Bates S M, Weitz J I
McMaster University and Hamilton Civic Hospitals Research Centre, Ontario, Canada.
Am J Cardiol. 1998 Oct 22;82(8B):12P-18P. doi: 10.1016/s0002-9149(98)00660-2.
Given the central role of thrombin in arterial thrombogenesis, most treatment strategies for acute coronary syndromes are aimed at inhibiting its generation or blocking its activity. Although heparin has been widely used, it has limitations in the setting of arterial thrombosis. These limitations reflect the inability of heparin to inactivate thrombin bound to fibrin, a major stimulus for thrombus growth. In addition, the anticoagulant response to heparin varies from patient to patient, and heparin is neutralized by platelet Factor IV, large quantities of which are released from platelets activated at sites of plaque rupture. Consequently, heparin requires careful laboratory monitoring to ensure an adequate anticoagulant effect. Direct thrombin inhibitors, such as hirudin and bivalirudin, overcome the limitations of heparin. These agents inhibit fibrin-bound thrombin, as well as fluid-phase thrombin, and produce a predictable anticoagulant response. Bivalirudin has both safety and potential efficacy advantages over hirudin. Bivalirudin appears to have a wider therapeutic window than hirudin, possibly because bivalirudin only transiently inhibits the active site of thrombin. The better safety profile of bivalirudin permits administration of higher doses, which may give it an efficacy advantage. Hirudin prevents thrombin from activating protein C, thereby suppressing this natural anticoagulant pathway. In contrast, bivalirudin may promote protein C activation by transiently inhibiting thrombin until it can be bound by thrombomodulin. Differences between bivalirudin and hirudin, as well as other direct thrombin inhibitors, highlight the pitfalls of considering all direct thrombin inhibitors to have equivalent risk-benefit profiles.
鉴于凝血酶在动脉血栓形成中的核心作用，大多数急性冠脉综合征的治疗策略旨在抑制其生成或阻断其活性。尽管肝素已被广泛使用，但它在动脉血栓形成的情况下存在局限性。这些局限性反映了肝素无法使与纤维蛋白结合的凝血酶失活，而纤维蛋白是血栓生长的主要刺激因素。此外，患者对肝素的抗凝反应因人而异，并且肝素会被血小板因子IV中和，大量的血小板因子IV从斑块破裂部位激活的血小板中释放出来。因此，肝素需要仔细的实验室监测以确保足够的抗凝效果。直接凝血酶抑制剂，如水蛭素和比伐卢定，克服了肝素的局限性。这些药物既能抑制与纤维蛋白结合的凝血酶，也能抑制液相凝血酶，并产生可预测的抗凝反应。与水蛭素相比，比伐卢定具有安全性和潜在疗效优势。比伐卢定的治疗窗似乎比水蛭素更宽，可能是因为比伐卢定仅短暂抑制凝血酶的活性位点。比伐卢定更好的安全性允许给予更高剂量，这可能使其具有疗效优势。水蛭素可阻止凝血酶激活蛋白C，从而抑制这种天然抗凝途径。相比之下，比伐卢定可能通过短暂抑制凝血酶直到它能被血栓调节蛋白结合来促进蛋白C的激活。比伐卢定与水蛭素以及其他直接凝血酶抑制剂之间的差异，凸显了认为所有直接凝血酶抑制剂具有相同风险效益的陷阱。
