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1.
Int J Mol Sci ; 22(24)2021 Dec 20.
Article in English | MEDLINE | ID: covidwho-1580687

ABSTRACT

COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients.


Subject(s)
Blood Platelets/physiology , COVID-19/blood , Thrombosis/pathology , Blood Coagulation , Blood Coagulation Disorders/etiology , Blood Platelets/metabolism , Blood Platelets/virology , COVID-19/metabolism , Cytokine Release Syndrome , Endothelial Cells/pathology , Fibrin Fibrinogen Degradation Products , Hemostasis , Humans , Inflammation , Phenotype , Platelet Activation/physiology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Thrombocytopenia/metabolism , Thrombosis/metabolism , Thrombosis/virology
2.
Clin Appl Thromb Hemost ; 27: 10760296211051764, 2021.
Article in English | MEDLINE | ID: covidwho-1511654

ABSTRACT

The precise mechanisms of pathology in severe COVID-19 remains elusive. Current evidence suggests that inflammatory mediators are responsible for the manifestation of clinical symptoms that precedes a fatal response to infection. This review examines the nature of platelet activating factor and emphasizes the similarities between the physiological effects of platelet activating factor and the clinical complications of severe COVID-19.


Subject(s)
COVID-19/metabolism , Platelet Activating Factor/metabolism , Animals , COVID-19/complications , COVID-19/mortality , COVID-19/pathology , Humans , Inflammation/complications , Inflammation/metabolism , Inflammation/mortality , Inflammation/pathology , Multiple Organ Failure/complications , Multiple Organ Failure/metabolism , Multiple Organ Failure/mortality , Multiple Organ Failure/pathology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/pathology , SARS-CoV-2/physiology , Severity of Illness Index , Thrombosis/complications , Thrombosis/metabolism , Thrombosis/mortality , Thrombosis/pathology
3.
Int J Mol Sci ; 22(20)2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1470887

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has infected >235 million people and killed over 4.8 million individuals worldwide. Although vaccines have been developed for prophylactic management, there are no clinically proven antivirals to treat the viral infection. Continuous efforts are being made all over the world to develop effective drugs but these are being delayed by periodic outbreak of mutated SARS-CoV-2 and a lack of knowledge of molecular mechanisms underlying viral pathogenesis and post-infection complications. In this regard, the involvement of Annexin A2 (AnxA2), a lipid-raft related phospholipid-binding protein, in SARS-CoV-2 attachment, internalization, and replication has been discussed. In addition to the evidence from published literature, we have performed in silico docking of viral spike glycoprotein and RNA-dependent RNA polymerase with human AnxA2 to find the molecular interactions. Overall, this review provides the molecular insights into a potential role of AnxA2 in the SARS-CoV-2 pathogenesis and post-infection complications, especially thrombosis, cytokine storm, and insulin resistance.


Subject(s)
Annexin A2/metabolism , COVID-19/pathology , Annexin A2/chemistry , COVID-19/virology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/pathology , Humans , Molecular Docking Simulation , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/metabolism , Thrombosis/pathology , Virus Internalization
4.
Ophthalmic Res ; 64(5): 785-792, 2021.
Article in English | MEDLINE | ID: covidwho-1443682

ABSTRACT

INTRODUCTION: In December 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic broke out. The virus rapidly spread globally, resulting in a major world public-health crisis. The major disease manifestation occurs in the respiratory tract. However, further studies documented other systemic involvement. This study investigates histopathologic eye changes in postmortem material of coronavirus disease 2019 (COVID-19) patients. METHODS: Sections of formalin-fixed, paraffin-embedded eyes from 5 patients (10 eyes) who died of COVID-19 at the University Hospital in Basel were included. Gross examination and histological evaluation were performed by 3 independent ophthalmopathologists. Immunohistochemical staining was performed using antibodies against fibrin, cleaved caspase 3, and ACE-2. Five enucleated eyes of patients not infected with SARS-CoV-2 served as control group. All cases have been studied for presence of SARS-CoV-2 RNA by means of reverse transcription PCR and RNA in situ hybridization (ISH). The choroidal vessels of one case were analyzed with electron microscope. RESULTS: Ophthalmopathologically, 8 eyes from 4 patients displayed swollen endothelial cells in congested choroidal vessels. No further evidence of specific eye involvement of SARS-CoV-2 was found in any of the patients. In the 8 eyes with evidence of changes due to SARS-CoV-2, immunohistochemical staining demonstrated fibrin microthrombi, apoptotic changes of endothelial and inflammatory cells. In control eyes, ACE-2 was detectable in the conjunctiva, cornea, retina, and choroidea and displayed significantly lower amounts of stained cells as in COVID-19 eyes. SARS-CoV-2 RNA was detectable in both bulbi of 2/5 patients, yet ISH failed to visualize viruses. Electron microscopy showed no significant results due to the artifacts. DISCUSSION/CONCLUSION: As already described in other organs of COVID-19 patients, the ophthalmological examination revealed-microthrombi, that is, hypercoagulation and vasculopathy most probably due to endothelial damage. A possible viral spread to the endothelial cells via ACE-2 provides one pathophysiological explanation. The expression of ACE-2 receptors in the conjunctiva hints toward its susceptibility to infection. To what extend eyes, function is disrupted by SARS-CoV-2 is subject to further studies, especially in the clinic.


