Efficacy of prothrombin complex concentrate to reverse the anticoagulant effect of the pentasaccharide fondaparinux in a rabbit model

Anne Godier; Marion Durand; Joseph Emmerich; Blandine Dizier; Thomas Lecompte; Charles-Marc Samama

doi:10.1160/TH10-07-0434

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 105(01): 161-168
DOI: 10.1160/TH10-07-0434

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Efficacy of prothrombin complex concentrate to reverse the anticoagulant effect of the pentasaccharide fondaparinux in a rabbit model

Authors

Anne Godier

¹INSERM U765, Paris, France

²Department of Anaesthesia and Critical Care, Paris Descartes University, Hôtel-Dieu Hospital, Paris, France
Marion Durand

³Department of Thoracic Surgery, Nancy University Hospital, CHU, Nancy, France

⁴INSERM U961, Nancy, France
Joseph Emmerich

¹INSERM U765, Paris, France
Blandine Dizier

¹INSERM U765, Paris, France
Thomas Lecompte

⁴INSERM U961, Nancy, France

⁵Laboratory of Haemostasis, Nancy University Hospital, CHU, Nancy, France
Charles-Marc Samama

¹INSERM U765, Paris, France

²Department of Anaesthesia and Critical Care, Paris Descartes University, Hôtel-Dieu Hospital, Paris, France

Abstract

Summary

As a potent anticoagulant agent, fondaparinux exposes a risk of bleeding. An effective way to reverse its effects is needed. It was the objective to study efficacy and safety of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of fondaparinux in a rabbit model of bleeding and thrombosis. In anaesthetised and ventilated rabbits, the Folts model was applied: a stenosis (75%) and an injury were carried out on the carotid artery, inducing thrombosis. Blood flow decreased as thrombus size increased until the pressure gradient was such that the thrombus was released and local blood flow was suddenly restored. This is known as a cyclic flow reduction (CFR). After the first CFR, rabbits were randomised into three groups: control (saline and saline after 1 minute), fondaparinux (fondaparinux [3 mg.kg⁻¹] and saline), PCC (fondaparinux and PCC [40 UI.kg⁻¹]). Then CFRs were recorded over 20 minutes. The following were measured: ear immersion bleeding time (BT), haemoglobin blood level (Hb1) and thrombelasto-metric parameters (ROTEM^®). Finally, a hepatosplenic section was performed; 15 minutes later, the amount of blood loss was recorded as primary endpoint and Hb2 was measured. Blood loss was increased with fondaparinux and normalised with PCC. Regarding ROTEM^® INTEM, fondaparinux increased clotting time and clotting formation time. PCC normalised these parameters. EXTEM and FIBTEM tests were not modified. Regarding safety, PCC did not increase CFRs. PCC reduced bleeding without increasing thrombosis and was effective to reverse the haemorrhagic effect of fondaparinux in this rabbit model.

Keywords

Arterial thrombosis - coagulation factors - haemostasis - animal models - coagulation inhibitors

