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Ertan-Bolelli T, Bolelli K, Elçi SD, Belen-Apak FB. Promising Drug Fondaparinux for the Treatment of COVID-19: an In Silico Analysis of Low Molecular Weight Heparin, Direct Oral Anticoagulant, and Antiplatelet Drug Interactions with Host Protease Furin. Cardiovasc Drugs Ther 2024; 38:425-432. [PMID: 36401727 PMCID: PMC9676724 DOI: 10.1007/s10557-022-07406-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/07/2022] [Indexed: 11/21/2022]
Abstract
PURPOSE As of July 2022, the COVID-19 pandemic has affected over 555 million worldwide confirmed cases and caused more than 6.3 million deaths. The studies showed that the D-dimer levels were increased in non-survivors compared to survivors and heparin treatment has begun to be administered to the patients in severe clinics. As we knew that the entrance of SARS-CoV-2 to the host cell needs to be facilitated by host proteases; we published our hypothesis that heparin as a serine protease inhibitor may block the interaction between spike protein receptor-binding domain and host proteases. In our study, we aimed to investigate the interactions between not only heparins but also other antiplatelet and anticoagulant drugs including fondaparinux. METHODS In this study, docking studies were carried out to evaluate the interactions between low molecular weight heparins (LMWHs) (enoxaparin, dalteparin, tinzaparin), direct oral anticoagulant, and antiplatelet drugs with host proteases. Molecular docking studies were performed by using Schrödinger molecular modeling software. 3D structures of the ligands were obtained from the 2D structures by assigning the OPLS-2005 force field using the Maestro 12.7. The 3D crystal structure of the furin complexed with an inhibitor, 2,5-dideoksistreptamin derivative, was extracted from the Protein Data Bank (PDB ID: 5MIM). Docking studies were carried out using the Grid-based Ligand Docking with Energetics module of the Schrödinger Software. RESULTS The docking studies revealed that fondaparinux was the most relevant molecule to interact with furin with a docking score of - 12.74. It showed better interaction than the natural ligand of furin with an increased score compared to the docking score of - 8.155 of the natural ligand. AnaGA*IsA structure representing LMWH structure has shown a docking score of - 11.562 which was also better than the score of the natural ligand of furin. CONCLUSION Our findings have shown that LMWHs and fondaparinux can be used for their possible antiviral effects in COVID-19 patients. Our results have shown that in accordance with heparin and LMWH, fondaparinux can also be a candidate for "drug repurposing" in COVID-19 therapy, not only because of their anticoagulant but also possible antiviral effects.
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Affiliation(s)
- Tugba Ertan-Bolelli
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06560 Ankara, Turkey
- Bolelli Lab LLC, Stone Mountain, GA 30083 USA
| | - Kayhan Bolelli
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06560 Ankara, Turkey
- Bolelli Lab LLC, Stone Mountain, GA 30083 USA
- LumiLabs, Ulus, Ankara, 06610 Turkey
| | | | - F. Burcu Belen-Apak
- Department of Pediatric Hematology and Oncology, Medical Faculty, Baskent University, Sehit Temel Kuguluoglu Street No 24, 06490 Bahcelievler/Ankara, Turkey
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Gilyazova I, Timasheva Y, Karunas A, Kazantseva A, Sufianov A, Mashkin A, Korytina G, Wang Y, Gareev I, Khusnutdinova E. COVID-19: Mechanisms, risk factors, genetics, non-coding RNAs and neurologic impairments. Noncoding RNA Res 2023; 8:240-254. [PMID: 36852336 PMCID: PMC9946734 DOI: 10.1016/j.ncrna.2023.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/18/2023] [Accepted: 02/18/2023] [Indexed: 02/24/2023] Open
Abstract
The novel coronavirus infection (COVID-19) causes a severe acute illness with the development of respiratory distress syndrome in some cases. COVID-19 is a global problem of mankind to this day. Among its most important aspects that require in-depth study are pathogenesis and molecular changes in severe forms of the disease. A lot of literature data is devoted to the pathogenetic mechanisms of COVID-19. Without dwelling in detail on some paths of pathogenesis discussed, we note that at present there are many factors of development and progression. Among them, this is the direct role of both viral non-coding RNAs (ncRNAs) and host ncRNAs. One such class of ncRNAs that has been extensively studied in COVID-19 is microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Moreover, Initially, it was believed that this COVID-19 was limited to damage to the respiratory system. It has now become clear that COVID-19 affects not only the liver and kidneys, but also the nervous system. In this review, we summarized the current knowledge of mechanisms, risk factors, genetics and neurologic impairments in COVID-19. In addition, we discuss and evaluate evidence demonstrating the involvement of miRNAs and lnRNAs in COVID-19 and use this information to propose hypotheses for future research directions.
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Affiliation(s)
- Irina Gilyazova
- Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences, 450054, Ufa, Russia
- Bashkir State Medical University, 450008, Ufa, Russia
| | - Yanina Timasheva
- Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences, 450054, Ufa, Russia
| | - Alexandra Karunas
- Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences, 450054, Ufa, Russia
- Federal State Educational Institution of Higher Education, Ufa University of Science and Technology, 450076, Ufa, Russia
| | - Anastasiya Kazantseva
- Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences, 450054, Ufa, Russia
- Federal State Educational Institution of Higher Education, Ufa University of Science and Technology, 450076, Ufa, Russia
| | - Albert Sufianov
- Рeoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow, 117198, Russia
- Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), 119435, Moscow, Russia
| | - Andrey Mashkin
- Рeoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow, 117198, Russia
| | - Gulnaz Korytina
- Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences, 450054, Ufa, Russia
| | - Yaolou Wang
- Harbin Medical University, 157 Baojian Rd, Nangang, Harbin, Heilongjiang, 150088, China
| | - Ilgiz Gareev
- Bashkir State Medical University, 450008, Ufa, Russia
| | - Elza Khusnutdinova
- Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences, 450054, Ufa, Russia
- Federal State Educational Institution of Higher Education, Ufa University of Science and Technology, 450076, Ufa, Russia
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Vizzoni L, Migone C, Grassiri B, Zambito Y, Ferro B, Roncucci P, Mori F, Salvatore A, Ascione E, Crea R, Esin S, Batoni G, Piras AM. Biopharmaceutical Assessment of Mesh Aerosolised Plasminogen, a Step towards ARDS Treatment. Pharmaceutics 2023; 15:1618. [PMID: 37376068 PMCID: PMC10300680 DOI: 10.3390/pharmaceutics15061618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/18/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a severe complication of lung injuries, commonly associated with bacterial, fungal and viral infections, including SARS-CoV-2 viral infections. ARDS is strongly correlated with patient mortality and its clinical management is very complex, with no effective treatment presently available. ARDS involves severe respiratory failure, fibrin deposition in both airways and lung parenchyma, with the development of an obstructing hyaline membrane drastically limiting gas exchange. Moreover, hypercoagulation is related to deep lung inflammation, and a pharmacological action toward both aspects is expected to be beneficial. Plasminogen (PLG) is a main component of the fibrinolytic system playing key roles in various inflammation regulatory processes. The inhalation of PLG has been proposed in the form of the off-label administration of an eyedrop solution, namely, a plasminogen-based orphan medicinal product (PLG-OMP), by means of jet nebulisation. Being a protein, PLG is susceptible to partial inactivation under jet nebulisation. The aim of the present work is to demonstrate the efficacy of the mesh nebulisation of PLG-OMP in an in vitro simulation of clinical off-label administration, considering both the enzymatic and immunomodulating activities of PLG. Biopharmaceutical aspects are also investigated to corroborate the feasibility of PLG-OMP administration by inhalation. The nebulisation of the solution was performed using an Aerogen® SoloTM vibrating-mesh nebuliser. Aerosolised PLG showed an optimal in vitro deposition profile, with 90% of the active ingredient impacting the lower portions of a glass impinger. The nebulised PLG remained in its monomeric form, with no alteration of glycoform composition and 94% of enzymatic activity maintenance. Activity loss was observed only when PLG-OMP nebulisation was performed under simulated clinical oxygen administration. In vitro investigations evidenced good penetration of aerosolised PLG through artificial airway mucus, as well as poor permeation across an Air-Liquid Interface model of pulmonary epithelium. The results suggest a good safety profile of inhalable PLG, excluding high systemic absorption but with good mucus diffusion. Most importantly, the aerosolised PLG was capable of reversing the effects of an LPS-activated macrophage RAW 264.7 cell line, demonstrating the immunomodulating activity of PLG in an already induced inflammatory state. All physical, biochemical and biopharmaceutical assessments of mesh aerosolised PLG-OMP provided evidence for its potential off-label administration as a treatment for ARDS patients.
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Affiliation(s)
- Lucia Vizzoni
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
- Department of Life Sciences, University of Siena, 53100 Siena, Italy
| | - Chiara Migone
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
| | | | - Ylenia Zambito
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
- Research Centre for Nutraceutical and Healthy Foods “NUTRAFOOD”, University of Pisa, 56124 Pisa, Italy
| | - Baldassare Ferro
- Anestesia e Rianimazione, Azienda USL Toscana Nord Ovest, 57124 Livorno, Italy
| | - Paolo Roncucci
- Anestesia e Rianimazione, Azienda USL Toscana Nord Ovest, 57124 Livorno, Italy
| | - Filippo Mori
- Kedrion S.p.A., Via di Fondovalle, Loc. Bolognana, 55027 Gallicano, Italy
| | - Alfonso Salvatore
- Kedrion S.p.A., Via di Fondovalle, Loc. Bolognana, 55027 Gallicano, Italy
| | - Ester Ascione
- Kedrion S.p.A., Via di Fondovalle, Loc. Bolognana, 55027 Gallicano, Italy
| | - Roberto Crea
- Kedrion S.p.A., Via di Fondovalle, Loc. Bolognana, 55027 Gallicano, Italy
| | - Semih Esin
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
- Centre for Instrument Sharing of University of Pisa (CISUP), 56126 Pisa, Italy
| | - Giovanna Batoni
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
- Centre for Instrument Sharing of University of Pisa (CISUP), 56126 Pisa, Italy
| | - Anna Maria Piras
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
- Centre for Instrument Sharing of University of Pisa (CISUP), 56126 Pisa, Italy
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Sinus node dysfunction and atrial fibrillation-Relationships, clinical phenotypes, new mechanisms, and treatment approaches. Ageing Res Rev 2023; 86:101890. [PMID: 36813137 DOI: 10.1016/j.arr.2023.101890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/15/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023]
Abstract
Although the anatomical basis of the pathogenesis of sinus node dysfunction (SND) and atrial fibrillation (AF) is located primarily in the left and right atria, increasing evidence suggests a strong correlation between SND and AF, in terms of both clinical presentation and formation mechanisms. However, the exact mechanisms underlying this association are unclear. The relationship between SND and AF may not be causal, but is likely to involve common factors and mechanisms, including ion channel remodeling, gap junction abnormalities, structural remodeling, genetic mutations, neuromodulation abnormalities, the effects of adenosine on cardiomyocytes, oxidative stress, and viral infections. Ion channel remodeling manifests primarily as alterations in the "funny" current (If) and Ca2+ clock associated with cardiomyocyte autoregulation, and gap junction abnormalities are manifested primarily as decreased expression of connexins (Cxs) mediating electrical impulse propagation in cardiomyocytes. Structural remodeling refers primarily to fibrosis and cardiac amyloidosis (CA). Some genetic mutations can also cause arrhythmias, such as SCN5A, HCN4, EMD, and PITX2. The intrinsic cardiac autonomic nervous system (ICANS), a regulator of the heart's physiological functions, triggers arrhythmias.In addition, we discuss arrhythmias caused by viral infections, notably Coronavirus Disease 2019 (COVID-19). Similarly to upstream treatments for atrial cardiomyopathy such as alleviating CA, ganglionated plexus (GP) ablation acts on the common mechanisms between SND and AF, thus achieving a dual therapeutic effect.
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Schmidt W, Pawlak-Buś K, Jóźwiak B, Leszczyński P. Identification of Clinical Response Predictors of Tocilizumab Treatment in Patients with Severe COVID-19 Based on Single-Center Experience. J Clin Med 2023; 12:jcm12062429. [PMID: 36983429 PMCID: PMC10051490 DOI: 10.3390/jcm12062429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/19/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Hyperinflammation in COVID-19 plays a crucial role in pathogenesis and severity; thus, many immunomodulatory agents are applied in its treatment. We aimed to identify good clinical response predictors of tocilizumab (TCZ) treatment in severe COVID-19, among clinical, laboratory, and radiological variables. We conducted a prospective, observational study with 120 patients with severe COVID-19 not improving despite dexamethasone (DEX) treatment. We used parametric and non-parametric statistics, univariate logistic regression, receiver operating characteristic (ROC) curves, and nonlinear factors tertile analysis. In total, 86 (71.7%) patients achieved the primary outcome of a good clinical response to TCZ. We identified forty-nine predictive factors with potential utility in patient selection and treatment monitoring. The strongest included time from symptom onset between 9 and 12 days, less than 70% of estimated radiological lung involvement, and lower activity of lactate dehydrogenase. Additional predictors were associated with respiratory function, vitamin D concentration, comorbidities, and inflammatory/organ damage biomarkers. Adverse events analysis proved the safety of such a regimen. Our study confirmed that using TCZ early in the hyperinflammatory phase, before severe respiratory failure development, is most beneficial. Considering the described predictive factors, employing simple and widely available laboratory, radiological, and clinical tools can optimize patient selection for immunomodulatory treatment with TCZ.
