An algal sulfated galactan has an unusual dual effect on venous thrombosis due to activation of factor XII and inhibition of the coagulation proteases.
Sulfated galactan from the red alga Botryocladia occidentalis has a potent anticoagulant activity, due to its ability to enhance thrombin and factor Xa inhibition by antithrombin and/or heparin cofactor II. It is less active than unfractionated heparin in arterial thrombosis, but in a venous thrombosis presents a dual effect, inhibiting thrombosis in low but not in high doses. This dual effect on venous thrombosis is a consequence of two actions, one that inhibits thrombin and factor Xa and one that induces factor XII activation. In order to dissociate these effects, we prepared derivatives of the sulfated galactan with low molecular weights. Two fractions that were similar in size to unfractionated heparin and low-molecular-weight heparin were obtained. As the molecular weight decreased, the ability to activate factor XII and to promote inhibition of coagulation proteases in the presence of antithrombin and heparin cofactor II diminished. At approximately 5 kDa, the sulfated galactan fragment had no effect on factor XII activation, and showed the same effect as unfractionated heparin in a venous thrombosis model. The approximately 5-kDa fragment is an antithrombotic with several advantages: i) It is as active as unfractionated heparin in venous thrombosis, but it has little activity in arterial thrombosis; ii) It inhibits venous thrombosis with very little anticoagulant effect; iii) It does not cause bleeding; and iv) It is not obtained from mammals.
Melo
Fábio R
FR
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.
Mourão
Paulo A S
PA
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000302:isolation & purification / Q000494:pharmacology*; D000991:Antithrombins / Q000378:metabolism; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015956:Factor XIIa / Q000378:metabolism*; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000302:isolation & purification / Q000494:pharmacology*; D005685:Galactans / Q000009:adverse effects / Q000302:isolation & purification / Q000494:pharmacology*; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000494:pharmacology; D015844:Heparin Cofactor II / Q000378:metabolism; D006801:Humans; D008297:Male; D008970:Molecular Weight; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000461:Rhodophyta / Q000737:chemistry*; D013431:Sulfates / Q000009:adverse effects / Q000302:isolation & purification / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*; D020246:Venous Thrombosis / Q000097:blood / Q000517:prevention & control
D000925:Anticoagulants; D000991:Antithrombins; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D005685:Galactans; D011480:Protease Inhibitors; D013431:Sulfates; D015844:Heparin Cofactor II; D006493:Heparin; D015956:Factor XIIa; D013917:Thrombin; D015951:Factor Xa