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1.
Biochem J ; 479(6): 731-750, 2022 03 31.
Article in English | MEDLINE | ID: covidwho-1764226

ABSTRACT

The interplay between innate immunity and coagulation after infection or injury, termed immunothrombosis, is the primary cause of disseminated intravascular coagulation (DIC), a condition that occurs in sepsis. Thrombosis associated with DIC is the leading cause of death worldwide. Interest in immunothrombosis has grown because of COVID-19, the respiratory disease caused by SARS-CoV-2, which has been termed a syndrome of dysregulated immunothrombosis. As the relatively new field of immunothrombosis expands at a rapid pace, the focus of academic and pharmacological research has shifted from generating treatments targeted at the traditional 'waterfall' model of coagulation to therapies better directed towards immune components that drive coagulopathies. Immunothrombosis can be initiated in macrophages by cleavage of the non-canonical inflammasome which contains caspase-11. This leads to release of tissue factor (TF), a membrane glycoprotein receptor that forms a high-affinity complex with coagulation factor VII/VIIa to proteolytically activate factors IX to IXa and X to Xa, generating thrombin and leading to fibrin formation and platelet activation. The mechanism involves the post-translational activation of TF, termed decryption, and release of decrypted TF via caspase-11-mediated pyroptosis. During aberrant immunothrombosis, decryption of TF leads to thromboinflammation, sepsis, and DIC. Therefore, developing therapies to target pyroptosis have emerged as an attractive concept to counteract dysregulated immunothrombosis. In this review, we detail the three mechanisms of TF control: concurrent induction of TF, caspase-11, and NLRP3 (signal 1); TF decryption, which increases its procoagulant activity (signal 2); and accelerated release of TF into the intravascular space via pyroptosis (signal 3). In this way, decryption of TF is analogous to the two signals of NLRP3 inflammasome activation, whereby induction of pro-IL-1ß and NLRP3 (signal 1) is followed by activation of NLRP3 (signal 2). We describe in detail TF decryption, which involves pathogen-induced alterations in the composition of the plasma membrane and modification of key cysteines on TF, particularly at the location of the critical, allosterically regulated disulfide bond of TF in its 219-residue extracellular domain. In addition, we speculate towards the importance of identifying new therapeutics to block immunothrombotic triggering of TF, which can involve inhibition of pyroptosis to limit TF release, or the direct targeting of TF decryption using cysteine-modifying therapeutics.


Subject(s)
COVID-19 , Thrombosis , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , COVID-19/drug therapy , Humans , Inflammation/complications , Pyroptosis , SARS-CoV-2 , Thromboplastin/metabolism
2.
Int J Mol Sci ; 23(3)2022 Feb 05.
Article in English | MEDLINE | ID: covidwho-1674671

ABSTRACT

Inflammation and thrombosis are closely intertwined in numerous disorders, including ischemic events and sepsis, as well as coronavirus disease 2019 (COVID-19). Thrombotic complications are markers of disease severity in both sepsis and COVID-19 and are associated with multiorgan failure and increased mortality. Immunothrombosis is driven by the complement/tissue factor/neutrophil axis, as well as by activated platelets, which can trigger the release of neutrophil extracellular traps (NETs) and release further effectors of immunothrombosis, including platelet factor 4 (PF4/CXCL4) and high-mobility box 1 protein (HMGB1). Many of the central effectors of deregulated immunothrombosis, including activated platelets and platelet-derived extracellular vesicles (pEVs) expressing PF4, soluble PF4, HMGB1, histones, as well as histone-decorated NETs, are positively charged and thus bind to heparin. Here, we provide evidence that adsorbents functionalized with endpoint-attached heparin efficiently deplete activated platelets, pEVs, PF4, HMGB1 and histones/nucleosomes. We propose that this elimination of central effectors of immunothrombosis, rather than direct binding of pathogens, could be of clinical relevance for mitigating thrombotic complications in sepsis or COVID-19 using heparin-functionalized adsorbents.


