The NIH supports a broad program of research on hemophilia and other bleeding disorders. NIH institutes with large research portfolios relevant to hemophilia and other bleeding disorders include the NHLBI, the NIAID, the NIDDK, and the NHGRI. NHLBI research focuses on ensuring the safety and adequacy of the blood supply, while both the NHLBI and the NIH Clinical Center support research on the basic mechanisms of bleeding and clotting. The NIAID directs its research toward prevention of HIV infection and its complications, as well as discovery, development, and evaluation of therapeutic strategies and interventions for HIV/AIDS and its complications. The NIAID also has a strong program in basic, translational, and clinical research on HBV and HCV infection and disease in both its intramural and extramural research programs. The NIDDK has an extensive intramural and extramural research program on HCV infection in persons both with and without hemophilia. The NHGRI supports a strong intramural gene therapy research program that includes gene therapy for hemophilia and for patients who develop inhibitors to coagulation factors used to prevent bleeding. In addition, the NHGRI is involved in development of a non-human primate model for use in hemophilia gene therapy studies. A summary of NIH-supported research follows.
Mechanisms of Bleeding and Clotting
Bleeding, or hemorrhage, is part of the natural course of hemophilia; internal hemorrhages can be severe in the brain, abdominal cavity, and throat, and resultant compression of vital organs and nerves can be life-threatening or severely disabling.
Researchers have identified the components of the coagulation system and the mechanisms that regulate formation and dissolution of blood clots. NHLBI- and Clinical Center-supported research has improved understanding of how clot formation is inhibited in bleeding disorders, as well as of how the unwanted clots are formed that cause heart attacks, stroke, and pulmonary embolism.
Basic studies that include cutting-edge research on factors VIII and IX will almost certainly continue to improve treatment for patients with hemophilia. Based on genetic, protein biochemistry, and functional information, factor VIII and IX molecules are being modified to improve stability, promote higher activity, reduce immunogenicity, and increase expression levels. Although further testing is needed in animal models, they have the potential to improve the effectiveness and lower the cost of future treatment with recombinant proteins. In addition to factors VIII and IX, deficiencies or mutations that can also result in bleeding have been identified in other coagulation factors such as vWF and factors XI, X, and VII.
Physicians who treat hemophilia have noted with concern an increase in bleeding in hemophilia patients with AIDS who have been treated with protease inhibitors. The NHLBI, NIDDK, NIAID, and National Cancer Institute (NCI) issued a Program Announcement (PA) in 1996 and again in 1998 inviting applications for research on hematologic abnormalities in AIDS. The hemophilia research community is invited to take advantage of this currently available mechanism to elucidate the pathophysiology of the increased bleeding and to develop a therapeutic approach.
Basic vWD research supported by the NHLBI and the NIH Clinical Center Hematology Service has led to in-depth understanding of the role that vWF plays in clotting and bleeding and its interrelationship with factor VIII, and has elucidated the molecular abnormalities underlying vWD variants.
Thrombocytopenia, a condition in which a low number of platelets results in risk of hemorrhage into the brain and elsewhere, is of considerable interest to the NHLBI and the Clinical Center Hematology Service. In 1992, the Institute released a Request for Applications (RFA) on Thrombocytenias in Women and Neonates to encourage research to characterize antiplatelet antibodies in immune thrombocytopenia. The most common antigen associated with thrombocytopenia, the PlA antigen, was cloned and its polymorphism defined. Key outcomes of the research included development of assays for screening pregnant women and creation of a mouse model of heritable thrombocytopenia. In 1998, a new RFA on Thrombocytopenia: Pathogenesis and Treatment was released that emphasized HIV-related thrombocytopenia. The seven new grants awarded under the RFA include both basic and clinical research.
The NIH will continue its strong support of investigator-initiated basic research into the mechanisms of bleeding and clotting. Applications for research on increased bleeding in HIV-infected hemophilia patients treated with protease inhibitors are being encouraged actively, as are applications for studies that focus on the pathogenesis and treatment of thrombocytopenia. Investigators supported under the 1998 RFA on Thrombocytopenia: Pathogenesis and Treatment will be convened annually to encourage collaborative studies and information sharing.
Diagnosis of vWD, particularly Type 2 vWD, is currently complex and labor-intensive. The Clinical Center Hematology Service is developing more easily performed tests for vWD and the NHLBI is considering a research initiative to develop better diagnostic tests for vWD variants. Since it would be critical to move new tests to market as soon as possible, the program may target the small business community.
