NHLBI Working Group: Hemophilia and Thrombosis Disorders Executive Summary
On November 13, 2009 the National Heart, Lung and Blood Institute convened a Working Group of senior scientists from both academia and government to define mechanisms whereby important clinical research can be developed and implemented for hemophilia and other rare hemostatic and thrombotic disorders. The objective was to identify and evaluate existing data resources, clinical trial capacities, candidate grant mechanisms and collaborative opportunities. Dr. Keith Hoots, Director of the Division of Blood Diseases and Resources, welcomed the participants and requested their advice and recommendations to advance clinical research.
Hemophilia is a rare bleeding disorder that is caused by a deficiency in either blood coagulation factor VIII or IX. Current treatment with infusion of plasma derived or recombinant factor to replace the missing protein, has greatly reduced morbidity and mortality associated with the disease. A recent study demonstrated that prophylaxis treatment with recombinant factor VIII prevented joint damage and bleeds in young children. However, the importance of continuation of this invasive, costly treatment into adulthood is unknown. In addition, approximately 20% to 30% of severe hemophilia A patients develop antibodies to factor VIII and standard factor replacement therapy becomes ineffective. Deficiencies in eight other coagulation factors, which can result in a bleeding disorder, have been documented. Few treatment options are available for these very rare bleeding disorders and clinical studies are difficult with the small number of patients. There are also rare inherited disorders, such as deficiencies in protein C, protein S or antithrombin that leads to thrombosis. Severe deficiencies often need lifelong treatment to prevent disabling or deadly thrombotic events. The need for prophylaxis and duration of therapy for these individuals with inherited or acquired bleeding or clotting disorders is often unclear. In addition, it is difficult to conduct clinical studies in rare patient populations. The Center for Disease Control (CDC) and Health Resources and Services Administration (HRSA) support a network of Hemophilia Treatment Centers (HTCs) across the United States. These centers provide comprehensive health management and prevention services to persons with bleeding and clotting disorders. Organizations such as the Hemophilia and Thrombosis Research Society (HTRS) and the American Thrombosis and Hemostasis Network (ATHN) provide a network of experienced investigators and clinicians, mentorship for new investigators, resource of clinical data and database infrastructure.
Clinical Research Topics:
Examples of clinical research needs for hemophilia and rare bleeding and clotting disorders discussed:
- Clinical study to transition young adult hemophilia subjects on primary prophylaxis regimens to an individually tailored (dose/frequency) replacement therapy
- Prospective, multicenter studies on the best therapeutic option and assessment of genetic and environmental risk factors for inhibitor formation in both pediatric and the adult hemophilia population
- National registry of infants with perinatal stroke which encompasses infant-mother pairs and infant and maternal thrombophilia
- Study of the use of catheter-directed low-dose t-PA versus anticoagulation alone for children with high-risk deep venous thrombosis
- Development of standardized validated clinical or surrogate endpoints of bleeding in bleeding disorders to monitor therapy and evaluate new hemostatic agents
- Clinical/observational trials in newborns with inherited bleeding disorders (hemophilia, rare bleeding disorders) and symptomatic and asymptomatic intracranial hemorrhage
- Clinical studies to identify risk factors for antibody development and thrombotic complications for immune-mediated thrombotic disorders (antiphospholipid syndrome (APS) and heparin induced thrombocytopenia (HIT) )
- Studies to increase the range of therapeutics for rare disorders
- Development of a national database on individuals with rare disorders
Clinical Research Challenges:
The committee identified several barriers that impede clinical research that could improve health for individuals with rare bleeding and clotting disorders. The challenges include:
- Cumbersome regulatory requirements
- Difficulties and delays for Institutional Review Board (IRB) approvals for multi-site studies
- Academic centers that lack infrastructure, organization, and expertise to conduct large multi-center clinical trials
- Educating the public to foster clinical research
- Need for physician scientists interested in hematology
In order to meet the need for evidence based treatment guidelines for rare bleeding and clotting disorders, new approaches are required for conducting clinical research and collecting outcomes data. A collaboration of federal agencies, research organizations and academic investigators focused on advancing clinical research for hemophilia and rare hemostasis and thrombosis disorders could have a significant impact. The committee’s recommendations to NHLBI include:
- Promote collaboration between NHLBI, CDC, HRSA and organizations such as HTRS and ATHN
- Promote investigator initiated clinical research by providing mechanisms and resources to aid in development and successful completion of studies
- Develop programs that would provide expertise and assist in organization for multi-site clinical studies
- Design programs that could utilize existing infrastructure, such as the Hemophilia Treatment Centers, to conduct clinical research
- Encourage availability and utilization of existing sample and data resources
- Encourage cross-collaboration among disciplines
- Foster collaborations between government agencies, professional societies and advocacy groups for support of clinical research and training of next generation of investigators
- Promote effective training and career development for non-malignant hematology research
Working Group Members:
- Harold Roberts, M.D., Chair, (University of North Carolina)
- Valder Arruda, M.D., Ph.D. (Children’s Hospital of Philadelphia)
- Kenneth Bauer, M.SD. (Beth Israel Deaconess Medical Center)
- Donna DiMichele, M.D. (New York Presbyterian Hospital)
- Eric Grabowski, M.D. (Massachusetts General Hospital)
- Craig Kessler, M.D. (Georgetown University Medical center)
- Nigel Key, M.D. (University of North Carolina)
- Roshni Kulkarni, M. D. (Michigan State University)
- Penny Kyler (Health Services and Resources Administration)
- Diane Nugent, M.D. (Children’s Hospital of Orange County, CA.)
- Thomas Ortel, M.D., Ph.D. (Duke University)
- Michele A. Lloyd-Puryear, M.D., Ph.D. (Health Services and Resources Administration)
- Amy Shapiro, M.D. (Indiana Hemostasis and Thrombosis Center)
- Mike Soucie, Ph.D (Center for Disease Control)
NHLBI Staff Members:
- W. Keith Hoots, M.D.
- Jonathan Goldsmith, M.D.
- Mary Joyce, RN, MSN, MBA
- Liana Harvath, Ph.D.
- Andrei Kindzelski, M.D.
- Rebecca Link, Ph.D.
- Harvey Luksenburg, M.D.
- Ellen Werner, Ph.D.
Last Updated February 2011