Download PDF
Thromb Haemost 2007; 97(02): 296-303
DOI: 10.1160/TH06-08-0429
Animal Models
Schattauer GmbH

Recombinant human activated factor VII is thrombogenic in a rabbit model of cyclic flow reduction and does not reduce intra-abdominal bleeding

Sonia Charbonneau
1   Departments of Anesthesiology, CHUM, Hôpital Notre-Dame, Montréal, Québec, Canada
,
François Girard
1   Departments of Anesthesiology, CHUM, Hôpital Notre-Dame, Montréal, Québec, Canada
,
Daniel Boudreault
1   Departments of Anesthesiology, CHUM, Hôpital Notre-Dame, Montréal, Québec, Canada
,
Monique Ruel
1   Departments of Anesthesiology, CHUM, Hôpital Notre-Dame, Montréal, Québec, Canada
,
Normand Blais
2   Departments of Hematology, CHUM, Hôpital Notre-Dame, Montréal, Québec, Canada
,
Jean-François Hardy
1   Departments of Anesthesiology, CHUM, Hôpital Notre-Dame, Montréal, Québec, Canada
› Author AffiliationsFinancial support: This study was supported in part by the Organon Award of the Department of Anesthesiology of the University of Montreal and by the Rosario Denis Award of the Association des Anesthésiologistes du Québec.
Further Information

Publication History

Received 04 August 2006

Accepted after resubmission 01 January 2006

Publication Date:
25 November 2017 (online)

    Permissions and Reprints

Summary

Recombinant human activated factor VII (rHuFVIIa) can reduce bleeding but may be associated with arterial thrombosis. We hypothesized that rHuFVIIa would increase the occurrence of cyclic flow reductions (CFR) and reduce intra-abdominal bleeding in an experimental model. An adapted Folts’ model of carotid artery lesion and stenosis was used. Twenty four rabbits were randomized to receive rHuFVIIa (group F) or placebo (group P) in a double-blind fashion. A standardized injury to the common carotid artery resulted in CFR and/or thrombosis. Hematological values, coagulation and thromboelastographic (TEG) variables were compared. Intra-abdominal bleeding was evaluated by measuring blood loss from standardized hepatosplenic lesions. The median number (range) of spontaneous CFR [group P: 6 (0–15); group F: 8 (0–16)] was comparable between groups. The number of induced CFR (by “shaking” of the artery) needed to avert thrombosis (group F: 2; group P: 0 ; p < 0.05) and the incidence of complete carotid artery thrombosis (group F: 3; group P : 0; p < 0.05) were higher in group F. Intra-abdominal bleeding was similar in both groups. TEG analysis demonstrated a hypercoagulable state in both groups but the magnitude of the change was statistically more important in group F. rHuFVIIa increases thrombosis in a rabbit model of carotid artery injury. The bleeding from hepatic and splenic lesions is not reduced by administration of rHuFVIIa despite a hypercoagulable state confirmed by standard TEG analysis.

