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Recombinant biologics for treatment of bleeding disorders

Key Points

  • Bleeding disorders and haemorrhage have an enormous social, medical and financial impact worldwide.

  • Haemostasis is the process that arrests bleeding through the concerted activities of the vasculature, platelets and the plasma coagulation factors.

  • Bleeding disorders can result from congenital deficiencies in one or more of the key coagulation factors. For example, factor VIII (FVIII) and FIX are deficient in haemophilias A and B, respectively. Alternatively, acquired bleeding disorders arise from the loss of procoagulant function, hyperactivity of fibrinolytic pathways or the dysfunction of cellular elements such as platelets.

  • Haemostatic disorders can require transfusions of blood, blood products and coagulation factor concentrates. These are the medical mainstay in treating uncontrolled bleeding, but carry an intrinsic risk of viral and prion disease transmission and transfusion reactions.

  • FVIII and FIX concentrates prepared from blood made home treatment of haemophilias possible. However, these concentrates were prepared using some donors infected with hepatitis and human immunodeficiency virus, and haemophilia patients were infected.

  • Safety concerns led to the commercial development of recombinant FVIII and FIX. Recombinant FVIIa is also now commercially available for haemophilia patients who have developed neutralizing antibodies to FVIII and FIX.

  • Thrombin directly catalyses clot formation, and FXIII crosslinks fibrin and thereby hardens clots. Both are being developed as recombinant products for use as topical haemostatic agents, either combined or for stand-alone applications.

  • Recombinant FXIII is currently being evaluated for treatment and prevention of bleeding arising from congenital and acquired FXIII deficiencies.

  • Basic research is providing novel therapeutic avenues of intervention in bleeding disorders; from applied research, the future could lead to new methods of economical protein production and reduced cost to patients.

Abstract

Bleeding disorders and haemorrhage cause considerable morbidity and mortality in the industrialized world, as shown by the more than 2 million patients who received treatment for serious blood loss in 2002. Historically, these disorders have been treated with products derived from human plasma or animal sources. With the advent of recombinant technologies, new products have been developed that are generally perceived as safer and which have well-defined specificity of action and potency. Recombinant biologics have also provided some unforeseen benefits, yielding new insights into the mechanism of haemostasis as well as novel pharmacological strategies.

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Figure 1: Estimates of patients treated for major bleeding events and haemophilia prophylaxis in the industrialized world (2002).
Figure 2: The key enzymatic and cellular events leading to clot formation.
Figure 3: Enzymatic relationships within the coagulation pathway.

References

  1. 1

    Bakaltcheva, I. & Reid, T. Effects of blood product storage protectants on blood coagulation. Transfus. Med. Rev. 17, 263–271 (2003).

    PubMed  Google Scholar 

  2. 2

    Sullivan, M. T., McCullough, J., Schreiber, G. B. & Wallace, E. L. Blood collection and transfusion in the United States in 1997. Transfusion 42, 1253–1260 (2002). The authors have carefully documented blood collection and transfusion in the United States through a series of publications spaning more than 20 years.

    PubMed  Google Scholar 

  3. 3

    Varney, S. J. & Guest, J. F. The annual cost of blood transfusions in the UK. Transfus. Med. 13, 205–218 (2003).

    CAS  PubMed  Google Scholar 

  4. 4

    Lawson, J. H. & Mann, K. G. Cooperative activation of human factor IX by the human extrinsic pathway of blood coagulation. J. Biol. Chem. 266, 11317–11327 (1991).

    CAS  PubMed  Google Scholar 

  5. 5

    Thorelli, E., Kaufman, R. J. & Dahlback, B. Cleavage requirements for activation of factor V by factor Xa. Eur. J. Biochem. 247, 12–20 (1997).

    CAS  PubMed  Google Scholar 

  6. 6

    Lollar, P., Knutson, G. J. & Fass, D. N. Activation of porcine factor VIII:C by thrombin and factor Xa. Biochemistry 24, 8056–8064 (1985).

