rFVIIai in Acute Coronary Syndromes

 

 Buy Article Permissions and Reprints

ABSTRACT

Following vessel wall injury, tissue factor (TF) is exposed and forms complexes with already activated factor VII (FVIIa) present in the circulating blood, thereby initiating the hemostatic process. After the first FXa is formed, the TF pathway inhibitor (TFPI) forms a complex with FXa, and a quaternary complex is formed, TF/FVIIa/ FXa/TFPI, which inhibits the first step of the hemostatic pathway. Recombinant activated FVII (rFVIIa) has been developed for use as a hemostatic agent (NovoNordisk A/S, Denmark). Active site-inactivated rFVIIa (rFVIIai) has also been prepared and was shown to have a faster association to and a slower dissociation from TF than rFVIIa, resulting in a lower calculated Kd of rFVIIai compared with rFVIIa. In various animal models rFVIIai has been demonstrated to prevent or diminish immediate thrombus formation at the site of vessel wall injury (athroplasty or other forms of mechanical injury) as well as the development of long-term intima thickening. The inflammatory response following endotoxin-induced sepsis was shown to decrease after administration of rFVIIai. Also, survival increased in the rFVIIai-treated animals in this study. In addition, ischemia-reperfusion injury was mitigated by rFVIIai. In a limited number of patients undergoing percutaneous transluminal coronary angioplasty (PTCA), rFVIIai was observed to allow PTCA to be performed at lower doses of heparin than what has been reported previously.

