Bernard-Soulier Syndrome

  • Bahare Ghasemi
  • Akbar Dorgalaleh


Bernard-Soulier syndrome (BSS) is a rare mostly autosomal recessive platelet function disorder that is characterized by variable bleeding tendency, macrothrombocytopenia, impaired platelet agglutination in response to ristocetin, and defect in the glycoprotein (GP) Ib-IX-V complex. This disorder is due to mutations in one of the GPIb-IX-V complex encoding genes. BSS is usually present early in life with different bleeding diathesis including epistaxis, gingival bleeding, and purpura. Although diagnosis of some of severe inherited platelet function disorders (IPFD) such as BSS and Glanzmann thrombasthenia (GT) is straightforward, misdiagnosis is a challenge in BSS such as in many other IPFD. A considerable number of these patients initially are misdiagnosed as immune thrombocytopenic purpura (ITP), but further studies can resolve this issue. In addition to routine laboratory assessments, more specific laboratory studies such as aggregometry assays, flow cytometry, and molecular analysis can help to precise and timely diagnosis of disorder. BSS treatment includes supportive cares as well as specific treatment of bleeding episodes.


Bernard-Soulier syndrome Inherited platelet function disorders Macrothrombocytopenia Bleeding Glycoprotein 


  1. 1.
    Lanza F. Bernard-Soulier syndrome (hemorrhagiparous thrombocytic dystrophy). Orphanet J Rare Dis. 2006;1(1):46.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Berndt MC, Andrews RK. Bernard-Soulier syndrome. Haematologica. 2011;96:355.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Kunishima S, Kamiya T, Saito H. Genetic abnormalities of Bernard-Soulier syndrome. Int J Hematol. 2002;76(4):319–27.CrossRefPubMedGoogle Scholar
  4. 4.
    Afrabiasi A, Artoni A, Karimi M, Peyvandi F, Ashouri E, Mannucci P. Glanzmann thrombasthenia and Bernard–Soulier syndrome in south Iran. Int J Lab Hematol. 2005;27(5):324–7.Google Scholar
  5. 5.
    Savoia A, Pastore A, De Rocco D, Civaschi E, Di Stazio M, Bottega R, et al. Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations. Haematologica. 2011;96(3):417–23.CrossRefPubMedGoogle Scholar
  6. 6.
    Ali S, Ghosh K, Shetty S. Novel genetic abnormalities in Bernard-Soulier syndrome in India. Ann Hematol. 2014;93(3):381–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Boeckelmann D, Hengartner H, Greinacher A, Nowak-Göttl U, Sachs U, Peter K, et al. Patients with Bernard-Soulier syndrome and different severity of the bleeding phenotype. Blood Cell Mol Dis. 2017;67:69.CrossRefGoogle Scholar
  8. 8.
    Takata Y, Kanaji T, Moroi M, Seki R, Sano M, Nakazato S, et al. Platelets with a W127X mutation in GPIX express sufficient residual amounts of GPIbα to support adhesion to von Willebrand factor and collagen. Int J Hematol. 2012;96(6):733–42.CrossRefPubMedGoogle Scholar
  9. 9.
    Savoia A, Kunishima S, De Rocco D, Zieger B, Rand ML, Pujol-Moix N, et al. Spectrum of the mutations in Bernard–Soulier syndrome. Hum Mutat. 2014;35(9):1033–45.CrossRefPubMedGoogle Scholar
  10. 10.
    Andrews RK, Berndt MC. Bernard–Soulier syndrome: an update. Semi Thromb Hemost. 2013;39:656.CrossRefGoogle Scholar
  11. 11.
    Diz-Küçükkaya R. Inherited platelet disorders including Glanzmann thrombasthenia and Bernard-Soulier syndrome. Hematology Am Soc Hematol Educ Program. 2013;2013(1):268–75.PubMedGoogle Scholar
  12. 12.
    López JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-soulier syndrome. Blood. 1998;91(12):4397–418.PubMedGoogle Scholar
  13. 13.
    Alamelu J, Liesner R. Modern management of severe platelet function disorders. Br J Haematol. 2010;149(6):813–23.CrossRefPubMedGoogle Scholar
  14. 14.
