Development and Applications of Recombinant Activated Factor VII
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Published:
Sep 3, 2017
Keywords:
rVIIa development application bleeding
Main Article Content
Abstract
Recombinant activated factor VII (rFVIIa) was initially developed for treatment and prevention of bleeding during surgery and invasive procedures in congenital hemophilia with inhibitors against coagulation factors. Extensive research over the last few decades has contributed to the development of rFVIIa. These thorough studies not only helped to improve the biological activity and half-life of rFVIIa but also to enhance the knowledge regarding the mechanisms of action of rFVIIa to re-establish normal hemostasis. Since rFVIIa has been successfully in use for hemophilia treatment, it has been extended to other coagulopathies which characterized by the impairment of thrombin generation, including acquired hemophilia, Glanzmann’s thrombasthenia, and congenital FVII deficiency. The development, the mechanism of action, and the clinical applications of rFVIIa are reviewed in this article.
Article Details
How to Cite
Intasai, N. (2017). Development and Applications of Recombinant Activated Factor VII. Journal of Associated Medical Sciences, 50(3), 525. Retrieved from https://he01.tci-thaijo.org/index.php/bulletinAMS/article/view/71873
Section
Research Articles
Personal views expressed by the contributors in their articles are not necessarily those of the Journal of Associated Medical Sciences, Faculty of Associated Medical Sciences, Chiang Mai University.
References
1. Hedner U, Brun NC. Recombinant factor VIIa (rFVIIa): its potential role as a hemostatic agent. Neuroradiology. 2007;49(10):789-93.
2. Oldenburg J, Schroder J, Brackmann HH, Muller-Reible C, Schwaab R, Tuddenham E. Environmental and genetic factors influencing inhibitor development. Semin Hematol. 2004;41(1 Suppl 1):82-8.
3. Miller CH, Benson J, Ellingsen D, Driggers J, Payne A, Kelly FM, et al. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012;18(3):375-82.
4. Astermark J, Oldenburg J, Carlson J, Pavlova A, Kavakli K, Berntorp E, et al. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Blood. 2006;108(12):3739-45.
5. Astermark J, Oldenburg J, Pavlova A, Berntorp E, Lefvert AK, Group MS. Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A. Blood. 2006;107(8):3167-72.
6. Athale AH, Marcucci M, Iorio A. Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B. Cochrane Database Syst Rev. 2014;4:CD010561.
7. Cromwell C, Aledort LM. FEIBA: a prohemostatic agent. Semin Thromb Hemost. 2012;38(3):265-7.
8. Lusher JM. Thrombogenicity associated with factor IX complex concentrates. Semin Hematol. 1991;28(3 Suppl 6):3-5.
9. 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):1836-41.
10. Blajchman MA, Vamvakas EC. The continuing risk of transfusion-transmitted infections. N Engl J Med. 2006;355(13):1303-5.
11. Tapper ML. Emerging viral diseases and infectious disease risks. Haemophilia. 2006;12 Suppl 1:3-7; discussion 26-8.
12. Kisiel W. Recollections on the discovery of factor VIIa as a novel therapeutic agent for hemophiliacs with inhibitors. J Thromb Haemost. 2009; 7(7): 1053-6.
13. Hedner U. Factor VIIa and its potential therapeutic use in bleeding-associated pathologies. Thromb Haemost. 2008; 100(4): 557-62.
14. Hedner U, Lee CA. First 20 years with recombinant FVIIa (NovoSeven). Haemophilia. 2011; 17(1): e172-82.
15. Franchini M, Lippi G. Recombinant activated factor VII: mechanisms of action and current indications. Semin Thromb Hemost. 2010; 36(5): 485-92.
16. Millar DS, Kemball-Cook G, McVey JH, Tuddenham EG, Mumford AD, Attock GB, et al. Molecular analysis of the genotype-phenotype relationship in factor VII deficiency. Hum Genet. 2000; 107(4): 327-42.
17. O’Hara PJ, Grant FJ, Haldeman BA, Gray CL, Insley MY, Hagen FS, et al. Nucleotide sequence of the gene coding for human factor VII, a vitamin K-dependent protein participating in blood coagulation. Proc Natl Acad Sci U S A. 1987; 84(15): 5158-62.
