Antithrombotic Activity of Dermatan Sulphates, Heparins and their Combination in an Animal Model of Arterial Thrombosis

Abstract

SummaryDermatan sulphates have been shown to inhibit thrombus formation and thrombus growth in different experimental models of venous thrombosis. At variance with heparins, they show a remarkably low haemorrhagic potential. On the other hand, very few data are available on the effect of dermatan sulphates on arterial thrombus formation. We evaluated the effects of a low molecular weight (LMW)-dermatan sulphate, a high molecular weight (HMW)-dermatan sulphate and sulo-dexide (a mixture of fast-moving heparin fraction and dermatan sulphate) in comparison with LMW- and HMW-heparin, in a model of arterial thrombosis in rats. The insertion of an artificial prosthesis into the abdominal aorta of the animals induced the formation of an occluding thrombus within 2-5 days. The time in which 50% of the loops became occluded (OT50) was also calculated and used to compare the efficacy of the different drug treatments. This was 2.84 days for control animals and 4.25 and 5.80 days for HMW- and LMW-dermatan sulphate, respectively. Neither drug changed the “template” bleeding time, even at higher doses. In contrast, HMW-heparin at doses (8 mg/kg, sc, twice a day) inducing an antithrombotic activity comparable to that of dermatan sulphates, dramatically prolonged the bleeding time. LMW-heparin at the same doses was ineffective. Sulodexide (10 mg/Kg, sc, twice a day) prolonged the occlusion time to the same extent as HMW-heparin (OT50 5.10 vs. 4.14 days), with less an effect on the bleeding time (144 ± 6 s vs. >300 s, respectively). Histological examination confirms that the prolongation of occlusion time induced by the drugs is really related to thrombus formation inhibition at the site of arterial wall injury.Acetyl salicylic acid (ASA) (100 mg/kg/day in drinking water as lysine acetylsalicylate) did not modify the effect of Desmin 370 and Sulodexide on both occlusion and bleeding time. However, while it did not increase the antithrombotic activity of HMW-heparin, it significantly prolonged its haemorrhagic effect. In conclusion, dermatan sulphates are effective inhibitors of arterial thrombosis in rats, without inducing bleeding complications.

Sulodexide for the Prevention of Recurrent Venous Thromboembolism: The Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis (SURVET) Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

“…19 Sulodexide exerts its actions through complexation with antithrombin and heparin cofactor II and the attending inhibition of some factors of the coagulation cascade. [20][21][22] It also exerts favorable effects on endothelial dysfunction, release of cytokines and chemokines, and metalloprotease-9 secretion from white blood cells. 23,24 The pharmacological and clinical profiles suggest that oral sulodexide may have a role in the prevention of recurrent VTE when classic anticoagulation is discontinued.…”

Neutralization of DHG, a New Depolymerized Holothurian Glycosaminoglycan, by Protamine Sulfate and Platelet Factor 4

“…In experimental animals, it was demonstrated that DHG does not prolong the bleeding time even though it prolongs APTT ex vivo mark edly [19]. Moreover, high-MW dermatan sul fate (100 mg/kg s.c.) prolonged the APTT without significant prolongation of bleeding time [27]. From these findings, inactivation of thrombin might play a key role to prolong bleeding time caused by GAGs in the rat tran section model, and neutralization of inhibi tion of thrombin but not that of APTT pro longation might reduce the hemorrhagic ef fect.…”

Covalent Heparin Cofactor II-Heparin and Heparin Cofactor II-Dermatan Sulfate Complexes

“…GAGs, commonly heparin but also DS, are used clinically for both prophylaxis and treatment of thrombosis (34,35). The disadvantages of these GAGs, to differing degrees, include risk of bleeding (35)(36)(37)(38), resistance of clot bound thrombin, short intravenous halflife compared with the plasma protein inhibitors (antithrombin and HC), whose action they catalyze (24,25,39), and decreased activity due to binding to proteins in vivo (14,20,23). We have produced and investigated the properties of two HC-GAG covalent complexes (HCH and HCD), which have a number of desirable properties that suggest they may have clinical applications related to selective thrombin inhibition.…”