    CAS  PubMed  Google Scholar 

  7. 7

    Loewy, A. G., McDonagh, J., Mikkola, H., Teller, D. C. & Yee, V. C. in Hemostasis and Thrombosis: Basic Principles and Clinical Practice (ed. Colman, R. W.) 233–247 (Lippincott Williams and Wilkins, Philadelphia, 2001).

    Google Scholar 

  8. 8

    Muszbek, L., Yee, V. C. & Hevessy, Z. Blood coagulation factor XIII: structure and function. Thromb. Res. 94, 271–305 (1999).

    CAS  PubMed  Google Scholar 

  9. 9

    Kimura, S. & Aoki, N. Cross-linking site in fibrinogen for α2-plasmin inhibitor. J. Biol. Chem. 261, 15591–15595 (1986).

    CAS  PubMed  Google Scholar 

  10. 10

    Jensen, P. H., Lorand, L., Ebbesen, P. & Gliemann, J. Type-2 plasminogen-activator inhibitor is a substrate for trophoblast transglutaminase and factor XIIIa. Transglutaminase-catalyzed cross-linking to cellular and extracellular structures. Eur. J. Biochem. 214, 141–146 (1993).

    CAS  PubMed  Google Scholar 

  11. 11

    Valnickova, Z. & Enghild, J. J. Human procarboxypeptidase U, or thrombin-activable fibrinolysis inhibitor, is a substrate for transglutaminases. Evidence for transglutaminase-catalyzed cross-linking to fibrin. J. Biol. Chem. 273, 27220–27224 (1998).

    CAS  PubMed  Google Scholar 

  12. 12

    Bajzar, L., Manuel, R. & Nesheim, M. E. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J. Biol. Chem. 270, 14477–14484 (1995).

    CAS  PubMed  Google Scholar 

  13. 13

    Bajzar, L., Morser, J. & Nesheim, M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J. Biol. Chem. 271, 16603–16608 (1996).

    CAS  PubMed  Google Scholar 

  14. 14

    Hogan, K. A., Weiler, H. & Lord, S. T. Mouse models in coagulation. Thromb. Haemost. 87, 563–574 (2002).

    CAS  PubMed  Google Scholar 

  15. 15

    Lawson, J. H. & Murphy, M. P. Challenges for providing effective hemostasis in surgery and trauma. Semin. Hematol. 41, 55–64 (2004).

    CAS  PubMed  Google Scholar 

  16. 16

    Harker, L. A. Hemostasis Manual (F. A. Davis, Philadelphia, 1981). A concise manual that still provides practical insights on haemostasis.

    Google Scholar 

  17. 17

    Rosner, F. Hemophilia in the Talmud and rabbinic writings. Ann. Intern. Med. 70, 833–837 (1969).

    CAS  PubMed  Google Scholar 

  18. 18

    McKusick, V. A. The Royal Hemophilia. Sci. Am. 213, 88–95 (1965). A classic review that illustrates the impact of the genetics of haemophilia on world events.

    CAS  PubMed  Google Scholar 

  19. 19

    Lane, S. Haemorrhagic diathesis. Successful transfusion of bood. Lancet 1, 185–188 (1840).

    Google Scholar 

  20. 20

    Patek, A. T., FHL. Hemophilia II. Some properties of a substance obtained form normal plasma effective in accelerating the coagulation of hemophilic blood. J. Clin. Invest. 16, 113–134 (1937).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Owen, C. A. A History of Blood Coagulation (Mayo Clinic, Rochester, 2001). A facinating historical account of the evolution of the modern theory of haemostasis.

    Google Scholar 

  22. 22

    Bidstrup, B. P., Royston, D., Sapsford, R. N. & Taylor, K. M. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J. Thorac. Cardiovasc. Surg. 97, 364–372 (1989).

    CAS  PubMed  Google Scholar 

  23. 23

    Mannucci, P. M. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 90, 2515–2521 (1997).

    CAS  PubMed  Google Scholar 

  24. 24

    Hewson, J. R. Homeostatic alterations with major trauma. Massive transfusion. Can. Anaesth. Soc. J. 32, 239–240 (1985).

