FIX Activation on the Surface of Activate Platelets by rFVIIa in the Absence of Tissue Factor

Abstract number: P1260

Gabriel DA, Monroe DM, Roberts HR

The clinical utility of infusion of pharmacologic doses of rFVIIa in patients with severe hemorrhagic events in non-hemophilic patients is well established, but the mechanism by which rFVIIa induces hemostasis is not. We present evidence that at least one procoagulant event resulting from rFVIIa infusion is activation of factor IX (FIX) bound to the surface of activated platelets (AP). Binding coefficients for FIX and FIXa to AP are 8 nM and 2 nM respectively. When FVIIIa is present on the AP surface, FIXa binds more tightly (Kd 0.6 nM). At rFVIIa concentrations <100 nM, no binding to AP can be detected. However, in the presence of FIX interaction of rFVIIa with FIX occurs at concentrations of 1 nM rFVIIa can be detected as evidenced by a decrease in the FIX Kd from 8 to 1.6 nM. When rFVIIa is added to AP in the presence of both FIX and FVIIIa, the Kd for FIX decreases to 0.6 nM, suggesting that rFVIIa activates FIX on the surface of AP in the absence of tissue factor. The activation of FIX by FVIIa on AP can also be demonstrated by a functional assay for FIXa. These data show that pharmacologic doses of rFVIIa results in the direct activation of FIX by rFVIIa to form additional tenase complexes ultimately resulting in improved thrombin generation. These results may explain the mechanism of action of rFVIIa in hemorrhagic conditions seen in otherwise normal patients who develop an acquired coagulopathy due to trauma, surgery or other events in which rFVIIa has been found to be effective.