18. Hagen FS, Gray CL, O’Hara P, Grant FJ, Saari GC, Woodbury RG, et al. Characterization of a cDNA coding for human factor VII. Proc Natl Acad Sci U S A. 1986; 83(8): 2412-6.
19. Kaufman RJ. Post-translational modifications required for coagulation factor secretion and function. Thromb Haemost. 1998; 79(6): 1068-79.
20. Bolt G, Steenstrup TD, Kristensen C. All post-translational modifications except propeptide cleavage are required for optimal secretion of coagulation factor VII. Thromb Haemost. 2007; 98(5): 988-97.
21. Iino M, Foster DC, Kisiel W. Functional consequences of mutations in Ser-52 and Ser-60 in human blood coagulation factor VII. Arch Biochem Biophys. 1998; 352(2): 182-92.
22. Kao YH, Lee GF, Wang Y, Starovasnik MA, Kelley RF, Spellman MW, et al. The effect of O-fucosylation on the first EGF-like domain from human blood coagulation factor VII. Biochemistry. 1999; 38(22): 7097-110.
23. Hoffman M, Volovyk Z, Persson E, Gabriel DA, Ezban M, Monroe DM. Platelet binding and activity of a factor VIIa variant with enhanced tissue factor independent activity. J Thromb Haemost. 2011; 9(4): 759-66.
24. Thim L, Bjoern S, Christensen M, Nicolaisen EM, Lund-Hansen T, Pedersen AH, et al. Amino acid sequence and posttranslational modifications of human factor VIIa from plasma and transfected baby hamster kidney cells. Biochemistry. 1988; 27(20): 7785-93.
25. Bjoern S, Foster DC, Thim L, Wiberg FC, Christensen M, Komiyama Y, 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(17): 11051-7.
26. Fenaille F, Groseil C, Ramon C, Riande S, Siret L, Chtourou S, et al. Mass spectrometric characterization of N- and O-glycans of plasma-derived coagulation factor VII. Glycoconj J. 2008; 25(9): 827-42.
27. Sutkeviciute I, Mistiniene E, Sereikaite J, Bumelis VA. The influence of different glycosylation patterns on factor VII biological activity. Biochimie. 2009; 91(9): 1123-30.
28. Hedner U, Ljundberg J, Lund-Hansen T. Comparison of the effect of plasma-derived and recombinant human FVIIa in vitro and in a rabbit model. Blood Coagul Fibrinolysis. 1990; 1(2):145-51.
29. Bohm E, Seyfried BK, Dockal M, Graninger M, Hasslacher M, Neurath M, et al. Differences in N-glycosylation of recombinant human coagulation factor VII derived from BHK, CHO, and HEK293 cells. BMC Biotechnol. 2015; 15: 87.
30. Morfini M, Jimenez-Yuste V, Eichler H, Fischer R, Kirchmaier CM, Scharling B, et al. Pharmacokinetic properties of two different recombinant activated factor VII formulations. Haemophilia. 2012; 18(3): 431-6.
31. Dickinson CD, Kelly CR, Ruf W. Identification of surface residues mediating tissue factor binding and catalytic function of the serine protease factor VIIa. Proc Natl Acad Sci U S A. 1996; 93(25): 14379-84.
32. Dickinson CD, Ruf W. Active site modification of factor VIIa affects interactions of the protease domain with tissue factor. J Biol Chem. 1997; 272(32): 19875-9.
33. Persson E, Nielsen LS, Olsen OH. Substitution of aspartic acid for methionine-306 in factor VIIa abolishes the allosteric linkage between the active site and the binding interface with tissue factor. Biochemistry. 2001; 40(11): 3251-6.
34. Persson E, Bak H, Olsen OH. Substitution of valine for leucine 305 in factor VIIa increases the intrinsic enzymatic activity. J Biol Chem. 2001; 276(31): 29195-9.
35. Persson E, Kjalke M, Olsen OH. Rational design of coagulation factor VIIa variants with substantially increased intrinsic activity. Proc Natl Acad Sci U S A. 2001; 98(24): 13583-8.
