Neurocritical Care

, Volume 1, Issue 1, pp 19–29 | Cite as

The emerging role of recombinant-activated factor VII in neurocritical care

Review Article


Recombinant-activated factor VII (rFVIIa; NovoSeven®, Novo Nordisk, Denmark) was developed specifically for the management of bleeding in hemophiliacs with inhibitors to factors VIII or IX. Several recent case reports and small clinical studies also suggest that rFVIIa may be useful as a general hemostatic agent in nonhemophilic patients. The mechanism by which rFVIIa acts is controversial with both tissue factor-dependent and -independent mechanisms proposed. Regardless of the specific mechanism, rFVIIa enhances hemostasis at the site of injury without systemic activation of the coagulation cascade. Several features make rFVIIa an ideal candidate for reversal of coagulopathy in central nervous system (CNS) hemorrhage. It acts almost immediately, requires negligible volume for infusion, poses no risk of transfer of blood-borne pathogens, and has few apparent complications. To date, clinically proven efficacy for rFVIIa by randomized controlled trials has been accomplished mainly for hemophilic patients. However, there are ongoing or planned clinical trials for rapid reversal of coagulopathy in trauma and liver disease, as well as CNS hemorrhage associated with oral anticoagulation and minimization of hematoma expansion after intracerebral hemorrhage. These trials will hopefully answer unresolved questions regarding risk-benefit ratio, therapeutic index, efficacy, safety, indications, optimal dosing, monitoring, and cost-effectiveness of rFVIIa in nonhemophilic patients.

