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Review

The Role of Platelet Molecules in Risk Stratification of Patients with COVID-19

1
Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza 60430-275, Brazil
2
Central Unity, Molecular Biology Laboratory, Clementino Fraga Group, Fortaleza 60115-170, Brazil
*
Author to whom correspondence should be addressed.
Hemato 2023, 4(4), 364-383; https://doi.org/10.3390/hemato4040029
Submission received: 20 September 2023 / Revised: 1 November 2023 / Accepted: 9 November 2023 / Published: 30 November 2023
(This article belongs to the Section Coagulation)

Abstract

:
The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in China and is responsible for Coronavirus disease (COVID-19). Despite being well tolerated by most patients, a fraction of cases evolve into a potentially fatal condition requiring intensive care. In addition to respiratory complications, several studies have reported cases of patients who developed intense thrombosis, including acute myocardial infarction and ischemic stroke, as well as the presence of elevated coagulation markers. Evidence has shown that the virus can interact directly with platelets and modulate their thrombotic and inflammatory functions, with significant prognostic implications. It is important to highlight that the emerging literature shows that when hyperactive these cells can act as pro-viral infections both in transporting their particles and in increasing inflammation, leading to a hyperinflammatory state and consequent clinical worsening. In this review, we searched for studies available in public databases and discussed the interaction of platelet biomarkers in the pathogenesis of COVID-19. In this context, understanding the mechanism of SARS-CoV-2 and these cells in different clinical conditions could help us to understand the coagulation and inflammation profiles of critically ill patients with the disease, guiding faster clinical management and enabling the reuse and targeting of more efficient therapies.

1. Introduction

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an enveloped positive-sense single-stranded RNA virus belonging to the Coronaviridae family which has in common with others of the same species the presence of four proteins—Spike protein (S), envelope protein (E), membrane protein (M) and nucleocapsid protein (N)—which are closely related to the toxicity and infectivity of these coronaviruses and are responsible for viral maintenance and replication [1,2,3,4].
The S protein has a vital role in the infection and pathogenesis of COVID-19, in addition to being the glycoprotein that determines the fusion of the virus in cells. This protein is further subdivided, where the ectodomain is divided into subunits: S1, which helps in binding to the ACE-2 receptor on the surface of the host cell, and the second, S2, which is responsible for membrane fusion (Figure 1) [5,6].
SARS-CoV-2 became known for its mutagenesis, and despite being less pathogenic when compared to other coronaviruses, a high transmission rate was observed due to its rapid spread from person to person [8]. Through the transmembrane protease serine 2 (TMPRSS2), a serine protease that acts in the proteolytic cleavage and activation of the Spike protein, SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE-2) in order to contribute to the fusion of the virus to the host’s cell membrane and then entry of the viral genome into the cell [6,8,9].
Even though infection by this virus presents tropism for respiratory endothelial cells, studies indicate cases of patients who developed intense thrombosis, including myocardial infarction and ischemic stroke [5,10]. Despite being considered the main effector cells of hemostasis and playing an important role in thrombus formation, platelets are also responsible for mediating inflammatory and immunological responses [11,12].
Since platelet activation occurs through inflammatory or infectious events, these are commonly associated with a prothrombotic response and, consequently, with platelet hyperactivity, as is observed in several viral infections [2], including the human immunodeficiency virus (HIV) [13,14], influenza virus [15], dengue virus [16,17] and human cytomegalovirus [18]. Similar to the process of thrombocytopathy, coagulopathy and inflammation are observed in patients infected by SARS-CoV-2, leading to a significant increase in thrombotic and embolic events [4,9].
Therefore, a systematic understanding of the thrombotic effects of SARS-CoV-2 represents a promising strategy for redirecting and developing therapies capable of minimizing the damage associated with this disease [19].

2. Pathophysiology and Pathogenesis of SARS-CoV-2

SARS-CoV-2 infection begins when the Spike protein binds to its receptor on the host cell membrane, with ACE-2 being considered the main enzyme responsible for the virus’s entry into the cell. In addition, the high expression of ACE-2 in the nasal and oral mucosa makes its entry via inhalation possible. After binding to ACE-2, the TMPRSS2 protease cleaves and activates the spike protein to favor the fusion of the viral envelope with the cell membrane [20,21,22].
Depending on the availability of proteases on the surface of the host cell, the Spike protein enables virus entry by endocytosis or via direct fusion. Within the alveoli, due to considerable expression of ACE-2 and TMPRSS2, epithelial cells lining the lower airways are the primary target. From then on, the structural proteins move along the secretory pathway to the Golgi complex, where the viral progeny will be assembled and then released from the host cell by exocytosis [8,23] (Figure 2).
As epithelial cells are infected, the virus induces apoptosis as part of the replication cycle, which is related to the vascular leakage that initiates local infection and the recruitment of immune cells in an attempt to contain the infection. In this context, the increase in cytokines in the lungs can aggravate this inflammatory response and lead to pneumonia [24,25].
Even though most patients have mild symptoms and a good prognosis, a fraction of these individuals may develop severe COVID-19 [26,27], with the occurrence of thrombosis and abnormal platelet parameters such as decreased platelet count as well as changes in the coagulation profile, including decreased prothrombin time (PT) and increased activated partial thromboplastin time (aPTT), D-dimer and fibrinogen, which are associated with the severity and prognosis of the disease [28,29,30,31].
Abnormalities range from coagulopathies commonly associated with serious infections, such as disseminated intravascular coagulation (DIC) [32,33], to deep venous and arterial thrombosis—which can cause ischemic stroke, systemic arterial embolism, acute coronary syndrome and limb ischemia [34]—and pulmonary embolism [35], with prevalences in patients in intensive treatment units (ITU) [36].
Although its pathophysiology has not been completely explained, an uninterrupted and disproportionate immune-inflammatory response is observed, mainly from platelet-derived signaling proteins that mediate and regulate the immune response [37].

3. Immunothrombosis and SARS-CoV-2 Infection

Platelet activation generally occurs in response to inflammatory and/or infectious diseases. The infection stimulates a systemic inflammatory response in which activation of the host’s defense systems results in the activation of coagulation pathways, leading to the formation of thrombin as a component of communication between humoral and cellular immunity, called immunothrombosis [38].
Once the pathogen is recognized by platelets, they increase the immune response through the release of cytokines and antimicrobial peptides and through the platelet–leukocyte interaction [4,39,40]. During this process, a type of physical barrier is formed by platelets and immune cells with the aim of preventing the spread and survival of the pathogen [4,38,41]. However, the accumulation of immune cells, mainly monocytes and neutrophils, can lead to adverse immunological and hemostatic responses, contributing to a worse clinical context, with the development of thrombosis and organ failure [4].
The platelet–leukocyte interaction plays a role in the pathophysiology of different viral infections [42,43,44], being seen as a driver of vascular disease, and is considered the main factor responsible for thromboinflammatory responses during COVID-19, associated with serious disease and elevation of coagulation markers, such as fibrinogen and D-dimer, where its increase was described in patients in need of ventilatory support and in those who died in hospital [40].
When in contact with the respiratory system, the virus increases inflammation, triggering a storm of cytokines that are responsible for recruiting immune cells, establishing the cycle of inflammation of the lung epithelium and thrombotic events [10]. Polyphosphates derived from microorganisms activate platelets, mast cells and factor XII (FXII), while the exacerbated release of cytokines increases the recruitment of leukocytes to the site of injury, promoting the formation of neutrophil extracellular traps (NETs) which, together with FXII, stimulate the formation of thrombin and induce a thromboinflammatory state. As vascular endothelial damage increases, the passage of fluids to the lung cavity is made possible, leading to respiratory failure (Figure 3) [4,10,44].

4. Viral Infections, including SARS-CoV-2 and Its Interaction with Platelets

Platelets are widely known for their contributions to thrombosis and hemostasis and for having a broad expression of immune and adhesion receptors [12]. However, their interaction and favorability with viral infections have aroused increasing interest among researchers [12,16].
The involvement of these cells in viral defenses occurs through their direct activity, where specific receptors are released. Also, the virus can be phagocytosed through the formation of complexes with the virus and platelets, leading to thrombocytopenia. Through indirect routes, the virus is neutralized through the formation of aggregates with leukocytes, platelet apoptosis and/or activation of the vascular endothelium [45].
Platelets play an important role in the host’s immune defense against viruses; they engulf viral particles and thus reduce viremia. However, they can also contribute to increased inflammation and tissue damage in these infections [46], such as influenza [15,43], HIV [14,15], hepatitis C [47,48], dengue [16,17], HSV-1 (herpes simplex virus A) [49] and cytomegalovirus [18], acting on the internalization of virions, platelet activation and contributing to the transport of these particles [50,51].
Additionally, the interaction of platelets in the pathogenesis of COVID-19 has been discussed. One study identified the presence of viral particles in the lungs and in megakaryocytes morphologically active in the production of platelets in bone marrow in patients who died from the disease. The same particles were also observed in circulating platelets, suggesting that SARS-CoV-2 is transferred from megakaryocytes to platelets or phagocytized by them when circulating [19].
Another two studies described platelet activation in patients with severe COVID-19, demonstrating increased levels of platelet aggregates and immune cells [4,51]. In addition, one of them showed that the platelets of these patients contained viral RNA, suggesting that these cells can absorb SARS-CoV-2 mRNA as well as present changes in the expression of platelet genes, similar to those observed in patients infected with the H1N1 virus [4].
In this context, understanding the mechanistic role of SARS-CoV-2 with platelets and its development of a cascade of pro-coagulatory events proves to be a key tool for early diagnostic screening and therapeutic targeting of thrombotic complications of severe COVID-19 [19,43].

5. Platelet Markers and COVID-19

Platelets are small cellular fragments derived from megakaryocytes which, in addition to acting in the establishment of hemostasis, play important roles in the immune response. When activated, platelets release substances responsible for recruiting defense cells to the site of injury/inflammation and promote their adhesion to platelet thrombi, thus modulating the functional response of leukocytes [12,52].
Although it is considered an effective way to help protect the body, its critical contributions to thrombosis are already known. During various infections—viral or bacterial—activated platelets adhere to the subendothelium and their hyperactivity results in the formation of thrombi, leading to arterial ischemia and even pulmonary embolisms [4,12,41].
The cytoplasm of platelets contains three main types of granules: α, dense and lysosomes. Alpha granules are larger and more abundant and store a wide variety of proteins. Dense granules are smaller and less present [53]. Lambda granules are sparse and composed of glycohydrolases and lysosomal enzymes. When stimulated, the granules undergo exocytosis and release their contents into the extracellular environment, contributing to platelet activation and thrombus formation [54,55]. Also, many of these mediators participate in the recruitment of leukocytes and inflammatory cells, which help in the establishment of the hyperinflammatory state [55,56].
As knowledge about severe COVID-19 advances, hypercoagulability is identified as the central pathological characteristic of clinical complications since evidence shows that the virus can interact directly with platelets and modulate their thrombotic and inflammatory functions [4,57]. In addition to the severity of the disease, thrombotic events associated with increased levels of coagulation markers have been shown to be important in determining the prognosis of patients with COVID-19 [58,59]. The identification of new platelet markers, in addition to enabling a better understanding of the thrombotic complications caused by SARS-CoV-2, during evaluation of these molecules during hospital admission would indicate sick patients with a predisposition to thrombosis and optimize therapeutic management [60].
Table 1 is made up of a series of platelet molecules acting in thromboinflammatory processes in the clinical context of COVID-19, followed by their methods of detection. And, although they have not been sufficiently tested in clinical practice, different studies have highlighted the influence of these markers on the risk stratification of the disease, providing sustainable data for future research.

5.1. P-Selectin

The study by Manne et al. described changes in the expression profile of circulating platelets in patients with COVID-19. Despite the normal morphology of these cells, they were hyperreactive and an increase in the expression of basal P-selectin and a greater formation of circulating platelet–leukocyte aggregates were also evidenced [4]. Therefore, P-selectin may play a crucial role in endotheliopathy and platelet hyperactivation in SARS-CoV-2 infection [29].
P-selectin is an inflammatory marker of coagulation which is present in the alpha granules of platelets, the Weibel–Palade bodies of the endothelium and the platelet membrane, acting as an adhesion receptor to support the rolling and emigration of leukocytes to the site of inflammation. In its soluble form (sP-selectin), it is responsible for modulating blood cell and endothelial cell interactions [61,62].
In agreement, other authors also demonstrate increased expression of surface P-selectin in patients with severe COVID-19 [39], as well as being correlated with higher levels of platelet–monocyte aggregates in infected individuals admitted to the ITU [63]. In addition, the levels of soluble selectins have been identified as a predictor of thrombosis in patients with the disease and in identifying the need for therapeutic intervention with prophylactic anticoagulants [39].

