The Molecular Pathogenesis of Hemophilia A

Hemophilia A (OMIM 306700) is caused by defects in the gene coding the coagulation factor VIII. A total absence or partial reduction of factor VIII coagulation activity is observed in the plasma of patients. Hemophilia is classified as severe (<1%), moderate (1-5%) or mild (5-40%), depending on the scale of the deficit. The severity of bleeding symptoms correlates quite accurately with the scale of the deficit. Patients with the severe form of hemophilia typically bleed several times a month, often spontaneously, especially into weightbearing joints and muscles. Patients with milder forms of the disease have excessive bleeding during small traumatic injuries or during surgical or dental procedures. For research purposes, the coagulation activity in plasma (FVIII:C) can be compared with plasmatic level of the antigen (FVIII:Ag, CRM - cross-reactive material). This allows to distinguish the CRMnegative phenotype, i. e. the total absence of factor VIII in plasma, the CRM-positive phenotype, i. e. the presence of dysfunctional factor VIII in plasma (defined as a FVIII:C/FVIII:Ag ratio of <0.3), and hemophilia A with reduced CRM, when plasma levels of functional factor VIII are reduced. The most serious complication of replacement therapy in hemophilia A is the creation of factor VIII inhibiting antibodies. This occurs in 10-35% of patients with the severe form of the disease. An inhibitor of the activity of one Bethesda unit reduces factor VIII activity in normal plasma by 50 per cent.

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