Key Words

Recombinant-activated factor VII NovoSeven coagulopathy intracranial hemorrhage 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Al Douri M, Shafi T, Al Khudairi D, et al. Effect of the administration of recombinant activated factor VII (recombinant activated factor VII; NovoSeven) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery. Blood Coagul Fibrinolysis 2000;11(Suppl 1):S121-S127.PubMedGoogle Scholar
  2. 2.
    Aledort LM. Recombinant factor VIIa is a panhemostatic agent? Thromb Haemost 2000;83:637–638.PubMedGoogle Scholar
  3. 3.
    Arkin S, Cooper HA, Hutter JJ, et al. Activated recombinant human coagulation factor VII therapy for intracranial hemorrhage in patients with hemophilia A or B with inhibitors. Results of the novoseven emergency-use program. Haemostasis 1998;28:93–98.PubMedCrossRefGoogle Scholar
  4. 4.
    Boulis N, Bobek M, Schmaier A, Hoff J. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999;45:1113–1119.PubMedCrossRefGoogle Scholar
  5. 5.
    Broderick JP, Brott T, Tomsick T, Miller R, Huster G. Intracerebral hemorrhage is more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993;78:188–191.PubMedCrossRefGoogle Scholar
  6. 6.
    Broderick JP, Brott TG, Duldner JE. Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality. Stroke 1993;24:987–993.PubMedGoogle Scholar
  7. 7.
    Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997;28:1–5.PubMedGoogle Scholar
  8. 8.
    Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 2000;14:458–461.PubMedCrossRefGoogle Scholar
  9. 9.
    Deveras RE, Kessler CM. Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 2002;137:884–888.PubMedGoogle Scholar
  10. 10.
    Erhardtsen E, Nony P, Dechavanne M. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an international normalized ratio above 2.0. Blood Coagul Fibrinolysis 1998;9:741–748.PubMedCrossRefGoogle Scholar
  11. 11.
    Erhardtsen E. Pharmacokinetics of recombinant activated factor VII. Semin Thromb Hemost 2000;26:385–391.PubMedCrossRefGoogle Scholar
  12. 12.
    Erhardtsen E. Ongoing Novoseven trials. Intensive Care Med 2002;28:S248-S255.PubMedCrossRefGoogle Scholar
  13. 13.
    Friederich PW, Geerdink MG, Spataro M, et al. The effect of 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 1):S129-S132.PubMedGoogle Scholar
  14. 14.
    Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke 1998;29:1160–1166.PubMedGoogle Scholar
  15. 15.
    Galan AM, Tonda R, Altisent C, et al. Recombinant factor VIIa (NovoSeven) restores deficient coagulation: experience from an ex vivo model. Semin Hematol 2001;38(Suppl 12):10–14.PubMedCrossRefGoogle Scholar
  16. 16.
    Gerlach R, Marquardt G, Wissing H, et al. Application of recombinant activated factor VII during surgery for a giant skull base hemangiopericytoma to achieve safe hemostasis. J Neurosurg 2002;96:946–948.PubMedGoogle Scholar
  17. 17.
    Grossmann RE, Geisen U, Schwender S, Keller F. Continuous infusion of recombinant Factor VIIa (NovoSeven) in the treatment of a patient with Type III von Willebrand’s disease and alloantibodies against von Willebrand factor. Thromb Haemost 2000(letter);83:633–634.PubMedGoogle Scholar
  18. 18.
    Hedner U, Schulman S, Alberts KA, et al. Successful use of rFVIIa in a patient with severe haemophilia A subjected to synovectomy. Lancet 1988;2:1193.PubMedCrossRefGoogle Scholar
  19. 19.
    Hedner U. Dosing and monitoring NovoSeven treatment. Haemostasis 1996;26(Suppl 1):102–108.PubMedGoogle Scholar
  20. 20.
    Hedner U. Recombinant activated factor VII as a universal hemostatic agent. Blood Coagul Fibrinolysis 1998;9(Suppl 1):S147-S152.PubMedGoogle Scholar
  21. 21.
    Hendriks HG, Meijer K, de Wolf JT, et al. Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study. Transplantation 2001;71:402–405.PubMedCrossRefGoogle Scholar
  22. 22.
    Hendriks HG, van der Maaten JM, de Wolf J, et al. An effective treatment of severe intractable bleeding after valve repair by one single dose of activated recombinant factor VII. Anesth Analg 2001;93:287–289.PubMedCrossRefGoogle Scholar
  23. 23.
    Hoffman M, Monroe DM III, Roberts HR. Activated factor VII activates factors IX and X on the service of activated platelets: thoughts on the mechanism of action of high-dose activated factor VII. Blood Coagul Fibrinolysis 1998;9(Suppl 1):S61-S65.PubMedGoogle Scholar
  24. 24.
