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Inherited thrombocytopenia caused by reduced platelet production in mice
with the gunmetal pigment gene mutation
EK Novak, M Reddington, L Zhen, PE Stenberg, CW Jackson, MP McGarry and RT Swank
Molecular and Cellular Biology Department, Roswell Park Cancer Institute,
Buffalo, NY 14263, USA.
Hereditary macrothrombocytopenia and prolonged bleeding times are
associated with the recessive mouse pigment dilution gene gunmetal (gm).
Other platelet abnormalities include a mild storage pool deficiency and
abnormal expression of two low-molecular-weight guanosine triphosphate
binding proteins. These studies were designed to further elucidate the
cause of the macrothrombocytopenia. The life span of gunmetal mouse
platelets was not significantly different from normal. However, rates of
platelet synthesis, measured by sulfate incorporation, were decreased to
25% of normal values. Bone marrow transplantation of normal marrow cells
corrected the thrombocytopenia. Furthermore, direct morphologic analysis of
mature mutant marrow megakaryocytes by transmission electron microscopy
showed reductions in the normal cytoplasmic demarcation membrane system,
areas of abnormal membrane complexes, and an increased incidence of
emperipolesis. Mutant platelets were relatively more heterogeneous in size
and contained unusual elongated and striated inclusions. Mutant
megakaryocyte numbers were increased threefold to fivefold over normal
numbers in marrow and spleen. Thus, the efficiency of platelet production
from gunmetal megakaryocytes is reduced by an order of magnitude. Mutant
marrow had a greater proportion of 32N and a smaller proportion of 8N
megakaryocytes. Collectively, the results indicate that the gunmetal gene
acts intrinsically in megakaryocytes and that an abnormality in this gene
causes significant qualitative and quantitative effects on platelet
production.
Volume 85,
Issue 7,
pp. 1781-1789,
04/01/1995
Copyright © 1995 by The American Society of Hematology
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