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Thromb Haemost 1997; 78(04): 1202-1208
DOI: 10.1055/s-0038-1657715
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Schattauer GmbH Stuttgart

The Effect of Active Site-inhibited Factor VIIa on Tissue Factor-initiated Coagulation Using Platelets before and after Aspirin Administration

Marianne Kjalke
1   The Center for Thrombosis and Hemostasis, University of North Carolina at Chapel Hill, NC, USA
3   The Vessel Wall Biology, Novo Nordisk, Gentofte, Denmark
,
Julie A Oliver
1   The Center for Thrombosis and Hemostasis, University of North Carolina at Chapel Hill, NC, USA
2   The Department of Pathology, Duke University, Durham, NC, USA
,
Dougald M Monroe
1   The Center for Thrombosis and Hemostasis, University of North Carolina at Chapel Hill, NC, USA
,
Maureane Hoffman
2   The Department of Pathology, Duke University, Durham, NC, USA
,
Mirella Ezban
3   The Vessel Wall Biology, Novo Nordisk, Gentofte, Denmark
,
Ulla Hedner
3   The Vessel Wall Biology, Novo Nordisk, Gentofte, Denmark
,
Harold R Roberts
1   The Center for Thrombosis and Hemostasis, University of North Carolina at Chapel Hill, NC, USA
› Author Affiliations
Further Information

Publication History

Received 01 1997

Accepted after revision 13 June 1997

Publication Date:
12 July 2018 (online)

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Summary

Active site-inactivated factor VIIa has potential as an antithrombotic agent. The effects of D-Phe-L-Phe-L-Arg-chloromethyl ketone-treated factor VIla (FFR-FVIIa) were evaluated in a cell-based system mimicking in vivo initiation of coagulation. FFR-FVIIa inhibited platelet activation (as measured by expression of P-selectin) and subsequent large-scale thrombin generation in a dose-dependent manner with IC50 values of 1.4 ± 0.8 nM (n = 8) and 0.9 ± 0.7 nM (n = 7), respectively. Kd for factor VIIa binding to monocytes ki for FFR-FVIIa competing with factor VIIa were similar (11.4 ± 0.8 pM and 10.6 ± 1.1 pM, respectively), showing that FFR-FVIIa binds to tissue factor in the tenase complex with the same affinity as factor VIIa. Using platelets from volunteers before and after ingestion of aspirin (1.3 g), there were no significant differences in the IC50 values of FFR-FVIIa [after aspirin ingestion, the IC50 values were 1.7 ± 0.9 nM (n = 8) for P-selectin expression, p = 0.37, and 1.4 ± 1.3 nM (n = 7) for thrombin generation, p = 0.38]. This shows that aspirin treatment of platelets does not influence the inhibition of tissue factor-initiated coagulation by FFR-FVIIa, probably because thrombin activation of platelets is not entirely dependent upon expression of thromboxane A2.

 

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