TBD Meeting (5335-21)

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.

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.

Type 3 von Willebrand disease (VWD) is rare, but this form of the disease is associated with severe bleeding, particularly in muscles and joints, a bleeding disorders expert said.

“There’s a virtually complete deficiency in von Willebrand factor [in type 3 disease], so usually it’s defined as below 5 or in some studies below 3 IU/dL, but also due to the very low levels of von Willebrand factor, there’s also a very low level of factor VIII,” said Jeroen Eikenboom, MD, PhD, from Leiden (the Netherlands) University Medical Center.

“The inheritance pattern is autosomal recessive, and the prevalence is about 1 in a million,” he said during the annual congress of the European Association for Haemophilia and Allied Disorders.

Erik Adolf von Willenbrand, MD, PhD, first described this form of VWD in a family from the Åland Islands, an autonomous region of Finland. The disease, later discovered to be caused in this family by a cytosine deletion in exon 18 of the von Willebrand factor (VWF) gene, was associated with fatal bleeding events in several family members.

“As VWF is the carrier protein of factor VIII, the very low VWF level leads to a strongly reduced factor VIII level, comparable to the levels seen in mild to moderate hemophilia A. As a consequence, VWD type 3 has the combined characteristics of a primary as well as a secondary hemostasis defect,” Dr. Eikenboom explained in an abstract accompanying his talk.

Compared with VWD type 1 or 2, type 3 VWD is associated with bleeding episodes more commonly seen in patients with hemophilia A, notably mucocutaneous bleeding, bleeding after trauma or during surgery, and bleeding into joints and/or muscles.
 

Treatment

The goals of treatment for patients with type 3 VWD are to correct the dual hemostasis defects of impaired platelet adhesion because of low VWF levels, and the intrinsic coagulation defect because of levels of factor VIII.

Desmopressin is not effective in type 3 VWD, Dr. Eikenboom said, so treatment requires the use of either plasma-derived VWF, with or without factor VIII, or recombinant VWF.

In the United States, the only standalone VWF concentrate approved by the Food and Drug Administration is a recombinant product (Vonvendi), Three other human plasma–derived concentrates containing both VWF and factor VIII are also licensed (Alpanate, Humate-P, Wilate).

Clinicians prescribing the combined factor concentrates need to be aware of differences in pharmacokinetics between the products.

For example, following infusion of Wilate, which has equal amounts of von Willebrand factor and factor VIII, there is an increase in circulation of both von Willebrand factor and factor VIII and a similar decline in each factor over time.

In contrast, following an infusion of Humate-P, which contains lower levels of factor VIII, “interestingly, you see a secondary rise of factor VIII in Humate-P–infused patients, whereas the secondary rise is not visible in the Wilate patients,” he said.

Approximately 22% of patients with type 3 VWD also receive prophylaxis with VWF concentrate, which has been shown to decrease the median annualized bleeding rate from 25% to 6.1%.

Dr. Eikenboom cautioned that 5%-10% of patients with type 3 VWD may develop allo-antibodies against VWF concentrates, which can complicate treatment and carries risk of anaphylactic shock.

“It’s also been mentioned in literature that there may be an association with partial or complete von Willebrand factor gene deletions or nonsense mutations and the development of allo-antibodies,” he said.
 

Prophylaxis burdensome but helpful

Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee, who specializes in the treatment of patients with von Willebrand disease, follows a number of both girls and boys with type 3 VWD.

“Those are the people who will have bleeding into their joints, and for the girls, worse periods than some of those with other types of von Willebrand disease, and it is true that if you want to stop their bleeding, you cannot use desmopressin like we use in most other von Willebrand patients. They will need factor, although for the heavy menstrual bleeding you can use hormones or tranexamic acid – there are some other options for that,” she said in an interview.

She also noted that type 3 von Willebrand disease can be highly variable. For patients with especially frequent joint bleeding, her center recommends prophylaxis.

“Prophylaxis can be very burdensome for patients. You’re talking about IV therapy several times a week, but it’s very helpful for the joint bleeds. Episodic prophylaxis can be very helpful for heavy menstrual bleeding, and we actually have type 2, type 3, and some type 1 patients with bad enough nose bleeds that they end up on prophylaxis,” she said.

Patients with gastrointestinal bleeding are the most challenging to care for, she noted.

“You can put them on factor prophylaxis, but even that isn’t always enough to help some adults with bad GI bleeding, and we’re investigating other options for that,” she said.

Dr. Eikenboom disclosed research support from CSL Behring and honoraria (directed to his institution) for educational activities sponsored by Roche and Celgene. Dr. Flood reported having no conflicts of interest to disclose.

Type 3 von Willebrand disease (VWD) is rare, but this form of the disease is associated with severe bleeding, particularly in muscles and joints, a bleeding disorders expert said.

“There’s a virtually complete deficiency in von Willebrand factor [in type 3 disease], so usually it’s defined as below 5 or in some studies below 3 IU/dL, but also due to the very low levels of von Willebrand factor, there’s also a very low level of factor VIII,” said Jeroen Eikenboom, MD, PhD, from Leiden (the Netherlands) University Medical Center.

“The inheritance pattern is autosomal recessive, and the prevalence is about 1 in a million,” he said during the annual congress of the European Association for Haemophilia and Allied Disorders.

Erik Adolf von Willenbrand, MD, PhD, first described this form of VWD in a family from the Åland Islands, an autonomous region of Finland. The disease, later discovered to be caused in this family by a cytosine deletion in exon 18 of the von Willebrand factor (VWF) gene, was associated with fatal bleeding events in several family members.

“As VWF is the carrier protein of factor VIII, the very low VWF level leads to a strongly reduced factor VIII level, comparable to the levels seen in mild to moderate hemophilia A. As a consequence, VWD type 3 has the combined characteristics of a primary as well as a secondary hemostasis defect,” Dr. Eikenboom explained in an abstract accompanying his talk.

Compared with VWD type 1 or 2, type 3 VWD is associated with bleeding episodes more commonly seen in patients with hemophilia A, notably mucocutaneous bleeding, bleeding after trauma or during surgery, and bleeding into joints and/or muscles.
 

