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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1330-1335
Inhibition of thrombin generation by the zymogen factor VII:
implications for the treatment of hemophilia A by factor
VIIa
Cornelis van 't Veer,
Neal J. Golden, and
Kenneth G. Mann
From the Department of Biochemistry, University of Vermont,
Burlington, VT.
Factor VII circulates as a single chain inactive zymogen (10 nmol/L)
and a trace (~10-100 pmol/L) circulates as the 2-chain form, factor
VIIa. Factor VII and factor VIIa were studied in a coagulation model
using plasma concentrations of purified coagulation factors with
reactions initiated with relipidated tissue factor (TF). Factor VII (10 nmol/L) extended the lag 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 both extended the lag phase of the reaction
and depressed the rate of thrombin generation. The inhibition of factor
Xa generation by factor VII is consistent with its competition with
factor VIIa for TF. Thrombin generation with TF concentrations >100
pmol/L was not inhibited by factor VII. At low tissue factor
concentrations (<25 pmol/L) thrombin generation becomes sensitive to
the absence of factor VIII. In the absence of factor VIII, factor VII
significantly inhibits TF-initiated thrombin generation by 100 pmol/L
factor VIIa. In this hemophilia A model, approximately 2 nmol/L factor VIIa is needed to overcome the inhibition of physiologic (10 nmol/L) factor VII. At 10 nmol/L, factor VIIa provided a thrombin generation response in the hemophilia model (0% factor VIII, 10 nmol/L factor VII) equivalent to that observed 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.
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