Innate immune response in acute critical illness: a narrative review.

BACKGROUND: Activation of innate immunity is a first line of host defense during acute critical illness (ACI) that aims to contain injury and avoid tissue damages. Aberrant activation of innate immunity may also participate in the occurrence of organ failures during critical illness. This review aims to provide a narrative overview of recent advances in the field of innate immunity in critical illness, and to consider future potential therapeutic strategies. MAIN TEXT: Understanding the underlying biological concepts supporting therapeutic strategies modulating immune response is essential in decision-making. We will develop the multiple facets of innate immune response, especially its cellular aspects, and its interaction with other defense mechanisms. We will first describe the pathophysiological mechanisms of initiation of innate immune response and its implication during ACI. We will then develop the amplification of innate immunity mediated by multiple effectors. Our review will mainly focus on myeloid and lymphoid cellular effectors, the major actors involved in innate immune-mediated organ failure. We will third discuss the interaction and integration of innate immune response in a global view of host defense, thus considering interaction with non-immune cells through immunothrombosis, immunometabolism and long-term reprogramming via trained immunity. The last part of this review will focus on the specificities of the immune response in children and the older population. CONCLUSIONS: Recent understanding of the innate immune response integrates immunity in a highly dynamic global vision of host response. A better knowledge of the implicated mechanisms and their tissue-compartmentalization allows to characterize the individual immune profile, and one day eventually, to develop individualized bench-to-bedside immunomodulation approaches as an adjuvant resuscitation strategy.

Platelet HMGB1 steers intravascular immunity and thrombosis.

Platelets navigate the fine balance between homeostasis and injury. They regulate vascular homeostasis and drive repair after injury amidst leukocyte extravasation. Crucially, platelets initiate extracellular traps generation and promote immunothrombosis. In chronic human diseases, platelet action often extends beyond its normative role, sparking sustained reciprocal activation of leukocytes and mural cells, culminating in adverse vascular remodeling. Studies in the last decade have spotlighted a novel key player in platelet activation, the high mobility group box 1 (HMGB1) protein. Despite its initial characterization as a chromatin molecule, anucleated platelets express abundant HMGB1, which has emerged as a linchpin in thromboinflammatory risks and microvascular remodeling. We propose that a comprehensive assessment of platelet HMGB1, spanning quantification of content, membrane localization, and accumulation of HMGB1-expressing vesicles in biological fluids should be integral to dissecting and quantifying platelet activation. This review provides evidence supporting this claim and underscores the significance of platelet HMGB1 as a biomarker in conditions associated with heightened thrombotic risks and systemic microvascular involvement, spanning cardiovascular, autoimmune, and infectious diseases.

A Novel Pathway of Platelet Activation in ACS Mediated by LL-37 Immunoglobulin G Autoantibody Immune Complexes.

The cathelicidin antimicrobial peptide LL-37 is a self-antigen in neutrophil extracellular traps that provokes autoantibody responses in autoimmune/autoinflammatory conditions. LL-37 immunoglobulin (Ig) G autoantibody levels were measured in subjects with and without atherosclerotic cardiovascular disease assessed using the coronary artery calcium score, in patients who had a future myocardial infarction and in a cohort of acute coronary syndrome (ACS) patients. LL-37 IgG levels were not associated with coronary artery calcium score, but future myocardial infarction patients had significantly higher LL-37 IgG at baseline. Reduced LL-37 IgG in ACS was associated with increased LL-37 IgG-immune complex. ACS plasma increased activated CD62P+ platelets from healthy donors mediated in part by LL-37 IgG-immune complexes and platelet Fc gamma receptor 2a.

Cardiovascular disease and thrombosis: Intersections with the immune system, inflammation, and the coagulation system.

