Renal Vein Thrombosis Secondary to Pyelonephritis: Targeting a Thrombo-Inflammatory Entity.

Renal vein thrombosis (RVT) is a relatively uncommon condition that is most frequently observed in individuals with nephrotic syndrome. While rare, pyelonephritis (PN) may serve as a predisposing factor for secondary RVT. In such cases, one should consider the possibility of RVT when patients fail to respond to appropriate antibiotic treatment. Typically, these patients require additional anticoagulation therapy for a duration of 3 to 6 months, with a generally favorable prognosis. In this report, we present the case of a 74-year-old female who developed RVT due to Klebsiella pneumoniae PN. Additionally, we reviewed 11 cases of PN complicated by RVT, which were documented in the PubMed database over a span of 40 years, emphasizing key elements in diagnostic and therapeutic approaches. Lastly, we elaborated upon the role of thrombo-inflammation, especially in the context of sepsis.

NET burden in left atrial blood is associated with biomarkers of thrombosis and cardiac injury in patients with enlarged left atria.

BACKGROUND: Emerging data suggest an association between left atrial (LA) enlargement, thrombus formation, and ischemic stroke. However, it is unknown what may mediate such clot formation in LA dysfunction. Neutrophils promote large vessel occlusion and microthrombosis via neutrophil extracellular trap (NET) release, thus lying at the interface of inflammation, thrombosis, and fibrosis. APPROACH: We conducted a prospective all-comers cohort study in patients undergoing catheterization procedures with atrial transseptal access (MitraClip, MC; left atrial appendage closure, LAAC; pulmonary vein ablation, PVA; patent foramen ovale closure, PFO). We measured NETs, cytokines, thrombotic factors, and cardiac injury markers in paired blood samples collected from peripheral blood and within the left atrium. We correlated these biomarkers with echocardiographic measures of LA structure and function (including left atrial volume index, LAVI). Data were analyzed by procedure type, and stratified by LAVI or atrial fibrillation (AF) status. RESULTS: We enrolled 70 patients (mean age 64 years, 53% women). NETs, but not other markers, were elevated in LA compared to peripheral blood samples. Most thrombotic, inflammatory, and cardiac damage markers were elevated in LAs from MC or LAAC compared to PFO patients. Overall, NET biomarkers positively correlated with VWF, LAVI, and markers of cardiac injury and negatively with ADAMTS13 activity. LA enlargement and the presence of AF similarly stratified patients based on thromboinflammation measurements, but this was not limited to AF at the time of sample collection. CONCLUSION: Elevated NETs and VWF in patients with enlarged LA or AF suggest enhanced thromboinflammation within the LA.

Delayed plasma kallikrein inhibition fosters post-stroke recovery by reducing thrombo-inflammation.

Activation of the kallikrein-kinin system promotes vascular leakage, inflammation, and neurodegeneration in ischemic stroke. Inhibition of plasma kallikrein (PK) - a key component of the KKS - in the acute phase of ischemic stroke has been reported to reduce thrombosis, inflammation, and damage to the blood-brain barrier. However, the role of PK during the recovery phase after cerebral ischemia is unknown. To this end, we evaluated the effect of subacute PK inhibition starting from day 3 on the recovery process after transient middle artery occlusion (tMCAO). Our study demonstrated a protective effect of PK inhibition by reducing infarct volume and improving functional outcome at day 7 after tMCAO. In addition, we observed reduced thrombus formation in cerebral microvessels, fewer infiltrated immune cells, and an improvement in blood-brain barrier integrity. This protective effect was facilitated by promoting tight junction reintegration, reducing detrimental matrix metalloproteinases, and upregulating regenerative angiogenic markers. Our findings suggest that PK inhibition in the subacute phase might be a promising approach to accelerate the post-stroke recovery process.