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Affiliation(s)
- Wiktor Schmidt
- Department of Rheumatology, Systemic Connective Tissue Diseases and Immunotherapy of Rheumatic Diseases, J. Strus Municipal Hospital, 61-285 Poznan, Poland
- Department of Internal Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland
- Doctoral School, Poznan University of Medical Sciences, 60-812 Poznan, Poland
| | - Katarzyna Pawlak-Buś
- Department of Rheumatology, Systemic Connective Tissue Diseases and Immunotherapy of Rheumatic Diseases, J. Strus Municipal Hospital, 61-285 Poznan, Poland
- Department of Internal Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Barbara Jóźwiak
- Department of Rheumatology, Systemic Connective Tissue Diseases and Immunotherapy of Rheumatic Diseases, J. Strus Municipal Hospital, 61-285 Poznan, Poland
| | - Piotr Leszczyński
- Department of Rheumatology, Systemic Connective Tissue Diseases and Immunotherapy of Rheumatic Diseases, J. Strus Municipal Hospital, 61-285 Poznan, Poland
- Department of Internal Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland
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Nesterova IV, Atazhakhova MG, Teterin YV, Matushkina VA, Chudilova GA, Mitropanova MN. THE ROLE OF NEUTROPHIL EXTRACELLULAR TRAPS (NETS)
IN THE IMMUNOPATHOGENESIS OF SEVERE COVID-19: POTENTIAL IMMUNOTHERAPEUTIC STRATEGIES REGULATING NET FORMATION AND ACTIVITY. RUSSIAN JOURNAL OF INFECTION AND IMMUNITY 2023. [DOI: 10.15789/2220-7619-tro-2058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
The role of neutrophil granulocytes (NG) in the pathogenesis of COVID-19 is associated with the recruitment of NG into inflammatory foci, activation of their functions and enhanced formation of neutrophil extracellular networks (NETs). In this review, we analyzed a fairly large volume of scientific literature devoted to the peculiarities of the formation of NETs, their role in the pathogenesis of COVID-19, participation in the occurrence of immunothrombosis, vasculitis, acute respiratory distress syndrome, cytokine storm syndrome, multi-organ lesions. Convincing data are presented that clearly indicate the significant involvement of NETs in the immunopathogenesis of COVID-19 and the associated severe complications resulting from the intensification of the inflammation process, which is key for the course of infection caused by the SARS-CoV-2 virus. The presented role of NG and NETs, along with the role of other immune system cells and pro-inflammatory cytokines, is extremely important in understanding the development of an overactive immune response in severe COVID-19. The obtained scientific results, available today, allow identifying the possibilities of regulatory effects on hyperactivated NG, on the formation of NETs at various stages and on limiting the negative impact of already formed NETs on various tissues and organs. All of the above should help in the creation of new, specialized immunotherapy strategies designed to increase the chances of survival, reduce the severity of clinical manifestations in patients with COVID-19, as well as significantly reduce mortality rates. Currently, it is possible to use existing drugs and a number of new drugs are being developed, the action of which can regulate the amount of NG, positively affect the functions of NG and limit the intensity of NETs formation. Continuing research on the role of hyperactive NG and netosis, as well as understanding the mechanisms of regulation of the phenomenon of formation and restriction of NETs activity in severe COVID-19, apparently, are a priority, since in the future the new data obtained could become the basis for the development of targeted approaches not only to immunotherapy aimed at limiting education and blocking negative effects already formed NETs in severe COVID-19, but also to immunotherapy, which could be used in the complex treatment of other netopathies, first of all, autoimmune diseases, auto-inflammatory syndromes, severe purulent-inflammatory processes, including bacterial sepsis and hematogenous osteomyelitis.
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Belen Apak FB, Yuce G, Topcu DI, Gultekingil A, Felek YE, Sencelikel T. Coagulopathy is Initiated with Endothelial Dysfunction and Disrupted Fibrinolysis in Patients with COVID-19 Disease. Indian J Clin Biochem 2023; 38:220-230. [PMID: 36816717 PMCID: PMC9922102 DOI: 10.1007/s12291-023-01118-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 01/31/2023] [Indexed: 02/12/2023]
Abstract
A substantial group of patients suffer from Covid-19 (CAC) coagulopathy and are presented with thrombosis. The pathogenesis involved in CAC is not fully understood. We evaluated the hemostatic and inflammatory parameters of 51 hospitalized Covid-19 adult patients and 21 controls. The parameters analyzed were danger signal molecule (High molecular weight group box protein-1/HMGBP-1), platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, fibrinogen, endothelial protein C receptor (EPCR), soluble E-selectin, soluble P-selectin, thrombomodulin, tissue plasminogen activator (TPA), plasminogen activator inhibitor-1 (PAI-1), soluble fibrin monomer complex (SFMC), platelet-derived microparticles (PDMP), β-thromboglobulin, antithrombin and protein C. The main objective of our study was to investigate which part of the hemostatic system was mostly affected at the admission of Covid-19 patients and whether these parameters could differentiate intensive care unit (ICU) and non-ICU patients. In this prospective case-control study, 51 patients ≥ 18 years who are hospitalized with the diagnosis of Covid-19 and 21 healthy control subjects were included. We divided the patients into two groups according to their medical progress, either in ICU or non-ICU group. Regarding the outcome, patients were again categorized as a survivor and non-survivor groups. Blood samples were collected from patients at admission at the time of hospitalization before the administration of any treatment for Covid-19. The analyzes of the study were made with the IBM SPSS V22 program. p < 0.05 was considered statistically significant. A total of 51 adult patients (F/M: 24/27) (13 ICU and 38 non-ICU) were included in the study cohort. The mean age of the patients was 68.1 ± 14.4 years. The control group consisted of 21 age and sex-matched healthy individuals. All of the patients were hospitalized. In a group of 13 patients, Covid-19 progressed to a severe form, and were hospitalized in ICU. We found out that the levels of fibrinogen, prothrombin time (PT), endothelial protein-C receptor (EPCR), D-dimer, soluble E-selectin, soluble P-selectin, plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (TPA) were increased; whereas, the levels of soluble fibrin monomer complex (SFMC), platelet-derived microparticles (PDMP), antithrombin and protein-C were decreased in Covid-19 patients compared to the control group at hospital admission. Tissue plasminogen activator was the only marker with a significantly different median level between ICU and non-ICU groups (p < 0.001). In accordance with the previous literature, we showed that Covid-19 associated coagulopathy is distinct from sepsis-induced DIC with prominent early endothelial involvement and fibrinolytic shut-down. Reconstruction of endothelial function at early stages of infection may protect patients from progressing to ICU hospitalization. We believe that after considering the patient's bleeding risk, early administration of LMWH therapy for Covid-19, even in an outpatient setting, may be helpful both for restoring endothelial function and anticoagulation. The intensity of anticoagulation in non-ICU and ICU Covid-19 patients should be clarified with further studies. Supplementary Information The online version contains supplementary material available at 10.1007/s12291-023-01118-3.
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Affiliation(s)
- Fatma Burcu Belen Apak
- grid.411548.d0000 0001 1457 1144Department of Pediatric Hematology and Oncology, Baskent University Medical Faculty, Sehit Temel Kuguoglu Street No 24, 06490 Bahcelievler/Ankara, Turkey
| | - Gulbahar Yuce
- grid.411548.d0000 0001 1457 1144Department of Chest Diseases, Baskent University Medical Faculty, Ankara, Turkey
| | - Deniz Ilhan Topcu
- grid.411548.d0000 0001 1457 1144Department of Biochemistry, Baskent University Medical Faculty, Ankara, Turkey
| | - Ayse Gultekingil
- grid.411548.d0000 0001 1457 1144Department of Pediatric Emergency, Baskent University Medical Faculty, Ankara, Turkey
| | - Yunus Emre Felek
- grid.411548.d0000 0001 1457 1144Department of Emergency Services, Baskent University Medical Faculty, Ankara, Turkey
| | - Tugce Sencelikel
- Department of Biostatistics, Faculty of Medicine, Ankara Medipol University, Ankara, Turkey
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Coagulation Disorders in Sepsis and COVID-19-Two Sides of the Same Coin? A Review of Inflammation-Coagulation Crosstalk in Bacterial Sepsis and COVID-19. J Clin Med 2023; 12:jcm12020601. [PMID: 36675530 PMCID: PMC9866352 DOI: 10.3390/jcm12020601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/27/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Sepsis is a major cause of morbidity and mortality worldwide. Sepsis-associated coagulation disorders are involved in the pathogenesis of multiorgan failure and lead to a subsequently worsening prognosis. Alongside the global impact of the COVID-19 pandemic, a great number of research papers have focused on SARS-CoV-2 pathogenesis and treatment. Significant progress has been made in this regard and coagulation disturbances were once again found to underlie some of the most serious adverse outcomes of SARS-CoV-2 infection, such as acute lung injury and multiorgan dysfunction. In the attempt of untangling the mechanisms behind COVID-19-associated coagulopathy (CAC), a series of similarities with sepsis-induced coagulopathy (SIC) became apparent. Whether they are, in fact, the same disease has not been established yet. The clinical picture of CAC shows the unique feature of an initial phase of intravascular coagulation confined to the respiratory system. Only later on, patients can develop a clinically significant form of systemic coagulopathy, possibly with a consumptive pattern, but, unlike SIC, it is not a key feature. Deepening our understanding of CAC pathogenesis has to remain a major goal for the research community, in order to design and validate accurate definitions and classification criteria.
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Dai MF, Xin WX, Kong S, Ding HY, Fang L. Effectiveness and safety of extended thromboprophylaxis in post-discharge patients with COVID-19: A systematic review and meta-analysis. Thromb Res 2023; 221:105-112. [PMID: 36502592 PMCID: PMC9691269 DOI: 10.1016/j.thromres.2022.11.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND The effect of extended thromboprophylaxis in improving the prognosis of adult patients with coronavirus disease 2019 (COVID-19) after discharge remains debatable. This meta-analysis was aimed to determine the advantages and disadvantages of extended thromboprophylaxis in these patients. METHODS Different databases such as PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for studies that evaluated the effects of extended thromboprophylaxis in post-discharge patients with COVID-19 until 13 June 2022. The primary efficacy outcome was defined by the composite outcome of thromboembolism and all-cause mortality, and the safety outcome was defined by bleeding events. The odds ratios (ORs) and 95 % confidence intervals (CIs) of efficacy and safety outcomes were calculated using fixed- or random-effects model. Interaction analysis was performed to assess and compare observational studies and randomised controlled trials (RCTs). A sensitivity analysis was performed after excluding studies of poor quality. RESULTS Eight studies involving 10,148 patients were included. The results confirmed that extended thromboprophylaxis, primarily prophylactic use of anticoagulants for <35 days, was significantly associated with reduced composite outcome in high-risk post-discharge patients with COVID-19 (OR: 0.52; 95 % CI: 0.41-0.67, P = 0.000). Interaction analysis revealed that the effect estimates were consistent between the RCT and observational studies (Pinteraction = 0.310). Furthermore, extended thromboprophylaxis did not increase the risk of major bleeding events (OR: 1.64; 95 % CI: 0.95-2.82, P = 0.075). CONCLUSION In post-discharge patients with COVID-19 at high risk of thromboembolism, extended thromboprophylaxis, primarily prophylactic use of anticoagulants for <35 days, can significantly reduce the risk of thrombosis and all-cause mortality without increasing the risk of major bleeding events. REGISTRATION PROSPERO CRD42022339399.
