Effects of oversulfated and fucosylated chondroitin sulfates on coagulation. Challenges for the study of anticoagulant polysaccharides.
We report the effects of a chemically oversulfated chondroitin sulfate and a naturally fucosylated chondroitin sulfate on the coagulation system. The former has been recently identified as a contaminant of heparin preparations and the latter has been proposed as an alternative anticoagulant. The mechanism of action of these polymers on coagulation is complex and target different components of the coagulation system. They have serpin-independent anticoagulant activity, which preponderates in plasma. They also have serpin-dependent anticoagulant activity but differ significantly in the target coagulation protease and preferential serpin. Their anticoagulant effects differ even more markedly when tested as inhibitors of coagulation proteases using plasma as a source of serpins. It is possible that the difference is due to the high availability of fucosylated chondroitin sulfate whereas oversulfated chondroitin sulfate has strong unspecific binding to plasma protein and low availability for the binding to serpins. When tested using a venous thrombosis experimental model, oversulfated chondroitin sulfate is less potent as an antithrombotic agent than fucosylated chondroitin sulfate. These highly sulfated chondroitin sulfates activate factor XII in in vitro assays, based on kallikrein release. However, only fucosylated chondroitin sulfate induces hypotension when intravenously injected into rats. In conclusion, the complexity of the regulatory mechanisms involved in the action of highly sulfated polysaccharides in coagulation requires their analysis by a combination of in vitro and in vivo assays. Our results are relevant due to the urgent need for new anticoagulant drugs or alternative sources of heparin.
Fonseca
Roberto J C
RJ
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.
Oliveira
Stephan-Nicollas M C G
SN
Pomin
Vitor H
VH
Mecawi
André S
AS
Araujo
Iracema G
IG
Mourão
Paulo A S
PA
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D002846:Chromatography, Affinity; D004285:Dogs; D005174:Factor XII / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use; D006736:Horses; D006801:Humans; D023421:Models, Animal; D010314:Partial Thromboplastin Time; D051381:Rats; D013925:Thromboplastin / Q000008:administration & dosage; D020246:Venous Thrombosis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*
D000925:Anticoagulants; C517150:fucosylated chondroitin sulfate; D005174:Factor XII; D006493:Heparin; D002809:Chondroitin Sulfates; D013925:Thromboplastin