Low-dose recombinant factor VIIa for massive bleeding
QUESTIONS UNDER STUDY: recombinant activated factor VII (rFVIIa) is used off-label for massive bleeding. There is no convincing evidence of the benefits of this practice and the minimal effective dose is unknown. The aim of the study was to evaluate our in-house guideline recommending a low dose of 60 μg/kg for off-label use of rFVIIa.
METHODS:observational cohort study at the Inselspital Bern, a tertiary care University Hospital in Switzerland. All patients with massive bleeding treated off-label with rFVIIa between January 2005 and December 2007 were included.Survival, change of bleeding and transfusion rates, coagulation parameters and complications were analysed.
RESULTS: seventy-three patients received rFVIIa. Severe haemorrhage was documented by a bleeding rate of 1000 mL/h (median; interquartile range 350–3000) and total volume replacement of 11.9 L (6.6–15.2) before administration of rFVIIa. The median rFVIIa-dose was 64 μg/kg (56–71). rFVIIa was administered once in 79% patients, twice in 18%. The bleeding rate was reduced in 82% of the patients. Transfused packed red blood cells decreased from 14 units (8–22) over 4.9 h (2.5–8.8) before rFVIIa to 2 (0–6) in 24 h thereafter, platelet concentrates from 2 units (1–3) to 1 (0–2) and FFP from 11 units (6–16) to 2 (0–9). In-hospital mortality was 14% within 24 h and 32% at day 30. There were two arterial thromboembolic complications possibly related to rFVIIa.
CONCLUSION: a single injection of 60 μg/kg rFVIIa, a lower dose than usually recommended, appears to be efficacious in controlling massive bleeding with a very low complication rate.
- Hoots WK. Challenges in the therapeutic use of a “so-called” universal hemostatic agent: recombinant factor VIIa. Hematology Am Soc Hematol Educ Program. 2006:426–31.
- MacLaren R, Weber LA, Brake H, Gardner MA, Tanzi M. A multicenter assessment of recombinant factor VIIa off-label usage: clinical experiences and associated outcomes. Transfusion. 2005;45:1434–42.
- Fishman PE, Drumheller BC, Dubon ME, Slesinger TL. Recombinant activated factor VII use in the emergency department. Emerg Med J. 2008;25:625–30.
- Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg. 2008;248:61–8.
- Johansson PI. Off-label use of recombinant factor VIIa for treatment of haemorrhage: results from randomized clinical trials. Vox Sang. 2008;95:1–7.
- Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Use of recombinant factor VIIa for the prevention and treatment of bleeding in patients without hemophilia: a systematic review and meta-analysis. CMAJ. 2011;183:E9–19.
- Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. Management of bleeding following major trauma: an updated European guideline. Crit Care. 2010;14:R52.
- Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777–85.
- Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358:2127–37.
- Boffard KD, Riou B, Warren B, Choong PI, Rizoli S, Rossaint R, 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.
- Harrison TD, Laskosky J, Jazaeri O, Pasquale MD, Cipolle M. “Low-dose” recombinant activated factor VII results in less blood and blood product use in traumatic hemorrhage. J Trauma. 2005;59:150–4.
- Stein DM, Dutton RP, Hess JR, Scalea TM. Low-dose recombinant factor VIIa for trauma patients with coagulopathy. Injury. 2008;39:1054–61.
- Hyllner M, Houltz E, Jeppsson A. Recombinant activated factor VII in the management of life-threatening bleeding in cardiac surgery. Eur J Cardiothorac Surg. 2005;28:254–8.
- Franchini M, Lippi G, Franchi M. The use of recombinant activated factor VII in obstetric and gynaecological haemorrhage. BJOG. 2007;114:8–15.
- Friederich PW, Henny CP, Messelink EJ, Geerdink MG, Keller T, Kurth KH, 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;361:201–5.
- Levy JH. Massive transfusion coagulopathy. Semin Hematol. 2006;43:S59–63.