REFERENCES

• 1 Rapaport S I, Rao L V. Initiation and regulation of tissue factor-dependent blood coagulation.  Arterioscler Thromb . 1992;  12 1111-1121
  CrossrefPubMedGoogle Scholar
• 2 Rapaport S I, Rao L VM. The tissue factor pathway: how it has become a `prima ballerina.' Thromb Haemost .  1995;  74 7-17
  PubMedGoogle Scholar
• 3 Hamada K, Kuratsu J, Saitoh Y, Takeshima H, Nishi T, Ushio Y. Expression of tissue factor correlates with grade of malignancy in human glioma.  Cancer . 1996;  77 1877-1883
  CrossrefPubMedGoogle Scholar
• 4 Seto S, Onodera H, Kaido T. Tissue factor expression in human colorectal carcinoma-correlation with hepatic metastasis and impact on prognosis.  Cancer . 2000;  88 295-301
  CrossrefPubMedGoogle Scholar
• 5 Ernofsson M, Siegbahn A. Platelet-derived growth factor-BB and monocyte chemotactic protein-1 induce human peripheral blood monocytes to express tissue factor.  Thromb Res . 1996;  83 307-320
  CrossrefPubMedGoogle Scholar
• 6 Rauch U, Bonderman D, Bohrmann B. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor.  Blood . 2000;  96 170-175
  PubMedGoogle Scholar
• 7 Lupu F, Westmuckett A D, Taylor Jr B F. Cell and tissue-specific expression of tissue factor pathway proteins in a baboon model of lethal E coli sepsis.   Blood . 2002;  100 496a
  PubMedGoogle Scholar
• 8 Siggiqui F A, Desai H, Amirkhosravi A. Platelet microparticles from healthy donors contain tissue factor.  Blood . 2002;  100 1936
  PubMedGoogle Scholar
• 9 Monroe D, Hoffman M, Roberts H R. Platelets and thrombin generation.  Arterioscler Thromb Vasc Biol . 2002;  22 1381-1389
  CrossrefPubMedGoogle Scholar
• 10 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
  CrossrefPubMedGoogle Scholar
• 11 Hoffman M, Monroe D M, Oliver J A, Roberts H R. Factors IXa and Xa play distinct roles in tissue factor-dependent initiation of coagulation.  Blood . 1995;  86 1794-1801
  PubMedGoogle Scholar
• 12 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
  CrossrefPubMedGoogle Scholar
• 13 Kjalke M, Oliver J A, Monroe D M. The effect of active site-inhibited factor VIIa on tissue factor-initiated coagulation using platelets before and after aspirin administration.  Thromb Haemost . 1997;  78 1202-1208
  PubMedGoogle Scholar
• 14 Sorensen B B, Persson E, Freskgaard P O. Incorporation of an active site inhibitor in factor VIIa alters the affinity for tissue factor.  J Biol Chem . 1997;  272 11863-11868
  CrossrefPubMedGoogle Scholar
• 15 Hansen C B, Pyke C, Petersen L C, Rao L VM. Tissue factor-mediated endocytosis, recycling, and degradation of factor VIIa by a clathrin-independent mechanism not requiring the cytoplasmic domain of tissue factor.  Blood . 2001;  97 1712-1720
  CrossrefPubMedGoogle Scholar
• 16 Golino P, Ragni M, Cirillo P. Antithrombotic effects of recombinant human, active site-blocked factor VIIa in a rabbit model of recurrent arterial thrombosis.  Circ Res . 1998;  82 39-46
  PubMedGoogle Scholar
• 17 Pendurthi U R, Rao L VM. Factor VIIa/tissue factor-induced signaling: a link between clotting and disease. In: Litwick G, ed. Vitamins and Hormones-Advances in Research and Applications San Diego, CA: Academic Press 2002: 323-355
  Google Scholar
• 18 Rottingen J A, Enden T, Camerer E, Iversen J G, Prydz H. Binding of human factor VIIa to tissue factor induces cytosolic Ca²⁺ signals in J82 cells, transfected COS-1 cells, Madin-Darby canine kidney cells and in human endothelial cells induced to synthesize tissue factor.  J Biol Chem . 1995;  270 4650-4660
  CrossrefPubMedGoogle Scholar
• 19 Poulsen L K, Jacobsen N, Sorensen B B. Signal transduction via the mitogen-activated protein kinase pathway induced by binding of coagulation factor VIIa to tissue factor.  J Biol Chem . 1998;  273 6228-6232
  CrossrefPubMedGoogle Scholar
• 20 Versteeg H H, Hoedemaeker I, Diks S H. Factor VIIa/ tissue factor-induced signaling via activation of Src-like kinases, phosphatidylinositol 3-kinase, and Rac.  J Biol Chem . 2000;  275 28750-28756
  CrossrefPubMedGoogle Scholar
• 21 Taniguchi T, Kakkar A K, Tuddenham E GD, Williamson R CN, Lemoine N R. Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer.  Cancer Res . 1998;  58 4461-4467
  PubMedGoogle Scholar
• 22 Camerer E, Rottingen J A, Gjernes E. Coagulation factors VIIa and Xa induce cell signaling leading to up-regulation of the egr-1 gene.  J Biol Chem . 1999;  274 32225-32233
  CrossrefPubMedGoogle Scholar
• 23 Camerer E, Gjernes E, Wiiger M, Pringle S, Prydz H. Binding of factor VIIa to tissue factor on keratinocytes induces gene expression.  J Biol Chem . 2000;  275 6580-6585
  CrossrefPubMedGoogle Scholar
• 24 Pendurthi U R, Allen K E, Ezban M, Rao L VM. Factor VIIa and thrombin induce the expression of Cyr61 and connective tissue growth factor, extracellular matrix signaling proteins that could act as possible downstream mediators in factor VIIa center dot tissue factor-induced signal transduction.  J Biol Chem . 2000;  275 14632-14641