The Hematology Service will continue its active clinical referral service for studies, including molecular diagnostic studies, of patients with vWD and other coagulation factor deficiencies. The resulting information is expected to provide a clinical base for future pilot studies for gene therapy.
Five to 20 percent of patients with hemophilia A and one to four percent of those with factor IX deficiency (hemophilia B) develop antibodies to the coagulation factors used to prevent bleeding. In 60 to 80 percent of patients, antibodies can be suppressed by one of several drug regimens; however, costs of such treatment can exceed $1 million per year.
In November 1993, the NHLBI sponsored the Second International Symposium on Inhibitors to Coagulation Factors, organized by the University of North Carolina. The workshop highlighted scientific advances in both basic research and treatment over the previous 10 years. The Institute, in collaboration with the NIH Office of Rare Diseases, held a workshop in June 1997 on Immunogenetics of Inhibitor Formation in Hemophilia that focused on understanding the immune response in inhibitor formation. As a result, an RFA with the same title was released in 1998. Six new grants were awarded recently under the RFA to investigate the role of genetic factors in risk of inhibitor development, the feasibility of specific immunosuppressive treatments to block inhibitor formation, the potential of blocking antibodies to neutralize inhibitors, and the immune response to replacement factor or gene therapy in animal models.
NHGRI scientists report induction of immune tolerance in factor VIII-deficient mice following genetic modification of donor bone marrow cells with a retroviral vector encoding human factor VIII. This model system will prove useful for evaluation of genetic therapies for factor VIII immuno-modulation in patients. Induction of clotting factor tolerance by the gut epithelium is also being explored in studies using orally administering vectors containing genes for factors VIII and IX.
NHGRI scientists plan to extend studies of induction of immune tolerance in factor VIII-deficient mice to include evaluation of genetic therapies for factor VIII immuno-modulation in human patients. They will continue to study induction of clotting factor tolerance by gene therapy using the gut epithelium.
The NHGRI is considering an initiative in which hemophilia A and B will be the first genetic diseases systematically genotyped in every affected individual in the United States. With this information, it may ultimately be possible to identify individuals at risk for inhibitor formation.
The six grantees supported as a result of the NHLBI RFA on Immunogenetics of Inhibitor Formation in Hemophilia will meet annually to share data and establish collaborative studies.
In hemophilia patients, the immune reaction to treatment with factors VIII and IX has been overcome. If an understanding of the molecular mechanisms responsible for immune tolerance in hemophilia can be developed, it may be possible to apply that knowledge to numerous immunologic disorders such as lupus, myasthenia gravis, and various renal diseases. Hemophilia is, therefore, an important immune model.
Gene Therapy for Hemophilia
The often life-long reliance of patients with hemophilia or other bleeding disorders on replacement products will always be fraught with problems. Life-threatening bleeds and progressive joint destruction continue to be problems. Product availability and cost, as well as disruption of the lives of patients and their families due to a serious chronic, genetic disease, are additional concerns. If seriously ill patients could, themselves, produce only one percent of normal factor levels, their illness could be transformed to a milder form of the disease. Thus, transfer of a corrected gene to a patient, so that the patient's own body could produce the factor, potentially constitutes a cure. For a number of reasons, hemophilia is an ideal disease to target as the first to be cured by gene therapy. Low levels of factor production would alleviate the most severe symptoms and almost entirely eliminate dependence on replacement products. Factor VIII and IX production following gene therapy need not be tightly regulated, because the precise amount produced is not as critical an issue as in other disorders. However, there is concern that a substantial overproduction of factor following gene therapy may introduce risk of venous thromboembolism due to increased clotting. Moreover, effectiveness of the corrected gene product is not dependent on other gene products as is the case, for example, with hemoglobinopathies.