Scorch processing of rhubarb (Rheum tanguticum Maxim. ex Balf.) pyrolyzed anthraquinone glucosides into aglycones and improved the therapeutic effects on thromboinflammation via regulating the complement and coagulation cascades pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The pathophysiological mechanism of thromboinflammation involves the intricate interplay between the inflammatory responses and coagulation cascades. Rhubarb is frequently used in traditional Chinese medicine to treat thromboinflammatory diseases. The scorched rhubarb (prepared by stir-baking the dried raw rhubarb till it partly turns to charcoal) is believed to possess enhanced blood-cooling and stasis-removing functions compared to the raw rhubarb, thereby augmenting the therapeutic effects on thromboinflammation. AIM OF THE STUDY: This study aimed to explore the chemical and pharmacological foundations of the scorch processing of rhubarb in order to ensure and enhance the efficacy and safety of the scorched rhubarb for treating thromboinflammatory diseases. MATERIALS AND METHODS: The dried raw rhubarb pieces were subjected to stir-baking at 180 °C for 10∼80 min to obtain the rhubarbs with varying degrees of scorching. Typical ingredients present in rhubarb pieces and extracts were determined by high-performance liquid chromatography. The therapeutic effects of the raw and scorched rhubarb on thromboinflammation were evaluated using a rat model. Proteomics analysis was employed to screen potential biological pathways associated with thromboinflammation treatment by the raw and scorched rhubarb, which were further verified using a cell model. RESULTS: Morphological properties indicated that the rhubarb baked at 180 °C for 50 min in this research showed the optimal degree of scorching. Compared to the raw rhubarb, the properly scorched rhubarb exhibited lower levels of anthraquinone glucosides, higher levels of anthraquinone aglycones, superior anti-thromboinflammatory effects, and no purgative side effects. Proteomics analysis revealed that the complement and coagulation cascades pathway played a significant role in mediating the therapeutic effects of the raw and scorched rhubarb on thromboinflammation. Furthermore, it was found that anthraquinone aglycones were more effective than their glucoside counterparts in restoring the impaired vascular endothelial cells as well as regulating the complement and coagulation cascades pathway. CONCLUSIONS: Proper scorch processing may augment the therapeutic effects of rhubarb on thromboinflammation via relieving inflammation and oxidative stress, repairing vascular endothelial cells, restoring coagulation cascades and blood rheology, and regulating some other biological processes. This may be partly caused by the scorch-induced thermolysis of anthraquinone glucosides into their aglycone counterparts that seemed to perform better in regulating the complement and coagulation cascades pathway.

Assessment of associations between neutrophil extracellular trap biomarkers in blood and thrombi in acute ischemic stroke patients.

Inflammation including immunothrombosis by neutrophil extracellular traps (NETs) has important implications in acute ischemic stroke and can affect reperfusion status, susceptibility to stroke associated infections (SAI) as well as functional clinical outcome. NETs were shown to be prevalent in stroke thrombi and NET associated markers were found in stroke patients' blood. However, little is known whether blood derived NET markers reflect the amount of NETs in thrombi. Conclusions from blood derived markers to thrombus composition might open avenues for novel strategies in diagnostic and therapeutic approaches. We prospectively recruited 166 patients with acute ischemic stroke undergoing mechanical thrombectomy between March 2018 and May 2021. Available thrombi (n = 106) were stained for NET markers DNA-histone-1 complexes and myeloperoxidase (MPO). Cell free DNA (cfDNA), deoxyribonuclease (DNase) activity, MPO-histone complexes and a cytokine-panel were measured before thrombectomy and after seven days. Clinical data, including stroke etiology, reperfusion status, SAI and functional outcome after rehabilitation, were collected of all patients. NET markers were present in all thrombi. At onset the median concentration of cfDNA in blood was 0.19 µg/ml increasing to 0.30 µg/ml at 7 days. Median DNase activity at onset was 4.33 pmol/min/ml increasing to 4.96 pmol/min/ml at 7 days. Within thrombi DNA-histone-1 complexes and MPO correlated with each other (ρ = 0.792; p < 0.001). Moreover, our study provides evidence for an association between the amount of NETs and endogenous DNase activity in blood with amounts of NETs in cerebral thrombi. However, these associations need to be confirmed in larger cohorts, to investigate the potential clinical implications for individualized therapeutic and diagnostic approaches in acute ischemic stroke.

