Immune damage in Long Covid.

Links between the complement and coagulation systems could lead to Long Covid therapies.

A study of fibrinolytic system components in donor groups depending on various titers of circulating anti-SARS-CoV-2 IgG in the bloodstream.

The fibrinolytic system plays an important role in controlling blood coagulation at each stage, from thrombin generation to fibrin clot cleavage. Currently, long-term multiorgan dysfunction post-coronavirus disease 2019 (COVID-19) may include coagulation disorders. Little information is available about the potential causes of post-COVID-19 coagulopathy, but one of them may be subpopulation IgG produced by the immune system against SARS-CoV-2. This article describes the changes in the main parameters of the fibrinolytic system in donors with various titers of anti-SARS-CoV-2 IgG, which is part of a complex study of the hemostasis system in these donor groups. We determined the most significant parameters of the fibrinolytic system, such as potential activity and amount of plasminogen and tissue plasminogen activator (tPA), amount of plasminogen activator inhibitor-1 (PAI-1), inhibitory potentials of α-2-antiplasmin, α-1-antitrypsin, α-2-macroglobulin in the blood plasma of donor groups. The obtained results represent the maximum and minimum values of measurement parameters among donor groups with titers of anti-SARS-CoV-2 IgG at least 10 ±â€Š3 Index (S/C), and their statistical differences from the reference point [donor group with titer of anti-SARS-CoV-2 IgG 0 Index (S/C)]. We established the changes in fibrinolytic parameters depending on the titers of anti-SARS-CoV-2 IgG. One conclusion can be drawn from this: anti-SARS-CoV-2 IgG population may influence coagulation in the post-COVID-19 period. Further research in-vitro and in-vivo experimental models using selected and purified IgG may confirm our previous findings.

Why Does the Severity of COVID-19 Differ With Age?: Understanding the Mechanisms Underlying the Age Gradient in Outcome Following SARS-CoV-2 Infection.

Although there are many hypotheses for the age-related difference in the severity of COVID-19, differences in innate, adaptive and heterologous immunity, together with differences in endothelial and clotting function, are the most likely mechanisms underlying the marked age gradient. Children have a faster and stronger innate immune response to SARS-CoV-2, especially in the nasal mucosa, which rapidly controls the virus. In contrast, adults can have an overactive, dysregulated and less effective innate response that leads to uncontrolled pro-inflammatory cytokine production and tissue injury. More recent exposure to other viruses and routine vaccines in children might be associated with protective cross-reactive antibodies and T cells against SARS-CoV-2. There is less evidence to support other mechanisms that have been proposed to explain the age-related difference in outcome following SARS-CoV-2 infection, including pre-existing immunity from exposure to common circulating coronaviruses, differences in the distribution and expression of the entry receptors ACE2 and TMPRSS2, and difference in viral load.

Interplay between coagulation and inflammation in cancer: Limitations and therapeutic opportunities.

Advances in understanding the molecular mechanisms of tumor progression have achieved impressive progress in the treatment of cancer and so-called immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Indeed, antibody-based drugs blocking immune escape of tumor cells by modulation of T cell responses are increasingly utilized for a wide range of tumor entities. Nonetheless, response rates remain limited, and the development of secondary resistance is a common problem. In addition, by increasing the immune response a variety of severe side effects are provoked. Next to autoimmune responses, activation of the complement system and skin toxicity, an increased incidence for thrombotic complications has been observed associated with an increased mortality rate. Based on this, it can be postulated that the interplay of coagulation with inflammation in the tumor microenvironment is relevant for each step in the tumor life cycle. This review focuses on the coagulation as central player fostering mechanisms associated with tumor progression. Thus, a better understanding of the molecular pathways involved in the complex interaction of circulating tumor cells, the plasmatic coagulation and immune cells may help to improve therapeutic concepts reducing mortality and morbidity associated with cancer.