Recommendations from a March 1992 International Workshop on Gene Therapy for Hemophilia urged the NHLBI to proceed rapidly to develop gene therapy for hemophilia, not only because of the relative genetic simplicity of the disease but also because it could serve as a model system for other gene therapy efforts. The workshop led to a 1994 RFA on Gene Therapy for Hemophilia A and B that supported research on many viral and non-viral gene delivery systems and different target cells for gene expression. Study findings have contributed significantly to our understanding of events that regulate hemophilia gene expression. Approaches -- including use of lentiviruses, retroviruses, adenoviruses, adeno-associated viruses (AAV), and non-viral means of gene transfection -- are being developed to repair endogenous factor VIII and IX genes or to introduce new ones into cells, and to stimulate expression of sufficient functional protein. Hemophilic mouse and dog models, developed and maintained with NHLBI grant support, have shown that the vectors used to insert functional genes for factors VIII and IX often elicit an immune response themselves. Thus, not only do researchers need to develop an efficient system for transferring genes to patients, but they must also be certain that the patient does not produce antibodies to either the vector or the new gene product. Related NHLBI activities have included co-sponsorship of the Hemophilia 1996: Research for a Cure Workshop organized by the National Hemophilia Foundation and the International Symposium on Gene Therapy for Hemophilia organized by the University of North Carolina at Chapel Hill. The Institute also sponsors an annual RFA grantees' meeting to foster scientific collaboration.
The NHGRI has an active intramural hemophilia research unit that focuses on development of gene therapy for hemophilia A and B. Gene therapy initiatives include establishment of a CRADA (Cooperative Research and Development Agreement) to develop AAV vector-mediated gene transfer technology as a potential treatment for both factor VIII and factor IX deficiency. Plans are in place to investigate lentiviral vector systems as a new gene transfer system in preclinical studies. Lentiviral vectors offer significant advantages over existing retroviral vectors. Oral delivery to the intestinal epithelium of vectors containing functional factor VIII and IX genes is also being explored. Several NHGRI laboratories are developing whole new classes of gene transfer vectors including human artificial chromosomes, modified adenoviral vectors, and viral-based gene transfer vectors, including chimeric viral vectors. Some of these new approaches may be applicable to hemophilia gene therapy.
In addition to research directed specifically to hemophilia, the NIH supports a number of related activities that have significant potential application for hemophilia gene therapy. For example, the NHLBI program on Gene Transfer Principles for Heart, Lung and Blood Diseases, established in 1997, is fostering research in gene transfer technology and somatic gene transfer. The NHLBI also provides support for the National Gene Vector Laboratories that help qualified investigators develop and produce clinical-grade gene vectors for human gene therapy trials. Plans are under way to expand their scope to include preclinical toxicity testing as well. In addition, under the leadership of the NIH Office of Rare Diseases, several NIH institutes and the FDA are cooperating to identify special needs in the development of gene therapeutics for treatment of rare monogenic diseases.
The need for targeted support of preclinical and clinical studies of specific hemophilia gene therapy approaches is being evaluated to determine how best to move gene therapy to clinical use. Interest is high not only in providing a cure for hemophilia but also in applying the successful technology to other more complex diseases. Thus, hemophilia gene therapy will continue to be a high priority research area for the NIH.
NHGRI scientists plan to enter into a CRADA to further develop and apply a new experimental strategy to correct mutations in genomic DNA in order to repair point mutations in hemophilia B. In order to determine the efficacy of any gene therapy strategies prior to clinical testing, it will be important to evaluate them in animals that closely resemble humans.
The NHLBI extramural program and NHGRI intramural scientists will continue to support substantial research to develop safe, effective gene therapy for hemophilia A and B. The variety of approaches under study increases the likelihood that some of them will be applicable to gene therapy in humans. A second-generation version of the NHLBI RFA on gene therapy for hemophilia is being planned, that will focus on facilitating the transition from pre-clinical testing to testing in humans. National Gene Vector Laboratory support will continue to be used to produce clinical-grade gene vectors for human gene therapy trials.
Blood-Borne Infectious Agents
Although acquisition of blood-borne infectious agents is not a complication of hemophilia per se, it constitutes a significant complication in hemophilia patients who received blood products in the past. Today, approximately 20 percent of adult hemophilia patients in the United States are HIV-infected; about 56 percent and 89 percent, respectively, are infected with HBV and HCV. The percentages are substantially lower for children. HIV remains the most common cause of death among hemophilia patients; of the 400 who die each year, roughly 75 percent die as a result of HIV infection.
It is important to emphasize that, overall, strict blood donor screening procedures in conjunction with development of new assay systems for donated blood have reduced the risk of HIV transmission to 1:500,000 units transfused. The risk for HCV is now 1:103,000 units transfused, while that of HBV is 1:63,000 units.