Subject(s)
COVID-19/pathology , Choroid Diseases/pathology , Eye Infections, Viral/pathology , RNA, Viral/genetics , Retinal Diseases/pathology , SARS-CoV-2/genetics , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19 Nucleic Acid Testing , Caspase 3/metabolism , Choroid/blood supply , Choroid/pathology , Choroid Diseases/virology , Ciliary Body/blood supply , Ciliary Body/pathology , Conjunctiva/metabolism , Cornea/metabolism , Endothelial Cells/metabolism , Eye Infections, Viral/virology , Female , Fibrin/metabolism , Humans , Immunohistochemistry , In Situ Hybridization , Male , Real-Time Polymerase Chain Reaction , Retinal Diseases/virology , Retinal Vessels/pathology , Thrombosis/metabolism , Thrombosis/pathology
5.
Nature ; 599(7884): 283-289, 2021 11.
Article in English | MEDLINE | ID: covidwho-1404888

ABSTRACT

Derailed cytokine and immune cell networks account for the organ damage and the clinical severity of COVID-19 (refs. 1-4). Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells. Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and is accompanied by a senescence-associated secretory phenotype (SASP), which comprises pro-inflammatory cytokines, extracellular-matrix-active factors and pro-coagulatory mediators5-7. Patients with COVID-19 displayed markers of senescence in their airway mucosa in situ and increased serum levels of SASP factors. In vitro assays demonstrated macrophage activation with SASP-reminiscent secretion, complement lysis and SASP-amplifying secondary senescence of endothelial cells, which mirrored hallmark features of COVID-19 such as macrophage and neutrophil infiltration, endothelial damage and widespread thrombosis in affected lung tissue1,8,9. Moreover, supernatant from VIS cells, including SARS-CoV-2-induced senescence, induced neutrophil extracellular trap formation and activation of platelets and the clotting cascade. Senolytics such as navitoclax and a combination of dasatinib plus quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-infected hamsters and mice. Our findings mark VIS as a pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest that senolytic targeting of virus-infected cells is a treatment option against SARS-CoV-2 and perhaps other viral infections.


Subject(s)
COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Cellular Senescence/drug effects , Molecular Targeted Therapy , SARS-CoV-2/pathogenicity , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Animals , COVID-19/complications , Cell Line , Cricetinae , Dasatinib/pharmacology , Dasatinib/therapeutic use , Disease Models, Animal , Female , Humans , Male , Mice , Quercetin/pharmacology , Quercetin/therapeutic use , SARS-CoV-2/drug effects , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Thrombosis/complications , Thrombosis/immunology , Thrombosis/metabolism
6.
Med Sci Monit ; 27: e930776, 2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1344551

