The Effects of Dermatan Sulfate at Submicrogram/ml Concentrations on In Vitro Thrombin Generation

Abstract

Dermatan sulfate is an antithrombotic glycosaminoglycan which has been shown to be effective in preventing deep venous thrombosis in general surgery patients when present at concentrations less than 1 microgram/ml. It has also been found to circulate physiologically in similar concentrations in pregnant women at term and in cord blood. We investigated the ability of dermatan sulfate added to plasma at 0.2, 0.5 and 1.0 microgram/ml to inhibit thrombin generation initiated by low concentrations of recombinant human tissue factor in defibrinated plasma. A dose dependent decrease in thrombin potential was demonstrated at therapeutically relevant concentrations of dermatan sulfate (0.5 and 1.0 microgram/ml) but there was no induction of a lag phase in thrombin generation. We were unable to demonstrate a significant effect on thrombin potential of dermatan sulfate at a concentration similar to that found in pregnancy plasma (0.2 microgram/ml). This indicates that either the dermatan sulfate concentration found in pregnancy plasma is not physiologically relevant or that our experimental system (which lacks platelets and fibrin) does not accurately reflect physiologic conditions. The effect on the thrombin potential was somewhat greater at the lowest concentration of tissue factor and amounted to a maximum inhibition of approximately 50% at 1 microgram/ml dermatan sulfate. A dose dependent increase in formation of thrombin-heparin cofactor II complexes and a decrease in thrombin-antithrombin complex formation with increasing dermatan sulfate concentration were observed at all dermatan sulfate concentrations. Prothrombin consumption was not changed by any dose of dermatan sulfate. We conclude that dermatan sulfate, at the concentrations tested, catalyses inhibition of free thrombin by heparin cofactor II but not efficiently enough to inhibit prothrombinase formation.