Promising coagulation factor VIII bypassing strategies for patients with haemophilia A

Blood Coagulation and Fibrinolysis

Volumn 25, Issue 6, 2014, Pages 539-552

  Duan, Xunwei ^a   Tang, Mingqing ^a,b   Zhang, Junping ^a,b   Yu, Hao ^a   Xu, Ruian ^a,b  

^a HUAQIAO UNIVERSITY   (China)

^b BEIJING UNIVERSITY OF POSTS AND TELECOMMUNICATIONS   (China)

Author keywords

factor VIII; factor VIII bypassing; gene therapy; haemophilia A; neutralizing antibody

Indexed keywords

ACTIVATED PROTHROMBIN COMPLEX; BLOOD CLOTTING FACTOR; BLOOD CLOTTING FACTOR 10; BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING FACTOR 7; BLOOD CLOTTING FACTOR 7A; BLOOD CLOTTING FACTOR 8; COAGULATING AGENT; PROTHROMBIN; RECOMBINANT FACTOR VIII SQ; RECOMBINANT FVIIA; RECOMBINANT PROTEIN; THROMBIN;

BLOOD; DRUG EFFECTS; HEMOPHILIA A; HEMOSTASIS; HUMAN; METABOLISM; PATHOLOGY; THROMBOCYTE; THROMBOCYTE ACTIVATION;

BLOOD COAGULATION FACTORS; BLOOD PLATELETS; COAGULANTS; FACTOR VII; FACTOR VIIA; FACTOR VIII; FACTOR X; FACTOR XA; HEMOPHILIA A; HEMOSTASIS; HUMANS; PLATELET ACTIVATION; PROTHROMBIN; RECOMBINANT PROTEINS; THROMBIN;

EID: 84905861716     PISSN: 09575235     EISSN: 14735733     Source Type: Journal    
DOI: 10.1097/MBC.0000000000000098     Document Type: Article

References (110)

