Clinical Significance of protamine/heparin antibodies after CPB

CPB 后鱼精蛋白/肝素抗体的临床意义

• 批准号: 8174008
• 负责人: Gowthami M Arepally
• 金额: $ 23.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8174008
• 关键词: Acute; Adverse effects; Allergic Reaction; Anaphylaxis; Antibodies; Antibody Formation; Anticoagulants; Anticoagulation; Antigens; Area; Biologic Characteristic; Blood Platelets; Bypass; Cardiopulmonary Bypass; Characteristics; Charge; Clinical; Clinical Data; Clinical Research; Complex; Complication; Data; Development; Disease; Drug Hypersensitivity; Enrollment; Exposure to; Funding; Funding Mechanisms; Future; Goals; Heparin; Human; Hypersensitivity; Hypotension; Immune; Immune response; In Vitro; Incidence; Institutional Review Boards; Investigation; Laboratories; Life; Mediating; Minor; Modeling; Multicenter Studies; Mus; Operative Surgical Procedures; Outcome; Pathogenicity; Patients; Pharmaceutical Preparations; Plasma; Platelet Factor 4; Property; Protamine Sulfate; Protamines; Pulmonary Hypertension; Rattus; Reaction; Research Personnel; Risk Factors; Rodent; Sampling; Serological; Seroprevalences; Surgical Hemostasis; Symptoms; Testing; Therapeutic Agents; Thrombocytopenia; United States Food and Drug Administration; adverse outcome; bacterial H antigen; base; cationic antimicrobial protein CAP 37; clinical research site; clinically relevant; clinically significant; cohort; cross reactivity; human subject; immunogenic; immunogenicity; in vivo; monocyte; prospective; response; therapy development

DESCRIPTION (provided by applicant): Protamine (PRT) sulfate is the only commercially approved therapy for the reversal of heparin anticoagulation after cardiopulmonary bypass (CPB). Complications of PRT in CPB range from mild symptoms (hypotension) to rare life-threatening side-effects (acute pulmonary hypertension and/or anaphylaxis). In the course of studying immune complications of heparin (H), we have recently described a new and previously uncharacterized complication of protamine therapy, development of PRT/H antibodies (Abs). In preliminary studies, we show that ~40% of patients undergoing CPB develop PRT/H antibodies with minimal cross-reactivity to other heparin binding proteins, such as platelet factor 4 (PF4). Based on these observations, we hypothesize that PRT/H antibodies occur frequently after CPB and are associated with adverse clinical outcomes. To test this hypothesis, we will employ the R21 exploratory mechanism to investigate the clinical significance of PRT/H Abs in CPB patients. Specifically, we will: 1) Establish the incidence of PRT/H antibodies and investigate PRT/H antibody-associated clinical outcomes in a recently completed study of patients undergoing CPB (HIT 5801 Study). The HIT 5801 study is a recently completed study of ~1000 patients undergoing CPB in whom clinical data and plasma samples are available for further investigation. We have received IRB approval to examine the Duke cohort (n=783) for development of PRT/H antibodies and associated clinical outcomes. We will also establish the concurrent expression of PF4/H antibodies (causative antibodies in Heparin-Induced Thrombocytopenia or HIT) and determine if patients with PRT/H and PF4/H antibodies have worse outcomes. 2) Define the biologic characteristics of anti-PRT/H antibodies using in vitro and in vivo studies. Our preliminary studies indicate that the immune response to PRT/H and PF4/H share several biologic features. In this aim, we will examine the serologic and functional characteristics of PRT/H antibodies with respect to platelet and monocyte activation. In additional studies, we will utilize an existing rodent CPB model to study risk factors for and pathogenicity of PRT/H antibodies levels. Preliminary data obtained from this R21 funded study will allow us to document the clinical relevance of PRT/H Antibodies in CPB and enable future prospective investigations of outcomes related to antibody formation. PUBLIC HEALTH RELEVANCE: We have identified a new type of allergic reaction to a drug (protamine) that is routinely used in all patients undergoing cardiopulmonary bypass surgery to reverse the blood-thinning effects of heparin. This allergy is caused by the combination of exposure to protamine and heparin and has not been previously described. We propose to study if this drug allergy poses harm to patients after surgery.

描述（由申请人提供）：硫酸精蛋白（PRT）是唯一经过商业批准的治疗疗法，用于逆转心肺旁路后肝素抗凝（CPB）。 CPB中PRT的并发症范围从轻度症状（低血压）到罕见的威胁生命的副作用（急性肺动脉高压和/或过敏反应）。在研究肝素（H）的免疫并发症的过程中，我们最近描述了一种新的且以前未表征的精蛋白治疗并发症，PRT/H抗体的发展（ABS）。在初步研究中，我们表明约有40％的患者正在接受CPB的患者，对其他肝素结合蛋白（例如血小板因子4（PF4））的交叉反应最低（PF4）。基于这些观察结果，我们假设PRT/H抗体经常发生在CPB之后，并且与不良临床结局有关。为了检验该假设，我们将采用R21探索机制来研究CPB患者PRT/H ABS的临床意义。具体而言，我们将：1）在最近完成的CPB患者的研究中，确定PRT/H抗体的发生率并研究PRT/H抗体相关的临床结果（HIT 5801研究）。 HIT 5801研究是对约有1000名接受CPB患者的研究，其中有临床数据和血浆样品可供进一步研究。我们已获得IRB批准，以检查杜克队队（n = 783），以开发PRT/H抗体和相关的临床结果。我们还将建立PF4/H抗体的同时表达（肝素诱导的血小板减少症中的致病抗体或命中），并确定PRT/H和PF4/H抗体的患者的预后较差。 2）使用体外和体内研究定义抗PRT/H抗体的生物学特征。我们的初步研究表明，对PRT/H和PF4/H的免疫反应具有多种生物学特征。在此目标中，我们将检查有关血小板和单核细胞激活的PRT/H抗体的血清学和功能特征。在其他研究中，我们将利用现有的啮齿动物CPB模型来研究PRT/H抗体水平的风险因素和致病性。从这项R21资助的研究中获得的初步数据将使我们能够记录CPB中PRT/H抗体的临床相关性，并能够对与抗体形成相关的结果进行未来的前瞻性研究。 公共卫生相关性：我们已经确定了一种对药物（精蛋白）的新型过敏反应，该反应通常用于所有接受心肺旁路手术的患者，以扭转肝素的血液稀释作用。这种过敏是由暴露于精蛋白和肝素的结合引起的，并未被描述。我们建议研究这种药物过敏是否在手术后对患者造成伤害。