Mechanism of Action of Factor VIIa in the Treatment of Coagulopathies

ABSTRACT

Recombinant factor VIIa (rFVIIa) has been developed for treatment of bleeding in patients with hemophilia who have inhibitors against factor VIII (FVIII) or FIX, and has been found to induce hemostasis during major orthopedic surgery. The use of rFVIIa treatment for hemophilia is a new concept and is based on the low-affinity binding of FVIIa to the surface of thrombin-activated platelets. Administration of pharmacologic doses of exogenous rFVIIa enhances thrombin generation on the platelet surface at the site of injury independently of the presence of FVIII or FIX. Pharmacologic doses of rFVIIa induce hemostasis not only in hemophilia patients, but also in patients with thrombocytopenia, functional platelet defects, and with profuse bleeding triggered by extensive surgery or trauma. The general mechanism of action of rFVIIa to induce hemostasis under these conditions may be its capacity to generate a tight fibrin hemostatic plug through increased thrombin generation. A tight fibrin plug will aid in resisting the overwhelming local release of fibrinolytic activity triggered by vast tissue damage occurring in extensive trauma. Local fibrinolytic activity also occurs in the gastrointestinal tract as well as during profuse postpartum bleeding. Pharmacologic doses of rFVIIa induce hemostasis in these cases also.

KEYWORDS

Recombinant factor VIIa - hemophilia - bleeding disorders - thrombin generation - posttraumatic bleeding

