Semin Thromb Hemost 2011; 37(6): 698-706
DOI: 10.1055/s-0031-1291380
© Thieme Medical Publishers

Glanzmann Thrombasthenia-Like Syndromes Associated with Macrothrombocytopenias and Mutations in the Genes Encoding the αIIbβ3 Integrin

Alan T. Nurden1 , 2 , Xavier Pillois1 , Mathieu Fiore1 , Roland Heilig2 , Paquita Nurden1
  • 1Centre de Référence des Pathologies Plaquettaires, Plateforme Technologique et d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France
  • 2Génoscope - Centre National de Séquençage, Evry Cedex, France
Further Information

Publication History

Publication Date:
18 November 2011 (online)

ABSTRACT

Glanzmann thrombasthenia (GT) is the most widely studied inherited disorder of platelets; it is caused by the absence of platelet aggregation due to quantitative and/or qualitative deficiencies of the αIIbβ3 integrin coded by the ITGA2B and ITGB3 genes located at 17q21–23. Although platelet count and platelet volume (and morphology) are normal in classic GT, some reports have inferred a role for αIIbβ3 in megakaryocytopoiesis and some novel but rare point mutations in either of the ITGA2B and ITGB3 genes have been associated with an altered platelet production and selective deficiencies in platelet function. This was brought to light by the discovery of mutations at Arg995 in αIIb and Asp723 in β3 that lead to platelet anisotropy (increased size variation) and thrombocytopenia. Significantly, Arg995 and Asp723 form a salt linkage binding the cytoplasmic tails of αIIbβ3 together keeping the integrin in a bent resting state. Mutations weakening this link (if not abolishing it) increase the activation state of αIIbβ3 and interfere with megakaryocytopoiesis. Other mutations affecting platelet production involve extracellular but membrane proximal domains of β3. Our purpose is to review the mutations in the ITGA2B and ITGB3 genes that lead to anisotropy and to discuss mechanisms by which this can be brought about.

