Lam S C, Dieter J P, Strebel L C, Taylor T M, Muscolino G, Feinberg H, Le Breton G C
Department of Pharmacology, University of Illinois, Chicago.
J Pharmacol Exp Ther. 1991 Dec;259(3):1371-8.
Thrombin promotes the formation of arterial thrombi by converting fibrinogen to fibrin and by causing platelets to aggregate. We have examined the combined effects of plasminogen activators and inhibitors of platelet aggregation on the lysis of platelet-rich fibrin clots formed by alpha-thrombin in citrated platelet-rich plasma. The extent of platelet aggregation and clot formation were measured by recording light transmission in an aggregometer. Immediately after the formation of platelet-rich fibrin clots, addition of 2,000 U/ml streptokinase or 50 micrograms/ml recombinant tissue-type plasminogen activator alone resulted in the degradation of polymerized fibrin and the release of trapped platelet aggregates without causing significant platelet deaggregation. Preincubation of the platelet-rich plasma with 20 microM indomethacin for 1 min before thrombin stimulation or simultaneous addition of prostaglandin E1 (10 microM) with the plasminogen activators after thrombin stimulation resulted in spontaneous platelet deaggregation. Because platelet aggregation is, in part, mediated by the binding of Arg-Gly-Asp-containing adhesive proteins to activated platelets, the effect of Arg-Gly-Asp peptides on platelet deaggregation was examined. By itself, Gly-Arg-Gly-Asp-Ser-Pro specifically caused dose- and time-dependent deaggregation of platelet aggregates formed by ADP or by thrombin in the presence of 1 mM Gly-Pro-Arg-Pro, but had no effect on the dissociation of thrombin-induced platelet-rich fibrin clots. In combination with streptokinase or recombinant tissue-type plasminogen activator, Gly-Arg-Gly-Asp-Ser-Pro enhanced the rate of lysis of platelet-rich fibrin clots. The control Gly-Arg-Gly-Glu-Ser-Pro peptide was completely ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)
凝血酶通过将纤维蛋白原转化为纤维蛋白以及使血小板聚集来促进动脉血栓形成。我们研究了纤溶酶原激活剂和血小板聚集抑制剂对枸橼酸化富血小板血浆中由α-凝血酶形成的富含血小板的纤维蛋白凝块溶解的联合作用。通过在聚集仪中记录光透射来测量血小板聚集和凝块形成的程度。在富含血小板的纤维蛋白凝块形成后立即单独添加2000 U/ml链激酶或50μg/ml重组组织型纤溶酶原激活剂，导致聚合纤维蛋白降解并释放被困的血小板聚集体，而不会引起明显的血小板解聚。在凝血酶刺激前将富血小板血浆与20μM吲哚美辛预孵育1分钟，或在凝血酶刺激后与纤溶酶原激活剂同时添加前列腺素E1（10μM），会导致血小板自发解聚。由于血小板聚集部分是由含精氨酸-甘氨酸-天冬氨酸的粘附蛋白与活化血小板的结合介导的，因此研究了精氨酸-甘氨酸-天冬氨酸肽对血小板解聚的影响。单独使用时，甘氨酸-精氨酸-甘氨酸-天冬氨酸-丝氨酸-脯氨酸在1 mM甘氨酸-脯氨酸-精氨酸-脯氨酸存在下能特异性地引起由ADP或凝血酶形成的血小板聚集体发生剂量和时间依赖性解聚，但对凝血酶诱导的富含血小板的纤维蛋白凝块的解离没有影响。与链激酶或重组组织型纤溶酶原激活剂联合使用时，甘氨酸-精氨酸-甘氨酸-天冬氨酸-丝氨酸-脯氨酸可提高富含血小板的纤维蛋白凝块的溶解速率。对照肽甘氨酸-精氨酸-甘氨酸-谷氨酸-丝氨酸-脯氨酸则完全无效。（摘要截短至250字）
