Age Dependent Thrombotic Risk Factors in Heparin-induced Thrombocytopenia

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，其特征是炎症、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，常发生在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有很强的联系。我们认为这两种疾病在其病理生理学上具有某些基本特征，即炎症和血小板依赖性血管促凝途径的加速。我们提出以下研究来更好地理解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主要危险因素。特异性目的1：探讨血小板PF4含量、动脉粥样硬化严重程度与HIT抗原表达的关系。我们已经在小鼠模型中证明了血小板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累并形成hit样抗原复合物。我们现在提出，即使在肝素暴露之前，高水平的血小板PF4也易导致动脉粥样硬化的进展，并导致HIT抗体的产生。为了检验这些发现是否与临床环境相关，我们将对两组在瓣膜置换术前接受心导管插入术的患者（年龄25-45岁和60岁左右）进行研究。记录心导管置管时动脉粥样硬化的严重程度，取血评估血小板PF4总含量及HIT抗体水平。此外，一部分患者将接受皮肤穿刺活检，以分析血管损伤和PF4和HIT抗原性。特异性目的2：探讨血小板PF4含量与表面总PF4和HIT抗原复合物的关系。我们还发现（主要是在小鼠模型中）血小板表面结合的PF4/糖胺聚糖（GAG）复合物是HIT的抗原靶点。我们假设，高血小板PF4和更严重动脉粥样硬化（见上文）的患者将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。我们提出证明这样一个具有高表面PF4和HIT PF4/GAG抗原复合物的群体可以在一般人群中检测到。因此，我们建议在这两个人群以及健康儿童中测量血小板PF4含量、总表面PF4和HIT抗原性水平。

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.