The coagulation and immune system, both essential physiological systems in the human body, are intricately interconnected and play a critical role in determining the overall health of patients. These systems collaborate via various shared regulatory pathways, such as the Tissue Factor (TF) Pathway. Immunological cells that express TF and generate pro-inflammatory cytokines have the ability to affect coagulation. Conversely, coagulation factors and processes have a reciprocal effect on immunological responses by stimulating immune cells and regulating their functions. These interconnected pathways play a role in both preserving well-being and contributing to a range of pathological disorders. The close relationship between blood clotting and inflammation in the development of vascular disease has become a central focus of clinical study. This research specifically examines the crucial elements of this interaction within the contexts of cardiovascular disease and acute coronary syndrome. Tissue factor, the primary trigger of the extrinsic coagulation pathway, has a crucial function by inducing a proinflammatory reaction through the activation of coagulation factors. This, in turn, initiates coagulation and subsequent cellular signalling pathways. Protease-activated receptors establish the molecular connection between coagulation and inflammation by interacting with activated clotting factors II, X, and VII. Thrombosis, a condition characterised by the formation of blood clots, is the most dreaded consequence of cardiovascular disorders and a leading cause of death globally. Consequently, it poses a significant challenge to healthcare systems. Antithrombotic treatments efficiently target platelets and the coagulation cascade, but they come with the inherent danger of causing bleeding. Furthermore, antithrombotics are unable to fully eliminate thrombotic events, highlighting a treatment deficiency caused by a third mechanism that has not yet been sufficiently addressed, namely inflammation. Understanding these connections may aid in the development of novel approaches to mitigate the harmful mutual exacerbation of inflammation and coagulation. Gaining a comprehensive understanding of the intricate interaction among these systems is crucial for the management of diseases and the creation of efficacious remedies. Through the examination of these prevalent regulatory systems, we can discover novel therapeutic approaches that specifically target these complex illnesses. This paper provides a thorough examination of the reciprocal relationship between the coagulation and immune systems, emphasising its importance in maintaining health and understanding disease processes. This review examines the interplay between inflammation and thrombosis and its role in the development of thrombotic disorders.

GSDMD-Dependent Neutrophil Extracellular Traps Mediate Portal Vein Thrombosis and Associated Fibrosis in Cirrhosis.

Portal vein thrombosis (PVT) is a challenging and controversial complication of cirrhosis. Experimental models that reproduce cirrhotic PVT and effective pharmacological therapies are limited. We aimed to investigate the nature course and mechanisms of PVT in cirrhosis. A novel PVT model was developed via two-step total portal vein ligation in healthy and thioacetamide (TAA)-cirrhotic rats. Circulating and liver-infiltrating neutrophils were isolated from individuals with cirrhosis to examine neutrophil extracellular traps (NETs) and explore their unique characteristics and implications in PVT-associated fibrosis in cirrhosis. We further validated macrophage-myofibroblast transition (MMT) via multiplex immunofluorescence and single-cell sequencing. In the experimental model, cirrhosis promoted PVT development and portal vein intimal thickening. Interestingly, cirrhosis promoted spontaneous resolution of PVT due to instability of thrombus structure, along with pulmonary and intrahepatic clots. NETs-MMT mediate cirrhotic PVT and PVT-associated fibrosis, including fibrotic thrombus remodeling and increased hepatic collagen deposition. Mechanistically, caspase-4-dependent activation of neutrophils and GSDMD mediated the formation of NETs. The extracellular DNA of NETs promoted TGF-ß1/Smad3-driven MMT. Inhibiting GSDMD with disulfiram suppressed cirrhotic PVT and prevented associated fibrosis. The cirrhotic PVT model reflected the following three main characteristics of cirrhotic PVT: spontaneous resolution, immunothrombosis, and intimal fibrosis. Targeting NETs with GSDMD inhibitors may serve as a new therapeutic concept to treat cirrhotic PVT.

Antiphospholipid Syndrome: Insights into Molecular Mechanisms and Clinical Manifestations.

Antiphospholipid syndrome (APS) is a complex systemic autoimmune disorder characterized by a hypercoagulable state, leading to severe vascular thrombosis and obstetric complications. The 2023 ACR/EULAR guidelines have revolutionized the classification and understanding of APS, introducing broader diagnostic criteria that encompass previously overlooked cardiac, renal, and hematologic manifestations. Despite these advancements, diagnosing APS remains particularly challenging in seronegative patients, where traditional tests fail, yet clinical symptoms persist. Emerging non-criteria antiphospholipid antibodies offer promising new diagnostic and management avenues for these patients. Managing APS involves a strategic balance of cardiovascular risk mitigation and long-term anticoagulation therapy, though the use of direct oral anticoagulants remains contentious due to varying efficacy and safety profiles. This article delves into the intricate pathogenesis of APS, explores the latest classification criteria, and evaluates cutting-edge diagnostic tools and therapeutic strategies.