Aging is associated with an insufficient early inflammatory response of lung endothelial cells in SARS-CoV-2 infection.

Advanced age is associated with an increased susceptibility to Coronavirus Disease (COVID)-19 and more severe outcomes, although the underlying mechanisms are understudied. The lung endothelium is located next to infected epithelial cells and bystander inflammation may contribute to thromboinflammation and COVID-19-associated coagulopathy. Here, we investigated age-associated SARS-CoV-2 pathogenesis and endothelial inflammatory responses using humanized K18-hACE2 mice. Survival was reduced to 20% in aged mice (85-112 weeks) versus 50% in young mice (12-15 weeks) at 10 days post infection (dpi). Bulk RNA-sequencing of endothelial cells from mock and infected mice at 2dpi of both age groups (aged: 72-85 weeks; young: 15 weeks) showed substantially lower significant differentially regulated genes in infected aged mice than in young mice (712 versus 2294 genes). Viral recognition and anti-viral pathways such as RIG-I-like receptor signaling, NOD-like receptor signaling and interferon signaling were regulated in response to SARS-CoV-2. Young mice showed several fold higher interferon responses (Ifitm3, Ifit1, Isg15, Stat1) and interferon-induced chemokines (Cxcl10 and Cxcl11) than aged mice. Endothelial cells from infected young mice displayed elevated expression of chemokines (Cxcl9, Ccl2) and leukocyte adhesion markers (Icam1) underscoring that inflammation of lung endothelium during infection could facilitate leukocyte adhesion and thromboinflammation. TREM1 and acute phase response signaling were particularly prominent in endothelial cells from infected young mice. Immunohistochemistry was unable to detect viral protein in pulmonary endothelium. In conclusion, our data demonstrate that the early host response of the endothelium to SARS-CoV-2 infection declines with aging, which could be a potential contributor to disease severity.

[Clinical development of anti-FXII therapeutics as a target in thrombo-inflammation]. / Développement clinique des thérapeutiques anti-facteur XII ciblant la thrombo-inflammation.

The history of anticoagulation has evolved considerably, from non-specific drugs to molecules that directly target specific coagulation factors, such as direct oral anticoagulants (DOACs). Since last decade, DOACs are widely used in clinical practice because of their ease to use with favorable pharmacological profile and not requiring monitoring. New therapeutics targeting the contact phase of coagulation are currently under development, and could make it possible to prevent thrombotic risk without altering hemostasis, thereby reducing the risk of bleeding. Factor XII, being at the crossroads between hemostasis and inflammation, appears to be an interesting target that could limit thrombo-inflammation without increasing bleeding risk. The aim of this article is to summarize the main information concerning FXII inhibitors and to review the results of various clinical trials available to date, focusing on applications beyond hemostasis, such as in the management of hereditary angioedema.

Unraveling the Intricate Web: Complement Activation Shapes the Pathogenesis of Sepsis-Induced Coagulopathy.

BACKGROUND: Sepsis-associated coagulopathy specifically refers to widespread systemic coagulation activation accompanied by a high risk of hemorrhage and organ damage, which in severe cases manifests as disseminated intravascular coagulation (DIC), or even develops into multiple organ dysfunction syndrome (MODS). The complement system and the coagulation system as the main columns of innate immunity and hemostasis, respectively, undergo substantial activation after sepsis. SUMMARY: Dysfunction of the complement, coagulation/fibrinolytic cascades caused by sepsis leads to "thromboinflammation," which ultimately amplifies the systemic inflammatory response and accelerates the development of MODS. Recent studies have revealed that massive activation of the complement system exacerbates sepsis-induced coagulation and even results in DIC, which suggests that inhibition of complement activation may have therapeutic potential in the treatment of septic coagulopathy. KEY MESSAGES: Sepsis-associated thrombosis involves the upregulation or activation of procoagulant factors, down-regulation or inactivation of anticoagulant factors, and impairment of the fibrinolytic mechanism. This review aims to summarize the latest literature and analyze the underlying molecular mechanisms of the activation of the complement system on the abnormal coagulation cascades in sepsis.

