Pathogenesis of heparin contaminant mediated vascular and hemostatic responses in animal models

Abstract

Earlier this year, unfractionated heparin (UFH) and low molecular weight heparins (LMWH) were found to be contaminated with oversulfated chondroitin sulfate (OSCS) and high molecular weight dermatan sulfate (DS). The main contaminant, OSCS, had a molecular weight (MW) similar to UFH, but exhibited different biologic actions. OSCS does not interact with antithrombin, but activates the complement, kallikrein‐kinin and fibrinolytic systems via contact activation. To investigate the hemodynamic and hemostatic responses, contaminated (CH) and non‐contaminated heparin and isolated OSCS were administered to groups of rats and parameters such as blood pressure, bleeding time (BT) and antithrombotic actions (ATA) were measured. CH produced markedly higher ATA and BT responses relative to UFH. OSCS did not produce a strong hemodynamic effect at doses up to 2 mg/kg IV. However, when mixed with UFH, an augmentation of the hemodynamic, ATA and BT effects was seen. No significant differences were noted between OSCS and LMWH at doses up to 2 mg/kg (either IV or SC). OSCS isolated from heparin or LMWHs exhibited MW differences, but both produced similar effects on the contact system and platelet activation. These studies suggest that OCSC not only produces anticoagulant effects but also exerts pharamcodynamic effects/interactions with UFH. The presence of exogenous DS may further impact on their pharmacologic effects.