Recombinant Activated Factor VII: Mechanisms of Action and Current Indications

 

 Buy Article Permissions and Reprints

ABSTRACT

Recombinant activated factor VII (rFVIIa) was initially developed to overcome the limitations of existing treatments for patients with congenital hemophilia and inhibitors. Clinical success in this arena led to experimental use in other coagulopathies characterized by impaired thrombin generation, and approval for use in acquired hemophilia, factor VII deficiency, and Glanzmann's thrombasthenia soon followed. Extensive research and growing experience in the clinical setting has increased our knowledge of rFVIIa and improved our understanding of how its mechanism of action leads to effective bleeding control. This article reviews current understanding of the mechanisms of action of rFVIIa before providing a brief overview of clinical experience to date in its licensed indications. The agent's safety profile is also examined, along with recent advances in rFVIIa dosing and storage that may help to improve both clinical outcomes and patient quality of life.

REFERENCES

• 1 Sjamsoedin L J, Heijnen L, Mauser-Bunschoten E P et al.. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. A double-blind clinical trial.  N Engl J Med. 1981;  305(13) 717-721
  CrossrefPubMedGoogle Scholar
• 2 Young G, Shafer F E, Rojas P, Seremetis S. Single 270 microg kg(-1)-dose rFVIIa vs. standard 90 microg kg(-1)-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison.  Haemophilia. 2008;  14(2) 287-294
  CrossrefPubMedGoogle Scholar
• 3 Lusher J M. Thrombogenicity associated with factor IX complex concentrates.  Semin Hematol. 1991;  28(3, Suppl 6) 3-5
  PubMedGoogle Scholar
• 4 Rapaport S I, Rao L V. Initiation and regulation of tissue factor-dependent blood coagulation.  Arterioscler Thromb. 1992;  12(10) 1111-1121
  CrossrefPubMedGoogle Scholar
• 5 Hedner U, Nilsson I M, Bergentz S E. Studies on the thrombogenic activities in two prothrombin complex concentrates.  Thromb Haemost. 1979;  42(3) 1022-1032
  PubMedGoogle Scholar
• 6 Hedner U, Kisiel W. Use of human factor VIIa in the treatment of two hemophilia A patients with high-titer inhibitors.  J Clin Invest. 1983;  71(6) 1836-1841
  CrossrefPubMedGoogle Scholar
• 7 Kisiel W. Recollections on the discovery of factor VIIa as a novel therapeutic agent for hemophiliacs with inhibitors.  J Thromb Haemost. 2009;  7(7) 1053-1056
  CrossrefPubMedGoogle Scholar
• 8 Hedner U. Factor VIIa and its potential therapeutic use in bleeding-associated pathologies.  Thromb Haemost. 2008;  100(4) 557-562
  PubMedGoogle Scholar
• 9 Hoffman M. A cell-based model of coagulation and the role of factor VIIa.  Blood Rev. 2003;  17(Suppl 1) S1-S5
  CrossrefPubMedGoogle Scholar
• 10 Monroe D M, Hoffman M, Roberts H R. Platelets and thrombin generation.  Arterioscler Thromb Vasc Biol. 2002;  22(9) 1381-1389
  CrossrefPubMedGoogle Scholar
• 11 Monroe D M, Hoffman M, Oliver J A, Roberts H R. Platelet activity of high-dose factor VIIa is independent of tissue factor.  Br J Haematol. 1997;  99(3) 542-547
  CrossrefPubMedGoogle Scholar
• 12 Lisman T, Mosnier L O, Lambert T et al.. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A.  Blood. 2002;  99(1) 175-179
  CrossrefPubMedGoogle Scholar
• 13 He S, Blombäck M, Jacobsson Ekman G, Hedner U. The role of recombinant factor VIIa (FVIIa) in fibrin structure in the absence of FVIII/FIX.  J Thromb Haemost. 2003;  1(6) 1215-1219
  CrossrefPubMedGoogle Scholar