Treatment

The goals of treatment for patients with type 3 VWD are to correct the dual hemostasis defects of impaired platelet adhesion because of low VWF levels, and the intrinsic coagulation defect because of levels of factor VIII.

Desmopressin is not effective in type 3 VWD, Dr. Eikenboom said, so treatment requires the use of either plasma-derived VWF, with or without factor VIII, or recombinant VWF.

In the United States, the only standalone VWF concentrate approved by the Food and Drug Administration is a recombinant product (Vonvendi), Three other human plasma–derived concentrates containing both VWF and factor VIII are also licensed (Alpanate, Humate-P, Wilate).

Clinicians prescribing the combined factor concentrates need to be aware of differences in pharmacokinetics between the products.

For example, following infusion of Wilate, which has equal amounts of von Willebrand factor and factor VIII, there is an increase in circulation of both von Willebrand factor and factor VIII and a similar decline in each factor over time.

In contrast, following an infusion of Humate-P, which contains lower levels of factor VIII, “interestingly, you see a secondary rise of factor VIII in Humate-P–infused patients, whereas the secondary rise is not visible in the Wilate patients,” he said.

Approximately 22% of patients with type 3 VWD also receive prophylaxis with VWF concentrate, which has been shown to decrease the median annualized bleeding rate from 25% to 6.1%.

Dr. Eikenboom cautioned that 5%-10% of patients with type 3 VWD may develop allo-antibodies against VWF concentrates, which can complicate treatment and carries risk of anaphylactic shock.

“It’s also been mentioned in literature that there may be an association with partial or complete von Willebrand factor gene deletions or nonsense mutations and the development of allo-antibodies,” he said.
 

Prophylaxis burdensome but helpful

Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee, who specializes in the treatment of patients with von Willebrand disease, follows a number of both girls and boys with type 3 VWD.

“Those are the people who will have bleeding into their joints, and for the girls, worse periods than some of those with other types of von Willebrand disease, and it is true that if you want to stop their bleeding, you cannot use desmopressin like we use in most other von Willebrand patients. They will need factor, although for the heavy menstrual bleeding you can use hormones or tranexamic acid – there are some other options for that,” she said in an interview.

She also noted that type 3 von Willebrand disease can be highly variable. For patients with especially frequent joint bleeding, her center recommends prophylaxis.

“Prophylaxis can be very burdensome for patients. You’re talking about IV therapy several times a week, but it’s very helpful for the joint bleeds. Episodic prophylaxis can be very helpful for heavy menstrual bleeding, and we actually have type 2, type 3, and some type 1 patients with bad enough nose bleeds that they end up on prophylaxis,” she said.

Patients with gastrointestinal bleeding are the most challenging to care for, she noted.

“You can put them on factor prophylaxis, but even that isn’t always enough to help some adults with bad GI bleeding, and we’re investigating other options for that,” she said.

Dr. Eikenboom disclosed research support from CSL Behring and honoraria (directed to his institution) for educational activities sponsored by Roche and Celgene. Dr. Flood reported having no conflicts of interest to disclose.

Type 3 von Willebrand disease (VWD) is rare, but this form of the disease is associated with severe bleeding, particularly in muscles and joints, a bleeding disorders expert said.

“There’s a virtually complete deficiency in von Willebrand factor [in type 3 disease], so usually it’s defined as below 5 or in some studies below 3 IU/dL, but also due to the very low levels of von Willebrand factor, there’s also a very low level of factor VIII,” said Jeroen Eikenboom, MD, PhD, from Leiden (the Netherlands) University Medical Center.

“The inheritance pattern is autosomal recessive, and the prevalence is about 1 in a million,” he said during the annual congress of the European Association for Haemophilia and Allied Disorders.

Erik Adolf von Willenbrand, MD, PhD, first described this form of VWD in a family from the Åland Islands, an autonomous region of Finland. The disease, later discovered to be caused in this family by a cytosine deletion in exon 18 of the von Willebrand factor (VWF) gene, was associated with fatal bleeding events in several family members.

“As VWF is the carrier protein of factor VIII, the very low VWF level leads to a strongly reduced factor VIII level, comparable to the levels seen in mild to moderate hemophilia A. As a consequence, VWD type 3 has the combined characteristics of a primary as well as a secondary hemostasis defect,” Dr. Eikenboom explained in an abstract accompanying his talk.

Compared with VWD type 1 or 2, type 3 VWD is associated with bleeding episodes more commonly seen in patients with hemophilia A, notably mucocutaneous bleeding, bleeding after trauma or during surgery, and bleeding into joints and/or muscles.
 

Treatment

The goals of treatment for patients with type 3 VWD are to correct the dual hemostasis defects of impaired platelet adhesion because of low VWF levels, and the intrinsic coagulation defect because of levels of factor VIII.

Desmopressin is not effective in type 3 VWD, Dr. Eikenboom said, so treatment requires the use of either plasma-derived VWF, with or without factor VIII, or recombinant VWF.

In the United States, the only standalone VWF concentrate approved by the Food and Drug Administration is a recombinant product (Vonvendi), Three other human plasma–derived concentrates containing both VWF and factor VIII are also licensed (Alpanate, Humate-P, Wilate).

Clinicians prescribing the combined factor concentrates need to be aware of differences in pharmacokinetics between the products.

For example, following infusion of Wilate, which has equal amounts of von Willebrand factor and factor VIII, there is an increase in circulation of both von Willebrand factor and factor VIII and a similar decline in each factor over time.

In contrast, following an infusion of Humate-P, which contains lower levels of factor VIII, “interestingly, you see a secondary rise of factor VIII in Humate-P–infused patients, whereas the secondary rise is not visible in the Wilate patients,” he said.

Approximately 22% of patients with type 3 VWD also receive prophylaxis with VWF concentrate, which has been shown to decrease the median annualized bleeding rate from 25% to 6.1%.

Dr. Eikenboom cautioned that 5%-10% of patients with type 3 VWD may develop allo-antibodies against VWF concentrates, which can complicate treatment and carries risk of anaphylactic shock.

“It’s also been mentioned in literature that there may be an association with partial or complete von Willebrand factor gene deletions or nonsense mutations and the development of allo-antibodies,” he said.
 

