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Thromb Haemost 2004; 91(03): 531-537
DOI: 10.1160/TH03-07-0483
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Recombinant factor VIIa partially reverses the inhibitory effect of fondaparinux on thrombin generation after tissue factor activation in platelet rich plasma and whole blood

Grigoris T. Gerotziafas
1   Service d’Hématologie Biologique, Hôpital Hôtel-Dieu de Paris, France
2   LCL, Ivry sur Seine, France
,
François Depasse
2   LCL, Ivry sur Seine, France
,
Tahar Chakroun
1   Service d’Hématologie Biologique, Hôpital Hôtel-Dieu de Paris, France
,
Meyer M. Samama
1   Service d’Hématologie Biologique, Hôpital Hôtel-Dieu de Paris, France
2   LCL, Ivry sur Seine, France
,
Ismail Elalamy
1   Service d’Hématologie Biologique, Hôpital Hôtel-Dieu de Paris, France
› Author AffiliationsParts of this study have been presented as plenary lecture during the 17th International Congress on Thrombosis (Bologna, 26-30/10/2002) and as a poster presentation during the 44th American Society of Hematology Annual Meeting 2002.
Further Information

Publication History

Received 24 July 2003

Accepted after revision 05 February 2003

Publication Date:
05 December 2017 (online)

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Summary

Fondaparinux (Arixtra®), a specific AT-dependent FXa inhibitor, is effective and safe in the prevention and treatment of venous thromboembolism, but some major hemorrhagic events may occur. No specific antidote to fondaparinux has been proposed. Recombinant FVIIa (Novoseven®) could be used as an haemostatic treatment, but this option has not been well documented. We studied the effect of rFVIIa (1 µg/ml) on the inhibition of thrombin generation induced by fondaparinux (0.1µg/ml to 1 µg/ml). Coagulation was triggered in platelet rich plasma (PRP) or in whole blood by recalcification in the presence of diluted thromboplastin. In PRP thrombin generation was assessed using the thrombinoscope assay. In whole blood, prothrombin activation was assessed by measuring the kinetics of F1+2 formation using an ELISA assay. Fondaparinux at concentrations equal or greater than 0.5 µg/ml prolonged the initiation phase of thrombin generation, and reduced the velocity of prothrombin activation. It also decreased by 60% the endogenous thrombin potential. In the presence of fondaparinux (0.5 µg/ml to 1 µg/ml) rFVIIa accelerated the initiation phase of thrombin generation, but it did not significantly increase the endogenous thrombin potential. However, rFVIIa did not completely reverse the inhibitory effect of fondaparinux on the parameters of thrombin generation and prothrombin activation. This study shows that rFVIIa accelerates thrombin generation, but does not completely reverse the inhibitory effect of fondaparinux on thrombin generation. The potential clinical use of rFVIIa as haemostatic treatment of major bleedings related to fondaparinux has to be evaluated.

