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

我们之前已经证明，risstocetin是GPIb/IX/V的激活剂，通过人血小板产生TXA2诱导sCD40L的释放。在本研究中，我们研究了抗凝血素- iii （AT-III）对利斯托汀诱导的人血小板GPIb/IX/V活化的影响。AT-III抑制利斯托司汀刺激的血小板聚集。利斯托司汀诱导的11-脱氢- txb2 （TXA2的稳定代谢物）的产生和sCD40L的释放被AT-III抑制。AT-III还能减少利斯托司汀刺激的PDGF-AB分泌。AT-III未能影响TP受体激动剂U46619-诱导p38 MAP激酶磷酸化水平或sCD40L释放。AT-III降低了SZ2（一种针对GPIb α链硫酸化序列的单克隆抗体）与利斯托汀刺激的血小板的结合。这些结果强烈表明，AT-III通过抑制人血小板中TXA2的产生来减少利斯托汀刺激的sCD40L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.