de Haan J, van Oeveren W
Blood Interaction Research, Cardiopulmonary Surgery, University of Groningen, The Netherlands.
Thromb Res. 1998 Nov 15;92(4):171-9. doi: 10.1016/s0049-3848(98)00130-3.
Blood loss during and after open-heart surgery with cardiopulmonary bypass (CPB) is largely caused by platelet dysfunction. Previous studies indicate that plasmin can induce platelet dysfunction and affect primary hemostasis by proteolytic degradation and/or redistribution of essential platelet membrane glycoprotein complexes such as the glycoprotein Ib/IX complex. In this study, we present a model for plasmin generation localized on the platelet surface. Platelets treated with soluble fibrin or platelets in a mixture with soluble fibrin, t-PA, and plasminogen caused a significantly increased plasmin generation (p<0.01), dependent on t-PA, soluble fibrin, and platelet concentration. The plasmin generation resulted in a downregulation of platelet membrane glycoprotein Ib/IX glycoprotein complexes. Finally, we demonstrated that inhibitors of fibrinolysis, such as %2-antiplasmin, tranexamic acid, and aprotinin, can inhibit plasmin activity in the fluid phase. The downregulation of platelet glycoprotein Ib/IX complexes, however, was only prevented by aprotinin and not by alpha2-antiplasmin and tranexamic acid. These in vitro observations suggest a platelet localized activation of plasminogen, dependent on t-PA, enhanced by the presence of soluble fibrin. Since high concentrations of soluble fibrin and elevated levels of t-PA during CPB are observed, plasmin activity on the platelet surface during this period is anticipated. This plasmin activity reduces platelet metabolic functions and can be directed towards membrane glycoproteins such as glycoprotein Ib/IX complexes, thereby affecting hemostasis during and after CPB.
体外循环心脏直视手术期间及术后的失血主要是由血小板功能障碍引起的。先前的研究表明，纤溶酶可诱导血小板功能障碍，并通过对重要血小板膜糖蛋白复合物（如糖蛋白Ib/IX复合物）进行蛋白水解降解和/或重新分布来影响初级止血。在本研究中，我们提出了一种血小板表面纤溶酶生成的模型。用可溶性纤维蛋白处理的血小板或与可溶性纤维蛋白、组织型纤溶酶原激活物（t-PA）和纤溶酶原混合的血小板导致纤溶酶生成显著增加（p<0.01），这取决于t-PA、可溶性纤维蛋白和血小板浓度。纤溶酶的生成导致血小板膜糖蛋白Ib/IX糖蛋白复合物下调。最后，我们证明了纤维蛋白溶解抑制剂，如α2-抗纤溶酶、氨甲环酸和抑肽酶，可抑制液相中的纤溶酶活性。然而，血小板糖蛋白Ib/IX复合物的下调仅被抑肽酶阻止，而未被α2-抗纤溶酶和氨甲环酸阻止。这些体外观察结果表明，纤溶酶原在血小板局部激活，依赖于t-PA，并因可溶性纤维蛋白的存在而增强。由于在体外循环期间观察到高浓度的可溶性纤维蛋白和t-PA水平升高，预计在此期间血小板表面会有纤溶酶活性。这种纤溶酶活性会降低血小板代谢功能，并可作用于膜糖蛋白，如糖蛋白Ib/IX复合物，从而影响体外循环期间及术后的止血。
