Age Dependent Thrombotic Risk Factors in Heparin-induced Thrombocytopenia

描述（由申请方提供）：肝素诱导的血小板减少症（HIT）是一种典型的常见医源性血栓性疾病，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，通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，这两种疾病在其病理生理学上具有某些共同的基本特征，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这种疾病发展的危险因素。目的1：探讨血小板PF 4含量与动脉粥样硬化程度及HIT抗原表达的关系。我们已经证明，血小板PF 4含量与发展的动脉粥样硬化在小鼠模型，PF 4积累在人类动脉粥样硬化病变，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易于动脉粥样硬化的进展，并导致HIT抗体的发展，甚至在肝素暴露之前。为了测试这些发现是否与临床环境相关，将检查两个在瓣膜置换术前接受心导管插入术的患者人群（年龄25-45岁和>60岁）。将记录心导管检查时动脉粥样硬化的严重程度，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，分析血管损伤和PF 4和HIT抗原性。目的二：研究血小板表面PF 4含量与总PF 4和HIT抗原复合物的关系。我们还表明，主要是在小鼠模型中，但在人类中的支持性研究，血小板表面结合的PF 4/糖胺聚糖（GAG）复合物是HIT的抗原靶点。我们认为，血小板PF 4高和动脉粥样硬化更严重的患者（见上文）将有更广泛的慢性血小板活化和PF 4释放和更高水平的血小板结合表面PF 4和HIT抗原PF 4/GAG复合物。我们建议表明，这样的人口与高表面PF 4和HIT PF 4/GAG抗原复合物可以在一般人群中检测到。因此，我们建议在这两个群体中以及在健康儿童中测量血小板PF 4含量和总表面PF 4和HIT抗原性的水平。 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。这将导致需要肝素抗凝的老年患者的发病率和死亡率降低。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更高的风险患上这种疾病，并帮助我们针对这种并发症风险更高的个体，以便修改他们的治疗方法。这将改善需要用肝素药物稀释血液的患者的结局。

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.