Subject(s)
Blood Proteins/isolation & purification , Heparin/pharmacology , /drug therapy , Blood Coagulation/physiology , Blood Platelets/metabolism , Blood Proteins/metabolism , COVID-19/metabolism , Extracellular Traps/immunology , Extracellular Traps/metabolism , HMGB Proteins/isolation & purification , HMGB Proteins/metabolism , HMGB1 Protein/isolation & purification , HMGB1 Protein/metabolism , Heparin/metabolism , Histones/isolation & purification , Histones/metabolism , Humans , Neutrophils/metabolism , Platelet Activation/immunology , Platelet Factor 4/isolation & purification , Platelet Factor 4/metabolism , SARS-CoV-2/pathogenicity , Sepsis/blood , Sepsis/metabolism , Thromboplastin/metabolism , Thrombosis/drug therapy
3.
Biomolecules ; 11(11)2021 10 20.
Article in English | MEDLINE | ID: covidwho-1480577

ABSTRACT

SARS-CoV-2 contains certain molecules that are related to the presence of immunothrombosis. Here, we review the pathogen and damage-associated molecular patterns. We also study the imbalance of different molecules participating in immunothrombosis, such as tissue factor, factors of the contact system, histones, and the role of cells, such as endothelial cells, platelets, and neutrophil extracellular traps. Regarding the pathogenetic mechanism, we discuss clinical trials, case-control studies, comparative and translational studies, and observational studies of regulatory or inhibitory molecules, more specifically, extracellular DNA and RNA, histones, sensors for RNA and DNA, as well as heparin and heparinoids. Overall, it appears that a network of cells and molecules identified in this axis is simultaneously but differentially affecting patients at different stages of COVID-19, and this is characterized by endothelial damage, microthrombosis, and inflammation.


Subject(s)
Alarmins , COVID-19/virology , SARS-CoV-2 , Thrombosis/virology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Blood Coagulation , Blood Platelets/virology , COVID-19/complications , DNA/metabolism , Extracellular Traps , Heparin/metabolism , Histones/metabolism , Humans , Mice , Neuropilin-1/metabolism , RNA/metabolism , Signal Transduction , Thrombin/metabolism , Thromboplastin/metabolism , Thrombosis/complications
4.
J Clin Invest ; 130(11): 6151-6157, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-1435146

ABSTRACT

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.


Subject(s)
Betacoronavirus , Complement Membrane Attack Complex , Coronavirus Infections , Extracellular Traps , Neutrophils , Pandemics , Pneumonia, Viral , Thromboplastin , Thrombosis , Aged , Betacoronavirus/immunology , Betacoronavirus/metabolism , COVID-19 , Complement Activation/drug effects , Complement Membrane Attack Complex/immunology , Complement Membrane Attack Complex/metabolism , Coronavirus Infections/blood , Coronavirus Infections/immunology , Extracellular Traps/immunology , Extracellular Traps/metabolism , Female , Humans , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Peptides, Cyclic/pharmacology , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Receptor, Anaphylatoxin C5a/blood , Receptor, Anaphylatoxin C5a/immunology , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Thrombin/immunology , Thrombin/metabolism , Thromboplastin/immunology , Thromboplastin/metabolism , Thrombosis/blood , Thrombosis/immunology , Thrombosis/virology
6.
Eur Rev Med Pharmacol Sci ; 25(10): 3886-3897, 2021 May.
Article in English | MEDLINE | ID: covidwho-1264765

ABSTRACT

OBJECTIVE: Platelets, blood coagulation along with fibrinolysis are greatly involved in the pathophysiology of infectious diseases induced by bacteria, parasites and virus. This phenomenon is not surprising since both the innate immunity and the hemostatic systems are two ancestral mechanisms which closely cooperate favoring host's defense against foreign invaders. However, the excessive response of these systems may be dangerous for the host itself. MATERIALS AND METHODS: We searched and retrieved the articles, using the following electronic database: MedLine and Embase. We limited our search to articles published in English, but no restrictions in terms of article type, publication year, and geography were adopted. RESULTS: The hemostatic phenotype of the infectious diseases is variable depending on the points of attack of the different involved pathogens. Infectious diseases which show a prothrombotic phenotype are bacterial sepsis, SARS-CoV-2 and malaria. However, among the bacterial sepsis, Yersinia Pestis is characterized by a profibrinolytic behavior. On the contrary, the hemorrhagic fevers, due to Dengue and Ebola virus, mainly exploit the activation of fibrinolysis secondary to a huge endothelial damage which can release a large amount of t-PA in the early phase of the diseases. CONCLUSIONS: Blood coagulation and fibrinolysis are greatly activated based on the strategy of the different infectious agents which exploit the excess of response of both systems to achieve the greatest possible virulence.


