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Pro-hemostatic interactions between tumor cell-derived soluble factors/extracellular vesicles (EVs) and platelets. Tumor-derived EVs and/or tumor-derived soluble factors (such as adenosine diphosphate, thromboxane A2, and others) interact with platelets promoting their activation. Platelet activation accounts for integrin αIIbβ3 exposure and further interaction with fibrinogen, thus enabling platelet aggregation. In addition, platelet activation promotes P-selectin exposure which serves as a ligand for P-selectin glycoprotein ligand 1 (PSGL1)-containing EVs. EVs interaction with platelets favor their accumulation at the site of thrombotic injury. Together, both processes favor thrombus formation. Servier Medical Art, https://smart.servier.com/, was used to create this figure, licensed under a Creative Commons Attribution 3.0 Unported License.

Pro-hemostatic interactions between tumor cell-derived soluble factors/extracellular vesicles (EVs) and platelets. Tumor-derived EVs and/or tumor-derived soluble factors (such as adenosine diphosphate, thromboxane A2, and others) interact with platelets promoting their activation. Platelet activation accounts for integrin αIIbβ3 exposure and further interaction with fibrinogen, thus enabling platelet aggregation. In addition, platelet activation promotes P-selectin exposure which serves as a ligand for P-selectin glycoprotein ligand 1 (PSGL1)-containing EVs. EVs interaction with platelets favor their accumulation at the site of thrombotic injury. Together, both processes favor thrombus formation. Servier Medical Art, https://smart.servier.com/, was used to create this figure, licensed under a Creative Commons Attribution 3.0 Unported License.

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The establishment of prothrombotic states during cancer progression is well reported but the precise mechanisms underlying this process remain elusive. A number of studies have implicated the presence of the clotting initiator protein, tissue factor (TF), in circulating tumor-derived extracellular vesicles (EVs) with thrombotic manifestations in ce...

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... with a P-selectin blocking antibody, RGD peptide (a competitive inhibitor of the integrin-ligand interactions), clopidogrel or depletion of circulating platelets prevented the accumulation of tumor-derived microvesicles at the site of injury, reducing the incidence of thrombotic events in the animal models [35,99]. Figure 1 depicts the proposed interaction between soluble factors/EVs derived from tumor cells and platelets. ...

