Bara L, Bloch M F, Zitoun D, Samama M, Collignon F, Frydman A, Uzan A, Bouthier J
Laboratoire de Thrombose Expérimentale, Université Pierre et Marie Curie, Paris, France.
Thromb Res. 1993 Mar 1;69(5):443-52. doi: 10.1016/0049-3848(93)90233-e.
In a randomized crossover study twelve healthy male volunteers (23.5 +/- of 4.8 years, 73.0 +/- 6.4 kg, 180.8 +/- 5.7 cm) received one subcutaneous injection of either enoxaparin (EN) at 40 mg or 1 mg kg-1, or unfractionated heparin (UH) at 5,000 IU at one week intervals. Area under curves (AUC) of Anti-Xa and Anti-IIa activities correlated with EN dose. The relative effectiveness of EN versus UH 5,000 U as assessed by AUC ratio (EN/UH) was 7 and 15 for Anti-Xa activity, 1.3 and 3.1 for Anti-IIa activity after sc injection of EN 40 mg (4,000 Anti-Xa IU and 1,200 Anti-IIa U) and 1 mg kg-1 (7,300 +/- 640 Anti-Xa IU and 2,190 +/- 290 Anti-IIa IU) respectively. In volunteers receiving EN, a dose dependent inhibition of thrombin generation rate in platelet depleted plasma (PDP), measured with a new and simple chromogenic thrombin generation assay, was observed when compared with baseline values. Similarly, intrinsic prothrombin activation in whole blood, evidenced by measuring residual factor II in serum 2 hours after clotting (prothrombin consumption test: PC), was inhibited in a dose dependent manner. In UH treated volunteers, although the inhibition of thrombin generation rate in PDP was similar to that observed with EN 40 mg, prothrombin consumption in whole blood was not significantly modified. Tissue factor pathway inhibitor (TFPI) activity release was increased similarly for UH and EN 40 (1.4 fold increase above baseline values) and 1.9 fold for the higher dose of EN. The discrepancy between prothrombin consumption in whole blood and inhibition of thrombin generation rate in PDP in the UH and not in the EN group strongly suggests that UH and not EN is influenced by the presence of a platelet component. This could be formed during thrombin induced platelet activation. Platelet factor 4 is a possible candidate. Another hypothesis involves the role of TFPI-UH complex anticoagulant activity which might be inhibited more during whole blood coagulation than the TFPI-EN complex.
在一项随机交叉研究中，12名健康男性志愿者（年龄23.5±4.8岁，体重73.0±6.4千克，身高180.8±5.7厘米）每隔一周接受一次皮下注射，分别注射40毫克依诺肝素（EN）或1毫克/千克依诺肝素，或5000国际单位普通肝素（UH）。抗Xa和抗IIa活性的曲线下面积（AUC）与依诺肝素剂量相关。通过AUC比值（EN/UH）评估，依诺肝素与5000单位普通肝素相比，皮下注射40毫克依诺肝素（4000抗Xa国际单位和1200抗IIa单位）和1毫克/千克依诺肝素（7300±640抗Xa国际单位和2190±290抗IIa单位）后，抗Xa活性的相对效力分别为7和15，抗IIa活性的相对效力分别为1.3和3.1。在接受依诺肝素的志愿者中，与基线值相比，使用一种新的简单显色凝血酶生成试验测量发现，在血小板贫乏血浆（PDP）中凝血酶生成率受到剂量依赖性抑制。同样，通过测量凝血2小时后血清中的残余因子II（凝血酶原消耗试验：PC）来证明，全血中的内源性凝血酶原激活也受到剂量依赖性抑制。在接受普通肝素治疗的志愿者中，虽然PDP中凝血酶生成率的抑制与40毫克依诺肝素观察到的相似，但全血中的凝血酶原消耗没有显著改变。普通肝素和40毫克依诺肝素的组织因子途径抑制剂（TFPI）活性释放增加相似（比基线值增加1.4倍），高剂量依诺肝素增加1.9倍。普通肝素组全血中凝血酶原消耗与PDP中凝血酶生成率抑制之间的差异，而依诺肝素组没有这种差异，强烈表明普通肝素而非依诺肝素受血小板成分存在的影响。这可能在凝血酶诱导的血小板激活过程中形成。血小板因子4是一个可能的候选因素。另一种假设涉及TFPI - 普通肝素复合物的抗凝活性作用，在全血凝固过程中它可能比TFPI - 依诺肝素复合物受到更多抑制。
