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Semin Thromb Hemost 2013; 39(06): 656-662
DOI: 10.1055/s-0033-1353390
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Bernard–Soulier Syndrome: An Update

Robert K. Andrews
1   Department of Clinical Haematology, Monash University, Systems Haematology Laboratory, Australian Centre for Blood Diseases, Melbourne, Australia
,
Michael C. Berndt
2   Faculty of Health Sciences, Curtin University, Perth, Western Australia, Australia
› Author Affiliations
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Publication History

Publication Date:
08 August 2013 (online)

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Abstract

Bernard–Soulier syndrome (BSS) is a rare inherited platelet bleeding disorder characterized by low platelet count and abnormally large platelets (macrothrombocytopenia). Platelets from BSS patients are typically defective in surface expression of glycoprotein (GP)Ib-IX-V, a platelet-specific adhesion-signaling complex, composed of GPIbα disulfide linked to GPIbβ, and noncovalently associated with GPIX and GPV. The major ligand-binding subunit, GPIbα, binds the adhesive ligands von Willebrand factor (VWF) or thrombospondin, counterreceptors on activated endothelial cells (P-selectin) or activated leukocytes (integrin αMβ2), and coagulation factors (thrombin, factors XI and XII, high-molecular-weight kininogen). The cytoplasmic domain of GPIb-IX-V interacts with the cytoskeletal protein, filamin-A via a binding site within the GPIbα cytoplasmic tail, and with structural-signaling proteins including calmodulin, 14–3-3ζ and the p85 subunit of phosphoinositide 3-kinase. GPIbα is physically/functionally co-associated on the platelet surface with the major platelet collagen receptor, GPVI. As such, it is easy to see how genetic defects impacting GPIb-IX-V expression or function can have significant consequences on normal platelet size, adhesion to VWF/collagen and/or stable thrombus formation, and why BSS is often associated with clinical bleeding. Furthermore, the rarity, multiple genetic causes, and variable clinical phenotype of BSS can complicate routine diagnosis. Here, we discuss how studies of BSS have contributed to platelet biology and recent studies to improve diagnosis and treatment.

Keywords

Bernard–Soulier syndrome - bleeding disorders - glycoprotein Ib-IX-V complex - platelets - von Willebrand factor
 

  • References

  • 1 Bernard J, Soulier J-P. Sur une nouvelle variété de dystrophie thrombocytairehémorragipare congénitale. Sem Hop 1948; 24 (Spec. No.): 3217-3223
    PubMedGoogle Scholar
  • 2 López JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-Soulier syndrome. Blood 1998; 91 (12) 4397-4418
    PubMedGoogle Scholar
  • 3 Lanza F. Bernard-Soulier syndrome (hemorrhagiparous thrombocytic dystrophy). Orphanet J Rare Dis 2006; 1: 46
    CrossrefPubMedGoogle Scholar
  • 4 Berndt MC, Andrews RK. Bernard-Soulier syndrome. Haematologica 2011; 96 (3) 355-359
    CrossrefPubMedGoogle Scholar
  • 5 Althaus K, Greinacher A. MYH-9 related platelet disorders: strategies for management and diagnosis. Transfus Med Hemother 2010; 37 (5) 260-267
    PubMedGoogle Scholar
  • 6 Andrews R, Berndt M, Lopez J. The glycoprotein Ib-IX-V complex. In: Michelson AD, ed. Platelets (2nd edition). San Diego, CA: Academic Press; 2006: 145-64
    Google Scholar
