Mismetti P, Laporte-Simitsidis S, Navarro C, Sié P, d'Azemar P, Necciari J, Duret J P, Gaud C, Decousus H, Boneu B
Groupe de recherche sur la Thrombose, Saint-Etienne, France.
Thromb Haemost. 1998 Jun;79(6):1162-5.
Venous thromboembolism may be efficiently treated by one single daily administration of a high dose of low molecular weight heparin (LMWH). The present study investigates if the physiological deterioration of renal function associated with normal aging or the presence of an acute venous thromboembolism influences the pharmacodynamic pattern of the anti-factor Xa and anti-thrombin activities. Three groups of 12 subjects were investigated. The first 2 groups were composed of healthy volunteers differing by age (25 +/- 4 and 65 +/- 3 yrs) and creatinine clearance (114 +/- 15 and 62 +/- 6 ml x min(-1)). The third group was composed of patients hospitalized for deep vein thrombosis, having a mean age of 65 +/- 11 yrs and creatinine clearance of 76 +/- 8 ml x min(-1). Nadroparin was administered subcutaneously once daily at the dose of 180 anti-factor Xa IU.kg(-1) for 6 to 10 days. Serial sampling on day 1 and on the last day of administration (day n) allowed the pharmacodynamic parameters of the anti-factor Xa and anti-thrombin activities to be compared at the beginning and at the end of the treatment. The main findings were the following: (1) After repeated administration, a significant accumulation of the anti-factor Xa activity was observed in the healthy elderly and in the patients but not in the healthy young subjects (accumulation factor: 1.3). There was no evidence of accumulation of anti-thrombin activity; (2) There were significant correlations between the clearance of creatinine and the clearance of the anti-factor Xa activity but not with that of the anti-thrombin activity; (3) In the patients, the clearance of the anti-factor Xa and of the anti-thrombin activities were 1.4 and 2 times higher respectively than those calculated in the healthy elderly; (4) The mean ratio of the of anti-factor Xa and anti-thrombin clearances was close to 2 in the healthy subjects but equal to 5.4 in the patients. These results suggest that the mechanisms involved in the clearance of polysaccharide chains which support the anti-thrombin activity are different from those of the anti-factor Xa activity and that the enhanced binding properties of plasma proteins to unfractionated heparin reported in patients presenting an acute venous thromboembolism also exists for LMWH, predominantly for the anti-thrombin activity.
每日单次高剂量注射低分子量肝素（LMWH）可有效治疗静脉血栓栓塞症。本研究旨在探究与正常衰老相关的肾功能生理性衰退或急性静脉血栓栓塞症的存在是否会影响抗Xa因子和抗凝血酶活性的药效学模式。研究了三组，每组12名受试者。前两组由年龄不同（25±4岁和65±3岁）且肌酐清除率不同（114±15和62±6 ml·min⁻¹）的健康志愿者组成。第三组由因深静脉血栓形成住院的患者组成，平均年龄为65±11岁，肌酐清除率为76±8 ml·min⁻¹。以180抗Xa因子IU·kg⁻¹的剂量皮下注射那屈肝素，每日一次，持续6至10天。在给药第1天和最后一天（第n天）进行系列采样，以便比较治疗开始和结束时抗Xa因子和抗凝血酶活性的药效学参数。主要发现如下：（1）重复给药后，在健康老年人和患者中观察到抗Xa因子活性有显著积累，但在健康年轻受试者中未观察到（积累因子：1.3）。没有抗凝血酶活性积累的证据；（2）肌酐清除率与抗Xa因子活性清除率之间存在显著相关性，但与抗凝血酶活性清除率无关；（3）在患者中，抗Xa因子和抗凝血酶活性的清除率分别比健康老年人中计算出的清除率高1.4倍和2倍；（4）在健康受试者中，抗Xa因子与抗凝血酶清除率的平均比值接近2，但在患者中等于5.4。这些结果表明，支持抗凝血酶活性的多糖链清除机制与抗Xa因子活性的清除机制不同，并且在急性静脉血栓栓塞症患者中报道的血浆蛋白与普通肝素增强的结合特性在低分子量肝素中也存在，主要针对抗凝血酶活性。
