Download PDF
Thromb Haemost 1999; 81(03): 391-395
DOI: 10.1055/s-0037-1614484
Review Article
Schattauer GmbH

Antithrombotic and Anticoagulant Activities of a Low Molecular Weight Fucoidan by the Subcutaneous Route

J. Millet
1   From Laboratoires Fournier, Dijon, France
,
S. Colliec Jouault
2   IFREMER, Nantes, France
,
S. Mauray
3   Laboratoire d’Hématologie CHU Necker-Enfants Malades, Université Paris V, Villetaneuse, France
,
J. Theveniaux
1   From Laboratoires Fournier, Dijon, France
,
C. Sternberg
3   Laboratoire d’Hématologie CHU Necker-Enfants Malades, Université Paris V, Villetaneuse, France
,
Boisson C. Vidal
4   Université Paris-Nord, Villetaneuse, France
,
A. M. Fischer
3   Laboratoire d’Hématologie CHU Necker-Enfants Malades, Université Paris V, Villetaneuse, France
› Author Affiliations
Further Information

Publication History

Received02 June 1998

Accepted after resubmission18 November 1998

Publication Date:
09 December 2017 (online)

    Permissions and Reprints

Summary

Fucoidans (high-molecular-weight sulfated polysaccharides extracted from brown seaweeds) have anticoagulant and antithrombotic effects. They inhibit thrombin by catalyzing both serpins (antithrombin and heparin cofactor II) according to their chemical structures and origins. In this study, a low-molecular-weight (LMW) fucoidan of 8 kDa was obtained by chemical degradation of a high-molecular-weight fraction. The antithrombotic and anticoagulant activities of this new compound were compared to those of a low-molecular-weight heparin (LMWH), dalteparin, following subcutaneous administration to rabbits. This LMW fucoidan exhibited dose-related venous antithrombotic activity, with an ED80 of about 20 mg/kg, 2 h after a single subcutaneous injection. Its activity was comparable to that of dalteparin (close to 200 anti-Xa IU/kg) and was maximal 30 min after a single subcutaneous injection. The activity remained stable (about 70%) from 1 to 4 h after injection, but disappeared by 8 h. The antithrombotic activity was not associated with either a prolongation of the thrombin clotting time (TCT) or an increase in anti-Xa activity, contrary to dalteparin. A slight prolongation of APTT occurred with both compounds. This venous antithrombotic activity was associated with a decrease in ex vivo thrombin generation and with a significant increase in the lag phase in a thrombin generation test. LMW fucoidan thus has potent antithrombotic activity and a potentially weaker haemorrhagic effect (i.e. a smaller effect on coagulation tests and a smaller prolongation of the bleeding time) than dalteparin.

 

