Chapter 172

## Abstract

Abstract

1. Hemophilia A (MIM 206700; classic hemophilia) is an X-linked bleeding disorder characterized by a deficiency in the activity of factor VIII, a key component of the coagulation cascade. Approximately 1 in 5000 to 10,000 males are affected in all populations.

2. Affected individuals suffer joint and muscle hemorrhage, easy bruising, and prolonged bleeding from wounds. Because platelet function is not affected, blood loss from minor cuts and abrasions is not excessive. Of hemophilia A patients, 50 to 60 percent have severe hemophilia with factor VIII activity <1 percent, while the remainder have mild to moderate disease with factor VIII levels of 1 to 20 percent. Nearly all patients with severe disease have no factor VIII protein in their plasma (cross-reacting material negative or [CRM−]), but a small proportion of these patients (about 5 percent) have inactive factor VIII protein circulating in their plasma (CRM+).

3. Factor VIII functions as a cofactor in the activation of factor X to factor Xa in a reaction catalyzed by factor IXa on a phospholipid surface. Factor VIII is activated following specific proteolytic cleavages by thrombin and factor Xa, which results in an effective amplification of the signal through this step of the cascade. Factor VIII is inactivated by limited proteolysis by factor Xa or by activated protein C (APC).

4. Hemophilia A arises from a variety of mutations within the factor VIII gene, which is located near the telomere of the long arm of the X chromosome. The gene comprises 26 exons and spans 186 kb. The cDNA sequence reveals that factor VIII is synthesized as a large precursor molecule (2332 amino acids). The amino acid sequence of the protein has considerable sequence similarity to that of ceruloplasmin and coagulation factor V.

5. Approximately 43 percent of patients with severe disease and approximately 25 percent of all patients have an inversion at the tip of the X chromosome that disrupts the factor VIII gene. This mutation almost always has its origin in male meiosis. Of the remaining 75 percent of patients, approximately 95 percent have one of a large variety of point mutations. Although the functional consequences of some of the 400-odd point mutations producing the disease are known (for example, some alter a thrombin cleavage site, a factor IX binding site, or a von Willebrand factor binding site), the structure-function relationships of most mutations remain unknown.

6. Combined deficiency of factors V and VIII is an uncommon autosomal recessive disease with factor levels in the 5 to 30 percent range and symptoms similar to mild factor VIII deficiency. Recently, mutations in the ERGIC-53 gene were shown to cause this combined deficiency. The ERGIC-53 gene encodes a protein that likely transports proteins from the endoplasmic reticulum to the Golgi compartment. Deficiency of this protein in combined factor V and factor VIII deficiency suggests that it may act uniquely to facilitate the intracellular transport and secretion of these two coagulation factors.

7. Treatment of hemophilia A is accomplished by infusions of factor VIII, usually prepared by recombinant DNA technology, or sometimes prepared as concentrates from human plasma. The in vivo half-life of such preparations is approximately 12 h. Although such therapy is effective in most cases, approximately 15 percent of affected individuals eventually develop neutralizing antibodies (inhibitors) that complicate further therapy.

8. Gene therapy for hemophilia A is likely in the future. Animal model systems (affected dogs and mice) are greatly aiding experimentation in this rapidly advancing field. As of early 2000, there is substantial hope that clinical trials with an effective vector will be successful in the next few years.

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