Prophylaxis burdensome but helpful

Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee, who specializes in the treatment of patients with von Willebrand disease, follows a number of both girls and boys with type 3 VWD.

“Those are the people who will have bleeding into their joints, and for the girls, worse periods than some of those with other types of von Willebrand disease, and it is true that if you want to stop their bleeding, you cannot use desmopressin like we use in most other von Willebrand patients. They will need factor, although for the heavy menstrual bleeding you can use hormones or tranexamic acid – there are some other options for that,” she said in an interview.

She also noted that type 3 von Willebrand disease can be highly variable. For patients with especially frequent joint bleeding, her center recommends prophylaxis.

“Prophylaxis can be very burdensome for patients. You’re talking about IV therapy several times a week, but it’s very helpful for the joint bleeds. Episodic prophylaxis can be very helpful for heavy menstrual bleeding, and we actually have type 2, type 3, and some type 1 patients with bad enough nose bleeds that they end up on prophylaxis,” she said.

Patients with gastrointestinal bleeding are the most challenging to care for, she noted.

“You can put them on factor prophylaxis, but even that isn’t always enough to help some adults with bad GI bleeding, and we’re investigating other options for that,” she said.

Dr. Eikenboom disclosed research support from CSL Behring and honoraria (directed to his institution) for educational activities sponsored by Roche and Celgene. Dr. Flood reported having no conflicts of interest to disclose.

Diagnosis of bleeding disorders in girls and women can lag behind diagnosis in boys and men by more than a decade, meaning needless delays in treatment and poor quality of life for many with hemophilia or related conditions.

“There is increasing awareness about issues faced by women and girls with inherited bleeding disorders, but disparities still exist both in both access to diagnosis and treatment,” said Roseline D’Oiron, MD, from Hôpital Bicêtre in Paris.

“Diagnosis, when it is made, is often made late, particularly in women. Indeed, a recent study from the European Hemophilia Consortium including more than 700 women with bleeding disorders showed that the median age at diagnosis was 16 years old,” she said during the annual congress of the European Association for Haemophilia and Allied Disorders.

She said that delayed diagnosis of bleeding disorders in women and girls may be caused by a lack of knowledge by patients, families, and general practitioners about family history of bleeding disorders, abnormal bleeding events, and heavy menstrual bleeding. In addition, despite the frequency and severity of heavy bleeding events, patients, their families, and caregivers may underestimate the effect on the patient’s quality of life.
 

Disparities documented

Dr. D’Oiron pointed to several studies showing clear sex-based disparities in time to diagnosis. For example, a study published in Haemophilia showed that in 22 girls with hemophilia A or hemophilia B, the diagnosis of severe hemophilia was delayed by a median of 6.5 months compared with the diagnosis in boys, and a diagnosis of moderate hemophilia in girls was delayed by a median of 39 months.

In a second, single-center study comparing 44 women and girls with mild hemophilia (factor VIII or factor XI levels from 5 to 50 IU/dL) with 77 men and boys with mild hemophilia, the mean age at diagnosis was 31.63 years versus 19.18 years, respectively – a delay of 12.45 years.

A third study comparing 442 girls/women and 442 boys/men with mild hemophilia in France showed a difference of 6.07 years in diagnosis: the median age for girls/women at diagnosis was 16.91 years versus10.84 years for boys/men.
 

Why it matters

Dr. D’Oiron described the case of a patient named Clare, who first experienced, at age 8, 12 hours of bleeding following a dental procedure. At age 12.5, she began having heavy menstrual bleeding, causing her to miss school for a few days each month, to be feel tired, and have poor-quality sleep.

Despite repeated bleeding episodes, severe anemia, and iron deficiency, her hemophilia was not suspected until after her 16th birthday, and a definitive diagnosis of hemophilia in both Clare and her mother was finally made when Clare was past 17, when a nonsense variant factor in F8, the gene encoding for factor VIII, was detected.

“For Clare, it took more the 8 years after the first bleeding symptoms, and nearly 4 years after presenting with heavy menstrual bleeding to recognize that she had a bleeding problem,” she said.

In total, Clare had about 450 days of heavy menstrual bleeding, causing her to miss an estimated 140 days of school because of the delayed diagnosis and treatment.

“In my view, this is the main argument why it is urgent for these patients to achieve diagnosis early: this is to reduce the duration [of] a very poor quality of life,” Dr. D’Oiron said.
 

Barriers to diagnosis

Patients and families have reported difficulty distinguishing normal bleeding from abnormal symptoms, and girls may be reluctant to discuss their symptoms with their family or peers. In addition, primary care practitioners may not recognize the severity of the symptoms and therefore may not refer patients to hematologists for further workup.

These findings emphasize the need for improved tools to help patients differentiate between normal and abnormal bleeding, using symptom recognition–based language tools that can lead to early testing and application of accurate diagnostic tools, she said.

Standardization of definitions can help to improve screening and diagnosis, Dr. D’Oiron said, pointing to a recent study in Blood Advances proposing definitions for future research in von Willebrand disease.

For example, the authors of that study proposed a definition of heavy menstrual bleeding to include any of the following:

• Bleeding lasting 8 or more days
• Bleeding that consistently soaks through one or more sanitary protections every 2 hours on multiple days
• Requires use of more than one sanitary protection item at a time
• Requires changing sanitary protection during the night
• Is associated with repeat passing of blood clots
• Has a Pictorial Blood Assessment Chart score greater than 100.
•  

Problem and solutions

Answering the question posed in the title of her talk, Dr. D’Oiron said: “Yes, we do have a problem with the diagnosis of bleeding disorders in women and girls, but we also have solutions.”

The solutions include family and patient outreach efforts; communication to improve awareness; inclusion of general practitioners in the circle of care; and early screening, diagnosis, and treatment.

A bleeding disorders specialist who was not involved in the study said that Dr. D’Oiron’s report closely reflects what she sees in the clinic.

“I do pediatrics, and usually what happens is that I see a teenager with heavy menstrual bleeding and we take her history, and we find out that Mom and multiple female family members have had horrible menstrual bleeding, possibly many of whom have had hysterectomies for it, and then diagnosing the parents and other family members after diagnosing the girl that we’re seeing” said Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee.