    CAS  PubMed  Google Scholar 

  25. 25

    Lundblad, R. L. et al. A review of the therapeutic uses of thrombin. Thromb. Haemost. 91, 851–860 (2004).

    CAS  PubMed  Google Scholar 

  26. 26

    Spotnitz, W. D. Commercial fibrin sealants in surgical care. Am. J. Surg. 182, S8–S14 (2001).

    Google Scholar 

  27. 27

    Ortel, T. L., Mercer, M. C., Thames, E. H., Moore, K. D. & Lawson, J. H. Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin. Ann. Surg. 233, 88–96 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Chouhan, V. D. et al. Simultaneous occurrence of human antibodies directed against fibrinogen, thrombin, and factor V following exposure to bovine thrombin: effects on blood coagulation, protein C activation and platelet function. Thromb. Haemost. 77, 343–349 (1997).

    CAS  PubMed  Google Scholar 

  29. 29

    Schoenecker, J. G., Hauck, R. K., Mercer, M. C., Parker, W. & Lawson, J. H. Exposure to topical bovine thrombin during surgery elicits a response against the xenogeneic carbohydrate galactose α1-3galactose. J. Clin. Immunol. 20, 434–444 (2000). Demonstrates that vitually all surgery patients have antibodies to bovine proteins even when there is no documented previous exposure to bovine thrombin preparations.

    CAS  PubMed  Google Scholar 

  30. 30

    Evatt, B. L., Farrugia, A., Shapiro, A. D. & Wilde, J. T. Haemophilia 2002: emerging risks of treatment. Haemophilia 8, 221–229 (2002).

    CAS  PubMed  Google Scholar 

  31. 31

    Godje, O., Haushofer, M., Lamm, P. & Reichart, B. The effect of factor XIII on bleeding in coronary surgery. Thorac. Cardiovasc. Surg. 46, 263–267 (1998).

    CAS  PubMed  Google Scholar 

  32. 32

    Wozniak, G., Noll, T., Akinturk, H., Thul, J. & Muller, M. Factor XIII prevents development of myocardial edema in children undergoing surgery for congenital heart disease. Ann. NY Acad. Sci. 936, 617–620 (2001). This paper proposes a unique role for factor XIII in oedema formation.

    CAS  PubMed  Google Scholar 

  33. 33

    Herouy, Y., Hellstern, M. O., Vanscheidt, W., Schopf, E. & Norgauer, J. Factor XIII-mediated inhibition of fibrino-lysis and venous leg ulcers. Lancet 355, 1970–1971 (2000).

    CAS  PubMed  Google Scholar 

  34. 34

    Pihusch, R. et al. Factor XIII activity levels in patients with allogeneic haematopoietic stem cell transplantation and acute graft-versus-host disease of the gut. Br. J. Haematol. 117, 469–476 (2002).

    CAS  PubMed  Google Scholar 

  35. 35

    Fukui, H. et al. Clinical evaluation of a pasteurized factor XIII concentrate administration in Henoch-Schonlein purpura. Japanese Pediatric Group. Thromb. Res. 56, 667–675 (1989).

    CAS  PubMed  Google Scholar 

  36. 36

    Klein, H. G. Allogeneic transfusion risks in the surgical patient. Am. J. Surg. 170, S21–S26 (1995).

    Google Scholar 

  37. 37

    Goodnough, L. T., Brecher, M. E., Kanter, M. H. & AuBuchon, J. P. Transfusion medicine. First of two parts — blood transfusion. N. Engl. J. Med. 340, 438–447 (1999).

    CAS  PubMed  Google Scholar 

  38. 38

    Hebert, P. C. et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N. Engl. J. Med. 340, 409–417 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Vincent, J. L. et al. Anemia and blood transfusion in critically ill patients. JAMA 288, 1499–1507 (2002).

    PubMed  Google Scholar 

  40. 40

    Engoren, M. C. et al. Effect of blood transfusion on long-term survival after cardiac operation. Ann. Thorac. Surg. 74, 1180–1186 (2002).

    PubMed  Google Scholar 

  41. 41

    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. 99, 542–547 (1997).

