Effect of oversulfated dermatan sulfate derivatives on platelet aggregation

We have investigated the effect on human platelet aggregation of native dermatan sulfate (DS) and three oversulfated DS derivatives with different sulfur contents, and compared it with that of unfractionated heparin. An inhibitory effect on collagen-induced platelet aggregation was observed only with unfractionated heparin at high concentrations, whereas no inhibitory effect was observed when arachidonic acid was used. Heparin was the most potent inhibitor of the thrombin-induced platelet aggregation in platelet-rich plasma (PRP), whereas the oversulfated DS had a higher potency than the native DS. All these glycosaminoglycans (GAGs) also inhibited thrombin-induced aggregation of washed platelets in the presence of antithrombin (AT) or heparin cofactor II (HCII) but not in their absence. Heparin was by far the most potent inhibitor of washed platelet aggregation in the presence of AT, whereas the inhibitory effects of the DS (native or oversulfated) were lower but dependent on the sulfur content. In the presence of HCII, DSb, a slightly oversulfated DS, had the highest inhibitory effect, whereas heparin and DSd, the most oversulfated derivative, had lower potencies in this case. These data suggest that the inhibition of thrombin-induced platelet aggregation by the oversulfated DS derivatives is related to their ability to potentiate thrombin inactivation by AT or HCII. Hence, the oversulfated DS derivatives may not have an effect per se on the inhibition of platelet aggregation. They may constitute a new class of anticoagulants with enhanced anticoagulant effects in comparison with the native DS, but with only minor side-effects of bleeding in comparison with heparin.