Familial dominant thrombocytopenia: Clinical, biologic, and molecular studies

Inherited thrombocytopenias are a heterogenous group of disorders. Differen t criteria have been suggested to classify the forms, such as the inheritan ce mechanism and the platelet volume as well as the number and morphology o f megakaryocytes. However, the classification is often descriptive, and the precise mechanism of thrombocytopenia still remains unknown. We describe t he clinical, biologic, and molecular findings of an autosomal dominant thro mbocytopenia in a large family. The 17 patients had normocellular bone marr ow and normal platelet volume. Platelets also showed a normal aggregation t est and normal response to ADP and thrombopoietin (TPO). In the affected su bjects, the mean +/- SD levels of platelet count and plasma TPO were 62 +/- 25 and 258 +/- 151, respectively. Comparative analysis showed that the pat ients with platelet count <70000 had higher plasma TPO concentration. The d ata are consistent with a mild clinical form of the disease associated with only a few episodes of bleeding. To exclude the possible role of TPO and i ts receptor c-mpl in the etiology of this condition, linkage analysis was p erformed using microsatellite markers close to the TPO and c-mpl genes on c hromosomes 3q26.3-q27 and 1p34, respectively. The absence of cosegregation within the affected family indicated that these genes, as well as two other candidate loci on chromosomes 11 and 21, are not responsible for this here ditary dominant form of thrombscytopenia. A genome-wide search and subseque nt identification of the gene will provide new insight into the pathogenesi s of this disorder.