    Kirchmaier CM, Pillitteri D. Diagnosis and management of inherited platelet disorders. Transfus Med Hemother. 2010;37(5):237–46.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Seligsohn U. Treatment of inherited platelet disorders. Haemophilia. 2012;18(Suppl 4):161–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Li R, Emsley J. The organizing principle of the platelet glycoprotein Ib–IX–V complex. J Thromb Haemost. 2013;11(4):605–14.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Diz-Kücükkaya R, López JA. Inherited disorders of platelets. Hematol Oncol Clin North Am. 2013;27(3):613–27.CrossRefPubMedGoogle Scholar
  18. 18.
    Hayward CP, Rao A, Cattaneo M. Congenital platelet disorders: overview of their mechanisms, diagnostic evaluation and treatment. Haemophilia. 2006;12(Suppl 3):128–36.CrossRefPubMedGoogle Scholar
  19. 19.
    Andrews R, Gardiner E, Shen Y, Whisstock J, Berndt M. Glycoprotein Ib–IX–V. Int J Biochem Cell Biol. 2003;35(8):1170–4.CrossRefPubMedGoogle Scholar
  20. 20.
    Balduini CL, Iolascon A, Savoia A. Inherited thrombocytopenias: from genes to therapy. Haematologica. 2002;87(8):860–80.PubMedGoogle Scholar
  21. 21.
    Favier R, Raslova H. Progress in understanding the diagnosis and molecular genetics of macrothrombocytopenias. Br J Haematol. 2015;170(5):626–39.CrossRefPubMedGoogle Scholar
  22. 22.
    Rabbolini DJ, Morel-Kopp MC, Stevenson W, Ward CM. Inherited macrothrombocytopenias. Semin Thromb Hemost. 2014;40:774.CrossRefPubMedGoogle Scholar
  23. 23.
    Kunishima S, Imai T, Kobayashi R, Kato M, Ogawa S, Saito H. Bernard–Soulier syndrome caused by a hemizygous GPIbβ mutation and 22q11. 2 deletion. Pediatr Int. 2013;55(4):434–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Gardiner EE, Andrews RK. Platelet receptor expression and shedding: glycoprotein Ib-IX-V and glycoprotein VI. Transfus Med Rev. 2014;28(2):56–60.CrossRefPubMedGoogle Scholar
  25. 25.
    Pham A, Wang J. Bernard-Soulier syndrome: an inherited platelet disorder. Arch Pathol Lab Med. 2007;131(12):1834–6.PubMedGoogle Scholar
  26. 26.
    Naz A, Jamal MY, Amanat S, Najmuddin A, Patel H, Raziq F, et al. Autosomal recessive inherited bleeding disorders in Pakistan: a cross-sectional study from selected regions. Orphanet J Rare Dis. 2017;12(1):66.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Weiss HJ, Tschopp TB, Baumgartner HR, Sussman II, Johnson MM, Egan JJ. Decreased adhesion of giant (Bernard-Soulier) platelets to subendothelium. Further implications on the role of the von Willebrand factor in hemostasis. Am J Med. 1974;57:920.CrossRefPubMedGoogle Scholar
  28. 28.
    Nurden AT, Caen JP. Specific roles for platelet surface glycoproteins in platelet function. Nature. 1975;255(5511):720–2.CrossRefPubMedGoogle Scholar
  29. 29.
    Carubbi C, Masselli E, Nouvenne A, Russo D, Galli D, Mirandola P, et al. Laboratory diagnostics of inherited platelet disorders. Clin Chem Lab Med. 2014;52(8):1091–106.CrossRefPubMedGoogle Scholar
  30. 30.
    Shlebak A, Poles A, Manning R, Almuhareb S, De La Funte J, Mitchell M, et al. A novel homozygous c. 800C> G substitution in GP1BA exon 2 in a Kuwaiti Family with Bernard-Soulier Syndrome. Acta Haematol. 2015;134(3):193–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Matthews DC. Inherited disorders of platelet function. Pediatr Clin. 2013;60(6):1475–88.CrossRefGoogle Scholar
  32. 32.
    Simon D, Kunicki T, Nugent D. Platelet function defects. Haemophilia. 2008;14(6):1240–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Andrews RK, Berndt MC. Platelet adhesion: a game of catch and release. J Clin Invest. 2008;118(9):3009.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Nurden AT, Nurden P. Inherited defects of platelet function. Rev Clin Exp Hematol. 2001;5(4):314–34.CrossRefPubMedGoogle Scholar
  35. 35.
    Gothwal M, Sandrock-Lang K, Zieger B. Genetics of inherited platelet disorders. Hamostaseologie. 2014;34(2):133–41.CrossRefPubMedGoogle Scholar
  36. 36.
