A Randomised, Double-Blind, Placebo-Controlled Trial of Dermatan Sulphate for Prevention of Deep Vein Thrombosis in Hip Fracture

Agnelli, Giancarlo; Cosmi, Benilde; P, Di Filippo; Ranucci,; Veschi, F; Longetti, M.; Renga, Cinzia; Barzi, F; Gianese, F; Lupattelli, L

doi:10.1055/s-0038-1648413

Cited by 98 publications

(49 citation statements)

References 14 publications

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“…27 ‡Dermatan sulfate doses of 2.9 or 8.6 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 (which produced plasma levels of 3 to 8 g/mL) were significantly better than placebo at reducing postoperative deep vein thrombosis in hip surgery patients. 28 Vasoflux action are compared with those of unfractionated heparin and LMWH in Figure 9.…”

Section: Effect Of Vasoflux On Factor Xa Generationmentioning

confidence: 99%

Vasoflux, a New Anticoagulant With a Novel Mechanism of Action

Weitz¹,

Young²,

Johnston³

et al. 1999

Circulation

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Background-Heparin and direct thrombin inhibitors, such as hirudin, have limitations in the treatment of acute coronary syndromes. Heparin does not inactivate fibrin-bound thrombin, whereas hirudin fails to block thrombin generation. In contrast, Vasoflux is a novel anticoagulant that inactivates fibrin-bound thrombin and attenuates factor Xa generation. Methods and Results-Vasoflux is prepared by depolymerization of heparin, restricting molecular size to between 3000 and 8000 Da, and reducing antithrombin affinity by periodate oxidation. Vasoflux catalyzes fibrin-bound thrombin inactivation by heparin cofactor II (HCII) and inhibits factor IXa activation of factor X independently of antithrombin and HCII. Compared with other anticoagulants in a thrombogenic extracorporeal circuit, Vasoflux maintains filter patency at concentrations that produce an activated clotting time (ACT) of 220 seconds. In contrast, to maintain filter patency, heparin, low-molecular-weight heparin (LMWH), and hirudin require concentrations that produced an ACT of 720, 415, and Ͼ1500 seconds, respectively, whereas dermatan sulfate was ineffective at concentrations that produced an ACT of 360 seconds. Conclusions-Vasoflux is more effective than heparin and LMWH because it inactivates fibrin-bound thrombin and is superior to hirudin and dermatan sulfate because it also blocks factor Xa generation. (Circulation. 1999;99:682-689.)

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Section: Effect Of Vasoflux On Factor Xa Generationmentioning

confidence: 99%

Vasoflux, a New Anticoagulant With a Novel Mechanism of Action

Weitz¹,

Young²,

Johnston³

et al. 1999

Circulation

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“…Dermatan sulfate (DS), a sulfated glycosaminoglycan that has antithrombotic activity in laboratory animals (19,20) and in humans (21)(22)(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).…”

