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Multiple Coagulation Factor Deficiency

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Congenital Bleeding Disorders

Abstract

Bleeding disorders with low plasma activity of more than one coagulation factor have been described in several conditions. Multiple coagulation factor deficiency (MCFD) commonly represents as part of acquired conditions. The most well-known acquired causes are liver disease and disseminated intravascular coagulation (DIC) in which impaired synthesis or excessive consumption of coagulation factors occurs, respectively. Dilution states such as massive transfusion and cardiopulmonary bypass are also considered as conditions which lead to MCFD. Congenital deficiencies of more than one coagulation factor rarely have been also described. Such disorders can be rare autosomal bleeding disorder with extremely low incidence. Congenital MCFD may arise from coinheritance of isolated factor defects or may be a result of a single genetic defect. The latter which comprises most of cases is generally caused by defect of a single gene that is implicated in the process or production/activation of multiple factors. The best examples include combined FV and FVIII deficiency (F5F8D) and vitamin K-dependent coagulation factors (VKDCF) deficiency, which have been thoroughly characterized. Isolated combined coagulation factor deficiencies are extremely rare disorders and restricted to isolated case reports.

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References

  1. Seligsohn U, Zivelin A, Zwang E. Combined factor V and factor VIII deficiency among non-Ashkenazi Jews. N Engl J Med. 1982;307(19):1191.

    Article  CAS  PubMed  Google Scholar 

  2. Castaman G, Linari S. Diagnosis and treatment of von Willebrand disease and rare bleeding disorders. J Clin Med. 2017;6(4):45.

    Article  CAS  PubMed Central  Google Scholar 

  3. Peyvandi F, Tuddenham E, Akhtari A, Lak M, Mannucci P. Bleeding symptoms in 27 Iranian patients with the combined deficiency of factor V and factor VIII. Br J Haematol. 1998;100(4):733–4.

    Article  Google Scholar 

  4. Zhang B. Recent developments in the understanding of the combined deficiency of FV and FVIII. Br J Haematol. 2009;145(1):15–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang B, Ginsburg D. Familial multiple coagulation factor deficiencies: new biologic insight from rare genetic bleeding disorders. J Thromb Haemost. 2004;2(9):1564–72.

    Article  CAS  PubMed  Google Scholar 

  7. Zheng C, Liu H-H, Yuan S, Zhou J, Zhang B. Molecular basis of LMAN1 in coordinating LMAN1-MCFD2 cargo receptor formation and ER-to-Golgi transport of FV/FVIII. Blood. 2010;116(25):5698–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zheng C, Liu H-H, Zhou J, Zhang B. EF-hand domains of MCFD2 mediate interactions with both LMAN1 and coagulation factor V or VIII. Blood. 2010;115(5):1081–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Oeri J, Matter M, Isenschmid H, Hauser F, Koller F. Congenital factor V deficiency (parahemophilia) with true hemophilia in two brothers. Bibl Paediatr. 1954;58:575.

    PubMed  CAS  Google Scholar 

  10. Jin D-Y, Ingram BO, Stafford DW, Tie J-K. Molecular basis of the first reported clinical case of congenital combined deficiency of coagulation factors. Blood. 2017;130(7):948–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nichols WC, Seligsohn U, Zivelin A, Terry VH, Arnold ND, Siemieniak DR, et al. Linkage of combined factors V and VIII deficiency to chromosome 18q by homozygosity mapping. J Clin Investig. 1997;99(4):596.

    Article  CAS  PubMed  Google Scholar 

  12. Nichols WC, Seligsohn U, Zivelin A, Terry VH, Hertel CE, Wheatley MA, et al. Mutations in the ER–Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell. 1998;93(1):61–70.

    Article  CAS  PubMed  Google Scholar 

  13. Shetty S, Madkaikar M, Nair S, Pawar A, Baindur S, Pathare A, et al. Combined factor V and VIII deficiency in Indian population. Haemophilia. 2000;6:504–7.

    Article  CAS  PubMed  Google Scholar 

  14. Mansouritorgabeh H, Rezaieyazdi Z, Pourfathollah A, Rezai J, Esamaili H. Haemorrhagic symptoms in patients with combined factors V and VIII deficiency in North-Eastern Iran. Haemophilia. 2004;10(3):271–5.

    Article  CAS  PubMed  Google Scholar 

  15. Viswabandya A, Baidya S, Nair SC, Lakshmi KM, Mathews V, George B, et al. Clinical manifestations of combined factor V and VIII deficiency: a series of 37 cases from a single center in India. Am J Hematol. 2010;85(7):538–9.