5.2. Von Willebrand Factor (VWF)

Von Willebrand factor (VWF) is an essential glycoprotein regulating thrombosis and hemostasis, found in both endothelial cells and platelets [64]. During vascular injury, VWF assists in the recruitment of platelets to the site, promoting their adhesion and aggregation [64,65]. Elevated plasma concentrations of this factor are associated with an increased risk of venous thromboembolism [66] and its deficiency with bleeding disorders [67].
Different studies have described increased plasma levels of VWF in patients with COVID-19 [68,69,70], pointing out a strong correlation with disease severity and mortality, suggesting an important role in the pathogenesis of thrombosis in COVID-19 [69]. Furthermore, a French study carried out with adult hospitalized and outpatient patients described, through immunohistochemistry, an increase in the reaction to VWF in the pulmonary endothelium when the disease duration was longer than 10 days [68].
In addition to other authors describing the presence of higher levels of VWF in patients who died [71], in those admitted to the ITU and when compared to non-ITU patients [29], they were also associated with a greater severity of the disease [72].

5.3. Plasminogen Activator Inhibitor (PAI-1)

Plasminogen Activator Inhibitor-1 plays an important role in the fibrinolysis regulation process. This mechanism is regulated by plasminogen activators and inhibitors, in which a fibrin-rich thrombus is degraded and remodeled by proteases responsible for converting plasminogen into plasmin as the final product [73]. In patients with COVID-19, reduced clot lysis was evidenced, suggesting impaired fibrinolytic activity and an increased risk of thrombotic complications [74].
In inflammatory conditions, the release of PAI-1 through endothelial cells and activated platelets is stimulated, promoting a high concentration of it at the site, in which, persistent fibrin deposition in the lung parenchyma establishes the hypofibrinolytic state, which is a risk factor for venous thrombosis in severe COVID-19 [75].
Furthermore, some studies carried out with hospitalized patients demonstrated elevations in PAI-1 in critically ill patients [76,77], as well as being associated with a worse respiratory status and an unfavorable clinical outcome [76]. These high plasma levels were also highlighted as a possible explanation for the high incidence of serious infection in obese patients since adipose tissue contributes to the production of PAI-1 [78].

5.4. Platelet Factor 4 (PF4)

PF4 is a chemokine that is mostly present in platelet alpha granules and is released during platelet activation [79], playing an important role in coagulation, regulation of angiogenesis and inflammatory and infectious responses [80]. Due to its negative charge at physiological pH, PF4 binds to endogenous herapan sulfate, neutralizing the side chains of this glycosaminoglycan, promoting blood clotting and facilitating aggregation and thrombus formation [79].
Different studies performed in vitro [81,82] and in vivo [83] demonstrated that this chemokine can also affect hemostasis and thrombosis through inflammatory and vascular pathways. After pathogen recognition, platelets mediate and propagate the immune response, activating mechanisms such as the release of inflammatory cytokines and modulation of leukocyte migration to the site of inflammation/infection, inducing the formation of NETs, which are important mediators in the process of coagulopathy associated with COVID-19 [84,85], in addition to the increased formation of platelet–leukocyte aggregates that favor the triggering of immunothrombosis [39].
As an example, circulating PF4 levels were highly elevated in patients with the disease when compared to the control group, supporting the hypothesis of greater platelet activation [86]. In addition, its presence was quantified in tracheal aspirates from a patient with COVID-19 under mechanical ventilation, suggesting that platelet activation products can infiltrate the airways of patients with severe COVID-19 [39].
Furthermore, the formation of anti-PF4 autoantibodies by binding of PF4 to heparin has been reported in thrombotic patients with COVID-19 [87,88]. In cases of heparin-induced thrombocytopenia (HIT), the formation of PF4/heparin immune complexes occurs, which have the ability to bind to platelet receptors and induce platelet activation and aggregation, as well as the activation of coagulation pathways that lead to severe thrombotic syndrome [88,89,90]. High titers of anti-PF4 antibodies were observed in ITU patients treated with heparin and in those without prior exposure, suggesting that spontaneous HIT may occur during viral infection [91].

5.5. Transforming Growth Factor-Beta (TGF-β)

TGF-β is a pleiotropic cytokine stored in its latent form in platelet alpha granules, known for its participation in the regulation of inflammation, tissue healing and platelet aggregation [92,93,94]. However, its continuous stimulation during infectious processes triggers increased coagulation and immune dysregulation which can lead to tissue fibrosis, which is common in the inflammatory phase of COVID-19 [92].
Increasing evidence suggests that TGF-β signaling disorder is a feature of the microvascular coagulation and inflammatory injury observed in SARS-CoV-2 infection and such events could contribute to acute respiratory distress syndrome (ARDS), microthrombosis and pulmonary fibrosis seen in critically ill patients [92,95]. Furthermore, high serum levels of this cytokine have been correlated with increased severity of the disease [94,96], and it has also been shown that serum from these patients can inhibit the function of NK cells and early control of the virus [97].

5.6. Platelet-Activating Factor (PAF)

Another important effective mediator of inflammation in infectious processes is platelet-activating factor (PAF), expressed mainly on the surface of leukocytes, endothelial cells, mast cells and platelets [98,99]. Within platelet cells, PAF promotes aggregation and clot formation [99], which are linked to a variety of clinical conditions, such as heart failure, asthma, cancer, atherosclerosis and viral diseases [100,101].
Although PAF promotes a natural inflammatory response, its effect can become pathogenic in the presence of excessive or unregulated activity, resulting from changes in its synthesis and termination cycles as a result of diseases or genetic variations [99,102].
The similarities between the physiological effects of PAF and the clinical context of severe COVID-19 are discussed in different studies [102,103,104]. PAF release from platelets has been reported to stimulate mast cell activation and inflammation [105], and mast cell degranulation associated with interstitial edema and immunothrobosis has been observed in the alveoli of deceased COVID-19 patients [106] and increased levels of PAF have been found in the blood of patients with moderate COVID-19 [107].

5.7. MMP-2, MMP-9

Metalloproteinases (MMPs) are zinc- and calcium-dependent proteinases which have the ability to degrade extracellular matrix proteins. In their latent form, MMP-2 and MMP-9 are stored mainly in the cytoplasm of platelets, where they mediate inflammatory responses through the migration of immune cells to the site of infection [108,109], as well as inducing platelet–leukocyte aggregation [110].
MMPs participate in several physiological processes including embryonic development, coagulation cascade and fibrinolysis, as well as in pathological processes such as lung diseases, vascular changes, obesity, inflammation, cancer and atherosclerosis [108,109,110,111,112,113]. More recently, these enzymes were also associated with clinical manifestations during coronavirus infection [114,115,116].
In view of the known role of MMPs in the lung physiology and respiratory symptoms of severe COVID-19, a study carried out in patients admitted to the Intensive Care Unit (ICU) demonstrated higher MMP-9 levels in the COVID-19 group compared to the control. Also, hypertensive COVID-19 patients had higher levels of MMP-2 compared to the normotensive COVID-19 group. In addition, a survival analysis had associated greater mortality with increased levels of MMP-2 and MMP-9 [114].
Another study described higher plasma levels of MMP-9 and greater plasma activity of MMP-9 and MMP-2 in COVID-19 patients with ARDS compared to those without ARDS. Furthermore, increased levels of these enzymes were identified in the cerebrospinal fluid of COVID-19 patients, being associated with the neurological complications of the disease [116].

5.8. Platelet-Derived Growth Factor (PDGF)

PDGF is a protein responsible for regulating cell differentiation, proliferation and chemotaxis, as well as acting in the healing and fibrosis processes [117,118]. Present in platelet α-granules, under biological conditions this peptide is released from platelet activation during blood clotting. However, PDGF dysregulation is associated with different pathological contexts, such as atherosclerosis, pulmonary hypertension, diabetes and cancer [117].
In the context of viral infections, different authors have currently associated increased levels of PDGF with a more severe clinical condition of COVID-19 [4,39,119]. Furthermore, significant elevation of PDGF was detected in diabetic and obese COVID-19 patients compared to the control group [118]. In addition to the presence of this factor in tracheal aspirates from COVID-19 patients under mechanical ventilation, it is suggested that the secretory products of platelet activation have access to the airways in severe disease [39].

5.9. RANTES (CCL5)

Regulated on activation, normal T cell-expressed and -secreted (RANTES) is a chemokine abundantly stored in platelet α-granules and secreted after platelet activation [120]. The ability to induce monocyte recruitment [121] and T-cell activation and differentiation are well-defined characteristics of RANTES [122]. However, increased production is associated with a variety of diseases, such as asthma [123] and respiratory syncytial virus (RSV) infection [124]. Furthermore, it has been demonstrated that mutations in RANTES can attenuate aggregation induced by this chemokine [125].
Highly expressed during the inflammatory state, different studies have described an increased activity of CCL5 in COVID-19 patients, being mentioned as an aggravating factor in the lung damage observed in these patients [85,126]. Furthermore, the increase in its production has been described as influencing the release of neutrophil extracellular traps (NETs), which can lead to immunothrombosis [85].
Furthermore, another study carried out with ten critically ill patients with COVID-19 demonstrated that blocking its receptor (CCR5) with an antagonist resulted in the restoration of lymphopenia and a reduction in inflammation and plasma viremia, suggesting that this treatment route may be beneficial not only for its immunomodulatory effects on inflammation but also in establishing hemostasis in these patients [127].

5.10. Glutamate

The glutaminase enzyme is responsible for converting glutamine into glutamate, an important neurotransmitter released in large concentrations by platelet dense granules after their activation [128,129], in which the expression of ionotropic glutamate receptors in these cells, including N-methyl-D-aspartate (NMDA), has the function of regulating production and inhibiting platelet activation [128].
Despite the relatively high concentrations of this neurotransmitter in the central nervous system, studies aimed at using peripheral markers for neurological diseases demonstrate that increased stroke plasma glutamate levels that remain elevated for up to 2 weeks may contribute to a greater risk of thrombotic events [130,131]. Furthermore, different authors have demonstrated the involvement of altered glutamine metabolism in viral infections, as well as its role in viral proliferation and virus assembly [132,133].
More recently, changes in this metabolic pathway have been associated with the appearance of adverse effects due to SARS-CoV-2 infection such as lung damage, hypoxia and neurological impairment and, consequently, with more severe disease [134,135]. A metabolic analysis performed in African populations identified glutamine/glutamate metabolism as the most significant pathway associated with severe COVID-19 [134]. In addition, the metabotropic glutamate receptor subtype 2 (mGluR2) has been indicated as a facilitator for the internalization of SARS-CoV-2 into cells [136].

5.11. Serotonin (5-HT)

Among neurotransmitters, serotonin plays an important role in the immune system and in the regulation of inflammatory responses [137]. In the periphery, a large part of 5-HT is stored in the platelet dense granules and is mainly involved in the mechanisms of vasoconstriction, activation and differentiation of T-cells and platelet aggregation [138,139,140].
Some studies point to the involvement of serotonin and its receptors in the pathogenesis of chronic inflammatory conditions [141] and in the induction of systemic shock dependent on the release of 5-HT from platelets [142].
In the context of COVID-19, due to reports of neurological dysfunction in these patients, from encephalopathy to thromboembolic diseases, elevated plasma 5-HT levels have come to be seen as a possible indicator of disease severity [143,144], being associated with serotonergic toxicity [145] and increased platelet degranulation during SARS-CoV-2 infection [146]. It can also directly affect the integrity of vessels and promote the recruitment of leukocytes and the release of inflammatory cytokines [142,147].

5.12. C-Type Lectin-like Receptor 2 (CLEC-2)

CLEC-2 is an important platelet-activating receptor that is expressed on the membrane of these cells [148,149,150] and plays an important role in normal hemostasis, wound healing, maintenance of vascular integrity and platelet adhesion [151]. The soluble C-type lectin-like receptor 2 (sCLEC-2) has been introduced due to its potential as a marker for platelet activation and thrombotic complications [148,152,153,154].
Elevated plasma levels of sCLEC-2 have been reported in cases of cardiovascular diseases [154,155], ischemic stroke [156,157], traumatic brain injury [158] and in thrombotic microangiopathy [153,159]. In addition, CLEC-2 has been implicated as a facilitator of the spread of HIV-1 in infected patients [13]. In the current context, elevated levels of soluble CLEC-2 have been described in patients hospitalized with severe and critical COVID-19 and have been noted as a useful tool in assessing disease severity [160] and for the early diagnosis of sepsis-induced coagulopathy [148].

5.13. Microparticles (MPs)

MPs are a type of extracellular vesicles of phosphatidylserine, which is a phospholipid that stimulates the activation of the coagulation cascade. Their formation occurs in response to cell activation or apoptosis [161] and, although most MPs are of platelet origin, they can also be released by leukocytes, erythrocytes, macrophages or endothelial cells, being considered sensitive markers for vascular damage [162,163]. Evidence points to the role of these molecules in regulating inflammation, coagulation and cell proliferation and differentiation [164,165,166]. However, high levels have been associated with thrombotic disorders and systemic inflammatory conditions [167].
MPs derived from platelets and containing tissue factor are strong procoagulants, and due to abnormalities in coagulation markers in SARS-CoV-2 infection, detailed investigation of platelets in these patients is indicated [168,169,170]. One study reported higher levels of platelet-derived microvesicles and platelet–leukocyte aggregates in the circulation of COVID-19 ITU patients [170], in individuals with the disease associated with acute pulmonary embolism [171] and in cases with a fatal outcome, correlating with the severity and being indicated as a possible risk marker for the disease [172].

