Beviglia L, Poggi A, Rossi C, McLane M A, Calabrese R, Scanziani E, Cook J J, Niewiarowski S
Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), Italy.
Thromb Res. 1993 Aug 15;71(4):301-15. doi: 10.1016/0049-3848(93)90199-x.
The mouse antithrombotic assay represents a model of fatal pulmonary thromboembolism induced by intravenous injection of collagen and epinephrine. Mice were protected by low doses of two disintegrins, albolabrin (10 micrograms/mouse) and eristostatin (0.6 micrograms/mouse), whereas high doses of a thrombin inhibitor and an inhibitor of von Willebrand Factor binding to glycoprotein Ib were not effective. Injection of collagen and epinephrine resulted in the drop of platelet count and accumulation of platelet aggregates in the lung that appears to be the immediate cause of death. Albolabrin or eristostatin administration did not prevent the decrease of platelet count. Injection of albolabrin resulted in the formation of smaller and reversible platelet aggregates in the lungs and decreased accumulation of 51Cr-labeled platelets in the lung suggesting that this disintegrin decreases formation of platelet aggregates in vivo. We compared the effects of albolabrin and erisostatin on platelet aggregation, tail bleeding time, and survival of challenged animals. Eristostatin was about 5 times more potent in inhibiting platelet aggregation in vitro than albolabrin and 38 times more potent than albolabrin in protecting animals from sudden death. Both disintegrins, at the same doses (0.6-5 micrograms/mouse), caused similar dose-dependent prolongation of the bleeding time; however, only eristostatin exerted a protective effect. In conclusion, a) the mouse antithrombotic assay is a suitable model to screen and to evaluate the potency of platelet fibrinogen receptor antagonists in vivo; b) the results of the antithrombotic assay correlate better with the inhibition of platelet aggregation in vitro than with the prolongation of bleeding time.
小鼠抗血栓形成试验是一种通过静脉注射胶原蛋白和肾上腺素诱导致死性肺血栓栓塞的模型。低剂量的两种整合素，即白环蛇毒素（10微克/只小鼠）和抑肽素（0.6微克/只小鼠）可保护小鼠，而高剂量的凝血酶抑制剂以及抑制血管性血友病因子与糖蛋白Ib结合的抑制剂则无效。注射胶原蛋白和肾上腺素会导致血小板计数下降以及肺中血小板聚集体的积累，这似乎是死亡的直接原因。给予白环蛇毒素或抑肽素并不能阻止血小板计数的下降。注射白环蛇毒素会导致肺中形成较小且可逆的血小板聚集体，并减少51Cr标记的血小板在肺中的积累，这表明这种整合素可减少体内血小板聚集体的形成。我们比较了白环蛇毒素和抑肽素对血小板聚集、尾部出血时间以及受攻击动物存活率的影响。抑肽素在体外抑制血小板聚集的效力比白环蛇毒素高约5倍，在保护动物免于猝死方面比白环蛇毒素高38倍。两种整合素在相同剂量（0.6 - 5微克/只小鼠）下，都会引起类似的剂量依赖性出血时间延长；然而，只有抑肽素具有保护作用。总之，a）小鼠抗血栓形成试验是筛选和评估体内血小板纤维蛋白原受体拮抗剂效力的合适模型；b）抗血栓形成试验的结果与体外血小板聚集抑制的相关性比与出血时间延长的相关性更好。
