Description
Factor VIII (formerly referred to as antihemophilic globulin and Factor VIII:C) is a large glycoprotein (320 kDa) that circulates in plasma at approximately 200 ng/ml. Synthesized in the liver, the majority of Factor VIII is cleaved during expression, resulting in a heterogeneous mixture of partially cleaved forms of F.VIII ranging in size from 200-280 kDa. The F.VIII is stabilized by association with von Willebrand Factor to form a F.VIII-vWF complex required for the normal survival of F.VIII in vivo (t1/2 of 8-12 hours). F.VIII is a pro-cofactor that is activated through limited proteolysis by thrombin. In this process F.VIIIa dissociates from vWF to combine with activated Factor IX, calcium and a phospholipid surface where it is an essential cofactor in the assembly of the Factor X activator complex. Once dissociated from vWF, F.VIIIa is susceptible to inactivation by activated Protein C and by non-enzymatic decay. Hemophilia A is a congenital bleeding disorder resulting from an X-chromosome-linked deficiency of F.VIII. The severity of the deficiency generally correlates with the severity of the disease. Some Hemophiliacs (~10%) produce a F.VIII protein that is partially or totally inactive. The production of neutralizing antibodies to F.VIII also occurs in 5-20% of Hemophiliacs