6. Treatment and Thromboprophylaxis in COVID-19

Hypercoagulopathy is a common and deadly consequence of SARS-CoV-2 infection in hospitalized patients and was frequently associated with increased levels of the molecules discussed in this review. Although there are controversies in both the prevention and treatment of thromboinflammatory complications, some consensus statements and expert opinions are available on the prophylaxis and clinical management of these patients [173,174,175].
The International Society on Thrombosis and Hemostasis (ISTH) gathered evidence in an international panel and released recommendations on anticoagulants and antiplatelet agents for patients with COVID-19 in different clinical conditions. The guidelines suggest a weak recommendation for antiplatelet and anticoagulant therapy in non-hospitalized patients and strong recommendations for the use of prophylactic doses of low-molecular-weight heparin or unfractionated heparin (LMWH/UFH), for the preferable use of a therapeutic dose of LMWH/UFH, to the prophylactic dose, and against the addition of antiplatelets. For hospitalized critical patients, recommendations remain unclear [175]. In a severe COVID-19 patient population with non-invasive respiratory support, a full-dose prophylactic strategy reduced thrombotic complications without serious bleeding events [176], while thromboprophylaxis was not beneficial in patients with mild to moderate COVID-19 without requiring hospitalization [177].
Anticoagulation in hospitalized COVID-19 patients has been associated with improved survival; however, the ideal thrombosis prophylaxis strategy has not yet been defined [174,178]. Due to the common use of prophylactic doses of LMWH in hospitalized patients, for greater safety, factors such as renal function and body weight must be considered and its administration is contraindicated in individuals with a platelet count <50 × 109/L, hemoglobin < 8 g/dL, bleeding in the last 30 days and history of bleeding disorders [177].
And although to date there is no consensus on the ideal medication, start, duration and dosage of treatment [174,177,179], detailed study of these molecules would help in understanding the pathophysiology of the disease and could help expand therapeutic options. The markers discussed here suggest possible therapeutic targets for the treatment and thromboprophylaxis of patients hospitalized with COVID-19 and perhaps for other viral infections. However, more research is needed to clarify the scope of antithrombotic prophylaxis and examine the potential benefits of new prophylactic and therapeutic agents.

7. Conclusions

In the pandemic context, SARS-CoV-2 infection presented a variable clinical course of the disease, where severe cases were frequently associated with thrombotic changes and elevated coagulation parameters. Platelets are widely known for their role in hemostasis; however, their role as an enhancer in viral infections is well discussed. In this review, we highlight important platelet molecules associated with thromboinflammation and their possible role in the risk stratification of COVID-19, contributing to the early identification of serious disease as well as enabling drug reuse.

Author Contributions

Invitation received, C.A.M.-N.; Conceptualization, L.d.O.S., L.L.B.d.O., J.B.S.d.S., R.C.M. and C.A.M.-N.; Provision of data and subsequent analysis and interpretation, L.d.O.S., M.O.d.M.F., M.E.A.d.M. and C.A.M.-N.; Writing—original draft preparation, L.d.O.S. and C.A.M.-N.; Writing—review and editing, L.d.O.S. and C.A.M.-N.; Funding acquisition, R.C.M. and C.A.M.-N. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by Brazilian funding agencies: Coordination for the Improvement of Higher Education Personnel (CAPES; to J.B.S.d.S), National Council of Technological and Scientific Development (CNPq grant number 404213/2021-9 to C.A.M.-N.; and Productivity in Research PQ scholarships to M.O.d.M.F, M.E.A.d.M, R.C.M and C.A.M.-N.).

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript or in the decision to publish the results.

