Age Dependent Thrombotic Risk Factors in Heparin-induced Thrombocytopenia

肝素诱导的血小板减少症的年龄依赖性血栓形成危险因素

• 批准号: 7339757
• 负责人: Barbara A Konkle
• 金额: $ 21.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339757
• 关键词: Acceleration; Age; Animal Model; Antibodies; Anticoagulants; Anticoagulation; Antigens; Arterial Fatty Streak; Aspirin; Atherosclerosis; Binding; Blood; Blood Clot; Blood Platelets; Blood Vessels; Blood coagulation; Cardiac Catheterization Procedures; Cardiovascular system; Child; Chronic; Clinical; Clinical Trials; Complex; Complication; Condition; Development; Disease; Elderly; Etiology; Functional disorder; General Population; Glycosaminoglycans; Heparin; Human; Individual; Inflammation; Lead; Lesion; Link; Lung; Measures; Modeling; Morbidity - disease rate; Mus; Numbers; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Platelet Activation; Population; Procedures; Punch Biopsy; Resolution; Risk; Risk Factors; Role; Severities; Skin; Surface; Testing; Therapeutic Intervention; Thrombocytopenia; Thromboembolism; Thrombosis; Time; Venous; Venous Thrombosis; age related; base; disorder risk; improved; mortality; mouse model; novel strategies; novel therapeutics; older patient; prevent

DESCRIPTION (provided by applicant): Heparin-induced thrombocytopenia (HIT) is a prototypic, common, iatrogenic thrombotic disorder characterized by inflammation, platelet activation and venous thromboembolism (VTE). It occurs in 1-5% of heparinized patients and often in elderly patients with advanced atherosclerotic disease. Recent studies demonstrate a strong link between atherosclerosis and venous thromboembolism. We believe that both disorders share certain fundamental features in their pathophysiology, i.e. inflammation and platelet dependent acceleration of vascular procoagulant pathways. We propose studies below to better understand the mechanistic basis of HIT, explaining why atherosclerosis is central as a risk factor for the development of this disorder. Specific Aim 1: To examine the relationship between platelet PF4 content, severity of atherosclerosis and HIT antigen expression. We have demonstrated that platelet PF4 content correlates with development of atherosclerosis in a murine model, and that PF4 accumulates in human atherosclerotic lesions and forms HIT-like antigenic complexes. We now propose that high levels of platelet PF4 predispose to progression of atherosclerosis and lead to development of HIT antibodies even prior to heparin exposure. To test whether these findings are relevant to the clinical setting, two patient populations (ages 25-45 and >60) undergoing cardiac catheterization prior to valve replacement surgery will be examined. The severity of atherosclerosis on cardiac catheterization will be recorded and blood will be obtained to assess total platelet PF4 content and HIT antibody level. In addition, a subset of patients will undergo skin punch biopsies that will be analyzed for vascular damage and PF4 and HIT antigenicity. Specific Aim 2: To examine the relationship between platelet PF4 content and total surface PF4 and HIT antigenic complexes. We have also shown, mostly in murine models, but again with supportive studies in humans, that surface-bound PF4/glycosaminoglycan (GAG) complexes on platelets are antigenic targets in HIT. We posit that patients with high platelet PF4 and more severe atherosclerosis (see above) will have more extensive chronic platelet activation and PF4 release and higher levels of platelet-bound surface PF4 and HIT antigenic PF4/GAG complexes. We propose to show that such a population with high surface PF4 and HIT PF4/GAG antigenic complexes can be detected in the general population. We therefore propose to measure the level of platelet PF4 content and total surface PF4 and HIT antigenicity in these two populations and also in well children. These studies should allow us to identify high risk patients, and lay the groundwork for clinical trial(s) evaluating outcomes in patients stratified by risk and/or receiving targeted therapy. This should result in decreased morbidity and mortality in elderly patients requiring heparin anticoagulation. Patients who are hospitalized frequently receive the blood thinner heparin to prevent or treat blood clotting. These patients are at risk of a blood clotting condition called heparin-induced thrombocytopenia. These studies will clarify whether older patients are at increased risk for this disorder and help us target individuals at greater risk of this complication so that their treatment can be modified. This should improve the outcome of patients needing blood thinning with the medication heparin.

描述（由申请人提供）：肝素诱导的血小板减少症（HIT）是一种典型的、常见的医源性血栓性疾病，其特征为炎症、血小板活化和静脉血栓栓塞（VTE）。它发生在 1-5% 的肝素化患者中，并且经常发生在患有晚期动脉粥样硬化疾病的老年患者中。最近的研究表明动脉粥样硬化和静脉血栓栓塞之间存在密切联系。我们认为，这两种疾病在病理生理学上具有某些共同的基本特征，即炎症和血管促凝血途径的血小板依赖性加速。我们提出以下研究，以更好地了解 HIT 的机制基础，解释为什么动脉粥样硬化是这种疾病发展的核心危险因素。具体目的1：探讨血小板PF4含量、动脉粥样硬化严重程度与HIT抗原表达之间的关系。我们已经在小鼠模型中证明血小板 PF4 含量与动脉粥样硬化的发展相关，并且 PF4 在人类动脉粥样硬化病变中积聚并形成 HIT 样抗原复合物。我们现在提出，即使在接触肝素之前，高水平的血小板 PF4 也容易导致动脉粥样硬化的进展，并导致 HIT 抗体的产生。为了测试这些发现是否与临床环境相关，将对在瓣膜置换手术前接受心导管插入术的两个患者群体（年龄 25-45 岁和 >60 岁）进行检查。记录心导管检查中动脉粥样硬化的严重程度，并采集血液评估总血小板PF4含量和HIT抗体水平。此外，一部分患者将接受皮肤穿刺活检，分析血管损伤以及 PF4 和 HIT 抗原性。具体目标 2：检查血小板 PF4 含量与总表面 PF4 和 HIT 抗原复合物之间的关系。我们还表明，主要是在小鼠模型中，但在人类研究中也得到了支持，血小板上表面结合的 PF4/糖胺聚糖 (GAG) 复合物是 HIT 中的抗原靶标。我们假设患有高血小板 PF4 和更严重动脉粥样硬化（见上文）的患者将具有更广泛的慢性血小板活化和 PF4 释放以及更高水平的血小板结合表面 PF4 和 HIT 抗原 PF4/GAG 复合物。我们建议证明，在普通人群中可以检测到具有高表面 PF4 和 HIT PF4/GAG 抗原复合物的人群。因此，我们建议测量这两个人群以及健康儿童的血小板 PF4 含量以及总表面 PF4 和 HIT 抗原性水平。 这些研究应该使我们能够识别高风险患者，并为临床试验奠定基础 评估按风险分层和/或接受靶向治疗的患者的结果。这应该会降低需要肝素抗凝的老年患者的发病率和死亡率。住院患者经常接受血液稀释剂肝素来预防或治疗血液凝固。这些患者面临称为肝素诱导的血小板减少症的血液凝固疾病的风险。这些研究将阐明老年患者患这种疾病的风险是否增加，并帮助我们针对患这种并发症风险较高的个体，以便调整他们的治疗方法。这应该可以改善需要使用肝素药物进行血液稀释的患者的治疗结果。