Subject(s)
Blood Coagulation , COVID-19/pathology , Fibrinolysis , COVID-19/complications , COVID-19/virology , Endothelial Cells/cytology , Endothelial Cells/metabolism , Endothelial Cells/virology , Erythrocytes/cytology , Erythrocytes/metabolism , Erythrocytes/parasitology , Humans , Monocytes/cytology , Monocytes/metabolism , Monocytes/virology , SARS-CoV-2/isolation & purification , Thromboplastin/metabolism , Viruses/pathogenicity
7.
J Intern Med ; 290(3): 677-692, 2021 09.
Article in English | MEDLINE | ID: covidwho-1255442

ABSTRACT

BACKGROUND: Prognostic markers for disease severity and identification of therapeutic targets in COVID-19 are urgently needed. We have studied innate and adaptive immunity on protein and transcriptomic level in COVID-19 patients with different disease severity at admission and longitudinally during hospitalization. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected at three time points from 31 patients included in the Norwegian SARS-CoV-2 cohort study and analysed by flow cytometry and RNA sequencing. Patients were grouped as either mild/moderate (n = 14), severe (n = 11) or critical (n = 6) disease in accordance with WHO guidelines and compared with patients with SARS-CoV-2-negative bacterial sepsis (n = 5) and healthy controls (n = 10). RESULTS: COVID-19 severity was characterized by decreased interleukin 7 receptor alpha chain (CD127) expression in naïve CD4 and CD8 T cells. Activation (CD25 and HLA-DR) and exhaustion (PD-1) markers on T cells were increased compared with controls, but comparable between COVID-19 severity groups. Non-classical monocytes and monocytic HLA-DR expression decreased whereas monocytic PD-L1 and CD142 expression increased with COVID-19 severity. RNA sequencing exhibited increased plasma B-cell activity in critical COVID-19 and yet predominantly reduced transcripts related to immune response pathways compared with milder disease. CONCLUSION: Critical COVID-19 seems to be characterized by an immune profile of activated and exhausted T cells and monocytes. This immune phenotype may influence the capacity to mount an efficient T-cell immune response. Plasma B-cell activity and calprotectin were higher in critical COVID-19 while most transcripts related to immune functions were reduced, in particular affecting B cells. The potential of these cells as therapeutic targets in COVID-19 should be further explored.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Leukocytes, Mononuclear/immunology , Transcriptome , Adaptive Immunity , Adult , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Female , HLA-DR Antigens/immunology , Humans , Immunity, Innate , Interleukin-2 Receptor alpha Subunit/immunology , Interleukin-7/immunology , Leukocyte L1 Antigen Complex/blood , Male , Middle Aged , Monocytes/immunology , Phenotype , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes, Regulatory/immunology , Thromboplastin/immunology , Thromboplastin/metabolism
8.
Front Immunol ; 12: 664209, 2021.
Article in English | MEDLINE | ID: covidwho-1247863

ABSTRACT

Rationale: Systemic activation of procoagulant and inflammatory mechanisms has been implicated in the pathogenesis of COVID-19. Knowledge of activation of these host response pathways in the lung compartment of COVID-19 patients is limited. Objectives: To evaluate local and systemic activation of coagulation and interconnected inflammatory responses in critically ill COVID-19 patients with persistent acute respiratory distress syndrome. Methods: Paired bronchoalveolar lavage fluid and plasma samples were obtained from 17 patients with COVID-19 related persistent acute respiratory distress syndrome (mechanical ventilation > 7 days) 1 and 2 weeks after start mechanical ventilation and compared with 8 healthy controls. Thirty-four host response biomarkers stratified into five functional domains (coagulation, complement system, cytokines, chemokines and growth factors) were measured. Measurements and Main Results: In all patients, all functional domains were activated, especially in the bronchoalveolar compartment, with significantly increased levels of D-dimers, thrombin-antithrombin complexes, soluble tissue factor, C1-inhibitor antigen and activity levels, tissue type plasminogen activator, plasminogen activator inhibitor type I, soluble CD40 ligand and soluble P-selectin (coagulation), next to activation of C3bc and C4bc (complement) and multiple interrelated cytokines, chemokines and growth factors. In 10 patients in whom follow-up samples were obtained between 3 and 4 weeks after start mechanical ventilation many bronchoalveolar and plasma host response biomarkers had declined. Conclusions: Critically ill, ventilated patients with COVID-19 show strong responses relating to coagulation, the complement system, cytokines, chemokines and growth factors in the bronchoalveolar compartment. These results suggest a local pulmonary rather than a systemic procoagulant and inflammatory "storm" in severe COVID-19.


