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Congenital Bleeding Disorders

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Congenital Bleeding Disorders

Abstract

Congenital bleeding disorders (CBD) are heterogeneous group of disorders with variable clinical presentations ranging from asymptomatic condition, mostly in inherited platelet function disorders (IPFD), to severe life-threatening disorders, notably in factor (F) XIII deficiency. Most of these disorders including rare bleeding disorders (RBD) and IPFD are autosomal recessive disorders, while patients with hemophilia A and B had X-linked recessive manner of inheritance with a considerable percent of de novo mutations. The incidence of disorders is highly variable and can be as common as ~1% for von Willebrand disease (VWD) to 1 per 2 million for FXIII and FII deficiencies. Diagnosis of some CDB, such as Glanzmann thrombasthenia (GT), is straightforward, while others such as VWD and congenital fibrinogen disorders have more sophisticated diagnostic process. Most of CBD, notably IPFD, are mild bleeding disorders that never require medical intervention. The main therapeutic choice in most CBD is on-demand therapy, while in others, such as hemophilia A and B and FXIII deficiency, primary prophylaxis is the recommended treatment option. With timely diagnosis and appropriate management of CBD, the burden of disorders can be alleviated or significantly decreased.

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References

  1. Rick ME, Walsh CE, Key NS. Congenital bleeding disorders. ASH Education Program Book. 2003;2003(1):559–74.

    Google Scholar 

  2. Brown DL. Congenital bleeding disorders. Curr Probl Pediatr Adolesc Health Care. 2005;35(2):38–62.

    Article  PubMed  Google Scholar 

  3. Sadler J, Budde U, Eikenboom J, Favaloro E, Hill F, Holmberg L, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006;4(10):2103–14.

    Article  PubMed  CAS  Google Scholar 

  4. Dorgalaleh A, Tabibian S, Hosseini S, Shamsizadeh M. Guidelines for laboratory diagnosis of factor XIII deficiency. Blood Coagul Fibrinolysis. 2016;27(4):361–4.

    Article  CAS  PubMed  Google Scholar 

  5. Alavi SER, Jalalvand M, Assadollahi V, Tabibian S, Dorgalaleh A. Intracranial hemorrhage: a devastating outcome of congenital bleeding disorders—prevalence, diagnosis, and management, with a special focus on congenital factor XIII deficiency. Semin Thromb Hemost. 2017. https://doi.org/10.1055/s-0037-1604109.

  6. Dorgalaleh A, Tabibian S, Shamsizadeh M. Inherited platelet function disorders (IPFDs). Clin Lab. 2017;63(1):1–13.

    Google Scholar 

  7. Gresele P. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost. 2015;13(2):314–22.

    Article  CAS  PubMed  Google Scholar 

  8. Naderi M, Dorgalaleh A, Alizadeh S, Tabibian S, Hosseini S, Shamsizadeh M, et al. Clinical manifestations and management of life-threatening bleeding in the largest group of patients with severe factor XIII deficiency. Int J Hematol. 2014;100(5):443–9.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Biss T, Blanchette V, Clark D, Wakefield C, James P, Rand M. Use of a quantitative pediatric bleeding questionnaire to assess mucocutaneous bleeding symptoms in children with a platelet function disorder. J Thromb Haemost. 2010;8(6):1416–9.

    Article  CAS  PubMed  Google Scholar 

  11. Lowe GC, Lordkipanidzé M, Watson SP. Utility of the ISTH bleeding assessment tool in predicting platelet defects in participants with suspected inherited platelet function disorders. J Thromb Haemost. 2013;11(9):1663–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Toygar HU, Guzeldemir E. Excessive gingival bleeding in two patients with Glanzmann thrombasthenia. J Periodontol. 2007;78(6):1154–8.

    Article  PubMed  Google Scholar 

  13. Poon M-C, Di Minno G, d’Oiron R, Zotz R. New insights into the treatment of Glanzmann thrombasthenia. Transfus Med Rev. 2016;30(2):92–9.

