What is the mechanism of action of recombinant Factor VIIa in hemophilia?
  Patients with hemophilia who develop inhibitors (usually antibodies) to Factor VIII or Factor IX no longer respond to traditional replacement therapy because the inhibitors neutralize plasma-derived or recombinant factor VIII or factor IX, negating their effect on hemostasis. Inhibitors in persons with hemophilia A or hemophilia B are alloantibodies of the IgG class, usually subtypes IgG1 and IgG4. Inhibitors occur either in patients with congenital factor deficiencies, in which case they are alloimmune antibodies, or in previously unaffected individuals, in which case they are termed autoimmune antibodies, or acquired hemophilia. However, a high dose of recombinant Factor VIIa bypasses the need for Factor VIII or Factor IX, thus establishing effective hemostasis. Whenever bleeding occurs in a patient with a normal coagulation system, factor VII is naturally activated to Factor VIIa by its interaction with tissue factor (TF) at the site of injury. This Factor VIIa/TF complex initiates coagulation. Patients with hemophilia usually have normal levels of factor VII in their blood and minute amounts of factor VIIa. The concentration of factor VIII or factor IX is severely reduced and, as a result these patients cannot form a solid and stable fibrin clot despite the initiation of normal coagulation. The addition of recombinant Factor VIIa at 90 microgram/kg, corresponding to a plasma concentration of 300-500 times the normal level of Factor VIIa, can compensate for the lack of Factor VIII or Factor IX. Further, normal hemostasis requires activation of both Factor X and Factor IX. Factor VIIa/tissue factor (TF)-activated Factor Xa and Factor IXa play distinct roles in coagulation. Factor Xa cannot move to the platelet surface because of the presence of normal plasma inhibitors, but instead remains on the TF-bearing cell and activates a small amount of thrombin. This thrombin is not sufficient for fibrinogen cleavage but is critical for hemostasis since it can activate platelets, activate and release Factor VIII from von Willebrand factor (vWF), activate platelet and plasma Factor V, and activate Factor XI. Factor IXa moves to the platelet surface, where it forms a complex with FVIIIa and activates Factor X on the platelet surface. This platelet surface Factor Xa is relatively protected from normal plasma inhibitors and can complex with platelet surface Factor Va, where it activates thrombin in quantities sufficient to provide for fibrinogen cleavage. Recombinant factor VIIa thus bypasses the normal coagulation process and induces thrombin generation, that leads to the formation of a stabilized and solid fibrin hemostatic plug. This process is independent of inhibitor titre. In summary, in all hemophilia A and B patients with inhibitors recombinant Factor VIIa quickly and effectively activates the clotting process at the site of injury.
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