Because of their previous reliance on repeated factor concentrate infusions, hemophilia patients were exposed to HCV and many other blood-borne viral agents such as HBV, HIV, and cytomegalovirus (CMV). Although new anti-viral drugs may prolong the lives of HIV-infected hemophilia patients, bleeding and liver damage are possible drug side effects. Hemophilia patients with the misfortune of being infected with both HIV and HCV have particular problems, as co-infection may cause HCV to worsen. Further, liver failure resulting from HCV cannot be treated with transplantation in AIDS patients because of the risk of opportunistic infections resulting from post-transplant immunosuppressive regimens.
Human Immunodeficiency Virus (HIV)
The NIAID devotes substantial resources to discovery, development, and evaluation of innovative therapeutic strategies and interventions for HIV/AIDS and its complications. In addition to therapeutic research, the NIAID supports research on prevention of HIV infection and its complications.
The NIAID supports three large clinical trial networks -- the Adult AIDS Clinical Trials Group (AACTG), the Pediatric AIDS Clinical Trials Group (PACTG), and the Community Program for Clinical Research on AIDS (CPCRA). The major goals of the networks are to:
The AACTG and CPCRA have formed working groups to develop a research agenda to address hepatitis and HIV co-infection. The AACTG recently implemented a pilot study to determine the dynamics of HCV viral infection in HIV-infected individuals on highly active antiretroviral treatment. The interaction between the two viruses may influence ability to treat either virus. Information from the pilot study will assist in designing other HCV clinical trials.
HIV-positive persons with hemophilia have the opportunity to participate in the clinical trials through the three clinical trial networks. At present, approximately 50 AACTG, 8 CPCRA, and 25 PACTG protocols are open to enrollment. The AIDS Clinical Trials Service (telephone: 800 HIV-0440) is a resource for learning about clinical trials for HIV-infected individuals and the participating clinics.
The three NIAID clinical trial networks noted above focus on the pathogenesis of HIV, therapeutic antiretroviral agents, and OIs in persons with HIV. HIV-infected hemophilia patients, as well as patients with HIV alone, will continue to be included in these trials. In addition, the NIAID is planning an FY 1999 workshop to review and identify the scientific needs of the HIV-infected hemophilia population. Proposed attendees will include representatives from the NIAID and other NIH institutes, leading researchers, and hemophilia patients infected with HIV.
Hepatitis C Virus (HCV)
In FY 1999, the NHLBI is participating in a multi-institute RFA, Hepatitis C: Natural History, Pathogenesis, and Therapy. The Institute hopes to support research to define the natural history of HCV infection in specific populations that have received, and continue to receive, frequent transfusions. This would include participation of persons with hematologic disorders, such as hemophilia, in studies on the long-term morbidity and mortality of chronic HCV infection, including factors contributing to cirrhosis and hepatocellular carcinoma.
The NHLBI is collaborating with the NIAID to elucidate the role of T cells in disease progression. Researchers are studying a well-characterized population of hemophilia patients to compare the HCV-specific T cell responses in patients who have recovered from HCV infection with the responses of patients who have persistent chronic HCV infection.
Intramural NIDDK scientists have developed a system that uses insect cells for efficient assembly of HCV structural proteins into HCV-like particles. The noninfectious particles, in contrast to recombinant subunit vaccines, present viral proteins that mimic the native virus and may, therefore, be superior in eliciting a protective humoral and cellular immune response. The NIDDK and the NHLBI are collaborating to evaluate the immunogenicity of the HCV-like particles as a candidate vaccine. If developed, the vaccine could be of value for use in conjunction with HCV hyperimmune globulin to treat or modify the clinical manifestations of chronic HCV infection.
The NIAID Framework for Progress on HCV identifies key research areas and tools needed to accelerate the drug development process, including tissue culture and animal model systems with which to perform preclinical evaluation and closer examination of viral and host interactions. The NIAID emphasizes basic and clinical research on HCV infection and disease with minor emphasis on HCV infection in hemophilia patients who are chronic HCV carriers. Basic research on viral replication, persistence, pathogenesis, and natural history in non-hemophilic patients is ongoing especially through the Hepatitis C Cooperative Research Centers that began in 1996. Such research, as well as research supported through the SBIR program, may lead to development of new therapies that can be evaluated in, and eventually used to treat, hemophilia patients who are chronic HCV carriers.
