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      Effect of Low Molecular Weight Fucoidan and Low Molecular Weight Heparin in a Rabbit Model of Arterial Thrombosis

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          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<sup>–5</sup> M 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.

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          Most cited references 14

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          In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation: a clue to the understanding of the mechanisms of thrombotic plaque erosion.

          The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis. Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43+/-0.30 versus 0.93+/-0.44, respectively; P=0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments (P<0.01). Immunoreactivities for tissue factor, platelets, and fibrin were detectable within the thrombus. Addition of ZVAD-fmk (0.1 mmol/L) significantly reduced the occurrence of thrombosis (1 of 7 arteries or 14%, P=0.04). These results were confirmed in balloon-injured atheromatous arteries. In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.
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            Low-molecular-weight fucoidan promotes therapeutic revascularization in a rat model of critical hindlimb ischemia.

            The therapeutic potential of low-molecular-weight (LMW) fucoidan, a sulfated polysaccharide extracted from brown seaweed devoid of direct antithrombin effect, was investigated in vitro and in a model of critical hindlimb ischemia in rat. In vitro results showed that LMW fucoidan enhanced fibroblast growth factor (FGF)-2-induced [(3)H]thymidine incorporation in cultured rat smooth muscle cells. Intravenous injection in rats of LMW fucoidan significantly increased the stromal-derived factor (SDF)-1 level from 1.2 +/- 0.1 to 6.5 +/- 0.35 ng/ml in plasma. The therapeutic effect of LMW fucoidan (5 mg/kg/day), FGF-2 (1 micro g/kg/day), and LMW fucoidan combined with FGF-2 was assessed 14 days after induction of ischemia by 1) clinical evaluation of claudication, 2) tissue blood flow analysis, 3) histoenzymology of muscle metabolic activity, and 4) quantification of capillary density. Both LMW fucoidan and FGF-2 similarly improved residual muscle blood flow (62.5 +/- 6.5 and 64.5 +/- 4.5%, respectively) compared with the control group (42 +/- 3.5%, p < 0.0001). The combination of FGF-2 and LMW fucoidan showed further significant improvement in tissue blood flow (90.5 +/- 3%, p < 0.0001). These results were confirmed by phosphorylase activity, showing muscle regeneration in rats treated with the combination of FGF-2 and LMW fucoidan. Capillary density count increased from 9.6 +/- 0.7 capillaries/muscle section in untreated ischemic controls to 14.3 +/- 0.9 with LMW fucoidan, 14.5 +/- 0.9 with FGF-2, and 19.1 +/- 0.9 in combination (p < 0.001). Thus, LMW fucoidan potentiates FGF-2 activity, mobilizes SDF-1, and facilitates angiogenesis in a rat model. This natural compound could be of interest as an alternative for conventional treatment in critical ischemia.
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              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.


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                October 2008
                07 May 2008
                : 45
                : 6
                : 529-537
                aFaculté de Médecine, Université Paris Descartes, bINSERM Unité 849, cAssistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, dINSERM Unité 765, and eINSERM Unité 430, Paris, and fIFREMER, Laboratoire Biotechnologie et Molécules Marines, Nantes, France
                129687 J Vasc Res 2008;45:529–537
                © 2008 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 26, Pages: 9
                Research Paper


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