Subject(s)
COVID-19/immunology , Critical Illness , Lung/metabolism , Respiratory Distress Syndrome/immunology , SARS-CoV-2/physiology , Thromboplastin/metabolism , Aged , Blood Coagulation , Cohort Studies , Female , Fibrin Fibrinogen Degradation Products/metabolism , Follow-Up Studies , Humans , Immunity, Innate , Lung/pathology , Male , Middle Aged , Respiration, Artificial
9.
EBioMedicine ; 67: 103369, 2021 May.
Article in English | MEDLINE | ID: covidwho-1220821

ABSTRACT

BACKGROUND: Coronavirus-2 (SARS-CoV-2) infection causes an acute respiratory syndrome accompanied by multi-organ damage that implicates a prothrombotic state leading to widespread microvascular clots. The causes of such coagulation abnormalities are unknown. The receptor tissue factor, also known as CD142, is often associated with cell-released extracellular vesicles (EV). In this study, we aimed to characterize surface antigens profile of circulating EV in COVID-19 patients and their potential implication as procoagulant agents. METHODS: We analyzed serum-derived EV from 67 participants who underwent nasopharyngeal swabs molecular test for suspected SARS-CoV-2 infection (34 positives and 33 negatives) and from 16 healthy controls (HC), as referral. A sub-analysis was performed on subjects who developed pneumonia (n = 28). Serum-derived EV were characterized for their surface antigen profile and tested for their procoagulant activity. A validation experiment was performed pre-treating EV with anti-CD142 antibody or with recombinant FVIIa. Serum TNF-α levels were measured by ELISA. FINDINGS: Profiling of EV antigens revealed a surface marker signature that defines circulating EV in COVID-19. A combination of seven surface molecules (CD49e, CD209, CD86, CD133/1, CD69, CD142, and CD20) clustered COVID (+) versus COVID (-) patients and HC. CD142 showed the highest discriminating performance at both multivariate models and ROC curve analysis. Noteworthy, we found that CD142 exposed onto surface of EV was biologically active. CD142 activity was higher in COVID (+) patients and correlated with TNF-α serum levels. INTERPRETATION: In SARS-CoV-2 infection the systemic inflammatory response results in cell-release of substantial amounts of procoagulant EV that may act as clotting initiation agents, contributing to disease severity. FUNDING: Cardiocentro Ticino Institute, Ente ospedaliero Cantonale, Lugano-Switzerland.


Subject(s)
COVID-19/complications , Extracellular Vesicles/immunology , Thromboplastin/metabolism , Thrombosis/blood , Adult , Aged , Aged, 80 and over , Antigens, Surface/analysis , Biomarkers/analysis , COVID-19/blood , COVID-19/immunology , Case-Control Studies , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Nasopharynx/virology , SARS-CoV-2/isolation & purification , Switzerland , Thrombosis/etiology , Thrombosis/immunology , Tumor Necrosis Factor-alpha/blood
10.
Clin Appl Thromb Hemost ; 27: 10760296211003983, 2021.
Article in English | MEDLINE | ID: covidwho-1159169

