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Thromb Haemost 2009; 102(05): 829-836
DOI: 10.1160/TH08-11-0773
Theme Issue Article
Schattauer GmbH

Effects of polysaccharides enriched in 2,4-disulfated fucose units on coagulation, thrombosis and bleeding

Practical and conceptual implications
Roberto J. C. Fonseca
1   Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Programa de Glicobiologia, Instituto de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
,
Gustavo R. C. Santos
1   Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Programa de Glicobiologia, Instituto de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
,
Paulo A. S. Mourão
1   Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Programa de Glicobiologia, Instituto de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
› Author AffiliationsFinancial support: This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento do Pessoal de Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).
Further Information

Publication History

Received: 01 December 2008

Accepted after major revision: 08 February 2009

Publication Date:
27 November 2017 (online)

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Summary

Sulfated polysaccharides from marine invertebrates have welldefined 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.

Keywords

Sulfated fucans - fucoidan - anticoagulant activity - antithrombotic activity - heparin - invertebrate
 

  • References

  • 1 Mourão PA. Use of sulfated fucans as anticoagulant and antithrombotic agents: future perspectives. Curr Pharm Design 2004; 10: 967-981.
    CrossrefPubMedGoogle Scholar
  • 2 Xiao L, Yang C, Patterson PS. et al. Sulfated polyanions inhibit invasion of erythrocytes by plasmodial merozoites and cytoadherence of endothelial cells to parasitized erythrocytes. Infect Immun 1996; 64: 1373-1378.
    PubMedGoogle Scholar
  • 3 Hahnenberger R, Jakobson AM. Antiangiogenic effect of sulphated and nonsulphated glycosaminoglycans and polysaccharides in the chick embryo chorioallantoic membrane. Glycoconj J 1991; 08: 350-353.
    CrossrefPubMedGoogle Scholar
  • 4 Foxall C, Watson SR, Dowbenko D. et al. The three members of the selectin receptor family recognize a common carbohydrate epitope, the sialyl Lewis(x) oligosaccharide. J Cell Biol 1992; 117: 895-902.
    CrossrefPubMedGoogle Scholar
  • 5 Riov D, Colliec-Jovault S, Pinczon du Sel D. et al. Antitumor and antiproliferative effects of a fucan extracted from Ascophyllum nodosum against a non-small-cell bronchopulmonary carcinoma line. Anticancer Res 1996; 16: 1213-1218.
    PubMedGoogle Scholar
  • 6 McCaffrey TA, Falcone DJ, Borth W. et al. Fucoidan is a non-anticoagulant inhibitor of intimal hyperplasia. Biochem Biophys Res Commun 1992; 184: 773-781.
    CrossrefPubMedGoogle Scholar
  • 7 Logeart D, Prigent-Richard S, Jozefonvicz J. et al. Fucans, sulfated polysaccharides extracted from brown seaweeds, inhibit vascular smooth muscle cell proliferation. I. Comparison with heparin for antiproliferative activity, binding and internalization. Eur J Cell Biol 1997; 74: 376-384.
    PubMedGoogle Scholar
  • 8 Ferrao AV, Mason RM. The effect of heparin on cell proliferation and type-I collagen synthesis by adult human dermal fibroblasts. Biochim Biophys Acta 1993; 1180: 225-230.
    CrossrefPubMedGoogle Scholar
  • 9 Berteau O, Mulloy B. Sulfated fucans, fresh perspectives: structures, functions, and biological properties of sulfated fucans and an overview of enzymes active toward this class of polysaccharide. Glycobiology 2003; 13: 29-40.
    PubMedGoogle Scholar
  • 10 Chizhov AO, Dell A, Morris HR. et al. A study of fucoidan from the brown seaweed Chorda filum . Carbohydr Res 1999; 320: 108-119.
    CrossrefPubMedGoogle Scholar
  • 11 Bilan MI, Grachev AA, Ustuzhanina NE. et al. Structure of a fucoidan from the brown seaweed Fucus evanescens . Carbohydr Res 2002; 337: 719-730.
    CrossrefPubMedGoogle Scholar
  • 12 Ribeiro AC, Vieira RP, Mourão PAS. et al. A sulfated α-L-fucan from sea cucumber. Carbohydr Res 1994; 255: 225-240.
    CrossrefPubMedGoogle Scholar
  • 13 Mulloy B, Ribeiro AC, Alves AC. et al. Sulfated fucans from echinoderms have a regular tetrasaccharide repeating unit defined by specific patterns of sulfation at the 0-2 and 0-4 positions. J Biol Chem 1994; 296: 22113-22123.
    PubMedGoogle Scholar
  • 14 Vilela-Silva A-CES, Alves AP, Valente A-P. et al. Structure of the sulfated a-L-fucan from the egg jelly coat of the sea urchin Strongylocentrotus franciscanus: patterns of preferential 2-O-and 4-O-sulfation determine sperm cell recognition. Glycobiology 1999; 09: 927-933.
    CrossrefPubMedGoogle Scholar
  • 15 Pereira MS, Mulloy B, Mourão PAS. Structure and anticoagulant activity of sulfated fucans. Comparison between the regular, repetitive and linear fucans from echinoderms with the more heterogeneous and branched polymers from brown algae. J Biol Chem 1999; 274: 7656-7667.
    PubMedGoogle Scholar
