key: cord-0812675-0fbgukba
authors: Rolla, Roberta; Puricelli, Chiara; Bertoni, Alessandra; Boggio, Elena; Gigliotti, Casimiro Luca; Chiocchetti, Annalisa; Cappellano, Giuseppe; Dianzani, Umberto
title: Platelets: 'multiple choice' effectors in the immune response and their implication in COVID‐19 thromboinflammatory process
date: 2021-03-22
journal: Int J Lab Hematol
DOI: 10.1111/ijlh.13516
sha: 70743c20790fa81814a5033d3ad1c6e8619e2c31
doc_id: 812675
cord_uid: 0fbgukba

Although platelets are traditionally recognized for their central role in hemostasis, the presence of chemotactic factors, chemokines, adhesion molecules, and costimulatory molecules in their granules and membranes indicates that they may play an immunomodulatory role in the immune response, flanking their capacity to trigger blood coagulation and inflammation. Indeed, platelets play a role not only in the innate immune response, through the expression of Toll‐like receptors (TLRs) and release of inflammatory cytokines, but also in the adaptive immune response, through expression of key costimulatory molecules and major histocompatibility complex (MHC) molecules capable to activate T cells. Moreover, platelets release huge amounts of extracellular vesicles capable to interact with multiple immune players. The function of platelets thus extends beyond aggregation and implies a multifaceted interplay between hemostasis, inflammation, and the immune response, leading to the amplification of the body's defense processes on one hand, but also potentially degenerating into life‐threatening pathological processes on the other. This narrative review summarizes the current knowledge and the most recent updates on platelet immune functions and interactions with infectious agents, with a particular focus on their involvement in COVID‐19, whose pathogenesis involves a dysregulation of hemostatic and immune processes in which platelets may be determinant causative agents.

on their secretion. As a consequence of granule fusion with the platelet plasma membrane, several granule molecules may be expressed on the platelet surface or released as soluble molecules (eg, coagulation factors, mitogenic factors, angiogenic mediators, and chemokines) acting either locally at sites of vascular injury or even systemically (Figure 1 ). In addition, platelet activation is also essential for the initiation of many other innate defense mechanisms, acting by promoting the recruitment, migration, and interaction of immune cells.

Proteomic studies indicate that α-granules release more than 300 soluble proteins acting in processes such as blood coagulation, inflammation, immunity, cell adhesion and growth, and possibly other less known activities 2,3 (Table 1) 

EVs are cell-derived membrane particles, ranging from 30 to 5000 nm in size, that have been highly conserved during evolution.

Under physiological conditions, EVs circulate in the blood and other body fluids and are important mediators of intercellular communication: They act as shuttle vectors and signal transducers, both locally and at a distance from their site of origin. 4 Accumulating evidence shows that EVs are also emerging as biomarkers of several human disorders, including cancer, infections, and autoimmune diseases. 3, 4 The most abundant circulating EVs, accounting for 70%-90% of all EVs, are derived from platelets. 4 Since EVs transfer proteins, lipids, metabolites, miRNA, and nucleic acids, platelet-derived EVs (PDEVs) may influence various physiological and pathological functions of platelets themselves. Platelets mainly circulate in the blood, whereas PEDVs can reach also other tissues such as the lymph and lymph nodes tissues and might therefore influence both the afferent and efferent arms of the immune response. 5 Circulating PDEVs may originate from either megakaryocytes or platelets. 6 Those derived from megakaryocytes express on their surface the integrin subunits αIIb (GPIIb, CD41), and GPIb (CD42b), F I G U R E 1 Schematic representation of platelet functions in the hemostatic process and during inflammation. Platelet activation induces an increase in the expression on the plasma membrane of the active form of integrin αIIbβ3, followed by platelet aggregation promoting thrombin generation. Platelet-derived microparticles also favoring the coagulation process. Different types of biological mediators released by α and δ granules lead to pro-thrombotic and proinflammatory events. The interaction between P-selectin and leukocytes induces the release of proteases, production of ROS, and expression of TF. CD40L expression supports the recruitment of platelets to the endothelium of blood vessels, which in turn activates endothelial cells and vWF release. An increase in cytokine secretion by neutrophils and monocytes induces platelet activation, which favors inflammatory cytokine production by the platelets themselves. Abbreviations: MO, Monocyte; NE, neutrophil elastase; NETs, neutrophil extracellular traps; NEUT, Neutrophil; PLT, platelet; PS, phosphatidylserine; ROS, reactive oxygen species; TF, tissue factor; TXA2, Thromboxane A2; vWF, von Willebrand factor and contain filamin A, whereas those derived from activated platelets express markers of granule fusion with the plasma membrane, like CD62P. 6 During their activation and maturation platelets release two different types of EVs, that is, exosomes and microvesicles, respectively, 7 but it is not well known their potential extracellular function than the anticoagulant activity attributed to the latter. In general, PDEVs derived from activated platelets may be involved in the coagulation process, either directly or indirectly. Direct exposure of phosphatidylserine on PDEV surface leads to thrombin generation and blood clotting. Conversely, exposure of P-selectin, which binds glycoprotein ligand-1 on monocytes, leads to monocyte activation and production of tissue factor (CD142).

