ANTICOAGULANT AND ANTITHROMBOTIC ACTIONS OF A SEMISYNTHETIC BETA-1,3-GLUCAN SULFATE

Sulfation of the natural polysaccharide curdlan results in anticoagula ntly active beta-1,3-glucan sulfates whose activity depends on various structural parameters. In this study the anticoagulant and antithromb otic effects of one of these beta-1,3-glucan sulfates (GS) were compar ed with those of a porcine mucosal heparin. GS produced a concentratio n dependent anticoagulant effect in all the global coagulation assays with the exception of the anti-Xa assay. The best activity was found i n the APTT and the thrombin time assays indicating that protease gener ation and the direct inhibition of thrombin may be sites of actions of this agent. Whereas the anticoagulant activity of GS was approximatel y 5 fold lower compared to heparin, a 32 fold higher concentration (ED (50) = 550 mu g/kg) was needed for an antithrombotic effect similar to heparin (ED(50) = 17.2 mu g/kg) in a rabbit model of stasis thrombosi s. In contrast to this, when a rat model of clamping induced jugular v ein occlusion was used to produce vascular obstruction, GS produced si milar antithrombotic actions to heparin. At a 250 mu g/kg dosage, both agents doubled the number of clampings required for complete vascular obstruction. Since the mechanical injury to the blood vessel is the p rimary determinant of the thrombogenic response, GS may inhibit some o f the pathophysiologic mechanisms responsible for the occlusion of the blood vessel. The current study also points to the fact that the glob al anticoagulant effects may not reflect the antithrombotic potential of newer sulfated carbohydrate derived drugs.