Validity of the Newly Established Low-Molecular-Weight Heparin Standard in Cross-Referencing Low-Molecular-Weight Heparins

Abstract

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.