The cargo of PDEVs includes a variety of molecules ranging from miRNAs, mRNA, non-coding RNA, to cytokines and surface proteins. Pro-inflammatory cytokines are released on activated endothelium, promoting leukocyte recruitment, and thus contributing to inflammation during infection. Alternatively, they can directly affect endothelial cells (EC), participating in the development and progression of atherosclerosis. 8 In vitro, PDEVs promote the adhesion of neutrophil to EC even when P-selectin is not expressed on EVs surface. 9 Moreover, PDEVs released from activated platelets carry IL-1β and caspase-1, capable to promote platelet-neutrophil aggregation both in vivo and in vitro. 10 In Dengue infection, PDEVs released from activated platelets activate neutrophils and macrophages through the CLEC5A receptor, induce formation of neutrophil extracellular trap (NET, see below) and release of pro-inflammatory cytokines. 11 In systemic sclerosis and septic shock, PDEVs express HMGB1 (high mobility group B1), that can induce neutrophil activation by interacting with TLR4 12 leading to autophagy and NET production. 13 Moreover, HMGB1 expressed on the surface of PLT-derived EVs can be internalized by neutrophils and alter their function. PDEVs can bind also to classical and intermediate monocyte subsets, supporting their activation leading to secretion of inflammatory mediators such as IL-1β, IL-6, and TNFα, and adhesion to EC through GPIbα. 14 Regarding the miRNA content, it has been shown that the expression of miR-223 in PDEVs released from activated platelets regulates ICAM-1 expression via the NF-κB and MAPK pathways. 15 Two other miRNAs, that is, miR-15b-5p and miR-378a-3p, induce NET formation. 13 Another study showed that PDEVs can be internalized by primary human macrophages and deliver the functional miR-126-3, which modifies their transcriptome and reprograms their function toward a phagocytic phenotype. 17 Moreover, PDEVs are also involved in vascular and metabolic diseases, through upregulation of several miRNAs, for example, miR-144-3p, miR-486-5p, miR-142-5p, miR-451a, miR-25-3p, miR-145-5p, and let-7f-5p, having as targets mRNAs involved in vascular remodeling. Platelet-derived exosomes induce NET formation via miR-15b-5p and miR-378a-3p.

Lastly, circular RNA, which is a novel class of non-coding RNA, has been identified in PDEVs derived from activated platelets. 18

Platelets play a role in the innate immune response, through the ex- 

TLRs play key roles in the innate immune response, which subsequently leads to the activation of antigen-specific adaptive immu- Moreover, circulating pathogens may be bound and sequestered by platelet TLR4, which decreases their systemic dissemination. 20 Other platelet receptors that can interact with bacteria are integrin αIIbβ3, FcgRIIa, and glycoprotein Ib-IX. These trigger platelet activation, followed by the release of pro-inflammatory mediators and activation of the coagulation cascade, with positive feedback activity. 21

Platelets are considered as silos of CD40L: They express CD40L on their surface within minutes from activation, and they are the main source of the soluble circulating form of CD40L (sCD40L). sCD40L

can be produced by metalloprotease-dependent cleavage of the membrane form, or, alternatively, by splicing of the CD40L mRNA.