ABSTRACT

During the coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, patients presented with COVID-19 pneumonia of varying severity. The phenomenon of severe hypoxemia without signs of respiratory distress is also known as silent or hidden hypoxemia. Although silent hypoxemia is not unique to pneumonia due to SARS-CoV-2 infection, this phenomenon is now recognized to be associated with severe COVID-19 pneumonia. Proper management of critically ill patients is the key to reducing mortality. Herein, we summarize the possible and rare factors contributing to silent hypoxemia in patients with COVID-19. Microvascular thrombosis causes dead space ventilation in the lungs, and the flow of pulmonary capillaries is reduced, which leads to an imbalance in the V/Q ratio. The dissociation curve of oxyhemoglobin shifts to the left and limits the release of oxygen to the tissue. SARS-CoV-2 interferes with the synthesis of hemoglobin and reduces the ability to carry oxygen. The accumulation of endogenous carbon monoxide and carboxyhemoglobin will reduce the total oxygen carrying capacity and interfere with pulse oxygen saturation readings. There are also some non-specific factors that cause the difference between pulse oximetry and oxygen partial pressure. We propose some potentially more effective clinical alternatives and recommendations for optimizing the clinical management processes of patients with COVID-19. This review aims to describe the prevalence of silent hypoxemia in COVID-19 pneumonia, to provide an update on what is known of the pathophysiology, and to highlight the importance of diagnosing silent hypoxemia in patients with COVID-19 pneumonia.


Subject(s)
COVID-19/metabolism , Hypoxia/virology , Pneumonia, Viral/virology , Asymptomatic Diseases/epidemiology , COVID-19/epidemiology , COVID-19/virology , Humans , Hypoxia/epidemiology , Hypoxia/metabolism , Lung/cytology , Lung/metabolism , Lung/virology , Microvessels/metabolism , Oximetry , Oxygen/metabolism , Pneumonia, Viral/metabolism , Prevalence , SARS-CoV-2/isolation & purification , Thrombosis/metabolism , Thrombosis/virology
7.
Biochem Biophys Res Commun ; 565: 64-71, 2021 08 06.
Article in English | MEDLINE | ID: covidwho-1251023

ABSTRACT

Neutrophil extracellular traps (NETs) are extracellular webs of DNA, histones and granular contents that are released by neutrophils to control infections. However, NETs that is not properly regulated can propagate inflammation and thrombosis. It was recognized that viruses can induce NETs. As a synthetic analog of viral double-stranded (ds) RNA, polyinosinic-polycytidylic acid [poly(I:C)] is known to induce inflammation and thrombosis. However, whether and how poly(I:C) modulates NETs remains unclear. Here, we have demonstrated that poly(I:C) induced extracellular DNA traps in human neutrophils in a dose-dependent manner. Further, poly(I:C) or dsRNA virus elevated the levels of myeloperoxidase-DNA complexes and citrullinated histone H3, which are specific markers of NETs, in both neutrophil supernatants and mouse plasma. Interestingly, a potent peptidylarginine deiminase 4 (PAD4) inhibitor, BB-CL-Amidine (BB-CLA) or PAD4 knockdown effectively prevented poly(I:C)-induced NETs formation and release. In addition, BB-CLA abrogated poly(I:C)-triggered neutrophil activation and infiltration, and vascular permeability in lungs. BB-CLA also attenuated poly(I:C)-induced thrombocytopenia in circulation, fibrin deposition and thrombus formation in tissues. Taken together, these results suggest that viral mimetic poly(I:C) may induce NETs-dependent inflammation and thrombosis through PAD4, and that inhibiting PAD4 may become a good strategy to protect against viral infection-caused inflammation/thrombosis-related pathological conditions of diseases.


Subject(s)
Extracellular Traps/drug effects , Inflammation/metabolism , Neutrophils/drug effects , Poly I-C/pharmacology , Protein-Arginine Deiminase Type 4/metabolism , Thrombosis/metabolism , Amidines/pharmacology , Animals , Cells, Cultured , Chlorocebus aethiops , Humans , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Neutrophil Activation/drug effects , Neutrophils/metabolism , Protein-Arginine Deiminase Type 4/antagonists & inhibitors , Thrombosis/pathology
8.
Cytokine ; 146: 155634, 2021 10.
Article in English | MEDLINE | ID: covidwho-1293703

ABSTRACT

Thrombopoietin (TPO) is most recognized for its function as the primary regulator of megakaryocyte (MK) expansion and differentiation. MKs, in turn, are best known for their role in platelet production. Research indicates that MKs and platelets play an extensive role in the pathologic thrombosis at sites of high inflammation. TPO, therefore, is a key mediator of thromboinflammation. Silencing of TPO has been shown to decrease platelets levels and rates of pathologic thrombosis in patients with various inflammatory disorders (Barrett et al, 2020; Bunting et al, 1997; Desai et al, 2018; Kaser et al, 2001; Shirai et al, 2019). Given the high rates of thromboinflammmation in the novel coronavirus 2019 (COVID-19), as well as the well-documented aberrant MK activity in affected patients, TPO silencing offers a potential therapeutic modality in the treatment of COVID-19 and other pathologies associated with thromboinflammation. The current review explores the current clinical applications of TPO silencing and offers insight into a potential role in the treatment of COVID-19.