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Affiliation(s)
- Meng-Fei Dai
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Wen-Xiu Xin
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Sisi Kong
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Hai-Ying Ding
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
| | - Luo Fang
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
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Khaliullina SV, Anokhin VA, Khaertynov KS, Khoder MA, Pozdnyak VA, Raimova YA. Acute hepatitis as an independent form of mixed (herpetic and new coronavirus) infections in a child. ROSSIYSKIY VESTNIK PERINATOLOGII I PEDIATRII (RUSSIAN BULLETIN OF PERINATOLOGY AND PEDIATRICS) 2022. [DOI: 10.21508/1027-4065-2022-67-5-188-193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
To date, the association of SARS-CoV-2 infection with the reactivation of herpes viruses has been determined. This has been proven not only by the results of laboratory studies, but also by a clinically confirmed subsequent manifestation of the herpetic process. The article describes a clinical case of Epstein–Barr viral and cytomegalovirus infections reactivation after COVID-19. The child was diagnosed with anicteric form of hepatitis of herpetic etiology. Hepatitis, moderate anicteric form. During treatment, the patient’s condition improved. Complete clinical recovery with normalization of the activity of alanine and aspartate aminotransaminases occurred 1 month after the onset of the disease, but the level of lymphocytes and gamma-glutamyl transpeptidase still remained moderately elevated. According to the ultrasound of the abdominal organs, the size of the liver returned to normal. The presented case illustrates that mixed infections are a quite possible situation during the COVID-19 pandemic, which must be taken into account when working with such patients.
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11
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Wifi MN, Morad MA, El Sheemy R, Abdeen N, Afify S, Abdalgaber M, Abdellatef A, Zaghloul M, Alboraie M, El-Kassas M. Hemostatic system and COVID-19 crosstalk: A review of the available evidence. World J Methodol 2022; 12:331-349. [PMID: 36186748 PMCID: PMC9516549 DOI: 10.5662/wjm.v12.i5.331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 03/17/2022] [Accepted: 07/19/2022] [Indexed: 02/08/2023] Open
Abstract
Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant coronavirus disease 2019 (COVID-19) pandemic, respiratory manifestations have been the mainstay of clinical diagnosis, laboratory evaluations, and radiological investigations. As time passed, other pathological aspects of SARS-CoV-2 have been revealed. Various hemostatic abnormalities have been reported since the rise of the pandemic, which was sometimes superficial, transient, or fatal. Mild thrombocytopenia, thrombocytosis, venous, arterial thromboembolism, and disseminated intravascular coagulation are among the many hemostatic events associated with COVID-19. Venous thromboembolism necessitating therapeutic doses of anticoagulants is more frequently seen in severe cases of COVID-19, especially in patients admitted to intensive care units. Hemorrhagic complications rarely arise in COVID-19 patients either due to a hemostatic imbalance resulting from severe disease or as a complication of over anticoagulation. Although the pathogenesis of coagulation disturbance in SARS-CoV-2 infection is not yet understood, professional societies recommend prophylactic antithrombotic therapy in severe cases, especially in the presence of abnormal coagulation indices. The review article discusses the various available evidence on coagulation disorders, management strategies, outcomes, and prognosis associated with COVID-19 coagulopathy, which raises awareness about the importance of anticoagulation therapy for COVID-19 patients to guard against possible thromboembolic events.
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Affiliation(s)
- Mohamed-Naguib Wifi
- Department of Internal Medicine, Hepatogastro- enterology Unit, Kasr Al-Ainy School of Medicine, Cairo University, Cairo 11451, Egypt
| | - Mohamed Abdelkader Morad
- Clinical Hematology Unit, Department of Internal Medicine, Kasr Al-Ainy, Faculty of Medicine, Cairo University, Cairo 11451, Egypt
| | - Reem El Sheemy
- Department of Tropical Medicine, Minia Faculty of Medicine, Minia University, Minia 61511, Egypt
| | - Nermeen Abdeen
- Department of Tropical Medicine, Faculty of Medicine, Alexandria University, Alexandria 21523, Egypt
| | - Shimaa Afify
- Department of Gastroenterology, National Hepatology and Tropical Medicine, National Hepatology and Tropical Medicine Research Institute, Cairo 11451, Egypt
| | - Mohammad Abdalgaber
- Department of Gastroenterology and Hepatology, Police Authority Hospital, Agoza, Giza 12511, Egypt
| | - Abeer Abdellatef
- Department of Internal Medicine, Hepatogastro- enterology Unit, Kasr Al-Ainy School of Medicine, Cairo University, Cairo 11451, Egypt
| | - Mariam Zaghloul
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh 33511, Egypt
| | - Mohamed Alboraie
- Department of Internal Medicine, Al-Azhar University, Cairo 11884, Egypt
| | - Mohamed El-Kassas
- Department of Endemic Medicine, Faculty of Medicine, Helwan University, Helwan 11731, Egypt
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12
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Chen S, Liu Y, Ge J, Yin J, Shi T, Ntambara J, Cheng Z, Chu M, Gu H. Tetrandrine Treatment May Improve Clinical Outcome in Patients with COVID-19. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58091194. [PMID: 36143871 PMCID: PMC9503147 DOI: 10.3390/medicina58091194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/23/2022] [Accepted: 08/27/2022] [Indexed: 12/02/2022]
Abstract
Background and objectives: The COVID-19 pandemic continues worldwide, and there is no effective treatment to treat it. Chinese medicine is considered the recommended treatment for COVID-19 in China. This study aimed to examine the effectiveness of tetrandrine in treating COVID-19, which is originally derived from Chinese medicine. Materials and Methods: A total of 60 patients, categorized into three types (mild, moderate, severe), from Daye Hospital of Chinese Medicine with a diagnosis of COVID-19 were included in this study. Demographics, medical history, treatment, and results were collected. We defined two main groups according to the clinical outcome between improvement and recovery. All underlying factors including clinical outcomes were assessed in the total number of COVID-19 patients and moderate-type patients. Results: In a total of 60 patients, there were significant differences in the clinical outcome underlying treatment with antibiotics, tetrandrine, and arbidol (p < 0.05). When the comparison was limited to the moderate type, treatment with tetrandrine further increased recovery rate (p = 0.007). However, the difference disappeared, and no association was indicated between the clinical outcome and the treatment with and without antibiotic (p = 0.224) and arbidol (p = 0.318) in the moderate-type patients. In all-type and moderate-type patients, tetrandrine improved the rate of improvement in cough and fatigue on day 7 (p < 0.05). Conclusions: Tetrandrine may improve clinical outcome in COVID-19 patientsand could be a promising potential natural antiviral agent for the prevention and treatment of COVID-19.
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Affiliation(s)
- Shiyin Chen
- School of Medicine, Nantong University, Nantong 226000, China
| | - Yiran Liu
- Department of Epidemiology, School of Public Health, Nantong University, Nantong 226000, China
| | - Juan Ge
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), Nantong 226000, China
| | - Jianzhong Yin
- Department of Respiratory, Daye Hospital of Chinese Medicine, Daye 435100, China
| | - Ting Shi
- Department of Respiratory, Daye Hospital of Chinese Medicine, Daye 435100, China
| | - James Ntambara
- Department of Epidemiology, School of Public Health, Nantong University, Nantong 226000, China
| | - Zhounan Cheng
- Department of Epidemiology, School of Public Health, Nantong University, Nantong 226000, China
| | - Minjie Chu
- Department of Epidemiology, School of Public Health, Nantong University, Nantong 226000, China
- Correspondence: (M.C.); (H.G.)
| | - Hongyan Gu
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), Nantong 226000, China
- Correspondence: (M.C.); (H.G.)
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13
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Magoon R, Kashav R, Jose J, Walian A, Dey S. COVID-19 Positive Cohort Undergoing Cardiac Surgery: A Possible Un(3H)oly Trinity of Hypoxia-Hemolysis-Hyperinflammation. Braz J Cardiovasc Surg 2022; 37:587-590. [PMID: 35244375 PMCID: PMC9423808 DOI: 10.21470/1678-9741-2021-0077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 07/21/2021] [Indexed: 11/18/2022] Open
Abstract
While the fraternity continues to ponder on the mechanisms by which coronavirus disease (COVID-19) positivity affects the outcome of cardiac surgical subset, we put forth a 3H (Hypoxia-Hemolysis-Hyperinflammation) trilogy aimed at elucidating the liaison between cardiopulmonary bypass (commonly employed for cardiac surgical conduct) and COVID-19 infection. A sound comprehension of the same can doubtlessly assist the perioperative team in staging a well-directed pathophysiology-driven management approach.
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Affiliation(s)
- Rohan Magoon
- Department of Cardiac Anaesthesia, Atal Bihari Vajpayee
Institute of Medical Sciences (ABVIMS) and Dr. Ram Manohar Lohia Hospital, Baba
Kharak Singh Marg, New Delhi, India
| | - Ramesh Kashav
- Department of Cardiac Anaesthesia, Atal Bihari Vajpayee
Institute of Medical Sciences (ABVIMS) and Dr. Ram Manohar Lohia Hospital, Baba
Kharak Singh Marg, New Delhi, India
| | - Jes Jose
- Department of Anaesthesia, Atal Bihari Vajpayee
Institute of Medical Sciences (ABVIMS) and Dr. Ram Manohar Lohia Hospital, Baba
Kharak Singh Marg, New Delhi, India
| | - Ashish Walian
- Department of Cardiac Anaesthesia, Atal Bihari Vajpayee
Institute of Medical Sciences (ABVIMS) and Dr. Ram Manohar Lohia Hospital, Baba
Kharak Singh Marg, New Delhi, India
| | - Souvik Dey
- Department of Cardiac Anaesthesia, Atal Bihari Vajpayee
Institute of Medical Sciences (ABVIMS) and Dr. Ram Manohar Lohia Hospital, Baba
Kharak Singh Marg, New Delhi, India
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14
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Amini S, Rezabakhsh A, Hashemi J, Saghafi F, Azizi H, Sureda A, Habtemariam S, Khayat Kashani HR, Hesari Z, Sahebnasagh A. Pharmacotherapy consideration of thrombolytic medications in COVID-19-associated ARDS. J Intensive Care 2022; 10:38. [PMID: 35908022 PMCID: PMC9338522 DOI: 10.1186/s40560-022-00625-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 06/22/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is responsible for coronavirus disease (COVID-19), was identified as the new pathogen to lead pneumonia in Wuhan, China, which has spread all over the world and developed into a pandemic. Despite the over 1 year of pandemic, due to the lack of an effective treatment plan, the morbidity and mortality of COVID-19 remains high. Efforts are underway to find the optimal management for this viral disease. MAIN BODY SARS-CoV-2 could simultaneously affect multiple organs with variable degrees of severity, from mild to critical disease. Overproduction of pro-inflammatory mediators, exacerbated cellular and humoral immune responses, and coagulopathy such as Pulmonary Intravascular Coagulopathy (PIC) contributes to cell injuries. Considering the pathophysiology of the disease and multiple microthrombi developments in COVID-19, thrombolytic medications seem to play a role in the management of the disease. Beyond the anticoagulation, the exact role of thrombolytic medications in the management of patients with COVID-19-associated acute respiratory distress syndrome (ARDS) is not explicit. This review focuses on current progress in underlying mechanisms of COVID-19-associated pulmonary intravascular coagulopathy, the historical use of thrombolytic drugs in the management of ARDS, and pharmacotherapy considerations of thrombolytic therapy, their possible benefits, and pitfalls in COVID-19-associated ARDS. CONCLUSIONS Inhaled or intravenous administration of thrombolytics appears to be a salvage therapy for severe ARDS associated with COVID-19 by prompt attenuation of lung injury. Considering the pathogenesis of COVID-19-related ARDS and mechanism of action of thrombolytic agents, thrombolytics appear attractive options in stable patients without contraindications.
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Affiliation(s)
- Shahideh Amini
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Hashemi
- Department of Pathobiology and Laboratory Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Fatemeh Saghafi
- Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hossein Azizi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Antoni Sureda
- Research Group On Community Nutrition and Oxidative Stress, University of the Balearic Islands, Palma, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III, Madrid, Spain
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories and Herbal Analysis Services, University of Greenwich, Central Avenue, Chatham-Maritime, Kent, ME4 4TB UK
| | | | - Zahra Hesari
- Laboratory Sciences Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Adeleh Sahebnasagh
- Clinical Research Center, Department of Internal Medicine, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
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15
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Young LJ, Antwi-Boasiako S, Ferrall J, Wold LE, Mohler PJ, El Refaey M. Genetic and non-genetic risk factors associated with atrial fibrillation. Life Sci 2022; 299:120529. [PMID: 35385795 PMCID: PMC9058231 DOI: 10.1016/j.lfs.2022.120529] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/08/2022] [Accepted: 03/31/2022] [Indexed: 12/15/2022]
Abstract
Atrial fibrillation (AF) is the most common arrhythmic disorder and its prevalence in the United States is projected to increase to more than twelve million cases in 2030. AF increases the risk of other forms of cardiovascular disease, including stroke. As the incidence of atrial fibrillation increases dramatically with age, it is paramount to elucidate risk factors underlying AF pathogenesis. Here, we review tissue and cellular pathways underlying AF, as well as critical components that impact AF susceptibility including genetic and environmental risk factors. Finally, we provide the latest information on potential links between SARS-CoV-2 and human AF. Improved understanding of mechanistic pathways holds promise in preventative care and early diagnostics, and also introduces novel targeted forms of therapy that might attenuate AF progression and maintenance.