36. Persson E, Olsen OH. Assignment of molecular properties of a superactive coagulation factor VIIa variant to individual amino acid changes. Eur J Biochem. 2002; 269(23): 5950-5.
37. Mahlangu JN, Weldingh KN, Lentz SR, Kaicker S, Karim FA, Matsushita T, et al. Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. J Thromb Haemost. 2015; 13(11): 1989-98.
38. Allen GA, Persson E, Campbell RA, Ezban M, Hedner U, Wolberg AS. A variant of recombinant factor VIIa with enhanced procoagulant and antifibrinolytic activities in an in vitro model of hemophilia. Arterioscler Thromb Vasc Biol. 2007; 27(3): 683-9.
39. Tranholm M, Kristensen K, Kristensen AT, Pyke C, Rojkjaer R, Persson E. Improved hemostasis with superactive analogs of factor VIIa in a mouse model of hemophilia A. Blood. 2003; 102(10): 3615-20.
40. Persson E, Bak H, Ostergaard A, Olsen OH. Augmented intrinsic activity of Factor VIIa by replacement of residues 305, 314, 337 and 374: evidence of two unique mutational mechanisms of activity enhancement. Biochem J. 2004; 379(Pt 2): 497-503.
41. Maun HR, Eigenbrot C, Raab H, Arnott D, Phu L, Bullens S, et al. Disulfide locked variants of factor VIIa with a restricted beta-strand conformation have enhanced enzymatic activity. Protein Sci. 2005; 14(5): 1171-80.
42. Weimer T, Wormsbacher W, Kronthaler U, Lang W, Liebing U, Schulte S. Prolonged in-vivo half-life of factor VIIa by fusion to albumin. Thromb Haemost. 2008;99(4):659-67.
43. Schulte S. Use of albumin fusion technology to prolong the half-life of recombinant factor VIIa. Thromb Res. 2008; 122 Suppl 4: S14-9.
44. Moss J, Rosholm A, Lauren A. Safety and pharmacokinetics of a glycoPEGylated recombinant activated factor VII derivative: a randomized first human dose trial in healthy subjects. J Thromb Haemost. 2011; 9(7): 1368-74.
45. Ghosh S, Ezban M, Persson E, Pendurthi U, Hedner U, Rao LV. Activity and regulation of factor VIIa analogs with increased potency at the endothelial cell surface. J Thromb Haemost. 2007; 5(2): 336-46.
46. Pedersen AH, Lund-Hansen T, Bisgaard-Frantzen H, Olsen F, Petersen LC. Autoactivation of human recombinant coagulation factor VII. Biochemistry. 1989; 28(24): 9331-6.
47. Halabian R, Roudkenar MH, Esmaeili NS, Masroori N, Roushandeh AM, Najafabadi AJ. Establishment of a cell line expressing recombinant factor VII and its subsequent conversion to active form FVIIa through hepsin by genetic engineering method. Vox Sang. 2009; 96(4): 309-15.
48. Masroori N, Halabian R, Mohammadipour M, Roushandeh AM, Rouhbakhsh M, Najafabadi AJ, et al. High-level expression of functional recombinant human coagulation factor VII in insect cells. Biotechnol Lett. 2010; 32(6): 803-9.
49. Mirzaahmadi S, Asaadi-Tehrani G, Bandehpour M, Davoudi N, Tahmasbi L, Hosseinzadeh N, et al. Expression of recombinant human coagulation factor VII by the Lizard Leishmania expression system. J Biomed Biotechnol. 2011; 2011: 873874.
50. Peng L, Yu X, Li C, Cai Y, Chen Y, He Y, et al. Enhanced recombinant factor VII expression in Chinese hamster ovary cells by optimizing signal peptides and fed-batch medium. Bioengineered. 2016; 7(3): 189-97.
51. Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood Rev. 2003; 17 Suppl 1: S1-5.
52. Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol. 2002; 22(9): 1381-9.
53. Hoffman M, Dargaud Y. Mechanisms and monitoring of bypassing agent therapy. J Thromb Haemost. 2012; 10(8): 1478-85.
54. Allen GA, Wolberg AS, Oliver JA, Hoffman M, Roberts HR, Monroe DM. Impact of procoagulant concentration on rate, peak and total thrombin generation in a model system. J Thromb Haemost. 2004; 2(3): 402-13.