  • 7 Berndt MC, Andrews RK. Major platelet glycoproteins: A. Platelet glycoprotein Ib-IX-V. In: Marder VJ, Aird WC, Bennett JS, Schulman S, White GC, , eds. Hemostasis and Thrombosis (6th edition). Philadelphia, PA: Wolters Kluwer—Lippincott Williams & Wilkins; 2012: 382-385
    Google Scholar
  • 8 Burkhart JM, Vaudel M, Gambaryan S , et al. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood 2012; 120 (15) e73-e82
    CrossrefPubMedGoogle Scholar
  • 9 Lopez JA, Chung DW, Fujikawa K, Hagen FS, Papayannopoulou T, Roth GJ. Cloning of the alpha chain of human platelet glycoprotein Ib: a transmembrane protein with homology to leucine-rich alpha 2-glycoprotein. Proc Natl Acad Sci U S A 1987; 84 (16) 5615-5619
    CrossrefPubMedGoogle Scholar
  • 10 Lopez JA, Chung DW, Fujikawa K, Hagen FS, Davie EW, Roth GJ. The alpha and beta chains of human platelet glycoprotein Ib are both transmembrane proteins containing a leucine-rich amino acid sequence. Proc Natl Acad Sci U S A 1988; 85 (7) 2135-2139
    CrossrefPubMedGoogle Scholar
  • 11 Hickey MJ, Williams SA, Roth GJ. Human platelet glycoprotein IX: an adhesive prototype of leucine-rich glycoproteins with flank-center-flank structures. Proc Natl Acad Sci U S A 1989; 86 (17) 6773-6777
    CrossrefPubMedGoogle Scholar
  • 12 Hickey MJ, Hagen FS, Yagi M, Roth GJ. Human platelet glycoprotein V: characterization of the polypeptide and the related Ib-V-IX receptor system of adhesive, leucine-rich glycoproteins. Proc Natl Acad Sci U S A 1993; 90 (18) 8327-8331
    CrossrefPubMedGoogle Scholar
  • 13 Lanza F, Morales M, de La Salle C , et al. Cloning and characterization of the gene encoding the human platelet glycoprotein V. A member of the leucine-rich glycoprotein family cleaved during thrombin-induced platelet activation. J Biol Chem 1993; 268 (28) 20801-20807
    PubMedGoogle Scholar
  • 14 Shen Y, Romo GM, Dong JF , et al. Requirement of leucine-rich repeats of glycoprotein (GP) Ibalpha for shear-dependent and static binding of von Willebrand factor to the platelet membrane GP Ib-IX-V complex. Blood 2000; 95 (3) 903-910
    PubMedGoogle Scholar
  • 15 Shen Y, Dong Jf JF, Romo GM , et al. Functional analysis of the C-terminal flanking sequence of platelet glycoprotein Ib alpha using canine-human chimeras. Blood 2002; 99 (1) 145-150
    CrossrefPubMedGoogle Scholar
  • 16 Seligsohn U. Treatment of inherited platelet disorders. Haemophilia 2012; 18 (Suppl. 04) 161-165
    CrossrefPubMedGoogle Scholar
  • 17 Weeterings C, de Groot PG, Adelmeijer J, Lisman T. The glycoprotein Ib-IX-V complex contributes to tissue factor-independent thrombin generation by recombinant factor VIIa on the activated platelet surface. Blood 2008; 112 (8) 3227-3233
    CrossrefPubMedGoogle Scholar
  • 18 Arthur JF, Gardiner EE, Matzaris M , et al. Glycoprotein VI is associated with GPIb-IX-V on the membrane of resting and activated platelets. Thromb Haemost 2005; 93 (4) 716-723
    PubMedGoogle Scholar
  • 19 Moog S, Mangin P, Lenain N , et al. Platelet glycoprotein V binds to collagen and participates in platelet adhesion and aggregation. Blood 2001; 98 (4) 1038-1046
    CrossrefPubMedGoogle Scholar
  • 20 Ramakrishnan V, DeGuzman F, Bao M, Hall SW, Leung LL, Phillips DR. A thrombin receptor function for platelet glycoprotein Ib-IX unmasked by cleavage of glycoprotein V. Proc Natl Acad Sci U S A 2001; 98 (4) 1823-1828
    CrossrefPubMedGoogle Scholar
