Low molecular weight heparins: a developmental perspective

Abstract

Low molecular weight heparins (LMWHs) are now universally accepted as drugs of choice for post-surgical prophylaxis of deep vein thrombosis (DVT). Currently these agents are also being developed for the treatment of thrombosis and various cardiovascular indications. Due to manufacturing differences, each of the LMWHs exhibits a distinct pharmacological and biochemical profile. The specific activity of these agents in the anticoagulant assays ranges from 35 - 45 anti-IIa U/mg, whereas the specific activity in terms of anti-Xa units is designated as 80 - 145 anti-Xa U/mg. These LMWHs are capable of producing product-specific dose- and time-dependent antithrombotic effects in animal models of thrombosis. While the ex vivo effects are initially present at doses that are antithrombotic, these agents have been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. In experimental animal models and in various clinical trials, these agents have also been found to release tissue factor pathway inhibitor (TFPI) after both iv. and sc. administration. Repeated administration of LMWHs produces progressively stronger antithrombotic effects; however, the haemorrhagic responses vary and are largely dependent on the product used. The release of TFPI following iv. and sc. administration in a primate model also demonstrates product individuality and the relevance of this inhibitor to the actions of LMWHs. Furthermore, repeated administration, mimicking the post-surgical prophylaxis of DVT, leads to product-based augmentation of the antithrombotic or haemorrhagic effects. Antithrombotic and haemorrhagic studies are discussed, comparing the pharmacological profile of some of the available LMWHs. Product individuality, in terms of relative potency in different assays and the failure of standardisation protocols to provide any guidelines for product substitution and prediction of the clinical effects, is also addressed.