55. Augustsson C, Persson E. In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia. Blood. 2014; 124(20): 3172-4.
56. He S, Blomback 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): 1215-9.
57. Franchini M, Favaloro EJ, Lippi G. Glanzmann thrombasthenia: an update. Clin Chim Acta. 2010; 411(1-2): 1-6.
58. Kannan M, Ahmad F, Yadav BK, Kumar R, Choudhry VP, Saxena R. Molecular defects in ITGA2B and ITGB3 genes in patients with Glanzmann thrombasthenia. J Thromb Haemost. 2009; 7(11): 1878-85.
59. Poon MC. Clinical use of recombinant human activated factor VII (rFVIIa) in the prevention and treatment of bleeding episodes in patients with Glanzmann’s thrombasthenia. Vasc Health Risk Manag. 2007; 3(5): 655-64.
60. Bauer KA. Treatment of factor VII deficiency with recombinant factor VIIa. Haemostasis. 1996;26 Suppl 1:155-8.
61. Mariani G, Bernardi F. Factor VII Deficiency. Semin Thromb Hemost. 2009; 35(4): 400-6.
62. Midathada MV, Mehta P, Waner M, Fink LM. Recombinant factor VIIa in the treatment of bleeding. Am J Clin Pathol. 2004; 121(1): 124-37.
63. Poon MC. Use of recombinant factor VIIa in hereditary bleeding disorders. Curr Opin Hematol. 2001; 8(5): 312-8.
64. Chuansumrit A, Tangnararatchakit K, Lektakul Y, Pongthanapisith V, Nimjaroenniyom N, Thanarattanakorn P, et al. The use of recombinant activated factor VII for controlling life-threatening bleeding in Dengue Shock Syndrome. Blood Coagul Fibrinolysis. 2004; 15(4): 335-42.
65. Chuansumrit A, Wangruangsatid S, Lektrakul Y, Chua MN, Zeta Capeding MR, Bech OM, et al. Control of bleeding in children with Dengue hemorrhagic fever using recombinant activated factor VII: a randomized, double-blind, placebo-controlled study. Blood Coagul Fibrinolysis. 2005; 16(8): 549-55.
66. Agarwal A, Jain R, Sharma S, Airun M, Bharti B. Effectiveness of Recombinant Activated Factor VII (rFVII a) for Controlling Intractable Postpartum Bleeding in a case of Dengue Hemorrhagic Fever. J Obstet Gynaecol India. 2016; 66(3): 188-91.
67. Blatny J, Mathew P, Monagle P, Ovesna P, Fiamoli V. Safety and efficacy of recombinant activated factor VII in nonhemophilia children with severe or life-threatening bleeding: a report from the SeveNBleeP registry. Blood Coagul Fibrinolysis. 2014; 25(4): 326-32.
2. Oldenburg J, Schroder J, Brackmann HH, Muller-Reible C, Schwaab R, Tuddenham E. Environmental and genetic factors influencing inhibitor development. Semin Hematol. 2004;41(1 Suppl 1):82-8.
3. Miller CH, Benson J, Ellingsen D, Driggers J, Payne A, Kelly FM, et al. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012;18(3):375-82.
4. Astermark J, Oldenburg J, Carlson J, Pavlova A, Kavakli K, Berntorp E, et al. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Blood. 2006;108(12):3739-45.
5. Astermark J, Oldenburg J, Pavlova A, Berntorp E, Lefvert AK, Group MS. Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A. Blood. 2006;107(8):3167-72.
6. Athale AH, Marcucci M, Iorio A. Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B. Cochrane Database Syst Rev. 2014;4:CD010561.
7. Cromwell C, Aledort LM. FEIBA: a prohemostatic agent. Semin Thromb Hemost. 2012;38(3):265-7.
8. Lusher JM. Thrombogenicity associated with factor IX complex concentrates. Semin Hematol. 1991;28(3 Suppl 6):3-5.
9. 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):1836-41.
10. Blajchman MA, Vamvakas EC. The continuing risk of transfusion-transmitted infections. N Engl J Med. 2006;355(13):1303-5.
