Bal Dit Sollier Claire, Berge Natacha, Drouet Ludovic
aThrombosis and Atherosclerosis Research Unit, Vessels and Blood Institut, Lariboisiere Hospital bAnticoagulation Clinic (CREATIF), Hôpital Lariboisière cParis VII University EA 7334 REMES, Paris, France.
Blood Coagul Fibrinolysis. 2016 Oct;27(7):779-785. doi: 10.1097/MBC.0000000000000489.
The initial STACKENOX (STACK-on to ENOXaparin) study investigated the effect of stacking unfractionated heparin (UFH) onto a chronic treatment with enoxaparin, a common practice in interventional cardiology when a patient treated with enoxaparin receives an additional bolus of UFH at the time of percutaneous coronary intervention. The study brought to light some unexpected consequences on coagulation tests and hemorrhagic risk. This substudy was performed to provide a pharmacological explanation for these observations. Seventy-two healthy individuals previously treated with enoxaparin for 2.5 days received a stack-on of 70 IU/kg intravenous UFH dose 4, 6, or 10 h after the last enoxaparin dose. Anticoagulation activity was monitored by activated partial thromboplastin time, anti-Xa and anti-IIa activities and a thrombin generation test. In parallel, plasma samples of the individuals receiving the chronic enoxaparin treatment obtained at 4, 6, or 10 h after the last enoxaparin dose were spiked in vitro with a dose of UFH reproducing the concentration achieved in vivo after the bolus of UFH alone. In-vivo stack-on of UFH induced an over-anticoagulation identified by changes in anti-Xa and, less markedly, in anti-IIa and activated partial thromboplastin time levels, whereas in-vitro UFH spiking, only produced an additive effect. We hypothesize that the potentiation of UFH on anti-Xa activity observed in vivo may caused by the UFH bolus mobilizing enoxaparin chains stored in the endothelial glycocalyx during chronic pretreatment. This over-anticoagulation and its potential hemorrhagic risk after stack-on of UFH have obvious clinical implications.
最初的STACKENOX（在依诺肝素基础上加用）研究调查了在依诺肝素长期治疗基础上加用普通肝素（UFH）的效果，这是介入心脏病学中的一种常见做法，即接受依诺肝素治疗的患者在经皮冠状动脉介入治疗时额外推注一剂UFH。该研究揭示了凝血试验和出血风险方面的一些意外后果。进行这项子研究是为这些观察结果提供药理学解释。72名先前接受依诺肝素治疗2.5天的健康个体在最后一剂依诺肝素后4、6或10小时接受了70 IU/kg静脉注射UFH剂量的加用。通过活化部分凝血活酶时间、抗Xa和抗IIa活性以及凝血酶生成试验监测抗凝活性。同时，在最后一剂依诺肝素后4、6或10小时采集接受依诺肝素长期治疗个体的血浆样本，在体外加入一剂UFH，使其浓度与单独推注UFH后体内达到的浓度相同。UFH的体内加用导致抗Xa水平变化所确定的过度抗凝，抗IIa和活化部分凝血活酶时间水平变化不太明显，而体外加入UFH仅产生相加效应。我们推测，体内观察到的UFH对抗Xa活性的增强作用可能是由于UFH推注动员了慢性预处理期间储存在内皮糖萼中的依诺肝素链。UFH加用后的这种过度抗凝及其潜在的出血风险具有明显的临床意义。