ABSTRACT

COVID-19 (Coronavirus Disease 2019) is a highly contagious infection and associated with high mortality rates, primarily in elderly; patients with heart failure; high blood pressure; diabetes mellitus; and those who are smokers. These conditions are associated to increase in the level of the pulmonary epithelium expression of angiotensin-converting enzyme 2 (ACE-2), which is a recognized receptor of the S protein of the causative agent SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Severe cases are manifested by parenchymal lung involvement with a significant inflammatory response and the development of microvascular thrombosis. Several factors have been involved in developing this prothrombotic state, including the inflammatory reaction itself with the participation of proinflammatory cytokines, endothelial dysfunction/endotheliitis, the presence of antiphospholipid antibodies, and possibly the tissue factor (TF) overexpression. ARS-Cov-19 ACE-2 down-regulation has been associated with an increase in angiotensin 2 (AT2). The action of proinflammatory cytokines, the increase in AT2 and the presence of antiphospholipid antibodies are known factors for TF activation and overexpression. It is very likely that the overexpression of TF in COVID-19 may be related to the pathogenesis of the disease, hence the importance of knowing the aspects related to this protein and the therapeutic strategies that can be derived. Different therapeutic strategies are being built to curb the expression of TF as a therapeutic target for various prothrombotic events; therefore, analyzing this treatment strategy for COVID-19-associated coagulopathy is rational. Medications such as celecoxib, cyclosporine or colchicine can impact on COVID-19, in addition to its anti-inflammatory effect, through inhibition of TF.


Subject(s)
COVID-19/drug therapy , COVID-19/metabolism , Celecoxib/therapeutic use , Colchicine/therapeutic use , Cyclosporine/therapeutic use , SARS-CoV-2/metabolism , Thromboplastin/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , Cytokines/metabolism , Humans
11.
Infect Genet Evol ; 90: 104751, 2021 06.
Article in English | MEDLINE | ID: covidwho-1062516

ABSTRACT

COVID-19 is the currently evolving viral disease worldwide. It mainly targets the respiratory organs, tissues and causes illness. A plethora of studies has been performing to bring proper treatment and prevent people from the infection. Likewise, susceptibility to some infectious diseases has been associated with blood group phenotypes. The co-relationship of blood group with the occurrence of SARS-CoV-2 infection and death has been examined in numerous studies. This review explained the described studies regarding the correlation of blood group and the other essential factors with COVID-19.


Subject(s)
ABO Blood-Group System/genetics , COVID-19/epidemiology , COVID-19/etiology , Disease Susceptibility , Phenotype , SARS-CoV-2 , ABO Blood-Group System/chemistry , ABO Blood-Group System/immunology , ABO Blood-Group System/metabolism , Coronavirus/classification , Coronavirus/immunology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Structure-Activity Relationship , Thromboplastin/metabolism , von Willebrand Factor/metabolism
12.
Blood Adv ; 5(3): 628-634, 2021 02 09.
Article in English | MEDLINE | ID: covidwho-1058239

ABSTRACT

Coronavirus disease 2019 (COVID-19) has become one of the biggest public health challenges of this century. Severe forms of the disease are associated with a thrombo-inflammatory state that can turn into thrombosis. Because tissue factor (TF) conveyed by extracellular vesicles (EVs) has been implicated in thrombosis, we quantified the EV-TF activity in a cohort of hospitalized patients with COVID-19 (n = 111) and evaluated its link with inflammation, disease severity, and thrombotic events. Patients with severe disease were compared with those who had moderate disease and with patients who had septic shock not related to COVID-19 (n = 218). The EV-TF activity was notably increased in patients with severe COVID-19 compared with that observed in patients with moderate COVID-19 (median, 231 [25th to 75th percentile, 39-761] vs median, 25 [25th to 75th percentile, 12-59] fM; P < .0001); EV-TF was correlated with leukocytes, D-dimer, and inflammation parameters. High EV-TF values were associated with an increased thrombotic risk in multivariable models. Compared with patients who had septic shock, those with COVID-19 were characterized by a distinct coagulopathy profile with significantly higher EV-TF and EV-fibrinolytic activities that were not counterbalanced by an increase in plasminogen activator inhibitor-1 (PAI-1). Thus, this article is the first to describe the dissemination of extreme levels of EV-TF in patients with severe COVID-19, which supports the international recommendations of systematic preventive anticoagulation in hospitalized patients and potential intensification of anticoagulation in patients with severe disease.