Anti-platelet factor 4 immunothrombotic syndromes.

Anti-platelet factor 4 immunothrombotic syndromes comprise a group of disorders that include heparin-induced thrombocytopenia and vaccine-induced immune thrombocytopenia and thrombosis. These are highly prothrombotic, immunological disorders characterised by specific clinical and pathological criteria which include thrombocytopenia and thrombosis. While they are predominantly triggered by heparin and the adenoviral vector vaccines, respectively, other provoking factors have been described, as well as spontaneous forms. The unexplained co-occurrence of thrombocytopenia with thrombosis should raise suspicion and prompt testing. This nutshell review discusses the pathophysiology, presenting features and diagnostic criteria for these conditions.

The role of donor hypertension and angiotensin II in the occurrence of early pancreas allograft thrombosis.

Background: About 10-20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis. Methods: We conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers. Results: Pancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers. Conclusion: Donor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.

Angiopoietin2 is associated with coagulation activation and tissue factor expression in extracellular vesicles in COVID-19.

Coagulation activation in immunothrombosis involves various pathways distinct from classical hemostasis, offering potential therapeutic targets to control inflammation-induced hypercoagulability while potentially sparing hemostasis. The Angiopoietin/Tie2 pathway, previously linked to embryonic angiogenesis and sepsis-related endothelial barrier regulation, was recently associated with coagulation activation in sepsis and COVID-19. This study explores the connection between key mediators of the Angiopoietin/Tie2 pathway and coagulation activation. The study included COVID-19 patients with hypoxia and healthy controls. Blood samples were processed to obtain platelet-free plasma, and frozen until analysis. Extracellular vesicles (EVs) in plasma were characterized and quantified using flow cytometry, and their tissue factor (TF) procoagulant activity was measured using a kinetic chromogenic method. Several markers of hemostasis were assessed. Levels of ANGPT1, ANGPT2, and soluble Tie2 correlated with markers of coagulation and platelet activation. EVs from platelets and endothelial cells were increased in COVID-19 patients, and a significant increase in TF+ EVs derived from endothelial cells was observed. In addition, ANGPT2 levels were associated with TF expression and activity in EVs. In conclusion, we provide further evidence for the involvement of the Angiopoietin/Tie2 pathway in the coagulopathy of COVID-19 mediated in part by release of EVs as a potential source of TF activity.

1.8-cineole prevents platelet activation and aggregation by activating the cAMP pathway via the adenosine A2A receptor.

AIMS: Dysregulated platelet aggregation is a fatal condition in many bacterial- and virus-induced diseases. However, classical antithrombotics cannot completely prevent immunothrombosis, due to the unaddressed mechanisms towards inflammation. Thus, targeting platelet hyperactivation together with inflammation might provide new treatment options in diseases, characterized by immunothrombosis, such as COVID-19 and sepsis. The aim of this study was to investigate the antiaggregatory effect and mode of action of 1.8-cineole, a monoterpene derived from the essential oil of eucalyptus leaves, known for its anti-inflammatory proprieties. MAIN METHODS: Platelet activity was monitored by measuring the expression and release of platelet activation markers, i.e., P-selectin, CD63 and CCL5, as well as platelet aggregation, upon treatment with 1.8-cineole and stimulation with several classical stimuli and bacteria. A kinase activity assay was used to elucidate the mode of action, followed by a detailed analysis of the involvement of the adenylyl-cyclase (AC)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway by Western blot and ELISA. KEY FINDINGS: 1.8-cineole prevented the expression and release of platelet activation markers, as well as platelet aggregation, upon induction of aggregation with classical stimuli and immunological agonists. Mechanistically, 1.8- cineole influences the activation of the AC-cAMP-PKA pathway, leading to higher cAMP levels and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Finally, blocking the adenosine A2A receptor reversed the antithrombotic effect of 1.8-cineole. SIGNIFICANCE: Given the recognized anti-inflammatory attributes of 1.8-cineole, coupled with our findings, 1.8-cineole might emerge as a promising candidate for treating conditions marked by platelet activation and abnormal inflammation.