    Roth GJ, Yagi M, Bastian LS. The platelet glycoprotein Ib-V-IX system: regulation of gene expression. Stem Cells. 1996;14(S1):188–93.CrossRefPubMedGoogle Scholar
  37. 37.
    Yagi M, Edelhoff S, Disteche CM, Roth GJ. Human platelet glycoproteins V and IX: mapping of two leucine-rich glycoprotein genes to chromosome 3 and analysis of structures. Biochemistry. 1995;34(49):16132–7.CrossRefGoogle Scholar
  38. 38.
    Clemetson KJ. Platelet glycoproteins and their role in diseases. Transfus Clin Biol. 2001;8(3):155–62.CrossRefPubMedGoogle Scholar
  39. 39.
    Okoli S, Madan B, Mwirigi A, Moore G, Drew A, Mitchell M, et al. A diagnostic dilemma: variant Bernard-Soulier syndrome, a difficult clinical and genetic diagnosis. Haemophilia. 2015;21(6):e510–3.CrossRefPubMedGoogle Scholar
  40. 40.
    Freson K, Wijgaerts A, Van Geet C. Update on the causes of platelet disorders and functional consequences. Int J Lab Hematol. 2014;36(3):313–25.CrossRefPubMedGoogle Scholar
  41. 41.
    Zieger B, Jenny A, Tsakiris D, Bartsch I, Sandrock K, Schubart C, et al. A large Swiss family with Bernard-Soulier syndrome. Hamostaseologie. 2009;29(2):161–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Salles II, Feys HB, Iserbyt BF, De Meyer SF, Vanhoorelbeke K, Deckmyn H. Inherited traits affecting platelet function. Blood Rev. 2008;22(3):155–72.CrossRefPubMedGoogle Scholar
  43. 43.
    Kenny D, Morateck PA, Gill JC, Montgomery RR. The critical interaction of glycoprotein (GP) Ibβ with GPIX—a genetic cause of Bernard-Soulier syndrome. Blood. 1999;93(9):2968–75.PubMedGoogle Scholar
  44. 44.
    McEwan PA, Yang W, Carr KH, Mo X, Zheng X, Li R, et al. Quaternary organization of GPIb-IX complex and insights into Bernard-Soulier syndrome revealed by the structures of GPIbβ and a GPIbβ/GPIX chimera. Blood. 2011;118(19):5292–301.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Miller JL. Glycoprotein analysis for the diagnostic evaluation of platelet disorders. Semin Thromb Hemost. 2009;35:224.CrossRefPubMedGoogle Scholar
  46. 46.
    Noris P, Perrotta S, Bottega R, Pecci A, Melazzini F, Civaschi E, et al. Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation). Haematologica. 2012;97(1):82–8.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Rao AK, Songdej N. Parsing the repertoire of GPIb-IX-V disorders. Blood. 2017;129(4):403–4.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Sivapalaratnam S, Westbury SK, Stephens JC, Greene D, Downes K, Kelly AM, et al. Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia. Blood. 2017;129(4):520–4.CrossRefPubMedGoogle Scholar
  49. 49.
    Sánchez-Guiu I, Antón AI, Padilla J, Velasco F, Lucia JF, Lozano M, et al. Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: results from a collaborative study. Orphanet J Rare Dis. 2014;9(1):213.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Lanza F, De La Salle C, Baas MJ, Schwartz A, Boval B, Cazenave JP, et al. A Leu7Pro mutation in the signal peptide of platelet glycoprotein (GP) IX in a case of Bernard–Soulier syndrome abolishes surface expression of the GPIb–V–IX complex. Br J Haematol. 2002;118(1):260–6.CrossRefPubMedGoogle Scholar
  51. 51.
    HadjKacem B, Elleuch H, Trigui R, Gargouri J, Gargouri AF. The same genetic defect in three Tunisian families with Bernard Soulier syndrome: a probable founder Stop mutation in GPIbbeta. Ann Hematol. 2010;89(1):75–81.CrossRefPubMedGoogle Scholar
  52. 52.
    Nurden A. Qualitative disorders of platelets and megakaryocytes. J Thromb Haemost. 2005;3(8):1773–82.CrossRefPubMedGoogle Scholar
  53. 53.
    Nurden A, Nurden P. Advances in our understanding of the molecular basis of disorders of platelet function. J Thromb Haemost. 2011;9(Suppl 1):76–91.CrossRefPubMedGoogle Scholar
  54. 54.