    CAS  PubMed  Google Scholar 

  42. 42

    Hoffman, M. & Monroe, D. M. The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis. Semin. Hematol. 38, 6–9 (2001). Proposes that initiation of coagulation occurs through a series of overlapping stages: initiation; amplification; and propagation, in which large amounts of thrombin are generated on the platelet surface.

    CAS  PubMed  Google Scholar 

  43. 43

    Butenas, S., Brummel, K. E., Branda, R. F., Paradis, S. G. & Mann, K. G. Mechanism of factor VIIa-dependent coagulation in hemophilia blood. Blood 99, 923–930 (2002).

    CAS  PubMed  Google Scholar 

  44. 44

    Veldman, A., Hoffman, M. & Ehrenforth, S. New insights into the coagulation system and implications for new therapeutic options with recombinant factor VIIa. Curr. Med. Chem. 10, 797–811 (2003).

    CAS  PubMed  Google Scholar 

  45. 45

    Saenko, E. L., Ananyeva, N. M., Shima, M., Hauser, C. A. & Pipe, S. W. The future of recombinant coagulation factors. J. Thromb. Haemost. 1, 922–930 (2003). A recent perspective on the future of recombinant coagulation factors.

    CAS  PubMed  Google Scholar 

  46. 46

    Toole, J. J. et al. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 312, 342–347 (1984).

    CAS  PubMed  Google Scholar 

  47. 47

    Lusher, J. M., Arkin, S., Abildgaard, C. F. & Schwartz, R. S. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group. N. Engl. J. Med. 328, 453–459 (1993). Reviews the clinical evidence for the treatment of haemophilia with recombinant clotting factors VIIa, VIII and IX.

    CAS  PubMed  Google Scholar 

  48. 48

    Bray, G. L. et al. Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: a report from the Multi-Center Hemophilia Cohort Study. Am. J. Hematol. 42, 375–379 (1993).

    CAS  PubMed  Google Scholar 

  49. 49

    Lee, C. Recombinant clotting factors in the treatment of hemophilia. Thromb. Haemost. 82, 516–524 (1999).

    CAS  PubMed  Google Scholar 

  50. 50

    Lusher, J. M. Recombinant clotting factors: a review of current clinical status. BioDrugs 13, 289–298 (2000).

    CAS  PubMed  Google Scholar 

  51. 51

    Bray, G. L. et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood 83, 2428–2435 (1994).

    CAS  PubMed  Google Scholar 

  52. 52

    Mariani, G., Ghirardini, A. & Bellocco, R. Immune tolerance in hemophilia-principal results from the International Registry. Report of the factor VIII and IX Subcommittee. Thromb. Haemost. 72, 155–158 (1994).

    CAS  PubMed  Google Scholar 

  53. 53

    Hedner, U., Glazer, S. & Falch, J. Recombinant activated factor VII in the treatment of bleeding episodes in patients with inherited and acquired bleeding disorders. Transfus. Med. Rev. 7, 78–83 (1993).

    CAS  PubMed  Google Scholar 

  54. 54

    Kurachi, K. & Davie, E. W. Isolation and characterization of a cDNA coding for human factor IX. Proc. Natl Acad. Sci. USA 79, 6461–6464 (1982).

    CAS  PubMed  Google Scholar 

  55. 55

    Kaufman, R. J., Wasley, L. C., Furie, B. C., Furie, B. & Shoemaker, C. B. Expression, purification, and characterization of recombinant gamma-carboxylated factor IX synthesized in Chinese hamster ovary cells. J. Biol. Chem. 261, 9622–9628 (1986).

    CAS  PubMed  Google Scholar 

  56. 56

    White, G. C., Beebe, A. & Nielsen, B. Recombinant factor IX. Thromb. Haemost. 78, 261–265 (1997).

    CAS  PubMed  Google Scholar 

  57. 57

    Shapiro, A. et al. Recombinant Factor IX (rFIX) in the treatment of previously untreated patients (PUPS) with severe or moderately severe hemophilia. Blood 92, A356 (1998).

