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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3791-3799
Activated Platelets Release Two Types of Membrane Vesicles:
Microvesicles by Surface Shedding and Exosomes Derived From
Exocytosis of Multivesicular Bodies and  -Granules
Harry F.G. Heijnen,
Anja E. Schiel,
Rob Fijnheer,
Hans J. Geuze, and
Jan J. Sixma
From the Division on Thrombosis and Haemostasis, the Department of
Hematology, University Hospital Utrecht; and the Department of Cell
Biology, Medical Faculty, Institute of Biomembranes, Utrecht
University, Utrecht, The Netherlands.
Platelet activation leads to secretion of granule contents and to
the formation of microvesicles by shedding of membranes from the cell
surface. Recently, we have described small internal vesicles in
multivesicular bodies (MVBs) and  -granules, and suggested that these
vesicles are secreted during platelet activation, analogous to the
secretion of vesicles termed exosomes by other cell types. In the
present study we report that two different types of membrane vesicles
are released after stimulation of platelets with thrombin receptor
agonist peptide SFLLRN (TRAP) or -thrombin: microvesicles of 100 nm
to 1 µm, and exosomes measuring 40 to 100 nm in diameter, similar in
size as the internal vesicles in MVBs and -granules. Microvesicles
could be detected by flow cytometry but not the exosomes, probably
because of the small size of the latter. Western blot analysis showed
that isolated exosomes were selectively enriched in the tetraspan
protein CD63. Whole-mount immuno-electron microscopy (IEM) confirmed
this observation. Membrane proteins such as the integrin chains
IIb- 3 and 1, GPIb, and
P-selectin were predominantly present on the microvesicles. IEM of
platelet aggregates showed CD63+ internal vesicles in
fusion profiles of MVBs, and in the extracellular space between
platelet extensions. Annexin-V binding was mainly restricted to the
microvesicles and to a low extent to exosomes. Binding of factor X and
prothrombin was observed to the microvesicles but not to exosomes.
These observations and the selective presence of CD63 suggest that
released platelet exosomes may have an extracellular function other
than the procoagulant activity, attributed to platelet microvesicles.
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