PLATELET REACTIVITY AND DISORDERS OF PLATELET FUNCTION

血小板反应性和血小板功能障碍

• 批准号: 3339121
• 负责人: Harvey J. Weiss
• 金额: $ 24.59万
• 依托单位: ST. LUKE'S-ROOSEVELT INST FOR HLTH SCI
• 依托单位国家: 美国
• 财政年份: 1975
• 资助国家: 美国
• 起止时间: 1975-01-01 至 1989-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3339121
• 关键词: antithrombogenic surface; arachidonate; bioassay; bioenergetics; blood tests; calcium; cell adhesion; collagen; cyclic AMP; cytoskeleton; fatty acid metabolism; fibronectins; glycoproteins; hemostasis; histology; human subject; ionophores; lipid metabolism; phosphatidylinositols; phospholipids; phosphorylation; platelet aggregation; platelet disorder; prostaglandins; thrombocytopathy; thromboxanes; vascular endothelium; von Willebrand's disease

The overall aim of the proposal is to study the biochemical and physiological bases for the platelet abnormalities observed in patients with a wide variety of hemostatic defects. The project will study 1) In storage pool deficiency (SPD) (N=18) associated with heterogeneous defects in platelet Yield and dense granules, the nature of the granule defects (nucleotide and calcium transport, mepacrine and uranaffin studies) and their relation to the aggregation abnormalities, the pathogenesis of the secretion defect (role of ADP, abnormalities in prostaglandandin/TxA2 pathways), and contribution of platelet granules to platelet-subendothelial interaction. 2) In patients with primary secretion defects (N-15) who have been shown to have heterogeneous abnormalities in aggregation/secretion responses and TxA2 formation, the nature of these abnormalities through extensive studies on phospholipid and arachidonic acid (AA) metabolism (including stimulus-induced changes of phospholipid and 3H-AA metabolites (PA, TxB2, HHT, and HETE) and polyphosphoinositides, calcium mobilization, cAMP, energy metabolism, protein phosphorylation (including specific studies on possible abnormalities of 47K protein in granule extrusion), and possible cytoskeletal defects in resting and stimulated platelets. 3) In thrombasthenia (TSA) (N=5), possible defects in cytoskeletal proteins or assembly and the role of GPIIb-IIIa in mediating platelet adhesion. 4) In patients with new types of adhesion defects [different than the Bernard Soulier Syndrome (BSS)] the nature of the defect (contact vs spreading) utilizing appropriate flow conditions for maximizing defects in surface kinetics, and its possible basis, such as abnormalities in FVIII/VWF, glycoproteins and fibronectin. 5) Aspects of platelet procoagulant abnormalities, including possible defects of FVa binding in FXa-binding abnormality and the role of various platelet-related properties in coagulation by studying fibrin deposition and fibrinopeptide A release on subendothelium in patients with a variety of platelet disorders (FXa defect, TSA, BSS, SPD, and secretion defects) utilizing flow conditions in which differences between FVIII and FIX vs FXII and XI patients have been demonstrated. 6) In pseudo-von Willebrand's disease (and related disorders) possible defects in platelet glycoproteins, FVIII/VWF binding, platelet-subendothelial attachment, and possible therapy. 7) Utilizing a technique recently developed in our laboratory, primary hemostasis in a wide variety of patients with hemostatic defects by quantitative measurement of various bleeding time parameters and time-course studies on TxB2, 6-keto-PGF1alpha, PF4, and FPA.

该提案的总体目的是研究生化和 患者观察到的血小板异常的生理碱基 有多种止血缺陷。 该项目将研究1） 存储池缺乏症（SPD）（n = 18）与异质缺陷相关 在血小板的产量和致密颗粒中，颗粒缺陷的性质 （核苷酸和钙转运，巨氨酸和脉脉脉络素研究）和 它们与聚集异常的关系， 分泌缺陷（ADP的作用，异常在Prostaglandandin/txa2中的作用 途径），以及血小板颗粒对血小板肌层的贡献 相互作用。 2）在患有主要分泌缺陷的患者中（N-15） 被证明在聚集/分泌中具有异质异常 反应和TXA2形成，这些异常的性质 关于磷脂和花生四烯酸（AA）代谢的广泛研究 （包括刺激引起的磷脂和3H-AA代谢产物的变化 （PA，TXB2，HHT和HETE）和多磷酸肌醇，钙动员， 营地，能量代谢，蛋白质磷酸化（包括特定 研究颗粒挤出中47K蛋白的可能异常）和 静止和刺激血小板中可能的细胞骨架缺陷。 3）in 血栓性（TSA）（n = 5），细胞骨架蛋白或 组装和GPIIB-IIIA在介导血小板粘附中的作用。 4）in 具有新型粘附缺陷类型的患者[与Bernard不同 Soulier综合征（BSS）]缺陷的性质（接触与传播） 利用适当的流条件使表面中的缺陷最大化 动力学及其可能的基础，例如FVIII/VWF异常 糖蛋白和纤连蛋白。 5）血小板procogulant的各个方面 异常，包括FXA结合中FVA结合的可能缺陷 异常和各种血小板相关特性的作用 通过研究纤维蛋白沉积和纤维蛋白肽的凝结 多种血小板疾病患者的内皮（FXA） 缺陷，TSA，BSS，SPD和分泌缺陷）利用流动条件 FVIII和FIX与FXII和XI患者之间的差异是 证明。 6）在伪冯·威勒布兰氏病（及相关） 疾病）血小板糖蛋白，FVIII/VWF结合的可能缺陷， 血小板 - 肌关系附着和可能的治疗。 7）利用一个 最近在我们的实验室开发的技术，主要止血 各种各样的止血性缺陷的患者通过定量 测量各种出血时间参数和有关时间表的研究 TXB2，6-酮PGF1Alpha，PF4和FPA。