1. Mannucci PM, Tuddenham EG. The hemophilias: From royal genes to gene therapy. N Engl J Med 2001; 344:1773-1779.
2. Peake I. The molecular basis of haemophilia A. Haemophilia 1998; 4:346-349.
3. Lillicrap D. Molecular diagnosis of inherited bleeding disorders and thrombophilia. Semin Hematol 1999; 36:340-351.
4. Furie B, Furie BC. Molecular and cellular biology of blood coagulation. N Engl J Med 1992; 326:800-806.
5. Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85:958-965.
6. Manco-Johnson MJ, Nuss R, Geraghty S, Funk S, Kilcoyne R. Results of secondary prophylaxis in children with severe hemophilia. Am J Hematol 1994; 47:113-117.
7. Fischer KG, Deschler B, Lubbert M. Acquired high-titer factor VIII inhibitor: Fatal bleeding despite multimodal treatment including rituximab preceded by multiple plasmaphereses. Blood 2003; 101:3753-3754; author reply 3754-3755.
8. Iorio A, Halimeh S, Holzhauer S, Goldenberg N, Marchesini E, Marcucci M, et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: A systematic review. J Thromb Haemost 2010; 8:1256-1265.
9. 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; 27:7785-7793.
10. Pike AC, Brzozowski AM, Roberts SM, Olsen OH, Persson E. Structure of human factor VIIa and its implications for the triggering of blood coagulation. Proc Natl Acad Sci U S A 1999; 96:8925-8930.
11. Bolt G, Steenstrup TD, Kristensen C. All posttranslational modifications except propeptide cleavage are required for optimal secretion of coagulation factor VII. Thromb Haemost 2007; 98:988.
12. Persson E, Olsen OH. Current status on tissue factor activation of factor VIIa. Thromb Res 2010; 125:S11-S12.
13. Tanaka R, Nakashima D, Suzuki A, Miyawaki Y, Fujimori Y, Yamada T, et al. Impaired secretion of carboxyl-terminal truncated factor VII due to an F7 nonsense mutation associated with FVII deficiency. Thromb Res 2010; 125:262-266.
14. Hedner U. Recombinant factor VIIa (NovoSeven (R)) as a hemostatic agent. Semin Hematol 2001; 38:43-47.
15. Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood Rev 2003; 17:S1-S5.
16. Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscl Thromb Vas 2002; 22:1381-1389.
17. Lisman T, Mosnier LO, Lambert T, Mauser-Bunschoten EP, Meijers JC, Nieuwenhuis HK, et al. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A. Blood 2002; 99:175-179.
18. 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; 1:1215-1219.
19. Kristensen AT, Madsen MT, Nielsen GN, Ezban M. Recombinant human FVIIa dose dependently shortens the bleeding time in a rabbit model of antibody induced hemophilia A. Thromb Haemost 1999; S1:328-329.
20. Von Depka M. Managing acute bleeds in the patient with haemophilia and inhibitors: Options, efficacy and safety. Haemophilia 2005; 11:18-23.
21. Hedner U. Factor VIIa and its potential therapeutic use in bleedingassociated pathologies. Thromb Haemost 2008; 100:557-562.
22. Mathijssen NC, Masereeuw R, Holme PA, van Kraaij MG, Laros-van Gorkom BA, Peyvandi F, et al. Increased volume of distribution for recombinant activated factor VII and longer plasma-derived factor VII halflife may explain their long lasting prophylactic effect. Thromb Res 2013; 132:256-262.
23. Johansen PB, Bjorn SE, Agerso H, Thorup I, Hermit MB, Sorensen B, et al. Prolonged effect of GlycoPEGylated rFVIIa (40k-PEG-rFVIIa) in rabbits correlates to activity in plasma. Thromb Haemost 2010; 104:157-164.
24. Ohmori T, Ishiwata A, Kashiwakura Y, Madoiwa S, Mitomo K, Suzuki H, et al. Phenotypic correction of hemophilia A by ectopic expression of activated factor VII in platelets. Mol Ther 2008; 16:1359-1365.
25. Margaritis P, Roy E, Downey HD, Zhou SZ, Merricks E, Dillow A, et al. Gene transfer of canine FVIIa results in partial correction of canine hemophilia: A model for FVIII/FIX gene-based bypassing agents. Blood 2007; 110:65a-65a.
26. Margaritis P, Roy E, Aljamali MN, Downey HD, Giger U, Zhou S, et al. Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood 2009; 113:3682-3689.