References

  1. Hartenian, E.; Nandakumar, D.; Lari, A.; Ly, M.; Tucker, J.M.; Glaunsinger, B.A. The Molecular Virology of Coronaviruses. J. Biol. Chem. 2020, 295, 12910–12934. [Google Scholar] [CrossRef]
  2. Gu, S.X.; Tyagi, T.; Jain, K.; Gu, V.W.; Lee, S.H.; Hwa, J.M.; Kwan, J.M.; Krause, D.S.; Lee, A.I.; Halene, S.; et al. Thrombocytopathy and Endotheliopathy: Crucial Contributors to COVID-19 Thromboinflammation. Nat. Rev. Cardiol. 2021, 18, 194–209. [Google Scholar] [CrossRef]
  3. Kang, S.; Yang, M.; Hong, Z.; Zhang, L.; Huang, Z.; Chen, X.; He, S.; Zhou, Z.; Zhou, Z.; Chen, Q.; et al. Crystal Structure of SARS-CoV-2 Nucleocapsid Protein RNA Binding Domain Reveals Potential Unique Drug Targeting Sites. Acta Pharm. Sin. B 2020, 10, 1228–1238. [Google Scholar] [CrossRef] [PubMed]
  4. Manne, B.K.; Denorme, F.; Middleton, E.A.; Portier, I.; Rowley, J.W.; Stubben, C.; Petrey, A.C.; Tolley, N.D.; Guo, L.; Cody, M.; et al. Platelet Gene Expression and Function in Patients with COVID-19. Blood 2020, 136, 1317–1329. [Google Scholar] [CrossRef] [PubMed]
  5. Chilamakuri, R.; Agarwal, S. COVID-19: Characteristics and Therapeutics. Cells 2021, 10, 206. [Google Scholar] [CrossRef] [PubMed]
  6. Machhi, J.; Herskovitz, J.; Senan, A.M.; Dutta, D.; Nath, B.; Oleynikov, M.D.; Blomberg, W.R.; Meigs, D.D.; Hasan, M.; Patel, M.; et al. The Natural History, Pathobiology, and Clinical Manifestations of SARS-CoV-2 Infections. J. Neuroimmune Pharmacol. 2020, 15, 359–386. [Google Scholar] [CrossRef]
  7. Pillalamarri, N.; Abdullah; Ren, G.; Khan, L.; Ullah, A.; Jonnakuti, S.; Ullah, M. Exploring the Utility of Extracellular Vesicles in Ameliorating Viral Infection-Associated Inflammation, Cytokine Storm and Tissue Damage. Transl. Oncol. 2021, 14, 101095. [Google Scholar] [CrossRef]
  8. Dhama, K.; Khan, S.; Tiwari, R.; Sircar, S.; Bhat, S.; Malik, Y.S.; Singh, K.P.; Chaicumpa, W.; Bonilla-Aldana, D.K.; Rodriguez-Morales, A.J. Coronavirus Disease 2019-COVID-19. Clin. Microbiol. Rev. 2020, 33, e00028-20. [Google Scholar] [CrossRef]
  9. Zhang, S.; Liu, Y.; Wang, X.; Yang, L.; Li, H.; Wang, Y.; Liu, M.; Zhao, X.; Xie, Y.; Yang, Y.; et al. SARS-CoV-2 Binds Platelet ACE2 to Enhance Thrombosis in COVID-19. J. Hematol. Oncol. 2020, 13, 120. [Google Scholar] [CrossRef]
  10. Connors, J.M.; Levy, J.H. COVID-19 and Its Implications for Thrombosis and Anticoagulation. Blood 2020, 135, 2033–2040. [Google Scholar] [CrossRef]
  11. Middleton, E.A.; Weyrich, A.S.; Zimmerman, G.A. Platelets in Pulmonary Immune Responses and Inflammatory Lung Diseases. Physiol. Rev. 2016, 96, 1211–1259. [Google Scholar] [CrossRef]
  12. Koupenova, M.; Clancy, L.; Corkrey, H.A.; Freedman, J.E. Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis. Circ. Res. 2018, 122, 337–351. [Google Scholar] [CrossRef]
  13. Chaipan, C.; Soilleux, E.; Simpson, P.; Hofmann, H.; Gramberg, T.; Marzi, A.; Geier, M.; Stewart, E.; Eisemann, J.; Steinkasserer, A.; et al. DC-SIGN and CLEC-2 Mediate Human Immunodeficiency Virus Type 1 Capture by Platelets. J. Virol. 2006, 80, 8951–8960. [Google Scholar] [CrossRef] [PubMed]
  14. Solomon Tsegaye, T.; Gnirß, K.; Rahe-Meyer, N.; Kiene, M.; Krämer-Kühl, A.; Behrens, G.; Münch, J.; Pöhlmann, S. Platelet Activation Suppresses HIV-1 Infection of T Cells. Retrovirology 2013, 10, 48. [Google Scholar] [CrossRef] [PubMed]
  15. Guo, L.; Feng, K.; Wang, Y.C.; Mei, J.J.; Ning, R.T.; Zheng, H.W.; Wang, J.J.; Worthen, G.S.; Wang, X.; Song, J.; et al. Critical Role of CXCL4 in the Lung Pathogenesis of Influenza (H1N1) Respiratory Infection. Mucosal Immunol. 2017, 10, 1529–1541. [Google Scholar] [CrossRef]
  16. Simon, A.Y.; Sutherland, M.R.; Pryzdial, E.L.G. Dengue Virus Binding and Replication by Platelets. Blood 2015, 126, 378–385. [Google Scholar] [CrossRef] [PubMed]
  17. Ojha, A.; Bhasym, A.; Mukherjee, S.; Annarapu, G.K.; Bhakuni, T.; Akbar, I.; Seth, T.; Vikram, N.K.; Vrati, S.; Basu, A.; et al. Platelet Factor 4 Promotes Rapid Replication and Propagation of Dengue and Japanese Encephalitis Viruses. EBioMedicine 2019, 39, 332–347. [Google Scholar] [CrossRef]
  18. Assinger, A.; Kral, J.B.; Yaiw, K.C.; Schrottmaier, W.C.; Kurzejamska, E.; Wang, Y.; Mohammad, A.-A.; Religa, P.; Rahbar, A.; Schabbauer, G.; et al. Human Cytomegalovirus-Platelet Interaction Triggers Toll-like Receptor 2-Dependent Proinflammatory and Proangiogenic Responses. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 801–809. [Google Scholar] [CrossRef]
  19. Barrett, T.J.; Bilaloglu, S.; Cornwell, M.; Burgess, H.M.; Virginio, V.W.; Drenkova, K.; Ibrahim, H.; Yuriditsky, E.; Aphinyanaphongs, Y.; Lifshitz, M.; et al. Platelets Contribute to Disease Severity in COVID-19. J. Thromb. Haemost. 2021, 19, 3139–3153. [Google Scholar] [CrossRef]
  20. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280. [Google Scholar] [CrossRef]
  21. Sungnak, W.; Huang, N.; Bécavin, C.; Berg, M.; Queen, R.; Litvinukova, M.; Talavera-López, C.; Maatz, H.; Reichart, D.; Sampaziotis, F.; et al. SARS-CoV-2 Entry Factors Are Highly Expressed in Nasal Epithelial Cells Together with Innate Immune Genes. Nat. Med. 2020, 26, 681–687. [Google Scholar] [CrossRef]
  22. Xu, H.; Zhong, L.; Deng, J.; Peng, J.; Dan, H.; Zeng, X.; Li, T.; Chen, Q. High Expression of ACE2 Receptor of 2019-NCoV on the Epithelial Cells of Oral Mucosa. Int. J. Oral. Sci. 2020, 12, 8. [Google Scholar] [CrossRef] [PubMed]
  23. Zumla, A.; Chan, J.F.W.; Azhar, E.I.; Hui, D.S.C.; Yuen, K.-Y. Coronaviruses—Drug Discovery and Therapeutic Options. Nat. Rev. Drug Discov. 2016, 15, 327–347. [Google Scholar] [CrossRef]
  24. Cao, X. COVID-19: Immunopathology and Its Implications for Therapy. Nat. Rev. Immunol. 2020, 20, 269–270. [Google Scholar] [CrossRef]
  25. Shi, Y.; Wang, Y.; Shao, C.; Huang, J.; Gan, J.; Huang, X.; Bucci, E.; Piacentini, M.; Ippolito, G.; Melino, G. COVID-19 Infection: The Perspectives on Immune Responses. Cell Death Differ. 2020, 27, 1451–1454. [Google Scholar] [CrossRef] [PubMed]
  26. Henry, B.M.; de Oliveira, M.H.S.; Benoit, S.; Plebani, M.; Lippi, G. Hematologic, Biochemical and Immune Biomarker Abnormalities Associated with Severe Illness and Mortality in Coronavirus Disease 2019 (COVID-19): A Meta-Analysis. Clin. Chem. Lab. Med. 2020, 58, 1021–1028. [Google Scholar] [CrossRef] [PubMed]
  27. Zeng, F.; Huang, Y.; Guo, Y.; Yin, M.; Chen, X.; Xiao, L.; Deng, G. Association of Inflammatory Markers with the Severity of COVID-19: A Meta-Analysis. Int. J. Infect. Dis. 2020, 96, 467–474. [Google Scholar] [CrossRef]
  28. Bao, C.; Tao, X.; Cui, W.; Yi, B.; Pan, T.; Young, K.H.; Qian, W. SARS-CoV-2 Induced Thrombocytopenia as an Important Biomarker Significantly Correlated with Abnormal Coagulation Function, Increased Intravascular Blood Clot Risk and Mortality in COVID-19 Patients. Exp. Hematol. Oncol. 2020, 9, 16. [Google Scholar] [CrossRef]
  29. Goshua, G.; Pine, A.B.; Meizlish, M.L.; Chang, C.-H.; Zhang, H.; Bahel, P.; Baluha, A.; Bar, N.; Bona, R.D.; Burns, A.J.; et al. Endotheliopathy in COVID-19-Associated Coagulopathy: Evidence from a Single-Centre, Cross-Sectional Study. Lancet Haematol. 2020, 7, e575–e582. [Google Scholar] [CrossRef]
  30. Safiabadi Tali, S.H.; LeBlanc, J.J.; Sadiq, Z.; Oyewunmi, O.D.; Camargo, C.; Nikpour, B.; Armanfard, N.; Sagan, S.M.; Jahanshahi-Anbuhi, S. Tools and Techniques for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)/COVID-19 Detection. Clin. Microbiol. Rev. 2021, 34, e00228-20. [Google Scholar] [CrossRef]
  31. Zhang, Y.; Xiao, M.; Zhang, S.; Xia, P.; Cao, W.; Jiang, W.; Chen, H.; Ding, X.; Zhao, H.; Zhang, H.; et al. Coagulopathy and Antiphospholipid Antibodies in Patients with COVID-19. N. Engl. J. Med. 2020, 382, e38. [Google Scholar] [CrossRef] [PubMed]
  32. Iba, T.; Levy, J.H.; Levi, M.; Connors, J.M.; Thachil, J. Coagulopathy of Coronavirus Disease 2019. Crit. Care Med. 2020, 48, 1358–1364. [Google Scholar] [CrossRef] [PubMed]
  33. Peyvandi, F.; Artoni, A.; Novembrino, C.; Aliberti, S.; Panigada, M.; Boscarino, M.; Gualtierotti, R.; Rossi, F.; Palla, R.; Martinelli, I.; et al. Hemostatic Alterations in COVID-19. Haematologica 2021, 106, 1472–1475. [Google Scholar] [CrossRef]
  34. Lodigiani, C.; Iapichino, G.; Carenzo, L.; Cecconi, M.; Ferrazzi, P.; Sebastian, T.; Kucher, N.; Studt, J.-D.; Sacco, C.; Bertuzzi, A.; et al. Venous and Arterial Thromboembolic Complications in COVID-19 Patients Admitted to an Academic Hospital in Milan, Italy. Thromb. Res. 2020, 191, 9–14. [Google Scholar] [CrossRef] [PubMed]
  35. Poissy, J.; Goutay, J.; Caplan, M.; Parmentier, E.; Duburcq, T.; Lassalle, F.; Jeanpierre, E.; Rauch, A.; Labreuche, J.; Susen, S.; et al. Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence. Circulation 2020, 142, 184–186. [Google Scholar] [CrossRef] [PubMed]
  36. Klok, F.A.; Kruip, M.J.H.A.; van der Meer, N.J.M.; Arbous, M.S.; Gommers, D.; Kant, K.M.; Kaptein, F.H.J.; van Paassen, J.; Stals, M.a.M.; Huisman, M.V.; et al. Confirmation of the High Cumulative Incidence of Thrombotic Complications in Critically Ill ICU Patients with COVID-19: An Updated Analysis. Thromb. Res. 2020, 191, 148–150. [Google Scholar] [CrossRef]
  37. Darif, D.; Hammi, I.; Kihel, A.; El Idrissi Saik, I.; Guessous, F.; Akarid, K. The Pro-Inflammatory Cytokines in COVID-19 Pathogenesis: What Goes Wrong? Microb. Pathog. 2021, 153, 104799. [Google Scholar] [CrossRef] [PubMed]
  38. Delabranche, X.; Helms, J.; Meziani, F. Immunohaemostasis: A New View on Haemostasis during Sepsis. Ann. Intensive Care 2017, 7, 117. [Google Scholar] [CrossRef]
  39. Hottz, E.D.; Azevedo-Quintanilha, I.G.; Palhinha, L.; Teixeira, L.; Barreto, E.A.; Pão, C.R.R.; Righy, C.; Franco, S.; Souza, T.M.L.; Kurtz, P.; et al. Platelet Activation and Platelet-Monocyte Aggregate Formation Trigger Tissue Factor Expression in Patients with Severe COVID-19. Blood 2020, 136, 1330–1341. [Google Scholar] [CrossRef]
  40. Hottz, E.D.; Bozza, P.T. Platelet-Leukocyte Interactions in COVID-19: Contributions to Hypercoagulability, Inflammation, and Disease Severity. Res. Pract. Thromb. Haemost. 2022, 6, e12709. [Google Scholar] [CrossRef] [PubMed]
  41. Xu, P.; Zhou, Q.; Xu, J. Mechanism of Thrombocytopenia in COVID-19 Patients. Ann. Hematol. 2020, 99, 1205–1208. [Google Scholar] [CrossRef] [PubMed]
  42. Hottz, E.D.; Medeiros-de-Moraes, I.M.; Vieira-de-Abreu, A.; de Assis, E.F.; Vals-de-Souza, R.; Castro-Faria-Neto, H.C.; Weyrich, A.S.; Zimmerman, G.A.; Bozza, F.A.; Bozza, P.T. Platelet Activation and Apoptosis Modulate Monocyte Inflammatory Responses in Dengue. J. Immunol. 2014, 193, 1864–1872. [Google Scholar] [CrossRef] [PubMed]
  43. Koupenova, M.; Corkrey, H.A.; Vitseva, O.; Manni, G.; Pang, C.J.; Clancy, L.; Yao, C.; Rade, J.; Levy, D.; Wang, J.P.; et al. The Role of Platelets in Mediating a Response to Human Influenza Infection. Nat. Commun. 2019, 10, 1780. [Google Scholar] [CrossRef] [PubMed]
  44. Dib, P.R.B.; Quirino-Teixeira, A.C.; Merij, L.B.; Pinheiro, M.B.M.; Rozini, S.V.; Andrade, F.B.; Hottz, E.D. Innate Immune Receptors in Platelets and Platelet-Leukocyte Interactions. J. Leukoc. Biol. 2020, 108, 1157–1182. [Google Scholar] [CrossRef] [PubMed]
