**3.3 Monocyte-derived EVs**

Leukocytes play an important role in the maintenance of vascular homeostasis. The activation of monocytes leads to increased release of monocyte EVs, which contribute to the disturbance of the hemostatic balance (**Figure 2C**). Monocyte EVs adhere to endothelial cells via LFA-1-ICAM-1 adhesion, as shown by the blocking of LFA-1 [37]. Once internalized, EVs were able to induce extracellular signal-regulated protein kinase (ERK1/2) and nuclear factor-κB (NF-κB) signaling pathways that increase the expression of the adhesion molecules VCAM-1, ICAM-1, and E-selectin on endothelial cells [59]. On the other hand, Tang et al. suggested that monocyte EVs induce *de novo* synthesis of ICAM-1, chemokine C-C motif ligand 2 (CCL2) and IL-1β in endothelial cells. This occurs via the activation of toll like receptor 4 (TLR4)/Myeloid differentiation primary response gene 88 (MyD88)/ NF-κB [60]. An increase in the adhesion profile of endothelial cells makes them more susceptible to interactions with platelets and monocytes and increase the prothrombotic state of the vasculature. Monocyte EVs trigger immune dysfunction related proinflammatory pathways also by the transfer of different miRs to the recipient cells. Levels of miR-125a-5p, miR-146a, miR-146b, miR-155 were significantly increased and miR-222 levels were decreased in INFα and lipopolysaccharide stimulated monocyte EVs compared to unstimulated monocyte EVs. Monocyte EVs transfer functional EVs to endothelial cells and activate the TLR4/MyD88/NF-κB signaling leading to differential expression of immunomodulatory miR in endothelial cells [61]. Both monocytes and monocyte EVs are positive for TF [37], a primary cellular initiator of blood coagulation. In vascular injury, TF forms a complex with factor VIIa, which activates the coagulation protease cascade and eventually leads to fibrin deposition and platelet activation [62]. In addition, monocyte EVs reduce the expression of the anticoagulant TFPI and of thrombomodulin on endothelial cells [37].