Besides, CD40L can be released associated with platelet-derived mi- sCD40L may trigger activating stimuli on CD40, thanks to its ability to oligomerize, mimicking the activity of membrane-bound CD40L. However, sCD40L can also act as a competitive antagonist in the interaction between the membrane-bound forms of CD40 and CD40L, playing a role in down-modulating the immune response. 25 

Platelets also express class I major histocompatibility complex (MHC 

Activated platelets also express FasL, which triggers the death re- FasL expressed on platelets may also play a role in hemostasis and thrombosis, by interacting with Fas expressed on red blood cells.

Fas triggering induces externalization of phosphatidylserine on the red blood cell membrane, promoting hemostasis and thrombosis.

Inhibition or genetic deletion of either FasL or Fas results in decreased thrombin generation and thrombus formation in vitro, and in reduced protection from arterial thrombosis in vivo. 29 Another shutting down system of the immune response, which may be recruited by platelets, is the programmed cell death protein-1 (PD-1) system. PD-1 is a key negative receptor expressed by activated and exhausted T cells and acts as an immune checkpoint to down-regulate the immune response.

The normal blood platelet count is between 150 × 10 9 and 450 × 10 9

platelets/L; however, only a small proportion of them (10 × 10 9

platelets/L) is normally necessary to prevent bleeding, although se- 

Neutrophils not only are key early responders to tissue injury and infection, but are also able to release their nuclear content into the vascular system in order to deceive and capture circulating patho- Once activated, platelets can interact with neutrophils through platelet P-selectin directly engaging PSGL-1 (P-selectin glycoprotein ligand-1) on neutrophils and platelet GPIbα directly binding to neutrophil MAC-1. The latter interaction is particularly important to support the interactions between platelets and neutrophils at low shear rates such as those found in arteries. Platelets can also bind to neutrophils through the activated αIIbβ3 integrin that, on neutrophils,

can bind either directly the newly identified receptor SLC44A2 or indirectly MAC-1 through fibrinogen bridging. 31 The complex formed by platelets plus NETs leads to the formation of "immuno-thrombi,"

which appear to function as focal points for microbial elimination.

Immuno-thrombi act not only as three-dimensional networks trapping microbes, but also as platforms concentrating leukocytes and lytic enzymes, actively contributing to the elimination of pathogens, and actively modulating the immune response.

Furthermore, the negatively charged nucleotides of NETs are able to trigger the intrinsic coagulation pathway, whose activation leads to the formation of thrombin that, in turn, amplifies platelet activation being a potent agonist of protease-activated receptors (PAR). 3 Activated platelets increase their expression of C1qR and CD62P, which may recognize bacteria opsonized by C1q or C3, respectively, and even lead to internalization of bacteria as detected by electron microscopy. 32, 34 Platelets activated by thrombin or bacteria can also secrete platelet microbicidal proteins (PMPs), also known as thrombocidins, including platelet factor-4 (PF4), platelet basic protein (PBP), and fibrinopeptides. These proteins are activated by thrombin-mediated cleavage and act by both chemoattracting leukocytes and targeting bacterial membranes. Intriguingly, PF4 binds with high affinity LPS lipid A expressed by Gram-negative bacteria and, then, exposes a neo-epitope recognized by anti-PF4 antibodies. Since PF4 binds many different bacteria, these antibodies will be able to "aspecifically" opsonize all of them allowing their clearance by phagocytes expressing Fc receptors. 35 

Several platelet receptors mediate direct binding to viruses; they include integrin αIIbβ3, collagen receptor GPVI, complement receptor On the whole, platelet role in body defense against pathogens involves plenty of bidirectional and sometimes even redundant signaling pathways able to build up what has been elegantly termed an "immune syntax," that is, a coordinated strategy whose primary aim is the optimization of host defense.

Platelets play key roles in viral infections, and the recent severe Lymphopenia and thrombocytopenia are often already present at admission and are more prominent in severe cases. 40

A recent meta-analysis reported a significant association between thrombocytopenia and both COVID-19 severity and its mortality in 1 779 COVID-19 patients. 41 This finding is supported by other studies, showing that platelet count is an independent predictor of disease progression, with a high negative predictive value (NPV).