“It is unfortunately a very real thing,” she added.

Reasons for the delay likely include lack of awareness of bleeding disorders.

“If you present to a hematologist, we think about bleeding disorders, but if you present to a primary care physician, they don’t always have that on their radar,” she said.

Additionally, a girl from a family with a history of heavy menstrual bleeding may just assume that what she is experiencing is “normal,” despite the serious affect it has on her quality of life, Dr. Flood said.

Dr. D’Oiron’s research is supported by her institution, the French Hemophilia Association, FranceCoag and Mhemon, the European Hemophilia Consortium, and the World Federation of Hemophilia. She reported advisory board or invited speaker activities for multiple companies. Dr. Flood reported having no conflicts of interest to disclose.

Diagnosis of bleeding disorders in girls and women can lag behind diagnosis in boys and men by more than a decade, meaning needless delays in treatment and poor quality of life for many with hemophilia or related conditions.

“There is increasing awareness about issues faced by women and girls with inherited bleeding disorders, but disparities still exist both in both access to diagnosis and treatment,” said Roseline D’Oiron, MD, from Hôpital Bicêtre in Paris.

“Diagnosis, when it is made, is often made late, particularly in women. Indeed, a recent study from the European Hemophilia Consortium including more than 700 women with bleeding disorders showed that the median age at diagnosis was 16 years old,” she said during the annual congress of the European Association for Haemophilia and Allied Disorders.

She said that delayed diagnosis of bleeding disorders in women and girls may be caused by a lack of knowledge by patients, families, and general practitioners about family history of bleeding disorders, abnormal bleeding events, and heavy menstrual bleeding. In addition, despite the frequency and severity of heavy bleeding events, patients, their families, and caregivers may underestimate the effect on the patient’s quality of life.
 

Disparities documented

Dr. D’Oiron pointed to several studies showing clear sex-based disparities in time to diagnosis. For example, a study published in Haemophilia showed that in 22 girls with hemophilia A or hemophilia B, the diagnosis of severe hemophilia was delayed by a median of 6.5 months compared with the diagnosis in boys, and a diagnosis of moderate hemophilia in girls was delayed by a median of 39 months.

In a second, single-center study comparing 44 women and girls with mild hemophilia (factor VIII or factor XI levels from 5 to 50 IU/dL) with 77 men and boys with mild hemophilia, the mean age at diagnosis was 31.63 years versus 19.18 years, respectively – a delay of 12.45 years.

A third study comparing 442 girls/women and 442 boys/men with mild hemophilia in France showed a difference of 6.07 years in diagnosis: the median age for girls/women at diagnosis was 16.91 years versus10.84 years for boys/men.
 

Why it matters

Dr. D’Oiron described the case of a patient named Clare, who first experienced, at age 8, 12 hours of bleeding following a dental procedure. At age 12.5, she began having heavy menstrual bleeding, causing her to miss school for a few days each month, to be feel tired, and have poor-quality sleep.

Despite repeated bleeding episodes, severe anemia, and iron deficiency, her hemophilia was not suspected until after her 16th birthday, and a definitive diagnosis of hemophilia in both Clare and her mother was finally made when Clare was past 17, when a nonsense variant factor in F8, the gene encoding for factor VIII, was detected.

“For Clare, it took more the 8 years after the first bleeding symptoms, and nearly 4 years after presenting with heavy menstrual bleeding to recognize that she had a bleeding problem,” she said.

In total, Clare had about 450 days of heavy menstrual bleeding, causing her to miss an estimated 140 days of school because of the delayed diagnosis and treatment.

“In my view, this is the main argument why it is urgent for these patients to achieve diagnosis early: this is to reduce the duration [of] a very poor quality of life,” Dr. D’Oiron said.
 

Barriers to diagnosis

Patients and families have reported difficulty distinguishing normal bleeding from abnormal symptoms, and girls may be reluctant to discuss their symptoms with their family or peers. In addition, primary care practitioners may not recognize the severity of the symptoms and therefore may not refer patients to hematologists for further workup.

These findings emphasize the need for improved tools to help patients differentiate between normal and abnormal bleeding, using symptom recognition–based language tools that can lead to early testing and application of accurate diagnostic tools, she said.

Standardization of definitions can help to improve screening and diagnosis, Dr. D’Oiron said, pointing to a recent study in Blood Advances proposing definitions for future research in von Willebrand disease.

For example, the authors of that study proposed a definition of heavy menstrual bleeding to include any of the following:

• Bleeding lasting 8 or more days
• Bleeding that consistently soaks through one or more sanitary protections every 2 hours on multiple days
• Requires use of more than one sanitary protection item at a time
• Requires changing sanitary protection during the night
• Is associated with repeat passing of blood clots
• Has a Pictorial Blood Assessment Chart score greater than 100.
•  

Problem and solutions

Answering the question posed in the title of her talk, Dr. D’Oiron said: “Yes, we do have a problem with the diagnosis of bleeding disorders in women and girls, but we also have solutions.”

The solutions include family and patient outreach efforts; communication to improve awareness; inclusion of general practitioners in the circle of care; and early screening, diagnosis, and treatment.

A bleeding disorders specialist who was not involved in the study said that Dr. D’Oiron’s report closely reflects what she sees in the clinic.

“I do pediatrics, and usually what happens is that I see a teenager with heavy menstrual bleeding and we take her history, and we find out that Mom and multiple female family members have had horrible menstrual bleeding, possibly many of whom have had hysterectomies for it, and then diagnosing the parents and other family members after diagnosing the girl that we’re seeing” said Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee.

“It is unfortunately a very real thing,” she added.

Reasons for the delay likely include lack of awareness of bleeding disorders.

“If you present to a hematologist, we think about bleeding disorders, but if you present to a primary care physician, they don’t always have that on their radar,” she said.

Additionally, a girl from a family with a history of heavy menstrual bleeding may just assume that what she is experiencing is “normal,” despite the serious affect it has on her quality of life, Dr. Flood said.

Dr. D’Oiron’s research is supported by her institution, the French Hemophilia Association, FranceCoag and Mhemon, the European Hemophilia Consortium, and the World Federation of Hemophilia. She reported advisory board or invited speaker activities for multiple companies. Dr. Flood reported having no conflicts of interest to disclose.

