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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1330-1335
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Autosomal dominant macrothrombocytopenia in Italy is most
frequently a type of heterozygous Bernard-Soulier
syndrome
Anna Savoia,
Carlo L. Balduini,
Maria Savino,
Patrizia Noris,
Maria Del
Vecchio,
Silverio Perrotta,
Simona Belletti,
Vincenzo Poggi, and
Achille Iolascon
From the Medical Genetics Service, IRCCS Hospital CSS,
Foggia; the Department of Internal Medicine, IRCCS San
Matteo-University of Pavia; the Department of Pediatrics, II University
of Najoli; the Department of Pediatric Hematology, Azienda Santobono,
Pausilipon, Najoli; and the Department of Biomedicine of Evolutive Age,
University of Bari, Italy.
A form of autosomal dominant macrothrombocytopenia is
characterized by mild or no clinical symptoms, normal platelet
function, and normal megakaryocyte count. Because this condition
has so far received little attention, patients are subject to
misdiagnosis and inappropriate therapy. To identify the molecular basis
of this disease, 12 Italian families were studied by linkage analysis and mutation screening. Flow cytometry evaluations of platelet membrane
glycoproteins (GPs) were also performed. Linkage analysis in 2 large
families localized the gene to chromosome 17p, in an interval
containing an excellent candidate, the GPIb gene. GPIb, together
with other proteins, constitutes the plasma von Willebrand factor (vWF)
receptor, which is altered in Bernard-Soulier syndrome (BSS). In 6 of
12 families, a heterozygous Ala156Val missense substitution was
identified. Platelet membrane GP studies were performed in 10 patients.
Eight were distinguished by a reduction of GPs comparable to that found
in a BSS heterozygous condition, whereas the other 2, without the
Ala156Val mutation, had a normal content of platelet GPs. In
conclusion, the current study provides evidence that most (10 of 12)
patients with an original diagnosis of autosomal dominant
macrothrombocytopenia shared clinical and molecular features with the
heterozygous BSS phenotype. The remaining 2 affected subjects
represented patients with "true" autosomal dominant
macrothrombocytopenia; the GPIb/IX/V complex was normally distributed
on the surface of their platelets. Thus, the diagnosis of heterozygous
BSS must always be suspected in patients with inherited
thrombocytopenia and platelet macrocytosis.
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