Associated Risk of Recombinant Activated Factor VIIa Application
DOI:
https://doi.org/10.1532/HSF98.20121127Abstract
Background: The recombinant human coagulation FVIIa was approved for the treatment of bleeding in hemophilia patients. The reports of a good hemostatic effect were followed by studies and applications without a regulatory extension of the therapeutic indication (off-label use). The aim of this retrospective study is the evaluation of thromboembolic adverse events and side effects in a large cohort of patients with FVIIa therapy.
Methods: In the period from January 2009 to March 2011, a total of 143/2453 (5.8%) cardiac surgical patients (69% male; age 67 ± 11 years; 39% thoracic aorta) were treated with different doses (mean, 6.1 mg; range, 1 to 27.2 mg) of factor VIIa. The administration of FVIIa was seen as a last therapeutic option and administered at the end of the treatment algorithm for severe bleeding.
Results: Due to an acute bleeding situation in 143 patients, 7.9 ± 5.8 units of packed red blood cells, 9.5 ± 6.1 units of fresh frozen plasma, 1740 ± 1860 IU PPSB (Prothrombin-Proconvertin-Stuart Factor-Antihemophilic Factor B), 5.6 ± 4 g fibrinogen, and 7.9 ± 7.6 units of platelets were administered. A re-thoracotomy was necessary, despite maximal procoagulant therapy, in 55% of patients. The in-hospital mortality was 36% (51/2453 = 2%). Thrombotic complications occurred with a frequency of 16% (mesenteric infarction, n = 9; stroke/transient ischemic attack, n = 3; myocardial infarction, n = 3; other, n = 8).
Conclusion: The proof of direct causality of the events in relation to the administration of FVIIa is difficult because the temporal and therapeutic relationships with concomitant vasoconstrictive and procoagulant therapies were not obvious. However, there remains a suspicion that a higher rate of mesenteric infarctions may be provoked by the administration of FVIIa.
References
Boffard KD, Riou B, Warren B, et al. 2005. 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 59:8-5.nBui JD, Despotis GD, Trulock EP, Patterson GA, Goodnough LT. 2002. Fatal thrombosis after administration of activated prothrombin complex concentrates in a patient supported by extracorporeal membrane oxygenation who had received activated recombinant factor VII. J Thorac Cardiovasc Surg 124:852-4.nDietrich W, Spannagl M. 2002. Caveat against the use of activated recombinant factor VII for intractable bleeding in cardiac surgery. Anaesth Analg 94:1369-70.nDiprose P, Herbertson MJ, O'Shaughnessy D, Deakin CD, Gill RS. 2005. Reducing allogeneic transfusion in cardiac surgery: a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. Br J Anaesth 94:271-8.nEngoren MC, Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ. 2002. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg 74:1180-6.nFriedrich PW, Levi M, Bauer KA, et al. 2001. Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects. Circulation 103:2555-9.nGoodnough LT, Lublin DM, Zhang L, Despotis G, Eby C. 2004. Transfusion medicine service policies for recombinant factor VIIa administration. Transfusion 44:1325-31.nHay CR, Negrier C, Ludlam CA. 1997. The treatment of bleeding in acquired haemophilia with recombinant factor VIIa: a multicentre study. Thromb Haemost 78:1463-7.nHedner U, Kisiel W. 1983. Use of human factor VIIa in the treatment of two hemophilia A patients with high-titer inhibitors. J Clin Invest 71:1836-41.nHoffman M, Monroe DM 3rd. 2001. A cell-based model of hemostasis. Thromb Haemost 85:958-65.nJámbor C, Bremerich D, Moritz A, Seifried E, Zwissler B. 2008. Management of hemostasis disorders after extracorporeal circulation. A clinical therapy algorithm [in German]. Anaesthesist 57:374-81.nJurlander B, Thim L, Klausen NK, et al. 2001. Recombinant activated factor VII (rFVIIa): characterization, manufacturing, and clinical development. Semin Thromb Hemost 27:373-84.nKarkouti K, Beattie WS, Wijeysundera DN, e al. 2005. Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion 45:26-34.nKenet G, Walden R, Eldad A, Martinowitz U. 1999. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet 354:1879.nKeogh B, Kinsman R. 2004. Fifth National Adult Cardiac Surgical Database Report 2003: Improving Outcomes for Patients. Reading, Massachusetts: Society of Cardiothoracic Surgeons of Great Britain and Ireland, Dendrite Clinical Systems Ltd.nKoch CG, Khandwala F, Li L, Estafanous FG, Loop FD, Blackstone EH. 2006. Persistent effect of red cell transfusion on health-related quality of life after cardiac surgery. Ann Thorac Surg 82:13-20.nKoch CG, Li L, Duncan AI, et al. 2006. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med 34:1608-16.nLevi M, Levy JH, Andersen HF, Truloff D. 2010. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 363:1791-800.nMcGill N, O'Shaughnessy D, Pickering R, Herbertson M, Gill R. 2002. Mechanical methods of reducing blood transfusion in cardiac surgery: randomised controlled trial. BMJ 324:1299.nMurphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. 2007. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation 116:2544-52.nNuttall GA, Oliver WC, Ereth MH, et al. 2000. Comparison of blood-conservation strategies in cardiac surgery patients at high risk for bleeding. Anesthesiology 92:674-82.nO'Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. 2006. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 295:293-8.nVeldman A, Hoffman M, Ehrenforth S. 2003. New insights into the coagulation system and implications for new therapeutic options with recombinant factor VIIa. Curr Med Chem 10:797-811.nWoodman RC, Harker LA. 1990. Bleeding complications associated with cardiopulmonary bypass. Blood 76:1680-97.nYank V, Tuohy CV, Logan AC, et al. 2011. Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications. Ann Intern Med 154:529-40.n