REFERENCES

  • 1 Nurden A, George J N. Inherited abnormalities of the platelet membrane: Glanzmann thrombasthenia, Bernard-Soulier syndrome, and other disorders. In: Colman R W, Marder V J, Clowes A W, et al, eds. Haemostasis and Thrombosis Basic Principles & Clinical Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006: 987-1010
  • 2 Nurden P, George J N, Nurden A. Inherited thrombocytopenias. In: Colman R W, Marder V J, Clowes A W, et al, eds. Haemostasis and Thrombosis: Basic Principles & Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006: 975-986
  • 3 Nurden P, Nurden A T. Congenital disorders associated with platelet dysfunctions.  Thromb Haemost. 2008;  99 (2) 253-263
  • 4 Nurden A T. Glanzmann thrombasthenia.  Orphanet J Rare Dis. 2006;  1 10-18
  • 5 George J N, Caen J P, Nurden A T. Glanzmann's thrombasthenia: the spectrum of clinical disease.  Blood. 1990;  75 (7) 1383-1395
  • 6 Hodivala-Dilke K M, McHugh K P, Tsakiris D A et al.. β3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.  J Clin Invest. 1999;  103 (2) 229-238
  • 7 Poujol C, Tronik-Le Roux D, Tropel P et al.. Ultrastructural analysis of bone marrow hematopoiesis in mice transgenic for the thymidine kinase gene driven by the αIIb promoter.  Blood. 1998;  92 (6) 2012-2023
  • 8 Larson M K, Watson S P. Regulation of proplatelet formation and platelet release by integrin αIIbβ3.  Blood. 2006;  108 (5) 1509-1514
  • 9 Mazharian A, Thomas S G, Dhanjal T S, Buckley C D, Watson S P. Critical role of Src-Syk-PLCγ2 signaling in megakaryocyte migration and thrombopoiesis.  Blood. 2010;  116 (5) 793-800
  • 10 Xiao T, Takagi J, Coller B S, Wang J H, Springer T A. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics.  Nature. 2004;  432 (7013) 59-67
  • 11 Hughes P E, Diaz-Gonzalez F, Leong L et al.. Breaking the integrin hinge. A defined structural constraint regulates integrin signaling.  J Biol Chem. 1996;  271 (12) 6571-6574
  • 12 Yang J, Ma Y Q, Page R C, Misra S, Plow E F, Qin J. Structure of an integrin alphaIIbβ3 transmembrane-cytoplasmic heterocomplex provides insight into integrin activation.  Proc Natl Acad Sci U S A. 2009;  106 (42) 17729-17734
  • 13 Coller B S, Shattil S J. The GPIIb/IIIa Integrin alphaIIbbeta3 odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend.  Blood. 2008;  112 (8) 3011-3025
  • 14 Hardisty R, Pidard D, Cox A et al.. A defect of platelet aggregation associated with an abnormal distribution of glycoprotein IIb-IIIa complexes within the platelet: the cause of a lifelong bleeding disorder.  Blood. 1992;  80 (3) 696-708
  • 15 Peyruchaud O, Nurden A T, Milet S et al.. R to Q amino acid substitution in the GFFKR sequence of the cytoplasmic domain of the integrin IIb subunit in a patient with a Glanzmann's thrombasthenia-like syndrome.  Blood. 1998;  92 (11) 4178-4187
  • 16 Kunishima S, Kashiwagi H, Ito Y et al.. A heterozygous ITGA2B R995W mutation causes constitutive activation of the αIIbβ3 receptor and results in congenital macrothrombocytopenia.  J Thromb Haemost. 2009;  7 (Suppl 2) PP-TH-081(abstr)
  • 17 Ghevaert C, Salsmann A, Watkins N A et al.. A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the alphaIIbbeta3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia.  Blood. 2008;  111 (7) 3407-3414
  • 18 Schaffner-Reckinger E, Salsmann A, Debili N et al.. Overexpression of the partially activated αIIbβ3D723H integrin salt bridge mutant downregulates RhoA activity and induces microtubule-dependent proplatelet-like extensions in Chinese hamster ovary cells.  J Thromb Haemost. 2009;  7 (7) 1207-1217
  • 19 Jayo A, Conde I, Lastres P et al.. L718P mutation in the membrane-proximal cytoplasmic tail of β3 promotes abnormal αIIbβ3 clustering and lipid microdomain coalescence, and associates with a thrombasthenia-like phenotype.  Haematologica. 2010;  95 (7) 1158-1166
  • 20 Gresele P, Falcinelli E, Giannini S et al.. Dominant inheritance of a novel integrin β3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families.  Haematologica. 2009;  94 (5) 663-669
  • 21 Vanhoorelbeke K, De Meyer S F, Pareyn I et al.. The novel S527F mutation in the integrin β3 chain induces a high affinity alphaIIbbeta3 receptor by hindering adoption of the bent conformation.  J Biol Chem. 2009;  284 (22) 14914-14920
  • 22 Kamata T, Ambo H, Puzon-McLaughlin W et al.. Critical cysteine residues for regulation of integrin alphaIIbbeta3 are clustered in the epidermal growth factor domains of the β3 subunit.  Biochem J. 2004;  378 (Pt 3) 1079-1082
