Clinical Significance of protamine/heparin antibodies after CPB

描述(申请人提供)：鱼精蛋白(PRT)硫酸盐是唯一经商业批准的体外循环(CPB)后肝素抗凝逆转的治疗方法。CPB中PRT的并发症从轻微的症状(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个新的和以前没有特征的并发症--PRT/H抗体(Abs)的发展。在初步研究中，我们发现大约40%的CPB患者出现PRT/H抗体，与其他肝素结合蛋白，如血小板第4因子(PF4)的交叉反应很小。基于这些观察，我们假设PRT/H抗体在体外循环后频繁出现，并与不良临床结局相关。为了验证这一假设，我们将使用R21探索机制来探讨PRT/H抗体在体外循环患者中的临床意义。具体地说，我们将：1)在最近完成的一项对CPB患者的研究(HIT 5801研究)中，确定PRT/H抗体的发生率，并调查与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，对大约1000名接受CPB的患者进行了研究，在这些患者中，临床数据和血浆样本可用于进一步研究。我们已经获得了IRB的批准，可以检查Duke队列(n=783)，以开发PRT/H抗体和相关的临床结果。我们还将建立同时表达PF4/H抗体(导致肝素诱导的血小板减少症或HIT的抗体)，并确定PRT/H抗体和PF4/H抗体患者的预后是否更差。2)通过体外和体内研究，明确抗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的免疫应答具有几个生物学特征。为此，我们将研究PRT/H抗体与血小板和单核细胞活化相关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。从这项由R21资助的研究中获得的初步数据将使我们能够证明PRT/H抗体在体外循环中的临床相关性，并使未来能够对与抗体形成相关的结果进行前瞻性研究。 公共卫生相关性：我们已经确定了一种对一种药物(鱼精蛋白)的新型过敏反应，该药物通常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。这种过敏是由接触鱼精蛋白和肝素引起的，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.