• 14 Battistella L R. Maintenance of musculoskeletal function in people with haemophilia.  Haemophilia. 1998;  4(Suppl 2) 26-32
  PubMedGoogle Scholar
• 15 Hedner U, Brun N C. Recombinant factor VIIa (rFVIIa): its potential role as a hemostatic agent.  Neuroradiology. 2007;  49(10) 789-793
  CrossrefPubMedGoogle Scholar
• 16 Key N S, Aledort L M, Beardsley D et al.. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors.  Thromb Haemost. 1998;  80(6) 912-918
  PubMedGoogle Scholar
• 17 Lloyd Jones M, Wight J, Paisley S, Knight C. Control of bleeding in patients with haemophilia A with inhibitors: a systematic review.  Haemophilia. 2003;  9(4) 464-520
  CrossrefPubMedGoogle Scholar
• 18 Levi M, Peters M, Büller H R. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review.  Crit Care Med. 2005;  33(4) 883-890
  CrossrefPubMedGoogle Scholar
• 19 Lusher J M. Recombinant factor VIIa (NovoSeven) in the treatment of internal bleeding in patients with factor VIII and IX inhibitors.  Haemostasis. 1996;  26(Suppl 1) 124-130
  PubMedGoogle Scholar
• 20 Scharrer I. Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency.  Haemophilia. 1999;  5(4) 253-259
  CrossrefPubMedGoogle Scholar
• 21 Liebman H A, Chediak J, Fink K I, Galvez A G, Shah P C, Sham R L. Activated recombinant human coagulation factor VII (rFVIIa) therapy for abdominal bleeding in patients with inhibitory antibodies to factor VIII.  Am J Hematol. 2000;  63(3) 109-113
  CrossrefPubMedGoogle Scholar
• 22 Arkin S, Cooper H A, Hutter J J 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(2) 93-98
  CrossrefPubMedGoogle Scholar
• 23 Knight C, Danø A M, Kennedy-Martin T. Systematic review of efficacy of rFVIIa and aPCC treatment for hemophilia patients with inhibitors.  Adv Ther. 2009;  26(1) 68-88
  CrossrefPubMedGoogle Scholar
• 24 Treur M J, McCracken F, Heeg B et al.. Efficacy of recombinant activated factor VII vs. activated prothrombin complex concentrate for patients suffering from haemophilia complicated with inhibitors: a Bayesian meta-regression.  Haemophilia. 2009;  15(2) 420-436
  CrossrefPubMedGoogle Scholar
• 25 Holme P A, Glomstein A, Grønhaug S, Tjønnfjord G E. Home treatment with bypassing products in inhibitor patients: a 7.5-year experience.  Haemophilia. 2009;  15(3) 727-732
  CrossrefPubMedGoogle Scholar
• 26 Santagostino E, Gringeri A, Mannucci P M. Home treatment with recombinant activated factor VII in patients with factor VIII inhibitors: the advantages of early intervention.  Br J Haematol. 1999;  104(1) 22-26
  CrossrefPubMedGoogle Scholar
• 27 Salaj P, Brabec P, Penka M et al.. Effect of rFVIIa dose and time to treatment on patients with haemophilia and inhibitors: analysis of HemoRec registry data from the Czech Republic.  Haemophilia. 2009;  15(3) 752-759
  CrossrefPubMedGoogle Scholar
• 28 Kavakli K, Makris M, Zulfikar B, Erhardtsen E, Abrams Z S, Kenet G. NovoSeven trial (F7HAEM-1510) investigators . Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial.  Thromb Haemost. 2006;  95(4) 600-605
  PubMedGoogle Scholar
• 29 Santagostino E, Mancuso M E, Rocino A, Mancuso G, Scaraggi F, Mannucci P M. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors.  J Thromb Haemost. 2006;  4(2) 367-371
  CrossrefPubMedGoogle Scholar
• 30 Pan-Petesch B, Laguna P, Mital A et al.. Single-dose (270 microg kg(-1)) recombinant activated factor VII for the treatment and prevention of bleeds in haemophilia A patients with inhibitors: experience from seven European haemophilia centres.  Haemophilia. 2009;  15(3) 760-765
