Novel Biomarkers Predictive of Heparin-Induced Thrombocytopenia

预测肝素引起的血小板减少症的新型生物标志物

• 批准号: 7992566
• 负责人: Barbara A Konkle
• 金额: $ 49.75万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992566
• 关键词: Biological Markers; Heparin; Thrombocytopenia; novel

DESCRIPTION (provided by applicant): This proposal addresses the Broad Challenge Area of (03) Biomarker Discovery and Validation, specifically (03-HL-101), to identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac and respiratory tract dysfunction. Thrombosis is the major cause of death in the United States and heparin, in unfractionated (UFH) or low molecular weight form, is uniformly used for anticoagulation in the hospital setting. Heparin-induced thrombocytopenia (HIT) occurs in 1-5% of patients exposed to heparin, can have severe consequences with loss of limbs or life, and often occurs in elderly patients with advanced atherosclerotic disease and increased baseline risks of both thrombosis and hemorrhage. While alternative anticoagulants are available, they are associated with increased risks of bleeding and increased costs, and have not replaced UFH for common surgeries requiring cardiopulmonary bypass (CPB). If patients who are at greatest risk of HIT can be identified prior to heparin exposure, targeted alternative anticoagulation could be used. HIT is caused by antibodies against a complex of heparin/platelet factor 4 (PF4). Our laboratory studies, including animal models and human ex-vivo studies of platelet and vascular PF4 and glycosoaminoglycan/PF4 complex immunogenicity, support our ability to utilize novel biomarkers and clinical factors to determine the risk of HIT. We are currently studying platelet biomarkers of risk in patients undergoing cardiac catheterization and are now poised to validate these biomarkers, and markers of incipient antibody development, in a patient population at high risk of forming antiheparin/ PF4 antibodies. We hypothesize that a constellation of biomarkers and clinical factors will predict risk of heparin/PF4 antibody formation and HIT, and propose studies to evaluate this through Specific Aims: 1) To determine if novel platelet biomarkers and clinical factors predict anti-heparin/PF4 antibody formation post- CPB; 2) To evaluate expression of antigen-specific B cells and evolution of antiheparin/PF4 antibody isotype and titer as precursors of HIT; and, 3) To observe if anti-heparin/PF4 antibody formation or platelet biomarkers predict in-hospital and 30 day cardiovascular and all cause morbidity and mortality. The University Of Pennsylvania School Of Medicine contributes substantially to the local economy. In 2008, the School of Medicine created 37,000 jobs and $5.4 billion in regional economic activity, with the areas highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. Through the proposed studies we will retain and increase staff employment (2.5 jobs) and our studies should improve use of a commonly prescribed medication and decrease adverse clinical events and medical costs. These goals are consistent with the purpose of the American Recovery and Reinvestment Act of 2009 to preserve and create jobs, and to promote economic recovery by spurring advances in science and health. PUBLIC HEALTH RELEVANCE: Heparin is a commonly used blood thinner in all hospitals in the U.S. Heparin-induced thrombocytopenia (HIT) is a serious adverse effect of heparin that can result in loss of limbs or death. This study will help identify patients most at risk of developing HIT with heparin therapy so that the approach to their care can be altered, and thus, improved.

描述（由申请人提供）：本提案涉及（03）生物标志物发现和验证的广泛挑战领域，特别是（03-HL-101），以识别和验证血液、血管、心脏和呼吸道功能障碍的诊断和治疗反应的临床相关、可定量生物标志物。血栓形成是美国的主要死亡原因，普通肝素（UFH）或低分子量肝素在医院中统一用于抗凝治疗。肝素诱导的血小板减少症（HIT）发生在1-5%暴露于肝素的患者中，可能导致肢体丧失或生命丧失的严重后果，并且通常发生在患有晚期动脉粥样硬化疾病且血栓形成和出血的基线风险增加的老年患者中。虽然替代抗凝剂是可用的，但它们与出血风险增加和成本增加有关，并且尚未取代UFH用于需要心肺转流（CPB）的常见手术。如果在肝素暴露前可以确定HIT风险最高的患者，则可以使用靶向替代抗凝治疗。HIT是由抗肝素/血小板因子4（PF 4）复合物的抗体引起的。我们的实验室研究，包括动物模型和血小板和血管PF 4和糖氨基聚糖/PF 4复合物免疫原性的人体离体研究，支持我们利用新的生物标志物和临床因素来确定HIT风险的能力。我们目前正在研究接受心导管插入术患者的血小板风险生物标志物，现在准备在形成抗肝素/PF 4抗体的高风险患者人群中验证这些生物标志物和早期抗体形成的标志物。我们假设一系列生物标志物和临床因素将预测肝素/PF 4抗体形成和HIT的风险，并提出通过特定目的进行评估的研究：1）确定新的血小板生物标志物和临床因素是否预测CPB后抗肝素/PF 4抗体形成; 2）评估作为HIT前体的抗原特异性B细胞的表达和抗肝素/PF 4抗体同种型和滴度的演变;以及3）观察抗肝素/PF 4抗体形成或血小板生物标志物是否预测住院和30天心血管和所有原因的发病率和死亡率。宾夕法尼亚大学医学院为当地经济做出了巨大贡献。2008年，医学院在区域经济活动中创造了37，000个就业机会和54亿美元，该地区训练有素的劳动力为宾夕法尼亚大学840个开放的研究职位提供了24，600多份申请。通过拟议的研究，我们将保留和增加工作人员就业（2.5个工作岗位），我们的研究应改善常用处方药的使用，减少不良临床事件和医疗费用。这些目标与2009年《美国复苏和再投资法案》的目的一致，即保护和创造就业机会，并通过刺激科学和健康进步来促进经济复苏。 公共卫生关系：肝素是美国所有医院常用的血液稀释剂。肝素诱导的血小板减少症（HIT）是肝素的一种严重不良反应，可导致肢体丧失或死亡。 这项研究将有助于确定最有风险的病人发展HIT与肝素治疗，使他们的护理方法可以改变，从而改善。