Phillips M D, Moake J L, Nolasco L, Turner N
Baylor College of Medicine, Methodist Hospital, Houston, TX 77030.
Blood. 1988 Dec;72(6):1898-903.
Shear stress activated platelets undergo aggregation in the presence of large or unusually large von Willebrand factor (vWF) multimers without the addition of ristocetin or any other exogenous chemical. This phenomenon may be analogous to the platelet aggregation that leads to thrombosis in the narrowed arteries and arterioles of patients with atherosclerosis or vasospasm. A triphenyl-methyl compound, aurin tricarboxylic acid (ATA), inhibits shear-induced, vWF-mediated platelet aggregation in platelet-rich plasma (PRP) in concentrations above 200 mumol/L and in buffer suspensions of washed platelets at a concentration of 0.1 mumol/L. In a concentration-dependent manner, ATA also inhibits ristocetin-induced, vWF-mediated platelet clumping in both fresh and formaldehyde-fixed platelet suspensions. This inhibition can be overcome by increasing the concentration of vWF, following the kinetics of first order competitive inhibition. ATA prevents the attachment to platelets of the largest vWF multimeric forms found in normal plasma and of the unusually large vWF multimers derived from endothelial cells. The rate of aggregation and degree of inhibition by ATA is not accounted for by the binding of ristocetin or calcium. Arachidonic acid- and adenosine diphosphate (ADP)-induced aggregation are not inhibited by ATA. Platelets incubated with ATA can be easily separated from the compound. However, ATA binds to large vWF multimeric forms and inhibits their ristocetin-induced interaction with platelet glycoprotein Ib. Because ATA also inhibits shear-induced, vWF-mediated platelet aggregation in vitro in the absence of ristocetin, it may be a useful prototype compound to impede the development of arterial thrombosis in vivo.
在不添加瑞斯托霉素或任何其他外源性化学物质的情况下，剪切应力激活的血小板在存在大的或异常大的血管性血友病因子（vWF）多聚体时会发生聚集。这种现象可能类似于导致动脉粥样硬化或血管痉挛患者狭窄动脉和小动脉中血栓形成的血小板聚集。一种三苯甲基化合物，金精三羧酸（ATA），在浓度高于200μmol/L时可抑制富含血小板血浆（PRP）中剪切诱导的、vWF介导的血小板聚集，在洗涤血小板的缓冲液悬浮液中浓度为0.1μmol/L时也可抑制。ATA还以浓度依赖的方式抑制新鲜和甲醛固定的血小板悬浮液中瑞斯托霉素诱导的、vWF介导的血小板聚集。遵循一级竞争性抑制动力学，增加vWF浓度可克服这种抑制作用。ATA可阻止正常血浆中发现的最大vWF多聚体形式以及源自内皮细胞的异常大vWF多聚体与血小板的附着。ATA的聚集速率和抑制程度不能用瑞斯托霉素或钙的结合来解释。花生四烯酸和二磷酸腺苷（ADP）诱导的聚集不受ATA抑制。与ATA孵育的血小板很容易与该化合物分离。然而，ATA与大的vWF多聚体形式结合并抑制它们与血小板糖蛋白Ib的瑞斯托霉素诱导的相互作用。由于ATA在没有瑞斯托霉素的情况下也能在体外抑制剪切诱导的、vWF介导的血小板聚集，它可能是一种在体内阻碍动脉血栓形成的有用原型化合物。