Roles of the tissue-type plasminogen activator in immune response.

The COVID-19 pandemic has once again brought to the forefront the existence of a tight link between the coagulation/fibrinolytic system and the immunologic processes. Tissue-type plasminogen activator (tPA) is a serine protease with a key role in fibrinolysis by converting plasminogen into plasmin that can finally degrade fibrin clots. tPA is released in the blood by endothelial cells and hepatocytes but is also produced by various types of immune cells including T cells and monocytes. Beyond its role on hemostasis, tPA is also a potent modulator of inflammation and is involved in the regulation of several inflammatory diseases. Here, after a brief description of tPA structure, we review its new functions in adaptive immunity focusing on T cells and antigen presenting cells. We intend to synthesize the recent knowledge on proteolysis- and receptor-mediated effects of tPA on immune response in physiological and pathological context.

Haemocyte-mediated immunity in insects: Cells, processes and associated components in the fight against pathogens and parasites.

The host defence of insects includes a combination of cellular and humoral responses. The cellular arm of the insect innate immune system includes mechanisms that are directly mediated by haemocytes (e.g., phagocytosis, nodulation and encapsulation). In addition, melanization accompanying coagulation, clot formation and wound healing, nodulation and encapsulation processes leads to the formation of cytotoxic redox-cycling melanin precursors and reactive oxygen and nitrogen species. However, demarcation between cellular and humoral immune reactions as two distinct categories is not straightforward. This is because many humoral factors affect haemocyte functions and haemocytes themselves are an important source of many humoral molecules. There is also a considerable overlap between cellular and humoral immune functions that span from recognition of foreign intruders to clot formation. Here, we review these immune reactions starting with the cellular mechanisms that limit haemolymph loss and participate in wound healing and clot formation and advancing to cellular functions that are critical in restricting pathogen movement and replication. This information is important because it highlights that insect cellular immunity is controlled by a multilayered system, different components of which are activated by different pathogens or during the different stages of the infection.

Inflammasome-Dependent Coagulation Activation in Sepsis.

Sepsis is a potentially life-threatening, pathological condition caused by a dysregulated host response to infection. Pathologically, systemic inflammation can initiate coagulation activation, leading to organ dysfunction, and ultimately to multiple organ failure and septic death. The inflammasomes are cytosolic multiprotein signaling complexes that control the host response to diverse pathogen-associated molecular patterns (PAMPs) from microorganisms as well as damage-associated molecular patterns (DAMPs) from dead or dying host cells. Recent studies highlight that the activation of canonical and non-canonical inflammasomes not only mediate the maturation and secretion of interleukin-1 (IL1) family cytokines, but also trigger the release of coagulation factor III, tissue factor (F3, best known as TF) in activated macrophages and monocytes. These emerging functions of inflammasomes in immunocoagulation are further positively regulated by stimulator of interferon response cGAMP interactor 1 (STING1, also known as STING or TMEM173, a hub of the innate immune signaling network) and high mobility group box 1 (HMGB1, a nuclear DAMP). This mini-review will discuss the regulation and function of inflammasome-dependent coagulation activation in sepsis.

Crosstalk between coagulation and complement activation promotes cardiac dysfunction in arrhythmogenic right ventricular cardiomyopathy.