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Affiliation(s)
- Lindsay J Young
- The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
| | - Steve Antwi-Boasiako
- The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
| | - Joel Ferrall
- The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
| | - Loren E Wold
- The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA; College of Nursing, The Ohio State University, Columbus, OH, USA
| | - Peter J Mohler
- The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA; Department of Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA
| | - Mona El Refaey
- The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Surgery, Division of Cardiac Surgery, The Ohio State University, Columbus, OH, USA.
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16
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Huang P, Zuo Q, Li Y, Oduro PK, Tan F, Wang Y, Liu X, Li J, Wang Q, Guo F, Li Y, Yang L. A Vicious Cycle: In Severe and Critically Ill COVID-19 Patients. Front Immunol 2022; 13:930673. [PMID: 35784318 PMCID: PMC9240200 DOI: 10.3389/fimmu.2022.930673] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 05/12/2022] [Indexed: 01/08/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is one of the fastest-evolving viral diseases that has instigated a worldwide pandemic. Severe inflammatory syndrome and venous thrombosis are commonly noted in COVID-19 patients with severe and critical illness, contributing to the poor prognosis. Interleukin (IL)-6, a major complex inflammatory cytokine, is an independent factor in predicting the severity of COVID-19 disease in patients. IL-6 and tumor necrosis factor (TNF)-α participate in COVID-19-induced cytokine storm, causing endothelial cell damage and upregulation of plasminogen activator inhibitor-1 (PAI-1) levels. In addition, IL-6 and PAI-1 form a vicious cycle of inflammation and thrombosis, which may contribute to the poor prognosis of patients with severe COVID-19. Targeted inhibition of IL-6 and PAI-1 signal transduction appears to improve treatment outcomes in severely and critically ill COVID-19 patients suffering from cytokine storms and venous thrombosis. Motivated by studies highlighting the relationship between inflammatory cytokines and thrombosis in viral immunology, we provide an overview of the immunothrombosis and immunoinflammation vicious loop between IL-6 and PAI-1. Our goal is that understanding this ferocious circle will benefit critically ill patients with COVID-19 worldwide.
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Affiliation(s)
- Peifeng Huang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qingwei Zuo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yue Li
- School of Department of Clinical Training and Teaching of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Patrick Kwabena Oduro
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Fengxian Tan
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuanyuan Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaohui Liu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jing Li
- School of Department of Clinical Training and Teaching of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qilong Wang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Fei Guo
- National Health Commission of the People’s Republic of China Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology and Center for AIDS Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- *Correspondence: Fei Guo, ; Yue Li, ; Long Yang,
| | - Yue Li
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Fei Guo, ; Yue Li, ; Long Yang,
| | - Long Yang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Research Center for Infectious Diseases, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Fei Guo, ; Yue Li, ; Long Yang,
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17
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Ashkenazy N, Patel NA, Sridhar J, Yannuzzi NA, Belin PJ, Kaplan R, Kothari N, Benitez Bajandas GA, Kohly RP, Roizenblatt R, Pinhas A, Mundae R, Rosen RB, Ryan EH, Chiang A, Chang LK, Khurana RN, Finn AP. Hemi- and Central Retinal Vein Occlusion Associated with COVID-19 Infection in Young Patients without Known Risk Factors. Ophthalmol Retina 2022; 6:520-530. [PMID: 35278727 PMCID: PMC8907133 DOI: 10.1016/j.oret.2022.02.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/08/2022] [Accepted: 02/11/2022] [Indexed: 02/07/2023]
Abstract
PURPOSE Venous thromboembolic complications have been reported in association with coronavirus disease 2019 (COVID-19) infection. We raised awareness regarding a potential temporal association between COVID-19 infection and retinal vein occlusion (RVO). DESIGN Multicenter, retrospective, nonconsecutive case series. SUBJECTS Patients presenting with hemi-RVO (HRVO) or central RVO (CRVO) between March 2020 and March 2021, with confirmed COVID-19 infection, were included. The exclusion criteria were as follows: age >50 years, hypertension, diabetes, glaucoma, obesity, underlying hypercoagulable states, and those requiring intubation during hospitalization. METHODS This was a multicenter, retrospective, nonconsecutive case series including patients presenting with hemi-RVO (HRVO) or central RVO (CRVO) between March 2020 and March 2021, with confirmed COVID-19 infection. The exclusion criteria were as follows: age >50 years, hypertension, diabetes, glaucoma, obesity, underlying hypercoagulable states, and those requiring intubation during hospitalization. MAIN OUTCOME MEASURES Ophthalmic findings, including presenting and final visual acuity (VA), imaging findings, and clinical course. RESULTS Twelve eyes of 12 patients with CRVO (9 of 12) or HRVO (3 of 12) after COVID-19 infection were included. The median age was 32 years (range, 18-50 years). Three patients were hospitalized, but none were intubated. The median time from COVID-19 diagnosis to ophthalmic symptoms was 6.9 weeks. The presenting VA ranged from 20/20 to counting fingers, with over half (7 of 12) having a VA of ≥20/40. OCT revealed macular edema in 42% of the eyes; of these, 80% (4 of 5) were treated with anti-VEGF injections. Ninety-two percent (11 of 12) had partial or complete resolution of ocular findings at final follow-up. Four eyes (33%) had retinal thinning, as determined using OCT, by the end of the study interval. The final VA ranged from 20/20 to 20/60, with 11 of the 12 (92%) eyes achieving a VA of ≥20/40 at a median final follow-up period of 13 weeks (range, 4-52 weeks). CONCLUSIONS Although we acknowledge the high seroprevalence of COVID-19 and that a causal relationship cannot be established, we reported this series to raise awareness regarding the potential risk of retinal vascular events due to a heightened thromboinflammatory state associated with COVID-19 infection.
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Affiliation(s)
- Noy Ashkenazy
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida
| | - Nimesh A Patel
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida; Massachusetts Eye and Ear Infirmary, Harvard University, Boston, Massachusetts
| | - Jayanth Sridhar
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida
| | - Nicolas A Yannuzzi
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida
| | | | | | | | | | - Radha P Kohly
- Department of Ophthalmology, Sunnybrook Health Sciences Center, Toronto, Canada; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada
| | | | - Alexander Pinhas
- New York Eye and Ear Infirmary of Mount Sinai, New York, New York
| | - Rusdeep Mundae
- Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota
| | - Richard B Rosen
- New York Eye and Ear Infirmary of Mount Sinai, New York, New York
| | - Edwin H Ryan
- VitreoRetinal Surgery, PLLC, Minneapolis, Minnesota
| | - Allen Chiang
- Mid Atlantic Retina, Wills Eye Hospital Retina Service, Philadelphia, Pennsylvania
| | - Louis K Chang
- Northern California Retina Vitreous Associates, Mountain View, California
| | - Rahul N Khurana
- Northern California Retina Vitreous Associates, Mountain View, California; Department of Ophthalmology, University of California, San Francisco, California
| | - Avni P Finn
- Northern California Retina Vitreous Associates, Mountain View, California; Department of Ophthalmology, Vanderbilt University, Nashville, Tennessee.
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18
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Ilieva E, Boyapati A, Chervenkov L, Gulinac M, Borisov J, Genova K, Velikova T. Imaging related to underlying immunological and pathological processes in COVID-19. World J Clin Infect Dis 2022; 12:1-19. [DOI: 10.5495/wjcid.v12.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 11/09/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
The introduction of coronavirus disease-2019 (COVID-19) as a global pandemic has contributed to overall morbidity and mortality. With a focus on understanding the immunology and pathophysiology of the disease, these features can be linked with the respective findings of imaging studies. Thus, the constellation between clinical presentation, histological, laboratory, immunological, and imaging results is crucial for the proper management of patients. The purpose of this article is to examine the role of imaging during the particular stages of severe acute respiratory syndrome coronavirus 2 infection – asymptomatic stage, typical and atypical COVID-19 pneumonia, acute respiratory distress syndrome, multiorgan failure, and thrombosis. The use of imaging methods to assess the severity and duration of changes is crucial in patients with COVID-19. Radiography and computed tomography are among the methods that allow accurate characterization of changes.
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Affiliation(s)
- Elena Ilieva
- Department of Diagnostic Imaging, University Emergency Hospital (UMHATEM) "N. I. Pirogov”, Sofia 1606, Bulgaria
| | - Alexandra Boyapati
- Department of Diagnostic Imaging, University Emergency Hospital (UMHATEM) "N. I. Pirogov”, Sofia 1606, Bulgaria
| | - Lyubomir Chervenkov
- Department of Diagnostic Imaging, Medical University, Plovdiv, University Hospital "St George", Plovdiv 4000, Bulgaria
| | - Milena Gulinac
- Department of General and Clinical Pathology, Medical University, Plovdiv, University Hospital "St George", Plovdiv 4000, Bulgaria
| | - Jordan Borisov
- Department of Diagnostic Imaging, MBAL-Dobrich” AD, Dobrich 9300, Bulgaria
| | - Kamelia Genova
- Department of Diagnostic Imaging, University Emergency Hospital (UMHATEM) "N. I. Pirogov”, Sofia 1606, Bulgaria
| | - Tsvetelina Velikova
- Department of Clinical Immunology, University Hospital “Lozenetz”, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University “St. Kliment Ohridski”, Sofia 1407, Bulgaria
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19
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Abd El-Lateef AE, Alghamdi S, Ebid G, Khalil K, Kabrah S, Abdel Ghafar MT. Coagulation Profile in COVID-19 Patients and its Relation to Disease Severity and Overall Survival: A Single-Center Study. Br J Biomed Sci 2022; 79:10098. [PMID: 35996516 PMCID: PMC9302539 DOI: 10.3389/bjbs.2022.10098] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 03/18/2022] [Indexed: 01/08/2023]
Abstract
Objectives: This study aims to investigate hemostatic changes in patients with coronavirus disease (COVID-19) and their relationship to disease severity and survival.Methods: This study included 284 patients with COVID-19 who attended the Security Forces Hospital, Makkah, Saudi Arabia between October 2020 and March 2021, and retrospectively reviewed their demographic, radiological, and laboratory findings. The coagulation profile was assayed at the time of diagnosis for platelet counts using an automated hematology analyzer; Sysmex XN2000 while international normalized ratio (INR), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, factor VIII, ristocetin cofactor (RiCoF), and von Willebrand factor antigen (VWF-Ag) were measured by Stago kits on a Stago automated coagulation analyzer (STA Compact Max®).Results: In this study, 32.3% of the cases had severe disease, while 8.8% of the cases died. D-dimer, factor VIII, and RiCoF were the only independent predictors of disease severity, with factor VIII and RiCoF having significantly higher areas under the curve (AUCs) than D-dimer (all p < 0.001). Furthermore, age, aPTT, and factor VIII were associated with an increased risk of mortality in multivariate Cox regression analysis, with factor VIII having a higher AUC of 0.98 than aPTT with an optimal cut-off value of >314 IU/dl in predicting mortality. Cases with factor VIII levels >314 IU/dl, compared to those with factor VIII levels <314 IU/dl, were associated with a significantly shorter mean overall survival time (20.08 vs. 31.35 days, p < 0.001), a lower survival rate (30.3% vs. 99.2%, p < 0.001), and a 16.62-fold increased mortality risk.Conclusion: RiCoF is a novel predictor of disease severity in COVID-19, while factor VIII is confirmed as a predictor of severity and mortality in COVID-19 patients and is associated with lower overall survival and increased mortality risk.
