Experimental Studies on the Relative Efficacy of Dermatan Sulphate and Heparin as Antithrombotic Agents

Abstract

SummaryIn this study, the anticoagulant and antithrombotic properties of unfractionated heparin (UFH) and dermatan sulphate (DS) were compared. The ability of UFH and DS to impair thrombin generation in vitro and in ex vivo plasma samples was also studied. DS has minimal anticoagulant activity by conventional assays but impairs thrombin generation both in vitro and in ex vivo plasma samples. However, thrombin generation could not be suppressed below about 35% of control values at all doses of DS studied. While this was sufficient to impair experimental venous thrombosis during 10 minutes’ stasis, DS was ineffective in preventing thrombosis following 20 minutes’ stasis in doses up to 1.25 mg/kg. In contrast, 1 μg/ml of UFH completely suppressed thrombin generation in vitro, and 150 μg/kg prevented throm- bogenesis over a period of 20 minutes’ stasis. Neither drug prolonged the bleeding time (BT) at effective antithrombotic doses, but 2.5 mg/kg UFH significantly increased the BT, whereas DS did not. While DS has antithrombotic activity, it is less effective than UFH in inhibiting thrombin generation, and as an antithrombotic agent.

A Unique Dermatan Sulfate-like Glycosaminoglycan from Ascidian:

“…Dermatan sulfate, chondroitin sulfate, and heparan sulfate may all be components of connective tissue (2) or cell surface carbohydrates involved in the cell's interaction with and response to its surroundings (3). The anticoagulant glycosaminoglycan heparin is an important therapeutic agent used in the prophylaxis and treatment of thrombosis (4); dermatan sulfate is also an anticoagulant, although of lower potency than heparin (5)(6)(7).…”

Molecular Basis for the Susceptibility of Fibrin-bound Thrombin to Inactivation by Heparin Cofactor II in the Presence of Dermatan Sulfate but Not Heparin

“…Dermatan sulfate (DS), a sulfated glycosaminoglycan that has antithrombotic activity in laboratory animals (19,20) and in humans (21-23), acts as an anticoagulant by catalyzing only HCII. Because thrombin is the exclusive plasma target of HCII, DS is considered a selective inhibitor of thrombin (16).…”

“…Thrombin within the ternary complex is protected from inactivation by the heparin⅐heparin cofactor II (HCII) 1 complex to a greater extent than the heparin⅐antithrombin complex (15), because access of the amino terminus of HCII to exosite I on thrombin, an obligatory part of the HCII inhibitory mechanism (16, 17), is reduced. Allosteric changes in the active site of thrombin induced upon formation of the ternary heparin⅐thrombin⅐fibrin complex may also contribute to the protection of fibrin-bound thrombin from inactivation by heparin⅐antithrombin and heparin⅐HCII complexes by limiting inhibitor reactivity with fibrinbound thrombin (18).Dermatan sulfate (DS), a sulfated glycosaminoglycan that has antithrombotic activity in laboratory animals (19,20) and in humans (21-23), acts as an anticoagulant by catalyzing only HCII. Because thrombin is the exclusive plasma target of HCII, DS is considered a selective inhibitor of thrombin (16).…”

Functional Properties of Ascidians By-products: Nutritional and Medicinal Value

“…This process contributes to impairment on the immune system when persistent for a long period of time, as activated macrophages produce toxic factors (Medzhitov 2008 ). Nitric oxide Ascidia nigra Pavão et al ( 1995 ); Merton and Thomas ( 1987 ), Maggi et al ( 1987 ), Thomas et al ( 1989 ) 27 Functional Properties of Ascidians By-products… 572 (NO)/cyclooxygenase (COX) and nuclear factor-κB (NF-κB) are well-known infl ammatory pathways which induce the production of infl ammatory mediators such as prostaglandins, thromboxanes, leukotrienes, and cytokines. Thus, those kinds of infl ammatory mediators or cytokines are studied in order to search for sources having anti-infl ammatory activity, along with effects on the set of extracellular stimuli-dependent signal transduction cascades.…”