REFERENCES

• 1 Lusher J M, Blatt P M, Penner J A et al.. Autoplex versus proplex: a controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII.  Blood. 1983;  62 1135-1138
• 2 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;  305 717-721
• 3 Lusher J M. Thrombogenicity associated with factor IX complex concentrates.  Semin Hematol. 1991;  28 3-5
• 4 Ohga S, Saito M, Matsukazi A, Kai T, Ueda K. Disseminated intravascular coagulation in a patient with haemophilia B during factor IX replacement therapy.  Br J Haematol. 1993;  84 343-345
• 5 Hedner U, Nilsson I M, Bergentz S E. Studies on the thrombogenic activities in two prothrombin complex concentrates.  Thromb Haemost. 1979;  42 1022-1032
• 6 Hedner U, Bjoern S, Bernvil S S, Tengborn L, Stigendahl L. Clinical experience with human plasma-derived factor VIIa in patients with hemophilia A and high titer inhibitors.  Haemostasis. 1989;  19 335-343
• 7 Thim L, Bjoern S, Christensen M et al.. Amino acid sequence and posttranslational modifications of human factor VIIa from plasma and transfected baby hamster kidney cells.  Biochemistry. 1988;  27 7785-7793
• 8 Hagen F S, Gray C L, O'Hara P et al.. Characterization of a cDNA coding for human factor VII.  Proc Natl Acad Sci USA. 1986;  83 2412-2416
• 9 Bjoern S, Foster D C, Thim L et al.. Human plasma and recombinant factor VII. Characterization of O-glycosylations at serine residues 52 and 60 and effects of site-directed mutagenesis of serine 52 to alanine.  J Biol Chem. 1991;  266 11051-11057
• 10 Beeby T L, Chasseaud L F, Taylor T, Thomsen M K. Distribution of the recombinant coagulation factor 125I-rFVIIa in rats.  Thromb Haemost. 1993;  70 465-468
• 11 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;  2 899-909
• 12 Glazer S, Hedner U, Falch J F. Clinical update on the use of recombinant factor VII.  Adv Exp Med Biol. 1995;  386 163-174
• 13 Lusher J, Ingerslev J, Roberts H, Hedner U. Clinical experience with recombinant factor VIIa.  Blood Coagul Fibrinolysis. 1998;  9 119-128
• 14 Shapiro A D, Gilchrist G S, Hoots W K, Cooper H A, Gastineau D A. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery.  Thromb Haemost. 1998;  80 773-778
• 15 Hedner U, Ingerslev J. Clinical use of recombinant FVIIa (rFVIIa).  Transfus Sci. 1998;  19 163-176
• 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;  80 912-918
• 17 Monroe D M, Hoffman M, Roberts H R. Platelets and thrombin generation.  Arterioscler Thromb Vasc Biol. 2002;  22 1381-1389
• 18 Monroe D M, Hoffman M, Roberts H R. Transmission of a procoagulant signal from tissue factor-bearing cell to platelets.  Blood Coagul Fibrinolysis. 1996;  7 459-464
• 19 Wildgoose P, Nemerson Y, Hansen L L et al.. Measurement of basal levels of factor VIIa in hemophilia A and B patients.  Blood. 1992;  80 25-28
• 20 Rapaport S I, Rao L V. Initiation and regulation of tissue factor-dependent blood coagulation.  Arterioscler Thromb. 1992;  12 1111-1121
• 21 Giesen P L, Rauch U, Bohrmann B et al.. Blood-borne tissue factor: another view of thrombosis.  Proc Natl Acad Sci USA. 1999;  96 2311-2315
• 22 Chen V MY, Ruf W, Hogg P J. Mechanism of activiation of tissue factor.  J Thromb Haemost. 2005;  3 OR075 , (abstr)
• 23 Kempton C L, Hoffman M, Roberts H R, Monroe D M. Platelet heterogeneity: variation in coagulation complexes on platelet subpopulations.  Arterioscler Thromb Vasc Biol. 2005;  25 861-866
• 24 Allen G A, Monroe D M, Roberts H R, Hoffman M. The effect of Factor 7 level on thrombin generation and the procoagulant effect of activated factor VII in a cell-based model of coagulation.  Blood Coagul Fibrinolysis. 2000;  11(suppl 1) S3-S7
• 25 Koenig W. Fibrin(ogen) in cardiovascular disease: an update.  Thromb Haemost. 2003;  89 601-609
• 26 Okada M, Blombäck B. Factors influencing fibrin gel structure studied by flow measurement.  Ann N Y Acad Sci. 1983;  408 233-253
• 27 Blombäck B. Fibrinogen structure, activation, polymerization and fibrin gel structure.  Thromb Res. 1994;  75 327-328
• 28 Carr Jr M E, Alving B M. Effect of fibrin structure on plasmin-mediated dissolution of plasma clots.  Blood Coagul Fibrinolysis. 1995;  6 567-573
• 29 He S, Blombäck M, Jacobsson E G, Hedner U. The role of recombinant factor VIIa (FVIIa) in fibrin structure in the absence of FVIII/FIX.  J Thromb Haemost. 2003;  1 1215-1219
• 30 Gabriel D A, Muga K, Boothroyd E M. The effect of fibrin structure on fibrinolysis.  J Biol Chem. 1992;  267 24259-24263
• 31 Collet J P, Lesty C, Montalescot G, Weisel J W. Dynamic changes of fibrin architecture during fibrin formation and intrinsic fibrinolysis of fibrin-rich clots.  J Biol Chem. 2003;  278 21331-21335
• 32 Bajzar L, Manuel R, Nesheim M E. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor.  J Biol Chem. 1995;  270 14477-14484
• 33 Broze Jr G J, Higuchi D A. Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma.  Blood. 1996;  88 3815-3823
• 34 Von dem Borne P A, Bajzar L, Meijers J C, Nesheim M E, Bouma B N. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis.  J Clin Invest. 1997;  99 2323-2327
• 35 Bauer K A, Mannucci P M, Gringeri A et al.. Factor IXa-factor VIIIa-cell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo.  Blood. 1992;  79 2039-2047
• 36 Hedner U, Erhardtsen E. Potential role of recombinant factor VIIa as a hemostatic agent.  Clin Adv Hematol Oncol. 2003;  1 112-119
• 37 Dvorak H F, Brown L F, Detmar M, Dvorak A M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.  Am J Pathol. 1995;  146 1029-1039
• 38 Le D T, Borgs P, Toneff T W, Witte M H, Rapaport S I. Hemostatic factors in rabbit limb lymph: relationship to mechanisms regulating extravascular coagulation.  Am J Physiol. 1998;  274 H769-H776