Interestingly, a relevant predictive role was detected not only for the baseline platelet count but also for its evolution during the clinical course of the infection, so that in-hospital mortality is positively correlated with the magnitude of the decrease. 42 Even more specifically, an initial increase in platelet counts when the infection begins has been reported, followed by a rapid drop after the occurrence of severe illness, probably reflecting an initial acute phase reaction, followed by massive platelet activation and consumption. 43 COVID-19 thrombocytopenia is likely to be multifactorial. Firstly, it may be related to very high platelet consumption originating from the vasculopathy induced by generalized inflammation. Endothelial damage promotes platelet activation, by increasing the expression of adhesion molecules and receptors like CD40 and at the same time exposing collagen and tissue factor, the latter also being able to trigger the coagulation cascade. 44 Moreover, platelet activation results in a vicious circle, since the chemotactic function of active platelets recruits leukocytes and increases endothelial inflammation.

This process can be considered part of a more systemic phenomenon, occurring as a result of the cytokine storm following massive immune activation in response to the viral infection. 45, 46 In the worst cases, this defense mechanism may end up causing disseminated intravascular coagulation (DIC), a well-known complication of severe Exposure of endothelium, platelets, and leukocytes to PAMPs and damage-associated molecular patterns (DAMPs), and to proinflammatory cytokines (primarily IL-6), initiates a cascade of events leading to dysregulated thrombin generation and a thromboinflammatory process, in which pro-thrombotic phenomena prevail over hyperfibrinolysis. It seems that in COVID-19 this sepsis-induced coagulopathy (SIC), despite its potential to act systemically, especially targets the lungs and, in particular, the pulmonary microvasculature. Following the induction of primary and secondary hemostasis, microthrombi develop, gas exchange is impaired, and the patient eventually develops ARDS. 47 To further worsen the clinical scenario, mechanical ventilation, used in patients with respiratory failure, can also promote damage of alveolar epithelial and endothelial cells (ventilation-induced lung injury, or VILI), 48 thus initiating a self-amplifying process challenging patient survival.

A role in thrombocytopenia may also be played by a reduced production of platelets by the bone marrow. This possibility was already described for SARS but it might be true also for SARS-

CoV-2, which shows almost 80% of nucleotide identity with SARS-CoV, 49 even though this hypothesis has not been proven yet. The lung is known to be the primary site where megakaryocyte fragmentation into platelets occurs since it is the first vascular bed encountered after leaving the bone marrow. 50 A study to elucidate the possible pathogenesis of late neonatal thrombocytopenia using mouse models pointed to lung injury as a likely cause, since endothelial damage could impair the ability of pulmonary capillaries to retain megakaryocytes and favor platelet release. Thus not only do platelets have a reduced half-life due to their activation F I G U R E 3 Schematic representation of platelets and SARS-CoV-2 interaction leading to thrombocytopenia, neutrophilia, and lymphopenia. A) Thrombocytopenia is ascribable to platelet consumption, which originates from the vasculopathy induced by the cytokine storm, triggered by the viral infection. Increased expression of CD40 in damaged endothelium induces platelet activation, which favors endothelial inflammation. Platelet consumption is heightened by the impaired ability of pulmonary capillaries to retain megakaryocytes and favor platelet release; bone marrow viral infection also contributes to platelet reduction. Immune thrombosis plays a central role in thrombocytopenia; activation of platelets promotes the formation of immuno-thrombi, which act as focal points for microbial elimination, concentrating leukocytes and lytic enzymes. B) Neutrophilia is mainly due to platelet activation by pro-inflammatory cytokines induced by SARS-CoV-2 infection, and adhesion molecules expressed by damaged endothelium, which sets off a mutual interaction with neutrophils, enhancing their degranulation and DNA release to form NETs, favoring the coagulation cascade. C) Lymphopenia includes a marked reduction of CD4+ T helper, CD8+ T cytotoxic cells, and NK cells. It is mainly ascribable to cytolytic effects exerted by SARS-CoV-2 on infected lymphocytes, or to hyperinflammation induced by the infection, which increases lymphocyte apoptosis through Fas triggered by FasL expressed on activated platelets and consumption caused by the vasculopathy, but they also fail to be released from their precursors while in the pulmonary circulation. 51 Thus, the loss of the lung's function as "platelet manufacturer" after virus-induced microvascular damage provides an alternative explanation of the platelet count reduction also found in COVID-19.