11. Tapper ML. Emerging viral diseases and infectious disease risks. Haemophilia. 2006;12 Suppl 1:3-7; discussion 26-8.
12. Kisiel W. Recollections on the discovery of factor VIIa as a novel therapeutic agent for hemophiliacs with inhibitors. J Thromb Haemost. 2009; 7(7): 1053-6.
13. Hedner U. Factor VIIa and its potential therapeutic use in bleeding-associated pathologies. Thromb Haemost. 2008; 100(4): 557-62.
14. Hedner U, Lee CA. First 20 years with recombinant FVIIa (NovoSeven). Haemophilia. 2011; 17(1): e172-82.
15. Franchini M, Lippi G. Recombinant activated factor VII: mechanisms of action and current indications. Semin Thromb Hemost. 2010; 36(5): 485-92.
16. Millar DS, Kemball-Cook G, McVey JH, Tuddenham EG, Mumford AD, Attock GB, et al. Molecular analysis of the genotype-phenotype relationship in factor VII deficiency. Hum Genet. 2000; 107(4): 327-42.
17. O’Hara PJ, Grant FJ, Haldeman BA, Gray CL, Insley MY, Hagen FS, et al. Nucleotide sequence of the gene coding for human factor VII, a vitamin K-dependent protein participating in blood coagulation. Proc Natl Acad Sci U S A. 1987; 84(15): 5158-62.
18. Hagen FS, Gray CL, O’Hara P, Grant FJ, Saari GC, Woodbury RG, et al. Characterization of a cDNA coding for human factor VII. Proc Natl Acad Sci U S A. 1986; 83(8): 2412-6.
19. Kaufman RJ. Post-translational modifications required for coagulation factor secretion and function. Thromb Haemost. 1998; 79(6): 1068-79.
20. Bolt G, Steenstrup TD, Kristensen C. All post-translational modifications except propeptide cleavage are required for optimal secretion of coagulation factor VII. Thromb Haemost. 2007; 98(5): 988-97.
21. Iino M, Foster DC, Kisiel W. Functional consequences of mutations in Ser-52 and Ser-60 in human blood coagulation factor VII. Arch Biochem Biophys. 1998; 352(2): 182-92.
22. Kao YH, Lee GF, Wang Y, Starovasnik MA, Kelley RF, Spellman MW, et al. The effect of O-fucosylation on the first EGF-like domain from human blood coagulation factor VII. Biochemistry. 1999; 38(22): 7097-110.
23. Hoffman M, Volovyk Z, Persson E, Gabriel DA, Ezban M, Monroe DM. Platelet binding and activity of a factor VIIa variant with enhanced tissue factor independent activity. J Thromb Haemost. 2011; 9(4): 759-66.
24. Thim L, Bjoern S, Christensen M, Nicolaisen EM, Lund-Hansen T, Pedersen AH, et al. Amino acid sequence and posttranslational modifications of human factor VIIa from plasma and transfected baby hamster kidney cells. Biochemistry. 1988; 27(20): 7785-93.
25. Bjoern S, Foster DC, Thim L, Wiberg FC, Christensen M, Komiyama Y, 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(17): 11051-7.
26. Fenaille F, Groseil C, Ramon C, Riande S, Siret L, Chtourou S, et al. Mass spectrometric characterization of N- and O-glycans of plasma-derived coagulation factor VII. Glycoconj J. 2008; 25(9): 827-42.
27. Sutkeviciute I, Mistiniene E, Sereikaite J, Bumelis VA. The influence of different glycosylation patterns on factor VII biological activity. Biochimie. 2009; 91(9): 1123-30.
28. Hedner U, Ljundberg J, Lund-Hansen T. Comparison of the effect of plasma-derived and recombinant human FVIIa in vitro and in a rabbit model. Blood Coagul Fibrinolysis. 1990; 1(2):145-51.
29. Bohm E, Seyfried BK, Dockal M, Graninger M, Hasslacher M, Neurath M, et al. Differences in N-glycosylation of recombinant human coagulation factor VII derived from BHK, CHO, and HEK293 cells. BMC Biotechnol. 2015; 15: 87.