27. Margaritis P, Roy E, Faella A, Downey HD, Ivanciu L, Pavani G, et al. Catalytic domain modification and viral gene delivery of activated factor VII confers hemostasis at reduced expression levels and vector doses in vivo. Blood 2011; 117:3974-3982.
28. 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; 102:3615-3620.
29. Chen S, Greenberg D, Ye P, Davie E, Miao C. Nonviral gene transfer of factor VII as alternative treatment for hemophilia A. Mol Ther 2005; 11:237-1237.
30. 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. Arterioscl Thromb Vas 2007; 27:683-689.
31. Knudsen T, Kristensen AT, Nichols TC, Agerso H, Jensen AL, Kjalke M, et al. Pharmacokinetics, pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog. Haemophilia 2011; 17:962-970.
32. Dickneite G, Zollner S, Weimer T, Schurmann D, Schmidbauer S, Raquet E. Prolonged serum half-life of a recombinant fusion protein linking activated coagulation factor VII with albumin (FVIIA-FP) in different preclinical species. J Thromb Haemost 2011; 9:385.
33. Sim D, Koellnberger M, Gu J, Bornaes C, Kragh M, Clausen S. BAY 86- 6150, a novel recombinant factor VIIa variant, has a significantly higher therapeutic index than eptacog alfa (activated) in rabbit bleeding and thrombosis models. J Thromb Haemost 2011; 9:297.
34. Pittman D, Weston S, Shields K, Parng C, Arkin S, Madison E, et al. A novel FVIIa variant with increased potency and duration of effect compared to wildtype FVIIa. A study in a dog model of hemophilia A. Blood 2011; 118:979-980.
35. Friso S, Lotto V, Choi S-W, Girelli D, Pinotti M, Guarini P, et al. Promoter methylation in coagulation F7 gene influences plasma FVII concentrations and relates to coronary artery disease. J Med Genet 2012; 49:192-199.
36. Karpf DM, Sorensen BB, Hermit MB, Holmberg HL, Tranholm M, Bysted BV, et al. Prolonged half-life of glycoPEGylated rFVIIa variants compared to native rFVIIa. Thromb Res 2011; 128:191-195.
37. Plesner B, Westh P, Nielsen AD. The effect of GlycoPEGylation on the physical stability of human rFVIIa with increasing calcium chloride concentration. Eur J Pharm Biopharm 2011; 78:222-228.
38. Stennicke HR, Østergaard H, Bayer RJ, Kalo MS, Kinealy K, Holm PK, et al. Generation and biochemical characterization of glycoPEGylated factor VIIa derivatives. Tierärztliche Praxis Groβtiere 2008; 36:163-169.
39. Sen P, Ghosh S, Ezban M, Pendurthi U, Vijaya Mohan Rao L. Effect of glycoPEGylation on factor VIIa binding and internalization. Haemophilia 2010; 16:339-348.
40. Santagostino E, Morfini M, Rocino A, Baudo F, Scaraggi F, Gringeri A. Relationship between factor VII activity and cinical efficacy of recombinant factor VIIa given by continuous infusion to patients with factor VIII inhibitors. Thromb Haemost 2001; 86:954-958.
41. 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; 98:13583-13588.
42. Osterud B, Bouma B, Griffin J. Human blood coagulation factor IX. Purification, properties, and mechanism of activation by activated factor XI. J Biol Chem 1978; 253:5946-5951.
43. Schmidt AE, Bajaj SP. Structure-function relationships in factor IX and factor IXa. Trends Cardiovas Med 2003; 13:39-45.
44. Fribourg C, Meijer AB, Mertens K. The interface between the EGF2 domain and the protease domain in blood coagulation factor IX contributes to factor VIII binding and factor X activation. Biochemistry 2006; 45:10777-10785.
45. Rees D, Jones I, Handford P, Walter S, Esnouf M, Smith K, et al. The role of beta-hydroxyaspartate and adjacent carboxylate residues in the first EGF domain of human factor IX. EMBO J 1988; 7:2053-2061.
46. Sekiya F, Yamashita T, Atoda H, Komiyama Y, Morita T. Regulation of the tertiary structure and function of coagulation factor IX by magnesium (II) ions. J Biol Chem 1995; 270:14325-14331.
