Fareed J, Walenga J M, Racanelli A, Hoppensteadt D, Huan X, Messmore H L
Department of Pathology, Loyola University Medical Center, Maywood, Ill.
Haemostasis. 1988;18 Suppl 3:33-47. doi: 10.1159/000215866.
Four low-molecular-weight-heparin (LMWH) preparations have recently become available for clinical usage. Some ten preparations are currently under preclinical development. The safety/efficacy profile of each of these LMWHs is now known to be quite distinct from one and other. In order to minimize the variations in the pharmacologic responses and to cross-reference different products on a common scale, the WHO has recently introduced a LMWH standard. This standard is a nitrous-acid-depolymerized product provided by KabiVitrum (Stockholm, Sweden) with a specific physiochemical and biological profile. Although the in vitro characteristics of this standard are comparable to other LMWH, the in vivo behavior of this reference and the parent product, Fragmin, are quite different in comparison to other products. In a well-defined uniform biochemical and pharmacologic screening, seven LMWH were compared at WHO reference-adjusted potency using pharmacologically valid dose-response curves. Cross-referencing of various LMWHs against the WHO standard in terms of anti-Xa activity resulted in a marked elevation of the anti-IIa component of some of the LMWHs. Establishment of this WHO standard stipulated that the clinical performance of cross-referenced LMWHs would be equivalent to one another and variation in potency could be minimized. Our data suggest that utilizing the WHO, standard individual potency (anti-Xa)-adjusted LMWHs exhibit distinct safety/efficacy profiles which were not related in their observed in vitro potency. Each LMWH has distinct multiparametric molecular and biochemical characteristics which determine the pharmacologic activities of individual agents. Thus cross-referencing of LMWHs by one in vitro assay is of questionable value as it may result in serious dosimetric errors, resulting in serious thrombotic and bleeding complications.
四种低分子量肝素（LMWH）制剂最近已可供临床使用。目前约有十种制剂正处于临床前开发阶段。现已知道这些LMWH中的每一种的安全性/有效性概况彼此相当不同。为了尽量减少药理反应的差异并在共同尺度上对不同产品进行交叉参照，世界卫生组织（WHO）最近推出了一种LMWH标准。该标准是由瑞典斯德哥尔摩的卡比维特龙公司提供的一种亚硝酸解聚产物，具有特定的物理化学和生物学特性。虽然该标准的体外特性与其他LMWH相当，但该参比品与母体产品法安明的体内行为与其他产品相比有很大不同。在一项明确界定的统一生化和药理筛选中，使用药理学上有效的剂量反应曲线，按照WHO参比调整效价对七种LMWH进行了比较。根据抗Xa活性将各种LMWH与WHO标准进行交叉参照，结果导致一些LMWH的抗IIa成分明显升高。制定该WHO标准规定，交叉参照的LMWH的临床性能应彼此等效，并且效价差异可降至最低。我们的数据表明，使用WHO标准的个体效价（抗Xa）调整后的LMWH表现出不同的安全性/有效性概况，这些概况与其观察到的体外效价无关。每种LMWH都有独特的多参数分子和生化特性，这些特性决定了各个药物的药理活性。因此，通过一种体外测定对LMWH进行交叉参照的价值值得怀疑，因为这可能导致严重的剂量错误，从而导致严重的血栓形成和出血并发症。
