Published online 31 March 2009
Haematologica, Vol 94, Issue 5, 663-669 doi:10.3324/haematol.2008.002246
Copyright © 2009 by Ferrata Storti Foundation

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Platelet Disorders

Dominant inheritance of a novel integrin β₃ mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families

Paolo Gresele¹, Emanuela Falcinelli¹, Silvia Giannini¹, Pio D’Adamo², Angela D’Eustacchio², Teresa Corazzi¹, Anna Maria Mezzasoma¹, Filomena Di Bari³, Giuseppe Guglielmini¹, Luca Cecchetti¹, Patrizia Noris⁴, Carlo L. Balduini⁴, Anna Savoia²

¹ Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia
² Medical Genetics, Department of Reproductive and Developmental Science, Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", University of Trieste, Trieste
³ Telethon Institute of Genetics and Medicine, Naples
⁴ Department of Internal Medicine, University of Pavia and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Policlinico San Matteo Foundation, Pavia, Italy

Correspondence: Paolo Gresele, MD, PhD, Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Via E. dal Pozzo, 06126 Perugia, Italy. E-mail:grespa{at}unipg.it

Background: Defects of integrin _IIbβ₃ are typical of Glanzmann’s thrombasthenia, an inherited autosomal recessive bleeding disorder characterized by the failure of platelets to aggregate in response to all physiological agonists, but with no abnormalities in the number or size of platelets. Although large heterogeneity has been described for Glanzmann’s thrombasthenia, no family has so far been described as having an autosomal dominant form of this disease.

Design and Methods: We describe two Italian families with moderate thrombocytopenia with large platelets, defective platelet function and moderate/severe mucocutaneous bleeding, transmitted as an autosomal dominant trait and associated with a novel integrin β₃-gene (ITGB3) mutation.

Results: The characteristics of our families are moderate macrothrombocytopenia and defective platelet function associated with a mild reduction of surface _Ib β₃, impaired platelet aggregation to physiological agonists but not to ristocetin, normal clot retraction, reduced fibrinogen binding and expression of activated _IIbβ₃ upon stimulation, normal platelet adhesion to immobilized fibrinogen but reduced platelet spreading and tyrosine phosphorylation, indicating defective _IIbβ₃-mediated outside-in signaling. Molecular analysis revealed a novel mutation of ITGB3 that determines an in-frame deletion producing the loss of amino acids 647–686 of the βTD ectodomain of integrin β₃. Haplotype analysis indicated that the two families inherited the mutation from a common ancestral chromosome.

Conclusions: This novel autosomal dominant macrothrombocytopenia associated with platelet dysfunction raises interesting questions about the role of integrin β₃, and its βTD domain, in platelet formation and function.

Key words: glycoprotein IIb/IIIa, megakaryocytopoiesis, outside-in signaling, thrombo-cytopenia.

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