Advertisement

Recombinant Coagulation Factors and Thrombolytic Agents

  • Koen MertensEmail author
  • Alexander B. Meijer
Chapter

Abstract

Bleeding disorders and thrombosis are defects of the hemostatic system that often require therapeutic intervention with human plasma proteins. Several thereof, including coagulation factor VIII and tissue-type plasminogen activator, are low abundance proteins, which limits their availability for pharmaceutical production from human blood. In the early 1980s, the advent of biotechnology provided the perspective of unlimited access to such trace proteins, and plasminogen activator and factor VIII were among the first recombinant protein therapeutics that became available. The complexity of the hemostatic proteins have posed specific challenges with respect to post-translational modification and processing, and this has long been limiting their biotechnological development. More than a decade after the first recombinant coagulation factors, a few more became available, including factor IX and activated factor VII. The first generation of these recombinant products was designed to provide exact copies of their natural, human counterparts. Subsequent generations included engineered variants, with deletions or substitutions in order to improve expression, product safety or biological activity. During the last decade, the number of recombinant products has been rapidly increasing. The latest generation comprises more drastic modifications, including fusion proteins designed to improve pharmacokinetics. These novel agents pose new challenges in terms of dosage and patient monitoring. This makes protocols for individualized treatment complex, and more importantly, product-specific. The present chapter provides an overview of recombinant coagulation factors and thrombolytic agents that are currently licensed, with particular reference to the benefits and challenges using engineered biopharmaceuticals in this field.

Keywords

Blood coagulation Fibrinolysis Bleeding disorders Thrombosis Protein engineering Half-life extension 