    Article  PubMed  Google Scholar 

  14. Santagostino E, Mancuso M, Tripodi A, Chantarangkul V, Clerici M, Garagiola I, et al. Severe hemophilia with mild bleeding phenotype: molecular characterization and global coagulation profile. J Thromb Haemost. 2010;8(4):737–43.

    Article  CAS  PubMed  Google Scholar 

  15. Stieltjes N, Calvez T, Demiguel V, Torchet M, Briquel M, Fressinaud E, et al. Intracranial haemorrhages in French haemophilia patients (1991–2001): clinical presentation, management and prognosis factors for death. Haemophilia. 2005;11(5):452–8.

    Article  CAS  PubMed  Google Scholar 

  16. Den Uijl I, Fischer K, Van Der Bom J, Grobbee D, Rosendaal F, Plug I. Clinical outcome of moderate haemophilia compared with severe and mild haemophilia. Haemophilia. 2009;15(1):83–90.

    Article  Google Scholar 

  17. Van den Berg H, de Groot P, Fischer K. Phenotypic heterogeneity in severe hemophilia. J Thromb Haemost. 2007;5(s1):151–6.

    Article  PubMed  Google Scholar 

  18. Peyvandi F, Palla R, Menegatti M, Siboni S, Halimeh S, Faeser B, et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012;10(4):615–21.

    Article  CAS  PubMed  Google Scholar 

  19. Dorgalaleh A, Alavi SER, Tabibian S, Soori S, Moradi EH, Bamedi T, et al. Diagnosis, clinical manifestations and management of rare bleeding disorders in Iran. Hematology. 2017;22(4):224–30.

    Article  CAS  PubMed  Google Scholar 

  20. De Moerloose P, Neerman-Arbez M. Congenital fibrinogen disorders. Semin Thromb Hemost. 2009;35:356–66.

    Article  CAS  PubMed  Google Scholar 

  21. De Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost. 2013;39:585–95.

    Article  CAS  PubMed  Google Scholar 

  22. Inbal A, Muszbek L. Coagulation factor deficiencies and pregnancy loss. Semin Thromb Hemost. 2003;29:171–4.

    Article  CAS  PubMed  Google Scholar 

  23. Anwar R, Miloszewski KJ. Factor XIII deficiency. Br J Haematol. 1999;107(3):468–84.

    Article  CAS  PubMed  Google Scholar 

  24. Coopland A, Alkjaersig N, Fletcher AP. Reduction in plasma factor XIII (fibrin stabilizing factor) concentration during pregnancy. J Lab Clin Med. 1969;73(1):144–53.

    PubMed  CAS  Google Scholar 

  25. Padmanabhan L, Mhaskar R, Mhaskar A, Ross C. Factor XIII deficiency: a rare cause of repeated abortions. Singap Med J. 2004;45(4):186–7.

    CAS  Google Scholar 

  26. Dorgalaleh A, Naderi M, Shamsizadeh M. Morbidity and mortality in a large number of Iranian patients with severe congenital factor XIII deficiency. Ann Hematol. 2016;95(3):451–5.

    Article  CAS  PubMed  Google Scholar 

  27. Mosesson MW. Dysfibrinogenemia and thrombosis. Semin Thromb Hemost. 1999;25:311–9.

    Article  CAS  PubMed  Google Scholar 

  28. Girolami A, Ferrari S, Cosi E, Girolami B, Lombardi AM. Congenital prothrombin defects: they are not only associated with bleeding but also with thrombosis: a new classification is needed. Hematology. 2018;23(2):105–10.

    Article  CAS  PubMed  Google Scholar 

  29. Cramer TJ, Anderson K, Navaz K, Brown JM, Mosnier LO, von Drygalski A. Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male. Blood Cell Mol Dis. 2016;57:8–12.

