Effect of New Synthetic Heparin Mimetics on Whole Blood Thrombin Generation In Vivo and In Vitro in Rats

Hérault, Jean-Pascal; Bernat, A; Gaich, C.; Herbert, M. K.

doi:10.1055/s-0037-1612979

Cited by 10 publications

(9 citation statements)

References 25 publications

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“…FXa and FIIa inhibition The anti‐FXa and AT activities were determined by a modification of the amidolytic method described previously [15,16]. Anti‐FXa activities were determined by incubating 100 μL of human FXa (2.4 nkat mL −1 ) for 2 min with 100 μL of purified human AT (0.17 U mL −1 ) at 37 °C in the presence of 100 μL of increasing concentrations of the oligosaccharides in Tris–maleate 20 m m buffer (pH 7.4) and 150 m m NaCl.…”

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confidence: 99%

Reversible biotinylated oligosaccharides: a new approach for a better management of anticoagulant therapy

Savi

Hérault

Duchaussoy

et al. 2008

Journal of Thrombosis and Haemostasis

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To cite this article: Savi P, Herault JP, Duchaussoy P, Millet L, Schaeffer P, Petitou M, Bono F, Herbert JM. Reversible biotinylated oligosaccharides:a new approach for a better management of anticoagulant therapy. J Thromb Haemost 2008; 6: 1697-706.Summary. Objective: In order to obtain a neutralizable antithrombotic, a chimeric molecule (SSR126517E) containing the sequence of a long-lasting antithrombin (AT)-dependent anti-factor Xa pentasaccharide, idraparinux, linked to a biotin molecule was synthesized and tested for anticoagulant and antithrombotic activity. Methods: SSR126517E was tested in several models in vitro and in vivo for its pharmacological properties as well as its ability to be neutralized by avidin. Results: SSR126517E displayed exactly the same properties as idraparinux. In vitro, SSR126517E had a very high affinity for AT (K d < 1 nM) and showed a potent anti-FXa effect and inhibition of thrombin generation with IC 50 values similar to those of idraparinux. Ex vivo, after intravenous administration to rats, SSR126517E produced a potent and long-lasting antiFXa effect comparable to that obtained with idraparinux; as with idraparinux, the subcutaneous bioavailability was 100%. In vivo, SSR126517E was a potent antithrombotic in rat and mouse venous and arterial thrombosis models. Direct comparison in rats showed that SSR126517E was as active as idraparinux, when administered at the same molar dose. Furthermore, injection of avidin triggered the immediate elimination of SSR126517E from the bloodstream, resulting in complete neutralization of the antithrombotic activity of SSR126517E. Conclusions: These results show for the first time that coupling an oligosaccharide with biotin has no effect on the formerÕs pharmacokinetic and pharmacologic properties and renders neutralization easy by injection of avidin.

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confidence: 99%

Reversible biotinylated oligosaccharides: a new approach for a better management of anticoagulant therapy

Savi

Hérault

Duchaussoy

et al. 2008

Journal of Thrombosis and Haemostasis

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“…Platelet poor plasma was pooled from at least 3 mice, defibrinated, and 20 L-aliquots were used for continuous monitoring of tissue factor-induced thrombin generation 25 (see online data supplement), with or without addition of the pentasaccharide fondaparinux (Arixtra), 17,26 the heparin mimetic SanOrg123781A, 27 heparin, or hirudin (Sanofi-Synthélabo) as indicated. Thrombus formation in vivo was measured in a thromboplastin-induced vena cava stasis model with or without administration of fondaparinux (see online data supplement).…”

Section: Thrombin Generation In Plasma and Venous Thrombosis Modelmentioning

confidence: 99%

“…4,15,17 To develop a murine model of thrombosis suitable for evaluation of such anticoagulants, mutant mice with targeted Arg48-to-Cys substitution (R48C; corresponding to the human "Toyama" R47C mutation) were generated.…”

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Life-Threatening Thrombosis in Mice With Targeted Arg48-to-Cys Mutation of the Heparin-Binding Domain of Antithrombin