    Article  PubMed  Google Scholar 

  16. Zheng C, Zhang B. Combined deficiency of coagulation factors V and VIII: an update. Semin Thromb Hemost. 2013;39(6):613–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Karimi M, Cairo A, Safarpour MM, Haghpanah S, Ekramzadeh M, Afrasiabi A, et al. Genotype and phenotype report on patients with combined deficiency of factor V and factor VIII in Iran. Blood Coagul Fibrinolysis. 2014;25(4):360–3.

    Article  CAS  PubMed  Google Scholar 

  18. Hejer E, Adnen L, Asma J, Ibtihel M, Benammar-Elgaaied A, Gouider E. Identification of a novel mutation in the MCFD2 gene in a Tunisian family with combined factor V and VIII deficiency. Tunis Med. 2012;90(4):343–4.

    PubMed  Google Scholar 

  19. Wang A, Liu X, Wu J, Cai X, Zhu W, Sun Z. Combined FV and FVIII deficiency (F5F8D) in a Chinese family with a novel missense mutation in MCFD2 gene. Haemophilia. 2014;20(6):e436–8.

    Article  CAS  PubMed  Google Scholar 

  20. Genotypes of patients with combined factor V and VIII deficiency [internet]. 2011. https://c.ymcdn.com/sites/www.isth.org/resource/resmgr/publications/fv_and_viii_mutations-2011.pdf.

  21. Wang A, Duan Q, Ding K, Liu X, Wu J, Sun Z. Successful abdominal operation without replacement therapy in a patient with combined factor V (FV) and FVIII deficiency due to novel homozygous mutation in LMAN1. Haemophilia. 2015;21(6):e492–4.

    Article  CAS  PubMed  Google Scholar 

  22. Elmahmoudi H, Wigren E, Laatiri A, Jlizi A, Elgaaied A, Gouider E, et al. Analysis of newly detected mutations in the MCFD2 gene giving rise to combined deficiency of coagulation factors V and VIII. Haemophilia. 2011;17(5):e923–7.

    PubMed  CAS  Google Scholar 

  23. Zhang B, Spreafico M, Zheng C, Yang A, Platzer P, Callaghan MU, et al. Genotype-phenotype correlation in combined deficiency of factor V and factor VIII. Blood. 2008;111(12):5592–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Khoriaty R, Vasievich MP, Ginsburg D. The COPII pathway and hematologic disease. Blood. 2012;120(1):31–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Latif A, Aledort L. Inherited combined factor deficiency states. In: Hemostasis and thrombosis. Oxford: Wiley; 2014. p. 127–36.

    Chapter  Google Scholar 

  26. Mansouritorghabeh H, Shirdel A. Desmopressin acetate as a haemostatic elevator in individuals with combined deficiency of factors V and VIII: a clinical trial. J Thromb Haemost. 2016;14(2):336–9.

    Article  CAS  PubMed  Google Scholar 

  27. Peyvandi F, Menegatti M. Treatment of rare factor deficiencies in 2016. Hematology Am Soc Hematol Educ Program. 2016;2016(1):663–9.

    PubMed  Google Scholar 

  28. Oukkache B, El Graoui O, Zafad S. Combined factor V and VIII deficiency and pregnancy. Int J Hematol. 2012;96(6):786–8.

    Article  PubMed  Google Scholar 

  29. Brenner B, Kuperman AA, Watzka M, Oldenburg J. Vitamin K-dependent coagulation factors deficiency. Semin Thromb Hemost. 2009;35(4):439–46.

    Article  CAS  PubMed  Google Scholar 

  30. Napolitano M, Mariani G, Lapecorella M. Hereditary combined deficiency of the vitamin K-dependent clotting factors. Orphanet J Rare Dis. 2010;5(1):21.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Stafford D. The vitamin K cycle. J Thromb Haemost. 2005;3(8):1873–8.

    Article  CAS  PubMed  Google Scholar 

  32. Tie JK, Stafford DW. Structural and functional insights into enzymes of the vitamin K cycle. J Thromb Haemost. 2016;14(2):236–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Oldenburg J, Marinova M, Müller-Reible C, Watzka M. The vitamin K cycle. Vitam Horm. 2008;78:35–62.

    Article  CAS  PubMed  Google Scholar 

  34. Oldenburg J, Bevans CG, Müller CR, Watzka M. Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal. 2006;8(3-4):347–53.