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Affiliation(s)
- Amal Ezzat Abd El-Lateef
- Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
- Department of Laboratory Medicine, Faculty of Applied Medical Science, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Saad Alghamdi
- Department of Laboratory Medicine, Faculty of Applied Medical Science, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Gamal Ebid
- Department of Laboratory Medicine, Security Forces Hospital, Makkah, Saudi Arabia
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Khalid Khalil
- Department of Internal Medicine, Security Forces Hospital, Makkah, Saudi Arabia
| | - Saeed Kabrah
- Department of Laboratory Medicine, Faculty of Applied Medical Science, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Muhammad Tarek Abdel Ghafar
- Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
- *Correspondence: Muhammad Tarek Abdel Ghafar, , , orcid.org/0000-0002-0621-4291
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Dai MF, Guo ST, Ke YJ, Wang BY, Yu F, Xu H, Gu ZC, Ge WH. The Use of Oral Anticoagulation Is Not Associated With a Reduced Risk of Mortality in Patients With COVID-19: A Systematic Review and Meta-Analysis of Cohort Studies. Front Pharmacol 2022; 13:781192. [PMID: 35431952 PMCID: PMC9008218 DOI: 10.3389/fphar.2022.781192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Background: Hypercoagulability and thromboembolic events are associated with poor prognosis in coronavirus disease 2019 (COVID-19) patients. Whether chronic oral anticoagulation (OAC) improve the prognosis is yet controversial. The present study aimed to investigate the association between the chronic OAC and clinical outcomes in COVID-19 patients. Methods: PubMed, Embase, Web of Science, and the Cochrane Library were comprehensively searched to identify studies that evaluated OAC for COVID-19 until 24 July 2021. Random-effects model meta-analyses were performed to pool the relative risk (RR) and 95% confidence interval (CI) of all-cause mortality and intensive care unit (ICU) admission as primary and secondary outcomes, respectively. According to the type of oral anticoagulants [direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs)], subgroup and interaction analyses were performed to compare DOACs and VKAs. Meta-regression was performed to explore the potential confounders on all-cause mortality. Results: A total of 12 studies involving 30,646 patients met the inclusion criteria. The results confirmed that chronic OAC did not reduce the risk of all-cause mortality (RR: 0.92; 95% CI 0.82–1.03; p = 0.165) or ICU admission (RR: 0.65; 95% CI 0.40–1.04; p = 0.073) in patients with COVID-19 compared to those without OAC. The chronic use of DOACs did not reduce the risk of all-cause mortality compared to VKAs (Pinteraction = 0.497) in subgroup and interaction analyses. The meta-regression failed to detect any potential confounding on all-cause mortality. Conclusion: COVID-19 patients with chronic OAC were not associated with a lower risk of all-cause mortality and ICU admission compared to those without OAC, and the results were consistent across DOACs and VKA subgroups. Systematic Review Registration:clinicaltrials.gov, identifier CRD42021269764.
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Affiliation(s)
- Meng-Fei Dai
- Department of Pharmacy, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Si-Tong Guo
- Department of Pharmacy, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yi-Jun Ke
- Department of Pharmacy, The Anqing Hospital Affiliated to Anhui Medical University, Anqing, China
| | - Bao-Yan Wang
- Department of Pharmacy, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, China
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Feng Yu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Hang Xu
- Department of Pharmacy, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, China
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Hang Xu, ; Zhi-Chun Gu, ; Wei-Hong Ge,
| | - Zhi-Chun Gu
- Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Hang Xu, ; Zhi-Chun Gu, ; Wei-Hong Ge,
| | - Wei-Hong Ge
- Department of Pharmacy, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, China
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Hang Xu, ; Zhi-Chun Gu, ; Wei-Hong Ge,
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21
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COVID-19: cardiovascular manifestations-a review of the cardiac effects. J Geriatr Cardiol 2022; 19:245-250. [PMID: 35464648 PMCID: PMC9002085 DOI: 10.11909/j.issn.1671-5411.2022.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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22
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Obesity and Leptin Resistance in the Regulation of the Type I Interferon Early Response and the Increased Risk for Severe COVID-19. Nutrients 2022; 14:nu14071388. [PMID: 35406000 PMCID: PMC9002648 DOI: 10.3390/nu14071388] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/23/2022] [Accepted: 03/23/2022] [Indexed: 02/06/2023] Open
Abstract
Obesity, and obesity-associated conditions such as hypertension, chronic kidney disease, type 2 diabetes, and cardiovascular disease, are important risk factors for severe Coronavirus disease-2019 (COVID-19). The common denominator is metaflammation, a portmanteau of metabolism and inflammation, which is characterized by chronically elevated levels of leptin and pro-inflammatory cytokines. These induce the “Suppressor Of Cytokine Signaling 1 and 3” (SOCS1/3), which deactivates the leptin receptor and also other SOCS1/3 sensitive cytokine receptors in immune cells, impairing the type I and III interferon early responses. By also upregulating SOCS1/3, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 adds a significant boost to this. The ensuing consequence is a delayed but over-reactive immune response, characterized by high-grade inflammation (e.g., cytokine storm), endothelial damage, and hypercoagulation, thus leading to severe COVID-19. Superimposing an acute disturbance, such as a SARS-CoV-2 infection, on metaflammation severely tests resilience. In the long run, metaflammation causes the “typical western” conditions associated with metabolic syndrome. Severe COVID-19 and other serious infectious diseases can be added to the list of its short-term consequences. Therefore, preventive measures should include not only vaccination and the well-established actions intended to avoid infection, but also dietary and lifestyle interventions aimed at improving body composition and preventing or reversing metaflammation.
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Coagulopathy and Fibrinolytic Pathophysiology in COVID-19 and SARS-CoV-2 Vaccination. Int J Mol Sci 2022; 23:ijms23063338. [PMID: 35328761 PMCID: PMC8955234 DOI: 10.3390/ijms23063338] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/03/2022] [Accepted: 03/15/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is frequently complicated by thrombosis. In some cases of severe COVID-19, fibrinolysis may be markedly enhanced within a few days, resulting in fatal bleeding. In the treatment of COVID-19, attention should be paid to both coagulation activation and fibrinolytic activation. Various thromboses are known to occur after vaccination with SARS-CoV-2 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can occur after adenovirus-vectored vaccination, and is characterized by the detection of anti-platelet factor 4 antibodies by enzyme-linked immunosorbent assay and thrombosis in unusual locations such as cerebral venous sinuses and visceral veins. Treatment comprises high-dose immunoglobulin, argatroban, and fondaparinux. Some VITT cases show marked decreases in fibrinogen and platelets and marked increases in D-dimer, suggesting the presence of enhanced-fibrinolytic-type disseminated intravascular coagulation with a high risk of bleeding. In the treatment of VITT, evaluation of both coagulation activation and fibrinolytic activation is important, adjusting treatments accordingly to improve outcomes.
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Al-Kuraishy HM, Al-Gareeb AI, Al-Hussaniy HA, Al-Harcan NAH, Alexiou A, Batiha GES. Neutrophil Extracellular Traps (NETs) and Covid-19: A new frontiers for therapeutic modality. Int Immunopharmacol 2022; 104:108516. [PMID: 35032828 PMCID: PMC8733219 DOI: 10.1016/j.intimp.2021.108516] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 01/08/2023]
Abstract
Coronavirus disease 2019 (Covid-19) is a worldwide infectious disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). In severe SARS-CoV-2 infection, there is severe inflammatory reactions due to neutrophil recruitments and infiltration in the different organs with the formation of neutrophil extracellular traps (NETs), which involved various complications of SARS-CoV-2 infection. Therefore, the objective of the present review was to explore the potential role of NETs in the pathogenesis of SARS-CoV-2 infection and to identify the targeting drugs against NETs in Covid-19 patients. Different enzyme types are involved in the formation of NETs, such as neutrophil elastase (NE), which degrades nuclear protein and release histones, peptidyl arginine deiminase type 4 (PADA4), which releases chromosomal DNA and gasdermin D, which creates pores in the NTs cell membrane that facilitating expulsion of NT contents. Despite of the beneficial effects of NETs in controlling of invading pathogens, sustained formations of NETs during respiratory viral infections are associated with collateral tissue injury. Excessive development of NETs in SARS-CoV-2 infection is linked with the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) due to creation of the NETs-IL-1β loop. Also, aberrant NTs activation alone or through NETs formation may augment SARS-CoV-2-induced cytokine storm (CS) and macrophage activation syndrome (MAS) in patients with severe Covid-19. Furthermore, NETs formation in SARS-CoV-2 infection is associated with immuno-thrombosis and the development of ALI/ARDS. Therefore, anti-NETs therapy of natural or synthetic sources may mitigate SARS-CoV-2 infection-induced exaggerated immune response, hyperinflammation, immuno-thrombosis, and other complications.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq
| | | | - Nasser A Hadi Al-Harcan
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Rasheed University College, Bagdad, Iraq
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia; AFNP Med Austria, Wien, Austria.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Al Beheira, Egypt.
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Coagulopatía en la infección por el virus SARS-CoV-2 (COVID-19): de los mecanismos fisiopatológicos al diagnóstico y tratamiento. ACTA COLOMBIANA DE CUIDADO INTENSIVO 2022. [PMCID: PMC7659516 DOI: 10.1016/j.acci.2020.10.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
La presencia de coagulopatía en pacientes con infección por COVID-19 se asocia con un mayor riesgo de muerte. Además, la relevancia de dichas anomalías de la coagulación se ha convertido en un factor determinante en el desenlace de los pacientes más enfermos, a medida que una proporción sustancial de pacientes con manifestaciones clínicas graves desarrollan complicaciones tromboembólicas venosas y arteriales, muchas veces no diagnosticadas sino hasta hallazgos post mortem. La evidencia disponible derivada de observaciones clínicas y series de autopsias distingue la coagulopatía asociada a COVID-19 de la microangiopatía trombótica y la coagulación intravascular diseminada (CID) (coagulopatía inducida por sepsis). Se pueden observar posibles superposiciones en pacientes críticos en los que el colapso circulatorio, la falla orgánica multisistémica, la hipoxemia refractaria y el síndrome de dificultad respiratoria aguda causan una combinación de CID de bajo grado y microangiopatía trombótica pulmonar localizada, que podría tener un impacto sustancial en la disfunción orgánica en los pacientes más gravemente afectados.
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26
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Vitamin D Immune-Mediated Responses and SARS-CoV-2 Infection: Clinical Implications in COVID-19. IMMUNO 2021. [DOI: 10.3390/immuno2010001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Active vitamin D is a true steroid hormone with pleiotropic biological effects that go beyond the classical concept of bone metabolism regulation. In fact, adequate serum levels of 25-hydroxyvitamin D (>40 ng/mL) are required to support several biological functions, including the control of innate and adaptive immunity in course of infectious, inflammatory and autoimmune diseases. SARS-CoV-2 is responsible for the COVID-19 pandemic and deficient/insufficient serum levels of 25-hydroxyvitamin D are reported in very large cohorts of patients. Of note, vitamin D is involved in different pathophysiological processes, such as expression of SARS-CoV-2 receptor (ACE2), activation of innate (neutrophils with their extracellular traps, monocytes/macrophages, dendritic cells, natural killer cells) and adaptive (T and B lymphocytes) immune cells and clinical manifestations, such as coagulation/thrombotic disorders and acute respiratory distress syndrome. Randomized clinical trials regarding vitamin D supplementation in COVID-19 patients have shown favorable effects on the control of inflammation markers, arterial oxygen saturation/inspired fraction of oxygen ratio, admission to hospital intensive care units and mortality. A target of serum 25-hydroxyvitamin D > 50 ng/mL has been identified as protective for the course of COVID-19, potentially playing an ancillary role in the treatment of the disease.
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Poveda-Jaramillo R. Coronavirus disease 2019-induced hypercoagulability and its clinical implications. Asian Cardiovasc Thorac Ann 2021; 30:515-523. [PMID: 34930050 DOI: 10.1177/02184923211069185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Coronavirus disease 2019 is the disease produced by severe acute respiratory syndrome-coronavirus-2, which is introduced into the host's cell thanks to the angiotensin-converting enzyme 2 receptor. Once there, it uses the cell's machinery to multiply itself. In this process, it generates an immune response that stimulates the lymphocytes to produce cytokines and reactive oxygen species that begin to deteriorate the endothelial cell. Complement activation, through the complement attack complex and C5a, contributes to this endothelial damage. The different mediators further promote the expression of adhesion molecules on the endothelial surface, which encourages all blood cells to adhere to the endothelial surface to form small conglomerates, called clots, which obstruct the lumen of the small blood vessels. Furthermore, the mediators of clot lysis are inhibited. All this promotes a prothrombotic environment within the pulmonary capillaries that is reflected in the elevation of D-dimer. The only solution for this cascade of events seems to be the implementation of an effective anticoagulation protocol that early counteracts the changes induced by thrombi in the pulmonary circulation and reflected in the functioning of the right ventricle.