• 39 Wilcox J N, Smith K M, Schwartz S M, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque.  Proc Natl Acad Sci USA. 1989;  86 2839-2843
• 40 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;  99 542-547
• 41 Kjalke M, Ezban M, Monroe D M et al.. High-dose factor VIIa increases initial thrombin generation and mediates faster platelet activation in thrombocytopenia-like conditions in a cell-based model system.  Br J Haematol. 2001;  114 114-120
• 42 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;  99 175-179
• 43 Lisman T, de Groot P G, Lambert T, Røjkjaer R, Persson E. Enhanced in vitro procoagulant and antifibrinolytic potential of superactive variants of recombinant factor VIIa in severe hemophilia A.  J Thromb Haemost. 2003;  1 2175-2178
• 44 Lisman T, Adelmeijer J, Cauwenberghs S et al.. Recombinant factor VIIa enhances platelet adhesion and activation under flow conditions at normal and reduced platelet count.  J Thromb Haemost. 2005;  3 742-751
• 45 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
• 46 Roberts H R, Monroe III D M, Hoffman M. Safety profile of recombinant factor VIIa.  Semin Hematol. 2004;  41 101-108
• 47 Hedner U. NovoSeven as a universal haemostatic agent.  Blood Coagul Fibrinolysis. 2000;  11(suppl 1) S107-S111
• 48 Hedner U, Erhardtsen E. Potential role for rFVIIa in transfusion medicine.  Transfusion. 2002;  42 114-124
• 49 Galán A M, Tonda R, Pino M et al.. Increased local procoagulant action: a mechanism contributing to the favorable hemostatic effect of recombinant FVIIa in PLT disorders.  Transfusion. 2003;  43 885-892
• 50 Béguin S, Kumar R. Thrombin, fibrin and platelets: a resonance loop in which von Willebrand factor is a necessary link.  Thromb Haemost. 1997;  78 590-594
• 51 He S, Ekman G J, Hedner U. The effect of platelets on fibrin gel structure formed in the presence of recombinant factor VIIa in hemophilia plasma and in plasma from a patient with Glanzmann thrombasthenia.  J Thromb Haemost. 2005;  3 272-279
• 52 Tranholm M, Røjkjaer R, Pyke C et al.. Recombinant factor VIIa reduces bleeding in severely thrombocytopenic rabbits.  Thromb Res. 2003;  109 217-223
• 53 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
• 54 Vidarsson B, Onundarson P T. Recombinant factor VIIa for bleeding in refractory thrombocytopenia.  Thromb Haemost. 2000;  83 634-635
• 55 Pihusch M, Bacigalupo A, Szer J et al.. Recombinant activated factor VII in treatment of bleeding complications following hematopoietic stem cell transplantation.  J Thromb Haemost. 2005;  3 1935-1944
• 56 Stenberg B, Peterson H-I, Risberg B. Gastric tissue fibrinolytic activity in experimental ulcer disease. In: Davidson JF, Nilsson IM, Astedt B Progress in Fibrinolysis. Edinburgh; Churchill Livingstone 1981: 295-297
• 57 Poon M C, D'Oiron R, Von D M 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 1096-1103
• 58 Hendriks H G, Meijer K, de Wolf J T et al.. Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study.  Transplantation. 2001;  71 402-405
• 59 Lodge J P, Jonas S, Jones R M et al.. Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation.  Liver Transpl. 2005;  11 973-979
• 60 Planinsic R M, van der Meer J, Testa G et al.. Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease.  Liver Transpl. 2005;  11 895-900
• 61 Paramo J A, Rocha E. Hemostasis in advanced liver disease.  Semin Thromb Hemost. 1993;  19 184-190
• 62 Tonda R, Galán A M, Pino M et al.. Hemostatic effect of activated recombinant factor VII (rFVIIa) in liver disease: studies in an in vitro model.  J Hepatol. 2003;  39 954-959
• 63 Lisman T, Leebeek F W, Meijer K et al.. Recombinant factor VIIa improves clot formation but not fibrolytic potential in patients with cirrhosis and during liver transplantation.  Hepatology. 2002;  35 616-621
• 64 Meng Z H, Wolberg A S, Monroe III D M, Hoffman M. The effect of temperature and pH on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients.  J Trauma. 2003;  55 886-891
• 65 Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa.  Lancet. 1999;  354 1879
• 66 Martinowitz U, Michaelson M. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force.  J Thromb Haemost. 2005;  3 640-648
• 67 Segal S, Shemesh I Y, Blumenthal R et al.. Treatment of obstetric hemorrhage with recombinant activated factor VII (rFVIIa).  Arch Gynecol Obstet. 2003;  268 266-267
• 68 Eikelboom J W, Bird R, Blythe D et al.. Recombinant activated factor VII for the treatment of life-threatening haemorrhage.  Blood Coagul Fibrinolysis. 2003;  14 713-717
• 69 Ahonen J, Jokela R. Recombinant factor VIIa for life-threatening post-partum haemorrhage.  Br J Anaesth. 2005;  94 592-595
• 70 Boffard K D, Riou B, Warren B 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
• 71 Friederich P W, Henny C P, Messelink E J 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;  361 201-205
• 72 Astrup T. Fibrinolysis: past and present, a reflection of fifty years.  Semin Thromb Hemost. 1991;  17 161-174
• 73 Andersson L. Local fibrinolysis. In: Nilsson IM Haemorrhagic and Thrombotic Diseases. London; John Wiley & Sons 1974: 155-182
• 74 Broderick J P, Brott T G, Duldner J E, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality.  Stroke. 1993;  24 987-993
• 75 Mayer S A, Brun N C, Begtrup K et al.. Recombinant activated factor VII for acute intracerebral hemorrhage.  N Engl J Med. 2005;  352 777-785
• 76 Takashima S, Koga M, Tanaka K. Fibrinolytic activity of human brain and cerebrospinal fluid.  Br J Exp Pathol. 1969;  50 533-539
• 77 Tovi D, Nilsson I M. Increased fibrinolytic activity and fibrin degradation products after experimental intracerebral haemorrhage.  Acta Neurol Scand. 1972;  48 403-415