  45. Maouia, A.; Rebetz, J.; Kapur, R.; Semple, J.W. The Immune Nature of Platelets Revisited. Transfus. Med. Rev. 2020, 34, 209–220. [Google Scholar] [CrossRef]
  46. Antoniak, S.; Mackman, N. Platelets and Viruses. Platelets 2021, 32, 325–330. [Google Scholar] [CrossRef]
  47. Zhang, W.; Nardi, M.A.; Borkowsky, W.; Li, Z.; Karpatkin, S. Role of Molecular Mimicry of Hepatitis C Virus Protein with Platelet GPIIIa in Hepatitis C–Related Immunologic Thrombocytopenia. Blood 2009, 113, 4086–4093. [Google Scholar] [CrossRef]
  48. Pugliese, A.; Gennero, L.; Cutufia, M.; Enrietto, M.; Morra, E.; Pescarmona, P.; Ponzetto, A. HCV Infective Virions Can Be Carried by Human Platelets. Cell Biochem. Funct. 2004, 22, 353–358. [Google Scholar] [CrossRef] [PubMed]
  49. Forghani, B.; Schmidt, N.J. Association of Herpes Simplex Virus with Platelets of Experimentally Infected Mice. Arch. Virol. 1983, 76, 269–274. [Google Scholar] [CrossRef]
  50. Koupenova, M.; Freedman, J.E. Platelets and Immunity: Going Viral. Arterioscler. Thromb. Vasc. Biol. 2020, 40, 1605–1607. [Google Scholar] [CrossRef]
  51. Yeaman, M.R. 29—The Role of Platelets in Antimicrobial Host Defense. In Platelets, 4th ed.; Michelson, A.D., Ed.; Academic Press: Cambridge, MA, USA, 2019; pp. 523–546. ISBN 978-0-12-813456-6. [Google Scholar]
  52. Rayes, J.; Bourne, J.H.; Brill, A.; Watson, S.P. The Dual Role of Platelet-Innate Immune Cell Interactions in Thrombo-Inflammation. Res. Pract. Thromb. Haemost. 2020, 4, 23–35. [Google Scholar] [CrossRef] [PubMed]
  53. Maynard, D.M.; Heijnen, H.F.G.; Horne, M.K.; White, J.G.; Gahl, W.A. Proteomic Analysis of Platelet α-Granules Using Mass Spectrometry. J. Thromb. Haemost. 2007, 5, 1945–1955. [Google Scholar] [CrossRef] [PubMed]
  54. Lemons, P.P.; Chen, D.; Bernstein, A.M.; Bennett, M.K.; Whiteheart, S.W. Regulated Secretion in Platelets: Identification of Elements of the Platelet Exocytosis Machinery. Blood 1997, 90, 1490–1500. [Google Scholar] [CrossRef]
  55. Morrell, C.N.; Aggrey, A.A.; Chapman, L.M.; Modjeski, K.L. Emerging Roles for Platelets as Immune and Inflammatory Cells. Blood 2014, 123, 2759–2767. [Google Scholar] [CrossRef]
  56. Wang, Y.; Ouyang, Y.; Liu, B.; Ma, X.; Ding, R. Platelet Activation and Antiplatelet Therapy in Sepsis: A Narrative Review. Thromb. Res. 2018, 166, 28–36. [Google Scholar] [CrossRef] [PubMed]
  57. McFadyen, J.D.; Stevens, H.; Peter, K. The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications. Circ. Res. 2020, 127, 571–587. [Google Scholar] [CrossRef]
  58. Tang, N.; Li, D.; Wang, X.; Sun, Z. Abnormal Coagulation Parameters Are Associated with Poor Prognosis in Patients with Novel Coronavirus Pneumonia. J. Thromb. Haemost. 2020, 18, 844–847. [Google Scholar] [CrossRef]
  59. Zhang, L.; Feng, X.; Zhang, D.; Jiang, C.; Mei, H.; Wang, J.; Zhang, C.; Li, H.; Xia, X.; Kong, S.; et al. Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome. Circulation 2020, 142, 114–128. [Google Scholar] [CrossRef]
  60. Gorog, D.A.; Storey, R.F.; Gurbel, P.A.; Tantry, U.S.; Berger, J.S.; Chan, M.Y.; Duerschmied, D.; Smyth, S.S.; Parker, W.A.E.; Ajjan, R.A.; et al. Current and Novel Biomarkers of Thrombotic Risk in COVID-19: A Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium. Nat. Rev. Cardiol. 2022, 19, 475–495. [Google Scholar] [CrossRef]
  61. Blann, A.D.; Nadar, S.K.; Lip, G.Y.H. The Adhesion Molecule P-Selectin and Cardiovascular Disease. Eur. Heart J. 2003, 24, 2166–2179. [Google Scholar] [CrossRef]
  62. Cambien, B.; Wagner, D.D. A New Role in Hemostasis for the Adhesion Receptor P-Selectin. Trends Mol. Med. 2004, 10, 179–186. [Google Scholar] [CrossRef] [PubMed]
  63. Watany, M.M.; Abdou, S.; Elkolaly, R.; Elgharbawy, N.; Hodeib, H. Correction to: Evaluation of Admission Levels of P, E and L Selectins as Predictors for Thrombosis in Hospitalized COVID-19 Patients. Clin. Exp. Med. 2023, 23, 163. [Google Scholar] [CrossRef]
  64. Sadler, J.E. Biochemistry and Genetics of von Willebrand Factor. Annu. Rev. Biochem. 1998, 67, 395–424. [Google Scholar] [CrossRef]
  65. Chen, P.-C.; Kutzki, F.; Mojzisch, A.; Simon, B.; Xu, E.-R.; Aponte-Santamaría, C.; Horny, K.; Jeffries, C.; Schneppenheim, R.; Wilmanns, M.; et al. Structure and Dynamics of the von Willebrand Factor C6 Domain. J. Struct. Biol. 2022, 214, 107923. [Google Scholar] [CrossRef]
  66. Edvardsen, M.S.; Hindberg, K.; Hansen, E.-S.; Morelli, V.M.; Ueland, T.; Aukrust, P.; Brækkan, S.K.; Evensen, L.H.; Hansen, J.-B. Plasma Levels of von Willebrand Factor and Future Risk of Incident Venous Thromboembolism. Blood Adv. 2021, 5, 224–232. [Google Scholar] [CrossRef]
  67. Sadler, J.E.; Budde, U.; Eikenboom, J.C.J.; Favaloro, E.J.; Hill, F.G.H.; Holmberg, L.; Ingerslev, J.; Lee, C.A.; Lillicrap, D.; Mannucci, P.M.; et al. Update on the Pathophysiology and Classification of von Willebrand Disease: A Report of the Subcommittee on von Willebrand Factor. J. Thromb. Haemost. 2006, 4, 2103–2114. [Google Scholar] [CrossRef]
  68. Babkina, A.S.; Ostrova, I.V.; Yadgarov, M.Y.; Kuzovlev, A.N.; Grechko, A.V.; Volkov, A.V.; Golubev, A.M. The Role of Von Willebrand Factor in the Pathogenesis of Pulmonary Vascular Thrombosis in COVID-19. Viruses 2022, 14, 211. [Google Scholar] [CrossRef]
  69. Philippe, A.; Chocron, R.; Gendron, N.; Bory, O.; Beauvais, A.; Peron, N.; Khider, L.; Guerin, C.L.; Goudot, G.; Levasseur, F.; et al. Circulating Von Willebrand Factor and High Molecular Weight Multimers as Markers of Endothelial Injury Predict COVID-19 in-Hospital Mortality. Angiogenesis 2021, 24, 505–517. [Google Scholar] [CrossRef]
  70. Doevelaar, A.A.N.; Bachmann, M.; Hölzer, B.; Seibert, F.S.; Rohn, B.J.; Bauer, F.; Witzke, O.; Dittmer, U.; Bachmann, M.; Yilmaz, S.; et al. Von Willebrand Factor Multimer Formation Contributes to Immunothrombosis in Coronavirus Disease 2019. Crit. Care Med. 2021, 49, e512–e520. [Google Scholar] [CrossRef]
  71. Ladikou, E.E.; Sivaloganathan, H.; Milne, K.M.; Arter, W.E.; Ramasamy, R.; Saad, R.; Stoneham, S.M.; Philips, B.; Eziefula, A.C.; Chevassut, T. Von Willebrand Factor (VWF): Marker of Endothelial Damage and Thrombotic Risk in COVID-19? Clin. Med. 2020, 20, e178–e182. [Google Scholar] [CrossRef]
  72. Li, K.; Yao, L.; Wang, J.; Song, H.; Zhang, Y.-H.; Bai, X.; Zhang, K.; Zhou, D.-M.; Ai, D.; Zhu, Y. SARS-CoV-2 Spike Protein Promotes VWF Secretion and Thrombosis via Endothelial Cytoskeleton-Associated Protein 4 (CKAP4). Signal Transduct. Target. Ther. 2022, 7, 332. [Google Scholar] [CrossRef] [PubMed]
  73. Longstaff, C.; Kolev, K. Basic Mechanisms and Regulation of Fibrinolysis. J. Thromb. Haemost. 2015, 13 (Suppl. 1), S98–S105. [Google Scholar] [CrossRef]
  74. Wright, F.L.; Vogler, T.O.; Moore, E.E.; Moore, H.B.; Wohlauer, M.V.; Urban, S.; Nydam, T.L.; Moore, P.K.; McIntyre, R.C. Fibrinolysis Shutdown Correlation with Thromboembolic Events in Severe COVID-19 Infection. J. Am. Coll. Surg. 2020, 231, 193–203.e1. [Google Scholar] [CrossRef] [PubMed]
  75. Meltzer, M.E.; Lisman, T.; de Groot, P.G.; Meijers, J.C.M.; le Cessie, S.; Doggen, C.J.M.; Rosendaal, F.R. Venous Thrombosis Risk Associated with Plasma Hypofibrinolysis Is Explained by Elevated Plasma Levels of TAFI and PAI-1. Blood 2010, 116, 113–121. [Google Scholar] [CrossRef] [PubMed]
  76. Zuo, Y.; Warnock, M.; Harbaugh, A.; Yalavarthi, S.; Gockman, K.; Zuo, M.; Madison, J.A.; Knight, J.S.; Kanthi, Y.; Lawrence, D.A. Plasma Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Hospitalized COVID-19 Patients. Sci. Rep. 2021, 11, 1580. [Google Scholar] [CrossRef] [PubMed]
  77. Nougier, C.; Benoit, R.; Simon, M.; Desmurs-Clavel, H.; Marcotte, G.; Argaud, L.; David, J.S.; Bonnet, A.; Negrier, C.; Dargaud, Y. Hypofibrinolytic State and High Thrombin Generation May Play a Major Role in SARS-COV2 Associated Thrombosis. J. Thromb. Haemost. 2020, 18, 2215–2219. [Google Scholar] [CrossRef]
  78. Chen, R.; Yan, J.; Liu, P.; Wang, Z.; Wang, C. Plasminogen Activator Inhibitor Links Obesity and Thrombotic Cerebrovascular Diseases: The Roles of PAI-1 and Obesity on Stroke. Metab. Brain Dis. 2017, 32, 667–673. [Google Scholar] [CrossRef]
  79. Kowalska, M.A.; Rauova, L.; Poncz, M. Role of the Platelet Chemokine Platelet Factor 4 (PF4) in Hemostasis and Thrombosis. Thromb. Res. 2010, 125, 292–296. [Google Scholar] [CrossRef]
  80. Liu, Z.-Y.; Sun, M.-X.; Hua, M.-Q.; Zhang, H.-X.; Mu, G.-Y.; Zhou, S.; Wang, Z.; Xiang, Q.; Cui, Y.-M. New Perspectives on the Induction and Acceleration of Immune-Associated Thrombosis by PF4 and VWF. Front. Immunol. 2023, 14, 1098665. [Google Scholar] [CrossRef]
  81. Scheuerer, B.; Ernst, M.; Dürrbaum-Landmann, I.; Fleischer, J.; Grage-Griebenow, E.; Brandt, E.; Flad, H.-D.; Petersen, F. The CXC-Chemokine Platelet Factor 4 Promotes Monocyte Survival and Induces Monocyte Differentiation into Macrophages. Blood 2000, 95, 1158–1166. [Google Scholar] [CrossRef]
  82. Kasper, B.; Brandt, E.; Brandau, S.; Petersen, F. Platelet Factor 4 (CXC Chemokine Ligand 4) Differentially Regulates Respiratory Burst, Survival, and Cytokine Expression of Human Monocytes by Using Distinct Signaling Pathways. J. Immunol. 2007, 179, 2584–2591. [Google Scholar] [CrossRef] [PubMed]
  83. Eslin, D.E.; Zhang, C.; Samuels, K.J.; Rauova, L.; Zhai, L.; Niewiarowski, S.; Cines, D.B.; Poncz, M.; Kowalska, M.A. Transgenic Mice Studies Demonstrate a Role for Platelet Factor 4 in Thrombosis: Dissociation between Anticoagulant and Antithrombotic Effect of Heparin. Blood 2004, 104, 3173–3180. [Google Scholar] [CrossRef] [PubMed]
  84. Ebeyer-Masotta, M.; Eichhorn, T.; Weiss, R.; Lauková, L.; Weber, V. Activated Platelets and Platelet-Derived Extracellular Vesicles Mediate COVID-19-Associated Immunothrombosis. Front. Cell Dev. Biol. 2022, 10, 914891. [Google Scholar] [CrossRef] [PubMed]
  85. Middleton, E.A.; He, X.-Y.; Denorme, F.; Campbell, R.A.; Ng, D.; Salvatore, S.P.; Mostyka, M.; Baxter-Stoltzfus, A.; Borczuk, A.C.; Loda, M.; et al. Neutrophil Extracellular Traps Contribute to Immunothrombosis in COVID-19 Acute Respiratory Distress Syndrome. Blood 2020, 136, 1169–1179. [Google Scholar] [CrossRef] [PubMed]
  86. Comer, S.P.; Cullivan, S.; Szklanna, P.B.; Weiss, L.; Cullen, S.; Kelliher, S.; Smolenski, A.; Murphy, C.; Altaie, H.; Curran, J.; et al. COVID-19 Induces a Hyperactive Phenotype in Circulating Platelets. PLoS Biol. 2021, 19, e3001109. [Google Scholar] [CrossRef]
  87. Dragonetti, D.; Guarini, G.; Pizzuti, M. Detection of Anti-Heparin-PF4 Complex Antibodies in COVID-19 Patients on Heparin Therapy. Blood Transfus. 2020, 18, 328. [Google Scholar] [CrossRef]
  88. Brodard, J.; Kremer Hovinga, J.A.; Fontana, P.; Studt, J.-D.; Gruel, Y.; Greinacher, A. COVID-19 Patients Often Show High-Titer Non-Platelet-Activating Anti-PF4/Heparin IgG Antibodies. J. Thromb. Haemost. 2021, 19, 1294–1298. [Google Scholar] [CrossRef]
  89. Rauova, L.; Zhai, L.; Kowalska, M.A.; Arepally, G.M.; Cines, D.B.; Poncz, M. Role of Platelet Surface PF4 Antigenic Complexes in Heparin-Induced Thrombocytopenia Pathogenesis: Diagnostic and Therapeutic Implications. Blood 2006, 107, 2346–2353. [Google Scholar] [CrossRef]