Aims: We previously found that complement components are upregulated in the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and inhibiting the complement receptor C5aR reduces disease severity in desmin knockout (Des-/- ) mice, a model for ARVC. Here, we examined the mechanism underlying complement activation in ARVC, revealing a potential new therapeutic target. Methods: First, immunostaining, RT-PCR and western blot were used to detect the expression levels of complement and coagulation factors. Second, we knocked out the central complement component C3 in Des-/- mice (ARVC model) by crossing Des-/- mice with C3-/- mice to explore whether complement system activation occurs independently of the conventional pathway. Then, we evaluated whether a targeted intervention to coagulation system is effective to reduce myocardium injury. Finally, the plasma sC5b9 level was assessed to investigate the role in predicting adverse cardiac events in the ARVC cohort. Results: The complement system is activated in the myocardium in ARVC. Autoantibodies against myocardial proteins provided a possible mechanism underlying. Moreover, we found increased levels of myocardial C5 and the serum C5a in Des-/-C3-/- mice compared to wild-type mice, indicating that C5 is activated independently from the conventional pathway, presumably via the coagulation system. Crosstalk between the complement and coagulation systems exacerbated the myocardial injury in ARVC mice, and this injury was reduced by using the thrombin inhibitor lepirudin. In addition, we found significantly elevated plasma levels of sC5b9 and thrombin in patients, and this increase was correlated with all-cause mortality. Conclusions: These results suggest that crosstalk between the coagulation and complement systems plays a pathogenic role in cardiac dysfunction in ARVC. Thus, understanding this crosstalk may have important clinical implications with respect to diagnosing and treating ARVC.

Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and is associated with high morbidity and mortality. Circulating histones (CHs), a group of damage-associated molecular pattern molecules mainly derived from neutrophil extracellular traps, play a crucial role in sepsis by mediating inflammation response, organ injury and death through Toll-like receptors or inflammasome pathways. Herein, we first elucidate the molecular mechanisms of histone-induced inflammation amplification, endothelium injury and cascade coagulation activation, and discuss the close correlation between elevated level of CHs and disease severity as well as mortality in patients with sepsis. Furthermore, current state-of-the-art on anti-histone therapy with antibodies, histone-binding proteins (namely recombinant thrombomodulin and activated protein C), and heparin is summarized to propose promising approaches for sepsis treatment.

Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19.

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.

Platelets: Underestimated Regulators of Autoinflammation in Psoriasis.

Platelets have long been known as mediators of hemostasis and, more recently, as mediators of thromboinflammation, although their physiopathological role has mostly been investigated in the context of disease of internal organs, such as liver and kidney, or systemic disorders. Of late, exciting recent data suggest that platelets may also play a role in inflammation at distal sites such as the skin: recent studies show that platelets, by engaging polymorphonuclear neutrophils (PMNs), contribute to local inflammation in the frequent skin disorder, psoriasis. In an experimental model, systemic depletion of platelets drastically attenuated skin inflammation by preventing PMN infiltration of the skin. A broader role of platelets in different types of skin inflammation is therefore likely, and in this paper, we specifically review recent advances in psoriasis. Special emphasis is given to the crosstalk with systemic platelet effects, which may be of interest in psoriasis-related cardiovascular comorbidities. Furthermore, we discuss the potential for platelet-centered interventions in the therapy for psoriasis.

Epidemiological and Clinical Characteristics of 217 Cases of COVID-19 in Jiangsu Province, China.

BACKGROUND COVID-19 has become a worldwide epidemic disease and is a public health crisis. We aim to provide evidence for clinical diagnosis and assessment of severity by analyzing patients' clinical data and early laboratory results and exploring the correlation between laboratory results and clinical classification. MATERIAL AND METHODS We enrolled 283 cases of suspected and diagnosed COVID-19 from 16 hospitals in Jiangsu Province from January to April 2020. The routine laboratory blood examinations, T lymphocyte subsets, and biochemical and coagulation function among different populations were contrasted by t test and chi-square (χ²) test. RESULTS Cough, fever, and dyspnea could be helpful to diagnose COVID-19 infection (P<0.05). Patients who were older or had comorbidities tended to become severe and critical cases. Among all the patients, the most obvious abnormal laboratory results were higher neutrophil count, CRP, total bilirubin, BUN, CRE, APTT, PT, and D-dimer, and lower blood platelet and lymphocyte count. CD3⁺ T cell, CD4⁺ T cell, and CD8⁺ T cell counts gradually decreased with exacerbation of the disease (P<0.05). CONCLUSIONS Cough and fever were the most common symptom. Patients with comorbidities were in more serious condition. The detection of inflammatory indexes, coagulation function, lymphocyte subsets, and renal function can help diagnose and assess the severity of COVID-19.

