Molecular Basis of the Humoral Immune Response in Heparin-Induced Thrombocytopenia

项目摘要/摘要 肝素诱导的血小板减少症体液免疫反应的分子基础 肝素诱导的血小板减少症(HIT)是影响血细胞的最常见的药物不良反应。 尽管肝素是一种重要的抗凝血剂，在许多临床环境中广泛使用，但接触肝素经常 导致产生针对由血小板α表达的构象表位的抗体(Abs 颗粒趋化因子、血小板因子4(PF4)与肝素结合形成复合体(PF4/H)。在一些 患者，特别是手术后，这些抗体引发的打击，其特点是血小板减少，往往生活- 威胁到动脉或静脉血栓形成/血栓栓塞症。这种并发症被认为是导致，至少在 部分，从依赖于PF4的抗体与血小板、单核细胞和可能的其他靶细胞结合，导致细胞 通过Fc受体激活和产生促凝血活性。肝素诱导的机制 ABS引起的血小板减少和血栓形成尚有部分了解，但对ABS引起的 潜在免疫反应本身的分子基础。HIT的一个独特特征是25%-50%的患者 接触肝素产生识别PF4/H的抗体，但只有0.1%-1.0%的人经历了经典的打击 综合症。为什么肝素诱导的抗体有些是“良性的”或“非致病的”，而另一些则是“致病的” 不能仅凭抗体效价来解释。在本应用程序中，我们建议提供一个 一些肝素诱导的抗体导致病理而另一些可能识别的分子解释 同样，PF4/H也不会致病。我们的研究将通过与临床医生和 翻译科学家致力于研究以提高对HIT发病机制的理解并改善 这种情况的诊断和治疗。

Project Summary/Abstract Title: Molecular basis of the humoral immune response in heparin-induced thrombocytopenia Heparin induced thrombocytopenia (HIT) is the most common adverse drug reaction affecting blood cells. Although heparin is an important anticoagulant widely used in many clinic settings, heparin exposure often leads to production of antibodies (Abs) specific for conformational epitopes expressed by the platelet alpha granule chemokine, platelet factor 4 (PF4) when it binds to heparin to form a complex (PF4/H). In some patients, particularly after surgery, these Abs provoke HIT, characterized by thrombocytopenia and often life- threatening arterial or venous thrombosis/thromboembolism. This complication is thought to result, at least in part, from PF4-dependent Ab binding to platelets, monocytes and possibly other target cells, leading to cell activation via Fc receptors and generation of procoagulant activity. The mechanisms by which heparin-induced Abs cause thrombocytopenia and thrombosis are partially understood, but very little is known about the molecular basis of the underlying immune response itself. One unique feature of HIT is that 25-50% of patients exposed to heparin produce Abs that recognize PF4/H but only 0.1-1.0% experience the classical HIT syndrome. Why some heparin-induced Ab are “benign” or “non-pathogenic” and others are “pathogenic” cannot be accounted for on the basis of Ab potency alone. In this application, we propose to provide a molecular explanation for why some heparin-induced Abs cause pathology whereas others that may recognize PF4/H equally well fail to cause disease. Our studies will be facilitated by close collaboration with clinicians and translational scientists engaged in research to improve understanding of HIT pathogenesis and improve diagnosis and treatment of this condition.