Coagulation factor VIIa: prohemostatic drug and biomarker for thrombosis

Physiological activation of blood coagulation is initiated by activation of coagulation factor VII to VIIa. A recombinant version of coagulation factor VIIa (rFVIIa) has been developed to treat patients with hemophilia. rFVIIa is effective in the treatment and prevention of bleeding in hemophilia patients who have inhibitory antibodies and therefore cannot be treated anymore by supplementation of the missing coagulation factors FVIII or FIX. The effectiveness of rFVIIa prophylaxis is difficult to explain, because the half-life of rFVIIa is about 2 hours while clinical effects were seen at a once daily administration of the drug. In the first part of this thesis we have investigated possible mechanisms that could explain the pro-hemostatic effect of rFVIIa. Our studies suggest that the prophylactic effect of rFVIIa can be explained by the prolonged presence of low levels rFVIIa in plasma, and by the presence of low concentrations rFVIIa in platelets.

Venous thrombosis is a complex disease for which many risk factors have been identified. For example, traveling by air travel is associated with a 2-4 fold increased risk of developing venous thrombosis. The initiating trigger in the development of a venous thrombus is, however, at present still not known. We show that activation of coagulation during travelling by air probably not, and activation of coagulation in patients with acute venous thrombosis probably are initiated via the extrinsic (FVIIa-mediated) pathway.