Pathological events in platelets of Wiskott-Aldrich syndrome patients.
The Wiskott-Aldrich syndrome (WAS) is a severe X-linked platelet/immunological disorder arising from mutations of the gene WASP. At the clinical level, the major platelet abnormalities are small size and low number, both partially correctable by splenectomy. To identify underlying pathological events, we examined WAS platelets at various stages of their lifetime. In spleen sections from WAS patients, fluorescence microscopy showed dramatic co-localization of markers of platelets (CD41) and macrophages (CD68) compared to non-thrombocytopenic controls, suggesting that WAS splenic macrophages are involved in platelet removal. Study of isolated WAS blood platelets by flow cytometry showed substantial enhancement of surface exposure of phosphatidylserine (PS), a signal for engulfment by macrophages. Isolated resting WAS platelets were also aberrantly susceptible to microparticle release, and plasma samples of WAS patients contained > 5 times normal numbers of platelet-derived microparticles which may explain the small size of circulating platelets. Measurements with the Ca2+ sensitive dye fluo-3 revealed significantly increased Ca2+ levels, 310 +/- 13 nmol/l for WAS platelets versus 106 +/- 12 nmol/l for normal platelets, and also prolongation of agonist-induced Ca2+ flux. Cumulatively, these studies identify abnormal events occurring in WAS platelets: increased Ca2+ levels and enhancement of two Ca2+ dependent processes, PS exposure and microparticle release; these abnormal events may contribute to the in vivo decrease of platelet number and reduction of platelet size in this disease.
Shcherbina
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Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Rosen
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FS
Remold-O'Donnell
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D000328:Adult; D001791:Blood Platelet Disorders / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008297:Male; D010718:Phosphatidylserines / Q000502:physiology; D013917:Thrombin / Q000378:metabolism; D014923:Wiskott-Aldrich Syndrome / Q000097:blood* / Q000378:metabolism
D010718:Phosphatidylserines; D013917:Thrombin; D002118:Calcium