chondroitin-sulfates and Carotid-Artery-Thrombosis

Sulfated polysaccharides from marine invertebrates have well-defined structures and constitute a reliable class of molecules for structure-activity relationship studies. We tested the effects of two of these polysaccharides, namely a sulfated fucan and a fucosylated chondroitin sulfate, on coagulation, thrombosis and bleeding. The compounds share similar 2,4-disulfated fucose units, which are required for high anticoagulant activity in this class of polymer. These residues occur either as branches in fucosylated chondroitin sulfate or as components of the linear chain in the sulfated fucan. These polysaccharides possess anticoagulant activity but differ significantly in their mechanisms of action. The fucosylated chondroitin sulfate inhibits thrombin by heparin cofactor II, whereas sulfated fucan inhibits thrombin by both antithrombin and heparin cofactor II. In addition, these polysaccharides also have serpin-independent anticoagulant activities. Fucosylated chondroitin sulfate, but not sulfated fucan, activates factor XII. As a result of the complex anticoagulant mechanism, the invertebrate polysaccharides differ in their effects on experimental thrombosis. For instance, the sulfated fucan inhibits venous thrombosis at lower doses than fucosylated chondroitin sulfate. In contrast, fucosylated chondroitin sulfate is significantly more potent than sulfated fucan in arterial thrombosis. Finally, fucosylated chondroitin sulfate increases bleeding, while sulfated fucan has only a discrete effect. In conclusion, the location of 2,4-disulfated fucose units in the polysaccharide chains dictates the effects on coagulation, thrombosis and bleeding.

Topics: Animals; Anticoagulants; Blood Coagulation; Carbohydrate Conformation; Carbohydrate Sequence; Carotid Artery Thrombosis; Chondroitin Sulfates; Drug Evaluation, Preclinical; Enzyme Activation; Factor XII; Female; Fibrinolytic Agents; Fucose; Hemorrhage; Male; Molecular Sequence Data; Molecular Structure; Polysaccharides; Rats; Rats, Wistar; Sea Cucumbers; Structure-Activity Relationship; Thrombosis; Venous Thrombosis

Antithrombotic activity of catalase (CAT) and chondroitin sulfate (CHS) preparations was studied in a rat model of arterial injury induced by ferrous chloride. Equal doses (according to catalytically active CAT) were used to examine the effect of native CAT, CAT-CHS covalent conjugate and mixture of native CAT and free CHS in a ratio corresponding to their contents in the conjugate. The antithrombotic activity of the derivatives was determined by the time during which arterial occlusion developed (occlusion time) and by the mass of the formed thrombus. The antithrombotic activities of the conjugate and mixture were similar and markedly higher than that of native CAT. The conjugate was more effective with respect to deceleration and prevention of arterial occlusion. Small doses of the preparations altered the structure of the formed thrombus, promoting sustained blood flow. Further investigations of the antithrombotic activity of CAT, superoxide dismutase and CHS derivatives have been outlined.

Topics: Animals; Blood Flow Velocity; Carotid Artery Thrombosis; Catalase; Cerebrovascular Disorders; Chondroitin Sulfates; Coenzymes; Dose-Response Relationship, Drug; Drug Synergism; Male; Platelet Aggregation; Rats; Reactive Oxygen Species