Diagnosis of bleeding disorders in girls and women can lag behind diagnosis in boys and men by more than a decade, meaning needless delays in treatment and poor quality of life for many with hemophilia or related conditions.

“There is increasing awareness about issues faced by women and girls with inherited bleeding disorders, but disparities still exist both in both access to diagnosis and treatment,” said Roseline D’Oiron, MD, from Hôpital Bicêtre in Paris.

“Diagnosis, when it is made, is often made late, particularly in women. Indeed, a recent study from the European Hemophilia Consortium including more than 700 women with bleeding disorders showed that the median age at diagnosis was 16 years old,” she said during the annual congress of the European Association for Haemophilia and Allied Disorders.

She said that delayed diagnosis of bleeding disorders in women and girls may be caused by a lack of knowledge by patients, families, and general practitioners about family history of bleeding disorders, abnormal bleeding events, and heavy menstrual bleeding. In addition, despite the frequency and severity of heavy bleeding events, patients, their families, and caregivers may underestimate the effect on the patient’s quality of life.
 

Disparities documented

Dr. D’Oiron pointed to several studies showing clear sex-based disparities in time to diagnosis. For example, a study published in Haemophilia showed that in 22 girls with hemophilia A or hemophilia B, the diagnosis of severe hemophilia was delayed by a median of 6.5 months compared with the diagnosis in boys, and a diagnosis of moderate hemophilia in girls was delayed by a median of 39 months.

In a second, single-center study comparing 44 women and girls with mild hemophilia (factor VIII or factor XI levels from 5 to 50 IU/dL) with 77 men and boys with mild hemophilia, the mean age at diagnosis was 31.63 years versus 19.18 years, respectively – a delay of 12.45 years.

A third study comparing 442 girls/women and 442 boys/men with mild hemophilia in France showed a difference of 6.07 years in diagnosis: the median age for girls/women at diagnosis was 16.91 years versus10.84 years for boys/men.
 

Why it matters

Dr. D’Oiron described the case of a patient named Clare, who first experienced, at age 8, 12 hours of bleeding following a dental procedure. At age 12.5, she began having heavy menstrual bleeding, causing her to miss school for a few days each month, to be feel tired, and have poor-quality sleep.

Despite repeated bleeding episodes, severe anemia, and iron deficiency, her hemophilia was not suspected until after her 16th birthday, and a definitive diagnosis of hemophilia in both Clare and her mother was finally made when Clare was past 17, when a nonsense variant factor in F8, the gene encoding for factor VIII, was detected.

“For Clare, it took more the 8 years after the first bleeding symptoms, and nearly 4 years after presenting with heavy menstrual bleeding to recognize that she had a bleeding problem,” she said.

In total, Clare had about 450 days of heavy menstrual bleeding, causing her to miss an estimated 140 days of school because of the delayed diagnosis and treatment.

“In my view, this is the main argument why it is urgent for these patients to achieve diagnosis early: this is to reduce the duration [of] a very poor quality of life,” Dr. D’Oiron said.
 

Barriers to diagnosis

Patients and families have reported difficulty distinguishing normal bleeding from abnormal symptoms, and girls may be reluctant to discuss their symptoms with their family or peers. In addition, primary care practitioners may not recognize the severity of the symptoms and therefore may not refer patients to hematologists for further workup.

These findings emphasize the need for improved tools to help patients differentiate between normal and abnormal bleeding, using symptom recognition–based language tools that can lead to early testing and application of accurate diagnostic tools, she said.

Standardization of definitions can help to improve screening and diagnosis, Dr. D’Oiron said, pointing to a recent study in Blood Advances proposing definitions for future research in von Willebrand disease.

For example, the authors of that study proposed a definition of heavy menstrual bleeding to include any of the following:

• Bleeding lasting 8 or more days
• Bleeding that consistently soaks through one or more sanitary protections every 2 hours on multiple days
• Requires use of more than one sanitary protection item at a time
• Requires changing sanitary protection during the night
• Is associated with repeat passing of blood clots
• Has a Pictorial Blood Assessment Chart score greater than 100.
•  

Problem and solutions

Answering the question posed in the title of her talk, Dr. D’Oiron said: “Yes, we do have a problem with the diagnosis of bleeding disorders in women and girls, but we also have solutions.”

The solutions include family and patient outreach efforts; communication to improve awareness; inclusion of general practitioners in the circle of care; and early screening, diagnosis, and treatment.

A bleeding disorders specialist who was not involved in the study said that Dr. D’Oiron’s report closely reflects what she sees in the clinic.

“I do pediatrics, and usually what happens is that I see a teenager with heavy menstrual bleeding and we take her history, and we find out that Mom and multiple female family members have had horrible menstrual bleeding, possibly many of whom have had hysterectomies for it, and then diagnosing the parents and other family members after diagnosing the girl that we’re seeing” said Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee.

“It is unfortunately a very real thing,” she added.

Reasons for the delay likely include lack of awareness of bleeding disorders.

“If you present to a hematologist, we think about bleeding disorders, but if you present to a primary care physician, they don’t always have that on their radar,” she said.

Additionally, a girl from a family with a history of heavy menstrual bleeding may just assume that what she is experiencing is “normal,” despite the serious affect it has on her quality of life, Dr. Flood said.

Dr. D’Oiron’s research is supported by her institution, the French Hemophilia Association, FranceCoag and Mhemon, the European Hemophilia Consortium, and the World Federation of Hemophilia. She reported advisory board or invited speaker activities for multiple companies. Dr. Flood reported having no conflicts of interest to disclose.

Despite their similar functions, each current and emerging therapy for treating hemophilia has a unique safety profile, and each needs to be weighed apart from agents both within and outside its pharmacologic class, a hemophilia specialist said.

“My view is that each new molecule coming to the hemophilia space, including variant factor molecules, needs to be scrutinized separately, without class assumptions or extrapolations, and it’s clear that thrombosis risk has become a priority safety consideration,” said Dan Hart, MBChB, MRCP, FRCPath, PhD, from Barts and the London School of Medicine and Dentistry.

