Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 118-125
Autosomal dominant thrombocytopenia: incomplete megakaryocyte
differentiation and linkage to human chromosome 10
Jonathan G. Drachman,
Gail P. Jarvik, and
Michele
G. Mehaffey
From Puget Sound Blood Center, Seattle, WA; and the Divisions
of Hematology and Medical Genetics, Department of Medicine, University
of Washington, Seattle, WA.
We studied a large kindred with nonsyndromic autosomal dominant
thrombocytopenia to define the phenotype and used genomic linkage
analysis to determine the locus of the abnormal gene. Affected family
members are characterized by lifelong moderate thrombocytopenia
(mean = 42.7 × 109/L) with moderate propensity
toward easy bruising and minor bleeding. Megakaryocytes are present in
bone marrow with reduced frequency, and there are no apparent
abnormalities of myeloid or erythroid cells. This type of inherited
thrombocytopenia has no evident association with hematopoietic
malignancy or progression to aplastic anemia. In the past, members of
this family have failed therapeutic trials of immunosuppression and
splenectomy. In our investigation, we found that affected individuals
had normal platelet size compared with unaffected family members and
modestly increased thrombopoietin levels. Hematopoietic colony assays
from bone marrow and peripheral blood demonstrated that megakaryocyte
precursors (CFU-Mk) were dramatically increased in both number and size
in affected individuals. Bone marrow cells grown in liquid culture with
thrombopoietin failed to develop polyploid cells greater than 8N. Also,
electron microscopy demonstrated that megakaryocytes from an affected
individual had markedly delayed nuclear and cytoplasmic
differentiation. Genome-wide linkage analysis established a single
locus for the disease gene on the short arm of chromosome 10 with a
maximum 2-point lod score of 5.68 (at 
= 0). By recruiting
additional family members, the genomic region was narrowed to 17 centimorgans. We conclude that a gene in this locus plays an important
role in megakaryocyte endomitosis and terminal maturation.
