Vasconcelos AA et al. (2018), Anticoagulant and Antithrombotic Properties of ...

ECB-ART-46580

Mar Drugs 2018 Aug 30;169:. doi: 10.3390/md16090304.

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Anticoagulant and Antithrombotic Properties of Three Structurally Correlated Sea Urchin Sulfated Glycans and Their Low-Molecular-Weight Derivatives.

Vasconcelos AA , Sucupira ID , Guedes AL , Queiroz IN , Frattani FS , Fonseca RJ , Pomin VH .

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The anticoagulant and antithrombotic properties of three structurally correlated sea urchin-derived 3-linked sulfated α-glycans and their low molecular-weight derivatives were screened comparatively through various in vitro and in vivo methods. These methods include activated partial thromboplastin time, the inhibitory activity of antithrombin over thrombin and factor Xa, venous antithrombosis, the inhibition of platelet aggregation, the activation of factor XII, and bleeding. While the 2-sulfated fucan from Strongylocentrotus franciscanus was observed to be poorly active in most assays, the 4-sulfated fucan from Lytechinus variegatus, the 2-sulfated galactan from Echinometra lucunter and their derivatives showed multiple effects. All marine compounds showed no capacity to activate factor XII and similar low bleeding tendencies regardless of the dose concentrations used to achieve the highest antithrombotic effect observed. The 2-sulfated galactan showed the best combination of results. Our work improves the background about the structure-function relationship of the marine sulfated glycans in anticoagulation and antithrombosis. Besides confirming the negative effect of the 2-sulfated fucose and the positive effect of the 2-sulfated galactose on anticoagulation in vitro, our results also demonstrate the importance of this set of structural requirements on antithrombosis in vivo, and further support the involvement of high-molecular weight and 4-sulfated fucose in both activities.

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Genes referenced: LOC100887844 LOC100889101 LOC100893812 LOC583082

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	Figure 1. Structural representation (A–C), polyacrylamide gel electrophoresis (PAGE) (D) and 1H-13C dept-heteronuclear single quantum coherence (HSQC) spectra (E–L) of the three structurally correlated sea urchin sulfated glycans. Their structures are the 3-linked 4-sulfated α-fucan from Lytechinus variegatus (A), the 3-linked 2-sulfated α-fucan from Strongylocentrotus franciscanus (B), and the 3-linked 2-sulfated α-galactan from Echinometra lucunter (C). The molecular weight (MW) ranges of the native sulfated glycans, of their low-MW derivatives and of the standards unfractionated heparin (UFH) (MW~16 kDa) and low molecular-weight heparin (LMWH) (MW ~ 8 kDa) are comparatively analyzed through PAGE (D). The 1H-13C dept-HSQC spectra were recorded for UFH (E), L.v (F), S.f. (G), E.l. (H), LMWH (I), L.v. hd (J), S.f. hd (K), and E.l. hd (L). While cross-peaks from CH and CH3 (in-phase) are shown in blue, those from CH2 (anti-phase) are shown in red. In panels (E) and (I), peaks labeled with (A) and (I) stand for glucosamine and iduronate, respectively. In panel (F–H) and(J–L), (A) stands for the sulfated units and (B) stands for the desulfated units.
	Figure 2. Anticoagulant properties of the native sea urchin sulfated glycans (A,C,E) and their low-MW derivatives (B,D,F) screened by aPTT (A,B) and by AT-mediated IIa (C,D) and Xa (E,F) inhibition.
	Figure 3. Antithrombotic properties of the native sea urchin sulfated glycans (A,B) and their low-MW derivatives (C), in venous model of thrombosis, (A) and platelet aggregation (B,C).
	Figure 4. Effects of the native sea urchin sulfated glycans (A, and solid circles in panel C) and low-MW derivatives (B, and open circles in panel C) in assays of factor XII activation (A,B) and bleeding tendency (C).

References [+] :

Ahmed, Heparin induced thrombocytopenia: diagnosis and management update. 2007, Pubmed