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SUMMARY

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SUMMARY

Hemophilias A and B are the only two bleeding disorders inherited in a sex-linked fashion. The gene for both disorders is on the long arm of the X chromosome. Both disorders appear as otherwise clinically indistinguishable hemorrhagic diseases of mild, moderate, or life-threatening severity. In the most severe form, both hemophilias A and B are characterized by multiple bleeding episodes into joints and other tissues leading to chronic crippling hemarthropathy and internal organ hemorrhage unless treated early or prophylactically with factor VIII or IX concentrates, respectively. Even though phenotypically similar, both diseases are genetically heterogeneous, with more than 1000 mutations leading to the absence of or dysfunctional factor VIII or IX molecules that do not support normal thrombin generation or adequate fibrin clot formation.

Despite similarities in hemorrhagic symptoms, there are major differences between hemophilias A and B. Hemophilia A is about five times more common than hemophilia B and is caused by defects in the factor VIII gene, a large 186-kb gene with 26 exons. A common mutation results from inversion and crossing over of intron 22 during meiosis. This mutation leads to severe hemophilia, and because no factor VIII protein is made, these patients are prone to developing antibody inhibitors to therapeutically administered factor VIII that neutralize its coagulant function, making adequate therapy problematic. Approximately 20 percent of severely affected hemophilia A patients develop such inhibitors, whereas only 3 percent or fewer of severely affected hemophilia B patients develop inhibitors against factor IX. About one-third of the mutations in hemophilias A and B arise de novo at CpG “hotspots.” These mutations are apt to occur in the germ cells of a maternal grandfather whose daughters will be carriers and whose grandsons will have a 50 percent chance of having hemophilia.

Replacement therapy is available for both hemophilia A and hemophilia B patients. Safe, effective, and highly purified factor VIII and factor IX concentrates derived from plasma or made by recombinant technology are available for prophylactic therapy to prevent bleeding episodes or prompt treatment of hemorrhagic events. Prophylaxis is the treatment of choice and can prevent disabling joint disease and other hemorrhagic events such that patients can expect a relatively normal life span provided that adequate replacement therapy is available. For patients with inhibitors, factor VIIa and factor VIII inhibitor bypassing activity can be used to “bypass” the factor VIII or factor IX deficiency. Both disorders are good candidates for gene therapy that may eventually lead to their cure.

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Acronyms and Abbreviations:

AAV, adeno-associated virus; aPTT, activated partial thromboplastin time; BT, bleeding time; BU, Bethesda unit; CGA, cytosine, guanine, adenine; CJD, Creutzfeldt-Jakob disease; COX, cyclooxygenase; CRM, cross-reacting material; CT, computed tomography; DDAVP, 1-desamino-8-D-arginine vasopressin (desmopressin); DVT, deep vein thrombosis; EACA, ε-aminocaproic acid; FEIBA, factor VIII inhibitor bypassing activity; GLA, γ-carboxyglutamic acid; Ig, immunoglobulin; PT, prothrombin time; PTC, plasma thromboplastin component (factor IX); RFLP, restriction fragment length polymorphism; TCT, thrombin clotting time; VWD, von ...

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