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Hemophilia A and B are the only two bleeding disorders inherited in a sex-linked pattern. The gene for both disorders is on the long arm of the X-chromosome. Both hemophilias appear as severe, moderate, or mild hemorrhagic diseases each being clinically indistinguishable, at least in individual patients. In the severe form, both hemophilia A and B are characterized by multiple bleeding episodes into joints and other tissues leading to chronic crippling hemarthropathy 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 dysfunctional factor VIII or IX molecules that do not support normal thrombin generation nor adequate fibrin clot formation.

Despite similarities in hemorrhagic symptoms, there are major differences between hemophilia A and B. Hemophilia A is more common 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, resulting in homologous recombination between an a1 gene within intron 22 and extragenic homologous sequences 5′ to intron 22. This leads to severe hemophilia, and these patients are prone to developing antibody inhibitors that neutralize factor VIII coagulant function. Approximately 20 percent of severely affected hemophilia A patients develop 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 hemophilia 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 B patients. Safe, effective, and highly purified factor VIII and 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 “by-pass” the factor VIII or factor IX deficiency. Both disorders are good candidates for gene therapy that may eventually lead to their cure.

Acronyms and Abbreviations

Abbreviations and acronyms that appear in this chapter include: AAV, adeno-associated virus; aPTT, activated partial thromboplastin time; BT, bleeding time; BU, Bethesda unit; cDNA, complementary deoxyribonucleic acid; CGA, cytosine, guanine, adenine; CJD, Creutzfeldt-Jakob disease; COX, cyclooxygenase; CRM, cross-reacting material; CT, computerized 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; ...

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