47. Schmidt AE, Stewart JE, Mathur A, Krishnaswamy S, Bajaj SP. Na site in blood coagulation factor IXa: Effect on catalysis and factor VIIIa binding. J Mol Biol 2005; 350:78-91.
48. Dockal M, Hartmann R, Scheiflinger F. FIX-Mutant Proteins for Hemophilia B Treatment: U.S. Patent Application 12/022,071[P]. 2008-1-29.
49. Hopfner K-P, Lang A, Karcher A, Sichler K, Kopetzki E, Brandstetter H, et al. Coagulation factor IXa: The relaxed conformation of Tyr99 blocks substrate binding. Structure 1999; 7:989-996.
50. Huang M, Furie BC, Furie B. Crystal structure of the calcium-stabilized human factor IX Gla domain bound to a conformation-specific antifactor IX antibody. J Biol Chem 2004; 279:14338-14346.
51. van Dieijen G, Tans G, Rosing J, Hemker HC. The role of phospholipid and factor VIIIa in the activation of bovine factor X. J Biol Chem 1981; 256:3433-3442.
52. Sichler K, Kopetzki E, Huber R, Bode W, Hopfner KP, Brandstetter H. Physiological fIXa activation involves a cooperative conformational rearrangement of the 99-loop. J Biol Chem 2003; 278:4121-4126.
53. Poon MC. Pharmacokinetics of factors IX, recombinant human activated factor VII and factor XIII. Haemophilia 2006; 12:61-69.
54. Sabatino E, Arruda R. Muscle gene therapy for hemophilia. J Genet Syn & Gene Ther 2013; S1:010-017.
55. Milanov P, Ivanciu L, Abriss D, Quade-Lyssy P, Miesbach W, Alesci S, et al. Engineered factor IX variants bypass FVIII and correct hemophilia A phenotype in mice. Blood 2012; 119:602-611.
56. Karl-Peter H, Hans B, Annette K, Erhard K, Robert H, Engh RA, et al. Converting blood coagulation factor IXa into factor Xa: Dramatic increase in amidolytic activity identifies important active site determinants. EMBO J 1997; 16:6626-6635.
57. Hartmann R, Dockal M, Kammlander W, Panholzer E, Nicolaes GA, Fiedler C, et al. Factor IX mutants with enhanced catalytic activity. J Thromb Haemost 2009; 7:1656-1662.
58. Kolkman JA, Mertens K. Insertion loo 256-268 in coagulation factor IX restricts enzymatic activity in the absence but not in the presence of factor VIII. Biochemistry 2000; 39:7398-7405.
59. Kitazawa T, Igawa T, Sampei Z, Muto A, Kojima T, Soeda T, et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med 2012; 18:1570-1574.
60. Peters RT, Low SC, Kamphaus GD, Dumont JA, Amari JV, Lu Q, et al. Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood 2010; 115:2057-2064.
61. Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med 2009; 361:1671-1675.
62. Hartmann R, Dockal M, Kammlander W, Panholzer E, Nicolaes G, Fiedler C, et al. Factor IX mutants with enhanced catalytic activity. J Thromb Haemost 2009; 7:1656-1662.
63. Østergaard H, Bjelke JR, Hansen L, Petersen LC, Pedersen AA, Elm T, et al. Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. Blood 2011; 118:2333-2341.
64. Metzner HJ, Weimer T, Kronthaler U, Lang W, Schulte S. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 2009; 102:634-644.
65. Wootla B, Christophe OD, Mahendra A, Dimitrov JD, Repesse Y, Ollivier V, et al. Proteolytic antibodies activate factor IX in patients with acquired hemophilia. Blood 2011; 117:2257-2264.
66. Adler M, Davey DD, Phillips GB, Kim S-H, Jancarik J, Rumennik G, et al. Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa. Biochemistry 2000; 39:12534-12542.
67. Bunce MW, Toso R, Camire RM. Zymogen-like factor Xa variants restore thrombin generation and effectively bypass the intrinsic pathway in vitro. Blood 2011; 117:290-298.
68. Khan AR, James MN. Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes. Protein Sci 1998; 7:815-836.
69. Toso R, Zhu H, Camire RM. The conformational switch from the factor X zymogen to protease state mediates exosite expression and prothrombinase assembly. J Biol Chem 2008; 283:18627-18635.
70. Duffy EJ, Lollar P. Intrinsic pathway activation of factor X and its activation peptide-deficient derivative, factor Xdes-143-191. J Biol Chem 1992; 267:7821-7827.
