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: 7934006
• 负责人: Barbara A Konkle
• 金额: $ 49.91万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934006
• 关键词: Address; Adverse effects; American; Animal Model; Antibodies; Antibody Formation; Anticoagulants; Anticoagulation; Antigens; Area; B-Lymphocytes; Biological Markers; Blood; Blood Platelets; Blood Vessels; Cardiac; Cardiac Catheterization Procedures; Cardiopulmonary Bypass; Cardiovascular system; Caring; Cause of Death; Cessation of life; Clinical; Clinical Treatment; Complex; Development; Diagnostic; Disease; Economics; Employment; Event; Evolution; Functional disorder; Future; Goals; Health Sciences; Hemorrhage; Heparin; Hospitals; Human; Laboratory Study; Life; Limb structure; Medical; Molecular Weight; Morbidity - disease rate; Occupations; Operative Surgical Procedures; Patients; Pennsylvania; Pharmaceutical Preparations; Platelet Factor 4; Positioning Attribute; Principal Investigator; Recovery; Research; Respiratory System; Respiratory tract structure; Risk; Therapeutic; Thrombocytopenia; Thrombosis; Training; United States; Universities; Validation; clinically relevant; cost; high risk; immunogenicity; improved; medical schools; mortality; novel; older patient; patient population; programs; public health relevance; randomized trial; response

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)生物标记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、可量化的生物标记物。血栓形成是美国的主要死亡原因，普通肝素(UFH)或低分子形式的肝素在医院中被统一用于抗凝。肝素诱导的血小板减少症(HIT)发生在接触肝素的患者中的1-5%，可导致肢体或生命丧失的严重后果，通常发生在患有晚期动脉粥样硬化性疾病且基线风险增加的血栓和出血的老年患者中。虽然有替代抗凝剂可用，但它们与出血风险增加和成本增加有关，并未取代UFH用于需要体外循环(CPB)的常见手术。如果在接触肝素之前能够识别出最有可能被击中的患者，就可以使用靶向替代抗凝。HIT是由抗肝素/血小板因子4(PF4)复合体的抗体引起的。我们的实验室研究，包括动物模型和人类对血小板和血管PF4以及糖胺聚糖/PF4复合体免疫原性的体外研究，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。我们目前正在研究心脏导管置入术患者的血小板风险生物标记物，并准备在形成抗肝素/PF4抗体的高风险患者群体中验证这些生物标记物和早期抗体形成的标记物。我们假设一系列生物标记物和临床因素将预测肝素/PF4抗体形成和HIT的风险，并提出通过特定目标来评估这一点的研究：1)确定新的血小板生物标记物和临床因素是否预测CPB术后抗肝素/PF4抗体形成；2)评估抗原特异性B细胞的表达和抗肝素/PF4抗体亚型和滴度的演变作为HIT的前驱；以及3)观察抗肝素/PF4抗体形成或血小板生物标记物是否预测住院和30天内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，医学院创造了37,000个就业机会和54亿美元的区域经济活动，这些地区训练有素的劳动力仅为840个空缺的宾夕法尼亚大学教职员工研究职位就产生了24,600多份申请。通过拟议的研究，我们将保留和增加员工就业(2.5个工作岗位)，我们的研究应该改善常用处方药的使用，减少不良临床事件和医疗成本。这些目标与2009年《美国复苏和再投资法案》的目的一致，该法案旨在保持和创造就业机会，并通过刺激科学和卫生领域的进步来促进经济复苏。 公共卫生意义：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肝素治疗发生HIT的风险最大的患者，以便改变他们的护理方法，从而改善他们的护理。

项目成果

Atherosclerosis is not a risk factor for anti-platelet factor 4/heparin antibody formation after cardiopulmonary bypass surgery.

动脉粥样硬化不是体外循环手术后抗血小板因子4/肝素抗体形成的危险因素。

• DOI: 10.1160/th13-12-1012
• 发表时间: 2014
• 期刊: Thrombosis and haemostasis
• 影响因子: 6.7
• 作者: Cuker,Adam;Rauova,Lubica;Bolgiano,Douglas;MatthaiJr,WilliamH;Poncz,Mortimer;Konkle,BarbaraA
• 通讯作者: Konkle,BarbaraA