outcomes, and sensors for detecting abnormalities in gait that may signal joint dysfunction, she said.
Best practice
In the question-and-answer session following the talk, Fernando Zikan, MD, from the Federal University of Rio de Janeiro noted that, “in underdeveloped countries, we still find it very difficult to guide good practices for joint health control by the patient and family members. Which strategy do you think is fundamental for the patient to feel safe to notice changes in his body?”
“It would be useful to educate patients to come to the center whenever the patient has trauma and whenever an increase in his physical activity occurs. If this is far, a bedside ultrasound evaluation by the general practitioner could help avoid joint damage. Finally, a correct rehabilitation is fundamental,” Dr. Gualtierotti replied.
Asked by several others whether she used ultrasound in her daily practice, Dr. Gualtierotti said that “we use joint ultrasound in our clinical practice in the regular annual check-up examination and whenever the patient suspects and reports hemarthrosis.”
Dr. Gualtierotti reported participation in advisory boards for Biomarin, Pfizer, Bayer, and Takeda, and in educational seminars sponsored by Pfizer, Sobi, and Roche. She has received support for congress travel and/or attendance by Bayer and Pfizer. Dr. Zikan reported no relevant disclosures.
Novel therapies have transformed the treatment of hemophilia in recent decades, but these new approaches also raise new challenges for clinicians who monitor joint health in persons with hemophilia, a specialist said.
“Patient-reported outcomes should be combined with other, more objective outcome measures for joint health monitoring, and joint ultrasound is a promising tool for objective joint health monitoring, although, due to its relatively recent introduction in clinical practice, we lack objective data and standardization,” said Roberta Gualtierotti, MD, PhD, from the Università Degli Studi of Milan.
She reviewed the challenges and approaches to monitoring joint health in persons with hemophilia during the annual congress of the European Association for Haemophilia and Allied Disorders.
Over the last decades the target of hemophilia treatment has shifted from prolonging survival to improving joint health and quality of life, and care has improved with the introduction of novel therapies such as extended half-life replacement products, nonreplacement therapies, and gene therapy, she noted.
However, “due to different pharmacodynamics and pharmacokinetics profiles, the currently available therapies cannot be compared to each other on several levels,” Dr. Gualtierotti said.
Laboratory monitoring of replacement therapies with standard coagulation assays may be unreliable, and depending on the mechanism of action and type of administration of nonreplacement agents, patients may experience breakthrough bleeding, especially after traumatic injury, she said.
Until the specific noncoagulatory effects of factor VIII on bone and joint health is better understood, close monitoring of patients will be required, she added.
Outcome measures
Subjective measures of joint health include patient-reported bleeding rates and health-related quality of life. These are practical for home management, but patients may not be able to distinguish symptoms of acute joint bleeding from chronic arthritis pain, with the potential for either under- or overtreatment, and subjective reporting is likely to miss subclinical bleeding that can occur even when patients are on prophylaxis.
Health-related quality of life tools, whether generic or specific for hemophilia, are not sensitive to small improvements, and they are not always used in routine clinical practice.
Objective measures include physical examination with scoring according to the World Federation of Hemophilia (Gilbert Scale) score or Hemophilia Joint Health Score, but these measures have limited ability to identify early or subclinical joint abnormalities.
“Therefore, joint physical examination on its own is not a sufficient measure of treatment efficacy, and it should be used in combination with other tools more objective, such as imaging,” Dr. Gualtierotti said.
Get the picture?
Imaging with x-rays, MRI, and, recently in some centers, point-of-care ultrasound can provide clinicians with important real-time information about the joint stability and health.
Point-of-care ultrasound in particular offers promise as a practical tool, with no ionizing radiation and high sensitivity for synovial hyperplasia subclinical joint effusion. It’s relatively inexpensive, can be used to image multiple joints, and allows for ease of follow-up, she said. The technique requires specialized training, however, and there is a lack of prospective data about its utility in hemophilia.
Various ultrasound scoring systems have been proposed, and home-based ultrasound is currently being explored in several clinical trials, Dr. Gualtierotti noted.
Other avenues for remote joint health monitoring under consideration are serum or synovial biomarkers for joint bleeding and arthropathy that could be employed at bedside or at home, smartphone apps for breakthrough bleeding and patient-reported outcomes, and sensors for detecting abnormalities in gait that may signal joint dysfunction, she said.