    Ingerslev J, Freidman D, Gastineau D, et al. Major surgery in haemophilic patients with inhibitors using recombinant factor VIIa. Haemostasis 1996;26(Suppl 1):118–123.PubMedGoogle Scholar
  25. 25.
    Ingerslev J. Efficacy and safety of recombinant factor VIIa in the prophylaxis of bleeding in various surgical procedures in hemophilic patients with factor VIII and factor IX inhibitors. Semin Thromb Hemost 2000;26:425–432.PubMedCrossRefGoogle Scholar
  26. 26.
    Jurlander B, Thim L, Klausen NK. Recombinant activated factor VII (rFVIIa): Characterization, manufacturing, and clinical development. Semin Thromb Hemost 2001;27:373–383.PubMedCrossRefGoogle Scholar
  27. 27.
    Kawamata T, Takeshita M, Kubo O. Management of intracranial hemorrhage associated with anticoagulation therapy. Surg Neurol 1995; 44: 438–443.PubMedCrossRefGoogle Scholar
  28. 28.
    Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage: incidence and time course. Stroke 1996;27:1783–1787.PubMedGoogle Scholar
  29. 29.
    Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet 1999;354:1879.PubMedCrossRefGoogle Scholar
  30. 30.
    Kohler M, Hellstern P, Lechler E, Uberfuhr P, Muller-Berghaus G. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost 1998;80:399–402.PubMedGoogle Scholar
  31. 31.
    Kristensen J, Killander A, Hippe E, et al. Clinical experience with recombinant factor VIIa in patients with thrombocytopenia. Haemostasis 1996;26(Suppl 1):159–164.PubMedGoogle Scholar
  32. 32.
    Laffan MA, Cummins M. Recombinant factor VIIa for intractable surgical bleeding. Blood 2000;96(Suppl 1, Abstract 4048):85b.Google Scholar
  33. 33.
    Leach M, Makris M, Hampton KK, Preston FE. Spinal epidural haematoma in haemophilia A with inhibitors-efficacy of recombinant factor VIIa concentrate. Haemophilia 1999;5:209–212.PubMedCrossRefGoogle Scholar
  34. 34.
    Lin J, Hanigan WC, Tarantino M, Wang J. The use of recombinant activated factor VII to reverse warfarin-induced anticoagulation in patients with hemorrhages in the central nervous system: preliminary findings. J Neurosurg 2003;98:737–740.PubMedGoogle Scholar
  35. 35.
    Majumdar G, Phillips JK, Lavallee H, Savidge GF. Acquired haemophilia in association with type III von Willebrand’s disease: successful treatment with high purity von Willebrand’s factor and recombinant factor VIIa. Blood Coagul Fibrinolysis 1993;4:1035–1037.PubMedGoogle Scholar
  36. 36.
    Martinowitz U, Kenet G, Segal E, et al. Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma 2001;51:431–439.PubMedGoogle Scholar
  37. 37.
    Mathiesen T, Benediktsdottir K, Lindqvist M, von Holst H. Intracranial traumatic and non-traumatic hemorrhagic complications of warfarin treatment. Acta Neurol Scand 1995;91:208–214.PubMedCrossRefGoogle Scholar
  38. 38.
    Mayer SA. Intracerebral hemorrhage: natural history and rationale of ultra-early hemostatic therapy. Intensive Care Med 2002;28:S235-S240.PubMedCrossRefGoogle Scholar
  39. 39.
    McPherson J, Teague L, Lloyd J, et al. Experience with recombinant factor VIIa in Australia and New Zealand. Haemostasis 1996;26(Suppl 1):109–117.PubMedGoogle Scholar
  40. 40.
    Mindikoglu AL, Anantharaju A, George M, et al. Acute intracranial hemorrhage in a cirrhotic controlled with recombinant factor VIIa. Dig Dis Sci 2003;48:1130–1135.PubMedCrossRefGoogle Scholar
  41. 41.
    Morenski JD, Tobias JD, Jimenez DF. Recombinant activated factor VII for cerebral injury-induced coagulopathy in pediatric patients. J Neurosurg 2003;98:611–613.PubMedGoogle Scholar
  42. 42.
    Negrier C, Lienhart A. Overall experience with NovoSeven. Blood Coagul Fibrinolysis 2000; 11 (Suppl 1): S19-S24.PubMedGoogle Scholar
  43. 43.
    Oertel M, Kelly DE, McArthur D, et al. Progressive hemorrhage after head trauma: predictors and consequences of the evolving injury. J Neurosurg 2002;96:109–116.PubMedGoogle Scholar
  44. 44.
    O’Neill PA, Bluth M, Gloster ES, et al. Successful use of recombinant activated factor VII for trauma-associated hemorrhage in a patient without preexisting coagulopathy. J Trauma 2002;52:400–405.PubMedGoogle Scholar
  45. 45.
    Park P, Fewel ME, Garton HJ, Thompson BG, Hoff JT. Recombinant activated factor VII for the rapid correction of coagulopathy in non-hemophilic neurosurgical patients. Neurosurgery 2003;53:34–39.PubMedCrossRefGoogle Scholar
  46. 46.