Full Text

References

References
1 Hirsh J, Bauer KA, Donati MB. et al. American College of Chest Physicians.. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 141S-159S.
2 Ansell J, Hirsh J, Hylek E. et al. American College of Chest Physicians.. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 160S-198S.
3 Bijsterveld NR, Moons AH, Boekholdt SM. et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550-2554.
4 Vavra KA, Lutz MF, Smythe MA. Recombinant factor VIIa to manage major bleeding from newer parenteral anticoagulants. Ann Pharmacother 2010; 44: 718-726.
5 Holcomb JB. Traditional transfusion practices are changing. Crit Care 2010; 14: 162.
6 Gatt A, van Veen JJ, Woolley AM. et al. Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro. Thromb Haemost 2008; 100: 350-355.
7 Delaporte-Cerceau S, Samama CM, Riou B. et al. Ketorolac and enoxaparin affect arterial thrombosis and bleeding in the rabbit. Anesthesiology 1998; 88: 1310-1317.
8 Fattorutto M, Tourreau-Pham S, Mazoyer E. et al. Recombinant activated factor VII decreases bleeding without increasing arterial thrombosis in rabbits. Can J Anaesth 2004; 51: 672-679.
9 Godier A, Mazoyer E, Cymbalista F. et al. Recombinant activated factor VII efficacy and safety in a model of bleeding and thrombosis in hypothermic rabbits: a blind study. J Thromb Haemost 2007; 05: 244-249.
10 Golino P, Ragni M, Cirillo P. et al. Effects of recombinant active site-blocked activated factor VII in rabbit models of carotid stenosis and myocardial infarction. Blood Coag Fibrinolysis 2000; 11: 149-158.
11 Vogel GM, Meuleman DG, Van Dinther TG. et al. Antithrombotic properties of a direct thrombin inhibitor with a prolonged half-life and AT-mediated factor Xa inhibitory activity. J Thromb Haemost 2003; 01: 1945-1954.
12 Biemond BJ, Perzborn E, Friederich PW. et al. Prevention and treatment of experi-mental thrombosis in rabbits with rivaroxaban (BAY 597939)--an oral, direct factor Xa inhibitor. Thromb Haemost. 2007; 97: 471-477.
13 Dargaud Y, Desmurs-Clavel H, Marin S. et al. Comparison of the capacities of two prothrombin complex concentrates to restore thrombin generation in plasma from orally anticoagulated patients: an in vitro study. J Thromb Haemost 2008; 06: 962-968.
14 Pindur G, Morsdorf S. The use of prothrombin complex concentrates in the treatment of hemorrhages induced by oral anticoagulation. Thromb Res 1999; 04: S57-61.
15 Perzborn E, Tinel H. Prothrombin complex concentrate reverses the effects of high-dose rivaroxaban in rats. J Thromb Haemost. 2009 7 (Suppl 2): Abstract PPMO-183
16 Le Sache F, Le Bonniec B, Dizier B. et al. Efficacy and safety of prothrombin complex concentrate and recombinant activated factor VII versus placebo in a rabbit model of hemodilution, bleeding and thrombosis: a blind study. J Thromb Haemost. 2009 7: Abstract PP-MO-391.
17 Lang T, Bauters A, Braun SL. et al. Multi-centre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinolysis 2005; 16: 301-310.
18 Salooja N, Perry DJ. Thrombelastography. Blood Coagul Fibrinolysis 2001; 12: 327-337.
19 Siller-Matula JM, Plasenzotti R, Spiel A. et al. Interspecies differences in coagulation profile. Thromb Haemost 2008; 100: 397-404.
20 Cohen AT, Davidson BL, Gallus AS. et al. ARTEMIS Investigators.. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. Br Med J 2006; 332: 325-329.
21 Agnelli G, Bergqvist D, Cohen AT. et al. PEGASUS investigators.. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg 2005; 92: 1212-1220.
22 Eikelboom JW, Quinlan DJ, O’Donnell M. Major Bleeding, Mortality, and Efficacy of Fondaparinux in Venous Thromboembolism Prevention Trials. Circulation 2009; 120: 2006-2011.
23 Crowther MA, Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood 2008; 111: 4871-4879.
24 Levi MM, Eerenberg E, Löwenberg E. et al. Bleeding in patients using new anticoagulants or antiplatelet agents: risk factors and management. Neth J Med 2010; 68: 68-76.
25 Desmurs-Clavel H, Huchon C, Chatard B. et al. Reversal of the inhibitory effect of fondaparinux on thrombin generation by rFVIIa, aPCC and PCC. Thromb Res 2009; 123: 796-798.
26 Gerotziafas GT, Depasse F, Chakroun T. et al. Recombinant factor VIIa partially reverses the inhibitory effect of fondaparinux on thrombin generation after tissue factor activation in platelet rich plasma and whole blood. Thromb Haemost 2004; 91: 531-537.
27 Stanworth SJ, Birchall J, Doree CJ. et al. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev 2007; 02: CD005011.
28 Pernod G, Godier A, Gozalo C. et al. French clinical practice guidelines on the management of patients on vitamin K antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding). Thromb Res. 2010 prepub online.
29 Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care 2008; 12: R105.
30 Schick KS, Fertmann JM, Jauch KW. et al. Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding. Crit Care 2009; 13: R191.45.
31 Schöchl H, Nienaber U, Hofer G. et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM(R))-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care 2010; 14: R55.
32 Elg M, Carlsson S, Gustafsson D. Effects of agents, used to treat bleeding disorders, on bleeding time prolonged by a very high dose of a direct thrombin inhibitor in anesthesized rats and rabbits. Thromb Res 2001; 101: 159-170.
33 Elg M, Carlsson S, Gustafsson D. Effect of activated prothrombin complex concentrate or recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thromb Res 2001; 101: 145-157.
34 Lundblad RL, Bergstrom J, De Vreker R. et al. Measurement of active coagulation factors in Autoplex-T with colorimetric active site-specific assay technology. Thromb Haemost 1998; 80: 811-815.
35 Diehl KH, Römisch J, Hein B. et al. Investigation of activated prothrombin complex concentrate as potential hirudin antidote in animal models. Haemostasis 1995; 25: 182-192.
36 Köhler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res 1999; 95: S13-17.
37 Bershad EM, Suarez JI. Prothrombin complex concentrates for oral anticoagulant therapy-related intracranial hemorrhage: a review of the literature. Neurocrit Care 2010; 12: 403-413.
38 Köhler M, Hellstern P, Lechler E. et al. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost 1998; 80: 399-402.
39 Greaves M. Control of Anticoagulation Subcommittee of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis.. Limitations of the laboratory monitoring of heparin therapy. Scientific and Standardization Committee Communications: on behalf of the Control of Anticoagulation Subcommittee of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis. Thromb Haemost 2002; 87: 163-164.
40 Young G, Yonekawa KE, Nakagawa PA. et al. Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography. Blood Coagul Fibrinolysis 2007; 18: 547-553.
41 Gerotziafas GT, Depasse F, Chakroun T. et al. Comparison of the effect of fondaparinux and enoxaparin on thrombin generation during in-vitro clotting of whole blood and platelet-rich plasma. Blood Coagul Fibrinolysis 2004; 15: 149-156.
42 Roullet S, Pillot J, Freyburger G. et al. Rotation thromboelastometry detects thrombocytopenia and hypofibrinogenaemia during orthotopic liver transplantation. Br J Anaesth 2010; 104: 422-428.
43 Rugeri L, Levrat A, David JS. et al. Diagnosis of early coagulation abnormalities in trauma patients by rotation thrombelastography. J Thromb Haemost 2007; 05: 289-295.
44 Huissoud C, Carrabin N, Audibert F. et al. Bedside assessment of fibrinogen level in postpartum haemorrhage by thrombelastometry. Br J Obstet Gynecol 2009; 116: 1097-1102.
45 Young G, Yonekawa KE, Nakagawa PA, Blain RC, Lovejoy AE, Nugent DJ. Differential effects of direct thrombin inhibitors and antithrombin-dependent anticoagulants on the dynamics of clot formation. Blood Coagul Fibrinolysis 2007; 18: 97-103.