Subject(s)
COVID-19/pathology , Extracellular Vesicles/metabolism , Thromboplastin/metabolism , Aged , Aged, 80 and over , Area Under Curve , COVID-19/complications , COVID-19/virology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Logistic Models , Male , Middle Aged , Pilot Projects , Plasminogen Activator Inhibitor 1/metabolism , Proportional Hazards Models , ROC Curve , Risk , SARS-CoV-2/isolation & purification , Severity of Illness Index , Thrombosis/diagnosis , Thrombosis/etiology
13.
Rev Med Virol ; 31(3): e2177, 2021 05.
Article in English | MEDLINE | ID: covidwho-815925

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human respiratory viral infection that has rapidly progressed into a pandemic, causing significant morbidity and mortality. Blood clotting disorders and acute respiratory failure have surfaced as the major complications among the severe cases of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection. Remarkably, more than 70% of deaths related to COVID-19 are attributed to clotting-associated complications such as pulmonary embolism, strokes and multi-organ failure. These vascular complications have been confirmed by autopsy. This study summarizes the current understanding and explains the possible mechanisms of the blood clotting disorder, emphasizing the role of (1) hypoxia-related activation of coagulation factors like tissue factor, a significant player in triggering coagulation cascade, (2) cytokine storm and activation of neutrophils and the release of neutrophil extracellular traps and (3) immobility and ICU related risk factors.


Subject(s)
COVID-19/genetics , Cytokine Release Syndrome/genetics , Disseminated Intravascular Coagulation/genetics , Hypoxia/genetics , Pulmonary Embolism/genetics , Respiratory Insufficiency/genetics , SARS-CoV-2/pathogenicity , COVID-19/blood , COVID-19/pathology , COVID-19/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/pathology , Disseminated Intravascular Coagulation/virology , Extracellular Traps/metabolism , Extracellular Traps/virology , Gene Expression Regulation , Humans , Hypoxia/blood , Hypoxia/pathology , Hypoxia/virology , Hypoxia-Inducible Factor 1, alpha Subunit/blood , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Interleukin-6/blood , Interleukin-6/genetics , Neutrophils/pathology , Neutrophils/virology , Pulmonary Embolism/blood , Pulmonary Embolism/pathology , Pulmonary Embolism/virology , Respiratory Insufficiency/blood , Respiratory Insufficiency/pathology , Respiratory Insufficiency/virology , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Signal Transduction , Thromboplastin/genetics , Thromboplastin/metabolism
14.
Blood ; 136(11): 1330-1341, 2020 09 10.
Article in English | MEDLINE | ID: covidwho-788623

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent pathogen responsible for the coronavirus disease 2019 (COVID-19). Since its emergence, the novel coronavirus has rapidly achieved pandemic proportions causing remarkably increased morbidity and mortality around the world. A hypercoagulability state has been reported as a major pathologic event in COVID-19, and thromboembolic complications listed among life-threatening complications of the disease. Platelets are chief effector cells of hemostasis and pathological thrombosis. However, the participation of platelets in the pathogenesis of COVID-19 remains elusive. This report demonstrates that increased platelet activation and platelet-monocyte aggregate formation are observed in severe COVID-19 patients, but not in patients presenting mild COVID-19 syndrome. In addition, exposure to plasma from severe COVID-19 patients increased the activation of control platelets ex vivo. In our cohort of COVID-19 patients admitted to the intensive care unit, platelet-monocyte interaction was strongly associated with tissue factor (TF) expression by the monocytes. Platelet activation and monocyte TF expression were associated with markers of coagulation exacerbation as fibrinogen and D-dimers, and were increased in patients requiring invasive mechanical ventilation or patients who evolved with in-hospital mortality. Finally, platelets from severe COVID-19 patients were able to induce TF expression ex vivo in monocytes from healthy volunteers, a phenomenon that was inhibited by platelet P-selectin neutralization or integrin αIIb/ß3 blocking with the aggregation inhibitor abciximab. Altogether, these data shed light on new pathological mechanisms involving platelet activation and platelet-dependent monocyte TF expression, which were associated with COVID-19 severity and mortality.