mentioning

confidence: 99%

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

Liaw¹,

Becker

Stafford

et al. 2001

Journal of Biological Chemistry

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Although fibrin-bound thrombin is resistant to inactivation by heparin⅐antithrombin and heparin⅐heparin cofactor II complexes, indirect studies in plasma systems suggest that the dermatan sulfate⅐heparin cofactor II complex can inhibit fibrin-bound thrombin. Herein we demonstrate that fibrin monomer produces a 240-fold decrease in the heparin-catalyzed rate of thrombin inhibition by heparin cofactor II but reduces the dermatan sulfate-catalyzed rate only 3-fold. The protection of fibrinbound thrombin from inhibition by heparin⅐heparin cofactor II reflects heparin-mediated bridging of thrombin to fibrin that results in the formation of a ternary heparin⅐thrombin⅐fibrin complex. This complex, formed as a result of three binary interactions (thrombin⅐fibrin, thrombin⅐heparin, and heparin⅐fibrin), limits accessibility of heparin-catalyzed inhibitors to thrombin and induces conformational changes at the active site of the enzyme. In contrast, dermatan sulfate binds to thrombin but does not bind to fibrin. Although a ternary dermatan sulfate⅐ thrombin⅐fibrin complex forms, without dermatan sulfate-mediated bridging of thrombin to fibrin, only two binary interactions exist (thrombin⅐fibrin and thrombin⅐ dermatan sulfate). Consequently, thrombin remains susceptible to inactivation by heparin cofactor II. This study explains why fibrin-bound thrombin is susceptible to inactivation by heparin cofactor II in the presence of dermatan sulfate but not heparin.Heparin, a sulfated polysaccharide, acts as an anticoagulant by accelerating the inhibition of thrombin and factor Xa by antithrombin (1). Although heparin is widely used for the treatment of acute coronary ischemic syndromes, it has limitations in patients undergoing percutaneous coronary interventions (2) or when used as an adjunct to thrombolytic therapy (3-5). These limitations have been attributed to the inability of the antithrombin⅐heparin complex to inactivate clotting enzymes bound to components of the thrombus, particularly thrombin bound to fibrin (6, 7).Resistance of fibrin-bound thrombin to inactivation by the antithrombin⅐heparin complex reflects the incorporation of thrombin into a ternary heparin⅐thrombin⅐fibrin complex (8-10). To form this complex, heparin interacts with both exosite II on thrombin (11-13) and the D domain of fibrin (14), thereby bridging thrombin to fibrin via exosite II (8). This heightens exosite I-mediated binding of thrombin to fibrin and likely increases the overall affinity of thrombin for fibrin. The formation of the ternary complex, therefore, is a consequence of the presence of two exosites on thrombin, which independently bind fibrin and heparin. Recently, we demonstrated that protection requires ligation of both of thrombin's exosites within the ternary heparin⅐thrombin⅐fibrin complex, a process that impairs access of inhibitor-bound heparin to exosite II on thrombin (15). Thrombin within the ternary complex is protected from inactivation by the heparin⅐heparin cofactor II (HCII) 1 complex to a greater extent than the heparin...

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“…The first is its oral activity in a venous antithrombotic model [19,20]. It therefore constitutes a more easily available therapy than DS [21,22] which should be administered parenterally. The second is that the antithrombotic action of Iliparcil does not induce bleeding as a side effect.…”

Section: Discussionmentioning

confidence: 99%

The Beneficial Effect of a β-D-Xyloside, Iliparcil, in the Prevention of Postthrombolytic Rethrombosis in the Rat

Rademakers²,

Millet³

1998

Pathophysiol Haemos Thromb

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The effect of Iliparcil, a new orally active β-D-xyloside venous antithrombotic, was studied on the rethrombosis following thrombolytic therapy in rats, using a modified Umetsu model. The drug was administered by oral route prior to thrombolytic therapy, which consisted of administering a combination of heparin and urokinase (H/U) at 37.5 and 70,000 IU/kg, respectively. Time to reocclusion increased from 3.9 min with saline to 10.5 min following H/U injection. When Iliparcil (30 mg/kg, oral route) was administered 4 h before H/U injection, the time to reocclusion was increased by 250% compared with H/U alone (p < 0.001). Similarly, dermatan sulfate (DS), administered intravenously (3 mg/kg) 5 min before thrombus induction, also increased the time to reocclusion (300% compared with H/U alone; p < 0.001). It was also shown that times to reocclusion following Iliparcil or DS treatments were still increased even when heparin dosage was decreased. These results suggest that an antithrombotic product derived from the β-D-xyloside family could be advantageously used in combination with thrombolytic treatment instead of heparin, which causes complications and side effects.

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A Randomised, Double-Blind, Placebo-Controlled Trial of Dermatan Sulphate for Prevention of Deep Vein Thrombosis in Hip Fracture

Cited by 98 publications

References 14 publications

Vasoflux, a New Anticoagulant With a Novel Mechanism of Action

Vasoflux, a New Anticoagulant With a Novel Mechanism of Action

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

The Beneficial Effect of a β-D-Xyloside, Iliparcil, in the Prevention of Postthrombolytic Rethrombosis in the Rat

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