    Kunishima S, Saito H. Congenital macrothrombocytopenias. Blood Rev. 2006;20(2):111–21.CrossRefPubMedGoogle Scholar
  55. 55.
    Balduini C, Savoia A, Seri M. Inherited thrombocytopenias frequently diagnosed in adults. J Thromb Haemost. 2013;11(6):1006–19.CrossRefPubMedGoogle Scholar
  56. 56.
    Nurden A, Freson K, Seligsohn U. Inherited platelet disorders. Haemophilia. 2012;18(Suppl 4):154–60.CrossRefPubMedGoogle Scholar
  57. 57.
    Ali S, Shetty S, Ghosh K. A novel mutation in GP1BA gene leads to mono-allelic Bernard Soulier syndrome form of macrothrombocytopenia. Blood Coagul Fibrinolysis. 2017;28(1):94–5.CrossRefPubMedGoogle Scholar
  58. 58.
    Bragadottir G, Birgisdottir ER, Gudmundsdottir BR, Hilmarsdottir B, Vidarsson B, Magnusson MK, et al. Clinical phenotype in heterozygote and biallelic Bernard-Soulier syndrome—a case control study. Am J Hematol. 2015;90(2):149–55.CrossRefPubMedGoogle Scholar
  59. 59.
    Savoia A, Balduini CL, Savino M, Noris P, Del Vecchio M, Perrotta S, et al. Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome. Blood. 2001;97(5):1330–5.CrossRefGoogle Scholar
  60. 60.
    Balduini A, Malara A, Pecci A, Badalucco S, Bozzi V, Pallotta I, et al. Proplatelet formation in heterozygous Bernard-Soulier syndrome type Bolzano. J Thromb Haemost. 2009;7(3):478–84.CrossRefPubMedGoogle Scholar
  61. 61.
    Pecci A, Balduini CL. Lessons in platelet production from inherited thrombocytopenias. Br J Haematol. 2014;165(2):179–92.CrossRefPubMedGoogle Scholar
  62. 62.
    Toogeh G, Keyhani M, Sharifian R, Safaee R, Emami A, Dalili H. A study of Bernard-Soulier syndrome in Tehran, Iran. Arch Iran Med. 2010;13(6):549.PubMedGoogle Scholar
  63. 63.
    Gh T. Quantitative immunophemotyping of platelet surface glycoproteins among Iranian patients with Bernard-Soulier syndrome. Iran J Blood Cancer. 2014;7(1):3–9.Google Scholar
  64. 64.
    Gresele P. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost. 2015;13(2):314–22.CrossRefPubMedGoogle Scholar
  65. 65.
    Israels S. Laboratory testing for platelet function disorders. Int J Lab Hematol. 2015;37(Suppl 1):18–24.CrossRefPubMedGoogle Scholar
  66. 66.
    Gresele P, Harrison P, Bury L, Falcinelli E, Gachet C, Hayward C, et al. Diagnosis of suspected inherited platelet function disorders: results of a worldwide survey. J Thromb Haemost. 2014;12(9):1562–9.CrossRefPubMedGoogle Scholar
  67. 67.
    Krishnegowda M, Rajashekaraiah V. Platelet disorders: an overview. Blood Coagul Fibrinolysis. 2015;26(5):479–91.CrossRefPubMedGoogle Scholar
  68. 68.
    Li J, Dai K, Wang Z, Cao L, Bai X, Ruan C. Platelet functional alterations in a Bernard-Soulier syndrome patient with filamin A mutation. J Hematol Oncol. 2015;8(1):79.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Balduini A, Malara A, Balduini CL, Noris P. Megakaryocytes derived from patients with the classical form of Bernard-Soulier syndrome show no ability to extend proplatelets in vitro. Platelets. 2011;22(4):308–11.CrossRefPubMedGoogle Scholar
  70. 70.
    Strassel C, Eckly A, Léon C, Petitjean C, Freund M, Cazenave J-P, et al. Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome. Haematologica. 2009;94(6):800–10.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Paniccia R, Priora R, Liotta AA, Abbate R. Platelet function tests: a comparative review. Vasc Health Risk Manag. 2015;11:133.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Lordkipanidzé M. Platelet function tests. Semin Thromb Hemost. 2016;42:258.CrossRefPubMedGoogle Scholar
  73. 73.
    Bolton-Maggs PH, Chalmers EA, Collins PW, Harrison P, Kitchen S, Liesner RJ, et al. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol. 2006;135(5):603–33.CrossRefPubMedGoogle Scholar
  74. 74.