  90. Warkentin, T.E.; Levine, M.N.; Hirsh, J.; Horsewood, P.; Roberts, R.S.; Gent, M.; Kelton, J.G. Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin. N. Engl. J. Med. 1995, 332, 1330–1336. [Google Scholar] [CrossRef]
  91. Liu, X.; Zhang, X.; Xiao, Y.; Gao, T.; Wang, G.; Wang, Z.; Zhang, Z.; Hu, Y.; Dong, Q.; Zhao, S.; et al. Heparin-Induced Thrombocytopenia Is Associated with a High Risk of Mortality in Critical COVID-19 Patients Receiving Heparin-Involved Treatment. medRxiv 2020. [Google Scholar] [CrossRef]
  92. Arguinchona, L.M.; Zagona-Prizio, C.; Joyce, M.E.; Chan, E.D.; Maloney, J.P. Microvascular Significance of TGF-β Axis Activation in COVID-19. Front. Cardiovasc. Med. 2022, 9, 1054690. [Google Scholar] [CrossRef] [PubMed]
  93. Hoying, J.B.; Yin, M.; Diebold, R.; Ormsby, I.; Becker, A.; Doetschman, T. Transforming Growth Factor Β1 Enhances Platelet Aggregation through a Non-Transcriptional Effect on the Fibrinogen Receptor. J. Biol. Chem. 1999, 274, 31008–31013. [Google Scholar] [CrossRef]
  94. Ghazavi, A.; Ganji, A.; Keshavarzian, N.; Rabiemajd, S.; Mosayebi, G. Cytokine Profile and Disease Severity in Patients with COVID-19. Cytokine 2021, 137, 155323. [Google Scholar] [CrossRef] [PubMed]
  95. Colarusso, C.; Maglio, A.; Terlizzi, M.; Vitale, C.; Molino, A.; Pinto, A.; Vatrella, A.; Sorrentino, R. Post-COVID-19 Patients Who Develop Lung Fibrotic-like Changes Have Lower Circulating Levels of IFN-β but Higher Levels of IL-1α and TGF-β. Biomedicines 2021, 9, 1931. [Google Scholar] [CrossRef] [PubMed]
  96. Ferreira-Gomes, M.; Kruglov, A.; Durek, P.; Heinrich, F.; Tizian, C.; Heinz, G.A.; Pascual-Reguant, A.; Du, W.; Mothes, R.; Fan, C.; et al. SARS-CoV-2 in Severe COVID-19 Induces a TGF-β-Dominated Chronic Immune Response That Does Not Target Itself. Nat. Commun. 2021, 12, 1961. [Google Scholar] [CrossRef]
  97. Witkowski, M.; Tizian, C.; Ferreira-Gomes, M.; Niemeyer, D.; Jones, T.C.; Heinrich, F.; Frischbutter, S.; Angermair, S.; Hohnstein, T.; Mattiola, I.; et al. Untimely TGFβ Responses in COVID-19 Limit Antiviral Functions of NK Cells. Nature 2021, 600, 295–301. [Google Scholar] [CrossRef]
  98. Prescott, S.M.; Zimmerman, G.A.; Stafforini, D.M.; McIntyre, T.M. Platelet-Activating Factor and Related Lipid Mediators. Annu. Rev. Biochem. 2000, 69, 419–445. [Google Scholar] [CrossRef]
  99. Zimmerman, G.A.; McIntyre, T.M.; Prescott, S.M.; Stafforini, D.M. The Platelet-Activating Factor Signaling System and Its Regulators in Syndromes of Inflammation and Thrombosis. Crit. Care Med. 2002, 30, S294–S301. [Google Scholar] [CrossRef]
  100. Kelesidis, T.; Papakonstantinou, V.; Detopoulou, P.; Fragopoulou, E.; Chini, M.; Lazanas, M.C.; Antonopoulou, S. The Role of Platelet-Activating Factor in Chronic Inflammation, Immune Activation, and Comorbidities Associated with HIV Infection. AIDS Rev. 2015, 17, 191–201. [Google Scholar]
  101. Detopoulou, P.; Nomikos, T.; Fragopoulou, E.; Chrysohoou, C.; Antonopoulou, S. Platelet Activating Factor in Heart Failure: Potential Role in Disease Progression and Novel Target for Therapy. Curr. Heart Fail. Rep. 2013, 10, 122–129. [Google Scholar] [CrossRef]
  102. Klein, M.; Dao, V.; Khan, F. A Review of Platelet-Activating Factor As a Potential Contributor to Morbidity and Mortality Associated with Severe COVID-19. Clin. Appl. Thromb. Hemost. 2021, 27, 10760296211051764. [Google Scholar] [CrossRef] [PubMed]
  103. Theoharides, T.C.; Antonopoulou, S.; Demopoulos, C.A. Coronavirus 2019, Microthromboses, and Platelet Activating Factor. Clin. Ther. 2020, 42, 1850–1852. [Google Scholar] [CrossRef] [PubMed]
  104. Demopoulos, C.; Antonopoulou, S.; Theoharides, T.C. COVID-19, Microthromboses, Inflammation, and Platelet Activating Factor. Biofactors 2020, 46, 927–933. [Google Scholar] [CrossRef] [PubMed]
  105. Karhausen, J.; Choi, H.W.; Maddipati, K.R.; Mathew, J.P.; Ma, Q.; Boulaftali, Y.; Lee, R.H.; Bergmeier, W.; Abraham, S.N. Platelets Trigger Perivascular Mast Cell Degranulation to Cause Inflammatory Responses and Tissue Injury. Sci. Adv. 2020, 6, eaay6314. [Google Scholar] [CrossRef]
  106. Motta Junior, J.d.S.; Miggiolaro, A.F.R.D.S.; Nagashima, S.; de Paula, C.B.V.; Baena, C.P.; Scharfstein, J.; de Noronha, L. Mast Cells in Alveolar Septa of COVID-19 Patients: A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis. Front. Immunol. 2020, 11, 574862. [Google Scholar] [CrossRef]
  107. de Carvalho, J.C.S.; da Silva-Neto, P.V.; Toro, D.M.; Fuzo, C.A.; Nardini, V.; Pimentel, V.E.; Pérez, M.M.; Fraga-Silva, T.F.C.; Oliveira, C.N.S.; Degiovani, A.M.; et al. The Interplay among Glucocorticoid Therapy, Platelet-Activating Factor and Endocannabinoid Release Influences the Inflammatory Response to COVID-19. Viruses 2023, 15, 573. [Google Scholar] [CrossRef]
  108. Santos-Martínez, M.J.; Medina, C.; Jurasz, P.; Radomski, M.W. Role of Metalloproteinases in Platelet Function. Thromb. Res. 2008, 121, 535–542. [Google Scholar] [CrossRef]
  109. Parks, W.; Wilson, C.; López-Boado, Y. Parks WC, Wilson CL, Lopez-Boado YSMatrix Metalloproteinases as Modulators of Inflammation and Innate Immunity. Nat. Rev. Immunol. 2004, 4, 617–629. [Google Scholar] [CrossRef]
  110. Chung, A.W.Y.; Radomski, A.; Alonso-Escolano, D.; Jurasz, P.; Stewart, M.W.; Malinski, T.; Radomski, M.W. Platelet–Leukocyte Aggregation Induced by PAR Agonists: Regulation by Nitric Oxide and Matrix Metalloproteinases. Br. J. Pharmacol. 2004, 143, 845–855. [Google Scholar] [CrossRef]
  111. Unal, R.; Yao-Borengasser, A.; Varma, V.; Rasouli, N.; Labbate, C.; Kern, P.A.; Ranganathan, G. Matrix Metalloproteinase-9 Is Increased in Obese Subjects and Decreases in Response to Pioglitazone. J. Clin. Endocrinol. Metab. 2010, 95, 2993–3001. [Google Scholar] [CrossRef]
  112. Marchesi, C.; Dentali, F.; Nicolini, E.; Maresca, A.M.; Tayebjee, M.H.; Franz, M.; Guasti, L.; Venco, A.; Schiffrin, E.L.; Lip, G.Y.H.; et al. Plasma Levels of Matrix Metalloproteinases and Their Inhibitors in Hypertension: A Systematic Review and Meta-Analysis. J. Hypertens. 2012, 30, 3–16. [Google Scholar] [CrossRef]
  113. Kapoor, C.; Vaidya, S.; Wadhwan, V.; Hitesh; Kaur, G.; Pathak, A. Seesaw of Matrix Metalloproteinases (MMPs). J. Cancer Res. Ther. 2016, 12, 28–35. [Google Scholar] [CrossRef] [PubMed]
  114. Carolina, D.; Couto, A.E.; Campos, L.C.; Vasconcelos, T.F.; Michelon-Barbosa, J.; Corsi, C.A.; Mestriner, F.; Petroski-Moraes, B.C.; Garbellini-Diab, M.J.; Couto, D.M.; et al. MMP-2 and MMP-9 Levels in Plasma Are Altered and Associated with Mortality in COVID-19 Patients. Biomed. Pharmacother. 2021, 142, 112067. [Google Scholar] [CrossRef]
  115. Zingaropoli, M.A.; Latronico, T.; Pasculli, P.; Masci, G.M.; Merz, R.; Ciccone, F.; Dominelli, F.; Del Borgo, C.; Lichtner, M.; Iafrate, F.; et al. Tissue Inhibitor of Matrix Metalloproteinases-1 (TIMP-1) and Pulmonary Involvement in COVID-19 Pneumonia. Biomolecules 2023, 13, 1040. [Google Scholar] [CrossRef] [PubMed]
  116. Mohammadhosayni, M.; Sadat Mohammadi, F.; Ezzatifar, F.; Mahdavi Gorabi, A.; Khosrojerdi, A.; Aslani, S.; Hemmatzadeh, M.; Yazdani, S.; Arabi, M.; Marofi, F.; et al. Matrix Metalloproteinases Are Involved in the Development of Neurological Complications in Patients with Coronavirus Disease 2019. Int. Immunopharmacol. 2021, 100, 108076. [Google Scholar] [CrossRef]
  117. Razmi, N.; Baradaran, B.; Hejazi, M.; Hasanzadeh, M.; Mosafer, J.; Mokhtarzadeh, A.; de la Guardia, M. Recent Advances on Aptamer-Based Biosensors to Detection of Platelet-Derived Growth Factor. Biosens. Bioelectron. 2018, 113, 58–71. [Google Scholar] [CrossRef]
  118. Nasr El-Din, A.; Ata, K.A.E.-S.; Abdel-Gawad, A.R.; Fahmy, N.F. Impact of High Serum Levels of MMP-7, MMP-9, TGF-β and PDGF Macrophage Activation Markers on Severity of COVID-19 in Obese-Diabetic Patients. Infect. Drug Resist. 2021, 14, 4015–4025. [Google Scholar] [CrossRef]
  119. Petrey, A.C.; Qeadan, F.; Middleton, E.A.; Pinchuk, I.V.; Campbell, R.A.; Beswick, E.J. Cytokine Release Syndrome in COVID-19: Innate Immune, Vascular, and Platelet Pathogenic Factors Differ in Severity of Disease and Sex. J. Leukoc. Biol. 2021, 109, 55–66. [Google Scholar] [CrossRef]
  120. Marino, A.P.M.P.; da Silva, A.; dos Santos, P.; Pinto, L.M.d.O.; Gazzinelli, R.T.; Teixeira, M.M.; Lannes-Vieira, J. Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) Antagonist (Met-RANTES) Controls the Early Phase of Trypanosoma Cruzi-Elicited Myocarditis. Circulation 2004, 110, 1443–1449. [Google Scholar] [CrossRef]
  121. Alard, J.-E.; Ortega-Gomez, A.; Wichapong, K.; Bongiovanni, D.; Horckmans, M.; Megens, R.T.A.; Leoni, G.; Ferraro, B.; Rossaint, J.; Paulin, N.; et al. Recruitment of Classical Monocytes Can Be Inhibited by Disturbing Heteromers of Neutrophil HNP1 and Platelet CCL5. Sci. Transl. Med. 2015, 7, 317ra196. [Google Scholar] [CrossRef]
  122. Crawford, A.; Angelosanto, J.M.; Nadwodny, K.L.; Blackburn, S.D.; Wherry, E.J. A Role for the Chemokine RANTES in Regulating CD8 T Cell Responses during Chronic Viral Infection. PLoS Pathog. 2011, 7, e1002098. [Google Scholar] [CrossRef]
  123. Alam, R.; York, J.; Boyars, M.; Stafford, S.; Grant, J.A.; Lee, J.; Forsythe, P.; Sim, T.; Ida, N. Increased MCP-1, RANTES, and MIP-1alpha in Bronchoalveolar Lavage Fluid of Allergic Asthmatic Patients. Am. J. Respir. Crit. Care Med. 1996, 153, 1398–1404. [Google Scholar] [CrossRef]
  124. Olszewska-Pazdrak, B.; Casola, A.; Saito, T.; Alam, R.; Crowe, S.E.; Mei, F.; Ogra, P.L.; Garofalo, R.P. Cell-Specific Expression of RANTES, MCP-1, and MIP-1alpha by Lower Airway Epithelial Cells and Eosinophils Infected with Respiratory Syncytial Virus. J. Virol. 1998, 72, 4756–4764. [Google Scholar] [CrossRef] [PubMed]
  125. Martin, L.; Blanpain, C.; Garnier, P.; Wittamer, V.; Parmentier, M.; Vita, C. Structural and Functional Analysis of the RANTES-Glycosaminoglycans Interactions. Biochemistry 2001, 40, 6303–6318. [Google Scholar] [CrossRef] [PubMed]
  126. Li, S.; Jiang, L.; Li, X.; Lin, F.; Wang, Y.; Li, B.; Jiang, T.; An, W.; Liu, S.; Liu, H.; et al. Clinical and Pathological Investigation of Patients with Severe COVID-19. JCI Insight 2020, 5, e138070. [Google Scholar] [CrossRef]
  127. Patterson, B.K.; Seethamraju, H.; Dhody, K.; Corley, M.J.; Kazempour, K.; Lalezari, J.P.; Pang, A.P.; Sugai, C.; Francisco, E.B.; Pise, A.; et al. Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19. medRxiv 2020. [Google Scholar] [CrossRef]
  128. Morrell, C.N.; Sun, H.; Ikeda, M.; Beique, J.-C.; Swaim, A.M.; Mason, E.; Martin, T.V.; Thompson, L.E.; Gozen, O.; Ampagoomian, D.; et al. Glutamate Mediates Platelet Activation through the AMPA Receptor. J. Exp. Med. 2008, 205, 575–584. [Google Scholar] [CrossRef]
  129. Curi, R.; Lagranha, C.J.; Doi, S.Q.; Sellitti, D.F.; Procopio, J.; Pithon-Curi, T.C.; Corless, M.; Newsholme, P. Molecular Mechanisms of Glutamine Action. J. Cell Physiol. 2005, 204, 392–401. [Google Scholar] [CrossRef] [PubMed]
  130. Mallolas, J.; Hurtado, O.; Castellanos, M.; Blanco, M.; Sobrino, T.; Serena, J.; Vivancos, J.; Castillo, J.; Lizasoain, I.; Moro, M.A.; et al. A Polymorphism in the EAAT2 Promoter Is Associated with Higher Glutamate Concentrations and Higher Frequency of Progressing Stroke. J. Exp. Med. 2006, 203, 711–717. [Google Scholar] [CrossRef]