71. Mann K, Nesheim M, Church W, Haley P, Krishnaswamy S. Surfacedependent reactions of the vitamin K-dependent enzyme complexes. Blood 1990; 76:1-16.
72. Broze M Jr, George J. Tissue factor pathway inhibitor and the revised theory of coagulation. Annu Rev Med 1995; 46:103-112.
73. Jesty J. Analysis of the generation and inhibition of activated coagulation factor X in pure systems and in human plasma. J Biol Chem 1986; 261:8695-8702.
74. Giles AR, Mann KG, Nesheim ME. A combination of factor Xa and phosphatidylcholine-phosphatidylserine vesicles bypasses factor VIII in vivo. Br J Haematol 1988; 69:491-497.
75. Louvain-Quintard VB, Bianchini EP, Calmel-Tareau C, Tagzirt M, Le Bonniec BF. Thrombin-activable factor X re-establishes an intrinsic amplification in tenase-deficient plasmas. J Biol Chem 2005; 280:41352-41359.
76. Wolf DL, Lin PH, Hollenbach S, Wong A, Phillips DR, Sinha U. Procoagulant activity of reversibly acylated human factor Xa. Blood 1995; 86:4153-4157.
77. Rudolph AE, Mullane MP, Porche-Sorbet R, Daust HA, Miletich JP. The role of factor X activation peptide: A deletion mutagenesis approach. Thromb Haemost 2002; 88:756-762.
78. Kwan E, Guarna MM, Boraston AB, Gilkes NR, Haynes CA, Kilburn DG, et al. Self activating factor X derivative fused to the C terminus of a cellulose binding module: Production and properties. Biotechnol Bioeng 2002; 79:724-732.
79. Ivanciu L, Toso R, Margaritis P, Pavani G, Kim H, Schlachterman A, et al. A zymogen-like factor Xa variant corrects the coagulation defect in hemophilia. Nat Biotechnol 2011; 29:1028-1033.
80. Tomokiyo K, Nakatomi Y, Araki T, Teshima K, Nakano H, Nakagaki T, et al. A novel therapeutic approach combining human plasma-derived factors VIIa and X for haemophiliacs with inhibitors: Evidence of a higher thrombin generation rate in vitro and more sustained haemostatic activity in vivo than obtained with Factor VIIa alone. Vox Sang 2003; 85:290-299.
81. Nakatomi Y, Nakashima T, Gokudan S, Miyazaki H, Tsuji M, Hanada- Dateki T, et al. Combining FVIIa and FX into a mixture which imparts a unique thrombin generation potential to hemophilic plasma: An in vitro assessment of FVIIa/FX mixture as an alternative bypassing agent. Thromb Res 2010; 125:457-463.
82. Shirahata A, Fukutake K, Mimaya J, Takamatsu J, Shima M, Hanabusa H, et al. Clinical pharmacological study of a plasma derived factor VIIa and factor X mixture (MC710) in haemophilia patients with inhibitors - phase I trial. Haemophilia 2012; 18:94-101.
83. Shirahata A, Fukutake K, Takamatsu J, Shima M, Hanabusa H, Mugishima H, et al. A phase II clinical trial of a mixture of plasma derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors: Haemostatic efficacy, safety and pharmacokinetics/pharmacodynamics. Haemophilia 2013; 19:853-860.
84. Penner JA. Treatment of inhibitor patients with activated prothrombin complex concentrates. Prog Clin Biol Res 1984; 150:291-308.
85. Gallistl S, Cvirn G, Leschnik B, Muntean W. Respective roles of factors II, VII, IX, and X in the procoagulant activity of FEIBA. Blood Coagul Fibrin 2002; 13:653-655.
86. Luu H, Ewenstein B. FEIBA safety profile in multiple modes of clinical and home-therapy application. Haemophilia 2004; 10:10-16.
87. Lundblad RL, Bergstrom J, De Vreker R, Bray G, Gomperts E, Baker D, et al. Measurement of active coagulation factors in autoplex-T with colorimetric active site-specific assay technology. Thromb Haemost 1998; 80:811-815.
88. Wilde JT. Evidence for the use of activated prothrombin complex concentrates (aPCCs) in the treatment of patients with haemophilia and inhibitors. Pathophysiol Haemost T 2002; 32:9-12.
89. Yada K, Nogami K, Ogiwara K, Shima M. Activated prothrombin complex concentrate (APCC)-mediated activation of factor (F)VIII in mixtures of FVIII and APCC enhances hemostatic effectiveness. J Thromb Haemost 2013; 11:902-910.