- Dutton R, Hauser C, Boffard K, Dimsitts J, Bernard G, Holcomb J, et al. Scientific and logistical challenges in designing the CONTROL trial: recombinant factor VIIa in severe trauma patients with refractory bleeding. Clin Trials. 2009;6:467–79.
- O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA. 2006;295:293–8.
- Raivio P, Suojaranta-Ylinen R, Kuitunen AH. Recombinant factor VIIa in the treatment of postoperative hemorrhage after cardiac surgery. Ann Thorac Surg. 2005;80:66–71.
- Mazer CD, Leong-Poi H, Mahoney J, Latter D, Strauss BH, Teitel JM. Vascular injury and thrombotic potential: a note of caution about recombinant factor VIIa. Semin Cardiothorac Vasc Anesth. 2007;11:261–4.
- Howes JL, Smith RS, Helmer SD, Taylor SM. Complications of recombinant activated human coagulation factor VII. Am J Surg. 2009;198:895–9.
- Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363:1791–800.
- Berkhof FF, Eikenboom JC. Efficacy of recombinant activated Factor VII in patients with massive uncontrolled bleeding: a retrospective observational analysis. Transfusion. 2009;49:570–7.
- Masud F, Bostan F, Chi E, Pass SE, Samir H, Stuebing K, Liebl MG. Recombinant factor VIIa treatment of severe bleeding in cardiac surgery patients: a retrospective analysis of dosing, efficacy, and safety outcomes. J Cardiothorac Vasc Anesth. 2009;23:28–33.
- Gill R, Herbertson M, Vuylsteke A, Olsen PS, von Heymann C, Mythen M, et al. Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation. 2009;120:21–7.
- Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol. 1997;99:542–7.
- Alberio L, Lammle B, Esmon CT. Protein C replacement in severe meningococcemia: rationale and clinical experience. Clin Infect Dis. 2001;32:1338–46.
- Barber PA, Hach S, Tippett LJ, Ross L, Merry AF, Milsom P. Cerebral ischemic lesions on diffusion-weighted imaging are associated with neurocognitive decline after cardiac surgery. Stroke. 2008;39:1427–33.
- Filsoufi F, Castillo JG, Rahmanian PB, Scurlock C, Fischer G, Adams DH. Effective management of refractory postcardiotomy bleeding with the use of recombinant activated factor VII. Ann Thorac Surg. 2006;82:1779–83.
- Isbister J, Phillips L, Dunkley S, Jankelowitz G, McNeil J, Cameron P. Recombinant activated factor VII in critical bleeding: experience from the Australian and New Zealand Haemostasis Register. Intern Med J. 2008;38:156–65.
- Sihler KC, Napolitano LM. Massive transfusion: new insights. Chest. 2009;136:1654–67.
- Pihusch M, Bacigalupo A, Szer J, von Depka Prondzinski M, Gaspar-Blaudschun B, Hyveled L, et al. Recombinant activated factor VII in treatment of bleeding complications following hematopoietic stem cell transplantation. J Thromb Haemost. 2005;3:1935–44.
- Kissela BM, Eckman MH. Cost effectiveness of recombinant factor VIIa for treatment of intracerebral hemorrhage. BMC Neurol. 2008;8:17.
- Grottke O, Braunschweig T, Zimmermann L, Kopp R, Lauritzen B, Coburn M, et al. Recombinant factor VIIa reduces bleeding after blunt liver injury in coagulopathic, hypofibrinogenaemic pigs. Br J Anaesth. 2010;105:789–97.
- Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet. 1999;354:1879.
- Martinowitz U, Kenet G, Segal E, Luboshitz J, Lubetsky A, Ingerslev J, et al. Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma. 2001;51:431–8.
- O’Connell NM, Perry DJ, Hodgson AJ, O’Shaughnessy DF, Laffan MA, Smith OP. Recombinant FVIIa in the management of uncontrolled hemorrhage. Transfusion. 2003;43:1711–6.