Recombinant activated factor VII does not reduce bleeding in rabbits treated with aspirin and clopidogrel

Clemence Hindy-François; Christilla Bachelot-Loza; Bernard Le Bonniec; Francoise Grelac; Blandine Dizier; Anne Godier; Joseph Emmerich; Pascale Gaussem; Charles-Marc Samama

doi:10.1160/TH10-01-0039

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 104(04): 823-830
DOI: 10.1160/TH10-01-0039

Animal Models

Schattauer GmbH

Recombinant activated factor VII does not reduce bleeding in rabbits treated with aspirin and clopidogrel

Clemence Hindy-François

¹Inserm UMRS 765, Pharmaceutical Sciences University, Paris, France

²AP-HP, Department of Anaesthesiology and Intensive Care, Necker University Hospital, Paris, France

,

Christilla Bachelot-Loza

¹Inserm UMRS 765, Pharmaceutical Sciences University, Paris, France

,

Bernard Le Bonniec

¹Inserm UMRS 765, Pharmaceutical Sciences University, Paris, France

,

Francoise Grelac

¹Inserm UMRS 765, Pharmaceutical Sciences University, Paris, France

,

Blandine Dizier

¹Inserm UMRS 765, Pharmaceutical Sciences University, Paris, France

,

Anne Godier

¹Inserm UMRS 765, Pharmaceutical Sciences University, Paris, France

³AP-HP, Department of Anaesthesiology and Intensive Care, Hôtel-Dieu University Hospital, Paris, France

,

Joseph Emmerich

¹Inserm UMRS 765, Pharmaceutical Sciences University, Paris, France

⁴University Paris Descartes, Paris, France

,

Pascale Gaussem

¹Inserm UMRS 765, Pharmaceutical Sciences University, Paris, France

⁴University Paris Descartes, Paris, France

,

Charles-Marc Samama

¹Inserm UMRS 765, Pharmaceutical Sciences University, Paris, France

³AP-HP, Department of Anaesthesiology and Intensive Care, Hôtel-Dieu University Hospital, Paris, France

⁴University Paris Descartes, Paris, France

› Author Affiliations

Abstract

Summary

Combined antiplatelet agents (cAPA), aspirin plus clopidogrel, increase the risk of bleeding. We hypothesised that recombinant activated FVIIa (rFVIIa), which normalises thrombin generation in platelet-rich plasma from patients treated with cAPA, could limit this bleeding risk. It was the objective of this study to investigate the efficacy and safety of rFVIIa compared to placebo, in a bleeding and thrombosis model in rabbits treated with aspirin and clopidogrel. New-Zealand rabbits, randomised into two groups (Placebo1, n=36 ; cAPA, n=34), were anaesthetised, ventilated and monitored for blood pressure, temperature and carotid blood flow. The Folts model was applied to a carotid artery. Cyclic flow reductions (CFR) were recorded over a first 20-min period (Obs1). Each rabbit was then randomly assigned into one of three subgroups (Placebo2, 40 μg/kg rFVIIa, 160 μg/kg rFVIIa) and CFR were monitored for a second 20-min period (Obs2). Ear bleeding time (BT) was measured at the end of each period. Hepatosplenic (HS) section was performed at the end of the experiment and HS blood loss defines the primary endpoint. Secondary endpoints were thrombosis (CFR), prothrombin time, platelet aggregation, and thrombin generation. Non- parametric statistical tests were used (p<0.05). cAPA significantly increased HS blood loss, BT and suppressed CFR compared to Placebo1 (p<0.05). rFVIIa injection did not modify HS blood loss, BT or CFR rate in Placebo1 rabbits nor in cAPA animals. These effects were unaffected by either rFVIIa dose. rFVIIa accelerated thrombin generation but had no effect on platelet aggregation in citrated platelet-rich plasma. rFVIIa did not modify HS blood loss associated with cAPA in rabbits.