Direct neuronal protection by the protease-activated receptor PAR4 antagonist ML354 after experimental stroke in mice.

BACKGROUND AND PURPOSE: Thrombo-inflammation is a key feature of stroke pathophysiology and provides multiple candidate drug targets. Thrombin exerts coagulation-independent actions via protease-activated receptors (PAR), of which PAR1 has been implicated in stroke-associated neuroinflammation. The role of PAR4 in this context is less clear. This study examined if the selective PAR4 antagonist ML354 provides neuroprotection in experimental stroke and explored the underlying mechanisms. EXPERIMENTAL APPROACH: Mouse primary cortical neurons were exposed to oxygen-glucose deprivation (OGD) and simulated reperfusion ± ML354. For comparison, functional Ca2+-imaging was performed upon acute stimulation with a PAR4 activating peptide or glutamate. Male mice underwent sham operation or transient middle cerebral artery occlusion (tMCAO), with ML354 or vehicle treatment beginning at recanalization. A subset of mice received a platelet-depleting antibody. Stroke size and functional outcomes were assessed. Abundance of target genes, proteins, and cell markers was determined in cultured cells and tissues by qPCR, immunoblotting, and immunofluorescence. KEY RESULTS: Stroke up-regulated PAR4 expression in cortical neurons in vitro and in vivo. OGD augments spontaneous and PAR4-mediated neuronal activity; ML354 suppresses OGD-induced neuronal excitotoxicity and apoptosis. ML354 applied in vivo after tMCAO reduced infarct size, apoptotic markers, macrophage accumulation, and interleukin-1ß expression. Platelet depletion did not affect infarct size in mice with tMCAO ± ML354. CONCLUSIONS AND IMPLICATIONS: Selective PAR4 inhibition during reperfusion improves infarct size and neurological function after experimental stroke by blunting neuronal excitability, apoptosis, and local inflammation. PAR4 antagonists may provide additional neuroprotective benefits in patients with acute stroke beyond their canonical antiplatelet action.

Dissecting thrombus-directed chemotaxis and random movement in neutrophil near-thrombus motion in flow chambers.

BACKGROUND: Thromboinflammation is caused by mutual activation of platelets and neutrophils. The site of thromboinflammation is determined by chemoattracting agents release by endothelium, immune cells, and platelets. Impaired neutrophil chemotaxis contributes to the pathogenesis of Shwachman-Diamond syndrome (SDS). In this hereditary disorder, neutrophils are known to have aberrant chemoattractant-induced F-actin properties. Here, we aim to determine whether neutrophil chemotaxis could be analyzed using our previously developed ex vivo assay of the neutrophils crawling among the growing thrombi. METHODS: Adult and pediatric healthy donors, alongside with pediatric patients with SDS, were recruited for the study. Thrombus formation and granulocyte movement in hirudinated whole blood were visualized by fluorescent microscopy in fibrillar collagen-coated parallel-plate flow chambers. Alternatively, fibrinogen, fibronectin, vWF, or single tumor cells immobilized on coverslips were used. A computational model of chemokine distribution in flow chamber with a virtual neutrophil moving in it was used to analyze the observed data. RESULTS: The movement of healthy donor neutrophils predominantly occurred in the direction and vicinity of thrombi grown on collagen or around tumor cells. For SDS patients or on coatings other than collagen, the movement was characterized by randomness and significantly reduced velocities. Increase in wall shear rates to 300-500 1/s led to an increase in the proportion of rolling neutrophils. A stochastic algorithm simulating leucocyte chemotaxis movement in the calculated chemoattractant field could reproduce the experimental trajectories of moving neutrophils for 72% of cells. CONCLUSIONS: In samples from healthy donors, but not SDS patients, neutrophils move in the direction of large, chemoattractant-releasing platelet thrombi growing on collagen.

Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling.

BACKGROUND: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities in patients, suggests that environmental, genetic, or biological factors act as disease modifiers. Still, the underlying mechanisms are not entirely understood. Here, we report that mild hypoxia accelerates CCM disease by promoting angiogenesis, neuroinflammation, and vascular thrombosis in the brains of CCM mouse models. METHODS: We used genetic studies, RNA sequencing, spatial transcriptome, micro-computed tomography, fluorescence-activated cell sorting, multiplex immunofluorescence, coculture studies, and imaging techniques to reveal that sustained mild hypoxia via the CX3CR1-CX3CL1 (CX3C motif chemokine receptor 1/chemokine [CX3C motif] ligand 1) signaling pathway influences cell-specific neuroinflammatory interactions, contributing to heterogeneity in CCM severity. RESULTS: Histological and expression profiles of CCM neurovascular lesions (Slco1c1-iCreERT2;Pdcd10fl/fl; Pdcd10BECKO) in male and female mice found that sustained mild hypoxia (12% O2, 7 days) accelerates CCM disease. Our findings indicate that a small reduction in oxygen levels can significantly increase angiogenesis, neuroinflammation, and thrombosis in CCM disease by enhancing the interactions between endothelium, astrocytes, and immune cells. Our study indicates that the interactions between CX3CR1 and CX3CL1 are crucial in the maturation of CCM lesions and propensity to CCM immunothrombosis. In particular, this pathway regulates the recruitment and activation of microglia and other immune cells in CCM lesions, which leads to lesion growth and thrombosis. We found that human CX3CR1 variants are linked to lower lesion burden in familial CCMs, proving it is a genetic modifier in human disease and a potential marker for aggressiveness. Moreover, monoclonal blocking antibody against CX3CL1 or reducing 1 copy of the Cx3cr1 gene significantly reduces hypoxia-induced CCM immunothrombosis. CONCLUSIONS: Our study reveals that interactions between CX3CR1 and CX3CL1 can modify CCM neuropathology when lesions are accelerated by environmental hypoxia. Moreover, a hypoxic environment or hypoxia signaling caused by CCM disease influences the balance between neuroinflammation and neuroprotection mediated by CX3CR1-CX3CL1 signaling. These results establish CX3CR1 as a genetic marker for patient stratification and a potential predictor of CCM aggressiveness.

Characterization of Biomarkers of Thrombo-Inflammation in Patients with First-Diagnosed Atrial Fibrillation.

Patients with first-diagnosed atrial fibrillation (FDAF) exhibit major adverse cardiovascular events (MACEs) during follow-up. Preclinical models have demonstrated that thrombo-inflammation mediates adverse cardiac remodeling and atherothrombotic events. We have hypothesized that thrombin activity (FIIa) links coagulation with inflammation and cardiac fibrosis/dysfunction. Surrogate markers of the thrombo-inflammatory response in plasma have not been characterized in FDAF. In this prospective longitudinal study, patients presenting with FDAF (n = 80), and 20 matched controls, were included. FIIa generation and activity in plasma were increased in the patients with early AF compared to the patients with chronic cardiovascular disease without AF (controls; p < 0.0001). This increase was accompanied by elevated biomarkers (ELISA) of platelet and endothelial activation in plasma. Pro-inflammatory peripheral immune cells (TNF-α+ or IL-6+) that expressed FIIa-activated protease-activated receptor 1 (PAR1) (flow cytometry) circulated more frequently in patients with FDAF compared to the controls (p < 0.0001). FIIa activity correlated with cardiac fibrosis (collagen turnover) and cardiac dysfunction (NT-pro ANP/NT-pro BNP) surrogate markers. FIIa activity in plasma was higher in patients with FDAF who experienced MACE. Signaling via FIIa might be a presumed link between the coagulation system (tissue factor-FXa/FIIa-PAR1 axis), inflammation, and pro-fibrotic pathways (thrombo-inflammation) in FDAF.

