Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa

Factor VII circulates as a single chain inactive zymogen (10 nmol/L) and a trace (similar to 10-100 pmol/L) circulates as the 2-chain form, factor VII a. Factor VII and factor VIIa were studied in a coagulation model using pla sma concentrations of purified coagulation factors with reactions initiated with relipidated tissue factor (TF). Factor VII (10 nmol/L) extended the l ag phase of thrombin generation initiated by 100 pmol/L factor VIIa and low TF. With the coagulation inhibitors TFPI and AT-III present, factor VII bo th extended the lag phase of the reaction and depressed the rate of thrombi n generation. The inhibition of factor Xa generation by factor VII is consi stent with its competition with factor VIIa for TF Thrombin generation with TF concentrations >100 pmol/L was not inhibited by factor VII. At low tiss ue factor concentrations (<25 pmol/L) thrombin generation becomes sensitive to the absence of factor VIII. In the absence of factor VIII, factor VII s ignificantly inhibits TF-initiated thrombin generation by 100 pmol/L factor VIIa, In this hemophilia A model, approximately 2 nmol/L factor VIIa is ne eded to overcome the inhibition of physiologic (10 nmol/L) factor VII. At 1 0 nmol/L, factor VIIa provided a thrombin generation response in the hemoph ilia model (0% factor VIII, 10 nmol/L factor VII) equivalent to that observ ed with normal plasma, (100% factor VIII, 10 nmol/L factor VII, 100 pmol/L factor VIIa). These results suggest that the therapeutic efficacy of factor VIIa in the medical treatment of hemophiliacs with inhibitors is, in part, based on overcoming the factor VII inhibitory effect, (C) 2000 by The Amer ican Society of Hematology.