He reviewed the comparative safety of standard and novel therapies for hemophilia at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

Factor inhibitors

Inhibitors occur in both hemophilia A and hemophilia B, and are primarily seen in patients with childhood exposure to factor concentrates. Inhibitors, which include anti–factor VIII and factor IX alloantibodies, are more common among patients with severe hemophilia and those with more disruptive factor VIII and factor IX mutations.

“There can be transient vs. persistent inhibitors, and arguably the more you look, the more you find, but clinically we never miss high-titer inhibitors that have a big impact on individuals and the subsequent decisions about management,” he said.
 

Hamster vs. human

It’s currently unclear whether there is an immunologic advantage for previously untreated patients to be started on factor VIII concentrates derived from recombinant human cells lines, or from products derived from Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines, Dr. Hart said.

“We need to ensure that we’re not selective about comparator choice for new products in the absence of head-to-head studies,” he said.
 

Route of administration matters

Inhibitors appear to be a more common occurrence among patients who received factor concentrates subcutaneously, compared with intravenously, Dr. Hart noted, pointing to a 2011 study indicating a background annual risk of 5 cases of inhibitor development per 1,000 treatment years in previously treated patients who received intravenous therapy (Blood. 2011 Jun 9;117[23]:6367-70).

In contrast, in a phase 1 trial of subcutaneous turoctocog alfa pegol, 5 out of 26 patients had detectable N8-GP–binding antibodies after 42-91 exposure days. Of these patients, one developed an inhibitor to factor VIII, and anti–N8-GP antibody appearance was associated with a decline in factor VIII plasma activity in four of the five patients. In addition, five patients reported a total of nine bleeding episodes requiring treatment during prophylaxis. As a result of this trial, further clinical development of the subcutaneous version was suspended. (J Thromb Haemost. 2020 Feb;18[2]:341-51).

Other subcutaneously administered factors are currently in development, Dr. Hart noted.
 

Nonfactor inhibitors?

“The nonfactor agents do have the risk of generating antibodies: Monoclonal antibodies outside the hemophilia setting provoke antidrug antibodies,” he said.

Although there is no consensus regarding which assay can best monitor antidrug antibodies (ADA), enzyme-linked immunosorbent assay (ELISA) can detect neutralizing antibodies and other antibodies.

In the hemophilia setting, surrogate markers for loss of drug efficacy include longer activated partial thromboplastin time (ATTP) or a drop in serum drug levels. Worsening bleeding phenotype can also be a marker for loss of efficacy, albeit an imperfect one.

Emicizumab (Hemlibara), the first nonfactor monoclonal agent to make it to market, has the largest dataset available, and evidence suggests a rate of neutralizing antibodies with this agent of less than 1% in the HAVEN clinical trial series, but 5.2% in the single-arm STASEY trial.

“We shouldn’t assume that other biophenotypics will have a similar ADA rate, and this needs to be evaluated for each molecule, as it will need to be for other monoclonals” such as anti–tissue factor pathway (TFPI) antibodies, Dr. Hart emphasized.
 

Pegylation

Pegylated compounds include polyethylene glycol, an inert polymer, covalently bound to the therapeutic protein to extend its half-life, and theoretically, reduce immunogenicity.

Many patients may already have exposure to pegylated products in the form of peginterferon to treat hepatitis C, consumer products such as toothpaste, cough medicine, and cosmetics, and, more recently, in vaccines against COVID-19.

Safety considerations with pegylated agents in hemophilia include concerns about accumulation of polyethylene glycol (PEG), although “some of the preclinical models looking at excretion of PEG are difficult to interpret in my view, and people debate about whether studies are long enough, but it’s undoubtedly the case that toxicology dosing is order of magnitude higher than the routine dosing in hemophilia,” he said.

After more than 5 years of experience with pegylated products there is no clinical evidence of concern, although “it’s not clear, actually, what we’re looking for, whether it’s a clinical parameter, or imaging or histological parameter.”

Patients may also not have lifelong exposure to pegylated products, as it is unlikely that they will stay on the same product for decades, Dr. Hart said.
 

Thrombosis

As of June 30, 2020, more than 7,200 persons with hemophilia have received emicizumab, and there have been 23 reported thrombotic events, 19 of which occurred in the postmarketing period. Of the reported cases, six patients had a myocardial infarction, and all of these patients had at least one cardiovascular risk factor.

The antithrombin agent fitusiran was associated with one fatal thrombotic event in a phase 2, open-label extension trial, leading to a pause and resumption with mitigation protocols, but that trial has since been paused again because of additional, nonfatal thrombotic events.

Nonfatal thrombotic events have also occurred in clinical trials for the investigational anti-TFPI monoclonal antibodies BAY 1093884 and concizumab, but none have thus far been reported in phase 3 trial of marstacimab.

“We need renewed efforts for prospective reporting and independent review of all adverse events of all agents, old and new: This will need some guidance nationally and internationally, and I think the relevant trial [serious adverse events] need to be reported in peer review literature, and clinicaltrials.gov updated in a timely manner, regardless of whether that strategy was successful or unsuccessful,” Dr. Hart said.
 

Risk with longer-acting agents?

In the question and answer following his presentation, Christoph Königs, MD, PhD, from University Hospital Frankfurt, asked whether there was potential for increased thrombosis risk with second-generation extended half-life (EHL) molecules in clinical trials.

“As we edge towards normalization of hemostasis, clearly the other non–hemophilia dependent issues of thrombosis risk come into play,” Dr. Hart acknowledged. “I think it will be an inevitability that there will be events, and we need to understand what the denominators are – hence my pitch for there being a renewed effort to try and collate sufficient data that we can really define events happening with people treated with standard half-life [products] through into the novel agents,” he said.

Dr. Hart disclosed grant/research support and speaker bureau activities for Bayer, Octapharma, Takeda, and others. Dr. Königs has reported no relevant disclosures.

Despite their similar functions, each current and emerging therapy for treating hemophilia has a unique safety profile, and each needs to be weighed apart from agents both within and outside its pharmacologic class, a hemophilia specialist said.

“My view is that each new molecule coming to the hemophilia space, including variant factor molecules, needs to be scrutinized separately, without class assumptions or extrapolations, and it’s clear that thrombosis risk has become a priority safety consideration,” said Dan Hart, MBChB, MRCP, FRCPath, PhD, from Barts and the London School of Medicine and Dentistry.