Platelet hyperresponsiveness and increased platelet-neutrophil aggregates in dogs with myxomatous mitral valve disease and pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) in dogs with myxomatous mitral valve disease (MMVD) is caused by increased pulmonary venous pressure. Thrombosis, vascular remodeling, and vasoconstriction mediated by platelets could exacerbate PH. HYPOTHESIS: Dogs with PH will exhibit a hypercoagulable state, characterized by increased platelet activation, platelet-leukocyte, and platelet-neutrophil aggregate formation. ANIMALS: Eleven dogs (≥3.5 kg) diagnosed with MMVD and PH and 10 dogs with MMVD lacking PH. METHODS: Prospective cohort ex vivo study. All dogs underwent echocardiographic examination, CBC, 3-view thoracic radiographs, and heartworm antigen testing. Severity of PH and MMVD were assessed by echocardiography. Viscoelastic monitoring of coagulation was assessed using thromboelastography (TEG). Platelet activation and platelet-leukocyte/platelet-neutrophil interactions were assessed using flow cytometry. Plasma serotonin concentrations were measured by ELISA. RESULTS: Unstimulated platelets from dogs with MMVD and PH expressed more surface P-selectin than MMVD controls (P = .03). Platelets from dogs with MMVD and PH had persistent activation in response to agonists. The number of platelet-leukocyte aggregates was higher in dogs with MMVD and PH compared with MMVD controls (P = .01). Ex vivo stimulation of whole blood resulted in higher numbers of platelet-neutrophil aggregates in dogs with MMVD and PH (P = .01). Assessment of hypercoagulability based on TEG or plasma serotonin concentrations did not differ between groups. CONCLUSION AND CLINICAL IMPORTANCE: Platelet hyperresponsiveness and increased platelet-neutrophil interaction occur in dogs with MMVD and PH, suggesting that platelets play a role of in the pathogenesis of PH. Clinical benefits of antiplatelet drugs in dogs with MMVD and PH require further investigation.

Balancing efficacy and safety of complement inhibitors.

Complement inhibitors have been approved for several immune-mediated diseases and they are considered the next paradigm-shifting approach in the treatment of glomerulonephritis. The hierarchical organization of the complement system offers numerous molecular targets for therapeutic intervention. However, complement is an integral element of host defense and therefore complement inhibition can be associated with serious infectious complications. Here we give a closer look to the hierarchical complement system and how interfering with proximal versus distal or selective versus unselective molecular targets could determine efficacy and safety. Furthermore, we propose to consider the type of disease, immunological activity, and patient immunocompetence when stratifying patients, e.g., proximal/unselective targets for highly active and potentially fatal diseases while distal and selective targets may suit more chronic disease conditions with low or moderate disease activity requiring persistent complement blockade in patients with concomitant immunodeficiency. Certainly, there exists substantial promise for anti-complement therapeutics. However, balancing efficacy and safety will be key to establish powerful treatment effects with minimal adverse events, especially when complement blockade is continued over longer periods of time in chronic disorders.

Immunothrombosis versus thrombo-inflammation: platelets in cerebrovascular complications.

A State-of-the Art lecture titled "Thrombo-Neuroinflammatory Disease" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. First, we would like to advocate for discrimination between immunothrombosis and thrombo-inflammation, as immunothrombosis describes an overshooting inflammatory reaction that results in detrimental thrombotic activity. In contrast, thrombo-inflammation describes the interplay of platelets and coagulation with the immunovascular system, resulting in the recruitment of immune cells and loss of barrier function (hence, hallmarks of inflammation). Both processes can be observed in the brain, with cerebral venous thrombosis being a prime example of immunothrombosis, while infarct progression in response to ischemic stroke is a paradigmatic example of thrombo-inflammation. Here, we review the pathomechanisms underlying cerebral venous thrombosis and ischemic stroke from a platelet-centric perspective and discuss translational implications. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress.

Impact of age on the host response to sepsis in a murine model of fecal-induced peritonitis.