Best practice
In the question-and-answer session following the talk, Fernando Zikan, MD, from the Federal University of Rio de Janeiro noted that, “in underdeveloped countries, we still find it very difficult to guide good practices for joint health control by the patient and family members. Which strategy do you think is fundamental for the patient to feel safe to notice changes in his body?”
“It would be useful to educate patients to come to the center whenever the patient has trauma and whenever an increase in his physical activity occurs. If this is far, a bedside ultrasound evaluation by the general practitioner could help avoid joint damage. Finally, a correct rehabilitation is fundamental,” Dr. Gualtierotti replied.
Asked by several others whether she used ultrasound in her daily practice, Dr. Gualtierotti said that “we use joint ultrasound in our clinical practice in the regular annual check-up examination and whenever the patient suspects and reports hemarthrosis.”
Dr. Gualtierotti reported participation in advisory boards for Biomarin, Pfizer, Bayer, and Takeda, and in educational seminars sponsored by Pfizer, Sobi, and Roche. She has received support for congress travel and/or attendance by Bayer and Pfizer. Dr. Zikan reported no relevant disclosures.
FROM EAHAD 2021
Joint pain in patients with hemophilia may be neuropathic
Nearly one-third of persons with hemophilia had neuropathic pain or altered central pain mechanisms, investigators in a small study found.
Among 30 patients with hemophilia, 9 (30%) had scores of 4 or greater on the 10-point Diabetic Neuropathy 4 (DN4) scale, indicating significant neuropathic pain, reported Nathalie Roussel, PhD, from the University of Antwerp (Belgium), at the annual congress of the European Association for Haemophilia and Allied Disorders.
“The results of this study show us that a large difference exists in pain assessments when we have consecutive sample of patients with hemophilia. These results also show that there are subgroups of patients with altered central pain mechanisms and other subgroups with neuropathic pain, and patients with neuropathic pain have a significantly worse quality of life that is not associated with joint structure and joint function,” she said.
“This is a very good abstract in my opinion, and it deserves more study,” commented hemophilia specialist Rajiv K. Pruthi, MBBS, from the Mayo Clinic in Rochester, Minn., who was not involved in the study.
Structural and functional tests
To get a better understanding of the complexities of ankle pain in persons with hemophilia, Dr. Roussel and colleagues recruited 30 adults followed at their center for moderate or severe hemophilia A or B who were on replacement therapy with factor VIII or factor IX concentrate.
They used MRI without contrast to look for structural alterations in both the talocrural and subtalar joints of both ankles in all patients using the International Prophylaxis Study Group Score, adapted for subtalar joint assessment.
The investigators also used the hemophilia joint health score to assess joint funding, and tests for limits on physical activity, including the Timed Up and Go Test, 2-minute walk test, and Hemophilia Activities Lists.
In addition, they assessed pain with Quantitative Sensory Testing, a noninvasive method for evaluating patient responses to heat, cold, and mechanical pressure. Other measures included questionnaires regarding neuropathic pain and quality of life.
The participants included 23 patients with severe and 3 with moderate hemophilia A, and 1 patient with severe and 3 with moderate hemophilia B. The mean patient age was 39.4 years.
In all, 24 of the 30 patients (80%) were on prophylaxis, and 9 (30%) reported using pain medications; 25 patients reported having some degree of pain.
On MRI, 48/60 (80%) of talocrural joints imaged had pathological findings, as did 41 of 60 (68%) subtalar joints.
“Despite the fact that these patients do not all suffer from ankle joint pain, a lot of them have signs of joint pathology,” Dr. Roussel said.
On the Brief Pain Inventory, only 5 patients had no reported pain, but 14 patients reported either three, five, or six painful locations, and 20 out of 30 patients reported that their ankles were the most affected joints.
Although the sample size was not large enough for statistical comparisons, there were also large variations in pain perception across hemophilia severity.
“This is an important finding, that also patients with moderate hemophilia can have intense pain,” Dr. Roussel said.
On the DN4 questionnaire, nine patients had scores of 4 or greater, indicating that their pain was neuropathic in origin.
When they compared the patients with neuropathic pain with those suffering from nonneuropathic pain, the investigators observed similar structural and joint function between the groups, but significantly worse reported quality of life for patients with neuropathic pain.
“This is a finding that merits further attention,” she commented.
In correlation analyses, the investigators also found that MRI scores did not correlate significantly with either hemophilia joint health score, physical function, participation in activities, or pressure pain thresholds.
Why the discrepancies?
Dr. Pruthi said in an interview that he has seen evidence from other studies showing that some patients with hemophilia who were on prophylaxis had MRI evidence of joint damage, while others who used on-demand therapy had none.