Keywords

Aspirin - bleeding - clopidogrel - rFVIIa - thrombosis - rabbit

Full Text

References

References
1 Patrono C, Bachmann F, Baigent C. et al. Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European society of cardiology. Eur Heart J 2004; 25: 166-181.
2 Gachet C. P2 receptors, platelet function and pharmacological implications. Thromb Haemost 2008; 99: 466-472.
3 Jones RL, Giembycz MA, Woodward DF. Prostanoid receptor antagonists: development strategies and therapeutic applications. Br J Pharmacol 2009; 158: 104-145.
4 Herbert JM, Savi P. P2Y₁₂, a new platelet ADP receptor, target of clopidogrel. Sem Vasc Med 2003; 3: 113-122.
5 Albaladejo P, Marret E, Piriou V. et al. Perioperative management of antiplatelet agents in patients with coronary stents: recommendations of a French Task Force. Br J Anaesth 2006; 97: 580-582.
6 Zeymer U, Gitt A, Junger C. et al. Clopidogrel in addition to aspirin reduces inhospital major cardiac and cerebrovascular events in unselected patients with acute ST segment elevation myocardial. Thromb Haemost 2008; 99: 155-160.
7 Hallas J, Dall M, Andries A. et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. Br Med J 2006; 333: 726.
8 Tauber M, Koller H, Moroder P. et al. Secondary intracranial hemorrhage after mild head injury in patients with low-dose acetylsalicylate acid prophylaxis. J Trauma 2009; 67: 521-525.
9 Weant KA, Flynn JF, Akers WS. Management of antiplatelet therapy for minimization of bleeding risk before cardiac surgery. Pharmacotherapy 2006; 26: 1616-1625.
10 Lecompte T, Hardy JF. Antiplatelet agents and perioperative bleeding. Can J Anaesth 2006; 53 (Suppl. 06) S103-112.
11 Samama CM, Djoudi R, Lecompte T. et al. Perioperative platelet transfusion: recommendations of the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSaPS) 2003. Can J Anaesth 2005; 52: 30-37.
12 Vilahur G, Choi BG, Zafar MU. et al. Normalization of platelet reactivity in clopidogrel-treated subjects. J Thromb Haemost 2007; 5: 82-90.
13 Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004; 104: 3858-3864.
14 Pipe SW. Recombinant clotting factors. Thromb Haemost 2008; 99: 840-850.
15 Altman R, Scazziota A, DELH M. et al. Recombinant factor VIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel on in vitro thrombin generation. J Thromb Haemost 2006; 4: 2022-2027.
16 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; 5: 244-249.
17 Charbonneau S, Girard F, Boudreault D. et al. Recombinant human activated factor VII is thrombogenic in a rabbit model of cyclic flow reduction and does not reduce intra-abdominal bleeding. Thromb Haemost 2007; 97: 296-303.
18 Folts J, Rowe G. Cyclical reductions in coronary blood flow in coronary arteries with fixed partial obstruction and their inhibition with aspirin. Fed Proc 1974; 33: 413.
19 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.
20 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.
21 Louvain-Quintard VB, Bianchini EP, Calmel-Tareau C. et al. Thrombin-activable factor X re-establishes an intrinsic amplification in tenase-deficient plasmas. J Biol Chem 2005; 280: 41352-41359.
22 Pusateri AE, Ryan KL, Delgado AV. et al. Effects of increasing doses of activated recombinant factor VII on haemostatic parameters in swine. Thromb Haemost 2005; 93: 275-283.
23 Martinowitz U, Holcomb JB, Pusateri AE. et al. Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries. J Trauma 2001; 50: 721-729.
24 Eriksson BI, Dahl OE, Rosencher N. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370: 949-956.
25 Neubauer H, Lask S, Engelhardt A. et al. How to optimise clopidogrel therapy? Reducing the low-response incidence by aggregometry-guided therapy modification. Thromb Haemost 2008; 99: 357-362.
26 Zimmermann N, Hohlfeld T. Clinical implications of aspirin resistance. Thromb Haemost 2008; 100: 379-390.
27 Howes JL, Smith RS, Helmer SD. et al. Complications of recombinant activated human coagulation factor VII. Am J Surg 2009; 198: 895-899.
28 Diringer MN, Skolnick BE, Mayer SA. et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Stroke 2010; 41: 48-53.
29 Bruckner BA, DiBardino DJ, Ning Q. et al. High incidence of thromboembolic events in left ventricular assist device patients treated with recombinant activated factor VII. J Heart Lung Transplant 2009; 28: 785-790.
30 Abshire T, Kenet G. Safety update on the use of recombinant factor VIIa and the treatment of congenital and acquired deficiency of factor VIII or IX with inhibitors. Haemophilia 2008; 14: 898-902.
31 Altman R, Scazziota A, Rouvier J. et al. Effect of sodium arachidonate on thrombin generation through platelet activation--inhibitory effect of aspirin. Thromb Haemost 2000; 84: 1109-1112.
32 Hedner U. Mechanism of action of recombinant activated factor VII: an update. Semin Hematol 2006; 43 (1 Suppl 1): S105-107.
33 Mayer SA, Brun NC, Begtrup K. et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005; 352: 777-785.
34 O’Connell KA, Wood JJ, Wise RP. et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. J Am Med Assoc 2006; 295: 293-298.
35 Sugg RM, Gonzales NR, Matherne DE. et al. Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa. Neurology 2006; 67: 1053-1055.