  CrossrefPubMedGoogle Scholar
• 31 Shapiro A D. Single-dose recombinant activated factor VII for the treatment of joint bleeds in hemophilia patients with inhibitors.  Clin Adv Hematol Oncol. 2008;  6(8) 579-586
  PubMedGoogle Scholar
• 32 Kenet G, Martinowitz U. Single-dose recombinant activated factor VII therapy in hemophilia patients with inhibitors.  Semin Hematol. 2008;  45(2, Suppl 1) S38-S41
  CrossrefPubMedGoogle Scholar
• 33 Hvid I, Rodriguez-Merchan E C. Orthopaedic surgery in haemophilic patients with inhibitors: an overview.  Haemophilia. 2002;  8(3) 288-291
  CrossrefPubMedGoogle Scholar
• 34 Obergfell A, Auvinen M K, Mathew P. Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the literature.  Haemophilia. 2008;  14(2) 233-241
  CrossrefPubMedGoogle Scholar
• 35 Hedner U, Glazer S, Pingel K et al.. Successful use of recombinant factor VIIa in patient with severe haemophilia A during synovectomy.  Lancet. 1988;  2(8621) 1193
  PubMedGoogle Scholar
• 36 Giangrande P L, Wilde J T, Madan B et al.. Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven] in elective orthopaedic surgery in haemophilic patients with inhibitors.  Haemophilia. 2009;  15(2) 501-508
  CrossrefPubMedGoogle Scholar
• 37 Bysted B V, Scharling B, Møller T, Hansen B L. A randomized, double-blind trial demonstrating bioequivalence of the current recombinant activated factor VII formulation and a new robust 25 degrees C stable formulation.  Haemophilia. 2007;  13(5) 527-532
  CrossrefPubMedGoogle Scholar
• 38 Mathew P, Cooper D, Bjerre J. Room temperature stable recombinant activated factor VII: implications for patients, physicians, hospitals and formulary decision makers.  Manag Care Interface. 2008;  21(3) 8-13
  PubMedGoogle Scholar
• 39 Sumner M J, Geldziler B D, Pedersen M, Seremetis S. Treatment of acquired haemophilia with recombinant activated FVII: a critical appraisal.  Haemophilia. 2007;  13(5) 451-461
  CrossrefPubMedGoogle Scholar
• 40 Huth-Kühne A, Baudo F, Collins P et al.. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A.  Haematologica. 2009;  94(4) 566-575
  CrossrefPubMedGoogle Scholar
• 41 Franchini M, Lippi G. Acquired factor VIII inhibitors.  Blood. 2008;  112(2) 250-255
  CrossrefPubMedGoogle Scholar
• 42 Hay C R, Negrier C, Ludlam C A. The treatment of bleeding in acquired haemophilia with recombinant factor VIIa: a multicentre study.  Thromb Haemost. 1997;  78(6) 1463-1467
  PubMedGoogle Scholar
• 43 Baudo F, de Cataldo F, Gaidano G. Italian registry of acquired hemophilia . Treatment of acquired factor VIII inhibitor with recombinant activated factor VIIa: data from the Italian registry of acquired hemophilia.  Haematologica. 2004;  89(6) 759-761
  PubMedGoogle Scholar
• 44 Lak M, Sharifian R A, Karimi K, Mansouritorghabeh H. Acquired hemophilia A: clinical features, surgery and treatment of 34 cases, and experience of using recombinant factor VIIa.  Clin Appl Thromb Hemost. 2009 February 11;  , (Epub ahead of print)
  PubMedGoogle Scholar
• 45 Baudo F, Collins P, Huth-Kühne A et al.. Hemostatic therapy in acquired haemophilia: data from the European Acquired Haemophilia (EACH2) registry.  J Thromb Haemost. 2009;  7(Suppl 2) 1-316 , Abstract OC-WE-058. Abstract presented at the XXII Congress of the International Society of Thrombosis and Haemostasis; July 11–16, 2009; Boston, MA
  PubMedGoogle Scholar
• 46 Mariani G, Bernardi F. Factor VII deficiency.  Semin Thromb Hemost. 2009;  35(4) 400-406