Subject(s)
Betacoronavirus/immunology , Blood Coagulation Disorders/pathology , Blood Platelets/pathology , Coronavirus Infections/complications , Monocytes/pathology , Pneumonia, Viral/complications , Thromboplastin/metabolism , Adult , Biomarkers/metabolism , Blood Coagulation Disorders/immunology , Blood Coagulation Disorders/metabolism , Blood Coagulation Disorders/virology , Blood Platelets/metabolism , Blood Platelets/virology , COVID-19 , Case-Control Studies , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Monocytes/metabolism , Monocytes/virology , P-Selectin/metabolism , Pandemics , Platelet Activation , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Prognosis , Prospective Studies , SARS-CoV-2 , Survival Rate
15.
Clin Radiol ; 75(11): 804-810, 2020 11.
Article in English | MEDLINE | ID: covidwho-693338

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease that has quickly become a worldwide threat to health, mainly causing severe acute respiratory syndrome. In addition to the widely described respiratory syndrome, COVID-19 may cause life-treating complications directly or indirectly related to this infection. Among these, thrombotic complications have emerged as an important issue in patients with COVID-19 infection, particularly in patients in intensive care units. Thrombotic complications due to COVID-19 are likely to occur due to a pro-coagulant pattern encountered in some of these patients or to a progressive endothelial thrombo-inflammatory syndrome causing microvascular disease. In the present authors' experience, from five different hospitals in Italy and the UK, imaging has proved its utility in identifying these COVID-19-related thrombotic complications, with translational clinical relevance. The aim of this review is to illustrate thromboembolic complications directly or indirectly related to COVID-19 disease. Specifically, this review will show complications related to thromboembolism due to a pro-coagulant pattern from those likely related to an endothelial thrombo-inflammatory syndrome.


Subject(s)
Anticoagulants/administration & dosage , Coronavirus Infections/complications , Pneumonia, Viral/complications , Pulmonary Embolism/etiology , Severe Acute Respiratory Syndrome/complications , Thromboembolism/drug therapy , Thromboembolism/etiology , Adult , Aged , Brain Ischemia/diagnostic imaging , Brain Ischemia/etiology , Brain Ischemia/mortality , COVID-19 , Cause of Death , Communicable Diseases, Emerging/epidemiology , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Female , Humans , Italy , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/drug therapy , Pulmonary Embolism/mortality , Radiography, Thoracic/methods , Severe Acute Respiratory Syndrome/diagnosis , Severe Acute Respiratory Syndrome/mortality , Survival Analysis , Thromboembolism/diagnostic imaging , Thromboembolism/mortality , Thromboplastin/metabolism , Tomography, X-Ray Computed/methods
16.
Sci China Life Sci ; 63(11): 1678-1687, 2020 11.
Article in English | MEDLINE | ID: covidwho-610883

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a global pandemic which has caused numerous deaths worldwide. The present study investigated the roles of hypoproteinemia in the clinical outcome and liver dysfunction of COVID-19 patients. In this retrospective study, we extracted data from 2,623 clinically confirmed adult COVID-19 patients (>18 years old) between January 29, 2020 and March 6, 2020 in Tongji Hospital, Wuhan, China. The patients were divided into three groups-non-critically ill, critically ill, and death groups-in accordance with the Chinese Clinical Guideline for COVID-19. Serum albumin, low-density lipoproteins cholesterol (LDL-C), and high-density lipoproteins cholesterol (HDL-C) concentrations and inflammatory cytokines levels were measured and compared among these three groups. The median age of these 2,623 patients was 64 years old (interquartile range (IQR), 52-71). Among the patients enrolled in the study, 2,008 (76.6%) were diagnosed as non-critically ill and 615 (23.4%) were critically ill patients, including 383 (14.6%) critically ill survivors and 232 (8.8%) critically ill deaths in the hospital. Marked hypoalbuminemia occurred in 38.2%, 71.2%, and 82.4% patients in non-critically ill, critically ill, and death groups, respectively, on admission and 45.9%, 77.7%, and 95.6% of these three groups, respectively, during hospitalization. We also discovered that serum low-density lipoprotein (LDL) and HDL levels were significantly lower in critically ill and death groups compared to non-critically ill group. Meanwhile, the patients displayed dramatically elevated levels of serum inflammatory factors, while a markedly prolonged activated partial thromboplastin time (APTT) in critically ill patients reflected coagulopathy. This study suggests that COVID-19-induced cytokine storm causes hepatotoxicity and subsequently critical hypoalbuminemia, which are associated with exacerbation of disease-associated inflammatory responses and progression of the disease and ultimately leads to death for some critically ill patients.


