Clinical Significance of protamine/heparin antibodies after CPB

CPB 后鱼精蛋白/肝素抗体的临床意义

基本信息

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
项目类别：
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

项目摘要

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）：硫酸鱼精蛋白（PRT）是唯一商业批准的用于逆转体外循环（CPB）后肝素抗凝作用的疗法。 CPB 中 PRT 的并发症范围从轻微症状（低血压）到罕见的危及生命的副作用（急性肺动脉高压和/或过敏反应）。在研究肝素 (H) 免疫并发症的过程中，我们最近描述了鱼精蛋白治疗的一种新的且以前未表征的并发症，即 PRT/H 抗体 (Abs) 的产生。在初步研究中，我们表明约 40% 接受 CPB 的患者会产生 PRT/H 抗体，与其他肝素结合蛋白（如血小板因子 4 (PF4)）的交叉反应性极小。基于这些观察结果，我们假设 PRT/H 抗体在 CPB 后频繁出现，并与不良临床结果相关。为了检验这一假设，我们将采用 R21 探索机制来研究 PRT/H Abs 在 CPB 患者中的临床意义。具体来说，我们将： 1) 在最近完成的一项针对接受 CPB 的患者的研究（HIT 5801 研究）中确定 PRT/H 抗体的发生率并调查 PRT/H 抗体相关的临床结果。 HIT 5801 研究是最近完成的一项研究，涉及约 1000 名接受 CPB 的患者，其中的临床数据和血浆样本可供进一步研究。我们已获得 IRB 批准检查杜克队列 (n=783) 的 PRT/H 抗体开发和相关临床结果。我们还将确定 PF4/H 抗体（肝素诱导的血小板减少症或 HIT 中的致病抗体）的同时表达，并确定具有 PRT/H 和 PF4/H 抗体的患者是否有更差的结果。 2) 使用体外和体内研究定义抗 PRT/H 抗体的生物学特性。我们的初步研究表明，对 PRT/H 和 PF4/H 的免疫反应有几个共同的生物学特征。为此，我们将检查 PRT/H 抗体在血小板和单核细胞活化方面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 抗体水平的危险因素和致病性。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 PRT/H 抗体在 CPB 中的临床相关性，并能够在未来对与抗体形成相关的结果进行前瞻性研究。公共健康相关性：我们发现了一种对药物（鱼精蛋白）的新型过敏反应，该药物常规用于所有接受体外循环手术的患者，以逆转肝素的血液稀释作用。这种过敏是由暴露于鱼精蛋白和肝素共同引起的，之前没有被描述过。我们建议研究这种药物过敏是否会对手术后的患者造成伤害。