    Google Scholar 

  58. 58

    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. 80, 773–778 (1998).

    CAS  PubMed  Google Scholar 

  59. 59

    Hagen, F. S. et al. Characterization of a cDNA coding for human factor VII. Proc. Natl Acad. Sci. USA 83, 2412–2416 (1986).

    CAS  PubMed  Google Scholar 

  60. 60

    O'Hara, P. J. 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. USA 84, 5158–5162 (1987).

    CAS  PubMed  Google Scholar 

  61. 61

    Hedner, U. Dosing with recombinant factor VIIa based on current evidence. Semin. Hematol. 41, 35–39 (2004).

    CAS  PubMed  Google Scholar 

  62. 62

    Ichinose, A. & Davie, E. W. Primary structure of human coagulation factor XIII. Adv. Exp. Med. Biol. 231, 15–27 (1988).

    CAS  PubMed  Google Scholar 

  63. 63

    Bishop, P. D. et al. Expression, purification, and characterization of human factor XIII in Saccharomyces cerevisiae. Biochemistry 29, 1861–1869 (1990).

    CAS  PubMed  Google Scholar 

  64. 64

    Chung, D. W., Rixon, M. W., Que, B. G. & Davie, E. W. Cloning of fibrinogen genes and their cDNA. Ann. NY Acad. Sci. 408, 449–456 (1983).

    CAS  PubMed  Google Scholar 

  65. 65

    Prunkard, D. et al. High-level expression of recombinant human fibrinogen in the milk of transgenic mice. Nature Biotechnol. 14, 867–871 (1996).

    CAS  Google Scholar 

  66. 66

    Lord, S. T., Binnie, C. G., Hettasch, J. M. & Strickland, E. Purification and characterization of recombinant human fibrinogen. Blood Coagul. Fibrinolysis 4, 55–59 (1993).

    CAS  PubMed  Google Scholar 

  67. 67

    Schwarz, H. P. et al. Recombinant von Willebrand factor-insight into structure and function through infusion studies in animals with severe von Willebrand disease. Semin. Thromb. Hemost. 28, 215–226 (2002).

    CAS  PubMed  Google Scholar 

  68. 68

    Plaimauer, B. et al. Recombinant von Willebrand factor: preclinical development. Semin. Thromb. Hemost. 27, 395–403 (2001).

    CAS  PubMed  Google Scholar 

  69. 69

    Sultan, Y., Kazatchkine, M. D., Maisonneuve, P. & Nydegger, U. E. Anti-idiotypic suppression of autoantibodies to factor VIII (antihaemophilic factor) by high-dose intravenous gammaglobulin. Lancet 2, 765–768 (1984).

    CAS  PubMed  Google Scholar 

  70. 70

    Jain, N. FDA recommendations for clinical trails [online] Workshop on FVIII Inhibitors (Meeting minutes, Miller Reporting Co., Inc.) <http://www.fda.gov/cber/minutes/fctrviii112103t.pdf> (2003).

  71. 71

    Pasi, K. J. Gene therapy for haemophilia. Br. J. Haematol. 115, 744–757 (2001).

    CAS  PubMed  Google Scholar 

  72. 72

    Nathwani, A. C., Nienhuis, A. W. & Davidoff, A. M. Current status of gene therapy for hemophilia. Curr. Hematol. Rep. 2, 319–327 (2003). A recent review of the application of gene therapy to the treatment of haemophilia.

    PubMed  Google Scholar 

  73. 73

    Ratko, T. A., Cummings, J. P., Blebea, J. & Matuszewski, K. A. Clinical gene therapy for nonmalignant disease. Am. J. Med. 115, 560–569 (2003).

    CAS  PubMed  Google Scholar 

  74. 74

    Adis [online; paid-service website] <http://www.adis.com> (2004).

  75. 75

    Lind, P. et al. Novel forms of B-domain-deleted recombinant factor VIII molecules. Construction and biochemical characterization. Eur. J. Biochem. 232, 19–27 (1995).

    CAS  PubMed  Google Scholar 

  76. 76

    Eriksson, R. K. et al. The manufacturing process for B-domain deleted recombinant factor VIII. Semin. Hematol. 38, 24–31 (2001).

