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: 7499548
• 负责人: Barbara A Konkle
• 金额: $ 23.91万
• 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/7499548
• 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

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.

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 其特征在于炎症、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，并且通常在患有晚期动脉粥样硬化疾病的老年患者中。最近的研究 证明动脉粥样硬化和静脉血栓栓塞之间有密切联系。我们相信无论 这些疾病在其病理生理学中共有某些基本特征，即炎症和血小板依赖性 血管促凝血途径的加速。我们建议进行以下研究，以更好地了解 HIT的机制基础，解释为什么动脉粥样硬化是核心的风险因素，为发展这一点， disorder. 目的1：探讨血小板PF 4含量与动脉粥样硬化严重程度的关系 和HIT抗原表达。我们已经证明，血小板PF 4含量与发育相关， 以及PF 4在人类动脉粥样硬化病变中积累并形成 HIT样抗原复合物。我们现在提出，高水平的血小板PF 4易导致 甚至在暴露于肝素之前，也会导致动脉粥样硬化并导致HIT抗体的产生。来测试是否 这些发现与临床环境有关，两个患者群体（年龄25-45岁和>60岁）经历了 将检查瓣膜置换手术前的心导管插入术。动脉粥样硬化的严重程度 将记录心导管插入术，并采集血液以评估总血小板PF 4含量和HIT 抗体水平此外，一部分患者将接受皮肤穿刺活检， 血管损伤和PF 4和HIT抗原性。 具体目的2：检测血小板PF 4含量与总表面PF 4和HIT之间的关系 抗原复合物我们还表明，主要是在小鼠模型中，但再次通过支持性研究， 血小板表面结合的PF 4/糖胺聚糖（GAG）复合物是人类中的抗原靶点， 击中。我们认为，高血小板PF 4和更严重的动脉粥样硬化患者（见上文）将有更多的 广泛的慢性血小板活化和PF 4释放以及血小板结合表面PF 4和HIT水平较高 抗原性PF 4/GAG复合物。我们建议表明，这种人口与高表面PF 4和HIT PF 4/GAG抗原复合物可在一般人群中检测到。因此，我们建议， 血小板PF 4含量、总表面PF 4和HIT抗原性在这两个群体中的水平，以及 孩子们。 这些研究应使我们能够识别高风险患者，并为临床试验奠定基础 评估按风险和/或接受靶向治疗分层的患者的结局。这将导致 降低需要肝素抗凝的老年患者的发病率和死亡率。经常住院的患者接受血液稀释剂肝素，以预防或治疗血液凝固。 这些患者有发生称为肝素诱导性血小板减少症的凝血状况的风险。这些 研究将澄清老年患者是否有患这种疾病的风险增加，并帮助我们针对 这种并发症的风险更大，因此可以修改治疗方法。这将改善 需要用肝素稀释血液的病人