Another cause of decreased thrombocytopoiesis is direct bone marrow infection by SARS-CoV-2, or induction of an autoimmune response against blood cells including megakaryocytes. 41 A role might also be played by liver dysfunction, due to direct liver infection (hepatocytes express ACE2), hyperinflammation, thrombotic microangiopathy, drug-mediated toxicity, and hemodynamic alterations, with hepatic ischemia due to cardiac failure, and hepatic venous congestion due to increased central venous pressure 52 ( Figure 3A ). in turn have a greater chance of interacting with platelets. 59 In this connection, histone-targeting drugs, but also polyphosphatetargeting substances such as alkaline phosphatase, might be considered as possible future therapeutic strategies also in COVID-19

patients developing coagulopathy ( Figure 3B ).

In the initial phases of the infection, blood lymphocyte counts are either normal or mildly decreased; however, when the "cytokine storm" blows up, substantial lymphopenia becomes evident, which is an atypical feature for viral infections. Lymphopenia involves a marked reduction of T cells, involving both CD4 + T helper and especially CD8 + T cytotoxic cells, and NK cells, whereas B-cell numbers are reported to be either reduced or normal. 42 An increased number of T cells express activation markers, such as CD69, CD38, CD44, OX40, 4-1BB, and exhaustion markers such as PD1. 60 Several mechanisms have been suggested to explain lymphope- 

Recent studies reported the emerging role of PDEVs in SARS-CoV-2

infection. We showed that the PDEV count is higher in SARS-CoV-2 + hospitalized patients compared to SARS-CoV-2ones and healthy controls. PDEVs showed also a good performance as diagnostic biomarkers in discriminating SARS-CoV-2 + from SARS-CoV-2 + patients, and might be possibly involved in the thromboembolism and vascular leakage, which are clinical hallmarks of SARS-CoV-2 infection. 61 A recent study showed that activation of the platelet inflammasome leads to release of PDEVs carrying IL-1β and caspase-1 that bind to neutrophils and promote platelet-neutrophil aggregation in lung arterioles. 10 Another study showed that, in COVID-19 patients, PDEVs are increased and platelets carry the SARS-CoV-2 RNA. The authors hypothesized that the presence of viral RNA in the endosomal compartment may activate platelet TLR-7, as reported also in influenza and encephalomyocarditis virus infections. 62 Moreover, we detected the SARS-CoV-2 RNA in the exosomal cargo from both critical and not critical SARS-CoV-2 + patients, and we suggested that the virus might use this route to spread the infection. 63

Platelets are true sentinels of our organism, the front line of a large army that quickly and efficiently coordinates the immune response.

Once the pathogen is revealed, platelets are rapidly activated and guide the inflammatory response, producing a wide spectrum of immunomodulatory cytokines, chemokines, and other mediators.

Platelets can simultaneously coordinate multiple cells with different functions, such as the endothelium (through adhesion molecules and chemokines), neutrophils (promoting phagocytosis and oxidative burst), and lymphocytes. Thanks to their wide range of adhesion molecules and preformed chemokines, platelets can also adhere directly to leukocytes and facilitate their recruitment to sites of tissue damage or infection, and they participate directly in the capture and sequestration of pathogens within the vascular system.

Moreover, thanks to platelet-neutrophil interactions, platelets induce the release of NETs in response to bacterial or viral infection and are capable of trapping pathogens within platelet aggregates.

Lastly, platelets provide an abundance of growth factors, cytokines, chemokines, and EVs, with local and systemic effects. All these features may play key roles in COVID-19 pathogenesis.

All authors disclose no financial or personal relationships with other people or organizations that could inappropriately influence (bias) this work. No study sponsors were involved in this manuscript. 

The data used for this review are available from the corresponding author.

https://orcid.org/0000-0003-0805-8285

Chiara Puricelli https://orcid.org/0000-0002-0416-6687

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Thrombin-activated plateletderived exosomes regulate endothelial cell expression of ICAM-1 via microRNA-223 during the thrombosis-inflammation response

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Selective release of circRNAs in platelet-derived extracellular vesicles

Toll-Like receptors

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multiple choice" effectors in the immune response and their implication in COVID-19 thromboinflammatory process