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Congenital Factor II Deficiency

  • Yadollah Farshi
  • Akbar Dorgalaleh
  • Shadi Tabibian
Chapter

Abstract

Coagulation factor (F) II (prothrombin) is a vitamin K-dependent coagulation factor which has an essential role in coagulation cascade. This protein is activated to thrombin by Factor X in the presence of FV and calcium. Congenital FII deficiency is an autosomal recessive bleeding disorder with an estimated incidence of 1:2,000,000 worldwide. This disorder mostly presents in regions with high rate of parental consanguinity and accounts for ~3% of all rare bleeding disorders (RBD). FII deficiency mostly presents with mucocutaneous hemorrhage, hematoma, and post-trauma bleeding. Life-threatening bleedings including central nervous bleeding and gastrointestinal bleeding rarely occurred in these patients. Approximately, 60 mutations have been reported within F2 gene; among them missense mutations are the most frequent. In general, family history, clinical manifestations, and routine coagulation laboratory tests should be used for diagnose of FII deficiency. FII deficiency is suspected through prolonged prothrombin time (PT) and activated thromboplastin time (aPTT) which was confirmed by a specific FII assay. As no specific prothrombin concentrate is available, prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) is currently used for treatment of prothrombin deficiency.

Keywords

Congenital factor II deficiency Rare bleeding disorder Diagnosis Management 

References

  1. 1.
    Pozzi N, Chen Z, Gohara DW, Niu W, Heyduk T, Di Cera E. Crystal structure of prothrombin reveals conformational flexibility and mechanism of activation. J Biol Chem. 2013;288(31):22734–44.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kamath P, Krishnaswamy S. Fate of membrane-bound reactants and products during the activation of human prothrombin by prothrombinase. J Biol Chem. 2008;283(44):30164–73.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lancellotti S, Basso M, De Cristofaro R. Congenital prothrombin deficiency: an update. Semin Thromb Hemost. 2013;39(6):596–606.CrossRefPubMedGoogle Scholar
  4. 4.
    Hassanian SM, Dinarvand P, Rezaie AR. Adenosine regulates the proinflammatory signaling function of thrombin in endothelial cells. J Cell Physiol. 2014;229(9):1292–300.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood. 2004;104(5):1243–52.CrossRefPubMedGoogle Scholar
  6. 6.
    Peyvandi F, Duga S, Akhavan S, Mannucci P. Rare coagulation deficiencies. Haemophilia. 2002;8(3):308–21.CrossRefPubMedGoogle Scholar
  7. 7.
    Akhavan S, Luciani M, Lavoretano S, Mannucci PM. Phenotypic and genetic analysis of a compound heterozygote for dys-and hypoprothrombinaemia. Br J Haematol. 2003;120(1):142–4.CrossRefPubMedGoogle Scholar
  8. 8.
    Rodriguez V, Warad D. Pediatric coagulation disorders. Pediatr Rev. 2016;37(7):279.CrossRefPubMedGoogle Scholar
  9. 9.
    Su K, Jin Y, Miao Z, Cheng X, Yang L, Wang M. Phenotypic and genetic analysis of dysprothrombinemia due to a novel homozygous mutation. Hematology. 2017;22(6):380–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Mumford AD, Ackroyd S, Alikhan R, Bowles L, Chowdary P, Grainger J, et al. Guideline for the diagnosis and management of the rare coagulation disorders. Br J Haematol. 2014;167(3):304–26.CrossRefPubMedGoogle Scholar
  11. 11.
    Huntington JA. How Na+ activates thrombin–a review of the functional and structural data. Biol Chem. 2008;389(8):1025–35.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bode W. The structure of thrombin: a janus-headed proteinase. Semin Thromb Hemost. 2006;32(Suppl 1):16–31.CrossRefPubMedGoogle Scholar
  13. 13.
    Bode W, Turk D, Karshikov A. The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships. Protein Sci. 1992;1(4):426–71.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Adams TE, Huntington JA. Thrombin-cofactor interactions: structural insights into regulatory mechanisms. Arterioscler Thromb Vasc Biol. 2006;26(8):1738–45.CrossRefPubMedGoogle Scholar
  15. 15.
    Crawley J, Zanardelli S, Chion C, Lane D. The central role of thrombin in hemostasis. J Thromb Haemost. 2007;5(s1):95–101.CrossRefPubMedGoogle Scholar
  16. 16.
    Carter IS, Vanden Hoek AL, Pryzdial EL, MacGillivray RT. Thrombin a-chain: activation remnant or allosteric effector? Thrombosis. 2010;2010:416167.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hansson K, Stenflo J. Post-translational modifications in proteins involved in blood coagulation. J Thromb Haemost. 2005;3(12):2633–48.CrossRefPubMedGoogle Scholar
