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.

A Standard for Low Molecular Weight Heparin?

“…Johnson and Fareed on the use of a standard preparation for the comparison of the activities of low molecu lar weight heparins. The discussion was pro voked by two articles from Dr. Fareed's lab oratory published in a supplement for Hae mostasis [1,2].…”

Low Molecular Weight Heparins: Differences and Similarities in Approved Preparations in the United States

“…Thu s. besides the antithrombin (AT) III affinity components responsible for the ant i-Xu activity, other factors may be relevant. Figure 5 illustrates the antithrombotic activity measured in an animal model at equivalent anti-Xa dosages in the intravenous studies (rabbit stasis model) (1)(2)(3)(4). It is noted that the lowest intravenous antithrombotic acti vity in this model is seen with ardeparin, the highest is noted with dalteparin, and intermediate antithrombotic activity…”

“…It is noted from Fig. 8 that enoxaparin and dalteparin are approximately equal in their ability to release TFPI, but they have less TFPI releasing activity than unfractionated heparin (1)(2)(3)(4).…”

“…Figure 2 illustrates that percentage of each preparation that is above the low molecular weight range (i.e., >7,500 d). It is noted that approximately 37% of enoxaparin, 25% of dalteparin, and 35% of ardeparin contain moieties of molecular weight >7,500 d (i.e., heparin moieties in the un fractionated heparin range) (1)(2)(3)(4). This molecular weight range includes chain lengths containing >20 hexose units.…”

“…Figure I compares the three available FDA approved LMWHs with respect to molecular weights <2.500 d, the range where relatively lillie anti-Xa or anti-I1a activity is detected. It is noted that approximately 15% of enoxaparin, 4% of dalteparin, and 6% of ardeparin is in this range (1)(2)(3)(4) …”