van Zanten G H, de Graaf S, Slootweg P J, Heijnen H F, Connolly T M, de Groot P G, Sixma J J
Department of Hematology, University Hospital Utrecht, The Netherlands.
J Clin Invest. 1994 Feb;93(2):615-32. doi: 10.1172/JCI117014.
A ruptured atherosclerotic plaque leads to exposure of deeper layers of the plaque to flowing blood and subsequently to thrombus formation. In contrast to the wealth of data on the occurrence of thrombi, little is known about the reasons why an atherosclerotic plaque is thrombogenic. One of the reasons is the relative inaccessibility of the atherosclerotic plaque. We have circumvented this problem by using 6-microns cryostat cross sections of human coronary arteries. These sections were mounted on coverslips that were exposed to flowing blood in a rectangular perfusion chamber. In normal-appearing arteries, platelet deposition was seen on the luminal side of the intima and on the adventitia. In atherosclerotic arteries, strongly increased platelet deposition was seen on the connective tissue of specific parts of the atherosclerotic plaque. The central lipid core of an advanced plaque was not reactive towards platelets. The results indicate that the atherosclerotic plaque by itself is more thrombogenic than the normal vessel wall. To study the cause of the increased thrombus formation on the atherosclerotic plaque, perfusion studies were combined with immunohistochemical studies. Immunohistochemical studies of adhesive proteins showed enrichment of collagen types I, III, V, and VI, vitronectin, fibronectin, fibrinogen/fibrin, and thrombospondin in the atherosclerotic plaque. Laminin and collagen type IV were not enriched. von Willebrand Factor (vWF) was not present in the plaque. The pattern of increased platelet deposition in serial cross sections corresponded best with areas in which collagen types I and III were enriched, but there were also areas in the plaque where both collagens were enriched but no increased reactivity was seen. Inhibition of platelet adhesion with a large range of antibodies or specific inhibitors showed that vWF from plasma and collagen types I and/or III in the plaque were involved. Fibronectin from plasma and fibronectin, fibrinogen, laminin, and thrombospondin in the vessel wall had no effect on platelet adhesion. We conclude that the increased thrombogenicity of atherosclerotic lesions is due to changes in quantity and nature of collagen types I and/or III.
破裂的动脉粥样硬化斑块会使斑块深层暴露于流动的血液中，随后导致血栓形成。与关于血栓形成的数据丰富相比，对于动脉粥样硬化斑块具有血栓形成倾向的原因却知之甚少。原因之一是动脉粥样硬化斑块相对难以触及。我们通过使用人类冠状动脉6微米厚的低温恒温器切片解决了这个问题。这些切片被安装在盖玻片上，放置在矩形灌注室中暴露于流动的血液中。在外观正常的动脉中，在内膜腔面和外膜上可见血小板沉积。在动脉粥样硬化的动脉中，在动脉粥样硬化斑块特定部位的结缔组织上可见血小板沉积显著增加。晚期斑块的中央脂质核心对血小板无反应。结果表明，动脉粥样硬化斑块本身比正常血管壁更具血栓形成倾向。为了研究动脉粥样硬化斑块上血栓形成增加的原因，将灌注研究与免疫组织化学研究相结合。对黏附蛋白的免疫组织化学研究表明，动脉粥样硬化斑块中I型、III型、V型和VI型胶原蛋白、玻连蛋白、纤连蛋白、纤维蛋白原/纤维蛋白和血小板反应蛋白富集。层粘连蛋白和IV型胶原蛋白未富集。斑块中不存在血管性血友病因子（vWF）。连续切片中血小板沉积增加的模式与I型和III型胶原蛋白富集的区域最相符，但斑块中也存在两种胶原蛋白都富集但未见反应性增加的区域。用多种抗体或特异性抑制剂抑制血小板黏附表明，血浆中的vWF以及斑块中的I型和/或III型胶原蛋白参与其中。血浆中的纤连蛋白以及血管壁中的纤连蛋白、纤维蛋白原、层粘连蛋白和血小板反应蛋白对血小板黏附无影响。我们得出结论，动脉粥样硬化病变血栓形成倾向增加是由于I型和/或III型胶原蛋白的数量和性质发生了变化。