Immune storm and coagulation storm in the pathogenesis of amniotic fluid embolism.

Amniotic fluid embolism (AFE) is a rare but severe obstetric complication with high mortality. To date, the pathogenesis of AFE has evolved from a simple theory of mechanical obstruction to an immunological theory. However, it is not yet fully understood. Here we elaborate on the immune storm and coagulation storm induced by the amniotic fluid entering the maternal circulation. These two storms contribute to a better understanding of the pathogenesis of typical and atypical AFE. Our theory needs to be confirmed by further clinical studies and basic research.

Lipid presentation by the protein C receptor links coagulation with autoimmunity.

Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.

Thrombotic Complications in Patients with COVID-19: Pathophysiological Mechanisms, Diagnosis, and Treatment.

INTRODUCTION: Emerging evidence points to an association between severe clinical presentation of COVID-19 and increased risk of thromboembolism. One-third of patients hospitalized due to severe COVID-19 develops macrovascular thrombotic complications, including venous thromboembolism, myocardial injury/infarction and stroke. Concurrently, the autopsy series indicate multiorgan damage pattern consistent with microvascular injury. PROPHYLAXIS, DIAGNOSIS AND TREATMENT: COVID-19 associated coagulopathy has distinct features, including markedly elevated D-dimers concentration with nearly normal activated partial thromboplastin time, prothrombin time and platelet count. The diagnosis may be challenging due to overlapping features between pulmonary embolism and severe COVID-19 disease, such as dyspnoea, high concentration of D-dimers, right ventricle with dysfunction or enlargement, and acute respiratory distress syndrome. Both macro- and microvascular complications are associated with an increased risk of in-hospital mortality. Therefore, early recognition of coagulation abnormalities among hospitalized COVID-19 patients are critical measures to identify patients with poor prognosis, guide antithrombotic prophylaxis or treatment, and improve patients' clinical outcomes. RECOMMENDATIONS FOR CLINICIANS: Most of the guidelines and consensus documents published on behalf of professional societies focused on thrombosis and hemostasis advocate the use of anticoagulants in all patients hospitalized with COVID-19, as well as 2-6 weeks post hospital discharge in the absence of contraindications. However, since there is no guidance for deciding the intensity and duration of anticoagulation, the decision-making process should be made in individual-case basis. CONCLUSIONS: Here, we review the mechanistic relationships between inflammation and thrombosis, discuss the macrovascular and microvascular complications and summarize the prophylaxis, diagnosis and treatment of thromboembolism in patients affected by COVID-19.

Anti-coagulation for COVID-19 treatment: both anti-thrombotic and anti-inflammatory?

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been linked to a higher risk of mortality compared to influenza, which is mainly due to severe secondary diseases, such as acute respiratory distress syndrome (ARDS). In turn, ARDS is characterized by an acute inflammation and an excessive activity of the coagulation cascade, rising the vulnerability for venous thromboembolic events. In order to investigate the relation of inflammation and the influence of coagulation factors on their release, human peripheral mononuclear blood cells (PBMCs) were treated with autologous serum, heparinized plasma and different doses of fibrin. Thereafter, the concentration of pro-inflammatory cytokines and chemokines in the secretome of PBMCs was measured by enzyme-linked immunosorbent assay. Our analyses revealed autologous serum to significantly increase the secretion of cytokines and chemokines after 24 h of incubation time. Furthermore, the addition of fibrin markedly increased the secretion of cytokines and chemokines by PBMCs in a dose-dependent manner. Consequently, in accordance with previous studies, our study outlines that anti-coagulation may constitute a promising tool for the treatment of SARS-CoV-2, reducing both, the cytokine storm, as well as the risk for thrombotic complications.