Keywords

Recombinant activated human factor VII - arterial thrombosis - hemorrhage
 

  • References

  • 1 Stewart AJ, Hanley JP, Ludlam CA. Safety, efficacy and cost-effectiveness of home therapy with recombinant activated factor VII in a patient with severe haemophilia A and an anti-factor VIII inhibitor. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S93-5.
    PubMedGoogle Scholar
  • 2 Roberts HR. Clinical experience with activated factor VII: focus on safety aspects. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S115-8.
    PubMedGoogle Scholar
  • 3 Guillet B, Pinganaud C, Proulle V. et al. Myocardial infarction occurring in a case of acquired haemophilia during the treatment course with recombinant activated factor VII. Thromb Haemost 2002; 88: 698-699.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Peerlinck K, Vermylen J. Acute myocardial infarction following administration of recombinant activated factor VII (Novo Seven) in a patient with haemophilia A and inhibitor. Thromb Haemost 1999; 82: 1775-1776.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Aldouri M. The use of recombinant factor VIIa in controlling surgical bleeding in non-haemophiliac patients. Pathophysiol Haemost Thromb 2002; 32 (Suppl. 01) 41-46.
    CrossrefPubMedGoogle Scholar
  • 6 Grounds M. Recombinant factor VIIa (rFVIIa) and its use in severe bleeding in surgery and trauma: a review. Blood Rev 2003; 17 (Suppl. 01) S11-21.
    CrossrefPubMedGoogle Scholar
  • 7 Friederich PW, Henny CP, Messelink EJ et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet 2003; 361: 201-205.
    CrossrefPubMedGoogle Scholar
  • 8 Karkouti K, Beattie WS, Wijeysundera DN. et al. Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion 2005; 45: 26-34.
    CrossrefPubMedGoogle Scholar
  • 9 Raobaikady R, Redman J, Ball JA. et al. Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis or pelvis and acetabulum: a double-blind, randomized, placebo-controlled trial. Br J Anaesth 2005; 94: 586-591.
    CrossrefPubMedGoogle Scholar
  • 10 Vanek T, Straka Z, Hrabak J. et al. Use of recombinant activated factor VII in cardiac surgery for an effective treatment of severe intractable bleeding. Jpn Heart J 2004; 45: 855-860.
    CrossrefPubMedGoogle Scholar
  • 11 Mayer SA, Brun NC, Begtrup K. et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005; 352: 777-785.
    CrossrefPubMedGoogle Scholar
  • 12 Folts J. An in vivo model of experimental arterial stenosis, intimal damage, and periodic thrombosis. Circulation 1991; 83: IV3-14.
    PubMedGoogle Scholar
  • 13 Folts JD, Crowell Jr. EB, Rowe GG. Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 1976; 54: 365-370.
    CrossrefPubMedGoogle Scholar
  • 14 Hill DS, Smith SR, Folts JD. The rabbit as a model for carotid artery stenosis and periodic acute thrombosis. Fed Proc 1987; 46: 421.
    PubMedGoogle Scholar
  • 15 Samama CM, Bonnin P, Bonneau M. et al. Comparative arterial antithrombotic activity of clopidogrel and acetyl salicylic acid in the pig. Thromb Haemost 1992; 68: 500-505.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 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.
    CrossrefPubMedGoogle Scholar
  • 17 Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2004; 2: 899-909.
    CrossrefPubMedGoogle Scholar
  • 18 Levi M, Peters M, Buller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Crit Care Med 2005; 33: 883-890.
    CrossrefPubMedGoogle Scholar
  • 19 Boffard KD, Riou B, Warren B. et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma 2005; 59: 8-15 discussion 18.
    CrossrefPubMedGoogle Scholar
  • 20 Bosch J, Thabut D, Bendtsen F. et al. Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial. Gastroenterology 2004; 127: 1123-1130.
    CrossrefPubMedGoogle Scholar
  • 21 Diprose P, Herbertson MJ, O'Shaughnessy D. et al. Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized doubleblind placebo-controlled pilot study. Br J Anaesth 2005; 95: 596-602.
    CrossrefPubMedGoogle Scholar
  • 22 Lodge JP, Jonas S, Jones RM. et al. Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl 2005; 11: 973-979.
    CrossrefPubMedGoogle Scholar
  • 23 Lodge JP, Jonas S, Oussoultzoglou E. et al. Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial. Anesthesiology 2005; 102: 269-275.