90. Turecek PL, Varadi K, Gritsch H, Auer W, Pichler L, Eder G, et al. Factor Xa and prothrombin: Mechanism of action of FEIBA. Vox Sang 1999; 77:72-79.
91. Nanishi E, Ohga S, Doi T, Ishimura M, Ihara K, Takada H, et al. Complete immunotolerance induction after FEIBA prophylaxis in a haemophilia A patient with high-titre inhibitor. Haemophilia 2012; 18:e75-e77.
92. Gruen DR, Winchester PH, Brill PW, Ramirez E. Magnetic resonance imaging of myocardial infarction during prothrombin complex concentrate therapy of hemophilia A. Pediatr Radiol 1997; 27:271-272.
93. Schneiderman J, Nugent D, Young G. Sequential therapy with activated prothrombin complex concentrate and recombinant factor VIIa in patients with severe haemophilia and inhibitors. Haemophilia 2004; 10:347-351.
94. Holmstrom M, Tran HTT, Holme PA. Combined treatment with APCC (FEIBA (R)) and tranexamic acid in patients with haemophilia A with inhibitors and in patients with acquired haemophilia A - A two-centre experience. Haemophilia 2012; 18:544-549.
95. Schneiderman J, Rubin E, Nugent DJ, Young G. Sequential therapy with activated prothrombin complex concentrates and recombinant FVIIa in patients with severe haemophilia and inhibitors: Update of our previous experience. Haemophilia 2007; 13:244-248.
96. Martinowitz U, Livnat T, Zivelin A, Kenet G. Concomitant infusion of low doses of rFVIIa and FEIBA in haemophilia patients with inhibitors. Haemophilia 2009; 15:904-910.
97. Klintman J, Astermark J, Berntorp E. Combination of FVIII and by-passing agent potentiates in vitro thrombin production in haemophilia A inhibitor plasma. Br J Haematol 2010; 151:381-386.
98. Yada K, Nogami K, Ogiwara K, Shima M. A novel mechanism of enhancing the haemostatic effect in the combination with recombinant factor VIII and activated prothrombin complex concentrate (APCC) in hemophilia A patients with inhibitor. Blood 2011; 118:532-1532.
99. Key NS, Christie B, Henderson N, Nelsestuen GL. Possible synergy between recombinant factor VIIa and prothrombin complex concentrate in hemophilia therapy. Thromb Haemost 2002; 88:60-65.
100. Dimichele D. Inhibitors: Resolving diagnostic and therapeutic dilemmas. Haemophilia 2002; 8:280-287.
101. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12:342-347.
102. Dobrzynski E, Herzog RW. Tolerance induction by viral in vivo gene transfer. Clin Med Res 2005; 3:234-240.
103. Gallo-Penn AM. Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs. Blood 2001; 97:107-113.
104. Schwaab R, Rost S, Schroder J, Muller-Reible CR, Oldenburg J. Genetics and clinical presentation of haemophilia A and B. Med Genet-Berlin 2008; 20:190-196.
105. Amy S, Ralph G, Ingrid PS Collins##PW, Charles RM, Schroth HP, et al. Integrated analysis of safety and efficacy of a plasma- And albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A. Expert Opin Biol Ther 2009; 9:273-283.
106. Elg M, Carlsson S, Gustafsson D. Effect of activated prothrombin complex concentrate or recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thromb Res 2001; 101:145-157.
107. Joshi AV, Stephens JM, Munro V, Mathew P, Botteman MF. Pharmacoeconomic analysis of recombinant factor VIIa versus APCC in the treatment of minor-to-moderate bleeds in hemophilia patients with inhibitors-. Curr Med Res Opin 2005; 22:23-31.
108. Young G, Shafer F, Rojas P, Seremetis S. Single 270mg kg-1-dose rFVIIa vs. standard 90mg kg-1-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: A randomized comparison. Haemophilia 2008; 14:287-294.
109. Bonnet PO, Yoon BS, Wong WY, Boswell K, Ewenstein BM. Cost minimization analysis to compare activated prothrombin complex concentrate (APCC) and recombinant factor VIIa for haemophilia patients with inhibitors undergoing major orthopaedic surgeries. Haemophilia 2009; 15:1083-1089.
110. Knight C, Dano AM, Kennedy-Martin T. Systematic review of efficacy of rFVIIa and aPCC treatment for hemophilia patients with inhibitors. Adv Ther 2009; 26:68-88.