COVID-19 associated pulmonary embolism: clinical, biochemical and CT imaging findings.

INTRODUCTION: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection represented a disruptive pathology that emerged in late 2019 with profound implications ranging from individual health to health systems and world economy. Our study aimed to evaluate clinical, biochemical and computerized tomography (CT) parameters values in determining the severity of pulmonary embolism (PE) associated with COVID-19. METHODS: We performed an observational cohort study evaluating demographic, clinical, biochemical, coagulation markers, as well as CT imaging parameters. RESULTS: In our study on 186 patients with COVID-19, we found that 31 patients (16,66%) had pulmonary embolism. Significant correlations for the patients with PE were detected in C-reactive protein, lactate dehydrogenase, serum ferritin, IL-6, serum myoglobin, NT-proBNP, D-dimers, serum proteins, transaminases as well as white cell blood counts. Patients with pulmonary embolism had a more severe lung involvement, with thrombi distribution mainly involving the lower lobes. CONCLUSION: Early identification of PE is an important step for timely and efficient treatment in the intensive care management of COVID-19 patients. Our study showed that high plasmatic values of lactate dehydrogenase, ferritin, IL-6, white blood cells and D-dimers and low proteins serum levels are strongly linked with COVID-19-associated pulmonary embolism.

Biomarkers Profile in Provoked Versus Unprovoked Deep Venous Thrombosis.

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), represents a substantial healthcare challenge. Provoked and unprovoked DVT cases carry distinct risks and treatment considerations. Recognizing the limitations of this classification, molecular markers may enhance diagnostic precision and guide anticoagulation therapy duration relying on patient history and risk factors. This preliminary, open-label, prospective cohort study was conducted including 15 patients (10 provoked DVT and 5 unprovoked DVT) and a control group of healthy plasmatic subjects. Plasma levels of 9 biomarkers were measured at diagnosis (baseline, day 0, and D0) and after 30 days (day 30-D30). Patient demographics, clinical data, and biomarker concentrations were analyzed. Serum concentrations of D-dimer, von Willebrand factor, C-reactive protein, and Anti-Xa were elevated in DVT groups at D0 compared to controls. No significant differences were observed between the provoked and unprovoked groups on the day of diagnosis and 30 days later. Over 30 days, the provoked group exhibited significant biomarker changes related to temporal assessment. No significant differences were noted in the biomarker profile between provoked and unprovoked DVT groups. This study is indicative of the concept of individualized thrombosis assessment and subsequent treatment for VTE. Larger cohorts are warranted to validate these findings and further define the most appropriate use of the molecular markers.

NETworking for Health and in Disease: Neutrophil Extracellular Traps in Pediatric Surgical Care.

This comprehensive review examines the role of Neutrophil Extracellular Traps (NETs) in pediatric surgery. Focusing on NET formation, functions, and implications, this study highlights their dual impact in infection control and contribution to tissue damage after surgery. It covers the role of NET formation in a range of pediatric conditions including immunothrombosis, formation of peritoneal adhesions, appendicitis, burns, gallstones, tumors, and necrotizing enterocolitis (NEC). The results underscore the significance of NETs in fighting infections and their association with complications like sepsis and delayed wound healing. The breakdown products of NETs as a diagnostic tool of the clinical course of acute appendicitis will also be discussed. Understanding NET formation in the pathophysiology can potentially help to find new therapeutic approaches such as the application of DNase and elastase inhibitors to change the clinical course of various diseases in pediatric surgery such as improvement of wound healing, adhesion formation, NEC, and many more.

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.

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.