INTRODUCTION: Despite older adults being more vulnerable to sepsis, most preclinical research on sepsis has been conducted using young animals. This results in decreased scientific validity since age is an independent predictor of poor outcome. In this study, we explored the impact of aging on the host response to sepsis using the fecal-induced peritonitis (FIP) model developed by the National Preclinical Sepsis Platform (NPSP). METHODS: C57BL/6 mice (3 or 12 months old) were injected intraperitoneally with rat fecal slurry (0.75 mg/g) or a control vehicle. To investigate the early stage of sepsis, mice were culled at 4 h, 8 h, or 12 h to investigate disease severity, immunothrombosis biomarkers, and organ injury. Mice received buprenorphine at 4 h post-FIP. A separate cohort of FIP mice were studied for 72 h (with buprenorphine given at 4 h, 12 h, and then every 12 h post-FIP and antibiotics/fluids starting at 12 h post-FIP). Organs were harvested, plasma levels of Interleukin (IL)-6, IL-10, monocyte chemoattract protein (MCP-1)/CCL2, thrombin-antithrombin (TAT) complexes, cell-free DNA (CFDNA), and ADAMTS13 activity were quantified, and bacterial loads were measured. RESULTS: In the 12 h time course study, aged FIP mice demonstrated increased inflammation and injury to the lungs compared to young FIP mice. In the 72 h study, aged FIP mice exhibited a higher mortality rate (89%) compared to young FIP mice (42%) (p < 0.001). Aged FIP non-survivors also exhibited a trend towards elevated IL-6, TAT, CFDNA, CCL2, and decreased IL-10, and impaired bacterial clearance compared to young FIP non-survivors. CONCLUSION: To our knowledge, this is the first study to investigate the impact of age on survival using the FIP model of sepsis. Our model includes clinically-relevant supportive therapies and inclusion of both sexes. The higher mortality rate in aged mice may reflect increased inflammation and worsened organ injury in the early stage of sepsis. We also observed trends in impaired bacterial clearance, increase in IL-6, TAT, CFDNA, CCL2, and decreased IL-10 and ADAMTS13 activity in aged septic non-survivors compared to young septic non-survivors. Our aging model may help to increase the scientific validity of preclinical research and may be useful for identifying mechanisms of age-related susceptibility to sepsis as well as age-specific treatment strategies.

Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation.

Thrombotic microangiopathy has been identified as a dominant mechanism for increased mortality and morbidity in coronavirus disease 2019 (COVID-19). In the context of severe COVID-19, patients may develop immunothrombosis within the microvasculature of the lungs, which contributes to the development of acute respiratory distress syndrome (ARDS), a leading cause of death in the disease. Immunothrombosis is thought to be mediated in part by increased levels of cytokines, fibrin clot formation, and oxidative stress. Glutathione (GSH), a well-known antioxidant molecule, may have therapeutic effects in countering this pathway of immunothrombosis as decreased levels of (GSH) have been associated with increased viral replication, cytokine levels, and thrombosis, suggesting that glutathione supplementation may be therapeutic for COVID-19. GSH supplementation has never been explored as a means of treating COVID-19. This study investigated the effectiveness of liposomal glutathione (GSH) as an adjunctive therapy for peripheral blood mononuclear cells (PBMC) treated with SARS CoV-2 spike protein. Upon the addition of GSH to cell cultures, cytokine levels, fibrin clot formation, oxidative stress, and intracellular GSH levels were measured. The addition of liposomal-GSH to PBMCs caused a statistically significant decrease in cytokine levels, fibrin clot formation, and oxidative stress. The addition of L-GSH to spike protein and untreated PBMCs increased total intracellular GSH, decreased IL-6, TGF-beta, and TNF-alpha levels, decreased oxidative stress, as demonstrated through MDA, and decreased fibrin clot formation, as detected by fluorescence microscopy. These findings demonstrate that L-GSH supplementation within a spike protein-treated PBMC cell culture model reduces these factors, suggesting that GSH supplementation should be explored as a means of reducing mediators of immunothrombosis in COVID-19.

Understanding COVID-19-associated endothelial dysfunction: role of PIEZO1 as a potential therapeutic target.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Due to its high infectivity, the pandemic has rapidly spread and become a global health crisis. Emerging evidence indicates that endothelial dysfunction may play a central role in the multiorgan injuries associated with COVID-19. Therefore, there is an urgent need to discover and validate novel therapeutic strategies targeting endothelial cells. PIEZO1, a mechanosensitive (MS) ion channel highly expressed in the blood vessels of various tissues, has garnered increasing attention for its potential involvement in the regulation of inflammation, thrombosis, and endothelial integrity. This review aims to provide a novel perspective on the potential role of PIEZO1 as a promising target for mitigating COVID-19-associated endothelial dysfunction.