Published
How to Cite
Issue
Section
Author Disclosure & Copyright Transfer Agreement
In order to publish the original work of another person(s), The Heart Surgery Forum® must receive an acknowledgment of the Author Agreement and Copyright Transfer Statement transferring to Forum Multimedia Publishing, L.L.C., a subsidiary of Carden Jennings Publishing Co., Ltd. the exclusive rights to print and distribute the author(s) work in all media forms. Failure to check Copyright Transfer agreement box below will delay publication of the manuscript.
A current form follows:
The author(s) hereby transfer(s), assign(s), or otherwise convey(s) all copyright ownership of the manuscript submitted to Forum Multimedia Publishing, LLC (Publisher). The copyright transfer covers the exclusive rights to reproduce and distribute the article and the material contained therein throughout the world in all languages and in all media of expression now known or later developed, including but not limited to reprints, photographic reproduction, microfilm, electronic data processing (including programming, storage, and transmission to other electronic data record(s), or any other reproductions of similar nature), and translations.
However, Publisher grants back to the author(s) the following:
- The right to make and distribute copies of all or part of this work for use of the author(s) in teaching;
- The right to use, after publication in The Heart Surgery Forum, all or part of the material from this work in a book by the author(s), or in a collection of work by the author(s);
- The royalty-free right to make copies of this work for internal distribution within the institution/company that employs the author(s) subject to the provisions below for a work-made-for-hire;
- The right to use figures and tables from this work, and up to 250 words of text, for any purpose;
- The right to make oral presentations of material from this work.
Publisher reserves the right to grant or refuse permission to third parties to republish all or part of the article or translations thereof. To republish, such third parties must obtain written permission from the Publisher. (This is in accordance with the Copyright Statute, United States Code, Title 17. Exception: If all authors were bona fide officers or employees of the U.S. Government at the time the paper was prepared, the work is a “work of the US Government” (prepared by an officer or employee of the US Government as part of official duties), and therefore is not subject to US copyright; such exception should be indicated on signature lines. If this work was prepared under US Government contract or grant, the US Government may reproduce, royalty-free, all or portions of this work and may authorize others to do so, for official US Government purposes only, if the US Government contract or grant so requires.
I have participated in the conception and design of this work and in the writing of the manuscript and take public responsibility for it. Neither this manuscript nor one with substantially similar content under my authorship has been published, has been submitted for publication elsewhere, or will be submitted for publication elsewhere while under consideration by The Heart Surgery Forum, except as described in an attachment. I have reviewed this manuscript (original version) and approve its submission. If I am listed above as corresponding author, I will provide all authors with information regarding this manuscript and will obtain their approval before submitting any revision. I attest to the validity, accuracy, and legitimacy of the content of the manuscript and understand that Publisher assumes no responsibility for the validity, accuracy, and legitimacy of its content. I warrant that this manuscript is original with me and that I have full power to make this Agreement. I warrant that it contains no matter that is libelous or otherwise unlawful or that invades individual privacy or infringes any copyright or other proprietary right. I agree to indemnify and hold Publisher harmless of and from any claim made against Publisher that relates to or arises out of the publication of the manuscript and agree that this indemnification shall include payment of all costs and expenses relating to the defense of any such claim, including all reasonable attorney’s fees.
I warrant that I have no financial interest in the drugs, devices, or procedures described in the manuscript (except as disclosed in the attached statement).
I state that the institutional Human Subjects Committee and/or the Ethics Committee approved the clinical protocol reported in this manuscript for the use of experimental techniques, drugs, or devices in human subjects and appropriate informed consent documents were utilized.
Furthermore, I state that any and all animals used for experimental purposes received humane care in USDA registered facilities in compliance with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 85-23, revised 1985).