  18. 18.
    Davie EW, Kulman JD. An overview of the structure and function of thrombin. Semin Thromb Hemost. 2006;32(Suppl 1):3–15.CrossRefPubMedGoogle Scholar
  19. 19.
    Mizuochi T, Fujii J, Kisiel W, Kobata A. Studies on the structures of the carbohydrate moiety of human prothrombin. J Biochem. 1981;90(4):1023–31.CrossRefPubMedGoogle Scholar
  20. 20.
    Krishnaswamy S. Prothrombinase complex assembly. Contributions of protein-protein and protein-membrane interactions toward complex formation. J Biol Chem. 1990;265(7):3708–18.PubMedGoogle Scholar
  21. 21.
    Krishnaswamy S. The transition of prothrombin to thrombin. J Thromb Haemost. 2013;11(s1):265–76.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Haynes LM, Bouchard BA, Tracy PB, Mann KG. Prothrombin activation by platelet-associated prothrombinase proceeds through the prethrombin-2 pathway via a concerted mechanism. J Biol Chem. 2012;287(46):38647–55.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Di Cera E, Dang Q, Ayala Y. Molecular mechanisms of thrombin function. CMLS. 1997;53(9):701–30.CrossRefPubMedGoogle Scholar
  24. 24.
    Boissel J, Le Bonniec B, Rabiet M, Labie D, Elion J. Covalent structures of beta and gamma autolytic derivatives of human alpha-thrombin. J Biol Chem. 1984;259(9):5691–7.PubMedGoogle Scholar
  25. 25.
    Mullin JL, Gorkun OV, Binnie CG, Lord ST. Recombinant fibrinogen studies reveal that thrombin specificity dictates order of fibrinopeptide release. J Biol Chem. 2000;275(33):25239–46.CrossRefPubMedGoogle Scholar
  26. 26.
    Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev. 2007;21(3):131–42.CrossRefPubMedGoogle Scholar
  27. 27.
    Standeven KF, Ariëns RA, Whitaker P, Ashcroft AE, Weisel JW, Grant PJ. The effect of dimethylbiguanide on thrombin activity, FXIII activation, fibrin polymerization, and fibrin clot formation. Diabetes. 2002;51(1):189–97.CrossRefPubMedGoogle Scholar
  28. 28.
    Narayanan S. Multifunctional roles of thrombin. Ann Clin Lab Sci. 1999;29(4):275–80.PubMedGoogle Scholar
  29. 29.
    Camire R, Bos M. The molecular basis of factor V and VIII procofactor activation. J Thromb Haemost. 2009;7(12):1951–61.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Myles T, Yun TH, Leung LL. Structural requirements for the activation of human factor VIII by thrombin. Blood. 2002;100(8):2820–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Bouma BN, Mosnier LO. Thrombin activatable fibrinolysis inhibitor (TAFI)—how does thrombin regulate fibrinolysis? Ann Med. 2006;38(6):378–88.CrossRefPubMedGoogle Scholar
  32. 32.
    Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407(6801):258–65.CrossRefPubMedGoogle Scholar
  33. 33.
    Andersen H, Greenberg DL, Fujikawa K, Xu W, Chung DW, Davie EW. Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity. Proc Natl Acad Sci. 1999;96(20):11189–93.CrossRefPubMedGoogle Scholar
  34. 34.
    Yang L, Manithody C, Rezaie AR. Activation of protein C by the thrombin–thrombomodulin complex: cooperative roles of Arg-35 of thrombin and Arg-67 of protein C. Proc Natl Acad Sci U S A. 2006;103(4):879–84.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Girolami A, Santarossa L, Scarparo P, Candeo N, Girolami B. True congenital prothrombin deficiency due to a ‘new’ mutation in the pre-propeptide (ARG-39 GLN). Acta Haematol. 2008;120(2):82–6.CrossRefPubMedGoogle Scholar
  36. 36.
    Acharya SS. Rare bleeding disorders in children: identification and primary care management. Pediatrics. 2013;132(5):882–92.CrossRefPubMedGoogle Scholar
  37. 37.
    Bajaj S, Rapaport S, Barclay S, Herbst K. Acquired hypoprothrombinemia due to non-neutralizing antibodies to prothrombin: mechanism and management. Blood. 1985;65(6):1538–43.PubMedGoogle Scholar
  38. 38.
    O’Marcaigh AS, Nichols WL, Hassinger NL, Mullins JD, Mallouh AA, Gilchrist GS, et al. Genetic analysis and functional characterization of prothrombins Corpus Christi (Arg382-Cys), Dhahran (Arg271-His), and hypoprothrombinemia. Blood. 1996;88(7):2611–8.PubMedGoogle Scholar
  39. 39.
    Lancellotti S, De Cristofaro R. Congenital prothrombin deficiency. Semin Thromb Hemost. 2009;35(4):367–81.CrossRefPubMedGoogle Scholar
  40. 40.
    Miyawaki Y, Suzuki A, Fujita J, Maki A, Okuyama E, Murata M, et al. Thrombosis from a prothrombin mutation conveying antithrombin resistance. N Engl J Med. 2012;366(25):2390–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Sun WY, Smirnow D, Jenkins ML, Degen SJ. Prothrombin scranton: substitution of an amino acid residue involved in the binding of Na+ (LYS-556 to THR) leads to dysprothrombinemia. Thromb Haemost. 2001;85(4):651–4.CrossRefPubMedGoogle Scholar
