Recombinant Activated Factor VII: Mechanisms of Action and Current Indications

Massimo Franchini; Giuseppe Lippi

doi:10.1055/s-0030-1255442

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2010; 36(5): 485-492
DOI: 10.1055/s-0030-1255442

Recombinant Activated Factor VII: Mechanisms of Action and Current Indications

Massimo Franchini¹ , Giuseppe Lippi²

¹Servizio di Immunoematologia e Medicina Trasfusionale, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
²Laboratorio di Analici Chimico-Cliniche, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

Abstract

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.

KEYWORDS

NovoSeven - FVII deficiency - Glanzmann's thrombasthenia - hemophilia - recombinant activated FVII - rFVIIa

Full Text

References

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
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
3 Lusher J M. Thrombogenicity associated with factor IX complex concentrates. Semin Hematol. 1991; 28(3, Suppl 6) 3-5
4 Rapaport S I, Rao L V. Initiation and regulation of tissue factor-dependent blood coagulation. Arterioscler Thromb. 1992; 12(10) 1111-1121
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
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
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
8 Hedner U. Factor VIIa and its potential therapeutic use in bleeding-associated pathologies. Thromb Haemost. 2008; 100(4) 557-562
9 Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood Rev. 2003; 17(Suppl 1) S1-S5
10 Monroe D M, Hoffman M, Roberts H R. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol. 2002; 22(9) 1381-1389
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
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
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
14 Battistella L R. Maintenance of musculoskeletal function in people with haemophilia. Haemophilia. 1998; 4(Suppl 2) 26-32
15 Hedner U, Brun N C. Recombinant factor VIIa (rFVIIa): its potential role as a hemostatic agent. Neuroradiology. 2007; 49(10) 789-793
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
33 Hvid I, Rodriguez-Merchan E C. Orthopaedic surgery in haemophilic patients with inhibitors: an overview. Haemophilia. 2002; 8(3) 288-291
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
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
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
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
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
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
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
41 Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood. 2008; 112(2) 250-255
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
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
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)
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
46 Mariani G, Bernardi F. Factor VII deficiency. Semin Thromb Hemost. 2009; 35(4) 400-406
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
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
49 Kannan M, Saxena R. Glanzmann's thrombasthenia: an overview. Clin Appl Thromb Hemost. 2009; 15(2) 152-165
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
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
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
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
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
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
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
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
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
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
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

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