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Bouillon R, Quesada‐Gomez JM. Vitamin D Endocrine System and COVID-19. JBMR Plus 2021; 5:e10576. [PMID: 34950831 PMCID: PMC8674769 DOI: 10.1002/jbm4.10576] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/25/2021] [Accepted: 10/31/2021] [Indexed: 12/19/2022] Open
Abstract
Preclinical data strongly suggest that the vitamin D endocrine system (VDES) may have extraskeletal effects. Cells of the immune and cardiovascular systems and lungs can express the vitamin D receptor, and overall these cells respond in a coherent fashion when exposed to 1,25-dihydroxyvitamin D, the main metabolite of the VDES. Supplementation of vitamin D-deficient subjects may decrease the risk of upper respiratory infections. The VDES also has broad anti-inflammatory and anti-thrombotic effects, and other mechanisms argue for a potential beneficial effect of a good vitamin D status on acute respiratory distress syndrome, a major complication of this SARS-2/COVID-19 infection. Activation of the VDES may thus have beneficial effects on the severity of COVID-19. Meta-analysis of observational data show that a better vitamin D status decreased the requirement of intensive care treatment or decreased mortality. A pilot study in Cordoba indicated that admission to intensive care was drastically reduced by administration of a high dose of calcifediol early after hospital admission for COVID-19. A large observational study in Barcelona confirmed that such therapy significantly decreased the odds ratio (OR) of mortality (OR = 0.52). This was also the conclusion of a retrospective study in five hospitals of Southern Spain. A retrospective study on all Andalusian patients hospitalized because of COVID-19, based on real-world data from the health care system, concluded that prescription of calcifediol (hazard ratio [HR] = 0.67) or vitamin D (HR = 0.75), 15 days before hospital admission decreased mortality within the first month. In conclusion, a good vitamin D status may have beneficial effects on the course of COVID-19. This needs to be confirmed by large, randomized trials, but in the meantime, we recommend (rapid) correction of 25 hydroxyvitamin D (25OHD) deficiency in subjects exposed to this coronavirus. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Roger Bouillon
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and AgeingKU LeuvenLeuvenBelgium
| | - José Manuel Quesada‐Gomez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina SofíaUniversidad de Córdoba, Fundación Progreso y SaludCórdobaSpain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES)MadridSpain
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Abstract
Coronavirus disease 2019 (COVID-19) is a systemic disease that can be
life-threatening involving immune and inflammatory responses, and that can
result in potentially lethal complications, including venous thrombo-embolism
(VTE). Forming an integrative approach to thrombo-prophylaxis and coagulation
treatment for COVID-19 patients ensues. We aim at reviewing the literature for
anticoagulation in the setting of COVID-19 infection to provide a summary on
anticoagulation for this patient population. COVID-19 infection is associated
with a state of continuous inflammation, which results in macrophage activation
syndrome and an increased rate of thrombosis. Risk assessment models to predict
the risk of thrombosis in critically ill patients have not yet been validated.
Currently published guidelines suggest the use of prophylactic intensity over
intermediate intensity or therapeutic intensity anticoagulant for patients with
critical illness or acute illness related to COVID-19 infection. Critically ill
COVID-19 patients who are diagnosed with acute VTE are considered to have a
provoking factor, and, therefore, treatment duration should be at least 3
months. Patients with proximal deep venous thrombosis or pulmonary embolism
should receive parenteral over oral anticoagulants with low-molecular-weight
heparin or fondaparinux preferred over unfractionated heparin. In patients with
impending hemodynamic compromise due to PE, and who are not at increased risk
for bleeding, reperfusion may be necessary. Internists should remain updated on
new emerging evidence regarding anticoagulation for COVID-19 patients. Awaiting
these findings, we invite internists to perform individualized decisions that
are unique for every patient and to base them on clinical judgment for risk
assessment.
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Affiliation(s)
- Firas Kreidieh
- 66984American University of Beirut Medical Center, Beirut, Lebanon
| | - Sally Temraz
- 66984American University of Beirut Medical Center, Beirut, Lebanon
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Raychaudhuri S, Pujani M, Menia R, Verma N, Singh M, Chauhan V, Jain M, Chandoke RK, Kaur H, Agrawal S, Singh A. COVID-19 Associated Coagulopathy in an Indian Scenario: A Correlation with Disease Severity and Survival Status. Indian J Hematol Blood Transfus 2021; 38:341-351. [PMID: 34426721 PMCID: PMC8374035 DOI: 10.1007/s12288-021-01465-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 06/24/2021] [Indexed: 01/08/2023] Open
Abstract
Covid-19 pandemic reveals that the virus causes Covid-19 associated coagulopathy and it is well known that thrombotic risk is associated with ethnicity. To describe the Covid-19 associated coagulopathy in Indian population and to correlate it with the disease severity and survivor status. A cross sectional descriptive study of 391 confirmed Covid-19 cases was carried out over a period of 1.5 months. Patients were categorised as mild to moderate, severe and very severe and also labelled as survivors and non survivors. Prothrombin time (PT), International normalised ratio (INR), activated partial thromboplastin time, D dimer, Fibrin degradation products (FDP), fibrinogen and thrombin time and platelet counts were investigated among the subgroups. Mean age was higher in patients with severe disease (57.62 ± 13.08) and among the non survivors (56.54 ± 12.78). Statistically significant differences in D dimer, FDP, PT, INR and age were seen among the 3 subgroups and survivors. Strong significant positive correlation was noted between D dimer and FDP (r = 0.838, p < .001), PT and INR (r = 0.986, p < 0.001). D dimer was the best single coagulation parameter as per the area under curve (AUC: 0.762, p < 0.001) and D dimer + FDP was the best combination parameter (AUC: 0.764, p = 0) to differentiate mild moderate from severe disease. Raised levels of D dimer, FDP, PT, PT INR and higher age correlated positively with disease severity and mortality in Indian Population.
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Affiliation(s)
| | - Mukta Pujani
- Department of Pathology, ESIC Medical College, Faridabad, Haryana India
| | - Reetika Menia
- Department of Pathology, ESIC Medical College, Faridabad, Haryana India
| | - Nikhil Verma
- Department of Medicine, ESIC Medical College, Faridabad, Haryana India
| | - Mitasha Singh
- Department of Community Medicine, ESIC Medical College, Faridabad, Haryana India
| | - Varsha Chauhan
- Department of Pathology, ESIC Medical College, Faridabad, Haryana India
| | - Manjula Jain
- Department of Pathology, ESIC Medical College, Faridabad, Haryana India
| | - R K Chandoke
- Department of Pathology, ESIC Medical College, Faridabad, Haryana India
| | - Harnam Kaur
- Department of Biochemistry, ESIC Medical College, Faridabad, Haryana India
| | - Snehil Agrawal
- Department of Pathology, ESIC Medical College, Faridabad, Haryana India
| | - Aparna Singh
- Department of Pathology, ESIC Medical College, Faridabad, Haryana India
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Mansory EM, Srigunapalan S, Lazo-Langner A. Venous Thromboembolism in Hospitalized Critical and Noncritical COVID-19 Patients: A Systematic Review and Meta-analysis. TH OPEN 2021; 5:e286-e294. [PMID: 34240001 PMCID: PMC8260281 DOI: 10.1055/s-0041-1730967] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/06/2021] [Indexed: 12/11/2022] Open
Abstract
Introduction Venous thromboembolism (VTE) has been observed as a frequent complication in patients with severe novel coronavirus disease 2019 (COVID-19) infection requiring hospital admission. Aim This study was aimed to evaluate the epidemiology of VTE in hospitalized intensive care unit (ICU) and non-ICU patients. Materials and Methods PubMed was searched up to November 13, 2020, and updated in December 12, 2020. We included studies that evaluated the epidemiology of VTE, including pulmonary embolism (PE) and/or deep vein thrombosis (DVT), in patients with COVID-19. Results A total of 91 studies reporting on 35,017 patients with COVID-19 was included. The overall frequency of VTE in all patients, ICU and non-ICU, was 12.8% (95% confidence interval [CI]: 11.103-14.605), 24.1% (95% CI: 20.070-28.280), and 7.7% (95% CI: 5.956-9.700), respectively. PE occurred in 8.5% (95% CI: 6.911-10.208), and proximal DVT occurred in 8.2% (95% CI: 6.675-9.874) of all hospitalized patients. The relative risk for VTE associated with ICU admission was 2.99 (95% CI: 2.301-3.887, p <0.001). DVT and PE estimated in studies that adopted some form of systematic screening were higher compared with studies with symptom-triggered screening. Analysis restricted to studies in the 5th quintile of sample size reported significantly lower VTE estimates. Conclusion This study confirmed a high risk of VTE in hospitalized COVID-19 patients, especially those admitted to the ICU. Nevertheless, sensitivity analysis suggests that previously reported frequencies of VTE in COVID-19 might have been overestimated.
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Affiliation(s)
- Eman M Mansory
- Division of Hematology, Department of Medicine, Western University, London, Ontario, Canada
- Department of Hematology, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Suthan Srigunapalan
- Division of Hematology, Department of Medicine, Western University, London, Ontario, Canada
| | - Alejandro Lazo-Langner
- Division of Hematology, Department of Medicine, Western University, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
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Franco‐Moreno A, Herrera‐Morueco M, Mestre‐Gómez B, Muñoz‐Rivas N, Abad‐Motos A, Salazar‐Chiriboga D, Duffort‐Falcó M, Medrano‐Izquierdo P, Bustamante‐Fermosel A, Pardo‐Guimera V, Ulla‐Anés M, Torres‐Macho J. Incidence of Deep Venous Thrombosis in Patients With COVID-19 and Pulmonary Embolism: Compression Ultrasound COVID Study. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2021; 40:1411-1416. [PMID: 33017480 PMCID: PMC7675470 DOI: 10.1002/jum.15524] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/01/2020] [Accepted: 09/08/2020] [Indexed: 05/17/2023]
Abstract
OBJECTIVES Several reports had observed a high risk of pulmonary embolism (PE) in patients with coronavirus disease 2019 (COVID-19), most of them in the intensive care unit. Reported findings indicate that a direct viral-mediated hyperinflammatory response leads to local thromboinflammation. According to those findings, the incidence of deep venous thrombosis (DVT) in patients with COVID-19 and PE should be low. The objective of this study was to evaluate the incidence of DVT in patients with COVID-19 who developed PE. METHODS In this prospective observational study, consecutive patients hospitalized in the internal medicine ward with a diagnosis of COVID-19 who developed PE were screened for DVT in the lower extremities with complete compression ultrasound. RESULTS The study comprised 26 patients. Fifteen patients (57.7%) were male. The median age was 60 years (interquartile range, 54-73 years). Compression ultrasound findings were positive for DVT in 2 patients (7.7%; 95% confidence interval, 3.6%-11.7%). Patients with DVT had central and bilateral PE. In both, venous thromboembolism was diagnosed in the emergency department, so they did not receive previous prophylactic therapy with low-molecular-weight heparin. Patients without DVT had higher median d-dimer levels: 25,688 μg/dL (interquartile range, 80,000-1210 μg/dL) versus 5310 μg/dL (P < .05). CONCLUSIONS Our study showed a low incidence of DVT in a cohort of patients with COVID-19 and PE. This observation suggests that PE in these patients could be produced mainly by a local thromboinflammatory syndrome induced by severe acute respiratory syndrome coronavirus 2 infection and not by a thromboembolic event.
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Affiliation(s)
| | | | | | - Nuria Muñoz‐Rivas
- Department of Internal MedicineInfanta Leonor University HospitalMadridSpain
| | - Ane Abad‐Motos
- Department of AnesthesiologyInfanta Leonor University HospitalMadridSpain
| | | | | | | | | | | | - Mariano Ulla‐Anés
- Department of Internal MedicineInfanta Leonor University HospitalMadridSpain
| | - Juan Torres‐Macho
- Department of Internal MedicineInfanta Leonor University HospitalMadridSpain
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Pathogenesis of hemorrhagic disease caused by elephant endotheliotropic herpesvirus (EEHV) in Asian elephants (Elephas maximus). Sci Rep 2021; 11:12998. [PMID: 34155304 PMCID: PMC8217522 DOI: 10.1038/s41598-021-92393-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/10/2021] [Indexed: 02/06/2023] Open
Abstract
Elephant endotheliotropic herpesvirus-hemorrhagic disease (EEHV-HD) is an acute fatal disease in elephants. Despite the fact that the underlying pathogenesis of EEHV-HD has been proposed, it remains undetermined as to what mechanisms drive these hemorrhagic and edematous lesions. In the present study, we have investigated and explained the pathogenesis of acute EEHV-HD using blood profiles of EEHV-HD and EEHV-infected cases, hematoxylin and eosin (H&E) stain, special stains, immunohistochemistry, quantitative polymerase chain reaction (PCR) and reverse transcriptase polymerase chain reaction (RT-PCR). It was found that EEHV genomes were predominantly detected in various internal organs of EEHV-HD cases. Damage to endothelial cells, vasculitis and vascular thrombosis of the small blood vessels were also predominantly observed. Increases in platelet endothelial cell adhesion molecules-1 (PECAM-1)- and von Willebrand factor (vWF)-immunolabeling positive cells were significantly noticed in injured blood vessels. The expression of pro-inflammatory cytokine mRNA was significantly up-regulated in EEHV-HD cases when compared to EEHV-negative controls. We have hypothesized that this could be attributed to the systemic inflammation and disruption of small blood vessels, followed by the disseminated intravascular coagulopathy that enhanced hemorrhagic and edematous lesions in EEHV-HD cases. Our findings have brought attention to the potential application of effective preventive and therapeutic protocols to treat EEHV infection in Asian elephants.
