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(Alphallb/Betas整合素)与纤维蛋白原和其他配体反应的药物 是一类很有前途的抗血栓药物，现在被广泛用于预防冠状动脉病变后的不良事件 血管成形术。急性、严重的血小板减少症，通常发生在首次接触其中一种病毒的数小时内 药物，是这类药物中公认的副作用。在之前的支持期间，我们获得了证据 药物特异性抗体可能是自然产生的(或至少是预先存在的)，是造成这种情况的主要原因。 并发症，这组疾病的临床和血清学方面的特征，并获得证据表明 负责任的抗体识别配体(药物)诱导的GPIIb/IIIa结构构象。我们现在建议 将这些观察结果扩展到以下具体目标： 1)鉴定引起患者血小板减少的抗体识别的GPIIb/IIIa表位 用GPIIb/IIIa抑制剂治疗。配体占据的GPIIb/IIIa上的表位，这显然是唯一的 免疫球蛋白的类别是特定的，将在分子水平上进行定义。 2)开发新的方法来鉴定在常规方法中未检测到的临床显著抗体 免疫分析。我们假设很大一部分患者的血小板破坏是由低血压引起的。 在大多数免疫分析中没有检测到亲和抗体，并建议通过以下分析来提高诊断效率 实时检测抗体结合和/或b)通过保持靶的结构完整性来增加KA。 3)描述先前存在的(“自然”)的发生率、临床意义和遗传来源 识别GPIIb/IIIa-抑制物复合体的免疫球蛋白(NA)。 一般人群中配基占位的GPIIb/IIIa的潜在“危险”NA，其遗传来源 以及它们与导致血小板减少的抗体的关系，以及它们对血小板的影响 将探索生理学和输血疗法以及“安全”的GPIIb/IIIa抑制剂的设计。 预计所做的发现将阐明一种以前未知的疾病机制，这种疾病是由 对整合素的配体或类似配体的药物诱导的构象变化的免疫反应和 促进对“天然”抗体在健康和疾病中的作用的理解。