Subject(s)
COVID-19/therapy , Gene Silencing , Inflammation/genetics , Thrombocytosis/genetics , Thrombopoietin/genetics , Thrombosis/genetics , COVID-19/complications , COVID-19/virology , Humans , Inflammation/complications , Inflammation/metabolism , Megakaryocytes/metabolism , SARS-CoV-2/physiology , Thrombocytosis/complications , Thrombocytosis/metabolism , Thrombopoiesis/genetics , Thrombopoietin/metabolism , Thrombosis/complications , Thrombosis/metabolism
9.
Angiogenesis ; 24(4): 755-788, 2021 11.
Article in English | MEDLINE | ID: covidwho-1286153

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 ß [IL-1ß] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.


Subject(s)
COVID-19/metabolism , Myelopoiesis , Neovascularization, Pathologic/metabolism , Respiratory Distress Syndrome/metabolism , SARS-CoV-2/metabolism , Thrombosis/metabolism , COVID-19/pathology , COVID-19/therapy , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelial Cells/virology , Fibrin Fibrinogen Degradation Products/metabolism , Fibroblast Growth Factor 2/metabolism , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Membrane Proteins/metabolism , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/therapy , Neovascularization, Pathologic/virology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/therapy , Respiratory Distress Syndrome/virology , Thrombosis/pathology , Thrombosis/therapy , Thrombosis/virology , Vascular Endothelial Growth Factor A/metabolism , von Willebrand Factor/metabolism
11.
Int J Mol Sci ; 22(12)2021 Jun 13.
Article in English | MEDLINE | ID: covidwho-1273455

ABSTRACT

Inflammation is an old concept that has started to be considered as an important factor in infection and chronic diseases. The role of leukocytes, the plasmatic components, then of the mediators such as prostaglandins, cytokines, and, in recent decades, of the endothelium has completed the concept of the inflammation process. The function of the endothelium appeared to be crucial as a regulator or the initiator of the inflammatory process. Culture of human endothelial cells and experimental systems made it possible to define the molecular basis of inflammation in vascular diseases, in diabetes mellitus, atherosclerosis, vasculitis and thromboembolic complications. Advanced glycation end product receptor (RAGE), present on endothelial cells (ECs) and monocytes, participates in the activation of these cells in inflammatory conditions. Inflammasome is a cytosolic multiprotein that controls the response to diverse microorganisms. It is positively regulated by stimulator of interferon response CGAMP interactor-1 (STING1). Angiogenesis and thrombotic events are dysregulated during inflammation. ECs appear to be a protector, but also a possible initiator of thrombosis.


Subject(s)
Atherosclerosis/pathology , Endothelium, Vascular/metabolism , Thrombosis/pathology , Atherosclerosis/metabolism , Endothelium, Vascular/cytology , Humans , Inflammasomes/metabolism , Membrane Proteins/metabolism , Neovascularization, Physiologic , Nitric Oxide/metabolism , Receptor for Advanced Glycation End Products/metabolism , Thrombosis/metabolism
12.
Nutrients ; 13(6)2021 Jun 09.
Article in English | MEDLINE | ID: covidwho-1264499

ABSTRACT

It has recently been hypothesized that vitamin K could play a role in COVID-19. We aimed to test the hypotheses that low vitamin K status is a common characteristic of patients hospitalized with COVID-19 compared to population controls and that low vitamin K status predicts mortality in COVID-19 patients. In a cohort of 138 COVID-19 patients and 138 population controls, we measured plasma dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP), which reflects the functional vitamin K status in peripheral tissue. Forty-three patients died within 90 days from admission. In patients, levels of dp-ucMGP differed significantly between survivors (mean 877; 95% CI: 778; 995) and non-survivors (mean 1445; 95% CI: 1148; 1820). Furthermore, levels of dp-ucMGP (pmol/L) were considerably higher in patients (mean 1022; 95% CI: 912; 1151) compared to controls (mean 509; 95% CI: 485; 540). Cox regression survival analysis showed that increasing levels of dp-ucMGP (reflecting low vitamin K status) were associated with higher mortality risk (sex- and age-adjusted hazard ratio per doubling of dp-ucMGP was 1.49, 95% CI: 1.03; 2.24). The association attenuated and became statistically insignificant after adjustment for co-morbidities (sex, age, CVD, diabetes, BMI, and eGFR adjusted hazard ratio per doubling of dp-ucMGP was 1.22, 95% CI: 0.82; 1.80). In conclusion, we found that low vitamin K status was associated with mortality in patients with COVID-19 in sex- and age-adjusted analyses, but not in analyses additionally adjusted for co-morbidities. Randomized clinical trials would be needed to clarify a potential role, if any, of vitamin K in the course of COVID-19.