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... Exosomes are made by all cells, and are present in all biofluids, including blood, urine, cerebrospinal fluid, saliva, amniotic fluid, milk, sweat, bile, vitreous, synovial fluid, bronchial lavage fluid, pleural effusions, and ascites (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Exosomes contribute to numerous basic cell biological processes, especially protein quality control (18)(19)(20)(21), formation and modulation of extracellular matrix (22)(23)(24)(25), and intercellular transfer of signals and molecules (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). As a signaling particle, exosomes are conceptually distinct from single soluble ligands in that they have the capacity to simultaneously engage and cluster multiple copies of multiple receptors, and thereby deliver signals that are unique in mode and tone (1). ...
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... First, secreted EVs may facilitate the formation of neutrophil extracellular traps (NETs), which may contribute to thrombus development and attenuate the counteracting effect of endogenous fibrinolytic systems [35,36]. Second, the presence of polyphosphate (polyP) in cell-derived EVs may promote thrombosis through a tissue factor-independent route, whereas these effects were initially described in cancer-associated thrombosis [37] and then extrapolated to others. ...
... In addition, platelet-derived and endothelial cell-derived MVs and exosomes can stimulate coagulation independently after the mechanical stimulation of the parental cells or due to hemolysis [44]. First, secreted EVs may facilitate the formation of neutrophil extracellular traps (NETs), which may contribute to thrombus development and attenuate the counteracting effect of endogenous fibrinolytic systems [35,36]. Second, the presence of polyphosphate (polyP) in cell-derived EVs may promote thrombosis through a tissue factor-independent route, whereas these effects were initially described in cancer-associated thrombosis [37] and then extrapolated to others. ...
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... The molecular mechanisms of coagulopathy in cancer stroke remain unclear, although an understanding of these would assist the development of therapeutic strategies against coagulopathy in these patients. A number of prothrombotic mechanisms have been proposed to explain cancer-related coagulopathy, which include the initiation of the extrinsic pathway by clotting initiator protein (tissue factor) and polyphosphate (polyP) in circulating tumor-derived extracellular vesicles (EVs), and the interaction of tumor-derived EVs with platelets or neutrophil extracellular traposis 2 of 11 (NETosis) [3]. We have shown that increased circulating cell-free DNA (cfDNA) levels are associated with cancer stroke, suggesting that NETosis is one of the molecular mechanisms of cancer stroke [4]. ...
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... Sera from patients with Covid-19 demonstrate elevated levels of these histones and DNA components (52). It has been hypothesized that excessive NET formation leads to cytokine storm and microthrombus (possibly independent of tissue factor), and ultimately acute respiratory distress syndrome (ARDS) in Covid-19 (54). Lymphopenia and neutrophil infiltration in pulmonary capillaries have been an important feature of severe Covid-19 disease (7,34,56,57). ...
... • Decreases neutrophil-extracellular traps (NETs), which are released from neutrophils and contain DNA, histones, and proteins that are microbiocidal (51,52 (55) Excessive NET formation leads to cytokine storm and microthrombus (possibly independent of tissue factor), and ARDS in Covid-19 (54). Neutrophil infiltration in pulmonary capillaries have been an important feature of severe Covid disease (7,34,56,57). ...
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There is an increasing interest in Extracellular Vesicles released by many cells through membrane shedding. In addition to cell signaling, these particles are true messenger cargos, which can carry cell surface proteins, miRNAs and non-coding RNAs to other and distant cells. They are part of the inter-cellular crosstalk and they contribute to transferring biological messages far away from the triggering event. EVs are biomarkers of many diseases, including thrombo-embolic pathology, infections, neurological or metabolic disorders, and malignancy. Their role and significance are presented and discussed in this short review, as consequences of disease and causes of its progression. But they can also be beneficial for tissue healing or repair, and they can be prepared in vitro to be used for cell- targeted treatments. Many identification and measurement methods for EV’s are sophisticated, which restricts their use to research studies, but they have, nevertheless, a high laboratory potential for diagnosis, prognosis and evolution as follow-up of many pathologies. New emerging laboratory tools offer more friendly and easy applications for characterizing EVs and testing their associated activity, especially for the procoagulant ones.
... The role of cytokines in inflammation and thrombosis has been acknowledged [76], while that of EVs is beginning to be clarified. Thus, they can promote thrombosis via various mechanisms (Table 1), including: the presence of phosphatidylserine (PS) in the phospholipid bilayer of EVs from activated neutrophils [77][78][79] promotes platelet activation and formation of blood clots ( Figure 2B) [80]; EVs express several integrins (such as Mac-1) that can interact with platelets, inducing platelet P-selectin expression and their activation ( Figure 2C) [81]; activation of the coagulation cascade by both intrinsic and extrinsic pathways due to the presence of TF and polyphosphates (PolyP) in the membrane of EVs ( Figure 2D) [77,82]; and the presence of MPO on EVs is associated with thrombosis, since MPO causes endothelial damage, promoting the adherence and activation of platelets ( Figure 2E) [64] ( Table 1). In the last decade, microvesicles have become increasingly important in the context of thrombosis, with many reports published about them ( Table 1). ...
... As we have discussed in the previous section, the presence of TF on the surface of microvesicles is widely associated with thrombotic events. Alternatively, other reported evidence suggests that the presence of PolyP in microvesicles promotes thrombosis through a TF-independent route [82]. PolyP is a highly anionic linear polymer synthesized from ATP, and affects numerous steps in the coagulation cascade, including the activation of FXII, thus enhancing the activation of FV and increasing the activity of the thrombin-activated fibrinolysis inhibitor and inhibiting the TF pathway inhibitor. ...
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Cardiovascular diseases are a leading cause of death. Blood–cell interactions and endothelial dysfunction are fundamental in thrombus formation, and so further knowledge of the pathways involved in such cellular crosstalk could lead to new therapeutical approaches. Neutrophils are secretory cells that release well-known soluble inflammatory signaling mediators and other complex cellular structures whose role is not fully understood. Studies have reported that neutrophil extracellular vesicles (EVs) and neutrophil extracellular traps (NETs) contribute to thrombosis. The objective of this review is to study the role of EVs and NETs as key factors in the transition from inflammation to thrombosis. The neutrophil secretome can promote thrombosis due to the presence of different factors in the EVs bilayer that can trigger blood clotting, and to the release of soluble mediators that induce platelet activation or aggregation. On the other hand, one of the main pathways by which NETs induce thrombosis is through the creation of a scaffold to which platelets and other blood cells adhere. In this context, platelet activation has been associated with the induction of NETs release. Hence, the structure and composition of EVs and NETs, as well as the feedback mechanism between the two processes that causes pathological thrombus formation, require exhaustive analysis to clarify their role in thrombosis.