    CAS  PubMed  Google Scholar 

  77. 77

    Schwaab, R. et al. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb. Haemost. 74, 1402–1406 (1995).

    CAS  PubMed  Google Scholar 

  78. 78

    Drake, T. A., Morrissey, J. H. & Edgington, T. S. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am. J. Pathol. 134, 1087–1097 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Rao, L. V. & Rapaport, S. I. Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation. Blood 69, 645–651 (1987).

    CAS  PubMed  Google Scholar 

  80. 80

    Brox, J. H., Osterud, B., Bjorklid, E. & Fenton, J. W. Production and availability of thromboplastin in endothelial cells: the effects of thrombin, endotoxin and platelets. Br. J. Haematol. 57, 239–246 (1984).

    CAS  PubMed  Google Scholar 

  81. 81

    Bevilacqua, M. P., Pober, J. S., Majeau, G. R., Cotran, R. S. & Gimbrone, M. A. Jr. Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J. Exp. Med. 160, 618–623 (1984).

    CAS  PubMed  Google Scholar 

  82. 82

    Jaffee, E. in Vascular Medicine (eds Loscalzo, J., Creager, M. A. & Dzau, C. M.) 3–46 (Little, Brown and Co., Boston, 1992).

    Google Scholar 

  83. 83

    Seyer, J. M. & Kang, A. H. in Vascular Medicine (eds Loscalzo, J., Creager, M. A. & Dzau, C. M.) 47–78 (Little, Brown and Co., Boston, 1992).

    Google Scholar 

  84. 84

    Hawiger, J. in Vascular Medicine (eds Loscalzo, J., Creager, M. A. & Dzau, C. M.) 205–232 (Little, Brown and Co., Boston, 1992).

    Google Scholar 

  85. 85

    Colman, R. W. & George, J. N. in Hemostasis and Thrombosis: Basic Principles and Clinical Practice (eds Colman, R. W., Hirsh, J., Marder, V. J., Clowes, A. W. & George, J. N.) 541–596 (Lippincott, Williams & Wilkins, Philadelphia, 2001).

    Google Scholar 

  86. 86

    Mannucci, P. M. Hemophilia: treatment options in the twenty-first century. J. Thromb. Haemost. 1, 1349–1355 (2003). A broad perspective of the future for the treatment of haemophilia.

    CAS  PubMed  Google Scholar 

  87. 87

    Dimichele, D., Miller, F. G. & Fins, J. J. Gene therapy ethics and haemophilia: an inevitable therapeutic future? Haemophilia 9, 145–152 (2003).

    CAS  PubMed  Google Scholar 

  88. 88

    Davie, E. W. & Ratnoff, O. D. Waterfall sequence for intrinsic blood clotting. Science 145, 1310–1312 (1964).

    CAS  PubMed  Google Scholar 

  89. 89

    Macfarlane, R. G. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature 202, 498–499 (1964). References 88 and 89 are seminal papers that set forth the concept of initiation of coagulation as a cascade of proteolytic activation steps.

    CAS  PubMed  Google Scholar 

  90. 90

    Mann, K. G., Brummel, K. & Butenas, S. What is all that thrombin for? J. Thromb. Haemost. 1, 1504–1514 (2003).

    CAS  PubMed  Google Scholar 

  91. 91

    Lawson, J. H., Kalafatis, M., Stram, S. & Mann, K. G. A model for the tissue factor pathway to thrombin. I. An empirical study. J. Biol. Chem. 269, 23357–23366 (1994).

    CAS  PubMed  Google Scholar 

  92. 92

    Osterud, B. & Rapaport, S. I. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc. Natl Acad. Sci. USA 74, 5260–5264 (1977).

    CAS  PubMed  Google Scholar 

  93. 93

    Bom, V. J. & Bertina, R. M. The contributions of Ca2+, phospholipids and tissue-factor apoprotein to the activation of human blood-coagulation factor X by activated factor VII. Biochem. J. 265, 327–336 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Lu, G., Broze, G. J. & Krishnaswamy, S. Formation of factors IXa and Xa by the extrinsic pathway: differential regulation by tissue factor pathway inhibitor and antithrombin III. J. Biol. Chem. (2004).