Subject(s)
COVID-19/blood , COVID-19/complications , Coronavirus Infections/blood , Coronavirus Infections/complications , Liver Diseases/etiology , Serum Albumin, Human/metabolism , Aged , COVID-19/mortality , China , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Coronavirus Infections/mortality , Critical Illness , Cytokines/blood , Female , Humans , Liver Diseases/blood , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , SARS-CoV-2 , Thromboplastin/metabolism , Time Factors
17.
Open Heart ; 7(1)2020 06.
Article in English | MEDLINE | ID: covidwho-595177

ABSTRACT

The high rate of thrombotic complications associated with COVID-19 seems likely to reflect viral infection of vascular endothelial cells, which express the ACE2 protein that enables SARS-CoV-2 to invade cells. Various proinflammatory stimuli can promote thrombosis by inducing luminal endothelial expression of tissue factor (TF), which interacts with circulating coagulation factor VII to trigger extrinsic coagulation. The signalling mechanism whereby these stimuli evoke TF expression entails activation of NADPH oxidase, upstream from activation of the NF-kappaB transcription factor that drives the induced transcription of the TF gene. When single-stranded RNA viruses are taken up into cellular endosomes, they stimulate endosomal formation and activation of NADPH oxidase complexes via RNA-responsive toll-like receptor 7. It is therefore proposed that SARS-CoV-2 infection of endothelial cells evokes the expression of TF which is contingent on endosomal NADPH oxidase activation. If this hypothesis is correct, hydroxychloroquine, spirulina (more specifically, its chromophore phycocyanobilin) and high-dose glycine may have practical potential for mitigating the elevated thrombotic risk associated with COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation , Coronavirus Infections/virology , Endosomes/virology , Endothelial Cells/virology , NADPH Oxidases/metabolism , Pneumonia, Viral/virology , Thromboplastin/metabolism , Thrombosis/virology , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Blood Coagulation/drug effects , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Coronavirus Infections/enzymology , Endosomes/drug effects , Endosomes/enzymology , Endothelial Cells/drug effects , Endothelial Cells/enzymology , Enzyme Activation , Fibrinolytic Agents/therapeutic use , Host-Pathogen Interactions , Humans , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pneumonia, Viral/enzymology , SARS-CoV-2 , Signal Transduction , Thrombosis/blood , Thrombosis/enzymology , Thrombosis/prevention & control
18.
J Thromb Thrombolysis ; 50(3): 479-483, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-591509

ABSTRACT

In December 2019, a new and highly contagious infectious disease emerged in Wuhan, China. The etiologic agent was identified as a novel coronavirus, now known as Severe Acute Syndrome Coronavirus-2 (SARS-CoV-2). Recent research has revealed that virus entry takes place upon the union of the virus S surface protein with the type I transmembrane metallo-carboxypeptidase, angiotensin converting enzyme 2 (ACE-2) identified on epithelial cells of the host respiratory tract. Virus triggers the synthesis and release of pro-inflammatory cytokines, including IL-6 and TNF-α and also promotes downregulation of ACE-2, which promotes a concomitant increase in levels of angiotensin II (AT-II). Both TNF-α and AT-II have been implicated in promoting overexpression of tissue factor (TF) in platelets and macrophages. Additionally, the generation of antiphospholipid antibodies associated with COVID-19 may also promote an increase in TF. TF may be a critical mediator associated with the development of thrombotic phenomena in COVID-19, and should be a target for future study.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation , Coronavirus Infections/virology , Pneumonia, Viral/virology , Thromboplastin/metabolism , Thrombosis/virology , Angiotensin-Converting Enzyme 2 , Animals , Blood Coagulation/drug effects , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Cytokines/metabolism , Fibrinolytic Agents/therapeutic use , Host-Pathogen Interactions , Humans , Inflammation Mediators/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/drug therapy
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