  • 21 Ramakrishnan V, Reeves PS, DeGuzman F , et al. Increased thrombin responsiveness in platelets from mice lacking glycoprotein V. Proc Natl Acad Sci U S A 1999; 96 (23) 13336-13341
    CrossrefPubMedGoogle Scholar
  • 22 Andrews RK, Karunakaran D, Gardiner EE, Berndt MC. Platelet receptor proteolysis: a mechanism for downregulating platelet reactivity. Arterioscler Thromb Vasc Biol 2007; 27 (7) 1511-1520
    CrossrefPubMedGoogle Scholar
  • 23 Berndt MC, Karunakaran D, Gardiner EE, Andrews RK. Programmed autologous cleavage of platelet receptors. J Thromb Haemost 2007; 5 (Suppl. 01) 212-219
    PubMedGoogle Scholar
  • 24 Qiao JL, Shen Y, Gardiner EE, Andrews RK. Proteolysis of platelet receptors in humans and other species. Biol Chem 2010; 391 (8) 893-900
    PubMedGoogle Scholar
  • 25 Coller BS, Kalomiris E, Steinberg M, Scudder LE. Evidence that glycocalicin circulates in normal plasma. J Clin Invest 1984; 73 (3) 794-799
    CrossrefPubMedGoogle Scholar
  • 26 Cranmer SL, Pikovski I, Mangin P , et al. Identification of a unique filamin A binding region within the cytoplasmic domain of glycoprotein Ibalpha. Biochem J 2005; 387 (Pt 3) 849-858
    CrossrefPubMedGoogle Scholar
  • 27 Cranmer SL, Ashworth KJ, Yao Y , et al. High shear-dependent loss of membrane integrity and defective platelet adhesion following disruption of the GPIbα-filamin interaction. Blood 2011; 117 (9) 2718-2727
    CrossrefPubMedGoogle Scholar
  • 28 Kanaji T, Ware J, Okamura T, Newman PJ. GPIbα regulates platelet size by controlling the subcellular localization of filamin. Blood 2012; 119 (12) 2906-2913
    CrossrefPubMedGoogle Scholar
  • 29 Falet H. New insights into the versatile roles of platelet FlnA. Platelets 2013; 24 (1) 1-5
    CrossrefPubMedGoogle Scholar
  • 30 Jurak Begonja A, Hoffmeister KM, Hartwig JH, Falet H. FlnA-null megakaryocytes prematurely release large and fragile platelets that circulate poorly. Blood 2011; 118 (8) 2285-2295
    CrossrefPubMedGoogle Scholar
  • 31 Andrews RK, Munday AD, Mitchell CA, Berndt MC. Interaction of calmodulin with the cytoplasmic domain of the platelet membrane glycoprotein Ib-IX-V complex. Blood 2001; 98 (3) 681-687
    CrossrefPubMedGoogle Scholar
  • 32 Andrews RK, Harris SJ, McNally T, Berndt MC. Binding of purified 14-3-3 zeta signaling protein to discrete amino acid sequences within the cytoplasmic domain of the platelet membrane glycoprotein Ib-IX-V complex. Biochemistry 1998; 37 (2) 638-647
    CrossrefPubMedGoogle Scholar
  • 33 Bialkowska K, Zaffran Y, Meyer SC, Fox JE. 14-3-3 zeta mediates integrin-induced activation of Cdc42 and Rac. Platelet glycoprotein Ib-IX regulates integrin-induced signaling by sequestering 14-3-3 zeta. J Biol Chem 2003; 278 (35) 33342-33350
    CrossrefPubMedGoogle Scholar
  • 34 Mu FT, Andrews RK, Arthur JF , et al. A functional 14-3-3zeta-independent association of PI3-kinase with glycoprotein Ib alpha, the major ligand-binding subunit of the platelet glycoprotein Ib-IX-V complex. Blood 2008; 111 (9) 4580-4587
    CrossrefPubMedGoogle Scholar
  • 35 Andrews RK, Du X, Berndt MC. The 14-3-3zeta-GPIb-IX-V complex as an antiplatelet target. Drug News Perspect 2007; 20 (5) 285-292
    CrossrefPubMedGoogle Scholar
  • 36 Mu FT, Cranmer SL, Andrews RK, Berndt MC. Functional association of phosphoinositide-3-kinase with platelet glycoprotein Ibalpha, the major ligand-binding subunit of the glycoprotein Ib-IX-V complex. J Thromb Haemost 2010; 8 (2) 324-330
    CrossrefPubMedGoogle Scholar