References

  1. Andersson LO, Forsman N, Huang K, Larsen K, Lundin A, Pavlu B, Sandberg H, Sewerin K, Smart J (1986) Isolation and characterization of human factor VIII: molecular forms in commercial factor VIII concentrate, cryoprecipitate and plasma. Proc Natl Acad Sci U S A 83:2979–2983CrossRefGoogle Scholar
  2. Björkman S, Berntorp E (2001) Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia. Clin Pharmacokinet 40:815–832CrossRefGoogle Scholar
  3. Cafuir LA, Kempton CL (2017) Current and emerging factor VIII replacement products for hemophilia A. Ther Adv Hematol 8:303–313CrossRefGoogle Scholar
  4. Castaman G, Linari S (2017) Diagnosis and treatment of von Willebrand disease and rare bleeding disorders. J Clin Med 6:E45CrossRefGoogle Scholar
  5. Choo KH, Gould KG, Rees DL, Brownlee GG (1982) Molecular cloning of the gene for human anti-haemophilic factor IX. Nature 299:178–180CrossRefGoogle Scholar
  6. Collen D, Lijnen HR (2004) Tissue-type plasminogen activator: a historical perspective and personal account. J Thromb Haemost 2:541–546CrossRefGoogle Scholar
  7. Collen D, Lijnen HR (2005) Thrombolytic agents. Thromb Haemost 93:627–630CrossRefGoogle Scholar
  8. Collins R, Peto R, Baigent C, Sleight P (1997) Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction. N Engl J Med 336:847–860CrossRefGoogle Scholar
  9. Davie EW, Ratnoff OD (1964) Waterfall sequence for intrinsic blood clotting. Science 145:1310–1312CrossRefGoogle Scholar
  10. Dietrich B, Schiviz A, Hoellriegl W, Horling F, Benamara K, Rottensteiner H, Turecek PL, Schwarz HP, Scheiflinger F, Muchitsch EM (2013) Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B. Int J Hematol 98:525–532CrossRefGoogle Scholar
  11. Edmunds T, Van Patten SM, Pollock J, Hanson E, Bernasconi R, Higgins E, Manvalan P, Ziomek C, Meade H, McPherson JM, Cole ES (1998) Transgenically produced human antithrombin: structural and functional comparison to human plasma-derived antithrombin. Blood 91:4561–4571PubMedGoogle Scholar
  12. Fay PJ (2004) Activation of factor VIII and mechanisms of cofactor action. Blood Rev 18:1–15CrossRefGoogle Scholar
  13. Franchini M, Mannucci PM (2013) Hemophilia A in the third millennium. Blood Rev 27:179–184CrossRefGoogle Scholar
  14. Franchini M, Mannucci PM (2016) Von Willebrand factor (Vonvendi®): the first recombinant product licensed for the treatment of von Willebrand disease. Expert Rev Hematol 9:825–830CrossRefGoogle Scholar
  15. Furie B, Furie BC (1988) The molecular basis of blood coagulation. Cell 53:505–518CrossRefGoogle Scholar
  16. Gill JC, Castaman G, Windyga J, Kouides P, Ragni M, Leebeek FWG, Obermann-Slupetzky O, Chapman M, Fritsch S, Pavlova BG, Presch I, Ewenstein B (2015) Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood 126:2038–2046CrossRefGoogle Scholar
  17. Guillermin A, Yan DJ, Perrier A, Marti C (2016) Safety and efficacy of tenecteplase versus alteplase in acute coronary syndrome: a systematic review and meta-analysis of randomized trials. Arch Med Sci 12:1181–1187CrossRefGoogle Scholar
  18. Harrison S, Adamson S, Bonam D, Brodeur S, Charlebois T, Clancy B, Costigan R, Drapeau D, Hamilton M, Hanley K, Kelley B, Knight A, Leonard M, McCarthy M, Oakes P, Sterl K, Switzer M, Walsh R, Foster W (1998) The manufacturing process for recombinant factor IX. Sem Hematol 35(Suppl 2):4–10Google Scholar
  19. Hedner U (2006) Mechanism of action, development and clinical experience of recombinant FVIIa. J Biotechnol 124:747–757CrossRefGoogle Scholar
  20. Hedner U, Ezban M (2008) Tissue factor and factor VIIa as therapeutic targets in disorders of hemostasis. Annu Rev Med 59:29–41CrossRefGoogle Scholar
  21. Hedner U, Kisiel W (1983) Use of human factor VIIa in the treatment of two hemophilia A patients with high-titer inhibitors. J Clin Invest 71:1836–1841CrossRefGoogle Scholar
  22. Huntington JA (2003) Mechanisms of glycosaminoglycan activation of the serpins in hemostasis. J Thromb Haemost 1:1535–1549CrossRefGoogle Scholar
  23. Inbal A, Oldenburg J, Carcao M, Rosholm A, Tehranchi R, Nugent D (2012) Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency. Blood 119:5111–5117CrossRefGoogle Scholar
  24. Iorio A (2017) Using pharmacokinetics to individualize hemophilia therapy. Hematology Am Soc Hematol Educ Program 2017:595–604PubMedPubMedCentralGoogle Scholar
  25. Jorgensen MJ, Cantor AB, Furie BC, Brown CL, Shoemaker CB, Furie B (1987) Recognition site directing vitamin K-dependent γ-carboxylation resides on the propeptide of factor IX. Cell 48:185–191CrossRefGoogle Scholar