  • 16 Pereira MS, Melo FR, Mourão PA. Is there a correlation between structure and anticoagulant action of sulfated galactans and sulfated fucans?. Glycobiology 2002; 12: 573-580.
    CrossrefPubMedGoogle Scholar
  • 17 Björk I, Lindahl U. Mechanism of the anticoagulant action of heparin. Mol Cell Biochem 1982; 48: 161-182.
    CrossrefPubMedGoogle Scholar
  • 18 Chavet P, Bienvenu JG, Theoret JF. et al. Inhibition of platelet-neutrophil interactions by fucoidan reduces adhesion and vasoconstriction after acute arterial injury by angioplasty in pigs. J Cardiovasc Pharm 1999; 34: 597-603.
    CrossrefPubMedGoogle Scholar
  • 19 Deux JF, Meddahi-Pelle A, Le Blanche AF. et al. Low molecular weight fucoidan prevents neointimal hyperplasia in rabbit iliac artery in stent restenosis model. Arterioscl Throm Vas Biol 2002; 22: 1604-1609.
    CrossrefPubMedGoogle Scholar
  • 20 Mauray S, Sternberg C, Theveniaux J. et al. Venous antithrombotic and anticoagulant activities of a fucoidan fraction. Thromb Haemost 1995; 74: 1280-1285.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Millet J, Jouault SC, Mauray S. et al. Antithrombotic and anticoagulant activities of a low molecular weight fucoidan by the subcutaneous route. Thromb Haemost 1999; 81: 391-395.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Thorlacius H, Vollmar B, Seyfert UT. et al. The polysaccharide fucoidan inhibits microvascular thrombus formation independently from P-and L-selectin function in vivo. Eur J Clin Invest 2000; 30: 804-810.
    CrossrefPubMedGoogle Scholar
  • 23 Fonseca RJC, Mourão PAS. Fucosylated chondroitin sulfate as a new oral antithrombotic agent. Thromb Haemost 2006; 96: 822-829.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Wessler S, Reimer SM, Sheps MC. Biological assay of a thrombosis inducing activity in human serum. J Appl Physiol 1959; 14: 943-946.
    CrossrefPubMedGoogle Scholar
  • 25 Eitzman DT, Westrick RJ, Nabel EG. et al. Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice. Blood 2000; 95: 577-580.
    PubMedGoogle Scholar
  • 26 Herbert JM, Bernat A, Maffrand JP. Importance of platelets in experimental venous thrombosis in rats. Blood 1992; 80: 2281-2286.
    PubMedGoogle Scholar
  • 27 Glauser BF, Pereira MS, Monteiro RQ. et al. Serpin-independent anticoagulant activity of a fucosylated chondroitin sulfate. Thromb Haemost 2008; 100: 420-428.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Kaplan AP, Joseph K, Silverberg M. Pathways for bradykinin formation and inflammatory disease. J Allergy Clin Immunol 2002; 109: 195-209.
    CrossrefPubMedGoogle Scholar
  • 29 Fonseca RJ, Oliveira SN, Melo FR. et al. Slight differences in sulfation of algal galactans account for differences in their anticoagulant and venous antithrombotic activities. Thromb Haemost 2008; 99: 539-545.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Soeda S, Ohmagari Y, Shimeno H. et al. Preparation of oversulfated fucoidan fragments and evaluation of their antithrombotic activities. Thromb Res 1993; 72: 247-256.
    CrossrefPubMedGoogle Scholar
  • 31 Haroun-Bouhedja F, Ellouali M, Sinquin C. et al. Relationship between sulfate groups and biological activities of fucans. Thromb Res 2000; 100: 453-459.
    CrossrefPubMedGoogle Scholar
  • 32 Boisson-Vidal C, Chaubet F, Chevolot L. et al. Relationship between antithrombotic activities of fucans and their structure. Drug Develop Res 2000; 51: 216-224.
    CrossrefPubMedGoogle Scholar
  • 33 Kishimoto TK, Viswanathan K, Ganguly T. et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 2008; 358: 2457-2467.
    CrossrefPubMedGoogle Scholar
  • 34 Heit JA. Risk factors for venous thromboembolism. Clin Chest Med 2003; 24: 1-12.
    CrossrefPubMedGoogle Scholar
  • 35 Kurabayashi H, Tamura J, Naruse T. et al. Possible existence of platelet activation before the onset of cerebral infarction. Atherosclerosis 2000; 153: 203-207.
    CrossrefPubMedGoogle Scholar
  • 36 Mourão PAS, Guimarães B, Mulloy B. et al. Antithrombotic activity of a fucosylated chondroitin sulfate from echinoderm: Sulfated fucose branches on the polysaccharide account for its antithrombotic action. Br J Haematol 1998; 101: 647-652.
    CrossrefPubMedGoogle Scholar
  • 37 Vicente CP, Zancan P, Peixoto LL. et al. Unbalanced effects of dermatan sulfates with different sulfation patterns on coagulation, thrombosis and bleeding. Thromb Haemost 2001; 86: 1215-1220.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Melo FR, Mourão PAS. An algal sulfated galactan has an unusual dual effect on venous thrombosis due to activation of factor XII and inhibition of the coagulation proteases. Thromb Haemost 2008; 99: 531-538.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Vieira RP, Mulloy B, Mourão PAS. Structure of a fucose-branched chondroitin sulfate from sea cucumber: evidence for the presence of 3-O-sulfo-β-D-glucuronosyl residues. J Biol Chem 1991; 266: 13530-13536.
    PubMedGoogle Scholar