Treatment of Hemophilia and Other Bleeding Disorders

Transfusion as a treatment for hemophilia was first reported in 1840, but rest, pressure dressings, immobilization, ice, and cauterization remained the mainstays of treatment until about 100 years later. In 1911, it was shown that a globulin fraction in normal plasma could correct the hemophilic defect. In the 1950s, fresh-frozen plasma, as well as concentrates containing antihemophilic factors (AHF), could be prepared.

In 1958, Swedish clinicians began treating patients prophylactically with AHF to prevent joint damage. The success of their efforts supported the concept of prophylaxis, which remains the treatment of choice today. In 1965, NIH-supported researchers developed an important technique that allowed the plasma component (now called factor VIII) to be made by precipitation in the cold (cryoprecipitate). Lysine analogues were also available to treat mucosal bleeding and for use during dental extractions. The hormone desmopressin (DDAVP) was found in 1977 to elevate factor VIII levels. It continues in use today to treat mild hemophilia and Type 1 von Willebrand disease (vWD) and some Type 2 variants. During the 1970s, freeze-dried, intermediate-purity factor VIII and IX concentrates were prepared from pools of over 2000 donors. Such innovations allowed home treatment of hemophilia patients, improved their quality of life, and increased their life expectancy from 11 years in 1931 to 60 years in 1980.

Among other inherited bleeding disorders, the most common one is vWD, which was first described in 1926. Although vWD is estimated to affect one to three percent of the United States population, it is often overlooked or underdiagnosed in women with bruisability, heavy menstrual flow, or postpartum bleeding. The disorder is caused by either a quantitative or a qualitative deficiency of von Willebrand factor (vWF), which functions in platelet adhesion and as a carrier for factor VIII. Treatment varies with the type of vWD and clinical condition. Mild symptoms often can be treated with a nasal spray of DDAVP that releases stored vWF. For the 10 to 15 percent of vWD patients who are moderately to severely affected, infusion of virally inactivated plasma products that contain vWF may be required.

Improvements in Blood Safety

In the early 1980s, use of large donor pools to prepare factor concentrates and lack of specific tests for infectious agents led to frequent infection by blood-borne viruses. At one time, up to 95 percent of those treated with unheated and dry heat-treated factor concentrates became infected with hepatitis C virus (HCV). About 90 percent of persons with severe hemophilia were infected with HIV-1 by 1985. Approximately half of all persons with hemophilia contracted HIV during the 1980s. The AIDS crisis spurred development of better tests for blood-borne infectious agents which led to purer material that was free of viral contamination. The next generation of replacement products, produced by affinity chromatography with monoclonal antibodies, significantly reduced transmission of infectious agents.

In the late 1970s and early 1980s, various studies including the NHLBI-sponsored Transfusion-Transmitted Viruses (TTV) Study, proved that an emerging form of hepatitis that was neither hepatitis A nor hepatitis B was transmitted by blood transfusions. It is now clear that at least 90 percent of the nonA-nonB infections were due to HCV. HCV could not be detected directly. However, use of a surrogate marker (a liver enzyme that becomes elevated in cases of infectious hepatitis) to screen donors reduced the incidence of post-transfusion hepatitis. Surrogate testing reduced the per-unit risk of HCV transmission to 0.19 percent. The cloning and sequencing of HCV in 1989 led to rapid introduction of the first-generation single-antigen anti-HCV assay in 1990 which further reduced the per-unit risk to 0.07 percent. After second-generation HCV testing was implemented, the per-unit risk dropped to 0.03 percent. A third-generation multi antigen assay introduced this past year has reduced the per-unit risk still further, to less than 0.001 percent.

Mandatory testing was initiated to screen blood donors for hepatitis B (HBV) in 1971, for HIV-1 in 1985, for HCV in 1990, and for HIV-2 in 1992. In addition, blood could be frozen and quarantined until the donor was re-tested after the window period for seroconversion. Lipid-enveloped viruses -- HIV-1, HBV, and HCV -- also could be inactivated by solvent-detergent treatment of plasma. HBV vaccine became available in 1982. Since 1986, no cases of HIV transmission from factor concentrates have occurred, although transmission of HCV is sometimes reported even with use of the latest tests.

To make hemophilia treatment safer for hemophilia patients, the factor VIII gene was cloned in 1984 and used to make recombinant factor VIII commercially. Two recombinant products have now been licensed by the Food and Drug Administration (FDA) as Recombinate® and Kogenate ®. The factor IX gene is smaller and was cloned earlier. A recombinant factor IX was approved in 1997. The two factors are very pure, but are currently being made even safer by excluding carrier proteins that might harbor infectious agents such as prions from human plasma.

During the 1970s, pools of donors for plasma products ranged from 15,000 to 60,000 people. In 1998, the House Government Reform and Oversight Subcommittee on Human Resources held a hearing at which manufacturers testified of recent pools with as many as 400,000 donors. Voluntary standards are now being adopted to limit pool size to 60,000, and a few manufacturers are seeking to reduce pool size to 15,000 donors for certain products.

The steps taken to achieve purer products that remove risk of infection have substantially increased their cost. As a result, use of transgenic animals, notably sheep and pigs that produce large quantities of coagulation factors in their milk, is being explored. Animal products may soon be able to meet FDA approval requirements.

Complications of Hemophilia

Major complications range from the psychological impact of a chronic disease on children, adolescents, and their families to life-threatening cerebral hemorrhage as well as infection with deadly viruses such as HIV. In addition, many hemophilia patients develop antibodies (inhibitors) to the coagulation factors used to prevent bleeding. In the absence of prophylactic therapy, now recommended to begin at one to two years of age, potentially disabling arthritis occurs in joints that have experienced hemorrhage (hemarthrosis). Pseudotumors -- cysts that arise from hemorrhage in muscle or the covering of the bone which then damage adjacent muscle, nerve, and bone -- also occur and must be excised completely to avoid recurrence. There are also life-long concerns about availability, cost, and purity of replacement factor products.

Complications of Other Bleeding Disorders

Complications of severe vWD are similar to those of hemophilia, but hemorrhages into joints appear to be less frequent. Women, whom the disorder affects disproportionally , may also suffer problems with heavy menstrual flow and postpartum bleeding. Mucosal bleeding from the nose, mouth, or GI tract can occur, and major injury or surgery creates a risk of prolonged bleeding.

Finding a Cure

Although purer factor replacement products have significantly reduced the risk of disease transmission, researchers are actively seeking a cure for hemophilia. Liver transplantation does cure hemophilia, but carries its own risks. Further, if the patient already has hepatitis, the transplanted liver or liver cells are themselves subject to infection. Currently, the most likely route to a cure is thought to be through gene therapy.

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