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Blood coagulation parameter abnormalities in hospitalized patients with confirmed COVID-19 in Ethiopia. PLoS One 2021; 16:e0252939. [PMID: 34153056 PMCID: PMC8216564 DOI: 10.1371/journal.pone.0252939] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 05/25/2021] [Indexed: 01/08/2023] Open
Abstract
Background Coagulopathy and thromboembolic events are among the complications of Corona Virus disease 2019 (COVID-19). Abnormal coagulation parameters in COVID-19 patients are important prognostic factors of disease severity. The aim of this study was to analyze coagulation profiles of hospitalized COVID-19 patients in Addis Ababa, Ethiopia. Methods This prospective cross-sectional study was conducted among 455 Covid-19 patients admitted at Millennium COVID-19 care and treatment center, Addis Ababa, Ethiopia from July 1- October 23, 2020. Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) and International normalized ratio (INR) were determined on HUMACLOT DUE PLUS® coagulation analyzer (Wiesbaden, Germany). In all statistical analysis of results, p<0.05 was defined as statistically significant. Result A prolonged prothrombin time was found in 46.8% of study participants with COVID-19 and a prolonged prothrombin time and elevated INR in 53.3% of study subjects with severe and 51% of critically COVID patients. Thrombocytopenia was detected in 22.1% of COVID-19 patients. 50.5% and 51.3% of COVID-19 patients older than 55 years had thrombocytopenia and prolonged APTT respectively. Conclusion In this study, prolonged prothrombin time and elevated INR were detected in more than 50% of severe and critical COVID-19 patients. Thrombocytopenia and prolonged APTT were dominant in COVID-19 patients older than 55 years. Thus, we recommend emphasis to be given for monitoring of platelet count, PT, APTT and INR in hospitalized and admitted COVID-19 patients.
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Kuznetsova TA, Andryukov BG, Makarenkova ID, Zaporozhets TS, Besednova NN, Fedyanina LN, Kryzhanovsky SP, Shchelkanov MY. The Potency of Seaweed Sulfated Polysaccharides for the Correction of Hemostasis Disorders in COVID-19. Molecules 2021; 26:2618. [PMID: 33947107 PMCID: PMC8124591 DOI: 10.3390/molecules26092618] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023] Open
Abstract
Hemostasis disorders play an important role in the pathogenesis, clinical manifestations, and outcome of COVID-19. First of all, the hemostasis system suffers due to a complicated and severe course of COVID-19. A significant number of COVID-19 patients develop signs of hypercoagulability, thrombocytopenia, and hyperfibrinolysis. Patients with severe COVID-19 have a tendency toward thrombotic complications in the venous and arterial systems, which is the leading cause of death in this disease. Despite the success achieved in the treatment of SARS-CoV-2, the search for new effective anticoagulants, thrombolytics, and fibrinolytics, as well as their optimal dose strategies, continues to be relevant. The wide therapeutic potential of seaweed sulfated polysaccharides (PSs), including anticoagulant, thrombolytic, and fibrinolytic activities, opens up new possibilities for their study in experimental and clinical trials. These natural compounds can be important complementary drugs for the recovery from hemostasis disorders due to their natural origin, safety, and low cost compared to synthetic drugs. In this review, the authors analyze possible pathophysiological mechanisms involved in the hemostasis disorders observed in the pathological progression of COVID-19, and also focus the attention of researchers on seaweed PSs as potential drugs aimed to correction these disorders in COVID-19 patients. Modern literature data on the anticoagulant, antithrombotic, and fibrinolytic activities of seaweed PSs are presented, depending on their structural features (content and position of sulfate groups on the main chain of PSs, molecular weight, monosaccharide composition and type of glycosidic bonds, the degree of PS chain branching, etc.). The mechanisms of PS action on the hemostasis system and the issues of oral bioavailability of PSs, important for their clinical use as oral anticoagulant and antithrombotic agents, are considered. The combination of the anticoagulant, thrombolytic, and fibrinolytic properties, along with low toxicity and relative cheapness of production, open up prospects for the clinical use of PSs as alternative sources of new anticoagulant and antithrombotic compounds. However, further investigation and clinical trials are needed to confirm their efficacy.
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Affiliation(s)
- Tatyana A. Kuznetsova
- G.P. Somov Institute of Epidemiology and Microbiology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 690087 Vladivostok, Russia; (B.G.A.); (I.D.M.); (T.S.Z.); (N.N.B.); (M.Y.S.)
| | - Boris G. Andryukov
- G.P. Somov Institute of Epidemiology and Microbiology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 690087 Vladivostok, Russia; (B.G.A.); (I.D.M.); (T.S.Z.); (N.N.B.); (M.Y.S.)
- School of Biomedicine, Far Eastern Federal University (FEFU), 690091 Vladivostok, Russia;
| | - Ilona D. Makarenkova
- G.P. Somov Institute of Epidemiology and Microbiology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 690087 Vladivostok, Russia; (B.G.A.); (I.D.M.); (T.S.Z.); (N.N.B.); (M.Y.S.)
| | - Tatyana S. Zaporozhets
- G.P. Somov Institute of Epidemiology and Microbiology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 690087 Vladivostok, Russia; (B.G.A.); (I.D.M.); (T.S.Z.); (N.N.B.); (M.Y.S.)
| | - Natalya N. Besednova
- G.P. Somov Institute of Epidemiology and Microbiology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 690087 Vladivostok, Russia; (B.G.A.); (I.D.M.); (T.S.Z.); (N.N.B.); (M.Y.S.)
| | - Ludmila N. Fedyanina
- School of Biomedicine, Far Eastern Federal University (FEFU), 690091 Vladivostok, Russia;
| | - Sergey P. Kryzhanovsky
- Medical Association of the Far Eastern Branch of the Russian Academy of Sciences, 690022 Vladivostok, Russia;
| | - Mikhail Yu. Shchelkanov
- G.P. Somov Institute of Epidemiology and Microbiology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 690087 Vladivostok, Russia; (B.G.A.); (I.D.M.); (T.S.Z.); (N.N.B.); (M.Y.S.)
- School of Biomedicine, Far Eastern Federal University (FEFU), 690091 Vladivostok, Russia;
- Federal Scientific Center of the Eastern Asia Terrestrial Biodiversity, Far Eastern Branch of Russian Academy of Sciences, 690091 Vladivostok, Russia
- National Scientific Center of Marine Biology, Far Eastern Branch of Russian Academy of Sciences, 690091 Vladivostok, Russia
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Spiegelenberg JP, van Gelder MMHJ, Maas ML, Hovens MMC, Esselink A, Dofferhoff ASM, Janssen R, van de Maat J, Janssen N, Blaauw M, Hassing RJ, van Apeldoorn M, Kerckhoffs A, Veerman K, Hoogerwerf J, Kramers C, Leentjens J. Prior use of therapeutic anticoagulation does not protect against COVID-19 related clinical outcomes in hospitalized patients: A propensity score-matched cohort study. Br J Clin Pharmacol 2021; 87:4839-4847. [PMID: 33899226 PMCID: PMC8250934 DOI: 10.1111/bcp.14877] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/21/2021] [Accepted: 04/11/2021] [Indexed: 02/06/2023] Open
Abstract
The hypercoagulable state observed in COVID‐19 could be responsible for morbidity and mortality. In this retrospective study we investigated whether therapeutic anticoagulation prior to infection has a beneficial effect in hospitalized COVID‐19 patients. This study included 1154 COVID‐19 patients admitted to 6 hospitals in the Netherlands between March and May 2020. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. In total, 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no associations between prior use of therapeutic anticoagulation and overall mortality (risk ratio 1.02 [95% confidence interval; 0.80–1.30]) or length of hospital stay (7.0 [4–12] vs. 7.0 [4–12] days, P = .69), although we observed a lower risk of pulmonary embolism (0.19 [0.05–0.80]). This study shows that prior use of therapeutic anticoagulation is not associated with improved clinical outcome in hospitalized COVID‐19 patients.
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Affiliation(s)
- Janneke P Spiegelenberg
- Department of Internal Medicine, Radboud university medical center, Nijmegen, the Netherlands.,Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands
| | - Marleen M H J van Gelder
- Department for Health Evidence, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, the Netherlands.,Radboud REshape Innovation Center, Radboud university medical center, Nijmegen, the Netherlands
| | - Martje L Maas
- Department of Internal Medicine, Bernhoven, Uden, the Netherlands
| | - Marcel M C Hovens
- Department of Internal Medicine, Rijnstate Hospital, Arnhem, the Netherlands
| | - Anne Esselink
- Department of Internal Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands
| | - Anton S M Dofferhoff
- Department of Internal Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands
| | - Rob Janssen
- Department of Pulmonary Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands
| | - Josephine van de Maat
- Department of Internal Medicine, Radboud university medical center, Nijmegen, the Netherlands.,Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands
| | - Nico Janssen
- Department of Internal Medicine, Radboud university medical center, Nijmegen, the Netherlands.,Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands
| | - Marc Blaauw
- Department of Internal Medicine, Radboud university medical center, Nijmegen, the Netherlands.,Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands
| | - Robert-Jan Hassing
- Department of Internal Medicine, Rijnstate Hospital, Arnhem, the Netherlands
| | - Marjan van Apeldoorn
- Department of Internal Medicin and Geriatricts, Jeroen Bosch Hospital, GZ,'s-Hertogenbosch, the Netherlands
| | - Angèle Kerckhoffs
- Department of Internal Medicin and Geriatricts, Jeroen Bosch Hospital, GZ,'s-Hertogenbosch, the Netherlands
| | - Karin Veerman
- Department of Internal Medicine, St. Maartenskliniek, Ubbergen, The Netherlands
| | - Jacobien Hoogerwerf
- Department of Internal Medicine, Radboud university medical center, Nijmegen, the Netherlands.,Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands
| | - Cornelis Kramers
- Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, the Netherlands.,Department of Pharmacy, Canisius Willhelmina Hospital, Nijmegen, the Netherlands
| | - Jenneke Leentjens
- Department of Internal Medicine, Radboud university medical center, Nijmegen, the Netherlands.,Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands
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Page EM, Ariëns RAS. Mechanisms of thrombosis and cardiovascular complications in COVID-19. Thromb Res 2021; 200:1-8. [PMID: 33493983 PMCID: PMC7813504 DOI: 10.1016/j.thromres.2021.01.005] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/16/2020] [Accepted: 01/08/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND The novel coronavirus SARS-CoV-2, responsible for the 2019-2020 global (COVID-19) pandemic, is a respiratory virus associated with the development of thromboembolic complications and respiratory failure in severe cases. Increased risk of pulmonary embolism and thrombosis has been identified in COVID-19 patients, alongside accompanying elevations in potential prognostic biomarkers, including D-dimer, IL-6 and cardiac specific troponins. Our aim was to provide a scoping review of the available literature regarding thrombosis risk, other cardiovascular implications, and their biomarkers in COVID-19 to highlight potential disease mechanisms. METHODS Authors conducted a literature search in PubMed using MeSH headings "disseminated intravascular coagulation", "pulmonary embolism", "thromb*", "stroke", "myocardial infarction" and "acute lung injury", as well as terms "COVID-19", "SARS-CoV-2", "2019 novel coronavirus" and "2019-nCoV". RESULTS AND CONCLUSIONS COVID-19 disease is characterised by the interactions between hyperactive coagulation and complement systems - induced by hyper-inflammatory conditions, resulting in a pro-thrombotic state and diffuse tissue injury. There are several promising prognostic markers of disease severity, with D-dimer the most significant. The presence of thrombocytopenia appears to be a key indicator of patient deterioration. Further research is required to understand the underlying pathophysiology in COVID-19 and its implications in disease progression and patient management. Randomised trials are urgently needed to determine the safety of proposed therapeutic anticoagulation with heparin and the role for anti-platelet agents, such as Ticagrelor, in patient management.
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Affiliation(s)
- Eden M Page
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK
| | - Robert A S Ariëns
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK.
