Anti-protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis
Anti-protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis
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DOI：
10.1182/blood-2012-10-460691
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发表时间：
2013-04-11
期刊：
影响因子：
20.3
通讯作者：
Greinacher, Andreas
中科院分区：
文献类型：
--
作者：
Bakchoul, Tamam;Zoellner, Heike;Greinacher, Andreas
鱼精蛋白通常用于心脏手术后逆转肝素的抗凝作用，已知其具有免疫原性。观察鱼精蛋白给药后血小板计数迅速下降但原因不明的患者，确定鱼精蛋白反应性抗体在心脏手术患者中的发生率和临床相关性。在体外，这些抗体以Fc γ RIIa依赖性方式活化洗涤的血小板。使用非肥胖糖尿病/严重联合免疫缺陷小鼠模型，这些抗体诱导血小板减少症时，鱼精蛋白和肝素，但不单独鱼精蛋白。在591例接受心肺转流手术的患者中，57例（9.6%）在基线时抗鱼精蛋白-肝素抗体检测呈阳性，154例（26.6%）在第10天检测呈阳性。糖尿病被确定为抗鱼精蛋白肝素抗体形成的危险因素。在大多数患者中，这些抗体是短暂的，4个月后滴度大幅下降（P <0.001）。7例患者在基线时有血小板活化、抗鱼精蛋白-肝素抗体，与抗体阴性患者相比，血小板计数下降幅度更大，时间更长（P = .003）。此外，这些患者中有2例发生早期动脉血栓栓塞并发症，而584例对照患者中有9例发生早期动脉血栓栓塞并发症（多变量分析：比值比，21.58; 95%置信区间，2.90-160.89; P = 0.003）。血小板活化抗鱼精蛋白-肝素抗体与抗血小板因子4-肝素抗体有几个相似之处，是术后早期血栓形成的潜在危险因素。
Protamine, which is routinely used after cardiac surgery to reverse the anticoagulant effects of heparin, is known to be immunogenic. Observing patients with an otherwise unexplained rapid decrease in platelet count directly after protamine administration, we determined the incidence and clinical relevance of protamine-reactive antibodies in patients undergoing cardiac-surgery. In vitro, these antibodies activated washed platelets in a Fc gamma RIIa-dependent fashion. Using a nonobese diabetic/severe combined immunodeficiency mouse model, those antibodies induced thrombocytopenia only when protamine and heparin were present but not with protamine alone. Of 591 patients undergoing cardiopulmonary bypass surgery, 57 (9.6%) tested positive for anti-protamine-heparin antibodies at baseline and 154 (26.6%) tested positive at day 10. Diabetes was identified as a risk factor for the development of anti-protamine-heparin antibodies. In the majority of the patients, these antibodies were transient and titers decreased substantially after 4 months (P < .001). Seven patients had platelet-activating, anti-protamine-heparin antibodies at baseline and showed a greater and more prolonged decline in platelet counts compared with antibody-negative patients (P = .003). In addition, 2 of those patients experienced early arterial thromboembolic complications vs 9 of 584 control patients (multivariate analysis: odds ratio, 21.58; 95% confidence interval, 2.90-160.89; P = .003). Platelet-activating antiprotamine-heparin antibodies show several similarities with anti-platelet factor 4-heparin antibodies and are a potential risk factor for early postoperative thrombosis.