PLATELET REACTIVITY AND DISORDERS OF PLATELET FUNCTION

血小板反应性和血小板功能障碍

• 批准号: 2216131
• 负责人: Harvey J. Weiss
• 金额: $ 30.53万
• 依托单位: ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
• 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 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2216131
• 关键词: G protein; adenosinetriphosphatase; blood coagulation; blood tests; calcium flux; calcium indicator; chemical structure function; fibrinogen; fibrinogen receptors; glycoproteins; granule; hemostasis; human subject; hydrogen; laboratory rabbit; membrane transport proteins; monoclonal antibody; phosphatidylinositols; phospholipase C; platelet activation; platelet aggregation; platelet disorder; platelet factor 4; sodium; thromboxanes; von Willebrand factor; von Willebrand's disease

The overall objectives are two-fold: 1) to continue to explore the biochemical, rheologic, and physiologic factors responsible for congenital disorders of hemostasis due to platelet dysfunction and 2) to utilize patients with well-characterized platelet dysfunction as a means of further defining the mechanisms which regulate normal platelet function. The specific studies toward these objectives are: 1) to examine activation mechanisms which could be abnormal in 7 patients with a new type of platelet dysfunction characterized by impaired platelet responses to weak platelet agonists, including studies on fibrinogen receptor exposure, calcium mobilization and responses, phospholipase C-mediated pathways, Na+/H+ exchange, and G-protein interactions. 2) to study, in patients with dense granule storage pool deficiency (delta-SPD), the basis for the storage defect and to examine no further detail (by measuring alpha-granule release and activation pathways linked to receptor occupancy) the secretion defect in these patients. 3) in SPD patients with combined defects of dense and alpha-granules (alpha/delta-SPD), to study whether the alpha- granule is absent (as distinct form the functionally defective granule in the gray platelet syndrome, alpha-SPD) by utilizing monoclonal antibodies to an alpha-granule specific protein, GMP-140. 4) to study further mechanisms involved in platelet adhesion and thrombus formation on subendothelium under conditions of controlled flow by examining a) the role of von Willebrand factor (vWf) and other adhesion molecules binding to GPIIb-IIIa in platelet adhesion and thrombus formation on subendothelium, utilizing antibodies to the 1737-1750 RGD-containing sequence in vWf, and homologous sequences in other adhesion molecules, which bind uniquely to each adhesive protein; b) the role and mechanism of platelet vWf utilizing platelets from patients with various types of von Willebrand's disease (vWd); c) the structure-function relationships of vWf that may be important for adhesion and thrombus formation utilizing plasmas from vWd patients (Type I, II variants, IIB, I-NY, and pseudo-vWd) that have been carefully characterized for vWf content, multimer characteristics, and platelet- binding properties; d) the hematocrit-dependent platelet adhesion defect in delta-SPD in order to assess further the role of ADP and red cells in promoting platelet adhesion. 4) to investigate further the basis for impaired platelet procoagulant activity (PPA) in Scott Syndrome (reduced Factor Xa binding and impaired phosphatidylserine expression) and to utilize platelets from Scott Syndrome and alpha/delta-SPD to test the hypothesis that the expression of PPA in response to agonists may be related to the fusion of alpha-granules with the plasma membrane and the formation of microvesicles with procoagulant activity. 5) to utilize a newly developed technique for assessing primary hemostasis, by obtaining, in a wide variety of patients with prolonged bleeding times and/or known platelet dysfunction, time-course studies on blood volume, thromboxane B2, platelet factor 4 and fibrinopeptide A in bleeding time blood.

