Dermatan sulphate in haemodialysis

Lane, David A.; Ryan, K; Ireland, H; Curtis, J. Randall; Nurmohamed, Michael T.; Krediet, R. T.; Roggekamp, M. C.; Stevens, P; Cate, J. W. Ten

doi:10.1016/0140-6736(92)91650-w

Cited by 27 publications

(13 citation statements)

References 4 publications

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“…A dose of 6 mg kg-' MF701 was equivalent to an individualized heparin regimen in suppressing TAT and ,-TG generation during dialysis. This provides confirmation of dose-finding data obtained in the same patients by visual inspection of the dialysis circuit (Lane et al, 1992). Effective suppression of coagulation activation by MF701 was accompanied by much less prolongation in APTT, as compared with that induced by heparin.…”

Section: Discussionsupporting

confidence: 80%

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The pharmacokinetics and pharmacodynamics of dermatan sulphate MF701 during haemodialysis for chronic renal failure.

Gianese

Nurmohamed

Imbimbo

et al. 1993

Brit J Clinical Pharma

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Single i.v. bolus doses of dermatan sulphate MF701 were administered before the onset of haemodialysis to patients with chronic renal failure, to prevent clotting in the extracorporeal circuit. Six patients received 2 mg kg‐1; six were given 2.5 and 3 mg kg‐1; 13 received 4.5 and 6 mg kg‐1. Plasma MF701 concentrations (chromogenic assay), activated partial thromboplastin time (APTT) and plasma markers of coagulation and platelet activation (TAT and beta‐TG) were measured over 4 or 8 h from the onset of dialysis. The disposition of MF701 was described by a monoexponential function. C(0) and AUC values increased proportionally with dose. Volumes of distribution (approximately 4 l) were dose‐independent. Half‐lives showed a non significant increase with dose (from 2.2 to 3.1 h) and were 2.5‐3 times longer than those reported for healthy subjects. There was a significant correlation between plasma MF701 concentration and its effects in prolonging APTT and suppressing TAT and beta‐TG generation during dialysis.

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Section: Discussionsupporting

confidence: 80%

“…We have recently reported the results of dose-finding studies with dermatan sulphate in patients undergoing haemodialysis for chronic renal failure (Lane et al, 1992). Using additional data from these studies, we now report the pharmacokinetics and pharmacodynamics of dermatan sulphate during dialysis.…”

Section: Introductionmentioning

confidence: 99%

The pharmacokinetics and pharmacodynamics of dermatan sulphate MF701 during haemodialysis for chronic renal failure.

Gianese

Nurmohamed

Imbimbo

et al. 1993

Brit J Clinical Pharma

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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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“…Recent studies suggest that dermatan sulfate is a more potent inhibitor than heparin of clotbound thrombin (Fernandez et al 1986) and that dermatan sulfate in combination with low molecular weight heparin may produce synergistic antithrombotic effect (Cosmi et al 1993). Human clinical trials have shown that dermatan sulfate prevents thrombosis during hemodialysis (Lane et al 1992) and that in the post-operative setting (Agnelli et al 1992, Prandoni et al 1992. However, the mechanism of antithrombotic activity of dermatan sulfate has not been clearly established yet.…”

Section: Antithrombotic Use Of Mammalian Glycosaminoglycansmentioning

confidence: 99%

Structure and anticoagulant properties of sulfated glycosaminoglycans from primitive Chordates

Pavão

2002

An. Acad. Bras. Ciênc.

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Dermatan sulfates and heparin, similar to the mammalian glycosaminoglycans, but with differences in the degree and position of sulfation were previously isolated from the body of the ascidian Styela plicata and Ascidia nigra. These differences produce profound effects on their anticoagulant properties. S. plicata dermatan sulfate composed by 2-O-sulfated α-L-iduronic acid and 4-O-sulfated N-acetyl-β-D-galactosamine residues is a potent anticoagulant due to a high heparin cofactor II activity. Surprisingly, it has a lower potency to prevent thrombus formation on an experimental model and a lower bleeding effect in rats than the mammalian dermatan sulfate. In contrast, A. nigra dermatan sulfate, also enriched in 2-O-sulfated α-Liduronic acid, but in this case sulfated at O-6 of the N-acetyl-β-D-galactosamine units, has no in vitro or in vivo anticoagulant activity, does not prevent thrombus formation but shows a bleeding effect similar to the mammalian glycosaminoglycan. Ascidian heparin, composed by 2-O-sulfated α-L-iduronic acid, N-and 6-O-sulfated glucosamine (75%) and α-L-iduronic acid, N-and 6-O-sulfated glucosamine (25%) disaccharide units has an anticoagulant activity 10 times lower than the mammalian heparin, is about 20 times less potent in the inhibition of thrombin by antithrombin, but has the same heparin cofactor II activity as mammalian heparin.

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Dermatan sulphate in haemodialysis

Cited by 27 publications

References 4 publications

The pharmacokinetics and pharmacodynamics of dermatan sulphate MF701 during haemodialysis for chronic renal failure.

The pharmacokinetics and pharmacodynamics of dermatan sulphate MF701 during haemodialysis for chronic renal failure.

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

Structure and anticoagulant properties of sulfated glycosaminoglycans from primitive Chordates

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