  26. Keyt BA, Paoni NF, Refino CJ, Berleau L, Nguyen H, Chow A, Lai J, Pena L, Pater C, Ogez J, Etscheverry T, Botstein D, Bennett WF (1994) A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci U S A 91:3670–3674CrossRefGoogle Scholar
  27. Kitchen S, Tiefenbacher S, Gosselin R (2017) Factor activity assays for monitoring extended half-life FVIII and factor IX replacement therapies. Sem Thromb Hemost 43:331–337CrossRefGoogle Scholar
  28. Komaromi I, Bagoly Z, Muszbek L (2011) factor XIII: novel structural and functional aspects. J Thromb Haemost 9:9–20CrossRefGoogle Scholar
  29. Kurachi K, Davie EW (1982) Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci U S A 79:6461–6464CrossRefGoogle Scholar
  30. Leksa NC, Chiu PL, Bou-Assaf GM, Quan C, Liu Z, Goodman AB, Chambers MG, Tsutakawa SE, Hammel M, Peters RT, Waltz T, Kulman JD (2017) The structural basis for the functional comparability of factor VIII and the long-acting variant factor VIII Fc fusion protein. J Thromb Haemost 15:1167–1179CrossRefGoogle Scholar
  31. Lenting PJ, van Mourik JA, Mertens K (1998) The life cycle of coagulation factor VIII in view of its structure and function. Blood 92:3983–3996PubMedGoogle Scholar
  32. Lovejoy AE, Reynolds TC, Visich JE, Butine MD, Young G, Belvedere MA, Blain RC, Pederson SM, Ishak LM, Nugent DJ (2006) Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency. Blood 108:57–62CrossRefGoogle Scholar
  33. Lusis AJ (2000) Atherosclerosis. Nature 407:233–241CrossRefGoogle Scholar
  34. Maas Enriquez M, Thrift J, Garger S, Katterle Y (2016) Bay 81-8973, a full-length recombinant factor VIII: human heat shock protein 70 improves the manufacturing process without affecting clinical safety. Prot Expr Purif 127:111–115CrossRefGoogle Scholar
  35. Macfarlane RG (1964) An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature 202:498–499CrossRefGoogle Scholar
  36. Mahlangu JN, Weldingh KN, Lentz SR, Kaicker S, Karim FA, Matsushita T, Recht M, Tomczak W, Windyga J, Ehrenfort S, Knobe K (2015) Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. J Thromb Haemost 13:1989–1998CrossRefGoogle Scholar
  37. Mann KG, Orfeo T, Butenas S, Undas A, Brummel-Ziedins K (2009) Blood coagulation dynamics in haemostasis. Hämostaseologie 29:7–16CrossRefGoogle Scholar
  38. Mannucci PM (2004) Treatment of von Willebrand’s disease. N Engl J Med 531:683–694CrossRefGoogle Scholar
  39. Mei B, Pan C, Jiang H, Tjandra H, Strauss J, Chen Y, Liu T, Zhang X, Severs J, Newgren J, Chen J, Gu J-M, Subramanyam B, Fournel MA, Pierce GF (2010) Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment. Blood 116:270–279CrossRefGoogle Scholar
  40. Metzner HJ, Weimer T, Kronthaler U, Lang W, Schulte S (2009) Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 102:634–644CrossRefGoogle Scholar
  41. Monroe DM, Jenny RJ, Van Cott KE, Buhay S, Saward LL (2016) Characterization of IXINITY (trenonacog alfa), a recombinant factor IX with primary sequence coresponding to the threonine-148 polymorph. Adv Hematol 2016:7678901CrossRefGoogle Scholar
  42. Moser M, Kohler B, Schmittner M, Bode C (1998) Recombinant plasminogen activators: a comparative review of the clinical pharmacology and therapeutic use of alteplase and reteplase. BioDrugs 9:455–463CrossRefGoogle Scholar
  43. Østergaard H, Bjelke JR, Hansen L, Petersen LC, Pedersen AA, Elm T, Møller F, Hermit MB, Holm PK, Krogh TN, Petersen LM, Ezban M, Sørensen BB, Andersen MD, Agersø H, Ahmandian H, Balling KW, Christiansen MLS, Knobe K, Nichols TC, Bjørn SE, Tranholm M (2011) Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. Blood 118:2333–2341CrossRefGoogle Scholar
  44. Paidas MJ, Forsyth C, Quéré I, Rodger M, Frieling JTM, Tait RC (2014) Perioperative and peripartum prevention of venous thromboembolism in patients with hereditary antithrombin deficiency using recombinant antithrombin therapy. Blood Coagul Fibrinolysis 25:444–450CrossRefGoogle Scholar
  45. Palla R, Peyvandi F, Shapiro A (2015) Rare bleeding disorders: diagnosis and treatment. Blood 125:2052–2061CrossRefGoogle Scholar
  46. Pennica D, Holmes WE, Kohr WJ, Harkins RN, Vehar GA, Ward CA, Bennett WF, Yelverton E, Seeburg PH, Heyneker HL, Goeddel DV, Collen D (1983) Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 301:214–221CrossRefGoogle Scholar
  47. Perera L, Darden T, Pedersen LG (2001) Modeling human zymogen factor IX. Thromb Haemost 85:596–603CrossRefGoogle Scholar
  48. Peters RT, Low SC, Kamphaus GD, Dumont JA, Amari JV, Lu Q, Zarbis-Papastoitsis G, Reidy TJ, Merricks EP, Nichols TC, Bitonti AJ (2010) Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood 115:2057–2064CrossRefGoogle Scholar
  49. Pipe SW, Montgomery RR, Pratt KP, Lenting PJ, Lillicrap D (2016) Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood 128:2007–2016CrossRefGoogle Scholar
