title: Influence of molecular weight of chemically sulfated citrus pectin fractions on their antithrombotic and bleeding effects.
abstract: Evaluated were the anticoagulant and antithrombotic activities, and bleeding effect of two chemically sulfated polysaccharides, obtained from citric pectin, with different average molar masses. Both low-molecular-weight (Pec-LWS, 3,600 g/mol) and high-molecular-weight sulfated pectins (Pec-HWS, 12,000 g/mol) had essentially the same structure, consisting of a (1-->4)-linked alpha-D-GalpA chain with almost all its HO-2 and HO-3 groups substituted by sulfate. Both polysaccharides had anticoagulant activity in vitro, although Pec-HWS was a more potent antithrombotic agent in vivo, giving rise to total inhibition of venous thrombosis at a dose of 3.5 mg/kg body weight. Surprisingly, in contrast with heparin, Pec-HWS and Pec-LWS are able to directly inhibit alpha-thrombin and factor Xa by a mechanism independent of antithrombin (AT) and/or heparin co-factor II (HCII). Moreover, Pec-HWS provided a lower risk of bleeding than heparin at a dose of 100% effectiveness against venous thrombosis, indicating it to be a promising antithrombotic agent.
authors.affiliation: Laboratório de Química de Carboidratos, Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, CP 19046, CEP 81.531-980, Curitiba, PR, Brazil.
authors.forename: Thales R
authors.initials: TR
authors.lastname: Cipriani
authors.forename: Ana Helena P
authors.initials: AH
authors.lastname: Gracher
authors.forename: Lauro M
authors.initials: LM
authors.lastname: de Souza
authors.forename: Roberto J C
authors.initials: RJ
authors.lastname: Fonseca
authors.forename: Celso L R
authors.initials: CL
authors.lastname: Belmiro
authors.forename: Philip A J
authors.initials: PA
authors.lastname: Gorin
authors.forename: Guilherme L
authors.initials: GL
authors.lastname: Sassaki
authors.forename: Marcello
authors.initials: M
authors.lastname: Iacomini
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D001777:Blood Coagulation / Q000187:drug effects*; D032084:Citrus sinensis / Q000737:chemistry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005260:Female; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008970:Molecular Weight; D010368:Pectins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D013917:Thrombin / Q000037:antagonists & inhibitors; D020246:Venous Thrombosis / Q000097:blood / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D013431:Sulfates; D010368:Pectins; D013917:Thrombin