    Article  CAS  Google Scholar 

  30. Girolami A, Cosi E, Ferrari S, Girolami B, Lombardi AM. Bleeding manifestations in heterozygotes with congenital FVII deficiency: a comparison with unaffected family members during a long observation period. Hematology. 2017;22(6):375–9.

    Article  CAS  PubMed  Google Scholar 

  31. Dorgalaleh A, Rashidpanah J. Blood coagulation factor XIII and factor XIII deficiency. Blood Rev. 2016;30(6):461–75.

    Article  CAS  PubMed  Google Scholar 

  32. Federici AB, Bucciarelli P, Castaman G, Mazzucconi MG, Morfini M, Rocino A, et al. The bleeding score predicts clinical outcomes and replacement therapy in adults with von Willebrand disease. Blood. 2014;123(26):4037–44.

    Article  CAS  PubMed  Google Scholar 

  33. Makris M. Gastrointestinal bleeding in von Willebrand disease. Thromb Res. 2006;118:S13–S7.

    Article  CAS  PubMed  Google Scholar 

  34. Neerman-Arbez M, Johnson K, Morris MA, McVey J, Peyvandi F, Nichols W, et al. Molecular analysis of the ERGIC-53 gene in 35 families with combined factor V-factor VIII deficiency. Blood. 1999;93(7):2253–60.

    PubMed  CAS  Google Scholar 

  35. Zhang B, McGee B, Yamaoka JS, Guglielmone H, Downes KA, Minoldo S, et al. Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2. Blood. 2006;107(5):1903–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 

  37. 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-stuttgart. 2000;84(6):937–41.

    CAS  Google Scholar 

  38. Dorgalaleh A, Dadashizadeh G, Bamedi T. Hemophilia in Iran. Hematology. 2016;21(5):300–10.

    Article  CAS  PubMed  Google Scholar 

  39. Bagnall RD, Waseem N, Green PM, Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood. 2002;99(1):168–74.

    Article  CAS  PubMed  Google Scholar 

  40. Jenkins P, Collins P, Goldman E, McCraw A, Riddell A, Lee C, et al. Analysis of intron 22 inversions of the factor VIII gene in severe hemophilia A: implications for genetic counseling. Blood. 1994;84(7):2197–201.

    PubMed  CAS  Google Scholar 

  41. Antonarakis SE, Rossiter J, Young M, Horst J, De Moerloose P, Sommer S, et al. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood. 1995;86(6):2206–12.

    PubMed  CAS  Google Scholar 

  42. Asselta R, Duga S, Tenchini M. The molecular basis of quantitative fibrinogen disorders. J Thromb Haemost. 2006;4(10):2115–29.

    Article  CAS  PubMed  Google Scholar 

  43. Dorgalaleh A, Tabibian S, Bamedi T, Tamaddon G, Naderi M, Varmaghani B, et al. Molecular genetic analysis of ten unrelated Iranian patients with congenital factor XIII deficiency. Int J Lab Hematol. 2016;39(2):e33–6

    Article  PubMed  Google Scholar 

  44. Vu D, Neerman-Arbez M. Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins. J Thromb Haemost. 2007;5(s1):125–31.

    Article  CAS  PubMed  Google Scholar 

  45. Neerman-Arbez M. The molecular basis of inherited afibrinogenaemia. Thromb Haemost. 2001;86(1):154–63.

    PubMed  CAS  Google Scholar 

  46. Bellucci S, Caen J. Molecular basis of Glanzmann’s thrombasthenia and current strategies in treatment. Blood Rev. 2002;16(3):193–202.

    Article  CAS  PubMed  Google Scholar 

  47. Nurden AT. Glanzmann thrombasthenia. Orphanet J Rare Dis. 2006;1(1):10.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Favaloro EJ. Von Willebrand disease: local diagnosis and management of a globally distributed bleeding disorder. Semin Thromb Hemost. 2011;37:440–55.

