Stringer H A, van Swieten P, Heijnen H F, Sixma J J, Pannekoek H
Department of Molecular Biology, Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Amsterdam.
Arterioscler Thromb. 1994 Sep;14(9):1452-8. doi: 10.1161/01.atv.14.9.1452.
To investigate the potential role of plasminogen activator inhibitor-1 (PAI-1), which is released from the alpha-granules of activated platelets, in thrombolysis resistance, we employed a model (the "Chandler loop") that mimics the formation of arterial thrombi in vivo and that can be manipulated in terms of rheological parameters and composition of blood cells. Light and electron microscopy revealed that the distribution of blood cells in Chandler thrombi is polarized, as it is in arterial thrombi, resulting in platelet-rich "white heads" and red blood cell-rich "red tails.". Resistance toward tissue-type plasminogen activator (TPA)-mediated thrombolysis parallels the presence of platelets that are fully activated in this system. We demonstrate that the PAI-1 released by the alpha-granules is preferentially retained within the thrombus and that the concentration of PAI-1 antigen is higher in the head than in the tail of the thrombus. The relative thrombolysis resistance of the heads of Chandler thrombi can be largely abolished by inclusion of an anti-PAI-1 monoclonal antibody that blocks that inhibitory activity of PAI-1 toward TPA. We propose that PAI-1, released from activated platelets, plays a key role in thrombolysis resistance and/or reocclusion after thrombolytic therapy. This is due to binding of PAI-1 to polymerized fibrin within the thrombus, followed by inhibition of TPA-mediated fibrinolysis.
为了研究从活化血小板的α颗粒释放的纤溶酶原激活物抑制剂-1（PAI-1）在溶栓抵抗中的潜在作用，我们采用了一种模型（“钱德勒环”），该模型模拟体内动脉血栓的形成，并且可以在流变学参数和血细胞组成方面进行操控。光学显微镜和电子显微镜显示，钱德勒血栓中的血细胞分布呈极化状态，就像在动脉血栓中一样，导致富含血小板的“白头”和富含红细胞的“红尾”。对组织型纤溶酶原激活物（TPA）介导的溶栓的抵抗与该系统中完全活化的血小板的存在情况平行。我们证明，α颗粒释放的PAI-1优先保留在血栓内，并且PAI-1抗原的浓度在血栓头部高于尾部。通过加入一种抗PAI-1单克隆抗体来阻断PAI-1对TPA的抑制活性，钱德勒血栓头部相对的溶栓抵抗在很大程度上可以被消除。我们提出，从活化血小板释放的PAI-1在溶栓抵抗和/或溶栓治疗后的再闭塞中起关键作用。这是由于PAI-1与血栓内聚合的纤维蛋白结合，随后抑制TPA介导的纤维蛋白溶解。
