Factor VIII Complex vWF polymer
Figure 17.2 Factor VIII complex is controlled by the X chromosome and an autosomal chromosome. This complex transports factor VIII into the circulation. vWF, von Willebrand factor; AHF, antihemophilic factor.
decreased level of clotting factor. Platelet counts are normal and blood vessel function is adequate. Perhaps the most debilitating bleeds are muscle bleeds or joint bleeds, which have the potential for causing long-term disability, reduced range of motion, and intense pain. Joints become painful, swollen, and engorged with blood. Hemarthrosis occurs in the joints as pooled blood damages the surrounding tissue while a clot eventually forms. The joint become less and less mobile, limiting physical activity (Fig. 17.3). Internal hemorrhages into the muscles and deep soft tissues may compress and damage nerves. Intracranial bleeding is a leading cause of death in hemophilia A individuals, and other complications like paralysis, coma, memory loss, or stroke may precede an eventual fatality. Female carriers for the hemophilia gene rarely have symptoms, yet there are occasions when carrier females may become symptomatic. The union of a hemophilia patient and a female carrier would likely produce a symptomatic female.
Laboratory diagnosis of hemophilia patients is fairly uncomplicated. Laboratory tests which are ordered include bleeding time, PT, aPTT, and factor assays. In hemophilia, the bleeding time test is normal, the PT is normal, and aPTT is elevated, due to the reduced factor VIII. Single factor assays provide a means of assessing the percent activity of a clotting factor. These assays are performed using the aPTT test. A standard curve is created using serial dilutions of normal plasma of known factor levels and assigning a 1:10 dilution of normal plasma as 100% activity. Commercially prepared factor deficient plasma is then mixed with a 1:10 dilution of patient plasma and aPTT is performed. An aPTT that is abnormal when mixed with a specific factor-deficient plasma suggests that the patient is missing the same clotting factor as that specific factor-deficient plasma. If the patient and deficient plasma give a normal result, then obviously the patient supplied the factor missing in the factor-deficient plasma. The aPTT result is plotted on the factor-activity curve, and the level of factor activity is derived from the standard curve.
Treatment for Hemophilia A Patients
Treatment options for hemophilia patients span decades and present one of the saddest treatment histories of any patient group with an inherited disorder. Factor VIII was discovered in 1937 and was termed anti-hemophilic globulin.1 In the early days, treatment of hemophilia A patients consisted of giving whole blood units to relieve symptoms. Not until 1957 was it realized that the deficient coagulation protein was a component of the plasma portion of blood. Cryoprecipitate, a plasma derivative, was discovered in 1964. This product is produced as an insoluble precipitate that results when a unit of fresh frozen plasma is thawed in a standard blood bank refrigerator. Cryoprecipitate contains fibrinogen, factor VIII, and vWF. This product is extracted from plasma and usually pooled before it is given to the patient according to weight and level of factor VIII. This product presented a major breakthrough for the hemophilia population because it was an easily transfusable product affording the maximum level of factor to the individual. Next in the chronology of treatment products for hemophilia was clotting factor products. These freeze-dried products were developed in the early 1970s. The products were lyophilized and freeze dried and could be reconstituted and infused at home. This treatment offered the hemophilia population an independence that they had never previously experienced. Finally they were in control because they could self-infuse when necessary and provide themselves with prompt care when a bleeding episode developed. But a dark cloud loomed over the bleeding community Approximately 80% to 90% of hemophilia A patients treated with factor concentrates became infected with the HIV virus. Factor concentrates were made from pooled plasma from a donor pool that was less than adequately screened. Additionally, manufacturing companies were less than stringent with sterilization methods and screening for HIV virus did not occur in blood banks until 1985. When each of these factors is brought to bear, the tragedy to the bleeding community is easily understood. According to the National Hemophilia Foundation,2 there are 17,000 to 18,000 hemophilia patients (hemophilia A and B) in the United States. Of those, 4200 are infected with HIV/AIDS. There are no numbers available for wives or children who could have been secondarily infected. Recombinant products became available in 1989 and represent the highest purity product because they are not human derived. Recombinant technology uses genetic engineering to insert a clone of the factor VIII gene into mammalian cells, which express the gene characteristic. Production expenses for this product are unfortunately the most costly, and these costs are passed on to potential users.
Having a child with severe hemophilia A or B presents special challenges to the parents and the family unit. The threat of hospitalizations, limited mobility, mainstreaming in schools, and the child's drive for independence present potentially stressful environments. Added to this is the cost of infusible factor, either recombinant or high purity products that could go as high as $50,000 if a patient has several bleeding episodes for which he needs to be hospitalized. Individuals with a chronic condition face many anxieties and may struggle with feelings of isolation, anger, and disappointment (Table 17.1). Fortunately, in the United States, there are hemophilia treatment centers that offer a network of needed services, and many states have local chapters of the National Hemophilia Foundation.2 Prophylaxis with factor concentrates limits bleeding episodes, and the use of magnetic resonance imaging offers the physician a more effective means of evaluating joint damage.3 Issues concerning medical insurance coverage continue to plague the hemophilia community.
The development of factor VIII inhibitors occurs in 15% to 20% of all hemophilia A individuals.4 These inhibitors are autoantibodies against factor VIII that are time and temperature dependent and capable of neutralizing the coagulant portion of factor VIII. Treatment for patients who develop inhibitors is difficult and treatment protocols follow various paths. When the inhibitor is low titer or the individual is a low responder, physicians may infuse an appropriate level of factor VIII in an attempt to neutralize the inhibitor.4 If this is not effective, patients must be treated with a factor sub-
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