Subject(s)
COVID-19/mortality , Calcium-Binding Proteins/metabolism , Extracellular Matrix Proteins/metabolism , Hospitalization , Vitamin K Deficiency/mortality , Vitamin K/blood , Adult , Aged , Biomarkers/blood , Blood Coagulation , COVID-19/complications , COVID-19/metabolism , Calcium-Binding Proteins/blood , Cohort Studies , Extracellular Matrix Proteins/blood , Female , Hospital Mortality , Humans , Male , Middle Aged , Proportional Hazards Models , Regression Analysis , SARS-CoV-2 , Thrombosis/metabolism , Vitamin K Deficiency/blood , Vitamin K Deficiency/complications , Young Adult
13.
Vasc Health Risk Manag ; 17: 273-298, 2021.
Article in English | MEDLINE | ID: covidwho-1262578

ABSTRACT

COVID-19 sepsis is characterized by acute respiratory distress syndrome (ARDS) as a consequence of pulmonary tropism of the virus and endothelial heterogeneity of the host. ARDS is a phenotype among patients with multiorgan dysfunction syndrome (MODS) due to disseminated vascular microthrombotic disease (VMTD). In response to the viral septicemia, the host activates the complement system which produces terminal complement complex C5b-9 to neutralize pathogen. C5b-9 causes pore formation on the membrane of host endothelial cells (ECs) if CD59 is underexpressed. Also, viral S protein attraction to endothelial ACE2 receptor damages ECs. Both affect ECs and provoke endotheliopathy. Disseminated endotheliopathy activates two molecular pathways: inflammatory and microthrombotic. The former releases inflammatory cytokines from ECs, which lead to inflammation. The latter initiates endothelial exocytosis of unusually large von Willebrand factor (ULVWF) multimers and FVIII from Weibel-Palade bodies. If ADAMTS13 is insufficient, ULVWF multimers activate intravascular hemostasis of ULVWF path. In activated ULVWF path, ULVWF multimers anchored to damaged endothelial cells recruit circulating platelets and trigger microthrombogenesis. This process produces "microthrombi strings" composed of platelet-ULVWF complexes, leading to endotheliopathy-associated VMTD (EA-VMTD). In COVID-19, microthrombosis initially affects the lungs per tropism causing ARDS, but EA-VMTD may orchestrate more complex clinical phenotypes, including thrombotic thrombocytopenic purpura (TTP)-like syndrome, hepatic coagulopathy, MODS and combined micro-macrothrombotic syndrome. In this pandemic, ARDS and pulmonary thromboembolism (PTE) have often coexisted. The analysis based on two hemostatic theories supports ARDS caused by activated ULVWF path is EA-VMTD and PTE caused by activated ULVWF and TF paths is macrothrombosis. The thrombotic disorder of COVID-19 sepsis is consistent with the notion that ARDS is virus-induced disseminated EA-VMTD and PTE is in-hospital vascular injury-related macrothrombosis which is not directly  related to viral pathogenesis. The pathogenesis-based therapeutic approach is discussed for the treatment of EA-VMTD with antimicrothrombotic regimen and the potential need of anticoagulation therapy for coinciding macrothrombosis in comprehensive COVID-19 care.


Subject(s)
COVID-19/epidemiology , Endothelial Cells/metabolism , Fibrinolytic Agents/therapeutic use , Hemostasis/physiology , SARS-CoV-2 , Sepsis/complications , Thrombosis/etiology , COVID-19/complications , Humans , Pandemics , Phenotype , Sepsis/metabolism , Thrombosis/drug therapy , Thrombosis/metabolism
14.
Int J Mol Sci ; 22(11)2021 May 31.
Article in English | MEDLINE | ID: covidwho-1256566