In addition to its HIV-based clinical trial groups, the NIAID also supports the Collaborative Antiviral Study Group that conducts clinical trials to evaluate candidate therapies for HBV and HCV infections. The current focus of the Collaborative Group is on combination therapies to increase positive responses to treatment and on evaluation of antibody therapy to prevent reinfection of new livers in hemophilia patients with chronic HCV who are sick enough to require transplants. It is important to note that liver biopsies, needed to monitor response to treatment, can be performed in hemophilia patients given factor replacement, thus giving them greater access to clinical trials.
Studies are being planned to define the long-term morbidity and mortality of chronic HCV infection and the role of T cells in disease progression. An 8-year NIDDK multicenter clinical study will begin shortly to evaluate long-term treatment (up to four years) of HCV-infected persons who did not respond to conventional treatment. Several ancillary studies will be included to determine how the virus causes liver damage and to develop noninvasive techniques to measure and predict progression of liver disease. These activities will be highly relevant for HCV-infected persons with hemophilia.
If results indicate that a newly developed HCV immune globulin effectively prevents HCV reinfection of transplanted livers, its application in treating HCV infection will warrant further clinical evaluation. Studies to evaluate HCV-like particles as candidate vaccines will continue. Such a vaccine might find use in conjunction with HCV hyper immune globulin or other antiviral therapies to cure or ameliorate the clinical manifestations of chronic HCV infection. The Hepatitis C Cooperative Research Centers supported by the NIAID are carrying out both basic and clinical research that may lead to new therapeutic avenues for treatment of all chronic HCV carriers including hemophilia patients.
The NHLBI and the NIDDK are currently preparing an initiative to support a multi-center study to evaluate the acquisition, infection rate, extent of viral co-infection, pathogenesis, natural history, risk factors for progression, and treatment of HCV in persons with hemophilia. Development of fibrosis, cirrhosis, and hepatocellular carcinoma, as well as the frequency of occurrence of manifestations of HCV infection other than in the liver, will be studied to determine if these outcomes are related to viral, host, or environmental factors.
One goal of research is to find a way to prevent reinfection of new livers transplanted into patients already infected with HCV. Passive immunization (HBV-specific immune globulin) already exists for hepatitis B and has been used alone and in combination with drug therapy to prevent or delay reinfection after liver transplants. This approach may also be useful in HCV-infected patients who need liver transplants, but has not been proven. Together with other institutes, the NHLBI is considering a proposal from a pharmaceutical firm to co-sponsor a trial to assess a newly developed HCV immune globulin.
The NHLBI supports a colony of chimpanzees for use in non-destructive experiments to advance hepatitis or AIDS research. Since the chimpanzee is the only animal susceptible to HCV infection, a major focus of the NHLBI colony will be to test the safety and efficacy of therapeutic agents and candidate HCV vaccines prior to human use.
Much hemophilia research is intimately related to the safety of the blood supply. NIH blood safety research related to HIV and HCV is described below, as are efforts to assess the danger to transfusion recipients of transmissible spongiform encephalopathy (TSE) agents such as Creutzfeldt-Jakob disease (CJD). Also described are ongoing general efforts to continuously monitor the blood supply.
HIV and Hepatitis
Efforts to develop a nucleic acid amplification detection system for HIV-1, HIV-2, HBV, and HCV in blood donors are being supported by the NHLBI through a contract. The resulting technology will reduce the "window period" between the time of HIV-1 infection and the ability to detect it from 16 days to 5 days. Significant reductions in the window periods of HBV and HCV detection also will be realized through the technology. Nucleotide amplification technology (NAT) will be able to detect small amounts of virus in infected persons that current screening methods cannot recognize. Approximately two-thirds of the United States blood supply will be tested using NAT technology for HIV and HCV by March or April 1999. It is expected that the entire blood supply can be tested by Fall 1999.
In the mid 1980s, the NHLBI supported research that led to development of a solvent-detergent technique for inactivating viruses in plasma products. The procedure is very effective against lipoprotein-enveloped viruses such as HIV, HBV, and HCV. However, non-enveloped viruses such as hepatitis A virus and parvovirus B-19 are resistant. The NHLBI is now supporting research on use of photochemical virucidal methods to inactivate a broader spectrum of infectious agents such as those that are resistant to solvent-detergent treatment. Photochemical virucidal methods are currently in Phase I clinical trials.