  CrossrefPubMedGoogle Scholar
• 25 Pendurthi U R, Alok D, Rao L V. Binding of factor VIIa to tissue factor induces alterations in gene expression in human fibroblast cells: up-regulation of poly(A) polymerase.  Proc Natl Acad Sci USA . 1997;  94 12598-12603
  CrossrefPubMedGoogle Scholar
• 26 Martin P. Wound healing-aiming for perfect skin regeneration.  Science . 1997;  276 75-81
  CrossrefPubMedGoogle Scholar
• 27 Osterud B, Bjorklid E. The tissue factor pathway in disseminated intravascular coagulation.  Semin Thromb Hemost . 2001;  27 605-617
  Article in Thieme ConnectPubMedGoogle Scholar
• 28 Taylor F B, Chang A, Ruf W. Lethal E coli septic shock is prevented by blocking tissue factor with monoclonal antibody.   Circ Shock . 1991;  33 127-134
  PubMedGoogle Scholar
• 29 Gando S, Kameue T, Nanzaki S, Hayakawa T, Nakanishi Y. Participation of tissue factor and thrombin in posttraumatic systemic inflammatory syndrome.  Crit Care Med . 1997;  25 1820-1826
  CrossrefPubMedGoogle Scholar
• 30 Harker L A, Hanson S R, Kelly A B. Antithrombotic benefits and hemorrhagic risks of direct thrombin antagonists.  Thromb Haemost . 1995;  74 464-472
  PubMedGoogle Scholar
• 31 Jang Y, Guzman L A, Lincoff A M. Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit atherosclerotic femoral artery injury model.  Circulation . 1995;  92 3041-3050
  PubMedGoogle Scholar
• 32 Sanchez-Gomez A, Casani L, Vilahur G, Badimon L. FFR-rFVIIa inhibits thrombosis triggered by ruptured and eroded vessel wall.  Thromb Haemost . 2001;  Suppl July OC999
  PubMedGoogle Scholar
• 33 Arnljots B, Ezban M, Hedner U. Prevention of experimental arterial thrombosis by topical administration of active site-inactivated factor VIIa.  J Vasc Surg . 1997;  25 341-346
  PubMedGoogle Scholar
• 34 Holst J, Kristensen A T, Kristensen H I, Ezban M, Hedner U. Local application of recombinant active-site inhibited human clotting factor VIIa reduces thrombus weight and improves patency in a rabbit venous thrombosis model.  Eur J Vasc Endovasc Surg . 1998;  15 515-520
  PubMedGoogle Scholar
• 35 Herskowitz A, Choi S, Ansari A A, Wesselingh S. Cytokine mRNA expression in postischemic/reperfused myocardium.  Am J Pathol . 1995;  146 419-428
  PubMedGoogle Scholar
• 36 Kranzhofer R, Clinton S K, Ishii K, Coughlin S R, Fenton I I, Libby P. Thrombin potently stimulates cytokine production in human vascular smooth muscle cells but not in mononuclear phagocytes.  Circ Res . 1996;  79 286-294
  PubMedGoogle Scholar
• 37 Ma X L, Lefer D J, Lefer A M, Rothlein R. Coronary endothelial and cardiac protective effects of a monoclonal antibody to intercellular adhesion molecule-1 in myocardial ischemia and reperfusion.  Circulation . 1992;  86 937-946
  PubMedGoogle Scholar
• 38 Golino P, Ragni M, Cirillo P. Effects of recombinant active site-blocked activated factor VII in rabbit models of carotid stenosis and myocardial infarction.  Blood Coagul Fibrinolysis . 2000;  11 S149-S158
  PubMedGoogle Scholar
• 39 Erlich J H, Boyle E M, Labriola J. Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation.  Am J Pathol . 2000;  157 1849-1862
  CrossrefPubMedGoogle Scholar
• 40 Osterholm C, Qi Z Q, Ekberg J. Initial inhibition of tissue factor signalling reduces chronic vascular changes in isogenic rat aortic transplants.  Am J Transplant . 2001;  1 29-37
  CrossrefPubMedGoogle Scholar
• 41 Taylor F B. Role of tissue factor and factor VIIa in the coagulant and inflammatory response to LD100 Escherichia coli in the baboon.  Haemostasis . 1996;  26 (suppl 1) 83-91
  PubMedGoogle Scholar
• 42 Creasey A A, Chang A C, Feigen L, Wün T C, Taylor F B, Hinshaw L B. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock.  J Clin Invest . 1993;  91 2850-2856
  CrossrefPubMedGoogle Scholar
• 43 Taylor F B, Chang A C, Peer G, Li A, Ezban M, Hedner U. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli Blood .  1998;  91 1609-1615
  PubMedGoogle Scholar
• 44 Erhardtsen E, Nilsson P, Johannessen M, Thomsen M S. Pharmacokinetics and safety of FFR-rFVIIa after single doses in healthy subjects.  J Clin Pharmacol . 2001;  41 880-885
  CrossrefPubMedGoogle Scholar
• 45 Lincoff A M. First clinical investigation of a tissue factor inhibitor administered during percutaneous coronary revascularizatoin: a randomized, double-blinded, dose-escalation trial-assessing safety and efficacy of FFR-rFVIIa in PTCA (ASIS) trial. Presentation of Late Breaking Clinical Trials in Interventional Cardiology at ACCIS 2000, March 2000
  Google Scholar
• 46 Lev E I, Marmur J D, Zdravkovic M. Antithrombotic effect of tissue factor inhibition by inactivated factor VIIa: an ex vivo human study.  Arterioscler Thromb Vasc Biol . 2002;  22 1036-1041
  PubMedGoogle Scholar
• 47 Jilma B, Marsik C, Mayr F. Pharmacodynamics of active site-inhibited factor VIIa in endotoxin-induced coagulation in humans.  Clin Pharmacol Ther . 2002;  72 403-410
  CrossrefPubMedGoogle Scholar