Age Dependent Thrombotic Risk Factors in Heparin-induced Thrombocytopenia

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 以炎症、血小板活化和静脉血栓栓塞症(VTE)为特征。它发生在1-5%的 肝素化患者，常见于老年晚期动脉粥样硬化性疾病患者。最新研究 证明动脉粥样硬化和静脉血栓栓塞症之间有很强的联系。我们相信这两个 疾病在病理生理学上有某些基本特征，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，解释了为什么动脉粥样硬化是HIT发展的主要危险因素 无序。 具体目的1：探讨血小板PF4含量与动脉粥样硬化严重程度的关系 并命中抗原表达。我们已经证明了血小板PF4含量与发育有关 在小鼠模型中的动脉粥样硬化，以及PF4在人类动脉粥样硬化的病变和形成中积聚 类似HIT的抗原性复合体。我们现在提出，高水平的血小板PF4易于进展为 甚至在接触肝素之前就会导致动脉粥样硬化，并导致HIT抗体的产生。来测试一下 这些发现与临床环境有关，两个患者群体(年龄分别为25-45岁和60岁)正在接受 心脏瓣膜置换术前需进行心导管检查。动脉粥样硬化的严重程度 心导管检查将被记录下来，并将采集血液以评估总的血小板PF4含量和HIT 抗体水平。此外，一部分患者将接受皮肤穿孔活检，分析是否有 血管损伤和PF4及HIT抗原性。 特异目的2：检测血小板PF4含量与总表面PF4和HIT的关系 抗原复合体。我们也显示了，主要是在小鼠模型中，但再次通过支持性研究 人，血小板表面结合的PF4/糖胺聚糖(GAG)复合体是抗肿瘤的靶点 打中了。我们假设，血小板PF4升高且动脉粥样硬化更严重(见上)的患者将会有更多 广泛的慢性血小板激活和PF4释放，以及更高水平的血小板结合表面PF4和HIT 抗原性PF4/GAG复合体。我们建议证明这样一个具有高表面PF4和HIT的种群 在一般人群中可检测到PF4/GAG抗原复合体。因此，我们建议衡量 这两个人群的血小板PF4含量和总表面PF4和HIT抗原性的水平 好了，孩子们。 这些研究应该使我们能够识别高危患者，并为临床试验奠定基础(S) 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。经常住院的患者会接受血液稀释剂肝素来预防或治疗血液凝结。 这些患者面临着一种名为肝素诱导的血小板减少症的凝血疾病的风险。这些 研究将澄清老年患者患这种疾病的风险是否增加，并帮助我们针对 这种并发症的风险更大，这样他们的治疗就可以改变。这应该会改善 需要使用药物肝素进行血液稀释的患者。

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.