**5. Extracellular vesicles in antiphospholipid syndrome: literature review and discussion**

The role of EVs as communicators between different types of cells involved in the pathology of APS have been studied *in vivo* by analyzing the characteristics of EVs from plasma of APS patients and *in vitro* after stimulation of cells with aPL. As discussed above, EVs can carry characteristic proteins that determine their origin (**Figure 3**, upper panel) and their prothrombotic profile (e.g. by the presence of TF, PS) (**Figure 3**, lower panel). However, all EVs carry also different receptors, adhesion molecules and cargo (nucleic acids, lipids and proteins), which together influence the interaction between different cells, as well as information transfer. Larger vesicles (microvesicles) usually carry surface TF, PS and annexins while smaller EVs (exosomes) carry surface tetraspanins (CD9, CD63, CD81) and flotillin and alix, clathrin and TSG101 proteins as their cargo (**Figure 3**, lower panel).

*Extracellular Vesicles: Intercellular Communication Mediators in Antiphospholipid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97412*

#### **Figure 3.**

*Characterization of endothelial, monocyte and platelet EVs. Schematic representation of commonly expressed surface protein markers of endothelial cells, monocytes and platelets, as well as markers currently associated with small and medium/large EVs. Endothelial EVs usually express CD51 (Integrin alpha V) which is a part of a complex that binds extracellular matrix proteins, CD144 (Vascular endothelial cadherin), an important cell adhesion molecule in the formation of adherent junctions, CD31 (PECAM-1; platelet endothelial cell adhesion molecule) mediates leukocyte- and platelet-endothelial cell adhesion, CD105 (Endoglin) is a type I membrane glycoprotein and a part of transforming growth factor β receptor complex. Monocyte EVs commonly express CD14 (Cluster of differentiation 14) a known monocyte marker and CD45 (PTPRC; protein tyrosine phosphatase receptor type C) that is leukocyte specific cell surface glycoprotein involved in various cellular processes. Platelet EVs usually express different glycoproteins (CD42; glycoprotein IX, CD41; glycoprotein IIb, CD61; glycoprotein IIIa) that are integrin complex proteins involved in platelet aggregation. All EVs carry adhesion molecules, receptors and lipids that are involved in interaction of EVs with different cells. Furthermore, they carry proteins, nucleic acids and lipids that can be transferred to a target cell. Membrane derived vesicles-microvesicles, are usually larger and express procoagulant molecules, such as TF (Tissue factor), annexins and PS (Phosphatidylserine), whereas tetraspanins (CD9, CD63, CD81) and specific luminal proteins (Clathrin, TSG101 and Alix) are specific for smaller vesicles of endosomal origin-exosomes. Created with BioRender.com.*

#### **5.1** *In vivo* **studies (characterization of EVs from plasma of APS patients)**

The role of EVs has been studied in many vascular pathologies, including deep vein thrombosis [7] and cardiovascular disease [38], whose common denominator is endothelial dysfunction. In addition, platelet EVs have been proposed as a useful biomarker for long-term follow-up after myocardial infarction [84], whereas increases in the number of endothelial EVs play a role in many inflammatory diseases, such as atherosclerosis [39]. Studies investigating EVs in patients with APS are limited and heterogeneous (**Table 2**). To date and to our knowledge, there have been 13 studies investigating EVs in thrombotic APS patients. With one exception, all of them have focused on medium/large EVs. Furthermore, the results of these studies are not completely comparable because the methods for isolating



#### *Extracellular Vesicles: Intercellular Communication Mediators in Antiphospholipid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97412*



**Table 2.**

*Isolation, quantification and characterization of EVs in plasma of APS patients.*

*Extracellular Vesicles: Intercellular Communication Mediators in Antiphospholipid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97412*

and characterizing EVs are not standardized, the sample sizes in some studies are small and the patient population studied is very heterogeneous (e.g. patients with concomitant autoimmune or other disease). Overall, the studies investigated EVs from the three major cell types involved in the pathogenesis of APS: endothelium, platelets, and monocytes. Studies in the field of cardiovascular diseases and EVs have shown that both platelet and endothelial EVs are elevated in patients with hypertension, compared to healthy blood donors [8], therefore it is important to note that certain proportion of EVs detected in plasma of APS patients might be associated with hypertension. Correlations between the levels of EVs and systolic and diastolic blood pressure needs to be evaluated when investigating EVs in APS patients.

## *5.1.1 Medium and large extracellular vesicles*
