Pathogenesis of Thrombocytopenia Induced by GPIIb/IIIa Inhibitors

GPIIb/IIIa抑制剂引起的血小板减少症的发病机制

• 批准号: 7140693
• 负责人: Richard Herbert Aster
• 金额: $ 31.71万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140693
• 关键词: CHO cells; blood coagulation; blood toxicology; blood transfusion; cellular pathology; clinical research; disease /disorder etiology; drug adverse effect; epitope mapping; human subject; immune response; immunoglobulin G; immunoglobulin M; immunotoxicity; inhibitor /antagonist; integrins; laboratory mouse; method development; molecular pathology; monoclonal antibody; neurotransmitter transport; selectins; serotonin; thrombocytopenia

Agents that inhibit the reaction of activated GPIIb/IIIa (alphallb/betaS integrin) with fibrinogen and other ligands are a promising family of anti-thrombotics now widely used to prevent adverse events following coronary angioplasty. Acute, severe thrombocytopenia, often occurring within hours of first exposure to one of these agents, is a recognized side effect of all drugs in this class. In the previous period of support, we obtained evidence that drug-specific antibodies, which can be naturally occurring (or at least pre-existing), are the major cause of this complication, characterized clinical and serologic aspects of this group of disorders and obtained evidence that the responsible antibodies recognize ligand (drug)-induced structural conformers of GPIIb/IIIa. We now propose to extend these observations with the following specific aims: 1) Characterize epitopes on GPIIb/IIIa recognized by antibodies causing thrombocytopenia in patients treated with GPIIb/IIIa inhibitors. Epitopes on ligand-occupied GPIIb/IIIa for which this apparently unique class of immunoglobulins is specific will be defined at the molecular level. 2) Develop new methods for identification of clinically significant antibodies not detected in conventional immunoassays. We hypothesize that platelet destruction in a significant subset of patients is caused by low affinity antibodies not detected in most immunoassays and propose to improve diagnostic yield with assays that a) detect antibody binding in real time and/or b) increase the Ka by preserving the structural integrity of the target. 3) Characterize the incidence, clinical significance and genetic origin of pre-existing ("naturally occurring") immunoglobulins (NA) that recognize GPIIb/IIIa-inhibitor complexes. The incidence of potentially "dangerous" NA specific for ligand-occupied GPIIb/IIIa in the general population, their genetic origin and their relationship to antibodies causing thrombocytopenia will be defined and their implications for platelet physiology and transfusion therapy and for the design of "safe" GPIIb/IIIa inhibitors will be explored. Findings made are expected to elucidate a previously unrecognized mechanism of disease resulting from the immune response to conformational changes induced in an integrin by its ligand or a ligand-mimetic drug and to advance understanding of the role of "natural" antibodies in health and disease.

抑制活化的GPIIb/IIIa（β-allb/β S整联蛋白）与纤维蛋白原和其他配体反应的药物 是一个很有前途的抗血栓药物家族，目前广泛用于预防冠状动脉粥样硬化性心脏病后的不良事件。 血管成形术急性，严重的血小板减少症，通常发生在第一次暴露于其中之一的小时内 药物，是该类药物的公认副作用。在前一段时间的支持中，我们获得了证据， 药物特异性抗体，可以是天然存在的（或至少是预先存在的），是主要原因。 并发症，这组疾病的临床和血清学方面的特点，并获得的证据表明， 负责的抗体识别配体（药物）诱导的GPIIb/IIIa的结构构象异构体。我们现建议 将这些意见扩展到以下具体目标： 1)表征引起患者血小板减少症的抗体识别的GPIIb/IIIa上的表位 用GPIIb/IIIa抑制剂治疗。配体占据的GPIIb/IIIa上的表位， 一类免疫球蛋白的特异性将在分子水平上定义。 2)开发新的方法，用于鉴定常规方法中未检测到的具有临床意义的抗体 免疫测定。我们假设在一个重要的患者亚群中血小板的破坏是由低水平的 在大多数免疫测定中未检测到亲和抗体，并提出用测定提高诊断率， 真实的实时检测抗体结合和/或B）通过保持靶标的结构完整性来增加Ka。 3)描述先前存在的（“自然”） 识别GPIIb/IIIa-抑制剂复合物的免疫球蛋白（NA）。的发生率 一般人群中配体占据的GPIIb/IIIa特异性的潜在“危险”NA，其遗传来源 以及它们与引起血小板减少的抗体的关系， 生理学和输血治疗以及“安全的”GPIIb/IIIa抑制剂的设计将被探索。 这些发现有望阐明一种以前未被认识到的疾病机制， 对由其配体或配体模拟药物诱导的整联蛋白构象变化的免疫应答，以及对 进一步了解“天然”抗体在健康和疾病中的作用。