ABSTRACT

Cells convey information among one another. One instrument employed to transmit data and constituents to specific (target) cells is extracellular vesicles (EVs). They originate from a variety of cells (endothelial, immune cells, platelets, mesenchymal stromal cells, etc.), and consequently, their surface characteristics and cargo vary according to the paternal cell. The cargo could be DNA, mRNA, microRNA, receptors, metabolites, cytoplasmic proteins, or pathological molecules, as a function of which EVs exert different effects upon endocytosis in recipient cells. Recently, EVs have become important participants in a variety of pathologies, including atherogenesis and coronavirus disease 2019 (COVID-19)-associated thrombosis. Herein, we summarize recent advances and some of our own results on the role of EVs in atherosclerotic cardiovascular diseases, and discuss their potential to function as signaling mediators, biomarkers and therapeutic agents. Since COVID-19 patients have a high rate of thrombotic events, a special section of the review is dedicated to the mechanism of thrombosis and the possible therapeutic potential of EVs in COVID-19-related thrombosis. Yet, EV mechanisms and their role in the transfer of information between cells in normal and pathological conditions remain to be explored.


Subject(s)
Atherosclerosis/metabolism , COVID-19/metabolism , Extracellular Vesicles/metabolism , Thrombosis/metabolism , Atherosclerosis/physiopathology , Atherosclerosis/therapy , Atherosclerosis/virology , Biomarkers/metabolism , COVID-19/complications , COVID-19/physiopathology , COVID-19/therapy , Endothelial Cells/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/virology , Mesenchymal Stem Cells/metabolism , Signal Transduction/immunology , Thrombosis/complications , Thrombosis/physiopathology , Thrombosis/virology
15.
Br J Haematol ; 194(1): 44-52, 2021 07.
Article in English | MEDLINE | ID: covidwho-1247138

ABSTRACT

The inflammatory response to SARS/CoV-2 (COVID-19) infection may contribute to the risk of thromboembolic complications. α-Defensins, antimicrobial peptides released from activated neutrophils, are anti-fibrinolytic and prothrombotic in vitro and in mouse models. In this prospective study of 176 patients with COVID-19 infection, we found that plasma levels of α-defensins were elevated, tracked with disease progression/mortality or resolution and with plasma levels of interleukin-6 (IL-6) and D-dimers. Immunohistochemistry revealed intense deposition of α-defensins in lung vasculature and thrombi. IL-6 stimulated the release of α-defensins from neutrophils, thereby accelerating coagulation and inhibiting fibrinolysis in human blood, imitating the coagulation pattern in COVID-19 patients. The procoagulant effect of IL-6 was inhibited by colchicine, which blocks neutrophil degranulation. These studies describe a link between inflammation and the risk of thromboembolism, and they identify a potential new approach to mitigate this risk in patients with COVID-19 and potentially in other inflammatory prothrombotic conditions.


Subject(s)
COVID-19/metabolism , Inflammation/metabolism , Thromboembolism/prevention & control , alpha-Defensins/blood , Adult , Aged , Animals , Blood Coagulation/drug effects , COVID-19/complications , COVID-19/diagnosis , COVID-19/virology , Case-Control Studies , Colchicine/pharmacology , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Inflammation/complications , Interleukin-6/blood , Interleukin-6/pharmacology , Male , Mice , Middle Aged , Models, Animal , Neutrophils/drug effects , Prospective Studies , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Severity of Illness Index , Thromboembolism/etiology , Thrombosis/etiology , Thrombosis/metabolism , Tubulin Modulators/pharmacology , alpha-Defensins/pharmacology
16.
Am J Pathol ; 191(8): 1374-1384, 2021 08.
Article in English | MEDLINE | ID: covidwho-1240148

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) who are critically ill develop vascular complications characterized by thrombosis of small, medium, and large vessels. Dysfunction of the vascular endothelium due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated in the pathogenesis of the COVID-19 vasculopathy. Although initial reports suggested that endothelial injury was caused directly by the virus, recent studies indicate that endothelial cells do not express angiotensin-converting enzyme 2, the receptor that SARS-CoV-2 uses to gain entry into cells, or express it at low levels and are resistant to the infection. These new findings, together with the observation that COVID-19 triggers a cytokine storm capable of injuring the endothelium and disrupting its antithrombogenic properties, favor an indirect mechanism of endothelial injury mediated locally by an augmented inflammatory reaction to infected nonendothelial cells, such as the bronchial and alveolar epithelium, and systemically by the excessive immune response to infection. Herein we review the vascular pathology of COVID-19 and critically discuss the potential mechanisms of endothelial injury in this disease.