    CrossrefPubMedGoogle Scholar
  • 24 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.
    CrossrefPubMedGoogle Scholar
  • 25 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
    CrossrefPubMedGoogle Scholar
  • 26 Schreiber MA, Holcomb JB, Rojkjaer R. Preclinical trauma studies of recombinant factor VIIa. Crit Care 2005; 9 (Suppl. 05) S25-8.
    PubMedGoogle Scholar
  • 27 Schreiber MA, Holcomb JB, Hedner U. et al. The effect of recombinant factor VIIa on coagulopathic pigs with grade V liver injuries. J Trauma 2002; 53: 252-257. discussion 7–9.
    CrossrefPubMedGoogle Scholar
  • 28 Schreiber MA, Holcomb JB, Hedner U. et al. The effect of recombinant factor VIIa on noncoagulopathic pigs with grade V liver injuries. J Am Coll Surg 2003; 196: 691-697.
    CrossrefPubMedGoogle Scholar
  • 29 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 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.
    CrossrefPubMedGoogle Scholar
  • 31 Martinowitz U, Kenet G, Lubetski A. et al. Possible role of recombinant activated factor VII (rFVIIa) in the control of hemorrhage associated with massive trauma. Can J Anesth 2002; 49: S15-20.
    PubMedGoogle Scholar
  • 32 Martinowitz U, Kenet G, Segal E. et al. Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma 2001; 51: 431-438.
    PubMedGoogle Scholar
  • 33 Bell CR, Cox DJ, Murdock PJ. et al. Thrombelastographic evaluation of coagulation in transurethral prostatectomy. Br J Urol 1996; 78: 737-741.
    CrossrefPubMedGoogle Scholar
  • 34 Goobie SM, Soriano SG, Zurakowski D. et al. Hemostatic changes in pediatric neurosurgical patients as evaluated by thrombelastograph. Anesth Analg 2001; 93: 887-892.
    CrossrefPubMedGoogle Scholar
  • 35 Samama CM, Thiry D, Elalamy I. et al. Perioperative activation of hemostasis in vascular surgery patients. Anesthesiology 2001; 94: 74-78.
    CrossrefPubMedGoogle Scholar
  • 36 Diness V, Bregengaard C, Erhardtsen E. et al. Recombinant human factor VIIa (rFVIIa) in a rabbit stasis model. Thromb Res 1992; 67: 233-41.
    CrossrefPubMedGoogle Scholar
  • 37 Lindley CM, Sawyer WT, Macik BG. et al. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther 1994; 55: 638-648.
    CrossrefPubMedGoogle Scholar
  • 38 Friederich PW, Geerdink MG, Spataro M. et al. The effect of the administration of recombinant activated factor VII (NovoSeven) on perioperative blood loss in patients undergoing transabdominal retropubic prostatectomy: the PROSE study. Blood Coagul Fibrinolysis 2000; 11 (Suppl. 01) S129-32.
    CrossrefPubMedGoogle Scholar
  • 39 Hendriks HG, Meijer K, de Wolf JT. et al. Effects of recombinant activated factor VII on coagulation measured by thromboelastography in liver transplantation. Blood Coagul Fibrinolysis 2002; 13: 309-313.
    CrossrefPubMedGoogle Scholar
  • 40 Telgt DS, Macik BG, McCord DM. et al. Mechanism by which recombinant factor VIIa shortens the aPTT: activation of factor X in the absence of tissue factor. Thromb Res 1989; 56: 603-609.
    CrossrefPubMedGoogle Scholar
  • 41 Yoshioka A, Nishio K, Shima M. Thrombelastgram as a hemostatic monitor during recombinant factor VIIa treatment in hemophilia A patients with inhibitor to factor VIII. Haemostasis 1996; 26 (Suppl. 01) 139-142.
    PubMedGoogle Scholar
  • 42 Keeney M, Allan DS, Lohmann RC. et al. Effect of activated recombinant human factor 7 (Niastase) on laboratory testing of inhibitors of factors VIII and IX. Lab Hematol 2005; 11: 118-123.
    CrossrefPubMedGoogle Scholar
  • 43 Murray D, Pennell B, Olson J. Variability of prothrombin time and activated partial thromboplastin time in the diagnosis of increased surgical bleeding. Transfusion 1999; 39: 56-62.
    CrossrefPubMedGoogle Scholar
  • 44 Kawaguchi C, Takahashi Y, Hanesaka Y. et al. The in vitro analysis of the coagulation mechanism of activated factor VII using thrombelastogram. Thromb Haemost 2002; 88: 768-772.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Tranholm M, Rojkjaer R, Pyke C. et al. Recombinant factor VIIa reduces bleeding in severely thrombocytopenic rabbits. Thromb Res 2003; 109: 217-223.
    CrossrefPubMedGoogle Scholar
  • 46 Sorensen B, Ingerslev J. Thromboelastography and recombinant factor VIIa-hemophilia and beyond. Semin Hematol 2004; 41: 140-144.
    CrossrefPubMedGoogle Scholar