Agnelli G, Iorio A, Renga C, Boschetti E, Nenci G G, Ofosu F A, Hirsh J
Istituto di Medicina Interna e di Medicina Vascolare, Università di Perugia, Italy.
Circulation. 1995 Nov 15;92(10):2819-24. doi: 10.1161/01.cir.92.10.2819.
The mechanism for the efficacy of once- or twice-daily subcutaneous injections of low-molecular-weight heparins (LMWHs) for the treatment of venous thromboembolism has been difficult to explain. The confusion exists because the observation from experimental studies that the antithrombin activity of LMWHs is necessary for their antithrombotic effect is inconsistent with the reported short half-life of the antithrombin activity of LMWHs. Previous pharmacokinetic studies were performed with lower doses of LMWHs than have been used in contemporary trials, and antithrombin activity was assessed with the barely sensitive chromogenic assay.
We performed a pharmacokinetic study to compare the relative half-lives of prophylactic and therapeutic doses of LMWHs assessing antithrombin activity with both the chromogenic and a more sensitive assay (plasma thrombin neutralization assay). An eight-way cross-over randomized study in healthy volunteers was performed. Enoxaparin (20 and 40 mg and 1 and 2 mg/kg) and nadroparin (7500 and 10,000 ICU and 225 and 450 ICU/kg) were administered subcutaneously. The maximal peak activity for aPTT ratio was 1.7. A dose-dependent peak activity was found for both antifactor Xa and antithrombin activities. Disappearance time of these activities after the highest dose of both LMWHs was longer than 16 hours. Overall mean antifactor Xa activity half-life was 4.6 hours. Overall mean antithrombin activity half-life was longer than 4 hours.
Our results provide an explanation for the effectiveness of LMWHs administered either once or twice daily. High and sustained plasma antithrombin activity is achieved when LMWHs are administered in therapeutic doses used in contemporary trials with only a moderate prolongation of the aPTT.
每日一次或两次皮下注射低分子量肝素（LMWH）治疗静脉血栓栓塞症的疗效机制一直难以解释。之所以存在这种困惑，是因为实验研究观察到LMWH的抗凝血酶活性对其抗血栓作用是必需的，这与报道的LMWH抗凝血酶活性的短半衰期不一致。以往的药代动力学研究使用的LMWH剂量低于当代试验中使用的剂量，并且使用灵敏度较低的发色底物法评估抗凝血酶活性。
我们进行了一项药代动力学研究，比较了预防性和治疗性剂量LMWH的相对半衰期，同时使用发色底物法和更灵敏的检测方法（血浆凝血酶中和试验）评估抗凝血酶活性。在健康志愿者中进行了一项八交叉随机研究。皮下注射依诺肝素（20毫克、40毫克、1毫克/千克和2毫克/千克）和那屈肝素（7500国际单位、10000国际单位、225国际单位/千克和450国际单位/千克）。活化部分凝血活酶时间（aPTT）比值的最大峰值活性为1.7。抗Xa因子和抗凝血酶活性均呈现剂量依赖性峰值活性。两种LMWH最高剂量后这些活性的消失时间均超过16小时。总体平均抗Xa因子活性半衰期为4.6小时。总体平均抗凝血酶活性半衰期超过4小时。
我们的结果为每日一次或两次给药的LMWH的有效性提供了解释。当以当代试验中使用的治疗剂量给予LMWH时，可实现高且持续的血浆抗凝血酶活性，同时aPTT仅适度延长。
