Background: Therapeutic use of unfractionated heparin and low molecular weight heparins (LMWHs) is limited by hemorrhagic adverse effects. We compared the antithrombotic effect of LMW fucoidan (LMWF) and LMWH in an experimental model. Methods: Thrombosis was induced in femoral arteries of male New Zealand White rabbits by in situ induction of endothelial apoptosis with staurosporine (10–5M for 30 min). Starting the day before apoptosis induction, the animals received subcutaneous LMWF (15 mg/kg), LMWH (enoxaparin 2.5 mg/kg) or saline solution (control group) twice a day for 4 days. Results: The degrees of apoptosis and endothelial denudation were similar in the 3 groups. The thrombotic score was significantly lower in the LMWF group than in the LMWH and control groups (p = 0.01). Tissue factor expression was significantly lower in the LMWF group than in the control and LMWH groups (p = 0.01). The plasma concentration of tissue factor pathway inhibitor was significantly increased after LMWF injection (137 ± 28 vs. 102 ± 17; p = 0.01), whereas no change was observed after LMWH treatment. LMWF did not prolong the bleeding time or decrease platelet aggregation. Conclusions: LMWF appeared to be more effective than LMWH for preventing arterial thrombosis in this experimental model. LMWF also had a lower hemorrhagic risk than LMWH.

1.
Nardella A, Chaubet F, Boisson-Vidal C, Blondin C, Durand P, Josefonvicz J: Anticoagulant low molecular weight fucans produced by radical process and ion exchange chromatography of high molecular weight fucans extracted from the brown seaweed Ascophyllum nodosum. Carbohydr Res 1996;289:201–208.
2.
Mauray S, Sternberg C, Theveniaux J, Millet J, Sinquin C, Tapon-Bretaudiere J, Fischer AM: Venous antithrombotic and anticoagulant activities of a fucoidan fraction. Thromb Haemost 1995;74:1280–1285.
3.
Bajaj MS, Kuppuswamy MN, Saito H, Spitzer SG, Bajaj SP: Cultured normal hepatocytes do not synthesize lipoprotein-associated coagulation inhibitor: evidence that endothelium is the principle site of its synthesis. Proc Natl Acad SciUSA 1990;87:8869–8873.
4.
Lupu C, Poulsen E, Roquefeuil S, Westmuckett AD, Kakkar VV, Lupu F: Cellular effects of heparin on the production and release of tissue factor pathway inhibitor in human endothelial cells in culture. Arterioscler Thromb Vasc Biol1999;19:2251–2262.
5.
Giraux JL, Tapon-Bretaudiere J, Matou S, Fischer AM: Fucoidan, as heparin, induces tissue factor pathway inhibitor release from cultured human endothelial cells. Thromb Haemost 1998;80:692–695.
6.
Millet J, Colliec Jouault S, Mauray S, Theveniaux J, Sternberg C, Boisson Vidal C, Fischer AM: Antithrombotic and anticoagulant activities of a low molecular weight fucoidan by the subcutaneous route. Thromb Haemost 1999;81:391–395.
7.
Colliec-Jouault S, Durand P, Fischer AM: Low molecular weight sulphated polysaccharide to obtain a medicine with antithrombotic activity. United States Patent No. 6,828,307, 2004.
8.
Durand E, Scoazec A, Lafont A, Al Haj Zen A, Addad F, Mirshahi M, Desnos M, Tedgui A, Mallat Z: In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation. Circulation 2004;109:2503–2506.
9.
D’Andrea D, Ravera M, Golino P, Rosica A, De Felice M, Ragni M, Cirillo P, Vigorito F, Corcione N, Tommasini P, Gargiulo A, Piro O, Calabro P, Chiariello M: Induction of tissue factor in the arterial wall during recurrent thrombus formation. Arterioscler Thromb Vasc Biol 2003;23:1684–1689.
10.
Carter CJ, Kelton JG, Hirsh J: Comparison of haemorrhagic effect of porcine and bovine heparin in the rabbits. Thromb Res 1979;15:581–586.
11.