  • 37 Arthur JF, Shen Y, Gardiner EE , et al. TNF Receptor-Associated Factor 4 (TRAF4) is a novel binding partner of glycoprotein Ib and glycoprotein VI in human platelets. J Thromb Haemost 2011; 9: 163-172 . Erratum in J Thromb Haemost 2011;2019:2523
    CrossrefPubMedGoogle Scholar
  • 38 Gardiner EE, Arthur JF, Shen Y , et al. GPIbalpha-selective activation of platelets induces platelet signaling events comparable to GPVI activation events. Platelets 2010; 21 (4) 244-252
    CrossrefPubMedGoogle Scholar
  • 39 Romo GM, Dong JF, Schade AJ , et al. The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J Exp Med 1999; 190 (6) 803-814
    CrossrefPubMedGoogle Scholar
  • 40 Chen J, Reheman A, Gushiken FC , et al. N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. J Clin Invest 2011; 121 (2) 593-603
    CrossrefPubMedGoogle Scholar
  • 41 Yago T, Lou J, Wu T , et al. Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF. J Clin Invest 2008; 118 (9) 3195-3207
    PubMedGoogle Scholar
  • 42 Kim J, Zhang CZ, Zhang X, Springer TA. A mechanically stabilized receptor-ligand flex-bond important in the vasculature. Nature 2010; 466 (7309) 992-995
    CrossrefPubMedGoogle Scholar
  • 43 Simon DI, Chen Z, Xu H , et al. Platelet glycoprotein Ibα is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192 (2) 193-204
    CrossrefPubMedGoogle Scholar
  • 44 Bergmeier W, Piffath CL, Goerge T , et al. The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proc Natl Acad Sci U S A 2006; 103 (45) 16900-16905
    CrossrefPubMedGoogle Scholar
  • 45 Bergmeier W, Chauhan AK, Wagner DD. Glycoprotein Ibalpha and von Willebrand factor in primary platelet adhesion and thrombus formation: lessons from mutant mice. Thromb Haemost 2008; 99 (2) 264-270
    PubMedGoogle Scholar
  • 46 Takahashi M, Yamashita A, Moriguchi-Goto S , et al. Critical role of von Willebrand factor and platelet interaction in venous thromboembolism. Histol Histopathol 2009; 24 (11) 1391-1398
    PubMedGoogle Scholar
  • 47 Joglekar MV, Ware J, Xu J, Fitzgerald ME, Gartner TK. Platelets, glycoprotein Ib-IX, and von Willebrand factor are required for FeCl3-induced occlusive thrombus formation in the inferior vena cava of mice. Platelets 2013; 24 (3) 205-212
    CrossrefPubMedGoogle Scholar
  • 48 Müller F, Mutch NJ, Schenk WA , et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139 (6) 1143-1156
    CrossrefPubMedGoogle Scholar
  • 49 Renné T. The procoagulant and proinflammatory plasma contact system. Semin Immunopathol 2012; 34 (1) 31-41
    CrossrefPubMedGoogle Scholar
  • 50 Montilla M, Hernández-Ruiz L, García-Cozar FJ, Alvarez-Laderas I, Rodríguez-Martorell J, Ruiz A. Polyphosphate binds to human von Willebrand factor in vivo and modulates its interaction with Glycoprotein Ib. J Thromb Haemost 2012; 10: 2315-2323
    CrossrefPubMedGoogle Scholar
  • 51 Noris P, Perrotta S, Bottega R , 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) 82-88
    CrossrefPubMedGoogle Scholar
  • 52 Bartsch I, Sandrock K, Lanza F , et al. Deletion of human GP1BB and SEPT5 is associated with Bernard-Soulier syndrome, platelet secretion defect, polymicrogyria, and developmental delay. Thromb Haemost 2011; 106 (3) 475-483
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Sarangi SN, Golightly M, Weber J, Chan EL. A family with Bolzano-type Bernard-Soulier syndrome carries a benign A1939T MYH9 mutation. Platelets 2013; 24 (1) 81-84
    CrossrefPubMedGoogle Scholar