30. Morfini M, Jimenez-Yuste V, Eichler H, Fischer R, Kirchmaier CM, Scharling B, et al. Pharmacokinetic properties of two different recombinant activated factor VII formulations. Haemophilia. 2012; 18(3): 431-6.
31. Dickinson CD, Kelly CR, Ruf W. Identification of surface residues mediating tissue factor binding and catalytic function of the serine protease factor VIIa. Proc Natl Acad Sci U S A. 1996; 93(25): 14379-84.
32. Dickinson CD, Ruf W. Active site modification of factor VIIa affects interactions of the protease domain with tissue factor. J Biol Chem. 1997; 272(32): 19875-9.
33. Persson E, Nielsen LS, Olsen OH. Substitution of aspartic acid for methionine-306 in factor VIIa abolishes the allosteric linkage between the active site and the binding interface with tissue factor. Biochemistry. 2001; 40(11): 3251-6.
34. Persson E, Bak H, Olsen OH. Substitution of valine for leucine 305 in factor VIIa increases the intrinsic enzymatic activity. J Biol Chem. 2001; 276(31): 29195-9.
35. Persson E, Kjalke M, Olsen OH. Rational design of coagulation factor VIIa variants with substantially increased intrinsic activity. Proc Natl Acad Sci U S A. 2001; 98(24): 13583-8.
36. Persson E, Olsen OH. Assignment of molecular properties of a superactive coagulation factor VIIa variant to individual amino acid changes. Eur J Biochem. 2002; 269(23): 5950-5.
37. Mahlangu JN, Weldingh KN, Lentz SR, Kaicker S, Karim FA, Matsushita T, et al. Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. J Thromb Haemost. 2015; 13(11): 1989-98.
38. Allen GA, Persson E, Campbell RA, Ezban M, Hedner U, Wolberg AS. A variant of recombinant factor VIIa with enhanced procoagulant and antifibrinolytic activities in an in vitro model of hemophilia. Arterioscler Thromb Vasc Biol. 2007; 27(3): 683-9.
39. Tranholm M, Kristensen K, Kristensen AT, Pyke C, Rojkjaer R, Persson E. Improved hemostasis with superactive analogs of factor VIIa in a mouse model of hemophilia A. Blood. 2003; 102(10): 3615-20.
40. Persson E, Bak H, Ostergaard A, Olsen OH. Augmented intrinsic activity of Factor VIIa by replacement of residues 305, 314, 337 and 374: evidence of two unique mutational mechanisms of activity enhancement. Biochem J. 2004; 379(Pt 2): 497-503.
41. Maun HR, Eigenbrot C, Raab H, Arnott D, Phu L, Bullens S, et al. Disulfide locked variants of factor VIIa with a restricted beta-strand conformation have enhanced enzymatic activity. Protein Sci. 2005; 14(5): 1171-80.
42. Weimer T, Wormsbacher W, Kronthaler U, Lang W, Liebing U, Schulte S. Prolonged in-vivo half-life of factor VIIa by fusion to albumin. Thromb Haemost. 2008;99(4):659-67.
43. Schulte S. Use of albumin fusion technology to prolong the half-life of recombinant factor VIIa. Thromb Res. 2008; 122 Suppl 4: S14-9.
44. Moss J, Rosholm A, Lauren A. Safety and pharmacokinetics of a glycoPEGylated recombinant activated factor VII derivative: a randomized first human dose trial in healthy subjects. J Thromb Haemost. 2011; 9(7): 1368-74.
45. Ghosh S, Ezban M, Persson E, Pendurthi U, Hedner U, Rao LV. Activity and regulation of factor VIIa analogs with increased potency at the endothelial cell surface. J Thromb Haemost. 2007; 5(2): 336-46.
46. Pedersen AH, Lund-Hansen T, Bisgaard-Frantzen H, Olsen F, Petersen LC. Autoactivation of human recombinant coagulation factor VII. Biochemistry. 1989; 28(24): 9331-6.
47. Halabian R, Roudkenar MH, Esmaeili NS, Masroori N, Roushandeh AM, Najafabadi AJ. Establishment of a cell line expressing recombinant factor VII and its subsequent conversion to active form FVIIa through hepsin by genetic engineering method. Vox Sang. 2009; 96(4): 309-15.
