Comparative efficacy of different low-molecular-weight heparins (LMWHs) and drug interactions with LMWH: implications for management of vascular disorders.

Abstract

The low-molecular-weight heparins (LMWHs) are more efficacious and safer than unfractionated heparin (UFH) in the prevention and treatment of venous thrombosis and to a certain extent in the treatment of acute ischemic syndromes. Because of their predictable pharmacokinetics and bioavailability after subcutaneous administration, LMWHs can be more convenient for outpatient use than UFH. Differences in the manufacturing process of LMWHs result in significant structural and molecular weight differences; thus, LMWHs have individual biochemical and pharmacological profiles and are not interchangeable on the basis of either mass or anti-Xa activity. Using thromboelastograph (TEG) and platelet aggregometry, this investigation compared the in vitro efficacy among various LMWHs and examined the interactions between LMWHs and platelet glycoprotein (GP) IIb/IIIa antagonists. TEG was used to determine the ability of platelet and fibrin interactions to augment blood clots, an effect measured under conditions of maximal platelet activation during clot formation accelerated by recombinant human tissue factor (TF). The comparative efficacy of LMWHs on different mediator-induced clot retraction in human blood was assessed by TEG, which demonstrated the potency of different LMWHs to inhibit various mediator-induced clot formations under shear. Tinzaparin was relatively more effective in inhibiting TF-, lipopolysaccharide-, factor (f) Xa-, and thrombin-induced clot formation under shear. Under these conditions, platelets significantly enhance clot strength (eightfold vs. platelet-free fibrin clots). LMWHs appear to have broader efficacy than other anticoagulants. Abciximab and roxifiban further inhibited clot strength by affecting the transmission of platelet contractile force to fibrin by platelet GPIIb/IIIa receptors. Subtherapeutic doses of tinzaparin combined with abciximab or roxifiban resulted in a distinct synergy that improved anticoagulant and antiplatelet efficacy mediated by TF, fXa, or thrombin. As these data suggest, the combination of low-dose tinzaparin with low-dose GPIIb/IIIa antagonists (abciximab, roxifiban) may be efficacious in the prevention and treatment of various thromboembolic disorders.