    Choi J-L, Li S, Han J-Y. Platelet function tests: a review of progresses in clinical application. Biomed Res Int. 2014;2014:456569.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Cox K, Price V, Kahr WH. Inherited platelet disorders: a clinical approach to diagnosis and management. Expert Rev Hematol. 2011;4(4):455–72.CrossRefPubMedGoogle Scholar
  76. 76.
    Hayward C, Harrison P, Cattaneo M, Ortel T, Rao A. Platelet function analyzer (PFA)-100® closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost. 2006;4(2):312–9.CrossRefPubMedGoogle Scholar
  77. 77.
    Hartman MJ, Caccamese JF, Bergman SA. Perioperative management of a patient with Bernard-Soulier syndrome for third molar surgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(5):626–9.CrossRefPubMedGoogle Scholar
  78. 78.
    Frontroth JP, Favaloro EJ. Ristocetin-induced platelet aggregation (RIPA) and RIPA mixing studies. Methods Mol Biol. 2017;1646:473–94.CrossRefPubMedGoogle Scholar
  79. 79.
    Gresele P, Bury L, Falcinelli E. Inherited platelet function disorders: algorithms for phenotypic and genetic investigation. Semin Thromb Hemost. 2016;42:292.CrossRefPubMedGoogle Scholar
  80. 80.
    Podda G, Femia EA, Pugliano M, Cattaneo M. Congenital defects of platelet function. Platelets. 2012;23(7):552–63.CrossRefPubMedGoogle Scholar
  81. 81.
    Knöfler R, Streif W. Strategies in clinical and laboratory diagnosis of inherited platelet function disorders in children. Transfus Med Hemother. 2010;37(5):231–5.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Koltai K, Kesmarky G, Feher G, Tibold A, Toth K. Platelet aggregometry testing: molecular mechanisms, techniques and clinical implications. Int J Mol Sci. 2017;18(8):1803.CrossRefPubMedCentralGoogle Scholar
  83. 83.
    Frontroth JP. Light transmission aggregometry. Methods Mol Biol. 2013;992:227–40.CrossRefPubMedGoogle Scholar
  84. 84.
    McGlasson DL, Fritsma GA. Whole blood platelet aggregometry and platelet function testing. Semin Thromb Hemost. 2009;35:168.CrossRefPubMedGoogle Scholar
  85. 85.
    Rechner A. Platelet function testing in clinical diagnostics. Hamostaseologie. 2011;31(2):79.CrossRefPubMedGoogle Scholar
  86. 86.
    Rubak P, Nissen PH, Kristensen SD, Hvas A-M. Investigation of platelet function and platelet disorders using flow cytometry. Platelets. 2016;27(1):66–74.CrossRefPubMedGoogle Scholar
  87. 87.
    Linden MD. Platelet flow cytometry. Methods Mol Biol. 2013;992:241–62.CrossRefPubMedGoogle Scholar
  88. 88.
    Michelson AD, Barnard MR, Krueger LA, Frelinger A, Furman MI. Evaluation of platelet function by flow cytometry. Methods. 2000;21(3):259–70.CrossRefPubMedGoogle Scholar
  89. 89.
    Saboor M, Moinuddin M, Ilyas S. New horizons in platelets flow cytometry. Malays J Med Sci. 2013;20(2):62.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Macêdo MB, de MM Brito J, da Silva Macêdo P, Brito JA. Primigravida with Bernard-Soulier syndrome: a case report. BMC Res Notes. 2015;8(1):178.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Prabu P, Parapia L. Bernard–Soulier syndrome in pregnancy. Int J Lab Hematol. 2006;28(3):198–201.Google Scholar
  92. 92.
    Uotila J, Tammela O, Mäkipernaa A. Fetomaternal platelet immunization associated with maternal Bernard-Soulier syndrome. Am J Perinatol. 2008;25(4):219–23.CrossRefPubMedGoogle Scholar
  93. 93.
    Valera MC, Kemoun P, Cousty S, Sie P, Payrastre B. Inherited platelet disorders and oral health. J Oral Pathol Med. 2013;42(2):115–24.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Bahare Ghasemi
    • 1
  • Akbar Dorgalaleh
    • 1
  1. 1.Department of Hematology and Blood TransfusionSchool of Allied Medicine, Iran University of Medical SciencesTehranIran

Personalised recommendations