  50. Rijken DC, Hoylaerts M, Collen D (1982) Fibrinolytic properties of one-chain and two-chain human extrinsic (tissue-type) plasminogen activator. J Biol Chem 257:2920–2925PubMedGoogle Scholar
  51. Rogaev EI, Grigorenko AP, Faskhutdinova G, Kittler ELW, Moliaka YK (2009) Science 326:817CrossRefGoogle Scholar
  52. Sandberg H, Kannicht C, Stenlund P, Dadaian M, Oswaldsson U, Cordula C, Walter O (2012) Functional characteristics of the novel, human-derived recombinant FVIII protein product, human-cl rhFVIII. Thromb Res 130:808–817CrossRefGoogle Scholar
  53. Schmidbauer S, Witzel R, Robbel L, Sebastian P, Grammel N, Metzner HJ, Schulte S (2015) Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII. Thromb Res 136:388–395CrossRefGoogle Scholar
  54. Simpson D, Siddiqui MAA, Scott LJ, Hilleman DE (2006) Reteplase: a review of its use in the management of thrombotic occlusive disorders. Am J Cardiovasc Drugs 6:265–285CrossRefGoogle Scholar
  55. Stennicke HR, Kjalke M, Karpf DM, Baling KW, Johansen PB, Elm T, Øvlisen K, Möller F, Holmberg HL, Gudme CN, Persson E, Hilden I, Pelzer H, Rahbeck-Nielsen H, Jespersgaard C, Bogsnes A, Pedersen AA, Kristensen AK, Peschke B, Kappers W, Rode F, Thim L, Tranholm M, Ezban M, Olsen EHN, Bjørn SE (2013) A novel B-domain O-glycoPEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in hemophilic mice models. Blood 121:2108–2116CrossRefGoogle Scholar
  56. Thim L, Vandahl B, Karlsson J, Klausen NK, Pedersen J, Krogh TN, Kjalke M, Petersen JM, Johnsen LB, Bolt G, Nørby PL, Steenstrup TD (2010) Purification and characterization of a new recombinant factor VIII (N8). Haemophilia 16:349–359CrossRefGoogle Scholar
  57. Tiede A, Tait RC, Shaffer DW, Baudo F, Boneu B, Dempfle CE, Horrelou MH, Klamroth R, Lazarchick J, Mumford AD, Schulman S, Shiach C, Bonfiglio LJ, Frieling JTM, Conard J, von Depka M (2008) Antithrombin alfa in hereditary antithrombin deficient patients: a phase 3 study of prophylactic intravenous administration in high risk situations. Thromb Haemost 99:616–622CrossRefGoogle Scholar
  58. Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Bueker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC, Amphlett GW, Foster WB, Coe ML, Knutson GJ, Fass DN, Hewick RM (1984) Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 312:342–347CrossRefGoogle Scholar
  59. Toole JJ, Pittman DD, Orr EC, Murtha P, Wasley LC, Kaufman RJ (1986) A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proc Natl Acad Sci U S A 83:5939–5942CrossRefGoogle Scholar
  60. Turecek PL, Bossard M, Graniger M, Gritsch H, Höllriegl W, Kaliwoda M, Matthiessen P, Mitterer A, Muchitsch E-M, Purtscher M, Rottensteiner H, Schiviz A, Schrenk G, Siekmann J, Varadi K, Riley T, Ehrlich HJ, Schwarz HP, Scheiflinger F (2012) BAX 855, a PEGylated rFVIII product with prolonged half-life: development, functional and structural characterisation. Hämostaseologie 32(Suppl 1):S29–S38CrossRefGoogle Scholar
  61. Turecek PL, Mitterer A, Matthiessen HP, Gritsch H, Varadi K, Siekmann J, Schnecker K, Plaimauer B, Kaliwoda M, Purtscher M, Woehrer W, Mundt W, Muchitsch E-M, Suiter T, Ewenstein BM, Ehrlich HJ, Schwarz HP (2009) Development of a plasma- and albumin-free recombinant von Willebrand factor. Hämostaseologie 29(Suppl 1):S32–S38CrossRefGoogle Scholar
  62. Vehar GA, Keyt B, Eaton D, Rodriguez H, O’Brien DP, Rotblatt F, Oppermann H, Keck R, Wood WI, Harkins RN, Tuddenham EGD, Lawn RM, Capon DJ (1984) Structure of human factor VIII. Nature 312:337–342CrossRefGoogle Scholar
  63. Wasley LC, Rehemtulla A, Bristol JA, Kaufman RJ (1993) PACE/furin can process the vitamin K-dependent pro-factor IX precursor within the secretory pathway. J Biol Chem 268:8458–8465PubMedGoogle Scholar
  64. Young G, Mahlangu JN (2016) Extended half-life clotting factor concentrates: results from published clinical trials. Haemophilia 22(Suppl 5):25–30CrossRefGoogle Scholar

Suggested Reading

  1. Bishop P, Lawson J (2004) Recombinant biologics for treatment of bleeding disorders. Nat Rev Drug Disc 3:684–694CrossRefGoogle Scholar
  2. Lubon H, Paleyanda RK, Velander WH, Drohan WN (1996) Blood proteins from transgenic animal bioreactors. Transf Med Rev 10(2):131–143CrossRefGoogle Scholar
  3. Mackman N (2008) Triggers, targets and treatments for thrombosis. Nature 451:914–918CrossRefGoogle Scholar
  4. Peyvandi F, Garagiola I, Seregni S (2013) Future of coagulation factor replacement therapy. J Thromb Haemost 11(Suppl 1):84–98CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesUtrecht Institute for Pharmaceutical Sciences, Utrecht UniversityUtrechtThe Netherlands

Personalised recommendations