Keywords

Pentasaccharide - fondaparinux - thrombin generation - novoseven - tissue factor
 

  • References

  • 1 Choay J, Petitou M, Lormeau JC. et al. Structure-activity of relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high antifactor Xa activity. Biochem Biophys Res Comm 1983; 116: 492-9.
    CrossrefPubMedGoogle Scholar
  • 2 Samama MM, Gerotziafas GT. Evaluation of the pharmacological properties and clinical results of the synthetic pentasaccharide (Fondaparinux). Thromb Res 2003; 109: 1-11.
    CrossrefPubMedGoogle Scholar
  • 3 Lormeau JC, Hérault JP. The effect of the synthetic pentasaccharide SR 90107/ORG 31540 on thrombin generation ex vivo is uniquely due to ATIII-mediated neutralization of factor Xa. Thromb Haemost 1995; 74: 1474-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Lormeau JC, Hérault JP. Comparative inhibition of extrinsic and intrinsic thrombin generation by standard heparin, a low molecular weight heparin and the synthetic AT-IIIbinding pentasaccharide. Thromb Haemost 1993; 69: 152-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Beguin S, Choay J, Hemker HC. The action of a synthetic pentasaccharide on thrombin generation in whole plasma. Thromb Haemost 1989; 61: 397-401.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Lassen MR, Bauer KA, Eriksson BI. et al. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomized double-blind comparison. Lancet 2002; 359: 1715-20.
    CrossrefPubMedGoogle Scholar
  • 7 Turpie AG, Bauer KA, Eriksson BI. et al. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomized double-blind trial. Lancet 2002; 359: 1721-6.
    CrossrefPubMedGoogle Scholar
  • 8 Bauer KA, Eriksson BI, Lassen MR. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-10.
    CrossrefPubMedGoogle Scholar
  • 9 Eriksson BI, Bauer KA, Lassen MR. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298-304.
    CrossrefPubMedGoogle Scholar
  • 10 Turpie AGG, Bauer KA, Eriksson BI. et al. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in major orhtopedic surgery. A metaanalysis of 4 randomized double-blind studies. Arch Intern Med 2002; 162: 1833-40.
    CrossrefPubMedGoogle Scholar
  • 11 The Matisse investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003; 349: 1695-702.
    CrossrefPubMedGoogle Scholar
  • 12 Coussement PK, Bassand JP, Convens C. et al. A synthetic factor-Xa inhibitor (ORG31540/ SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. Eur Heart J 2001; 22: 1716-24.
    CrossrefPubMedGoogle Scholar
  • 13 Hedner U. General haemostatic agents – fact or fiction. Pathophysiol Haemost Thromb 2002; 32 suppl 33-6.
    PubMedGoogle Scholar
  • 14 Friederich PW, Levi M, Bauer KA. et al. Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects. Circulation 2001; 103: 2555-9.
    CrossrefPubMedGoogle Scholar
  • 15 Deveras RAE, Kessler CM. Reversal of warfarin induced excessive anticoagulation with recombinant factor VIIa concentrate. Ann Intern Med 2002; 137: 884-8.
    CrossrefPubMedGoogle Scholar
  • 16 Sørensen B, Johansen P, Nielsen GL. et al. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003; 14: 469-77.
    CrossrefPubMedGoogle Scholar
  • 17 Hemker HC, Wielders S, Kessels H. et al. Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost 1993; 70: 617-24.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Hemker HC, Giesen PLA, Ramjee M. et al. The thrombogram: monitoring thrombin generation in platelet rich plasma. Thromb Haemost 2000; 83: 589-91.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Walenga JM, Petitou M, Lormeau JC. et al. Antithrombotic activity of a synthetic heparin pentasaccharide in a rabbit stasis thrombosis model using different thrombogenic challenges. Thromb Res 1987; 46: 187-98.
    CrossrefPubMedGoogle Scholar
  • 20 Boneu B, Necciari J, Cariou R. et al. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/ORG31540) with high affinity to antithrombin III in man. Thromb Haemost 1995; 74: 1468-73.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Gerotziafas GT, Zervas K, Arzoglou P. et al. On the mechanism of action of rFVIIa administered to patients with severe thrombocytopenia and life-threatening haemorrhage. Focus on prothrombin activation. Br J Haematol 2002; 117: 705-8.
    CrossrefPubMedGoogle Scholar
  • 22 Butenas S, Brummel KE, Branda RF. et al. Mechanism of factor VIIa–dependent coagulation in hemophilia blood. Blood 2002; 99: 923-30.
    CrossrefPubMedGoogle Scholar
  • 23 Kjalke M, Ezban M, Monroe DM. et al. High dose factor VIIa increases initial thrombin generation and mediates platelet activation in thrombocytopenia-like conditions in a cellbased model system. Br J Haematol 2001; 114: 114-20.
    CrossrefPubMedGoogle Scholar
  • 24 Rosing J, Tans G, Grovers-Riemslag JWP. et al. The role of phospholipids and factor Va in the prothrombinase complex. J Biol Chem 1980; 255: 274-83.
    PubMedGoogle Scholar
  • 25 Esmon CT, Owen WG, Jackson CM. A plausible mechanism for prothrombin activation by factor Xa, factor Va, phospholipid, and calcium ions. J Biol Chem 1974; 249: 8045-47.
    PubMedGoogle Scholar
  • 26 Carr ME, Martin EJ, Kuhn JG. et al. Effects of recombinant factor VIIa on platelet function and clot structure in blood with deficient prothrombin conversion. Thromb Haemost 2003; 89: 803-11.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 2003; 23: 17-25.
    CrossrefPubMedGoogle Scholar
  • 28 Hemker HC, Beguin S. Phenotyping the clotting system. Thromb Haemost 2000; 84: 741-51.
    PubMedGoogle Scholar
  • 29 Barrowcliffe TW, Havercroft SJ, Kemball-Cook G. et al. The effect of Ca2+, phospholipids and factor V on the anti-factor Xa activity of heparin and its oligosaccharides. Biochem J 1987; 243: 31-7.
    CrossrefPubMedGoogle Scholar
  • 30 Pieters J, Willemsg G, Hernker HC. et al. Inhibition of factor IXa and factor X, by Antithrombin III/Heparin during factor X activation. J Biol Chem 1988; 263: 15313-18.
    PubMedGoogle Scholar
  • 31 Rezaie AR. Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex. Blood 2001; 97: 2308-13.
    CrossrefPubMedGoogle Scholar
  • 32 Hemker HC, Choay J, Beguin S. Free factor Xa is on the main pathway of thrombin generation in clotting plasma. Biochimica et Biophysica Acta 1989; 992: 409-11.
    CrossrefPubMedGoogle Scholar
  • 33 Bijsterveld NR, Moons AH, Boekholdt AM. et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550-4.
    CrossrefPubMedGoogle Scholar