  • References

  • 1 Mauray S, Sternberg C, Theveniaux J, Millet J, Sinquin C, TaponBretaudiere J, Fischer AM. Venous antithrombotic and anticoagulant activities of a fucoidan fraction. Thromb Haemost 1995; 74: 1280-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Weitz JL. Drug Therapy: Low Molecular Weight Heparins. New Engl J Med 1997; 337: 688-99.
    CrossrefPubMedGoogle Scholar
  • 3 Iacoviello L, D’Adamo MC, Pawlak K, Polishchuck R, Wollny T, Buczko W, Donati MB. Antithrombotic activity of dermatan sulfates, heparins and their combination in an animal model of arterial thrombosis. Thromb Haemost 1996; 76: 1102-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Kretz JG, Chakfe N, Wiesel ML, Grunebaum L, Zamboni V, Palazzini E, Cazenave JP. The treatment of deep vein thrombosis with continuous intravenous low-molecular-weight dermatan sulphate (Desmin). A pilot study. Thromb Res 1996; 84: 391-8.
    CrossrefPubMedGoogle Scholar
  • 5 Colliec S, Boisson-Vidal C, Jozefonvicz J. A low molecular weight fucoidan fraction from the brown seaweed Pelvetia canaliculata. . Phytochem 1994; 35: 697-700.
    CrossrefPubMedGoogle Scholar
  • 6 Nardella A, Chaubet F, Boisson-Vidal C, Blondin C, Durand P, Jozefonvicz 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. . Carbohyd Res 1996; 289: 201-8.
    CrossrefPubMedGoogle Scholar
  • 7 Wessler S, Morris LE. Studies on intravascular coagulation IV. The effect of heparin and Dicoumarol on serum-induced venous thrombosis. Circulation 1955; 12: 553-6.
    CrossrefPubMedGoogle Scholar
  • 8 Wessler S, Reimer SM, Sheps MC. Biologic assay of a thrombosis inducing activity in human serum. J Appl Physiol 1959; 14: 943-6.
    CrossrefPubMedGoogle Scholar
  • 9 Millet J, Theveniaux J, Brown NL. The venous antithrombotic effect of LF 1351 in the rat following oral administration. Thromb Haemost 1992; 67: 176-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Ofosu FA, Modi GJ, Smith LM, Cerskus AL, Hirsh J, Blajchman MA. Heparan sulfate and dermatan sulfate inhibit the generation of thrombin activity in plasma by complementary pathways. Blood 1984; 64: 742-7.
    PubMedGoogle Scholar
  • 11 Chafa O, Chellali T, Sternberg C, Reghis A, Hamladji RM, Fischer AM. Severe hypofibrinogenemia associated with bilateral ischemic necrosis of toes and fingers. Blood Coag and Fibrinol 1995; 6: 549-52.
    PubMedGoogle Scholar
  • 12 Carter CJ, Kelton JG, Hirsh J. Comparison of haemorrhagic effects of porcine and bovine heparin in the rabbits. Thromb Res 1979; 15: 581-6.
    CrossrefPubMedGoogle Scholar
  • 13 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: 691-5.
    CrossrefPubMedGoogle Scholar
  • 14 Winstetter U, Huber K, Gulba DC. New antithrombotic agents: an overview. Fibrinol Proteol 1997; 11: 85-96.
    PubMedGoogle Scholar
  • 15 Nagase H, Enjyoji X, Minamiguchi K, Kitazato KT, Kitazato K, Saito H, Kato H. Depolymerized Holothurian glycosaminoglycan with novel anticoagulant actions: Antithrombin III and heparin cofactor II independent inhibition of factor X activation by factor IXa factor VIIIa complex and heparin cofactor II dependent inhibition of thrombin. Blood 1995; 6: 1527-34.
    PubMedGoogle Scholar
  • 16 Barbanti M, Calanni F, Babbini M, Bergonzini G, Parma B, Marchi E, Wassermann A. Antithrombotic activity of Desmin 370. Comparison with a high molecular weight dermatan sulfate. Thromb Res 1993; 71: 417-22.
    CrossrefPubMedGoogle Scholar
  • 17 Dol F, Petitou M, Lormeau JC, Choay J, Caranobe C, Sie P, Saaivin S, Houin G, Boneu B. Pharmacologic properties of a low molecular weight dermatan sulfate: comparison with unfractionated dermatan sulfate. J Lab Clin Med 1990; 115: 43-51.
    PubMedGoogle Scholar
  • 18 Linhardt RJ, Desai UR, Liu J, Pervin A, Hoppensteadt D, Fareed J. Low molecular weight dermatan sulfate as an antithrombotic agent. Structure-activity relationship studies. Biochem Pharm 1994; 47: 1241-52.
    CrossrefPubMedGoogle Scholar
  • 19 Millet J, Theveniaux J, Tachon G, Bogaievsky Y, Grippat JC, Samama M, Brown NL. The antithrombotic potential of dalteparin in man assessed indirectly by Wessler’s technique. Thromb Haemost 1996; 76: 989-92.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Buchanan MR, Boneu B, Hirsh J. The relative importance of thrombin inhibition and factor Xa inhibition to antithrombotic effects of heparin. Blood 1985; 65: 198-201.
    PubMedGoogle Scholar
  • 21 Ofosu FA, Modi GJ, Hirsh J, Buchanan MR, Blajchman MA. Mechanisms for Inhibition of the Generation of Thrombin Activity by Sulfated Polysaccharides. Ann N Y Acad Sci 1986; 485: 41-55.
    CrossrefPubMedGoogle Scholar
  • 22 Thomas DP, Merton RE, Gray E, Barrowcliffe TW. The relative antithrombotic effectiveness of heparin, a low molecular weight heparin, and a pentasaccharide fragment in an animal model. Thromb Haemost 1989; 61: 204-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Houbouyan L, Padilla A, Gray E Longstaff, Barrowcliffe TW. Inhibition of thrombin generation by heparin and LMW heparins: a comparison of chromogenic and clotting methods. Blood Coag Fibrinol 1996; 7: 24-30.
    CrossrefPubMedGoogle Scholar
  • 24 Dürig J, Bruhn T, Zurborn KH, Gutensohn K, Bruhn H, Beress L. Anticoagulant fucoidan fractions from Fucus vesiculus induce platelet activation in vitro. Thromb Res 1997; 85: 479-91.
    CrossrefPubMedGoogle Scholar
  • 25 Church FC, Meade JB, Treanor RE, Whinna HC. Antithrombin Activity of Fucoidan. The interaction of fucoidan with heparin cofactor II, antithrombin III, and thrombin. J Biol Chem 1989; 264: 3618-23.
    PubMedGoogle Scholar
  • 26 Colliec S, Fischer AM, Tapon Bretaudiere J, Boisson C, Durand P, Jozefonvicz J. Anticoagulant properties of a fucoidan fraction. Thromb Res 1991; 64: 143-54.
    CrossrefPubMedGoogle Scholar
  • 27 Beguin S, Lindhout T, Hemker H. The mode of action of heparin in plasma. Thromb Haemost 1988; 60: 457-62.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Lindhout T, Blezer R, Hemker HC. The anticoagulant mechanism of action of recombinant hirudin (CGP 39393) in plasma. Thromb Haemost 1990; 64: 464-8.
    Article in Thieme ConnectPubMedGoogle Scholar