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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 509-518
The Thrombocytopenia of Wiskott Aldrich Syndrome Is Not Related to
a Defect in Proplatelet Formation
Elie Haddad,
Elisabeth Cramer,
Christel Rivière,
Philippe Rameau,
Fawzia Louache,
Josette Guichard,
David L. Nelson,
Alain Fischer,
William Vainchenker, and
Najet Debili
From INSERM U 362, PR1, Institut Gustave Roussy, Villejuif, France;
INSERM U474, Hôpital Henri Mondor, Créteil, France; Service
d'Immuno-Hématologie pédiatrique, Hôpital Necker,
Paris, France; and the Metabolism Branch, Division of Clinical Science,
National Cancer Institute, National Institutes of Health, Bethesda, MD.
The Wiskott-Aldrich syndrome (WAS) is an X-linked hereditary disease
characterized by thrombocytopenia with small platelet size, eczema, and
increased susceptibility to infections. The gene responsible for WAS
was recently cloned. Although the precise function of WAS protein
(WASP) is unknown, it appears to play a critical role in the regulation
of cytoskeletal organization. The platelet defect, resulting in
thombocytopenia and small platelet size, is a consistent finding in
patients with mutations in the WASP gene. However, its exact mechanism
is unknown. Regarding WASP function in cytoskeletal organization, we
investigated whether these platelet abnormalities could be due to a
defect in proplatelet formation or in megakaryocyte (MK) migration.
CD34+ cells were isolated from blood and/or marrow of 14 WAS patients and five patients with hereditary X-linked
thrombocytopenia (XLT) and cultured in serum-free liquid medium
containing recombinant human Mpl-L (PEG-rHuMGDF) and stem-cell factor
(SCF) to study in vitro megakaryocytopoiesis. In all cases, under an
inverted microscope, normal MK differentiation and proplatelet
formation were observed. At the ultrastructural level, there was also
no abnormality in MK maturation, and normal filamentous MK were
present. Moreover, the in vitro produced platelets had a normal size,
while peripheral blood platelets of the same patients exhibited an
abnormally small size. However, despite this normal platelet
production, we observed that F-actin distribution was abnormal in MKs
from WAS patients. Indeed, F-actin was regularly and linearly
distributed under the cytoplasmic membrane in normal MKs, but it was
found concentrated in the center of the WAS MKs. After adhesion, normal MKs extended very long filopodia in which WASP could be detected. In
contrast, MKs from WAS patients showed shorter and less numerous filopodia. However, despite this abnormal filopodia formation, MKs from
WAS patients normally migrated in response to stroma-derived factor-1 (SDF-1), and actin normally polymerized
after SDF-1 or thrombin stimulation. These results suggest that the
platelet defect in WAS patients is not due to abnormal platelet
production, but instead to cytoskeletal changes occuring in platelets
during circulation.
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