Coated platelets function in platelet-dependent fibrin formation via integrin αIIbβ3 and transglutaminase factor XIII
Coated platelets function in platelet-dependent fibrin formation via integrin αIIbβ3 and transglutaminase factor XIII
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DOI：
10.3324/haematol.2015.131441
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发表时间：
2016-04-01
期刊：
影响因子：
10.1
通讯作者：
Cosemans, Judith M. E. M.
中科院分区：
文献类型：
--
作者：
Mattheij, Nadine J. A.;Swieringa, Frauke;Cosemans, Judith M. E. M.
由胶原和凝血酶激活形成的包被的血小板有不同的特征：i)形成一层α颗粒蛋白的蛋白涂层；ii)暴露于促凝血剂磷脂酰丝氨酸；或iii)高纤维蛋白原结合。然而，它们的功能作用仍不清楚。在这里，我们使用一种新型的谷氨酰胺转氨酶探针Rhod-A14来识别具有交联蛋白外壳的一组血小板，并使用一组功能分析将其与其他血小板亚组进行比较。血栓素/凝血酶刺激血小板导致整合素α(IIb)β(3)的初始激活，出现高纤维蛋白原结合的血小板群体(独立于激活的整合蛋白，但依赖于凝血酶的存在)，随后暴露于磷脂酰丝氨酸以及凝血因子Va和Xa的结合。暴露于磷脂酰丝氨酸的一个亚群的血小板在悬浮液中和胶原表面形成的血栓中与Rhod-A14结合。在悬浮液中，高纤维蛋白原和Rhod-A14的结合被联合抑制转谷氨酰胺酶活性和整合素α(IIb)β(3)所拮抗。值得注意的是，在转谷氨酰胺酶XIII缺乏的小鼠的血栓中，整合素α(IIb)β(3)的阻断取消了血小板驱动的纤维蛋白形成和Rhod-A14结合。反之亦然，当谷氨酰胺转氨酶活性被阻断时，缺乏α(IIb)β(3)(Glanzmann Thatbasthenia)的患者的血小板上的星状纤维蛋白形成被取消。我们的结论是，具有初始α(IIb)β(3)激活和高纤维蛋白原结合的包被血小板形成了暴露于磷脂酰丝氨酸的血小板的亚群，并通过转谷氨酰胺酶XIII和整合素α(IIb)β(3)在血小板依赖的星状纤维形成中发挥作用。
Coated platelets, formed by collagen and thrombin activation, have been characterized in different ways: i) by the formation of a protein coat of alpha-granular proteins; ii) by exposure of procoagulant phosphatidylserine; or iii) by high fibrinogen binding. Yet, their functional role has remained unclear. Here we used a novel transglutaminase probe, Rhod-A14, to identify a subpopulation of platelets with a cross-linked protein coat, and compared this with other platelet subpopulations using a panel of functional assays. Platelet stimulation with convulxin/thrombin resulted in initial integrin alpha(IIb)beta(3) activation, the appearance of a platelet population with high fibrinogen binding, (independently of active integrins, but dependent on the presence of thrombin) followed by phosphatidylserine exposure and binding of coagulation factors Va and Xa. A subpopulation of phosphatidylserine-exposing platelets bound Rhod-A14 both in suspension and in thrombi generated on a collagen surface. In suspension, high fibrinogen and Rhod-A14 binding were antagonized by combined inhibition of transglutaminase activity and integrin alpha(IIb)beta(3). Markedly, in thrombi from mice deficient in transglutaminase factor XIII, platelet-driven fibrin formation and Rhod-A14 binding were abolished by blockage of integrin alpha(IIb)beta(3). Vice versa, star-like fibrin formation from platelets of a patient with deficiency in alpha(IIb)beta(3) (Glanzmann thrombasthenia) was abolished upon blockage of transglutaminase activity. We conclude that coated platelets, with initial alpha(IIb)beta(3) activation and high fibrinogen binding, form a subpopulation of phosphatidylserine-exposing platelets, and function in platelet-dependent star-like fibrin fiber formation via transglutaminase factor XIII and integrin alpha(IIb)beta(3).