Research to increase the accuracy of detection and decrease the "window period" between the time of infection and ability to detect viruses in blood donors is on-going and will continue. NAT technology is being developed to detect HBV and HIV-2 in the blood supply. Subsequently, it is planned to further modify the NAT technology to detect other emerging agents. It may never be possible to have zero risk of infection associated with blood transfusions, but NAT is bringing us closer to that possibility. Since viruses may still enter the blood supply in the future, development of technologies to inactivate infectious agents while maintaining the efficacy of blood products will continue to be a priority.
CJD is a slow-moving disease of the central nervous system characterized by degeneration of the brain, progressive dementia, and motor dysfunction. The disease, which is rare and invariably fatal, is due to a transmissible agent and is classified as one of the TSEs. CJD is related to bovine spongiform encephalopathy (BSE or "mad cow disease") in England. Concern about its transmissibility by blood was heightened when a new variant of CJD that was found in over 25 people was possibly linked to the livestock epidemic and following reports of 37 people who donated gallons of blood between 1983 and 1997 prior to being clinically diagnosed with the disease.
Since hemophilia patients are exposed to thousands of donors through pooled factor VIII concentrate, they are considered at risk of contracting CJD through the blood supply. Recent research published in Transfusion (September 1998) showed CJD infectivity in cellular blood components, plasma, and certain plasma fractions of blood collected from mice clinically ill with a strain of human CJD that had been adapted to become more virulent in mice. Infectivity was demonstrated by intracerebral inoculation into susceptible mice. The research suggests a potential risk to humans of acquiring CJD from transfusion therapy. However, the intracerebral inoculation used in the animal model is not analogous to intravenous infusion of blood components and plasma derivatives in humans undergoing transfusion therapy. Hence, a second experimental protocol has been initiated with mouse-adapted CJD in which infectivity assays are also done by the intravenous route to simulate blood transfusion. In addition, two methods for removing the CJD agent from blood are being evaluated. This study, now in its final phase, should be completed early in 1999.
To date, no cases of CJD transmission by blood products have been reported, suggesting that the risk of acquiring CJD from blood products, even if it exists, is very small. The Centers for Disease Control and Prevention (CDC) has an ongoing surveillance program including a unit monitoring for CJD among hemophilia patients. Thus far, no evidence of CJD has been found in persons with hemophilia, and the few cases of death due to progressive dementia were clearly associated with HIV infection.
The study of CJD transmission has been hampered by lack of a rapid assay system. The Special Emphasis Panel on CJD and Blood Transfusion, convened by the NHLBI in September 1997, concluded that since "an unqualified and irreducible risk of exposure to CJD through blood and blood products does exist," a sensitive and specific test for the causative agent was needed to study and control CJD. Two laboratories have found monoclonal antibodies to distinguish between the "normal" CJD protein and an abnormal isoform, so an assay may be imminent. To expedite development of methods to detect preclinical CJD infection, the NHLBI announced a grant program in December 1998, Development of Assay Methods for Creutzfeldt-Jakob Disease (CJD) with awards to be made in September 1999. The ultimate goals of the research are to devise a test to screen blood and tissue donors and to determine with certainty whether or not CJD is transmissible by blood and blood products. In addition, the research could lead to development of a diagnostic tool to detect preclinical disease.
It should be noted that other NIH institutes that are not part of this action plan, such as the National Institute of Neurological Disorders and Stroke and the National Institute on Aging, support other aspects of research related to TSEs and CJD.
The NHLBI is responsible for supporting research to ensure the safety of the blood supply. To that end, future NHLBI-supported research will focus on developing a test or tests to screen blood and tissue donors as well as to detect preclinical disease. The test would also be used to determine more precisely the transmissibility of CJD by blood and blood products. In 1999, the NHLBI will support research relevant to these goals through its CJD initiative.
The NHLBI does not currently support any research on behavioral issues in patients with hemophilia. However, studies of pain management in sickle cell disease are being supported by the Institute. Other NIH Institutes, such as the National Institute of Mental Health, are documenting the effects of chronic diseases on patients and their families. Examples of such research include studies of adjustment of children and family members to chronic physical disorders; stress, social support, and depressive symptomology in children with congenital and acquired defects; and psychological maladjustment in chronically ill and handicapped children.
In November 1998, the NHLBI convened a working group to address ways of encouraging application of proven techniques in behavioral research to patients with genetic blood diseases such as hemophilia, vWD, sickle cell anemia, and Cooley's anemia. Topics identified for further research in the area of hemophilia include:
The NHLBI is currently considering the working group recommendations.