PHYSICAL FORCES EFFECTS ON PLATELETS

描述：(改编自研究人员摘要)血小板血栓 当血小板被激活，分泌血管活性物质和 促进聚集的物质和聚集体。这些血小板反应会产生 在调节特定分子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 证明病理性动脉壁切应力导致血浆von 与血小板膜糖蛋白Ib/Ix/V结合的Willebrand因子(VWF) 和GPIIb-IIIa复合体，这种结合导致血小板激活 与分泌和聚集有关。这项建议的目的是 为了准确地确定大型和异常大的VWF 多聚体在剪切力作用下与血小板结合，影响其阈值 剪切力诱导的血小板-VWF相互作用，并发出功能反应信号 会导致血小板血栓的形成。对这些机制的解释 将涉及正常受试者的血小板研究，以及 血栓性血小板减少性紫癜(TTP)患者和 其他障碍。全身性微血管血小板聚集，产生 器官缺血和血小板减少，是基本的病理生理事件 在患有TTP的患者中。血小板过多的确切解释 动脉血栓形成的体内激活和聚集 目前还不得而知。有间接证据表明VWF的倍增器， 尤其是异常大的VWF形式，可以从刺激或 TTP损伤内皮细胞。然而，尚不清楚血浆VWF是否 多聚体随后附着在血小板上并诱导高水平的聚集。 TTP患者微循环的剪切应力区。 调查人员将通过直接的流式细胞仪分析确定： VWF在体内是否与TTP患者的血小板结合；如果 因此，无论VWF与血小板的附着是否同时发生 血管内血小板活化、聚集和血小板减少 有慢性复发、单身的患者的TTP发作特征 发作和其他类型的TTP。他们还将决定是否启动， 早期或严重TTP发作的进展和恢复相关 与：与血小板结合的VWF、血小板激活、血小板聚集；以及 与这些血小板参数反应的体外剪切力。

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.