    Article  CAS  PubMed  Google Scholar 

  49. Favaloro EJ. Diagnosis and classification of von Willebrand disease: a review of the differential utility of various functional von Willebrand factor assays. Blood Coagul Fibrinolysis. 2011;22(7):553–64.

    Article  CAS  PubMed  Google Scholar 

  50. Martinez M, Graf L, Tsakiris DA. Congenital bleeding disorders. In: Marcucci C, Schoettker P, editors. Perioperative hemostasis. Berlin: Springer; 2015. p. 71–87.

    Google Scholar 

  51. Levinson B, Lehesjoki A, De La Chapelle A, Gitschier J. Molecular analysis of hemophilia A mutations in the Finnish population. Am J Hum Genet. 1990;46(1):53.

    PubMed  PubMed Central  CAS  Google Scholar 

  52. Vidaud M, Chabret C, Gazengel C, Grunebaum L, Cazenave J, Goossens MA. de novo intragenic deletion of the potential EGF domain of the factor IX gene in a family with severe hemophilia B. Blood. 1986;68(4):961–3.

    PubMed  CAS  Google Scholar 

  53. Cattaneo M. Inherited platelet-based bleeding disorders. J Thromb Haemost. 2003;1(7):1628–36.

    Article  CAS  PubMed  Google Scholar 

  54. Kern M, Blanchette V, Stain AM, Einarson TR, Feldman BM. Clinical and cost implications of target joints in Canadian boys with severe hemophilia A. J Pediatr. 2004;145(5):628–34.

    Article  PubMed  Google Scholar 

  55. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535–44.

    Article  CAS  PubMed  Google Scholar 

  56. Castaman G, Goodeve A, Eikenboom J. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica. 2013;98(5):667–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Castaman G, Rodeghiero F, Tosetto A, Cappelletti A, Baudo F, Eikenboom J, et al. Hemorrhagic symptoms and bleeding risk in obligatory carriers of type 3 von Willebrand disease: an international, multicenter study. J Thromb Haemost. 2006;4(10):2164–9.

    Article  CAS  PubMed  Google Scholar 

  58. Anwar R, Minford A, Gallivan L, Trinh CH, Markham AF. Delayed umbilical bleeding—a presenting feature for factor XIII deficiency: clinical features, genetics, and management. Pediatrics. 2002;109(2):e32.

    Article  PubMed  Google Scholar 

  59. Angles-Cano E, Mathonnet F, Dreyfus M, Claeyssens S, de Mazancourt P. A case of afibrinogenemia associated with A-alpha chain gene compound heterozygosity (HUMFIBRA c.[4110delA]+[3200+ 1G> T]). Blood Coagul Fibrinolysis. 2007;18(1):73–5.

    Article  PubMed  Google Scholar 

  60. Lebreton A, Casini A. Diagnosis of congenital fibrinogen disorders. Ann Biol Clin. 2016;74:405–12.

    Google Scholar 

  61. Dorgalaleh A, Kazemi A, Zaker F, Shamsizadeh M, Rashidpanah J, Mollaei M. Laboratory diagnosis of factor XIII deficiency, routine coagulation tests with quantitative and qualitative methods. Clin Lab. 2016;62(4):491–8.

    PubMed  CAS  Google Scholar 

  62. Awasthy N, Aggarwal K, Gupta H, Saluja S. Congenital hypofibrinogenemia. Indian Pediatr. 2004;41(2):185–6.

    PubMed  Google Scholar 

  63. Kihlberg K, Strandberg K, Rosén S, Ljung R, Astermark J. Discrepancies between the one-stage clotting assay and the chromogenic assay in haemophilia B. Haemophilia. 2017;23(4):620–7.

    Article  CAS  PubMed  Google Scholar 

  64. Barrowcliffe T. Monitoring haemophilia severity and treatment: new or old laboratory tests? Haemophilia. 2004;10(s4):109–14.

