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）是一种原型，常见的，医源性血栓形成障碍，其特征是炎症，血小板激活和静脉血栓栓塞（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，动脉粥样硬化与静脉血栓栓塞之间有着密切的联系。我们认为，这两种疾病在其病理生理学中具有某些基本特征，即血管促进途径的炎症和血小板依赖性加速。我们提出下面的研究，以更好地了解HIT的机理基础，并解释为什么动脉粥样硬化是该疾病发展的危险因素的中心。特定目的1：检查血小板PF4含量，动脉粥样硬化的严重程度和击中抗原表达之间的关系。我们已经证明了血小板PF4含量与鼠模型中动脉粥样硬化的发展相关，并且PF4在人动脉粥样硬化病变中积累并形成了命中样的抗原复合物。现在，我们提出，高水平的血小板PF4易于动脉粥样硬化的进展，并在肝素暴露之前甚至导致HIT抗体的发展。为了测试这些发现是否与临床环境相关，将检查两名患者人群（25-45和> 60岁）接受瓣膜置换手术前的心脏导管插入手术。将记录动脉粥样硬化在心脏导管插入术上的严重程度，并将获得血液以评估总血小板PF4含量并达到抗体水平。此外，一部分患者将进行皮肤打孔活检，这些活检将对血管损伤和PF4进行分析并击中抗原性。特定目的2：检查血小板PF4含量与总表面PF4与击中抗原复合物之间的关系。我们还大多在鼠模型中显示了，但是在人类中的支持性研究中，血小板上的表面结合的PF4/糖胺聚糖（GAG）复合物是抗原靶标。我们认为，高血小板PF4和更严重的动脉粥样硬化患者（见上文）将具有更广泛的慢性血小板激活和PF4释放，并且较高的血小板结合表面PF4并击中抗原性PF4/GAG复合物。我们建议表明，可以在一般人群中检测到具有高表面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含量和总表面PF4的水平，并击中抗原性。 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。 评估根据风险和/或接受靶向治疗分层的患者的结局。这应该导致需要肝素抗凝的老年患者的发病率和死亡率降低。住院的患者经常会接受血液较薄的肝素，以预防或治疗血液凝结。这些患者有血液凝结状况的风险，称为肝素诱导的血小板减少症。这些研究将阐明老年患者是否患有这种疾病的风险增加，并帮助我们针对更大的并发症风险的人，以便对他们的治疗进行修改。这应该改善需要用药物肝素稀疏的患者的结果。