    Article  CAS  PubMed  Google Scholar 

  35. Gallieni M, Fusaro M. Vitamin K and cardiovascular calcification in CKD: is patient supplementation on the horizon? Kidney Int. 2014;86(2):232.

    Article  CAS  PubMed  Google Scholar 

  36. McMillan CW, Roberts HR. Congenital combined deficiency of coagulation factors II, VII, IX and X: report of a case. N Engl J Med. 1966;274(23):1313–5.

    Article  CAS  PubMed  Google Scholar 

  37. Chung K-S, Bezeaud A, Goldsmith JC, McMillan CW, Menache D, Roberts HR. Congenital deficiency of blood clotting factors II, VII, IX, and X. Blood. 1979;53(4):776–87.

    PubMed  CAS  Google Scholar 

  38. Oldenburg J, Von Brederlow B, Fregin A, Rost S, Wolz W, Eberl W, et al. Congenital deficiency of vitamin K-dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex. Thromb Haemost. 2000;84(6):937–41.

    PubMed  CAS  Google Scholar 

  39. Brenner B, Sánchez-Vega B, Wu S-M, Lanir N, Stafford DW, Solera J. A missense mutation in γ-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood. 1998;92(12):4554–9.

    PubMed  CAS  Google Scholar 

  40. Spronk HM, Farah RA, Buchanan GR, Vermeer C, Soute BA. Novel mutation in the γ-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K–dependent blood coagulation factors. Blood. 2000;96(10):3650–2.

    PubMed  CAS  Google Scholar 

  41. Lunghi B, Redaelli R, Caimi T, Corno A, Bernardi F, Marchetti G. Novel phenotype and γ-glutamyl carboxylase mutations in combined deficiency of vitamin K-dependent coagulation factors. Haemophilia. 2011;17(5):822–4.

    PubMed  CAS  Google Scholar 

  42. Hauschka PV, Lian JB, Cole D, Gundberg CM. Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev. 1989;69(3):990–1047.

    Article  CAS  PubMed  Google Scholar 

  43. Pauli R, Lian J, Mosher D, Suttie J. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives. Am J Hum Genet. 1987;41(4):566.

    PubMed  PubMed Central  CAS  Google Scholar 

  44. Vanakker OM, Martin L, Gheduzzi D, Leroy BP, Loeys BL, Guerci VI, et al. Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity. J Investig Dermatol. 2007;127(3):581–7.

    Article  CAS  PubMed  Google Scholar 

  45. Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood. 2015;125(13):2052–61.

    Article  CAS  PubMed  Google Scholar 

  46. Thomas A, Stirling D. Four factor deficiency. Blood Coagul Fibrinolysis. 2003;14:S55–S7.

    Article  PubMed  Google Scholar 

  47. Prisco D, Ciuti G, Falciani M. Hemostatic changes in normal pregnancy. Haematol Rep. 2009;1:1–5.

    Article  CAS  Google Scholar 

  48. Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011;25(1):161–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381(9863):333–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Briggs BJ, Dickerman JD. Bleeding disorders in Noonan syndrome. Pediatr Blood Cancer. 2012;58(2):167–72.

    Article  PubMed  Google Scholar 

  51. Kurosawa H, Suzumura H, Okuya M, Fukushima K, Sugita K, Fujiwara T, et al. Haemostatic management of surgery for imperforate anus in a patient with 13q deletion syndrome with combined deficiency of factors VII and X. Haemophilia. 2009;15(1):398–400.

    Article  CAS  PubMed  Google Scholar 

  52. Pfeiffer R, Ott R, Gilgenkrantz S, Alexandre P. Deficiency of coagulation factors VII and X associated with deletion of a chromosome 13 (q34). Evidence from two cases with 46, XY, t (13; Y)(q11; q34). Hum Genet. 1982;62(4):358–60.

    Article  CAS  PubMed  Google Scholar 

  53. Chilcott J, Russell G, Mumford A. Combined deficiency of factors VII and X: clinical description of two cases and management of spinal surgery. Haemophilia. 2006;12(5):555–8.

    Article  CAS  PubMed  Google Scholar 

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Hosseini, M.S., Shams, M., Dorgalaleh, A., Mansouritorghabeh, H. (2018). Multiple Coagulation Factor Deficiency. In: Dorgalaleh, A. (eds) Congenital Bleeding Disorders . Springer, Cham. https://doi.org/10.1007/978-3-319-76723-9_9

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  • DOI: https://doi.org/10.1007/978-3-319-76723-9_9

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