Clinical Significance of protamine/heparin antibodies after CPB

描述（由申请人提供）：硫酸鱼精蛋白（PRT）是唯一一种用于心肺转流术（CPB）后逆转肝素抗凝的市售治疗方法。CPB中PRT的并发症范围从轻度症状（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）的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和以前未表征的并发症，PRT/H抗体（Abs）的产生。在初步研究中，我们发现约40%接受CPB的患者产生PRT/H抗体，与其他肝素结合蛋白（如血小板因子4（PF 4））的交叉反应性最小。基于这些观察结果，我们假设PRT/H抗体在CPB后频繁发生，并与不良临床结局相关。为了验证这一假设，我们将采用R21探索性机制来研究PRT/H Ab在CPB患者中的临床意义。具体而言，我们将：1）在最近完成的对接受CPB的患者的研究（HIT 5801研究）中，确定PRT/H抗体的发生率并研究PRT/H抗体相关的临床结局。HIT 5801研究是一项最近完成的研究，纳入了约1000例接受CPB的患者，这些患者的临床数据和血浆样本可用于进一步研究。我们已获得IRB批准，可以检查杜克队列（n=783）的PRT/H抗体和相关临床结局。我们还将确定PF 4/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PRT/H和PF 4/H抗体患者的结局是否更差。2)使用体外和体内研究确定抗PRT/H抗体的生物学特性。我们的初步研究表明，对PRT/H和PF 4/H的免疫应答具有一些共同的生物学特征。在这个目标中，我们将研究PRT/H抗体的血小板和单核细胞活化方面的血清学和功能特性。在其他研究中，我们将利用现有啮齿动物CPB模型研究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PRT/H抗体在CPB中的临床相关性，并使未来对抗体形成相关结局的前瞻性研究成为可能。 公共卫生相关性：我们发现了一种新型的对药物（鱼精蛋白）的过敏反应，该药物通常用于所有接受心肺转流手术的患者，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的组合引起的，以前没有描述过。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。

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.