  131. Ferrarese, C.; Sala, G.; Riva, R.; Begni, B.; Zoia, C.; Tremolizzo, L.; Galimberti, G.; Millul, A.; Bastone, A.; Mennini, T.; et al. Decreased Platelet Glutamate Uptake in Patients with Amyotrophic Lateral Sclerosis. Neurology 2001, 56, 270–272. [Google Scholar] [CrossRef]
  132. Zhu, Y.; Li, T.; Ramos da Silva, S.; Lee, J.-J.; Lu, C.; Eoh, H.; Jung, J.U.; Gao, S.-J. A Critical Role of Glutamine and Asparagine γ-Nitrogen in Nucleotide Biosynthesis in Cancer Cells Hijacked by an Oncogenic Virus. mBio 2017, 8, e01179-17. [Google Scholar] [CrossRef]
  133. Vastag, L.; Koyuncu, E.; Grady, S.L.; Shenk, T.E.; Rabinowitz, J.D. Divergent Effects of Human Cytomegalovirus and Herpes Simplex Virus-1 on Cellular Metabolism. PLoS Pathog. 2011, 7, e1002124. [Google Scholar] [CrossRef]
  134. Li, X.-K.; Tu, B.; Zhang, X.-A.; Xu, W.; Chen, J.-H.; Zhao, G.-Y.; Xu, B.; Zheng, J.-J.; Yan, Y.-F.; Hao, P.-F.; et al. Dysregulation of Glutamine/Glutamate Metabolism in COVID-19 Patients: A Metabolism Study in African Population and Mini Meta-Analysis. J. Med. Virol. 2023, 95, e28150. [Google Scholar] [CrossRef] [PubMed]
  135. Páez-Franco, J.C.; Torres-Ruiz, J.; Sosa-Hernández, V.A.; Cervantes-Díaz, R.; Romero-Ramírez, S.; Pérez-Fragoso, A.; Meza-Sánchez, D.E.; Germán-Acacio, J.M.; Maravillas-Montero, J.L.; Mejía-Domínguez, N.R.; et al. Metabolomics Analysis Reveals a Modified Amino Acid Metabolism That Correlates with Altered Oxygen Homeostasis in COVID-19 Patients. Sci. Rep. 2021, 11, 6350. [Google Scholar] [CrossRef] [PubMed]
  136. Wang, J.; Yang, G.; Wang, X.; Wen, Z.; Shuai, L.; Luo, J.; Wang, C.; Sun, Z.; Liu, R.; Ge, J.; et al. SARS-CoV-2 Uses Metabotropic Glutamate Receptor Subtype 2 as an Internalization Factor to Infect Cells. Cell Discov. 2021, 7, 119. [Google Scholar] [CrossRef] [PubMed]
  137. Eteraf-Oskouei, T.; Najafi, M. The Relationship between the Serotonergic System and COVID-19 Disease: A Review. Heliyon 2022, 8, e09544. [Google Scholar] [CrossRef]
  138. Adnot, S.; Houssaini, A.; Abid, S.; Marcos, E.; Amsellem, V. Serotonin Transporter and Serotonin Receptors. Handb. Exp. Pharmacol. 2013, 218, 365–380. [Google Scholar] [CrossRef]
  139. O’Connell, P.J.; Wang, X.; Leon-Ponte, M.; Griffiths, C.; Pingle, S.C.; Ahern, G.P. A Novel Form of Immune Signaling Revealed by Transmission of the Inflammatory Mediator Serotonin between Dendritic Cells and T Cells. Blood 2006, 107, 1010–1017. [Google Scholar] [CrossRef]
  140. León-Ponte, M.; Ahern, G.P.; O’Connell, P.J. Serotonin Provides an Accessory Signal to Enhance T-Cell Activation by Signaling through the 5-HT7 Receptor. Blood 2007, 109, 3139–3146. [Google Scholar] [CrossRef]
  141. Mikulski, Z.; Zaslona, Z.; Cakarova, L.; Hartmann, P.; Wilhelm, J.; Tecott, L.H.; Lohmeyer, J.; Kummer, W. Serotonin Activates Murine Alveolar Macrophages through 5-HT2C Receptors. Am. J. Physiol. Lung Cell Mol. Physiol. 2010, 299, L272–L280. [Google Scholar] [CrossRef]
  142. Cloutier, N.; Allaeys, I.; Marcoux, G.; Machlus, K.R.; Mailhot, B.; Zufferey, A.; Levesque, T.; Becker, Y.; Tessandier, N.; Melki, I.; et al. Platelets Release Pathogenic Serotonin and Return to Circulation after Immune Complex-Mediated Sequestration. Proc. Natl. Acad. Sci. USA 2018, 115, E1550–E1559. [Google Scholar] [CrossRef]
  143. Kumar, D.; Jahan, S.; Khan, A.; Siddiqui, A.J.; Redhu, N.S.; Wahajuddin; Khan, J.; Banwas, S.; Alshehri, B.; Alaidarous, M. Neurological Manifestation of SARS-CoV-2 Induced Inflammation and Possible Therapeutic Strategies Against COVID-19. Mol. Neurobiol. 2021, 58, 3417–3434. [Google Scholar] [CrossRef]
  144. Attademo, L.; Bernardini, F. Are Dopamine and Serotonin Involved in COVID-19 Pathophysiology? Eur. J. Psychiatry 2021, 35, 62–63. [Google Scholar] [CrossRef] [PubMed]
  145. Keith, P.; Saint-Jour, M.; Pusey, F.; Hodges, J.; Jalali, F.; Scott, L.K. Unprovoked Serotonin Syndrome-like Presentation of SARS-CoV-2 Infection: A Small Case Series. SAGE Open Med. Case Rep. 2021, 9, 2050313X211032089. [Google Scholar] [CrossRef] [PubMed]
  146. Zaid, Y.; Puhm, F.; Allaeys, I.; Naya, A.; Oudghiri, M.; Khalki, L.; Limami, Y.; Zaid, N.; Sadki, K.; Ben El Haj, R.; et al. Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19. Circ. Res. 2020, 127, 1404–1418. [Google Scholar] [CrossRef] [PubMed]
  147. Duerschmied, D.; Suidan, G.L.; Demers, M.; Herr, N.; Carbo, C.; Brill, A.; Cifuni, S.M.; Mauler, M.; Cicko, S.; Bader, M.; et al. Platelet Serotonin Promotes the Recruitment of Neutrophils to Sites of Acute Inflammation in Mice. Blood 2013, 121, 1008–1015. [Google Scholar] [CrossRef] [PubMed]
  148. Ishikura, H.; Irie, Y.; Kawamura, M.; Hoshino, K.; Nakamura, Y.; Mizunuma, M.; Maruyama, J.; Nakashio, M.; Suzuki-Inoue, K.; Kitamura, T. Early Recognition of Sepsis-Induced Coagulopathy Using the C2PAC Index: A Ratio of Soluble Type C Lectin-like Receptor 2 (SCLEC-2) Level and Platelet Count. Platelets 2022, 33, 935–944. [Google Scholar] [CrossRef]
  149. Suzuki-Inoue, K.; Tsukiji, N.; Shirai, T.; Osada, M.; Inoue, O.; Ozaki, Y. Platelet CLEC-2: Roles Beyond Hemostasis. Semin. Thromb. Hemost. 2018, 44, 126–134. [Google Scholar] [CrossRef]
  150. Navarro-Núñez, L.; Langan, S.A.; Nash, G.B.; Watson, S.P. The Physiological and Pathophysiological Roles of Platelet CLEC-2. Thromb. Haemost. 2013, 109, 991–998. [Google Scholar] [CrossRef]
  151. Meng, D.; Luo, M.; Liu, B. The Role of CLEC-2 and Its Ligands in Thromboinflammation. Front. Immunol. 2021, 12, 688643. [Google Scholar] [CrossRef]
  152. Suzuki-Inoue, K.; Fuller, G.L.J.; García, Á.; Eble, J.A.; Pöhlmann, S.; Inoue, O.; Gartner, T.K.; Hughan, S.C.; Pearce, A.C.; Laing, G.D.; et al. A Novel Syk-Dependent Mechanism of Platelet Activation by the C-Type Lectin Receptor CLEC-2. Blood 2006, 107, 542–549. [Google Scholar] [CrossRef] [PubMed]
  153. Yamashita, Y.; Suzuki, K.; Mastumoto, T.; Ikejiri, M.; Ohishi, K.; Katayama, N.; Suzuki-Inoue, K.; Wada, H. Elevated Plasma Levels of Soluble C-Type Lectin-like Receptor 2 (CLEC2) in Patients with Thrombotic Microangiopathy. Thromb. Res. 2019, 178, 54–58. [Google Scholar] [CrossRef] [PubMed]
  154. Inoue, O.; Osada, M.; Nakamura, J.; Kazama, F.; Shirai, T.; Tsukiji, N.; Sasaki, T.; Yokomichi, H.; Dohi, T.; Kaneko, M.; et al. Soluble CLEC-2 Is Generated Independently of ADAM10 and Is Increased in Plasma in Acute Coronary Syndrome: Comparison with Soluble GPVI. Int. J. Hematol. 2019, 110, 285–294. [Google Scholar] [CrossRef] [PubMed]
  155. Fei, M.; Xiang, L.; Chai, X.; Jin, J.; You, T.; Zhao, Y.; Ruan, C.; Hao, Y.; Zhu, L. Plasma Soluble C-Type Lectin-like Receptor-2 Is Associated with the Risk of Coronary Artery Disease. Front. Med. 2020, 14, 81–90. [Google Scholar] [CrossRef]
  156. Zhang, X.; Zhang, W.; Wu, X.; Li, H.; Zhang, C.; Huang, Z.; Shi, R.; You, T.; Shi, J.; Cao, Y. Prognostic Significance of Plasma CLEC-2 (C-Type Lectin-Like Receptor 2) in Patients With Acute Ischemic Stroke. Stroke 2019, 50, 45–52. [Google Scholar] [CrossRef] [PubMed]
  157. Nishigaki, A.; Ichikawa, Y.; Ezaki, M.; Yamamoto, A.; Suzuki, K.; Tachibana, K.; Kamon, T.; Horie, S.; Masuda, J.; Makino, K.; et al. Soluble C-Type Lectin-Like Receptor 2 Elevation in Patients with Acute Cerebral Infarction. J. Clin. Med. 2021, 10, 3408. [Google Scholar] [CrossRef] [PubMed]
  158. Guo, M.; Zhang, H.; Lv, Q.-W.; Huang, H.-B.; Shen, L.-J. Higher Plasma C-Type Lectin-like Receptor 2 Concentrations for Prediction of Higher Risk of 30-Day Mortality in Isolated Severe Blunt Traumatic Brain Injury. Clin. Chim. Acta 2019, 496, 1–6. [Google Scholar] [CrossRef]
  159. Yamamoto, A.; Wada, H.; Ichkawa, Y.; Tanaka, M.; Tashiro, H.; Shiraki, K.; Shimpo, H.; Yamashita, Y.; Mastumoto, T.; Shimaoka, M.; et al. Soluble C-Type Lectin-Like Receptor 2 Is a Biomarker for Disseminated Intravascular Coagulation. J. Clin. Med. 2021, 10, 2860. [Google Scholar] [CrossRef]
  160. Wada, H.; Ichikawa, Y.; Ezaki, M.; Yamamoto, A.; Tomida, M.; Yoshida, M.; Fukui, S.; Moritani, I.; Shiraki, K.; Shimaoka, M.; et al. Elevated Plasma Soluble C-Type Lectin-like Receptor 2 Is Associated with the Worsening of Coronavirus Disease 2019. J. Clin. Med. 2022, 11, 985. [Google Scholar] [CrossRef]
  161. Garnier, Y.; Claude, L.; Hermand, P.; Sachou, E.; Claes, A.; Desplan, K.; Chahim, B.; Roger, P.-M.; Martino, F.; Colin, Y.; et al. Plasma Microparticles of Intubated COVID-19 Patients Cause Endothelial Cell Death, Neutrophil Adhesion and Netosis, in a Phosphatidylserine-Dependent Manner. Br. J. Haematol. 2022, 196, 1159–1169. [Google Scholar] [CrossRef]
  162. Nomura, S.; Shimizu, M. Clinical Significance of Procoagulant Microparticles. J. Intensive Care 2015, 3, 2. [Google Scholar] [CrossRef]
  163. Nieri, D.; Neri, T.; Petrini, S.; Vagaggini, B.; Paggiaro, P.; Celi, A. Cell-Derived Microparticles and the Lung. Eur. Respir. Rev. 2016, 25, 266–277. [Google Scholar] [CrossRef] [PubMed]
  164. Morel, O.; Morel, N.; Freyssinet, J.-M.; Toti, F. Platelet Microparticles and Vascular Cells Interactions: A Checkpoint between the Haemostatic and Thrombotic Responses. Platelets 2008, 19, 9–23. [Google Scholar] [CrossRef] [PubMed]
  165. Théry, C.; Ostrowski, M.; Segura, E. Membrane Vesicles as Conveyors of Immune Responses. Nat. Rev. Immunol. 2009, 9, 581–593. [Google Scholar] [CrossRef]
  166. Hugel, B.; Martínez, M.C.; Kunzelmann, C.; Freyssinet, J.-M. Membrane Microparticles: Two Sides of the Coin. Physiology 2005, 20, 22–27. [Google Scholar] [CrossRef]
  167. Morel, O.; Toti, F.; Hugel, B.; Bakouboula, B.; Camoin-Jau, L.; Dignat-George, F.; Freyssinet, J.-M. Procoagulant Microparticles: Disrupting the Vascular Homeostasis Equation? Arterioscler. Thromb. Vasc. Biol. 2006, 26, 2594–2604. [Google Scholar] [CrossRef]
  168. Owens, A.P.; Mackman, N. Microparticles in Hemostasis and Thrombosis. Circ. Res. 2011, 108, 1284–1297. [Google Scholar] [CrossRef] [PubMed]
  169. Thachil, J.; Tang, N.; Gando, S.; Falanga, A.; Cattaneo, M.; Levi, M.; Clark, C.; Iba, T. ISTH Interim Guidance on Recognition and Management of Coagulopathy in COVID-19. J. Thromb. Haemost. 2020, 18, 1023–1026. [Google Scholar] [CrossRef]
  170. Kaur, S.; Singh, A.; Kaur, J.; Verma, N.; Pandey, A.K.; Das, S.; Bhattacharyya, S.; Guchhait, P. Upregulation of Cytokine Signalling in Platelets Increases Risk of Thrombophilia in Severe COVID-19 Patients. Blood Cells Mol. Dis. 2022, 94, 102653. [Google Scholar] [CrossRef]
  171. Morel, O.; Marchandot, B.; Jesel, L.; Sattler, L.; Trimaille, A.; Curtiaud, A.; Ohana, M.; Fafi-Kremer, S.; Schini-Kerth, V.; Grunebaum, L.; et al. Microparticles in COVID-19 as a Link between Lung Injury Extension and Thrombosis. ERJ Open Res. 2021, 7, 00954–02020. [Google Scholar] [CrossRef]
  172. Rausch, L.; Lutz, K.; Schifferer, M.; Winheim, E.; Gruber, R.; Oesterhaus, E.F.; Rinke, L.; Hellmuth, J.C.; Scherer, C.; Muenchhoff, M.; et al. Binding of Phosphatidylserine-Positive Microparticles by PBMCs Classifies Disease Severity in COVID-19 Patients. J. Extracell. Vesicles 2021, 10, e12173. [Google Scholar] [CrossRef]
