Division of Cardiology, Department of Medicine, University of Florida College of Medicine -Jacksonville, Shands Jacksonville, 655 West 8th St, Jacksonville, FL 32209, USA.
Eur Heart J. 2010 Jan;31(1):17-28. doi: 10.1093/eurheartj/ehp504. Epub 2009 Nov 30.
Clinical manifestations of atherothrombotic disease, such as acute coronary syndromes, cerebrovascular events, and peripheral arterial disease, are major causes of mortality and morbidity worldwide. Platelet activation and aggregation are ultimately responsible for the progression and clinical presentations of atherothrombotic disease. The current standard of care, dual oral antiplatelet therapy with aspirin and the P2Y(12) adenosine diphosphate (ADP) receptor inhibitor clopidogrel, has been shown to improve outcomes in patients with atherothrombotic disease. However, aspirin and P2Y(12) inhibitors target the thromboxane A(2) and the ADP P2Y(12) platelet activation pathways and minimally affect other pathways, while agonists such as thrombin, considered to be the most potent platelet activator, continue to stimulate platelet activation and thrombosis. This may help explain why patients continue to experience recurrent ischaemic events despite receiving such therapy. Furthermore, aspirin and P2Y(12) receptor antagonists are associated with bleeding risk, as the pathways they inhibit are critical for haemostasis. The challenge remains to develop therapies that more effectively inhibit platelet activation without increasing bleeding complications. The inhibition of the protease-activated receptor-1 (PAR-1) for thrombin has been shown to inhibit thrombin-mediated platelet activation without increasing bleeding in pre-clinical models and small-scale clinical trials. PAR-1 inhibition in fact does not interfere with thrombin-dependent fibrin generation and coagulation, which are essential for haemostasis. Thus PAR-1 antagonism coupled with existing dual oral antiplatelet therapy may potentially offer more comprehensive platelet inhibition without the liability of increased bleeding.
动脉粥样硬化血栓形成疾病的临床表现，如急性冠状动脉综合征、脑血管事件和外周动脉疾病，是全球死亡和发病的主要原因。血小板的激活和聚集是动脉粥样硬化血栓形成疾病进展和临床表现的最终原因。目前的标准治疗方法是双重口服抗血小板治疗，即阿司匹林和 P2Y(12)二磷酸腺苷（ADP）受体抑制剂氯吡格雷，已被证明可改善动脉粥样硬化血栓形成疾病患者的预后。然而，阿司匹林和 P2Y(12)抑制剂靶向血栓素 A(2)和 ADP P2Y(12)血小板激活途径，对其他途径的影响很小，而激动剂如凝血酶，被认为是最强的血小板激活剂，继续刺激血小板激活和血栓形成。这可能有助于解释为什么尽管接受了这种治疗，患者仍继续经历复发性缺血事件。此外，阿司匹林和 P2Y(12)受体拮抗剂与出血风险相关，因为它们抑制的途径对止血至关重要。仍然存在的挑战是开发更有效地抑制血小板激活而不增加出血并发症的治疗方法。在临床前模型和小规模临床试验中，已证明凝血酶的蛋白酶激活受体-1 (PAR-1)抑制剂可抑制凝血酶介导的血小板激活，而不会增加出血。事实上，PAR-1 抑制不会干扰依赖于凝血酶的纤维蛋白生成和凝血，这对止血至关重要。因此，PAR-1 拮抗剂与现有的双重口服抗血小板治疗相结合，可能在不增加出血风险的情况下提供更全面的血小板抑制作用。
