Autosomal dominant thrombocytopenias with reduced expression of glycoprotein Ia

Summary

We have recently studieda case series of 46 unrelated patients with inherited thrombocytopenias and identified 18 cases that did not fit any known platelet disorder. In two unrelated families, a mild thrombocytopenia with normal platelet size was transmitted in an autosomal dominant fashion. Bleeding time was prolonged in 5 investigated patients. In all of them, flow cytometry and SDS-PAGE of platelet glycoproteins (GP) showed a reduced content of GPIa, a subunit of the GPIa-IIa complex (also known as integrin α2β1) that is a major collagen receptor on platelets.All other membrane GPs were within the normal range. GPIa deficiency was associated with severely reduced in vitro platelet adhesion to molecules known to interact selectively with GPIa. In vitro platelet aggregation was normal in all subjects, except for a suboptimal platelet response to fibrillar collagen in two patients.A mild defect of α-granules was observed in all affected subjects. No mutation was identified in the genes encoding for GPIa or GPIIa. Since no other similar cases have been reported in the literature, we suggest that an autosomal dominant thrombocytopenia associated with GPIa deficiency and α-granule defect represents a new form of inherited thrombocytopenia.

Keywords

Inherited thrombocytopenia - glycoprotein Ia - integrin α2β₁ - collagen receptor

• References

• 1 Clemetson KJ, Clemetson JM. Platelet collagen receptors. Thromb Haemost 2001; 86: 189-97.
• 2 Kritzik M, Savage B, Nugent DJ. et al. Nucleotide polymorphisms in the α2 gene define multiple alleles that are associated with differences in platelet α2β1 density. Blood 1998; 92: 2382-8.
• 3 Jacquelin B, Rozenshteyn D, Kanaji S. et al. Characterization of inherited differences in transcription of the human integrin α2 gene. J Biol Chem 2001; 276: 23518-24.
• 4 Jacquelin B, Tarantino MD, Kritzik M. et al. Alleledependent transcriptional regulation of the human integrin a2 gene. Blood 2001; 97: 1721-6.
• 5 Corral J, Gonzalez-Conejero R, Rivera R. et al. Role of the 807 C/T polymorphism of the alpha2 gene in platelet GPIa collagen receptor expression and function. Thromb Haemost 1999; 81: 951-6.
• 6 Moshfegh K, Wuillemin WA, Redondo M. et al. Association of two silent polymorphisms of platelet glycoprotein Ia/IIa receptor with risk of myocardial infarction: a case-control study. Lancet 1999; 353: 351-4.
• 7 Santoso S, Kunichi TJ, Kroll H. et al. Association of the platelet glycoprotein Ia C807T gene polymorphism with nonfatal myocardial infarction in younger patients. Blood 1999; 93: 2449-53.
• 8 Alberio L, Dale GL. Platelet-collagen interactions: membrane receptors and intracellular signalling pathways. Eur J Clin Invest 1999; 29: 1066-76.
• 9 Matsubara Y, Murata M, Maruyama T. et al. Association between diabetic retinopathy and genetic variations in alpha2beta1 integrin, a platelet receptor for collagen. Blood 2000; 95: 1560-4.
• 10 Seri M, Pecci A, Di Bari F. et al. MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore) 2003; 82: 203-15.
• 11 Toomey KC, Kim HC, Kosmin M. et al. Clinical trial of a new disposable bleeding time device. Am J Clin Pathol 1986; 85: 610-6.
• 12 Savoia A, Balduini CL, Savino M. et al. Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome. Blood 2001; 97: 1330-5.
• 13 Noris P, Pecci A, Di Bari F. et al. Application of a diagnostic algorithm for inherited thrombocytopenias to 46 consecutive patients. Haematologica 2004; 89: 1218-25.
• 14 Balduini CL, Noris P, Giorgiani G. et al. Incompatibility for CD31 and human platelet antigens and acute graft-versus-host disease after bone marrow transplantation. Br J Haematol 1999; 106: 723-9.
• 15 Balduini CL, Pecci A, Loffredo G. et al. Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost 2004; 91: 129-40.
• 16 Torti M, Ramaschi G, Sinigaglia F. et al. Association of the low molecular weight GTP-binding protein rap2B with the cytoskeleton during platelet aggregation. Proc NatlAcad Sci USA 1993; 90: 7553-7.
• 17 Guidetti FG, Greco F, Bertoni A. et al. Platelet interaction with CNBr peptides from type II collagen via integrin α2β1. Biochem Biophys Acta 2003; 1640: 43-51.
• 18 Guidetti G, Bertoni A, Viola M. et al. The small proteoglycan decorin supports adhesion and activation of human platelets. Blood 2002; 100: 1707-4.
• 19 Balduini CL, Pecci A, Loffredo G. et al. Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost 2004; 91: 129-40.
• 20 Balduini CL, Cattaneo M, Fabris F. et al. Inherited thrombocytopenias: proposal of a diagnostic algorithm by the Italian “Gruppo di studio delle piastrine”. Haematologica 2003; 88: 582-92.
• 21 Zutter MM, Painter AA, Staatz WD. et al. Regulation of alpha 2 integrin gene expression in cells with megakaryocytic features: a common theme of three necessary elements. Blood 1995; 86: 3006-14.
• 22 Holtkotter O, Nieswandt B, Smyth N. et al. Integrin alpha 2-deficient mice develop normally, are fertile, but display partially defective platelet interaction with collagen. J Biol Chem 2002; 277: 10789-94.
• 23 Nakamura T, Kambayashi J, Okuma M. et al. Activation of the GP IIb-IIIa complex induced by platelet adhesion to collagen is mediated by both α2β1 integrin and GP VI. J Biol Chem 1999; 274: 11897-903.
• 24 Chen J, Diacovo TG, Grenache DG. et al. The α 2 integrin subunit-deficient mouse. A multifaced phenotype including defects of branching mrophogenesis and hemostasis A multifaced phenotype including defects of branching mrophogenesis and hemostasis. Am J Pathol 2002; 161: 337-44.
• 25 Nieuwenhuis HK, Akkerman JW, Houdijk WP. et al. Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. Nature 1985; 318: 470-2.
• 26 Kehrel B, Balleisen L, Kokott R. et al. Deficiency of intact thrombospondin and membrane glycoprotein Ia in platelets with defective collagen-induced aggregation and spontaneous loss of disorder. Blood 1988; 71: 1074-8.
• 27 Handa M, Watanabe K, Kawai Y. et al. Platelet unresponsiveness to collagen: involvement of glycoprotein Ia-IIa (alpha 2 beta 1 integrin) deficiency associated with a myeloproliferative disorder. Thromb Haemost 1995; 73: 521-8.
• 28 Deckmyn H, Chew SL, Vermylen J. Lack of platelet response to collagen associated with an autoantibody against glycoprotein Ia: a novel cause of acquired qualitative platelet dysfunction. Thromb Haemost 1990; 64: 74-9.
• 29 Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor?. Blood 2003; 102: 449-61.
• 30 Tong-Tong L, Larrucea S, Souza S. et al. Genetic variation responsible for mouse strain differences in integrin α2 expression is associated with altered platelet responses to collagen. Blood 2004; 103: 3396-402.