Because EVS circulate in the blood flow, they serve as shuttle modules and signaling transducers not only in their local environment find more but also at distance from their site of origin. Classification of membrane vesicles, protocols of their isolation and detection, molecular details of vesicular release, clearance

and biological functions are still under intense investigation. EVS have been identified in the blood circulation for a long time, and have been first considered as cell fragments. In fact, EVS are quite heterogeneous and at least two main distinct types have been identified: exosomes (EXS) and microparticles (MPS). Both EXS and MPS are detected in blood flow, and arose out of cells such as platelets, leukocytes and endothelial cells [20]. EXS are small (40–100 nm in diameter), spherical vesicles of endocytic origin that are secreted upon fusion of the limiting membrane of multivesicular bodies with the plasma membrane. Red blood cell (RBC)-derived vesicles (REVS) have

been also described in blood samples obtained from patients with many different diseases as well as a storage lesion from red blood cell Belnacasan preparations dedicated for transfusion [21] and [22]. EXS contain subproteome cytosolic proteins, mRNAs and miRNAs, and are involved in intercellular signaling. In contrast, MPS bud directly from the plasma membrane and their size ranges from 100 nm to 1 μm (Fig. 1) [23]. A model of MPS formation including translocases, lipid rafts, various protein STK38 modifications and irreversible membrane rearrangements has been proposed (Fig. 2) [24] and [25]. MPS are not cell fragments or “dust” without any biological function [26]. They play a role in various broad biological functions such as thrombosis and hemostasis [20], [27] and [28], inflammation [27] and [29] or immunosuppression [30] and [31]. However, numerous similarities exist between EXS and MPS with respect to their physical characteristics and

compositions. These similarities frequently hampered the separation and purification of these EVS in body fluids and brought confusion in the scientific literature. In this review, we will mainly focus on blood EVS, with a particular emphasis on platelet and RBC EVS, as well as on MPS released during storage of blood units. For clarity purposes, the term EVS will be used in the following sections, grouping both MPS and EXS. Quantification, proteomic analysis as well as the biology of RBC-derived EVS (REVS), platelet-derived EVS (PEVS), leukocyte-derived EVS (LEVS), and of endothelial cell-derived-EVS (EEVS) are different, even if they share many common determinants. This review will present proteomic data that are “specific” for each type of EVS and then, will give insights onto the physiology of the various forms of EVS that are normally present in the blood or in blood products.