He reviewed the comparative safety of standard and novel therapies for hemophilia at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

Factor inhibitors

Inhibitors occur in both hemophilia A and hemophilia B, and are primarily seen in patients with childhood exposure to factor concentrates. Inhibitors, which include anti–factor VIII and factor IX alloantibodies, are more common among patients with severe hemophilia and those with more disruptive factor VIII and factor IX mutations.

“There can be transient vs. persistent inhibitors, and arguably the more you look, the more you find, but clinically we never miss high-titer inhibitors that have a big impact on individuals and the subsequent decisions about management,” he said.
 

Hamster vs. human

It’s currently unclear whether there is an immunologic advantage for previously untreated patients to be started on factor VIII concentrates derived from recombinant human cells lines, or from products derived from Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines, Dr. Hart said.

“We need to ensure that we’re not selective about comparator choice for new products in the absence of head-to-head studies,” he said.
 

Route of administration matters

Inhibitors appear to be a more common occurrence among patients who received factor concentrates subcutaneously, compared with intravenously, Dr. Hart noted, pointing to a 2011 study indicating a background annual risk of 5 cases of inhibitor development per 1,000 treatment years in previously treated patients who received intravenous therapy (Blood. 2011 Jun 9;117[23]:6367-70).

In contrast, in a phase 1 trial of subcutaneous turoctocog alfa pegol, 5 out of 26 patients had detectable N8-GP–binding antibodies after 42-91 exposure days. Of these patients, one developed an inhibitor to factor VIII, and anti–N8-GP antibody appearance was associated with a decline in factor VIII plasma activity in four of the five patients. In addition, five patients reported a total of nine bleeding episodes requiring treatment during prophylaxis. As a result of this trial, further clinical development of the subcutaneous version was suspended. (J Thromb Haemost. 2020 Feb;18[2]:341-51).

Other subcutaneously administered factors are currently in development, Dr. Hart noted.
 

Nonfactor inhibitors?

“The nonfactor agents do have the risk of generating antibodies: Monoclonal antibodies outside the hemophilia setting provoke antidrug antibodies,” he said.

Although there is no consensus regarding which assay can best monitor antidrug antibodies (ADA), enzyme-linked immunosorbent assay (ELISA) can detect neutralizing antibodies and other antibodies.

In the hemophilia setting, surrogate markers for loss of drug efficacy include longer activated partial thromboplastin time (ATTP) or a drop in serum drug levels. Worsening bleeding phenotype can also be a marker for loss of efficacy, albeit an imperfect one.

Emicizumab (Hemlibara), the first nonfactor monoclonal agent to make it to market, has the largest dataset available, and evidence suggests a rate of neutralizing antibodies with this agent of less than 1% in the HAVEN clinical trial series, but 5.2% in the single-arm STASEY trial.

“We shouldn’t assume that other biophenotypics will have a similar ADA rate, and this needs to be evaluated for each molecule, as it will need to be for other monoclonals” such as anti–tissue factor pathway (TFPI) antibodies, Dr. Hart emphasized.
 

Pegylation

Pegylated compounds include polyethylene glycol, an inert polymer, covalently bound to the therapeutic protein to extend its half-life, and theoretically, reduce immunogenicity.

Many patients may already have exposure to pegylated products in the form of peginterferon to treat hepatitis C, consumer products such as toothpaste, cough medicine, and cosmetics, and, more recently, in vaccines against COVID-19.

Safety considerations with pegylated agents in hemophilia include concerns about accumulation of polyethylene glycol (PEG), although “some of the preclinical models looking at excretion of PEG are difficult to interpret in my view, and people debate about whether studies are long enough, but it’s undoubtedly the case that toxicology dosing is order of magnitude higher than the routine dosing in hemophilia,” he said.

After more than 5 years of experience with pegylated products there is no clinical evidence of concern, although “it’s not clear, actually, what we’re looking for, whether it’s a clinical parameter, or imaging or histological parameter.”

Patients may also not have lifelong exposure to pegylated products, as it is unlikely that they will stay on the same product for decades, Dr. Hart said.
 

Thrombosis

As of June 30, 2020, more than 7,200 persons with hemophilia have received emicizumab, and there have been 23 reported thrombotic events, 19 of which occurred in the postmarketing period. Of the reported cases, six patients had a myocardial infarction, and all of these patients had at least one cardiovascular risk factor.

The antithrombin agent fitusiran was associated with one fatal thrombotic event in a phase 2, open-label extension trial, leading to a pause and resumption with mitigation protocols, but that trial has since been paused again because of additional, nonfatal thrombotic events.

Nonfatal thrombotic events have also occurred in clinical trials for the investigational anti-TFPI monoclonal antibodies BAY 1093884 and concizumab, but none have thus far been reported in phase 3 trial of marstacimab.

“We need renewed efforts for prospective reporting and independent review of all adverse events of all agents, old and new: This will need some guidance nationally and internationally, and I think the relevant trial [serious adverse events] need to be reported in peer review literature, and clinicaltrials.gov updated in a timely manner, regardless of whether that strategy was successful or unsuccessful,” Dr. Hart said.
 

Risk with longer-acting agents?

In the question and answer following his presentation, Christoph Königs, MD, PhD, from University Hospital Frankfurt, asked whether there was potential for increased thrombosis risk with second-generation extended half-life (EHL) molecules in clinical trials.

“As we edge towards normalization of hemostasis, clearly the other non–hemophilia dependent issues of thrombosis risk come into play,” Dr. Hart acknowledged. “I think it will be an inevitability that there will be events, and we need to understand what the denominators are – hence my pitch for there being a renewed effort to try and collate sufficient data that we can really define events happening with people treated with standard half-life [products] through into the novel agents,” he said.

Dr. Hart disclosed grant/research support and speaker bureau activities for Bayer, Octapharma, Takeda, and others. Dr. Königs has reported no relevant disclosures.

Despite their similar functions, each current and emerging therapy for treating hemophilia has a unique safety profile, and each needs to be weighed apart from agents both within and outside its pharmacologic class, a hemophilia specialist said.