    Article  PubMed  Google Scholar 

  65. Castellone DD, Adcock DM. Factor VIII activity and inhibitor assays in the diagnosis and treatment of hemophilia A. Semin Thromb Hemost. 2017;43:320–30.

    Article  CAS  PubMed  Google Scholar 

  66. Verbruggen B, Meijer P, Novakova I, Van Heerde W. Diagnosis of factor VIII deficiency. Haemophilia. 2008;14(s3):76–82.

    Article  CAS  PubMed  Google Scholar 

  67. Cattaneo M, Hayward C, Moffat K, Pugliano M, Liu Y, Michelson AD. Results of a worldwide survey on the assessment of platelet function by light transmission aggregometry: a report from the platelet physiology subcommittee of the SSC of the ISTH. J Thromb Haemost. 2009;7(6):1029.

    Article  CAS  PubMed  Google Scholar 

  68. Cattaneo M, Cerletti C, Harrison P, Hayward C, Kenny D, Nugent D, et al. Recommendations for the standardization of light transmission aggregometry: a consensus of the working party from the platelet physiology subcommittee of SSC/ISTH. J Thromb Haemost. 2013;11(6):1183–9.

    Article  Google Scholar 

  69. Nair S, Ghosh K, Kulkarni B, Shetty S, Mohanty D. Glanzmann’s thrombasthenia: updated. Platelets. 2002;13(7):387–93.

    Article  CAS  PubMed  Google Scholar 

  70. Favaloro EJ, Pasalic L, Curnow J. Laboratory tests used to help diagnose von Willebrand disease: an update. Pathology. 2016;48(4):303–18.

    Article  CAS  PubMed  Google Scholar 

  71. Favaloro EJ, Soltani S, McDonald J, Grezchnik E, Easton L, Favaloro JW. Reassessment of ABO blood group, sex, and age on laboratory parameters used to diagnose von Willebrand disorder: potential influence on the diagnosis vs the potential association with risk of thrombosis. Am J Clin Pathol. 2005;124(6):910–7.

    Article  PubMed  Google Scholar 

  72. Royal S, Schramm W, Berntorp E, Giangrande P, Gringeri A, Ludlam C, et al. Quality-of-life differences between prophylactic and on-demand factor replacement therapy in European haemophilia patients. Haemophilia. 2002;8(1):44–50.

    Article  CAS  PubMed  Google Scholar 

  73. Valentino L, Mamonov V, Hellmann A, Quon D, Chybicka A, Schroth P, et al. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost. 2012;10(3):359–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. De Moerloose P, Neerman-Arbez M. Treatment of congenital fibrinogen disorders. Expert Opin Biol Ther. 2008;8(7):979–92.

    Article  PubMed  Google Scholar 

  75. Federici A, Castaman G, Mannucci P. Guidelines for the diagnosis and management of von Willebrand disease in Italy. Haemophilia. 2002;8(5):607–21.

    Article  CAS  PubMed  Google Scholar 

  76. 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 

  77. Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med. 2004;351(7):683–94.

    Article  CAS  PubMed  Google Scholar 

  78. Bertolini J, Goss N, Curling J. Production of plasma proteins for therapeutic use. Hoboken: Wiley; 2012.

    Google Scholar 

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Authors and Affiliations

  1. Department of Hematology and Blood Transfusion, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran

    Akbar Dorgalaleh

  2. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, yasuj, Iran

    Fariba Rad

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  1. Akbar Dorgalaleh
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  2. Fariba Rad
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  1. Iran University of Medical Sciences, Departement of Hematology and Blood TransfusionSchool of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran

    Akbar Dorgalaleh

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Dorgalaleh, A., Rad, F. (2018). Congenital Bleeding Disorders. In: Dorgalaleh, A. (eds) Congenital Bleeding Disorders . Springer, Cham. https://doi.org/10.1007/978-3-319-76723-9_2

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  • DOI: https://doi.org/10.1007/978-3-319-76723-9_2

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