Dewerchin

Hérault

Wallays

et al. 2003

Circulation Research

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Abstract-Antithrombin (AT) inhibits thrombin and some other coagulation factors in a reaction that is dramatically accelerated by binding of a pentasaccharide sequence present in heparin/heparan-sulfate to a heparin-binding site on AT.Based on the involvement of R47 in the heparin/AT interaction and the frequent occurrence of R47 mutations in AT deficiency patients, targeted knock-in of the corresponding R48C substitution in AT in mice was performed to generate a murine model of spontaneous thrombosis. The mutation efficiently abolished the effect of heparin-like molecules on coagulation inhibition in vitro and in vivo. Mice homozygous for the mutation (AT m/m mice) developed spontaneous, life-threatening thrombosis, occurring as early as the day of birth. Only 60% of the AT m/m offspring reached weaning age, with further loss at different ages. Thrombotic events in adult homozygotes were most prominent in the heart, liver, and in ocular, placental, and penile vessels. In the neonate, spontaneous death invariably was associated with major thrombosis in the heart. This severe thrombotic phenotype underlines a critical function of the heparin-binding site of antithrombin and its interaction with heparin/heparan-sulfate moieties in health, reproduction, and survival, and represents an in vivo model for comparative analysis of heparin-derived and other antithrombotic molecules.

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“…[8][9][10] Irreversible inhibition of thrombin primarily acts as an inhibitor of the thrombin-mediated positive feedback activation and thus retards thrombin generation, but it is ultimately unable to prevent the explosive appearance of thrombin. 11,12 At concentrations that approach those of (pro-)thrombin potentially available, the danger of too much inhibition and hence of bleeding is imminent. Reversible inhibitors theoretically can never inhibit thrombin completely and therefore may offer a broader therapeutic window than irreversible inhibitors do.…”

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confidence: 99%

“…It ranges from about 50% in UFH to 10% in some types of LMWH. 12 Only molecules consisting of more than 17 monosaccharides (>5.4 kDa) are able to inactivate both FXa and thrombin. Accordingly, the high-affinity material is subdivided into below the critical chain length material (BCLM) showing only aXa activity and above the critical chain length material (ACLM) with aXa as well as aIIa activity.…”

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confidence: 99%

Pharmacokinetic and Pharmacodynamic Characterization of a Medium-Molecular-Weight Heparin in Comparison with UFH and LMWH

Alban

Welzel²,

Hemker³

2002

Semin Thromb Hemost

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Despite the well-established medical use of heparins, the question arises whether the efficacy-safety ratio of the available heparins can still be improved. There{ore, a medium-molecular-weight heparin (MMWH), a new heparin with ^î average molecular weight of 10.5 kDa and a narrow molecular weight range (9.5 to 11.5 kDa) was developed. Its in vitro activities amount to 174.9 anti-factor Xa (aXa) U/mg and 170.0 antithrombin (aIIa) U/mg. In the presented randomized, double-blind, cross-over study in healthy volunteers, the pharmacokinetics and pharmacodynamics of MMWH are compared with those of an unfractionated heparin (UFH) and a low-molecular-weight heparin (LryVMH; enoxaparin). After subcutaneous administration of 9000 aXa-U of either heparin in 16 volunteers, the prolongation ofthe activated partial thromboplastin time (aPTT), the aXa activity, and the aIIa activities were determined at 11 time points spread over 24 hours after injection. The ex vivo analysis revealed striking pharmacodynamic and pharmacokinetic differences between the three heparins. UFH had the lowest bioavailability regarding the aPTl aXa, and aIIa activities. Enoxaparin exhibited only low aIIa activity but the highest aXa activity. Unlike UFH and enoxaparin, MMWH showed a high recovery of aIIa activiry which suggests that it combines the high potency to inhibit thrombin that characterizes UFH with the high bioavailability of the LMWHs. Consequently, substantially lower doses are needed to bring about effects comparable to those ofUFH and LMWFI.KEYWORDS: U nf ractionated hepari n, medi u m-molecu la r-weight hepa ri n, lowmolecular-weight heparin, pharmacokinetics, pharmacodynamics Objectives: Upon completion of this article, the reader should O" rO," to (1)list some of the properties of a newly developed medium-molecular-weight heparin as compared with unfractionated and low-molecular-weight heparins and (2) describe some of the findings related to the pharmacokinetics and pharmacodynamics of the new compound

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Effect of New Synthetic Heparin Mimetics on Whole Blood Thrombin Generation In Vivo and In Vitro in Rats

Cited by 10 publications

References 25 publications

Reversible biotinylated oligosaccharides: a new approach for a better management of anticoagulant therapy

Reversible biotinylated oligosaccharides: a new approach for a better management of anticoagulant therapy

Life-Threatening Thrombosis in Mice With Targeted Arg48-to-Cys Mutation of the Heparin-Binding Domain of Antithrombin

Pharmacokinetic and Pharmacodynamic Characterization of a Medium-Molecular-Weight Heparin in Comparison with UFH and LMWH

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