Mode of action for anticoagulant activities of non-anticoagulant sulphated polysaccharides (WFH 2012) - Jun 18, 2012 - U.p. fucoidan increased clotting time by 50% at 4lg/mL, which represents a two-fold higher anticoagulant effect than the other fucoidans; All fucoidans clearly increased HCII-mediated thrombin inhibition at concentrations below 1 lg/mL
MOA • Hemophilia
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Hemophilia 2012 Congress, 08 - 12 Jul 2012; France
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PO-TU-132
Fucoidans are sulfated polysaccharides extracted from brown seaweeds. They are described as non-anticoagulant sulfated polysaccharides (NASPs) and improve clotting in FVIII-deficient plasma (Liu et al., 2006), making them good candidates for haemophilia therapy. However, fucoidans have also been studied for their anticoagulant effects (Pereira et al., 1999), which occur at much higher concentrations than the procoagulant activity. Different anticoagulant mechanisms are activated by NASPs. Branched brown algae fucoidans have been shown to directly inhibit thrombin, while linear fucoidans from echinoderms activated antithrombin III (ATIII) or heparin cofactor II (HCII)-mediated thrombin inhibition (Pereira et al., 1999). In this study, we analyzed fucoidans from several brown algae species for their anticoagulant properties and mechanism to identify the candidate with the best procoagulant and lowest anticoagulant activity. Different anticoagulant activities were observed for NASPs from the brown algae species L.j., F.v. and U.p. in an aPTT assay. U.p. fucoidan increased clotting time by 50% at 4lg/mL, which represents a two-fold higher anticoagulant effect than the other fucoidans. NASPs were also analyzed in ATIII- and HCII-thrombin model assays. ATIII-mediated thrombin inhibition was only activated by L.j. fucoidan. However, all fucoidans clearly increased HCII-mediated thrombin inhibition at concentrations below 1 lg/mL. Our data suggest that HCII is the main target for the anticoagulant activity of fucoidans, which was confirmed by clotting assays in ATIII- and HCII-deficient plasma. Overall, we observed substantial differences between individual fucoidans which can be correlated to their structural properties. Our work describes the assessment of anticoagulant activities of different fucoidan species to better understand their intertwined pro- and anticoagulant effects. Important insights gained from these data will support the development of
hemophilia therapies.
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