Molecular mechanism of responses to stress in blood coagulation and fibrinolysis system

我们先前证明，GPIb/IX/V的激活剂Ristoclavin诱导 通过从人血小板产生TXA 2释放sCD 40 L。在 本研究观察了抗凝血酶-Ⅲ（antithrombin-III，AT-Ⅲ）对瑞斯托霉素诱导的人血小板GPIb/IX/V活化的影响。 AT-III抑制瑞斯托菌素刺激的血小板聚集。AT-III抑制瑞斯托菌素诱导的TXA 2稳定代谢产物11-dehydro-TXB 2的产生和sCD 40 L的释放。 AT-III还减少了瑞斯托菌素刺激的PDGF-AB的分泌。AT-III不能影响TP受体激动剂U46619-诱导的p38 MAP激酶磷酸化或sCD 40 L释放水平。AT-III降低了SZ 2（一种针对GPIb α链中硫酸化序列的单克隆抗体）与瑞斯托菌素刺激的血小板的结合。 这些结果强烈地表明，AT-III由于抑制人血小板中TXA 2的产生而减少瑞斯托菌素刺激的sCD 40 L的释放。

We previously demonstrated that ristocetin, an activator of GPIb/IX/V, induces release of sCD40L via TXA2 production from human platelets. In the present study, we investigated the effect of antithrombin-III (AT-III), an anticoagulant, on the ristocetin-induced GPIb/IX/V activation in human platelets. AT-III inhibited ristocetin-stimulated platelet aggregation. The ristocetin-induced production of 11-dehydro-TXB2, a stable metabolite of TXA2, and the release of sCD40L were suppressed by AT-III. AT-III also reduced the ristocetin-stimulated secretion of PDGF-AB. AT-III failed to affect the U46619-, a TP receptor agonist, induced levels of p38 MAP kinase phosphorylation or sCD40L release. AT-III reduced the binding of SZ2, a monoclonal antibody to the sulfated sequence in the alpha-chain of GPIb, to the ristocetin-stimulated platelets. These results strongly suggest that AT-III reduce ristocetin-stimulated release of sCD40L due to inhibiting TXA2 production in human platelets.