  Article in Thieme ConnectPubMedGoogle Scholar
• 47 Mariani G, Konkle B A, Ingerslev J. Congenital factor VII deficiency: therapy with recombinant activated factor VII—a critical appraisal.  Haemophilia. 2006;  12(1) 19-27
  CrossrefPubMedGoogle Scholar
• 48 Poon M C, Zotz R, Di Minno G, Abrams Z S, Knudsen J B, Laurian Y. Glanzmann's thrombasthenia treatment: a prospective observational registry on the use of recombinant human activated factor VII and other hemostatic agents.  Semin Hematol. 2006;  43(1, suppl 1) S33-S36
  CrossrefPubMedGoogle Scholar
• 49 Kannan M, Saxena R. Glanzmann's thrombasthenia: an overview.  Clin Appl Thromb Hemost. 2009;  15(2) 152-165
  CrossrefPubMedGoogle Scholar
• 50 Chuansumrit A, Sangkapreecha C, Hathirat P. Successful epistaxis control in a patient with Glanzmann thrombasthenia by increased bolus injection dose of recombinant factor VIIa.  Thromb Haemost. 1999;  82(6) 1778
  PubMedGoogle Scholar
• 51 Tengborn L, Petruson B. A patient with Glanzmann thrombasthenia and epistaxis successfully treated with recombinant factor VIIa.  Thromb Haemost. 1996;  75(6) 981-982
  PubMedGoogle Scholar
• 52 Poon M C, Demers C, Jobin F, Wu J W. Recombinant factor VIIa is effective for bleeding and surgery in patients with Glanzmann thrombasthenia.  Blood. 1999;  94(11) 3951-3953
  PubMedGoogle Scholar
• 53 d'Oiron R, Ménart C, Trzeciak M C et al.. Use of recombinant factor VIIa in 3 patients with inherited type I Glanzmann's thrombasthenia undergoing invasive procedures.  Thromb Haemost. 2000;  83(5) 644-647
  PubMedGoogle Scholar
• 54 Poon M C, D'Oiron R, Von Depka M International Data Collection on Recombinant Factor VIIa and Congenital Platelet Disorders Study Group et al. Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann's thrombasthenia: results of an international survey.  J Thromb Haemost. 2004;  2(7) 1096-1103
  CrossrefPubMedGoogle Scholar
• 55 Almeida A M, Khair K, Hann I, Liesner R. The use of recombinant factor VIIa in children with inherited platelet function disorders.  Br J Haematol. 2003;  121(3) 477-481
  CrossrefPubMedGoogle Scholar
• 56 Abshire T. Safety update on recombinant factor VIIa in the treatment of congenital and acquired hemophilia.  Semin Hematol. 2008;  45(2, Suppl 1) S3-S6
  CrossrefPubMedGoogle Scholar
• 57 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(6) 899-909
  CrossrefPubMedGoogle Scholar
• 58 Kavakli K, Yesilipek A, Antmen B et al.. The value of early treatment in patients with haemophilia and inhibitors.  J Thromb Haemost. 2009;  7(Suppl 2) 317-1168 , Abstract PP-MO-606. Abstract presented at the XXII Congress of the International Society of Thrombosis and Haemostasis; July 11–16, 2009; Boston, MA, USA
  CrossrefPubMedGoogle Scholar
• 59 Lyseng-Williamson K A, Plosker G L. Recombinant factor VIIa (eptacog alfa): a pharmacoeconomic review of its use in haemophilia in patients with inhibitors to clotting factors VIII or IX.  Pharmacoeconomics. 2007;  25(12) 1007-1029
  CrossrefPubMedGoogle Scholar
• 60 Knight C, Danø A M, Kennedy-Martin T. A systematic review of the cost-effectiveness of rFVIIa and APCC in the treatment of minor/moderate bleeding episodes for haemophilia patients with inhibitors.  Haemophilia. 2009;  15(2) 405-419
  CrossrefPubMedGoogle Scholar

Massimo FranchiniM.D. 

Director, Servizio di Immunoematologia e Medicina Trasfusionale, Dipartimento di Patologia e Medicina di Laboratorio

Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

Email: massimo.franchini@azosp.vr.it