Subject(s)
COVID-19/metabolism , Cytokine Release Syndrome/metabolism , Endothelium, Vascular/injuries , Endothelium, Vascular/metabolism , SARS-CoV-2/metabolism , Thrombosis/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Bronchi/metabolism , Bronchi/pathology , COVID-19/complications , COVID-19/pathology , COVID-19/therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/therapy , Endothelium, Vascular/pathology , Humans , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/pathology , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Thrombosis/etiology , Thrombosis/pathology , Thrombosis/therapy
17.
Biomolecules ; 11(5)2021 05 06.
Article in English | MEDLINE | ID: covidwho-1223942

ABSTRACT

SARS-CoV-2 is a member of the family of coronaviruses associated with severe outbreaks of respiratory diseases in recent decades and is the causative agent of the COVID-19 pandemic. The recognition by and activation of the innate immune response recruits neutrophils, which, through their different mechanisms of action, form extracellular neutrophil traps, playing a role in infection control and trapping viral, bacterial, and fungal etiological agents. However, in patients with COVID-19, activation at the vascular level, combined with other cells and inflammatory mediators, leads to thrombotic events and disseminated intravascular coagulation, thus leading to a series of clinical manifestations in cerebrovascular, cardiac, pulmonary, and kidney disease while promoting severe disease and mortality. Previous studies of hospitalized patients with COVID-19 have shown that elevated levels of markers specific for NETs, such as free DNA, MPO, and H3Cit, are strongly associated with the total neutrophil count; with acute phase reactants that include CRP, D-dimer, lactate dehydrogenase, and interleukin secretion; and with an increased risk of severe COVID-19. This study analyzed the interactions between NETs and the activation pathways involved in immunothrombotic processes in patients with COVID-19.


Subject(s)
COVID-19/pathology , Extracellular Traps/metabolism , Thrombosis/immunology , Thrombosis/pathology , Biomarkers/metabolism , COVID-19/immunology , COVID-19/virology , Complement System Proteins/metabolism , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/pathology , Disseminated Intravascular Coagulation/etiology , Disseminated Intravascular Coagulation/pathology , Humans , Neutrophils/cytology , Neutrophils/immunology , Neutrophils/metabolism , SARS-CoV-2/isolation & purification , Thrombosis/metabolism
18.
Clin Immunol ; 227: 108733, 2021 06.
Article in English | MEDLINE | ID: covidwho-1198654

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for many pathological processes, including altered vascular disease development, dysfunctional thrombosis and a heightened inflammatory response. However, there is limited work to determine the underlying cellular responses induced by exposure to SARS-CoV-2 structural proteins. Thus, our objective was to investigate how human arterial adventitial fibroblasts inflammation, thrombosis and diabetic disease markers are altered in response to Spike, Nucleocapsid and Membrane-Envelope proteins. We hypothesized that after a short-term exposure to SARS-CoV-2 proteins, adventitial fibroblasts would have a higher expression of inflammatory, thrombotic and diabetic proteins, which would support a mechanism for altered vascular disease progression. After incubation, the expression of gC1qR, ICAM-1, tissue factor, RAGE and GLUT-4 was significantly up-regulated. In general, the extent of expression was different for each SARS-CoV-2 protein, suggesting that SARS-CoV-2 proteins interact with cells through different mechanisms. Thus, SARS-CoV-2 protein interaction with vascular cells may regulate vascular disease responses.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/virology , Diabetes Mellitus/virology , Fibroblasts/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Thrombosis/virology , Aorta/cytology , Aorta/metabolism , Cardiovascular Diseases/complications , Cardiovascular Diseases/immunology , Cardiovascular Diseases/metabolism , Carrier Proteins/metabolism , Cell Survival/immunology , Cell Survival/physiology , Complement System Proteins/immunology , Coronavirus Envelope Proteins/immunology , Coronavirus Nucleocapsid Proteins/immunology , Coronavirus Nucleocapsid Proteins/metabolism , Diabetes Mellitus/metabolism , Glucose Transporter Type 4/metabolism , Humans , Inflammation/metabolism , Inflammation/virology , Intercellular Adhesion Molecule-1/metabolism , Mitochondrial Proteins/metabolism , Receptor for Advanced Glycation End Products/metabolism , Thrombosis/complications , Thrombosis/metabolism
19.
Life Sci ; 276: 119376, 2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1157590

