Characterization of the anticoagulant actions of a semisynthetic curdlan sulfate.
Sulfation of curdlan, a natural, linear beta-1,3-glucan results in potent anticoagulant and antithrombotic agents. The different activity characteristics in the classical coagulation assays were shown to depend on various structural parameters. To obtain more detailed information about their structure-dependent mechanisms of action, one representative of these beta-1,3-glucan sulfates (CurS), was further investigated using several coagulation assays and amidolytic tests with chromogenic substrates. The mode of action of CurS differs from that of heparin. CurS reduces the thrombin formation by principally inhibiting the intrinsic FXa generation. As shown by amidolytic assays, it eliminates already generated thrombin mainly by accelerating the HCII-mediated thrombin inactivation, whereas its AT-mediated anti-thrombin activity is considerably lower than that of heparin. Further, it prevents the thrombin-mediated fibrin polymerization by directly interfering with the thrombin action on fibrinogen as well as by binding to fibrinogen. Finally, CurS is capable to activate the contact system with the consequence of a potential fibrinolytic effect. In conclusion, beta-1,3-glucan sulfates do not inhibit the blood coagulation nonspecifically due to their anionic character, but in dependence on their individual structure, they interfere specifically with the coagulation process at several sites.
Alban
S
S
Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
Franz
G
G
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology*; D000991:Antithrombins / Q000494:pharmacology; D001780:Blood Coagulation Tests; D002863:Chromogenic Compounds; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015942:Factor VIIa / Q000494:pharmacology; D015951:Factor Xa / Q000096:biosynthesis; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000494:pharmacology; D005936:Glucans / Q000378:metabolism / Q000494:pharmacology*; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D015844:Heparin Cofactor II / Q000494:pharmacology; D006801:Humans; D011288:Prekallikrein / Q000187:drug effects / Q000378:metabolism; D011516:Prothrombin / Q000037:antagonists & inhibitors; D047071:beta-Glucans
D000925:Anticoagulants; D000991:Antithrombins; D002863:Chromogenic Compounds; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D005936:Glucans; D047071:beta-Glucans; D015844:Heparin Cofactor II; D011516:Prothrombin; C025337:Factor IIa; D006493:Heparin; D011288:Prekallikrein; D015942:Factor VIIa; D015951:Factor Xa; D000581:Amidohydrolases; C063130:curdlan sulfate