Doutremepuich C, Toulemonde F, Bousquet F, Bonini F: Comparison of haemorrhagic effect of unfractionated heparin and a low molecular weight heparin fraction (CY 216) in rabbits. Thromb Res 1986;43:691–695.
12.
Sandset PM, Warn-Cramer BJ, Rao VM, Maki SL, Rapaport SI: Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminate intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 1991;88:708–712.
13.
Cohen M: The role of low molecular weight heparin in the management of acute coronary syndromes. J Am Coll Cardiol 2003;41(suppl S):55S–61S.
14.
Giesen PL, Rauch U, Bohrmann B, Kling D, Roque M, Fallon JT, Badimon JJ, Himber J, Riederer MA, Nemerson Y: Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999;96:2311–2315.
15.
Tedgui A, Mallat Z: Apoptosis as a determinant of atherothrombosis. Thromb Haemost 2001;86:420–426.
16.
Moons AH, Levi M, Peters RJ: Tissue factor and coronary artery disease. Cardiovasc Res 2002;53:313–325.
17.
Ragni M, Golino P, Cirillo P, Scognamiglio A, Piro O, Esposito N, Battaglia C, Botticella F, Ponticelli P, Ramunno L, Chiariello M: Endogenous tissue factor pathway inhibitor modulates thrombus formation in an in vivo model of rabbit carotid artery stenosis and endothelial injury. Circulation 2000;102:113–117.
18.
Morange PE, Simon C, Alessi MC, Luc G, Arveiler D, Ferrieres J, Amouyel P, Evans A, Ducimetiere P, Juhan-Vague I, PRIME study group: Endothelial cell markers and the risk of coronary heart disease: the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study. Circulation 2004;109:1343–1348.
19.
Sundaram M, Qi Y, Shriver Z, Liu D, Zhao G, Venkataraman G, Langer R, Sasisekharan R: Rational design of low molecular weight heparins with improved in vivo activity. Proc Natl Acad Sci USA 2003;100:651–656.
20.
Thorlacius H, Vollmar B, Seyfert UT, Vestweber D, Menger MD: The polysaccharide fucoidan inhibits microvascular thrombus formation independently from P- and L-selectin function in vivo. Eur J Clin Invest 2000;30:804–810.
21.
Chabut D, Fischer AM, Colliec-Jouault S, Laurendeau I, Matou S, Le Bonniec B, Helley D: Low molecular weight fucoidan and heparin enhance the FGF-2 induced tube formation of endothelial cells through heparan sulfate-dependent alpha 6 over-expression. Mol Pharmacol 2003;64:696–702.
22.
Logeart D, Prigent-Richard S, Jozefonvicz J, Letourneur D: Fucans, sulfated polysaccharides extracted from brown seaweeds, inhibit vascular smooth muscle cell proliferation. 1. Comparison with heparin for antiproliferative activity, binding and internalization. Eur J Cell Biol 1997;74:376–384.
23.
Logeart D, Prigent-Richard S, Boisson-Vidal C, Chaubet F, Durand P, Jozefonvicz J, Letourneur D: Fucans, sulfated polysaccharides extracted from brown seaweeds, inhibit vascular smooth muscle cell proliferation. 2. Degradation and molecular weight effect. Eur J Cell Biol1997;74:385–390.
24.
Deux JF, Meddahi-Pelle A, Le Blanche AF, Feldman LJ, Colliec-Jouault S, Bree F, Boudghene F, Michel JB, Letourneur D: Low molecular weight fucoidan prevents neointimal hyperplasia in rabbit iliac artery in-stent restenosis model. Arterioscler Thromb Vasc Biol2002;22:1604–1609.
25.
Luyt CE, Meddahi-Pelle A, Ho-Tin-Noe B, Colliec-Jouault S, Guezennec J, Louedec L, Prats H, Jacob MP, Osborne-Pellegrin M, Letourneur D, Michel JB: Low molecular weight fucoidan promotes therapeutic revascularization in a rat model of critical hindlimb ischemia. J Pharmacol Exp Ther 2003;305:24–30.
26.
Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM: Lessons from sudden coronary death: a comprehensive morphological classification scheme for athero-sclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262–1275.
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