ABSTRACT

The severe forms and worsened outcomes of COVID-19 (coronavirus disease 19) are closely associated with hypertension and cardiovascular disease. Endothelial cells express Angiotensin-Converting Enzyme 2 (ACE2), which is the entrance door for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The hallmarks of severe illness caused by SARS-CoV-2 infection are increased levels of IL-6, C-reactive protein, D-dimer, ferritin, neutrophilia and lymphopenia, pulmonary intravascular coagulopathy and microthrombi of alveolar capillaries. The endothelial glycocalyx, a proteoglycan- and glycoprotein-rich layer covering the luminal side of endothelial cells, contributes to vascular homeostasis. It regulates vascular tonus and permeability, prevents thrombosis, and modulates leukocyte adhesion and inflammatory response. We hypothesized that cytokine production and reactive oxygen species (ROS) generation associated with COVID-19 leads to glycocalyx degradation. A cohort of 20 hospitalized patients with a confirmed COVID-19 diagnosis and healthy subjects were enrolled in this study. Mechanisms associated with glycocalyx degradation in COVID-19 were investigated. Increased plasma concentrations of IL-6 and IL1-ß, as well as increased lipid peroxidation and glycocalyx components were detected in plasma from COVID-19 patients compared to plasma from healthy subjects. Plasma from COVID-19 patients induced glycocalyx shedding in cultured human umbilical vein endothelial cells (HUVECs) and disrupted redox balance. Treatment of HUVECs with low molecular weight heparin inhibited the glycocalyx perturbation. In conclusion, plasma from COVID-19 patients promotes glycocalyx shedding and redox imbalance in endothelial cells, and heparin treatment potentially inhibits glycocalyx disruption.


Subject(s)
COVID-19/blood , COVID-19/pathology , Glycocalyx/pathology , Heparin/pharmacology , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/virology , COVID-19/metabolism , COVID-19 Testing , Case-Control Studies , Cell Adhesion/physiology , Endothelium, Vascular/metabolism , Female , Glycocalyx/metabolism , Glycocalyx/virology , Human Umbilical Vein Endothelial Cells , Humans , Interleukin-1beta/blood , Interleukin-6/blood , Male , Middle Aged , Oxidation-Reduction , SARS-CoV-2 , Thrombosis/metabolism
20.
J Intern Med ; 289(1): 97-115, 2021 01.
Article in English | MEDLINE | ID: covidwho-1153555

ABSTRACT

BACKGROUND: SARS-CoV-2 coronavirus infection ranges from asymptomatic through to fatal COVID-19 characterized by a 'cytokine storm' and lung failure. Vitamin D deficiency has been postulated as a determinant of severity. OBJECTIVES: To review the evidence relevant to vitamin D and COVID-19. METHODS: Narrative review. RESULTS: Regression modelling shows that more northerly countries in the Northern Hemisphere are currently (May 2020) showing relatively high COVID-19 mortality, with an estimated 4.4% increase in mortality for each 1 degree latitude north of 28 degrees North (P = 0.031) after adjustment for age of population. This supports a role for ultraviolet B acting via vitamin D synthesis. Factors associated with worse COVID-19 prognosis include old age, ethnicity, male sex, obesity, diabetes and hypertension and these also associate with deficiency of vitamin D or its response. Vitamin D deficiency is also linked to severity of childhood respiratory illness. Experimentally, vitamin D increases the ratio of angiotensin-converting enzyme 2 (ACE2) to ACE, thus increasing angiotensin II hydrolysis and reducing subsequent inflammatory cytokine response to pathogens and lung injury. CONCLUSIONS: Substantial evidence supports a link between vitamin D deficiency and COVID-19 severity but it is all indirect. Community-based placebo-controlled trials of vitamin D supplementation may be difficult. Further evidence could come from study of COVID-19 outcomes in large cohorts with information on prescribing data for vitamin D supplementation or assay of serum unbound 25(OH) vitamin D levels. Meanwhile, vitamin D supplementation should be strongly advised for people likely to be deficient.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/ethnology , SARS-CoV-2 , Thrombosis/etiology , Vitamin D Deficiency/ethnology , COVID-19/metabolism , Comorbidity , Global Health , Humans , Risk Factors , Thrombosis/ethnology , Thrombosis/metabolism , Vitamin D Deficiency/metabolism
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