  173. Barnes, G.D.; Burnett, A.; Allen, A.; Ansell, J.; Blumenstein, M.; Clark, N.P.; Crowther, M.; Dager, W.E.; Deitelzweig, S.B.; Ellsworth, S.; et al. Thromboembolic Prevention and Anticoagulant Therapy during the COVID-19 Pandemic: Updated Clinical Guidance from the Anticoagulation Forum. J. Thromb. Thrombolysis 2022, 54, 197–210. [Google Scholar] [CrossRef] [PubMed]
  174. Kyriakoulis, K.G.; Kollias, A.; Kyriakoulis, I.G.; Kyprianou, I.A.; Papachrysostomou, C.; Makaronis, P.; Kotronias, R.A.; Terentes-Printzios, D.; Toskas, I.; Mikhailidis, D.P. Thromboprophylaxis in Patients with COVID-19: Systematic Review of National and International Clinical Guidance Reports. Curr. Vasc. Pharmacol. 2022, 20, 96–110. [Google Scholar] [CrossRef]
  175. Schulman, S.; Sholzberg, M.; Spyropoulos, A.C.; Zarychanski, R.; Resnick, H.E.; Bradbury, C.A.; Broxmeyer, L.; Connors, J.M.; Falanga, A.; Iba, T.; et al. ISTH Guidelines for Antithrombotic Treatment in COVID-19. J. Thromb. Haemost. 2022, 20, 2214–2225. [Google Scholar] [CrossRef] [PubMed]
  176. Bohula, E.A.; Berg, D.D.; Lopes, M.S.; Connors, J.M.; Babar, I.; Barnett, C.F.; Chaudhry, S.-P.; Chopra, A.; Ginete, W.; Ieong, M.H.; et al. Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients With COVID-19: COVID-PACT. Circulation 2022, 146, 1344–1356. [Google Scholar] [CrossRef] [PubMed]
  177. Cuker, A.; Tseng, E.K.; Nieuwlaat, R.; Angchaisuksiri, P.; Blair, C.; Dane, K.; DeSancho, M.T.; Diuguid, D.; Griffin, D.O.; Kahn, S.R.; et al. American Society of Hematology Living Guidelines on the Use of Anticoagulation for Thromboprophylaxis in Patients with COVID-19: January 2022 Update on the Use of Therapeutic-Intensity Anticoagulation in Acutely Ill Patients. Blood Adv. 2022, 6, 4915–4923. [Google Scholar] [CrossRef]
  178. Kollias, A.; Kyriakoulis, K.G.; Trontzas, I.P.; Rapti, V.; Kyriakoulis, I.G.; Theochari, C.A.; Dimakakos, E.; Poulakou, G.; Syrigos, K. High versus Standard Intensity of Thromboprophylaxis in Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis. J. Clin. Med. 2021, 10, 5549. [Google Scholar] [CrossRef]
  179. Mohseni Afshar, Z.; Tavakoli Pirzaman, A.; Hosseinzadeh, R.; Babazadeh, A.; Taghizadeh Moghadam, M.A.; Miri, S.R.; Sio, T.T.; Sullman, M.J.M.; Barary, M.; Ebrahimpour, S. Anticoagulant Therapy in COVID-19: A Narrative Review. Clin. Transl. Sci. 2023, 16, 1510–1525. [Google Scholar] [CrossRef]
Figure 1. Structure and genomic organization of SARS-CoV-2. Adapted from Ref. [7]. (A) schematic representation of the structure of the SARS-CoV-2 virus and the positions of the Spike glycoproteins, envelope, membrane, nucleocapsid and viral genome. (B) enlarged schematic representation showing the S1 and S2 subunits of the SARS-CoV-2 spike glycoprotein. Created with BioRender.com, accessed on 17 August 2023.
Figure 1. Structure and genomic organization of SARS-CoV-2. Adapted from Ref. [7]. (A) schematic representation of the structure of the SARS-CoV-2 virus and the positions of the Spike glycoproteins, envelope, membrane, nucleocapsid and viral genome. (B) enlarged schematic representation showing the S1 and S2 subunits of the SARS-CoV-2 spike glycoprotein. Created with BioRender.com, accessed on 17 August 2023.
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Figure 2. Schematic representation of the entry mechanism and replication cycle of SARS-CoV-2. Adapted from Ref. [1]. The S protein of SARS-CoV-2 binds to ACE-2 and cleaves the S1/S2 subunits through TMPRSS2, enabling the entry of the virus into the host’s cells and the consequent translation of the viral genome. Transcription and replication occur in the Golgi complex, where subgenomic RNA is translated into structural and accessory proteins that are inserted into the genomic RNA in the nucleocapsid. Then, the virion is formed and released by exocytosis. ACE-2, Angiotensin Converting Enzyme 2; TMPRSS2, Transmembrane Protease Serine 2; nsps, Non-structural Proteins. Created with BioRender.com, accessed on 17 August 2023.
Figure 2. Schematic representation of the entry mechanism and replication cycle of SARS-CoV-2. Adapted from Ref. [1]. The S protein of SARS-CoV-2 binds to ACE-2 and cleaves the S1/S2 subunits through TMPRSS2, enabling the entry of the virus into the host’s cells and the consequent translation of the viral genome. Transcription and replication occur in the Golgi complex, where subgenomic RNA is translated into structural and accessory proteins that are inserted into the genomic RNA in the nucleocapsid. Then, the virion is formed and released by exocytosis. ACE-2, Angiotensin Converting Enzyme 2; TMPRSS2, Transmembrane Protease Serine 2; nsps, Non-structural Proteins. Created with BioRender.com, accessed on 17 August 2023.
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Figure 3. Schematic representation of the immunothrobosis mechanism triggered by SARS-CoV-2. Adapted from Ref. [7]. When immune cells recognize the virus, inflammatory cytokines are produced that attract defense cells in an attempt to contain the pathogen. In the presence of a deregulated immune response and the exacerbated production of these cytokines, the cycle of inflammation is established, mediated by the platelet–leukocyte interaction and the consequent thrombus formation. Compromising the vessel wall and resulting in the accumulation of fluids in the bronchioles and vasoconstriction via platelet activation, the oxygen exchange capacity is reduced. Created with BioRender.com, accessed on 25 October 2023.
Figure 3. Schematic representation of the immunothrobosis mechanism triggered by SARS-CoV-2. Adapted from Ref. [7]. When immune cells recognize the virus, inflammatory cytokines are produced that attract defense cells in an attempt to contain the pathogen. In the presence of a deregulated immune response and the exacerbated production of these cytokines, the cycle of inflammation is established, mediated by the platelet–leukocyte interaction and the consequent thrombus formation. Compromising the vessel wall and resulting in the accumulation of fluids in the bronchioles and vasoconstriction via platelet activation, the oxygen exchange capacity is reduced. Created with BioRender.com, accessed on 25 October 2023.
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Table 1. Main Platelet Molecules associated with thromboinflammation in severe COVID-19.
Table 1. Main Platelet Molecules associated with thromboinflammation in severe COVID-19.
MoleculeBiological FunctionMethodsPro-Infection MechanismClinical ComplicationsRef.
P-SelectinPlatelet activation; adhesion and modulation of platelet–leukocyte interaction.FlowcytometryIncreased surface expression.Platelet–leukocyte aggregates; increased platelet aggregation, adhesion and spread.[39,61,62,63]
VWFRecruitment of circulating platelets to the site of injury; platelet activation and aggregation.LIA, ELISA, immunohistologyIncreased plasma levels in patients on ITU support.Thrombosis; vasculopathy; greater severity and in-hospital mortality.[64,65,66,67,68,69,70,71,72]
PAI-1Fibrinolytic regulation.ELISASignificantly higher levels in ITU patients.Predisposition to thrombotic events; associated with worse respiratory status and unfavorable clinical outcome.[73,74,75,76,77,78]
PF4Coagulation; regulating angiogenesis and inflammatory and infectious responses.ELISAHigh expression in plasma and tracheal aspirate.Platelet hyperactivation associated with immunothrombosis and the formation of PF4/heparin immune complexes.[39,79,80,81,82,83,84,85,86,87,88,89,90,91]
TGF-βInflammatory regulation; coagulation; wound healing.ELISAHigh serum levels are associated with greater disease severity.Increased coagulation; immune dysregulation; pulmonary fibrosis.[92,93,94,95,96,97]
PAFLeukocyte chemotaxis; platelet aggregation; inflammatory mediator in infectious processes.ELISAIncreased levels were described in patients with moderate COVID-19.Increased inflammation; interstitial edema; immunothrombosis.[98,99,100,101,102,103,104,105,106,107]
MMP-2, MMP-9Degradation of extracellular matrix proteins; embryonic development and fibrinolysis.Zymography, ELISAElevated levels of MMP-2 and MMP-9 in severe COVID-19 patients.Increased mortality; respiratory complications; neurological syndrome.[108,109,110,111,112,113,114,115,116]
PDGFCell differentiation, proliferation and chemotaxis.ELISAHigh levels were associated with greater disease severity.Platelet activation; formation of platelet–leukocyte aggregates; lung damage.[4,39,117,118,119]
RANTES (CCL5)Monocyte recruitment; activation and differentiation of T cells.ELISAIncreased plasma levels and activity in critically ill patients.Lung damage; NETs; immunothrombosis.[85,120,121,122,123,124,125,126,127]
GlutamateRegulation of platelet production and activation.Chromatography, mass spectrometryLower glutamine levels and higher glutamate levels in severe COVID-19.Lung damage; hypoxia; neurological disability; thrombosis risk.[128,129,130,131,132,133,134,135,136]
SerotoninVasoconstriction; T cell activation and differentiation; platelet aggregation.ELISAHigh serum levels in severe COVID-19.Serotonergic toxicity; platelet degranulation; vascular injury.[137,138,139,140,141,142,143,144,145,146,147]
CLEC-2Hemostasis; healing; maintenance of vascular integrity; platelet adhesion.CLEIAElevated plasma levels in severe and critical COVID-19.Platelet activation; thrombotic syndrome.[13,148,149,150,151,152,153,154,155,156,157,158,159,160]
MPsRegulation of inflammation; coagulation; cell proliferation and differentiation.Flowcytometry, ELISAHigh levels of circulating MPs in ITU patients.Lung injury; increase in plateletleukocyte aggregates; worse clinical outcome.[161,162,163,164,165,166,167,168,169,170,171,172]
Legend: VWF, Von Willebrand Factor; ITU, Intensive Treatment Unit; PAI-1, Plasminogen Activator Inhibitor-1; PF4, Platelet Factor 4; TGF, Transforming Growth Factor; PAF, Platelet-Activating Factor; MMP, Metalloproteinase; PDGF, Platelet-derived Growth Factor; RANTES, Regulated on Activation Normal T cell expressed and secreted; CLEC-2, C-Type Lectin-Like Receptor; MPs, Microparticles; NETs, Neutrophil Extracellular Traps; LIA, Latex Immunoturbidimetric Assay; ELISA, Enzyme-linked Immunosorbent Assay; CLEIA, Chemiluminescent Enzyme Immunoassay.
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de Oliveira Sales, L.; de Oliveira, L.L.B.; da Silva, J.B.S.; de Moraes Filho, M.O.; de Moraes, M.E.A.; Montenegro, R.C.; Moreira-Nunes, C.A. The Role of Platelet Molecules in Risk Stratification of Patients with COVID-19. Hemato 2023, 4, 364-383. https://doi.org/10.3390/hemato4040029

AMA Style

de Oliveira Sales L, de Oliveira LLB, da Silva JBS, de Moraes Filho MO, de Moraes MEA, Montenegro RC, Moreira-Nunes CA. The Role of Platelet Molecules in Risk Stratification of Patients with COVID-19. Hemato. 2023; 4(4):364-383. https://doi.org/10.3390/hemato4040029

Chicago/Turabian Style

de Oliveira Sales, Lívia, Lais Lacerda Brasil de Oliveira, Jean Breno Silveira da Silva, Manoel Odorico de Moraes Filho, Maria Elisabete Amaral de Moraes, Raquel Carvalho Montenegro, and Caroline Aquino Moreira-Nunes. 2023. "The Role of Platelet Molecules in Risk Stratification of Patients with COVID-19" Hemato 4, no. 4: 364-383. https://doi.org/10.3390/hemato4040029

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