  42. 42.
    Flaujac C, Conard J, Horellou M, Le Flem L, Samama M. Atypical mutations of the prothrombin gene at positions 20 209 and 20 218, and a novel mutation at position 20 219. Report on 10 patients. J Thromb Haemost. 2007;5(5):1064–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Rabiet MJ, Furie BC, Furie B. Molecular defect of prothrombin Barcelona. Substitution of cysteine for arginine at residue 273. J Biol Chem. 1986;261(32):15045–8.PubMedGoogle Scholar
  44. 44.
    Lefkowitz JB, Haver T, Clarke S, Jacobson L, Weller A, Nuss R, et al. The prothrombin Denver patient has two different prothrombin point mutations resulting in Glu-300→ Lys and Glu-309→ Lys substitutions. Br J Haematol. 2000;108(1):182–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Bezeaud A, Vidaud D, Guillin M-C. Les déficits constitutionnels en prothrombine et les informations qu’ils peuvent nous apporter sur la structure et les fonctions de la prothrombine. Hématologie. 2005;11(6):397–407.Google Scholar
  46. 46.
    Varga EA, Moll S. Prothrombin 20210 mutation (factor II mutation). Circulation. 2004;110(3):e15-e8.CrossRefGoogle Scholar
  47. 47.
    Zivelin A, Rosenberg N, Faier S, Kornbrot N, Peretz H, Mannhalter C, et al. A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene. Blood. 1998;92(4):1119–24.PubMedGoogle Scholar
  48. 48.
    Pihusch R, Hiller E, Buchholz T, Rogenhofer N, Hasbargen U, Thaler CJ, et al. Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol. 2001;46(2):124–31.CrossRefPubMedGoogle Scholar
  49. 49.
    Carter AM, Sachchithananthan M, Stasinopoulos S, Maurer F, Medcalf RL. Prothrombin G20210A is a bifunctional gene polymorphism. Thromb Haemost. 2002;87(5):846–53.CrossRefPubMedGoogle Scholar
  50. 50.
    Warshawsky I, Makkar V, Rimmerman C, Kottke-Marchant K. Prothrombin 20209C> T: 16 new cases, association with the 19911A> G polymorphism, and literature review. J Thromb Haemost. 2009;7(9):1585–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Peyvandi F, Menegatti M, Palla R. Rare bleeding disorders: worldwide efforts for classification, diagnosis, and management. Semin Thromb Hemost. 2013;39(6):579–84.CrossRefPubMedGoogle Scholar
  52. 52.
    Meeks S, Abshire T. Abnormalities of prothrombin: a review of the pathophysiology, diagnosis, and treatment. Haemophilia. 2008;14(6):1159–63.CrossRefPubMedGoogle Scholar
  53. 53.
    Denson K, Borrett R, Biggs R. The specific assay of prothrombin using the Taipan snake venom. Br J Haematol. 1971;21(2):219–26.CrossRefPubMedGoogle Scholar
  54. 54.
    Girolami A, Scarano L, Saggiorato G, Girolami B, Bertomoro A, Marchiori A. Congenital deficiencies and abnormalities of prothrombin. Blood Coagul Fibrinolysis. 1998;9(7):557–70.CrossRefPubMedGoogle Scholar
  55. 55.
    Acharya S, Coughlin A, Dimichele DM. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost. 2004;2(2):248–56.CrossRefPubMedGoogle Scholar
  56. 56.
    Kershaw G, Favaloro EJ. Laboratory identification of factor inhibitors: an update. Pathology. 2012;44(4):293–302.CrossRefPubMedGoogle Scholar
  57. 57.
    Peyvandi F, Di Michele D, Bolton-Maggs P, Lee C, Tripodi A, Srivastava A. Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity. J Thromb Haemost. 2012;10(9):1938–43.CrossRefPubMedGoogle Scholar
  58. 58.
    Deangelo J, Jarrell D, Cosgrove R, Camamo J, Edwards C, Patanwala AE. Comparison of 3-factor versus 4-factor prothrombin complex concentrate with regard to warfarin reversal, blood product use, and costs. Am J Ther. 2017.  https://doi.org/10.1097/MJT.0000000000000643.
  59. 59.
    Bolton-Maggs P, Perry D, Chalmers E, Parapia L, Wilde J, Williams M, et al. The rare coagulation disorders–review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation. Haemophilia. 2004;10(5):593–628.CrossRefPubMedGoogle Scholar
  60. 60.
    Kadir R, Chi C, Bolton-Maggs P. Pregnancy and rare bleeding disorders. Haemophilia. 2009;15(5):990–1005.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Yadollah Farshi
    • 1
  • Akbar Dorgalaleh
    • 2
  • Shadi Tabibian
    • 2
  1. 1.Department of Hematology and Blood TransfusionSchool of Allied Medicine, Tehran University of Medical SciencesTehranIran
  2. 2.Department of Hematology and Blood TransfusionSchool of Allied Medicine, Iran University of Medical SciencesTehranIran

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