    Peerlinck K, Vermylen J. Acute myocardial infarction following administration of recombinant activated factor VII (NovoSeven) in a patient with haemophilia A and inhibitor. Thromb Haemost 1999;82:1775–1776.PubMedGoogle Scholar
  47. 47.
    Peters M, Heijboer H. Treatment of a patient with Bernard-Soulier syndrome and recurrent nosebleeds with recombinant factor VIIa. Thromb Haemost 1998;80:352.PubMedGoogle Scholar
  48. 48.
    Pickard JD, Kirkpatrick PJ, Melsen T, et al. Potential role of Novoseven in the prevention of rebleeding following aneurysmal subarachnoid hemorrhage. Blood Coagul Fibrinolysis 2000;11(Suppl 1):S117-S120.PubMedGoogle Scholar
  49. 49.
    Poon MC, d’Oiron R, Hann I, et al. Use of recombinant factor VIIa (NovoSeven) in patients with Glanzmann thrombasthenia. Semin Hematol 2001;38(4 Suppl 12):21–25.PubMedCrossRefGoogle Scholar
  50. 50.
    Rice KM, Savidge GF. NovoSeven (recombinant factor VIIa) in central nervous system bleeds. Haemostasis 1996;26(Suppl 1):131–134.PubMedGoogle Scholar
  51. 51.
    Roberts HR. Recombinant factor VIIa (NovoSeven) and the safety of treatment. Semin Hematol 2001;38(Suppl 12):48–50.PubMedCrossRefGoogle Scholar
  52. 52.
    Roos Y, Rinkel G, Vermeulen M, Algra A, van Gijn J. Antifibrinolytic therapy for aneurysmal subarachnoid hemorrhage: a major update of a cochrane review. Stroke 2003;34:2308–2309.PubMedCrossRefGoogle Scholar
  53. 53.
    Rosenfeld SB, Watkinson KK, Thompson BH, Macfarlane DE, Lentz SR. Pulmonary embolism after sequential use of recombinant factor VIIa and activated prothrombin complex concentrate in a factor VIII inhibitor patient. Thromb Haemost 2002;87:925–926.PubMedGoogle Scholar
  54. 54.
    Schmidt ML, Gamerman S, Smith HE, Scott JP, DiMichele DM. Recombinant activated factor VII (rFVIIa) therapy for intracranial hemorrhage in hemophilia A patients with inhibitors. Am J Hematol 1994;47:36–40.PubMedCrossRefGoogle Scholar
  55. 55.
    Shapiro AD, Gilchrist GS, Hoots WK, Cooper HA, Gastineau DA. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost 1998;80:773–778.PubMedGoogle Scholar
  56. 56.
    Shapiro AD. Recombinant Factor VIIa in the treatment of bleeding in hemophilic children with inhibitors. Semin Thromb Hemost 2000;26:413–419.PubMedCrossRefGoogle Scholar
  57. 57.
    Sorensen B, Johansen P, Nielsen GL, Sorensen JC, Ingerslev J. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003;14:469–477.PubMedCrossRefGoogle Scholar
  58. 58.
    Stein SF, Duncan A, Cutler D, Glazer S. Disseminated intravascular coagulation (DIC) in a hemophiliac treated with recombinant factor VIIa (Abstract). Blood 1990;76(Suppl):438a.Google Scholar
  59. 59.
    Tengborn L, Petruson B. A patient with Glanzmann thrombasthenia and epistaxis successfully treated with recombinant factor VIIa. Thromb Haemost 1996;75:981–982.PubMedGoogle Scholar
  60. 60.
    Thurman DJ, Alverson C, Dunn KA, Guerrero J, Sniezek JE. Traumatic brain injury in the United States: A public health perspective. J Head Trauma Rehabil 1999;14:602–615.PubMedGoogle Scholar
  61. 61.
    Tobias JD. Synthetic factor VIIa to treat dilutional coagulopathy during posterior spinal fusion in two children. Anesthesiology 2002;96:1522–1525.PubMedCrossRefGoogle Scholar
  62. 62.
    Van Buuren HR, Wielenga JJ. Successful surgery using recombinant factor VIIa for recurrent, idiopathic nonulcer duodenal bleeding in a patient with Glanzmann’s thrombasthenia. Dig Dis Sci 2002;47:2134–2136.PubMedCrossRefGoogle Scholar
  63. 63.
    Veshchev I, Elran H, Salame K. Recombinant coagulation factor VIIa for rapid preoperative correction of warfarin-related coagulopathy in patients with acute subdural hematoma. Med Sci Monit 2002;8:CS98-CS100.PubMedGoogle Scholar
  64. 64.
    Vidarsson B, Onundarson PT. Recombinant factor VIIa for bleeding in refractory thrombocytopenia. Thromb Haemost 2000;83:634–635.PubMedGoogle Scholar
  65. 65.
    White B, McHale J, Ravi N, et al. Successful use of recombinant FVIIa (NovoSeven) in the management of intractable post-surgical intra-abdominal hemorrhage. Br J Hematol 1999;107:677–678.CrossRefGoogle Scholar
  66. 66.
    Wong WY, Huang WC, Miller R. Clinical efficacy and recovery levels of recombinant FVIIa (NovoSeven) in the treatment of intracranial hemorrhage in severe neonatal FVIIa deficiency. Haemophilia 2000;6:50–54.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2004

Authors and Affiliations

  1. 1.Department of NeurosurgeryUniversity of Michigan Health SystemAnn Arbor

Personalised recommendations