“That opens up a whole can of worms as to what are we dealing with here. Why do some patients end up with damage and others don’t?” he asked.
He said that the finding that the origin of pain in a large proportion of patients was neuropathic rather than arthritic in origin was new to him.
“It raises a lot of good questions: maybe we need to be managing pain in these patients with nonnarcotic approaches, and in this day and age with the opioid crisis it’s even more important to do that,” he said.
He hypothesized that degenerative arthritis may irritate nearby nerves, resulting in neuropathic pain.
The study was funded by EAHAD, with support from participating institutions. Dr. Roussel and Dr. Pruthi reported no conflicts of interest to declare.
Nearly one-third of persons with hemophilia had neuropathic pain or altered central pain mechanisms, investigators in a small study found.
Among 30 patients with hemophilia, 9 (30%) had scores of 4 or greater on the 10-point Diabetic Neuropathy 4 (DN4) scale, indicating significant neuropathic pain, reported Nathalie Roussel, PhD, from the University of Antwerp (Belgium), at the annual congress of the European Association for Haemophilia and Allied Disorders.
“The results of this study show us that a large difference exists in pain assessments when we have consecutive sample of patients with hemophilia. These results also show that there are subgroups of patients with altered central pain mechanisms and other subgroups with neuropathic pain, and patients with neuropathic pain have a significantly worse quality of life that is not associated with joint structure and joint function,” she said.
“This is a very good abstract in my opinion, and it deserves more study,” commented hemophilia specialist Rajiv K. Pruthi, MBBS, from the Mayo Clinic in Rochester, Minn., who was not involved in the study.
Structural and functional tests
To get a better understanding of the complexities of ankle pain in persons with hemophilia, Dr. Roussel and colleagues recruited 30 adults followed at their center for moderate or severe hemophilia A or B who were on replacement therapy with factor VIII or factor IX concentrate.
They used MRI without contrast to look for structural alterations in both the talocrural and subtalar joints of both ankles in all patients using the International Prophylaxis Study Group Score, adapted for subtalar joint assessment.
The investigators also used the hemophilia joint health score to assess joint funding, and tests for limits on physical activity, including the Timed Up and Go Test, 2-minute walk test, and Hemophilia Activities Lists.
In addition, they assessed pain with Quantitative Sensory Testing, a noninvasive method for evaluating patient responses to heat, cold, and mechanical pressure. Other measures included questionnaires regarding neuropathic pain and quality of life.
The participants included 23 patients with severe and 3 with moderate hemophilia A, and 1 patient with severe and 3 with moderate hemophilia B. The mean patient age was 39.4 years.
In all, 24 of the 30 patients (80%) were on prophylaxis, and 9 (30%) reported using pain medications; 25 patients reported having some degree of pain.
On MRI, 48/60 (80%) of talocrural joints imaged had pathological findings, as did 41 of 60 (68%) subtalar joints.
“Despite the fact that these patients do not all suffer from ankle joint pain, a lot of them have signs of joint pathology,” Dr. Roussel said.
On the Brief Pain Inventory, only 5 patients had no reported pain, but 14 patients reported either three, five, or six painful locations, and 20 out of 30 patients reported that their ankles were the most affected joints.
Although the sample size was not large enough for statistical comparisons, there were also large variations in pain perception across hemophilia severity.
“This is an important finding, that also patients with moderate hemophilia can have intense pain,” Dr. Roussel said.
On the DN4 questionnaire, nine patients had scores of 4 or greater, indicating that their pain was neuropathic in origin.
When they compared the patients with neuropathic pain with those suffering from nonneuropathic pain, the investigators observed similar structural and joint function between the groups, but significantly worse reported quality of life for patients with neuropathic pain.
“This is a finding that merits further attention,” she commented.
In correlation analyses, the investigators also found that MRI scores did not correlate significantly with either hemophilia joint health score, physical function, participation in activities, or pressure pain thresholds.
Why the discrepancies?
Dr. Pruthi said in an interview that he has seen evidence from other studies showing that some patients with hemophilia who were on prophylaxis had MRI evidence of joint damage, while others who used on-demand therapy had none.
“That opens up a whole can of worms as to what are we dealing with here. Why do some patients end up with damage and others don’t?” he asked.
He said that the finding that the origin of pain in a large proportion of patients was neuropathic rather than arthritic in origin was new to him.