  95. 95

    Butenas, S., van 't Veer, C., Cawthern, K., Brummel, K. E. & Mann, K. G. Models of blood coagulation. Blood Coagul. Fibrinolysis 11 (Suppl. 1), S9–S13 (2000).

    CAS  PubMed  Google Scholar 

  96. 96

    Mann, K. G. Biochemistry and physiology of blood coagulation. Thromb. Haemost. 82, 165–174 (1999).

    CAS  PubMed  Google Scholar 

  97. 97

    Mann, K. G., van't Veer, C., Cawthern, K. & Butenas, S. The role of the tissue factor pathway in initiation of coagulation. Blood Coagul. Fibrinolysis 9 (Suppl. 1), S3–S7 (1998).

    CAS  PubMed  Google Scholar 

  98. 98

    Kane, W. H. & Davie, E. W. Blood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders. Blood 71, 539–555 (1988).

    CAS  PubMed  Google Scholar 

  99. 99

    Cohen, A. & Kitchens, C. M. in Consultative Hemostasis and Thrombosis (eds Kitchens, C. S., Alving, B. & Kessler, C. M.) 43–56 (W. B. Saunders Co., Philadelphia, 2002).

  100. 100

    Roberts, H. & Escobar, M. E. in Consultative Hemostasis and Thrombosis (eds Kitchens, C. S., Alving, B. & Kessler, C. M.) 57–74 (W. B. Saunders Co., Philadelphia, 2002).

    Google Scholar 

  101. 101

    Acharya, S. S., Coughlin, A. & Dimichele, D. M. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J. Thromb. Haemost. 2, 248–256 (2004).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Special thanks to D. Adler, D. Irwin, K. Lewis, G. McKnight, B. Wetzel and A. Yeomans (ZymoGenetics Inc.) for their assistance with this manuscript; and A. Thompson (Puget Sound Blood Center) for his discussions on blood-blanking issues.

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Competing interests

P. B. is currently an employee of ZymoGenetics, which is developing recombinant thrombin and factor XIII as discussed in the text.

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DATABASES

Entrez Gene

α2-plasmin inhibitor

fibronectin

fibrinogen

FV

FVIIa

FVIII

FIX

FX

FXIII

tissue factor

thrombin

thrombin-activated fibrinolysis inhibitor

type-2 plasminogen-activator inhibitor

vWF

Online Mendelian Inheritance in Man

Haemophilia A

Haemophilia B

vWD

FURTHER INFORMATION

American Hemotology Association

American Association of Blood Banks

Blood Centers of the Pacific

International Society for Fibrinolysis and Proteolysis

International Fibrinogen Research Society

The International Society on Thrombosis and Haemostasis

Trauma.org

World Blood Supply (haemonetics.com)

World Federation of Hemophilia

Glossary

HAEMATOMA

A collection of blood within soft tissue that results in swelling (tumour).

COAGULOPATHY

A disorder that prevents normal clotting of the blood.

IATROGENIC

'Iatros' means physician in Greek, and '-genic', means induced by. An iatrogenic disease is a disease that is caused by a physician.

HAEMORRHAGIC DIATHESIS

A condition in which the patient is more prone to bleeding than normal.

TENASE

Tenase is the complex of the cofactor factor VIIIa (FVIIIa) and the enzyme FIXa assembled on a membrane surface. The function of this multi-enzyme complex is to proteolytically activate FX (to FXa).

PROTHROMBINASE

Prothrombinase is the complex of the cofactor factor Va (FVa) and the enzyme FXa assembled on a membrane surface. The function of this multi-enzyme complex is to proteolytically activate prothrombin (FII) to a-thrombin (FIIa).

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Bishop, P., Lawson, J. Recombinant biologics for treatment of bleeding disorders. Nat Rev Drug Discov 3, 684–694 (2004). https://doi.org/10.1038/nrd1443

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