Thrombin Binding to Platelets Defines Functional Receptors: Inhibition of Thrombin-Induced Platelet Activation by Catalytically-Inactivated Thrombin

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Abstract
It has been widely questioned as to whether the observed binding of a-thrombin to intact platelets defines receptors coupled to signal transduction or merely thrombin binding sites. We have now shown that at α-thrombin concentrations sufficient to induce a full shape change response without aggregation (0.1 nM), PPACK-thrombin (that is, α-thrombin treated with the irreversible active site inhibitor D-phenylalanyl-L-prolyl-L-arginine chloromethylketone) dose-dependently inhibits platelet shape change (IC50∼70 nM), the concomitant increases in [Ca2+Ii (IC50∼75 nM) and ATP secretion (IC50∼50 nM). Since PPACK-thrombin competes fully in the binding of a-thrombin to high, moderate and low affinity sites on intact platelets, these results show that this binding defines functional receptors coupled to platelet activation.