VENOUS ANTITHROMBOTIC AND ANTICOAGULANT ACTIVITIES OF A FUCOIDAN FRACTION

Fucoidans catalyse thrombin inhibition by antithrombin (AT) and hepari n cofactor II (HCII); their affinity for each serpin varies according to the seaweed species from which they are extracted, as well as their chemical composition and molecular weight. We extracted a homogeneous fucoidan fraction from Ascophyllum nodosum, a brown seaweed, and test ed its anticoagulant and antithrombotic activities. At a fucoidan conc entration of 3.75 mu g/ml, thrombin inhibition mediated by AT showed a n apparent second-order rate constant. (kapp) of 2 X 10(8) M(-1) min(- 1), compared to 1.5 X 10(6) M(-1) min(-1) for the uncatalyzed reaction . The kapp value of thrombin inhibition via HCII was 1.17 X 10(9) M(-1 ) min(-1) at a fucoidan concentration of 50 mu g/ml, compared to 1.72 x 10(5) M(-1) min(-1) for the uncatalyzed reaction. In a Wessler model of venous thrombosis, the fucoidan fraction, injected intravenously t o rabbits 10 min before thrombosis induction, exhibited antithrombotic activity: 1.8 mg/kg was the dose which inhibited F Xa-induced thrombu s formation by 80% (ED(80)), compared to a heparin ED(80) of 0.1 mg/kg , At this ED(80) the antithrombotic effect of the fucoidan persisted l onger than that of heparin (30 min versus 15 min). The thrombin clotti ng time (TCT) was significantly prolonged (73 s versus control 29 s, c ompared to 53 s with heparin) 10 min after a fucoidan bolus infusion g iving a plasma fucoidan concentration of 14.6 +/- 2.7 mu g/ml. The ble eding time was slightly increased after fucoidan infusion at the ED(80 ). Fucoidan extracted from marine flora thus shows promise as an antit hrombotic drug.