总体目标是两个方面：1）继续探索 造成先天性的生化，流变和生理因素 由于血小板功能障碍而引起的止血疾病，2） 特征良好的血小板功能障碍的患者作为进一步的手段 定义调节正常血小板功能的机制。 这 针对这些目标的具体研究是：1）检查激活 7例患者可能是异常的机制 血小板功能障碍的特征是血小板对弱的血小板反应受损 血小板激动剂，包括有关纤维蛋白原受体暴露的研究， 钙动员和反应，磷脂酶C介导的途径， Na+/H+交换和G蛋白相互作用。 2）研究，在患者中 密集的颗粒存储池缺乏症（Delta-SPD），这是 储存缺陷和不进一步的细节（通过测量α颗粒 与受体占用相关的释放和激活途径）分泌 这些患者的缺陷。 3）在有缺陷的SPD患者中 致密和α颗粒（alpha/delta-spd），以研究alpha-是否存在 颗粒不存在（作为不同形式的功能有缺陷的颗粒 灰血小板综合征，α-SPD）通过利用单克隆抗体 到α颗粒特异性蛋白GMP-140。 4）进一步研究 涉及血小板粘附和血栓形成的机制 通过检查受控流量条件下的内皮下皮，通过检查a）角色 von Willebrand因子（VWF）和其他结合的粘附分子 GPIIB-IIIA在下皮下血小板粘附和血栓形成中， 利用VWF中含有RGD的1737-1750的抗体， 其他粘附分子中的同源序列，它们与 每个粘合剂蛋白； b）血小板VWF利用的作用和机制 来自不同类型的冯·威勒氏病的患者的血小板 （vwd）; c）VWF的结构功能关系可能很重要 用于使用VWD患者的血浆的粘附和血栓形成 （I型，II，IIB，IIB，I-NY和PSEUDO-VWD）已仔细 具有VWF含量，多聚体特征和血小板的特征 结合特性； d）血细胞比容依赖性血小板粘附缺陷 Delta-SPD为了进一步评估ADP和红细胞在 促进血小板粘附。 4）进一步研究 斯科特综合征中的血小板引发活性（PPA）受损（减少 因子Xa结合和磷脂酰丝氨酸表达受损）和对 利用Scott综合征和Alpha/Delta-SPD的血小板来测试 假设PPA对激动剂的表达可能是 与α颗粒与质膜的融合有关 具有凝聚活性的微泡的形成。 5）使用一个 新开发的技术，用于评估原发性止血，通过获得 在多种出血时间和/或已知的患者中 血小板功能障碍，关于血量的时间课程，血栓烷B2， 血小板因子4和纤维蛋白肽A在出血时间血液中。

项目成果

Scott syndrome: a disorder of platelet coagulant activity.

斯科特综合征：血小板凝血活性紊乱。

• 发表时间: 1994
• 期刊: Seminars in hematology
• 影响因子: 3.6
• 作者: Weiss,HJ

Inability of divalent cation complexes of A23187 to induce platelet secretion.

A23187 的二价阳离子复合物无法诱导血小板分泌。

• DOI: 10.1016/0049-3848(83)90132-9
• 发表时间: 1983
• 期刊: Thrombosis research
• 影响因子: 7.5
• 作者: Lages,B;Kruger,C
• 通讯作者: Kruger,C

Impaired platelet response to thromboxane-A2 and defective calcium mobilization in a patient with a bleeding disorder.

出血性疾病患者血小板对血栓素 A2 的反应受损，钙动员缺陷。

• 发表时间: 1981
• 期刊: Blood
• 影响因子: 20.3
• 作者: Lages,B;Malmsten,C;Weiss,HJ;Samuelsson,B
• 通讯作者: Samuelsson,B

Decreased platelet adhesion on vessel segments in von Willebrand's disease: a defect in initial platelet attachment.

冯维勒布兰德氏病血管段上血小板粘附减少：初始血小板粘附缺陷。

• 发表时间: 1983
• 期刊: The Journal of laboratory and clinical medicine
• 作者: Turitto,VT;Weiss,HJ;Baumgartner,HR
• 通讯作者: Baumgartner,HR

Evidence for a role of glycoprotein IIb-IIIa, distinct from its ability to support aggregation, in platelet activation by ionophores in the presence of extracellular divalent cations.

糖蛋白 IIb-IIIa 在细胞外二价阳离子存在的情况下通过离子载体激活血小板的作用不同于其支持聚集的能力的证据。

• 发表时间: 1994
• 期刊: Blood
• 影响因子: 20.3
• 作者: Lages,B;Weiss,HJ
• 通讯作者: Weiss,HJ