Deckmyn H
Centrum voor Trombose en Vasculair Onderzoek, K.U. Leuven.
Verh K Acad Geneeskd Belg. 1991;53(6):589-604.
When a blood vessel is disrupted, subendothelial structures such as collagen come into contact with circulating blood platelets. These will adhere and recruit additional platelets to form a platelet aggregate which will close the leak, but which can, under certain circumstances, give rise to the formation of a thrombus. In this work our personal contribution to a better understanding of this process is given. We could demonstrate the presence of an antibody interfering with the platelet-collagen interaction in two patients with a bleeding problem. One of the antibodies is directed against glycoprotein (GP) Ia, a known collagen receptor, the other one recognizes a less well characterized protein of 85-90 kD. It therefore can be concluded that activation of blood platelets requires the simultaneous interaction of collagen with multiple receptors. Activation of platelets following binding of an agonist in many instances involves activation of phospholipase C via a GTP-binding protein or G-protein. We have further studied this by using a direct stimulator of G-proteins, AlF4-, which in platelets indeed activates phospholipase C, together with other systems. Furthermore, we could demonstrate that activation of phospholipase C in a GTP-dependent manner also occurs in platelet cytosol, indicating that the action of G-proteins is not restricted to membrane-linked phenomena. Activation of phospholipase C gives rise to the formation of inositol phosphates, of which mainly inositol 1, 4, 5 trisphosphate increases intracellular Ca(2+)-levels. Following this, the Ca(2+)-dependent phospholipase A2 releases arachidonic acid from the membranes. In platelets arachidonic acid is metabolised to another platelet activator: thromboxane A2. We have studied the effects of the inhibition of this aggregation-amplifying pathway by using specific inhibitors of the synthesis of thromboxane A2 and of thromboxane A2 receptor antagonists both in vitro and in vivo. One of the conclusions that were reached from these studies was that theoretically the combination of these two classes of drugs should yield a significant stronger antiplatelet effect than either class used alone. We could later on confirm this hypothesis, which stimulated some pharmaceutical companies to look for dual action compounds, of which we have studied two so far.(ABSTRACT TRUNCATED AT 400 WORDS)
当血管受损时，诸如胶原蛋白等内皮下结构会与循环血液中的血小板接触。这些血小板会黏附并募集更多血小板，形成血小板聚集体，从而封闭血管破损处，但在某些情况下，这可能会导致血栓形成。在这项研究中，我们阐述了自己在深入理解这一过程方面所做的贡献。我们在两名有出血问题的患者体内发现了一种干扰血小板与胶原蛋白相互作用的抗体。其中一种抗体针对糖蛋白（GP）Ia，这是一种已知的胶原蛋白受体，另一种抗体识别的是一种特征尚不明确的85 - 90kD蛋白质。因此可以得出结论，血小板的激活需要胶原蛋白与多种受体同时相互作用。在许多情况下，激动剂结合后血小板的激活涉及通过鸟苷酸结合蛋白或G蛋白激活磷脂酶C。我们通过使用G蛋白的直接刺激剂AlF4 - 进一步研究了这一过程，AlF4 - 在血小板中确实能激活磷脂酶C以及其他系统。此外，我们还证明了磷脂酶C在血小板胞质溶胶中也以GTP依赖的方式被激活，这表明G蛋白的作用并不局限于膜相关现象。磷脂酶C的激活会导致肌醇磷酸的形成，其中主要是肌醇1,4,5 - 三磷酸会升高细胞内钙离子水平。在此之后，钙依赖性磷脂酶A2会从细胞膜释放花生四烯酸。在血小板中，花生四烯酸会代谢为另一种血小板激活剂：血栓素A2。我们使用血栓素A2合成的特异性抑制剂和血栓素A2受体拮抗剂，在体外和体内研究了抑制这一聚集放大途径的效果。这些研究得出的结论之一是，从理论上讲，这两类药物联合使用产生的抗血小板作用应比单独使用任何一类药物都要强得多。我们后来证实了这一假设，这促使一些制药公司去寻找具有双重作用的化合物，到目前为止我们已经研究了其中两种。（摘要截选至400字）
