Transmission of a procoagulant signal from tissue factor-bearing cell to platelets.

The goal of the current study was to examine the mechanism by which factor VIIa/tissue factor (TF) activity leads to platelet activation as the first step in initiation of coagulation. Adherent, endotoxin-treated monocytes were used as a cellular source of TF. The processes that led to platelet activation were rapid, since incubation of coagulation factors and platelets with TF for as little as 15 s initiated platelet activation. Further, direct contact between the TF source and platelets was not required since incubation of plasma levels of coagulation zymogens and inhibitors with TF generated the initiating signal for platelet activation. We hypothesized that thrombin generation on the cells that contained TF was the initiating signal for platelet activation. To test this hypothesis, factor VIIa, inhibitors, and different combinations of coagulation zymogens were incubated with TF-bearing cells. The supernatants were then transferred to a suspension of unactivated platelets with plasma concentrations of zymogen factors and inhibitors. Platelet activation was much more efficient when all the elements of the IIase complex (factors II, V and X) were preincubated with factor VIIa/TF than when only factor X was incubated with factor VIIa/TF. Finally, TF was incorporated into lipid vesicles containing phosphatidyl choline either with or without phosphatidyl serine. Vesicles without phosphatidyl serine have no IIase activity. Platelets were incubated with TF, coagulation zymogens and inhibitors. Platelet activation only occurred when the lipid vesicles could support IIase activity. We conclude that sufficient thrombin generation occurs on the TF-bearing cell (or TF-bearing vesicle) in the absence of platelets, to provide the procoagulant signal that leads to platelet activation. The activated platelet surface then provides sites for TF-activated factor IXa to recruit factor Xa to bind and assemble into functional Xase and IIase complexes.