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Effect of nafamostat mesilate, a synthetic protease inhibitor, on tissue factor-factor VIIa complex activity.
Thrombosis Research 1994 April 16
Nafamostat mesilate (NM), a synthetic protease inhibitor, is frequently used for the treatment of disseminated intravascular coagulation (DIC) in Japan. NM inhibits several proteases which may be importantly involved in the pathophysiology of DIC. Since tissue factor (TF) plays a critical role in DIC associated with septicemia, inhibition of the extrinsic pathway of coagulation by coagulation inhibitors may be useful for the treatment of DIC. NM inhibited extrinsic pathway activity (TF-F.VIIa mediated-F.Xa generation) in a concentration dependent manner; the IC50 was 1.0 x 10(-7) M. F.Xa was not inhibited by NM at the concentrations used in the experiment, suggesting that NM might inhibit TF-F.VIIa complex activity. When incubated with TF-F.VIIa complex, NM inhibited the complex activity with an IC50 of 1.5 x 10(-7) M, the same value that found for inhibition of extrinsic pathway activity. A Lineweaver-Bulk's plot of the inhibition demonstrated that NM inhibited TF-F.VIIa complex in a competitive fashion, with an inhibition constant (Ki) of 2.0 x 10(-7) M. These findings suggested that NM may be a potent inhibitor of TF-F.VIIa complex and the therapeutic effect of NM in DIC patients could be partly explained by inhibition of the extrinsic pathway of the coagulation system.
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