Verstraete M, Zoldhelyi P
Center for Molecular and Vascular Biology, University of Leuven, Belgium.
Drugs. 1995 Jun;49(6):856-84. doi: 10.2165/00003495-199549060-00002.
Platelet activation plays a critical role in thromboembolic disorders, and aspirin remains a keystone in preventive strategies. This remarkable efficacy is rather unexpected, as aspirin selectively inhibits platelet aggregation mediated through activation of the arachidonic-thromboxane pathway, but not platelet aggregation induced by adenosine diphosphate (ADP), collagen and low levels of thrombin. This apparent paradox has stimulated investigations on the effect of aspirin on eicosanoid-independent effects of aspirin on cellular signalling. It has also fostered the search for antiplatelet drugs inhibiting platelet aggregation at other levels than the acetylation of platelet cyclo-oxygenase, such as thromboxane synthase inhibitors and thromboxane receptor antagonists. The final step of all platelet agonists is the functional expression of glycoprotein (GP) IIb/IIIa on the platelet surface, which ligates fibrinogen to link platelets together as part of the aggregation process. Agents that interact between GPIIb/IIIa and fibrinogen have been developed, which block GPIIb/IIIa, such as monoclonal antibodies to GPIIb/IIIa, and natural and synthetic peptides (disintegrins) containing the Arg-Gly-Asp (RGD) recognition sequence in fibrinogen and other adhesion macromolecules. Also, some non-peptide RGD mimetics have been developed which are orally active prodrugs. Stable analogues of prostacyclin, some of which are orally active, are also available. Thrombin has a pivotal role in both platelet activation and fibrin generation. In addition to natural and recombinant human antithrombin III, direct antithrombin III-independent thrombin inhibitors have been developed as recombinant hirudin, hirulog, argatroban, boroarginine derivatives and single stranded DNA oligonucleotides (aptanes). Direct thrombin inhibitors do not affect thrombin generation and may leave some 'escaping' thrombin molecules unaffected. Inhibition of factor Xa can prevent thrombin generation and disrupt the thrombin feedback loop that amplifies thrombin production.
血小板活化在血栓栓塞性疾病中起关键作用，阿司匹林仍是预防策略的基石。这种显著的疗效相当出人意料，因为阿司匹林选择性抑制通过花生四烯酸 - 血栓素途径激活介导的血小板聚集，但不抑制由二磷酸腺苷（ADP）、胶原和低水平凝血酶诱导的血小板聚集。这一明显的矛盾激发了对阿司匹林对细胞信号转导中类花生酸非依赖性作用影响的研究。这也促使人们寻找在血小板环氧化酶乙酰化以外的其他水平抑制血小板聚集的抗血小板药物，如血栓素合酶抑制剂和血栓素受体拮抗剂。所有血小板激动剂的最后一步是血小板表面糖蛋白（GP）IIb/IIIa的功能性表达，在聚集过程中，它连接纤维蛋白原将血小板连接在一起。已经开发出了在GPIIb/IIIa和纤维蛋白原之间相互作用的药物，这些药物可阻断GPIIb/IIIa，如抗GPIIb/IIIa单克隆抗体，以及在纤维蛋白原和其他粘附大分子中含有精氨酸 - 甘氨酸 - 天冬氨酸（RGD）识别序列的天然和合成肽（去整合素）。此外，还开发了一些口服活性前药形式的非肽RGD模拟物。前列环素的稳定类似物也有一些是口服活性的。凝血酶在血小板活化和纤维蛋白生成中都起关键作用。除了天然和重组人抗凝血酶III外，还开发了直接非抗凝血酶III依赖性凝血酶抑制剂，如重组水蛭素、hirulog、阿加曲班、硼精氨酸衍生物和单链DNA寡核苷酸（适体）。直接凝血酶抑制剂不影响凝血酶的生成，可能会使一些“逃逸”的凝血酶分子不受影响。抑制因子Xa可防止凝血酶生成并破坏放大凝血酶产生的凝血酶反馈环。