48. Masroori N, Halabian R, Mohammadipour M, Roushandeh AM, Rouhbakhsh M, Najafabadi AJ, et al. High-level expression of functional recombinant human coagulation factor VII in insect cells. Biotechnol Lett. 2010; 32(6): 803-9.
49. Mirzaahmadi S, Asaadi-Tehrani G, Bandehpour M, Davoudi N, Tahmasbi L, Hosseinzadeh N, et al. Expression of recombinant human coagulation factor VII by the Lizard Leishmania expression system. J Biomed Biotechnol. 2011; 2011: 873874.
50. Peng L, Yu X, Li C, Cai Y, Chen Y, He Y, et al. Enhanced recombinant factor VII expression in Chinese hamster ovary cells by optimizing signal peptides and fed-batch medium. Bioengineered. 2016; 7(3): 189-97.
51. Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood Rev. 2003; 17 Suppl 1: S1-5.
52. Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol. 2002; 22(9): 1381-9.
53. Hoffman M, Dargaud Y. Mechanisms and monitoring of bypassing agent therapy. J Thromb Haemost. 2012; 10(8): 1478-85.
54. Allen GA, Wolberg AS, Oliver JA, Hoffman M, Roberts HR, Monroe DM. Impact of procoagulant concentration on rate, peak and total thrombin generation in a model system. J Thromb Haemost. 2004; 2(3): 402-13.
55. Augustsson C, Persson E. In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia. Blood. 2014; 124(20): 3172-4.
56. He S, Blomback 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): 1215-9.
57. Franchini M, Favaloro EJ, Lippi G. Glanzmann thrombasthenia: an update. Clin Chim Acta. 2010; 411(1-2): 1-6.
58. Kannan M, Ahmad F, Yadav BK, Kumar R, Choudhry VP, Saxena R. Molecular defects in ITGA2B and ITGB3 genes in patients with Glanzmann thrombasthenia. J Thromb Haemost. 2009; 7(11): 1878-85.
59. Poon MC. Clinical use of recombinant human activated factor VII (rFVIIa) in the prevention and treatment of bleeding episodes in patients with Glanzmann’s thrombasthenia. Vasc Health Risk Manag. 2007; 3(5): 655-64.
60. Bauer KA. Treatment of factor VII deficiency with recombinant factor VIIa. Haemostasis. 1996;26 Suppl 1:155-8.
61. Mariani G, Bernardi F. Factor VII Deficiency. Semin Thromb Hemost. 2009; 35(4): 400-6.
62. Midathada MV, Mehta P, Waner M, Fink LM. Recombinant factor VIIa in the treatment of bleeding. Am J Clin Pathol. 2004; 121(1): 124-37.
63. Poon MC. Use of recombinant factor VIIa in hereditary bleeding disorders. Curr Opin Hematol. 2001; 8(5): 312-8.
64. Chuansumrit A, Tangnararatchakit K, Lektakul Y, Pongthanapisith V, Nimjaroenniyom N, Thanarattanakorn P, et al. The use of recombinant activated factor VII for controlling life-threatening bleeding in Dengue Shock Syndrome. Blood Coagul Fibrinolysis. 2004; 15(4): 335-42.
65. Chuansumrit A, Wangruangsatid S, Lektrakul Y, Chua MN, Zeta Capeding MR, Bech OM, et al. Control of bleeding in children with Dengue hemorrhagic fever using recombinant activated factor VII: a randomized, double-blind, placebo-controlled study. Blood Coagul Fibrinolysis. 2005; 16(8): 549-55.
66. Agarwal A, Jain R, Sharma S, Airun M, Bharti B. Effectiveness of Recombinant Activated Factor VII (rFVII a) for Controlling Intractable Postpartum Bleeding in a case of Dengue Hemorrhagic Fever. J Obstet Gynaecol India. 2016; 66(3): 188-91.
67. Blatny J, Mathew P, Monagle P, Ovesna P, Fiamoli V. Safety and efficacy of recombinant activated factor VII in nonhemophilia children with severe or life-threatening bleeding: a report from the SeveNBleeP registry. Blood Coagul Fibrinolysis. 2014; 25(4): 326-32.