  • 54 Liang HP, Morel-Kopp MC, Curtin J , et al. Heterozygous loss of platelet glycoprotein (GP) Ib-V-IX variably affects platelet function in velocardiofacial syndrome (VCFS) patients. Thromb Haemost 2007; 98 (6) 1298-1308
    Article in Thieme ConnectPubMedGoogle Scholar
  • 55 Nurden AT, Caen JP. Specific roles for platelet surface glycoproteins in platelet function. Nature 1975; 255 (5511) 720-722
    CrossrefPubMedGoogle Scholar
  • 56 Savoia A, Pastore A, De Rocco D , et al. Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations. Haematologica 2011; 96 (3) 417-423
    CrossrefPubMedGoogle Scholar
  • 57 Sandrock K, Knöfler R, Greinacher A , et al. Novel mutation in Bernard-Soulier syndrome. Transfus Med Hemother 2010; 37 (5) 278-284
    PubMedGoogle Scholar
  • 58 Sumitha E, Jayandharan GR, David S , et al. Molecular basis of Bernard-Soulier syndrome in 27 patients from India. J Thromb Haemost 2011; 9 (8) 1590-1598
    CrossrefPubMedGoogle Scholar
  • 59 Liang HP, Morel-Kopp MC, Clemetson JM , et al. A common ancestral glycoprotein (GP) 9 1828A>G (Asn45Ser) gene mutation occurring in European families from Australia and Northern Europe with Bernard-Soulier Syndrome (BSS). Thromb Haemost 2005; 94 (3) 599-605
    PubMedGoogle Scholar
  • 60 De Marco L, Mazzucato M, Fabris F , et al. Variant Bernard-Soulier syndrome type bolzano. A congenital bleeding disorder due to a structural and functional abnormality of the platelet glycoprotein Ib-IX complex. J Clin Invest 1990; 86 (1) 25-31
    CrossrefPubMedGoogle Scholar
  • 61 Vettore S, Tezza F, Malara A , et al. A A386G biallelic GPIbα gene mutation with anomalous behavior: a new mechanism suggested for Bernard-Soulier syndrome pathogenesis. Haematologica 2011; 96 (12) 1878-1882
    CrossrefPubMedGoogle Scholar
  • 62 McEwan PA, Yang W, Carr KH , 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) 5292-5301
    CrossrefPubMedGoogle Scholar
  • 63 Kenny D, Morateck PA, Gill JC, Montgomery RR. The critical interaction of glycoprotein (GP) IBbeta with GPIX-a genetic cause of Bernard-Soulier syndrome. Blood 1999; 93 (9) 2968-2975
    PubMedGoogle Scholar
  • 64 Ware J, Russell S, Ruggeri ZM. Generation and rescue of a murine model of platelet dysfunction: the Bernard-Soulier syndrome. Proc Natl Acad Sci U S A 2000; 97 (6) 2803-2808
    CrossrefPubMedGoogle Scholar
  • 65 Kato K, Martinez C, Russell S , et al. Genetic deletion of mouse platelet glycoprotein Ibbeta produces a Bernard-Soulier phenotype with increased alpha-granule size. Blood 2004; 104 (8) 2339-2344
    CrossrefPubMedGoogle Scholar
  • 66 Kanaji T, Russell S, Ware J. Amelioration of the macrothrombocytopenia associated with the murine Bernard-Soulier syndrome. Blood 2002; 100 (6) 2102-2107
    CrossrefPubMedGoogle Scholar
  • 67 Kanaji S, Kuether EL, Fahs SA , et al. Correction of murine Bernard-Soulier syndrome by lentivirus-mediated gene therapy. Mol Ther 2012; 20 (3) 625-632
    CrossrefPubMedGoogle Scholar
  • 68 Glembotsky AC, Marta RF, Pecci A , et al. International collaboration as a tool for diagnosis of patients with inherited thrombocytopenia in the setting of a developing country. J Thromb Haemost 2012; 10 (8) 1653-1661
    CrossrefPubMedGoogle Scholar
  • 69 Takata Y, Kanaji T, Moroi M , 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) 733-742
    CrossrefPubMedGoogle Scholar
  • 70 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) 308-311
    CrossrefPubMedGoogle Scholar