Neutrophil extracellular traps - a potential trigger for the development of thrombocytopenia during extracorporeal membrane oxygenation.

Neutrophil extracellular traps (NETs) have recently emerged as a potential link between inflammation, immunity, and thrombosis, as well as other coagulation disorders which present a major challenge in the context of extracorporeal membrane oxygenation (ECMO). By examining blood from ECMO patients for NETs and their precursors and correlating them with clinical and laboratory biomarkers of coagulation and inflammation, this study aims to evaluate the association between the presence of NETs in the bloodstream of ECMO patients and the development of potentially severe coagulation disorders during ECMO therapy. Therefore, blood samples were collected from healthy volunteers (n=13) and patients receiving veno-venous (VV) ECMO therapy (n=10). To identify NETs and their precursors, DNA and myeloperoxidase as well as granulocyte marker CD66b were visualized simultaneously by immunofluorescence staining in serial blood smears. Differentiation of DNA-containing objects and identification of NETs and their precursors was performed semiautomatically by a specific algorithm using the shape and size of DNA staining and the intensity of MPO and CD66b signal. Neutrophil extracellular traps and their precursors could be detected in blood smears from patients requiring VV ECMO. Compared to volunteers, ECMO patients presented significantly higher rates of NETs and NET precursors as well as an increased proportion of neutrophil granulocytes in all detected nucleated cells. A high NET rate prior to the initiation of ECMO therapy was associated with both increased IL-6 and TNF-α levels as an expression of a high cytokine burden. These patients with increased NET release also presented an earlier and significantly more pronounced decrease in platelet counts and ATIII activity following initiation of therapy compared with patients with less elevated NETs. These findings provide further indications for the development of immune-mediated acquired thrombocytopenia in ECMO patients.

Immunothrombosis and its underlying biological mechanisms

Abstract The evolutionary conserved link between coagulation and innate immunity is a biological process characterized by the thrombosis formation stimulus of immune cells and specific thrombosis-related molecules. In physiological settings, the relationship between the immune system and thrombosis facilitates the recognition of pathogens and damaged cells and inhibits pathogen proliferation. However, when deregulated, the interplay between hemostasis and innate immunity becomes a pathological process named immunothrombosis, which is at the basis of several infectious and inflammation-related thrombotic disorders, including coronavirus disease 2019 (COVID-19). In advanced stages, alterations in both coagulation and immune cell function due to extreme inflammation lead to an increase in blood coagulability, with high rates of thrombosis and mortality. Therefore, understanding underlying mechanisms in immunothrombosis has become decisive for the development of more efficient therapies to treat and prevent thrombosis in COVID-19 and in other thrombotic disorders. In this review, we outline the existing knowledge on the molecular and cellular processes involved in immunothrombosis, focusing on the role of neutrophil extracellular traps (NETs), platelets and the coagulation pathway. We also describe how the deregulation of hemostasis is associated with pathological conditions and can significantly aggravate a patient's condition, using COVID-19 as a clinical model.

Immunothrombosis and its underlying biological mechanisms.

The evolutionary conserved link between coagulation and innate immunity is a biological process characterized by the thrombosis formation stimulus of immune cells and specific thrombosis-related molecules. In physiological settings, the relationship between the immune system and thrombosis facilitates the recognition of pathogens and damaged cells and inhibits pathogen proliferation. However, when deregulated, the interplay between hemostasis and innate immunity becomes a pathological process named immunothrombosis, which is at the basis of several infectious and inflammation-related thrombotic disorders, including coronavirus disease 2019 (COVID-19). In advanced stages, alterations in both coagulation and immune cell function due to extreme inflammation lead to an increase in blood coagulability, with high rates of thrombosis and mortality. Therefore, understanding underlying mechanisms in immunothrombosis has become decisive for the development of more efficient therapies to treat and prevent thrombosis in COVID-19 and in other thrombotic disorders. In this review, we outline the existing knowledge on the molecular and cellular processes involved in immunothrombosis, focusing on the role of neutrophil extracellular traps (NETs), platelets and the coagulation pathway. We also describe how the deregulation of hemostasis is associated with pathological conditions and can significantly aggravate a patient's condition, using COVID-19 as a clinical model.