“My view is that each new molecule coming to the hemophilia space, including variant factor molecules, needs to be scrutinized separately, without class assumptions or extrapolations, and it’s clear that thrombosis risk has become a priority safety consideration,” said Dan Hart, MBChB, MRCP, FRCPath, PhD, from Barts and the London School of Medicine and Dentistry.

He reviewed the comparative safety of standard and novel therapies for hemophilia at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

Factor inhibitors

Inhibitors occur in both hemophilia A and hemophilia B, and are primarily seen in patients with childhood exposure to factor concentrates. Inhibitors, which include anti–factor VIII and factor IX alloantibodies, are more common among patients with severe hemophilia and those with more disruptive factor VIII and factor IX mutations.

“There can be transient vs. persistent inhibitors, and arguably the more you look, the more you find, but clinically we never miss high-titer inhibitors that have a big impact on individuals and the subsequent decisions about management,” he said.
 

Hamster vs. human

It’s currently unclear whether there is an immunologic advantage for previously untreated patients to be started on factor VIII concentrates derived from recombinant human cells lines, or from products derived from Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines, Dr. Hart said.

“We need to ensure that we’re not selective about comparator choice for new products in the absence of head-to-head studies,” he said.
 

Route of administration matters

Inhibitors appear to be a more common occurrence among patients who received factor concentrates subcutaneously, compared with intravenously, Dr. Hart noted, pointing to a 2011 study indicating a background annual risk of 5 cases of inhibitor development per 1,000 treatment years in previously treated patients who received intravenous therapy (Blood. 2011 Jun 9;117[23]:6367-70).

In contrast, in a phase 1 trial of subcutaneous turoctocog alfa pegol, 5 out of 26 patients had detectable N8-GP–binding antibodies after 42-91 exposure days. Of these patients, one developed an inhibitor to factor VIII, and anti–N8-GP antibody appearance was associated with a decline in factor VIII plasma activity in four of the five patients. In addition, five patients reported a total of nine bleeding episodes requiring treatment during prophylaxis. As a result of this trial, further clinical development of the subcutaneous version was suspended. (J Thromb Haemost. 2020 Feb;18[2]:341-51).

Other subcutaneously administered factors are currently in development, Dr. Hart noted.
 

Nonfactor inhibitors?

“The nonfactor agents do have the risk of generating antibodies: Monoclonal antibodies outside the hemophilia setting provoke antidrug antibodies,” he said.

Although there is no consensus regarding which assay can best monitor antidrug antibodies (ADA), enzyme-linked immunosorbent assay (ELISA) can detect neutralizing antibodies and other antibodies.

In the hemophilia setting, surrogate markers for loss of drug efficacy include longer activated partial thromboplastin time (ATTP) or a drop in serum drug levels. Worsening bleeding phenotype can also be a marker for loss of efficacy, albeit an imperfect one.

Emicizumab (Hemlibara), the first nonfactor monoclonal agent to make it to market, has the largest dataset available, and evidence suggests a rate of neutralizing antibodies with this agent of less than 1% in the HAVEN clinical trial series, but 5.2% in the single-arm STASEY trial.

“We shouldn’t assume that other biophenotypics will have a similar ADA rate, and this needs to be evaluated for each molecule, as it will need to be for other monoclonals” such as anti–tissue factor pathway (TFPI) antibodies, Dr. Hart emphasized.
 

Pegylation

Pegylated compounds include polyethylene glycol, an inert polymer, covalently bound to the therapeutic protein to extend its half-life, and theoretically, reduce immunogenicity.

Many patients may already have exposure to pegylated products in the form of peginterferon to treat hepatitis C, consumer products such as toothpaste, cough medicine, and cosmetics, and, more recently, in vaccines against COVID-19.

Safety considerations with pegylated agents in hemophilia include concerns about accumulation of polyethylene glycol (PEG), although “some of the preclinical models looking at excretion of PEG are difficult to interpret in my view, and people debate about whether studies are long enough, but it’s undoubtedly the case that toxicology dosing is order of magnitude higher than the routine dosing in hemophilia,” he said.

After more than 5 years of experience with pegylated products there is no clinical evidence of concern, although “it’s not clear, actually, what we’re looking for, whether it’s a clinical parameter, or imaging or histological parameter.”

Patients may also not have lifelong exposure to pegylated products, as it is unlikely that they will stay on the same product for decades, Dr. Hart said.
 

Thrombosis

As of June 30, 2020, more than 7,200 persons with hemophilia have received emicizumab, and there have been 23 reported thrombotic events, 19 of which occurred in the postmarketing period. Of the reported cases, six patients had a myocardial infarction, and all of these patients had at least one cardiovascular risk factor.

The antithrombin agent fitusiran was associated with one fatal thrombotic event in a phase 2, open-label extension trial, leading to a pause and resumption with mitigation protocols, but that trial has since been paused again because of additional, nonfatal thrombotic events.

Nonfatal thrombotic events have also occurred in clinical trials for the investigational anti-TFPI monoclonal antibodies BAY 1093884 and concizumab, but none have thus far been reported in phase 3 trial of marstacimab.

“We need renewed efforts for prospective reporting and independent review of all adverse events of all agents, old and new: This will need some guidance nationally and internationally, and I think the relevant trial [serious adverse events] need to be reported in peer review literature, and clinicaltrials.gov updated in a timely manner, regardless of whether that strategy was successful or unsuccessful,” Dr. Hart said.
 

Risk with longer-acting agents?

In the question and answer following his presentation, Christoph Königs, MD, PhD, from University Hospital Frankfurt, asked whether there was potential for increased thrombosis risk with second-generation extended half-life (EHL) molecules in clinical trials.

“As we edge towards normalization of hemostasis, clearly the other non–hemophilia dependent issues of thrombosis risk come into play,” Dr. Hart acknowledged. “I think it will be an inevitability that there will be events, and we need to understand what the denominators are – hence my pitch for there being a renewed effort to try and collate sufficient data that we can really define events happening with people treated with standard half-life [products] through into the novel agents,” he said.

Dr. Hart disclosed grant/research support and speaker bureau activities for Bayer, Octapharma, Takeda, and others. Dr. Königs has reported no relevant disclosures.

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.