“It raises a lot of good questions: maybe we need to be managing pain in these patients with nonnarcotic approaches, and in this day and age with the opioid crisis it’s even more important to do that,” he said.
He hypothesized that degenerative arthritis may irritate nearby nerves, resulting in neuropathic pain.
The study was funded by EAHAD, with support from participating institutions. Dr. Roussel and Dr. Pruthi reported no conflicts of interest to declare.
Nearly one-third of persons with hemophilia had neuropathic pain or altered central pain mechanisms, investigators in a small study found.
Among 30 patients with hemophilia, 9 (30%) had scores of 4 or greater on the 10-point Diabetic Neuropathy 4 (DN4) scale, indicating significant neuropathic pain, reported Nathalie Roussel, PhD, from the University of Antwerp (Belgium), at the annual congress of the European Association for Haemophilia and Allied Disorders.
“The results of this study show us that a large difference exists in pain assessments when we have consecutive sample of patients with hemophilia. These results also show that there are subgroups of patients with altered central pain mechanisms and other subgroups with neuropathic pain, and patients with neuropathic pain have a significantly worse quality of life that is not associated with joint structure and joint function,” she said.
“This is a very good abstract in my opinion, and it deserves more study,” commented hemophilia specialist Rajiv K. Pruthi, MBBS, from the Mayo Clinic in Rochester, Minn., who was not involved in the study.
Structural and functional tests
To get a better understanding of the complexities of ankle pain in persons with hemophilia, Dr. Roussel and colleagues recruited 30 adults followed at their center for moderate or severe hemophilia A or B who were on replacement therapy with factor VIII or factor IX concentrate.
They used MRI without contrast to look for structural alterations in both the talocrural and subtalar joints of both ankles in all patients using the International Prophylaxis Study Group Score, adapted for subtalar joint assessment.
The investigators also used the hemophilia joint health score to assess joint funding, and tests for limits on physical activity, including the Timed Up and Go Test, 2-minute walk test, and Hemophilia Activities Lists.
In addition, they assessed pain with Quantitative Sensory Testing, a noninvasive method for evaluating patient responses to heat, cold, and mechanical pressure. Other measures included questionnaires regarding neuropathic pain and quality of life.
The participants included 23 patients with severe and 3 with moderate hemophilia A, and 1 patient with severe and 3 with moderate hemophilia B. The mean patient age was 39.4 years.
In all, 24 of the 30 patients (80%) were on prophylaxis, and 9 (30%) reported using pain medications; 25 patients reported having some degree of pain.
On MRI, 48/60 (80%) of talocrural joints imaged had pathological findings, as did 41 of 60 (68%) subtalar joints.
“Despite the fact that these patients do not all suffer from ankle joint pain, a lot of them have signs of joint pathology,” Dr. Roussel said.
On the Brief Pain Inventory, only 5 patients had no reported pain, but 14 patients reported either three, five, or six painful locations, and 20 out of 30 patients reported that their ankles were the most affected joints.
Although the sample size was not large enough for statistical comparisons, there were also large variations in pain perception across hemophilia severity.
“This is an important finding, that also patients with moderate hemophilia can have intense pain,” Dr. Roussel said.
On the DN4 questionnaire, nine patients had scores of 4 or greater, indicating that their pain was neuropathic in origin.
When they compared the patients with neuropathic pain with those suffering from nonneuropathic pain, the investigators observed similar structural and joint function between the groups, but significantly worse reported quality of life for patients with neuropathic pain.
“This is a finding that merits further attention,” she commented.
In correlation analyses, the investigators also found that MRI scores did not correlate significantly with either hemophilia joint health score, physical function, participation in activities, or pressure pain thresholds.
Why the discrepancies?
Dr. Pruthi said in an interview that he has seen evidence from other studies showing that some patients with hemophilia who were on prophylaxis had MRI evidence of joint damage, while others who used on-demand therapy had none.
“That opens up a whole can of worms as to what are we dealing with here. Why do some patients end up with damage and others don’t?” he asked.
He said that the finding that the origin of pain in a large proportion of patients was neuropathic rather than arthritic in origin was new to him.
“It raises a lot of good questions: maybe we need to be managing pain in these patients with nonnarcotic approaches, and in this day and age with the opioid crisis it’s even more important to do that,” he said.
He hypothesized that degenerative arthritis may irritate nearby nerves, resulting in neuropathic pain.
The study was funded by EAHAD, with support from participating institutions. Dr. Roussel and Dr. Pruthi reported no conflicts of interest to declare.
FROM EAHAD 2021