Fareed J, Walenga J M, Hoppensteadt D, Huan X, Racanelli A
Department of Pathology, Loyola University Medical Center, Maywood, Ill.
Haemostasis. 1988;18 Suppl 3:3-15. doi: 10.1159/000215861.
Different low-molecular-weight (LMW) heparins are produced by fractionation, enzymatic and chemical methods. Although the manufacturer's assigned molecular weights of these agents are similar (around 5,000 daltons), they exhibit considerable molecular structural heterogeneity due to the variations in the manufacturing process. In vitro standardization of these LMW heparins produces highly variable results due to the variability of assay specificity. In a comparative study with seven LMW heparins, differences were found in molecular weight distribution, antifactor Xa activity, antifactor IIa activity, Heptest activity, USP potency, platelet interactions, protamine and platelet factor 4 neutralization and charge density ratios. Relative antithrombotic actions varied between the seven agents and the ratio of the intravenous:subcutaneous effects were inconsistent with expected results based on in vitro properties or observed ex vivo effects. These products were not bioequivalent in equigravimetric or equipharmacopeial dosages (antifactor Xa, USP). Although the intravenous bioavailability was proportional to the potency for an individual agent, the subcutaneous bioavailability of the same agent showed differences from that of the intravenous regimen. In addition, significant differences between the bleeding profiles of these agents were noted in both intravenous and subcutaneous routes. The bleeding profiles did not correlate well with the relative proportion of the antifactor Xa component. However, some relationship to the bleeding effect was observed with the antifactor IIa and activated-partial-thromboplastin-time activities. These LMW heparins produced different effects on platelets as studied in the heparin-induced thrombocytopenia and platelet activation systems. These observations suggest that the individual composition of each LMW heparin determines its in vivo behavior which may account for the different safety/efficacy ratios observed in clinical trials.
不同的低分子量（LMW）肝素是通过分级分离、酶法和化学方法生产的。尽管这些药物的制造商指定分子量相似（约5000道尔顿），但由于生产过程中的差异，它们表现出相当大的分子结构异质性。由于检测特异性的变化，这些LMW肝素的体外标准化产生了高度可变的结果。在一项对七种LMW肝素的比较研究中，发现它们在分子量分布、抗Xa因子活性、抗IIa因子活性、Heptest活性、USP效价、血小板相互作用、鱼精蛋白和血小板因子4中和以及电荷密度比方面存在差异。七种药物之间的相对抗血栓作用各不相同，静脉注射与皮下注射效果的比例与基于体外特性或观察到的体内外效果的预期结果不一致。这些产品在等重量或等药典剂量（抗Xa因子，USP）下不具有生物等效性。虽然静脉生物利用度与单个药物的效价成正比，但同一药物的皮下生物利用度与静脉给药方案不同。此外，这些药物在静脉和皮下给药途径中的出血情况也存在显著差异。出血情况与抗Xa因子成分的相对比例相关性不佳。然而，观察到与抗IIa因子和活化部分凝血活酶时间活性存在一定的出血效应关系。在肝素诱导的血小板减少症和血小板激活系统中研究发现，这些LMW肝素对血小板产生不同的影响。这些观察结果表明，每种LMW肝素的个体组成决定了其体内行为，这可能解释了临床试验中观察到的不同安全/疗效比。