  • 23 Ruan J, Schmugge M, Clemetson K J et al.. Homozygous Cys542—> Arg substitution in GPIIIa in a Swiss patient with type I Glanzmann's thrombasthenia.  Br J Haematol. 1999;  105 (2) 523-531
  • 24 Milet-Marsal S, Breillat C, Peyruchaud O et al.. Two different β3 cysteine substitutions alter alphaIIbβ3 maturation and result in Glanzmann thrombasthenia.  Thromb Haemost. 2002;  88 (1) 104-110
  • 25 Grimaldi C M, Chen F, Scudder L E, Coller B S, French D L. A Cys374Tyr homozygous mutation of platelet glycoprotein IIIa (β 3) in a Chinese patient with Glanzmann's thrombasthenia.  Blood. 1996;  88 (5) 1666-1675
  • 26 Chen P, Melchior C, Brons N HC et al.. Probing conformation changes in the I-like domain and the cysteine-rich repeat of human β3 integrins following disulfide bond disruption by cysteine mutations identification of cysteine 598 involved in αIIbβ3 activation.  J Biol Chem. 2001;  276 38628-38635
  • 27 Mor-Cohen R, Rosenberg N, Peretz H et al.. Disulfide bond disruption by a β3-Cys549Arg mutation in six Jordanian families with Glanzmann thrombasthenia causes diminished production of constitutively active αIIbβ3.  Thromb Haemost. 2007;  98 (6) 1257-1265
  • 28 Ruiz C, Liu C Y, Sun Q H et al.. A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (alphaIIbbeta3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia-like phenotype.  Blood. 2001;  98 (8) 2432-2441
  • 29 Wilcox D A, Fang J, Northe P et al.. High mortality in mice with platelets expressing integrin αIIbβ3 locked in its high affinity state.  Blood (ASH Annual Meeting Abstracts). 2008;  112 Abstract 1832
  • 30 Nurden A T, Nurden P. Inherited thrombocytopenias.  Haematologica. 2007;  92 (9) 1158-1164
  • 31 Salles I I, Feys H B, Iserbyt B F, De Meyer S F, Vanhoorelbeke K, Deckmyn H. Inherited traits affecting platelet function.  Blood Rev. 2008;  22 (3) 155-172
  • 32 Nakamura F, Pudas R, Heikkinen O et al.. The structure of the GPIb-filamin A complex.  Blood. 2006;  107 (5) 1925-1932
  • 33 Poujol C, Ware J, Nieswandt B, Nurden A T, Nurden P. Absence of GPIbalpha is responsible for aberrant membrane development during megakaryocyte maturation: ultrastructural study using a transgenic model.  Exp Hematol. 2002;  30 (4) 352-360
  • 34 Eckly A, Strassel C, Freund M et al.. Abnormal megakaryocyte morphology and proplatelet formation in mice with megakaryocyte-restricted MYH9 inactivation.  Blood. 2009;  113 (14) 3182-3189
  • 35 Pecci A, Malara A, Badalucco S et al.. Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation.  Thromb Haemost. 2009;  102 (1) 90-96
  • 36 Freson K, Devriendt K, Matthijs G et al.. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation.  Blood. 2001;  98 (1) 85-92
  • 37 Geddis A E. Megakaryopoiesis.  Semin Hematol. 2010;  47 (3) 212-219
  • 38 Chen Z, Naveiras O, Balduini A et al.. The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway.  Blood. 2007;  110 (1) 171-179
  • 39 Sabri S, Jandrot-Perrus M, Bertoglio J et al.. Differential regulation of actin stress fiber assembly and proplatelet formation by α2β1 integrin and GPVI in human megakaryocytes.  Blood. 2004;  104 (10) 3117-3125
  • 40 Malara A, Gruppi C, Rebuzzini P et al.. Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A.  Blood. 2011;  117 (8) 2476-2483
  • 41 Zhu J, Luo B H, Barth P, Schonbrun J, Baker D, Springer T A. The structure of a receptor with two associating transmembrane domains on the cell surface: integrin alphaIIbbeta3.  Mol Cell. 2009;  34 (2) 234-249
  • 42 Metcalf D G, Moore D T, Wu Y et al.. NMR analysis of the alphaIIb β3 cytoplasmic interaction suggests a mechanism for integrin regulation.  Proc Natl Acad Sci U S A. 2010;  107 (52) 22481-22486
  • 43 Mitchell W B, Li J, Murcia M, Valentin N, Newman P J, Coller B S. Mapping early conformational changes in alphaIIb and β3 during biogenesis reveals a potential mechanism for alphaIIbbeta3 adopting its bent conformation.  Blood. 2007;  109 (9) 3725-3732
  • 44 Raab M, Daxecker H, Edwards R J, Treumann A, Murphy D, Moran N. Protein interactions with the platelet integrin αIIb regulatory motif.  Proteomics. 2010;  10 (15) 2790-2800
  • 45 Nurden A T. Sustaining platelet counts in chronic ITP.  Lancet. 2011;  377 (9763) 358-360
  • 46 Hourdillé P, Gralnick H R, Heilmann E et al.. von Willebrand factor bound to glycoprotein Ib is cleared from the platelet surface after platelet activation by thrombin.  Blood. 1992;  79 (8) 2011-2021

Alan T NurdenPh.D. 

Centre de Référence des Pathologies Plaquettaires, Plateforme Technologique et d'Innovation Biomédicale

Hôpital Xavier Arnozan, Pessac 33600, France

Email: Alan.Nurden@cnrshl.u-bordeaux2.fr

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