PHYSICAL FORCES EFFECTS ON PLATELETS

描述：（改编自研究者摘要）血小板血栓 当血小板被激活，分泌血管活性物质， 促聚集物质和聚集体。 这些血小板反应发展 在调节特定分子间相互作用的流动条件下， 血小板表面受体和细胞外配体。 以前的研究 表明病理性动脉壁剪切应力引起血浆血管内皮细胞生长因子， 维勒布兰德因子（Vwf）与血小板糖蛋白（GP）Ib/IX/V结合 和GPIIb-IIIa复合物，这种结合导致血小板活化 与分泌和聚集有关。 说这一点是为 为了精确地确定大的和异常大的Vwf 多聚体在剪切下与血小板结合， 剪切诱导的血小板-Vwf相互作用，并发出功能反应的信号 从而导致血小板血栓形成。 阐明这些机制 将涉及对正常受试者血小板的研究，以及对 血栓性血小板减少性紫癜（TTP）患者的血小板， 其他疾病。 全身性微血管血小板聚集，产生 器官缺血和血小板减少症，是基本的病理生理事件 在TTP患者中。 血小板过多的确切解释 在这种动脉血栓形成的范例中， 目前尚不清楚。 有间接证据表明Vwf多聚体， 特别是异常大的Vwf形式，可以从刺激或 TTP时内皮细胞受损。 然而，尚不清楚等离子体Vwf 多聚体随后附着于血小板并诱导高密度的血小板聚集。 TTP患者微循环的剪切应力区域。 研究者将通过直接流式细胞术分析确定： Vwf是否在体内与TTP患者的血小板结合;以及，如果 因此，无论Vwf与血小板的附着是否与 血管内血小板活化、聚集和血小板减少症， 描述慢性复发性、单次或多次TTP发作患者的特征 以及其他类型的TTP。 他们还将决定是否启动， 从初始或重度TTP发作的进展和恢复与 伴有：血小板结合Vwf、血小板活化、血小板聚集;以及 与这些血小板参数在体外剪切应力的反应。

DESCRIPTION: (Adapted from investigator's abstract) Platelet thrombus formation occurs when platelets become activated, secrete vasoactive and proaggregatory substances and aggregate. These platelet responses develop under flow conditions that modulate specific molecular interactions between platelet surface receptors and extracellular ligands. Previous studies demonstrate that pathological arterial wall shear stresses cause plasma von Willebrand factor (Vwf) to bind to the platelet glycoprotein (GP) Ib/IX/V and GPIIb-IIIa complexes, and that this binding leads to platelet activation associated with secretion and aggregation. The purpose of this proposal is to determine precisely the mechanisms by which large and unusually large Vwf multimers bind to platelets under shear, influence the threshold of shear-induced platelet-Vwf interaction, and signal the functional responses that lead to platelet thrombus formation. Elucidation of these mechanisms will involve studies on platelets from normal subjects, as well as on platelets from patients with thrombotic thrombocytopenic purpura (TTP) and other disorders. Systemic microvascular platelet aggregation, producing organ ischemia and thrombocytopenia, is the essential pathophysiologic event in patients with TTP. The precise explanation for excessive platelet activation and aggregation in vivo in this paradigm of arterial thrombosis is presently unknown. There is indirect evidence that Vwf multimers, especially unusually large Vwf forms, may be release from stimulated or injured endothelial cells in TTP. It is not known, however, if plasma Vwf multimers subsequently attach to platelets and induce aggregation in high shear stress regions of the microcirculation in TTP patients. The investigators will determine by direct flow cytometric analysis: whether or not Vwf binds to the platelets of TTP patients in vivo; and, if so, whether or not Vwf attachment to platelets occurs concurrently with the intravascular platelet activation, aggregation and thrombocytopenia that characterize TTP episodes in patients who have chronic relapsing, single episode and other types of TTP. They also will determine if the initiation, progression and recovery from incipient or severe TTP episodes correlates with: platelet-bound Vwf, platelet activation, platelet aggregation; and with the response of these platelet parameters in vitro shear stress.