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Muñoz-Rivas N, Abad-Motos A, Mestre-Gómez B, Sierra-Hidalgo F, Cortina-Camarero C, Lorente-Ramos RM, Torres-Rubio P, Arranz-García P, Franco-Moreno AI, Gómez-Mariscal E, Mauleón-Fernández C, Alonso-García S, Rogado J, Saez-Vaquero T, Such-Diaz A, Ryan P, Moya-Mateo E, Martín-Navarro JA, Hernández-Rivas JA, Torres-Macho J, Churruca J. Systemic thrombosis in a large cohort of COVID-19 patients despite thromboprophylaxis: A retrospective study. Thromb Res 2021; 199:132-142. [PMID: 33503547 PMCID: PMC7787910 DOI: 10.1016/j.thromres.2020.12.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 12/26/2020] [Accepted: 12/30/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Incidence of thrombotic events associated to Coronavirus disease-2019 (COVID-19) is difficult to assess and reported rates differ significantly. Optimal thromboprophylaxis is unclear. OBJECTIVES We aimed to analyze the characteristics of patients with a confirmed thrombotic complication including inflammatory and hemostatic parameters, compare patients affected by arterial vs venous events and examine differences between survivors and non-survivors. We reviewed compliance with thromboprophylaxis and explored how the implementation of a severity-adjusted protocol could have influenced outcome. METHODS Single-cohort retrospective study of COVID-19 patients admitted, from March 3 to May 3 2020, to the Infanta Leonor University Hospital in Madrid, epicenter of the Spanish outbreak. RESULTS Among 1127 patients, 80 thrombotic events were diagnosed in 69 patients (6.1% of the entire cohort). Forty-three patients (62%) suffered venous thromboembolism, 18 (26%) arterial episodes and 6 (9%) concurrent venous and arterial thrombosis. Most patients (90%) with a confirmed thrombotic complication where under low-molecular-weight heparin treatment. Overt disseminated intravascular coagulation (DIC) was rare. Initial ISTH DIC score and pre-event CRP were significantly higher among non-survivors. In multivariate analysis, arterial localization was an independent predictor of mortality (OR = 18, 95% CI: 2.4-142, p < .05). CONCLUSIONS Despite quasi-universal thromboprophylaxis, COVID-19 lead to a myriad of arterial and venous thrombotic events. Considering the subgroup of patients with thrombotic episodes, arterial events appeared earlier in the course of disease and conferred very poor prognosis, and an ISTH DIC score ≥ 3 at presentation was identified as a potential predictor of mortality. Severity-adjusted thromboprophylaxis seemed to decrease the number of events and could have influenced mortality. Randomized controlled trials are eagerly awaited.
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Affiliation(s)
- Nuria Muñoz-Rivas
- Internal Medicine Department, Infanta Leonor University Hospital, Spain
| | - Ane Abad-Motos
- Anesthesiology Department, Infanta Leonor University Hospital, Spain
| | | | | | | | | | | | - Paz Arranz-García
- Administration Department, Infanta Leonor University Hospital, Spain
| | | | | | | | | | - Jacobo Rogado
- Medical Oncology Department, Infanta Leonor University Hospital, Spain
| | | | - Ana Such-Diaz
- Department of Hospital Pharmacy, Infanta Leonor University Hospital, Spain
| | - Pablo Ryan
- Internal Medicine Department, Infanta Leonor University Hospital, Spain
| | - Eva Moya-Mateo
- Internal Medicine Department, Infanta Leonor University Hospital, Spain
| | | | - Jose Angel Hernández-Rivas
- Hematology and Haemostasis Department, Infanta Leonor University Hospital, Spain; Universidad Complutense de Madrid, Spain
| | - Juan Torres-Macho
- Internal Medicine Department, Infanta Leonor University Hospital, Spain; Universidad Complutense de Madrid, Spain
| | - Juan Churruca
- Hematology and Haemostasis Department, Infanta Leonor University Hospital, Spain.
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Mokra D, Mokry J. Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives? Int J Mol Sci 2021; 22:1929. [PMID: 33669167 PMCID: PMC7919656 DOI: 10.3390/ijms22041929] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/12/2021] [Accepted: 02/14/2021] [Indexed: 12/14/2022] Open
Abstract
Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial-endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.
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Affiliation(s)
- Daniela Mokra
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Juraj Mokry
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia;
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Vuorio A, Kovanen PT. Statins as Adjuvant Therapy for COVID-19 to Calm the Stormy Immunothrombosis and Beyond. Front Pharmacol 2021; 11:579548. [PMID: 33542685 PMCID: PMC7851087 DOI: 10.3389/fphar.2020.579548] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022] Open
Affiliation(s)
- Alpo Vuorio
- Mehiläinen Airport Health Centre, Vantaa, Finland.,Department of Forensic Medicine, University of Helsinki, Helsinki, Finland
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41
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Singh N, Singh P, Singh V, Krishna A, Singh S. Comprehensive study on clinical responses and socioeconomic characteristics of COVID-19 patients during outbreak. J Family Med Prim Care 2021; 10:4002-4008. [PMID: 35136759 PMCID: PMC8797082 DOI: 10.4103/jfmpc.jfmpc_579_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/26/2021] [Accepted: 07/31/2021] [Indexed: 12/15/2022] Open
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Escalante HDLL, Vivas JG, Hasan N, Delgado A, Soto S. A group of homoeopathic medicines for COVID-19: A systematic review of clinical features. INDIAN JOURNAL OF RESEARCH IN HOMOEOPATHY 2021. [DOI: 10.4103/ijrh.ijrh_106_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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El Tabaa MM, El Tabaa MM. New putative insights into neprilysin (NEP)-dependent pharmacotherapeutic role of roflumilast in treating COVID-19. Eur J Pharmacol 2020; 889:173615. [PMID: 33011243 PMCID: PMC7527794 DOI: 10.1016/j.ejphar.2020.173615] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/08/2020] [Accepted: 09/28/2020] [Indexed: 01/08/2023]
Abstract
Nowadays, coronavirus disease 2019 (COVID-19) represents the most serious inflammatory respiratory disease worldwide. Despite many proposed therapies, no effective medication has yet been approved. Neutrophils appear to be the key mediator for COVID-19-associated inflammatory immunopathologic, thromboembolic and fibrotic complications. Thus, for any therapeutic agent to be effective, it should greatly block the neutrophilic component of COVID-19. One of the effective therapeutic approaches investigated to reduce neutrophil-associated inflammatory lung diseases with few adverse effects was roflumilast. Being a highly selective phosphodiesterase-4 inhibitors (PDE4i), roflumilast acts by enhancing the level of cyclic adenosine monophosphate (cAMP), that probably potentiates its anti-inflammatory action via increasing neprilysin (NEP) activity. Because activating NEP was previously reported to mitigate several airway inflammatory ailments; this review thoroughly discusses the proposed NEP-based therapeutic properties of roflumilast, which may be of great importance in curing COVID-19. However, further clinical studies are required to confirm this strategy and to evaluate its in vivo preventive and therapeutic efficacy against COVID-19.
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Affiliation(s)
- Manar Mohammed El Tabaa
- Pharmacology & Environmental Toxicology, Environmental Studies & Research Institute, University of Sadat City, Egypt.
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Castro-Verdes M, Gkouma A, Wort J, Ridge C, Mirsadraee S, Padley S, Sheikh A, Singh S. Corona Virus Disease 2019 in situ arterial and venous thrombosis in critically ill patients: a case series. EUROPEAN HEART JOURNAL-CASE REPORTS 2020; 4:1-7. [PMID: 33442596 PMCID: PMC7793039 DOI: 10.1093/ehjcr/ytaa470] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/30/2020] [Accepted: 11/10/2020] [Indexed: 02/07/2023]
Abstract
Background Corona Virus Disease 2019 (COVID-19) pneumonitis associated with severe respiratory failure carries a high mortality. Coagulopathy has emerged as a significant contributor to thrombotic complications. Case summary We describe two cases of severe COVID-19 pneumonitis refractory to conventional mechanical ventilation and proning position, transferred to our specialist centre for cardiorespiratory failure. Cross-sectional imaging demonstrated concurrent venous and aortic thrombosis with end-organ ischaemic changes. One patient received thrombolysis with a partial response. This could not be offered to the other patient due to a recent haemorrhagic event. Both patients died of multi-organ failure in the hospital. Discussion Concurrent aortic and venous thromboses are rare. This finding in COVID-19 cases, who were both critically ill patients, likely reflects the strongly thrombogenic nature of this illness which ultimately contributed to poor outcomes. The absence of deep vein thrombosis or a potential systemic source of embolism suggests in situ thrombosis. Further, the management of anticoagulation and thrombolysis is challenging in patients where an attendant bleeding risk exists.
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Affiliation(s)
- Mireya Castro-Verdes
- Department of Cardiology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Antonia Gkouma
- Department of Cardiothoracic Surgery, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - John Wort
- Department of Cardiology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Carole Ridge
- Department of Radiology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Saeed Mirsadraee
- Department of Radiology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Simon Padley
- Department of Radiology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Awais Sheikh
- Department of Intensive Care, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Suveer Singh
- Department of Intensive Care, Royal Brompton and Harefield NHS Foundation Trust, London, UK
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Dhama K, Patel SK, Natesan S, Vora KS, Iqbal Yatoo M, Tiwari R, Saxena SK, Singh KP, Singh R, Malik YS. COVID-19 in the elderly people and advances in vaccination approaches. Hum Vaccin Immunother 2020; 16:2938-2943. [PMID: 33270497 PMCID: PMC8641606 DOI: 10.1080/21645515.2020.1842683] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/19/2020] [Accepted: 10/21/2020] [Indexed: 02/06/2023] Open
Abstract
The rapid worldwide spread of the COVID-19 pandemic, caused by the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in tens of millions of infections and over one million deaths. SARS-CoV-2 infection affects all age groups; however, those over 60 years old are affected more severely. Moreover, pre-existing co-morbidities result in higher COVID-19-associated mortality in the geriatric population. This article highlights the associated risk factors of SARS-CoV-2 infection in older people and progress in developing COVID-19 vaccines, especially for efficient vaccination of the older population. There is also a summary of immunomodulatory and immunotherapeutic approaches to ameliorate the outcome of COVID-19 in older individuals.
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Affiliation(s)
- Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Shailesh Kumar Patel
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Senthilkumar Natesan
- Department of Infectious Diseases, Indian Institute of Public Health Gandhinagar, Ganghinagar, Gujarat, India
| | - Kranti Suresh Vora
- Department of Infectious Diseases, Indian Institute of Public Health Gandhinagar, Ganghinagar, Gujarat, India
- Health Research Institut, University of Canberra, ACT, Australia
| | - Mohd Iqbal Yatoo
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, Shuhama, Alusteng Srinagar, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Ruchi Tiwari
- Department of Veterinary Microbiology and Immunology, College of Veterinary Sciences, Uttar Pradesh Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, India
| | - Shailendra K Saxena
- Centre for Advanced Research (CFAR), Faculty of Medicine, King George’s Medical University (KGMU), Lucknow, India
| | - Karam Pal Singh
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Rajendra Singh
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Yashpal Singh Malik
- Division of Biological Standardization, ICAR–Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
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Mescoli A, Maffei G, Pillo G, Bortone G, Marchesi S, Morandi E, Ranzi A, Rotondo F, Serra S, Vaccari M, Zauli Sajani S, Mascolo MG, Jacobs MN, Colacci A. The Secretive Liaison of Particulate Matter and SARS-CoV-2. A Hypothesis and Theory Investigation. Front Genet 2020; 11:579964. [PMID: 33240326 PMCID: PMC7680895 DOI: 10.3389/fgene.2020.579964] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/11/2020] [Indexed: 12/29/2022] Open
Abstract
As the novel coronavirus disease sweeps across the world, there is growing speculation on the role that atmospheric factors may have played on the different distribution of SARS-CoV-2, and on the epidemiological characteristics of COVID-19. Knowing the role that environmental factors play in influenza virus outbreaks, environmental pollution and, in particular, atmospheric airborne (particulate matter, PM) has been considered as a potential key factor in the spread and mortality of COVID-19. A possible role of the PM as the virus carrier has also been debated. The role of PM in exacerbating respiratory and cardiovascular disease has been well recognized. Accumulating evidence support the hypothesis that PM can trigger inflammatory response at molecular, cellular and organ levels. On this basis, we developed the hypothesis that PM may play a role as a booster of COVID-19 rather than as a carrier of SARS-CoV-2. To support our hypothesis, we analyzed the molecular signatures detected in cells exposed to PM samples collected in one of the most affected areas by the COVID-19 outbreak, in Italy. T47D human breast adenocarcinoma cells were chosen to explore the global gene expression changes induced by the treatment with organic extracts of PM 2.5. The analysis of the KEGG's pathways showed modulation of several gene networks related to the leucocyte transendothelial migration, cytoskeleton and adhesion system. Three major biological process were identified, including coagulation, growth control and immune response. The analysis of the modulated genes gave evidence for the involvement of PM in the endothelial disease, coagulation disorders, diabetes and reproductive toxicity, supporting the hypothesis that PM, directly or through molecular interplay, affects the same molecular targets as so far known for SARS-COV-2, contributing to the cytokines storm and to the aggravation of the symptoms triggered by COVID-19. We provide evidence for a plausible cooperation of receptors and transmembrane proteins, targeted by PM and involved in COVID-19, together with new insights into the molecular interplay of chemicals and pathogens that could be of importance for sustaining public health policies and developing new therapeutic approaches.
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Affiliation(s)
- Ada Mescoli
- Department of Experimental, Diagnostic and Specialty Medicine, Section of Cancerology, University of Bologna, Bologna, Italy
| | - Giangabriele Maffei
- Department of Experimental, Diagnostic and Specialty Medicine, Section of Cancerology, University of Bologna, Bologna, Italy
| | - Gelsomina Pillo
- Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy
| | - Giuseppe Bortone
- Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy
| | - Stefano Marchesi
- Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy
| | - Elena Morandi
- Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy
| | - Andrea Ranzi
- Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy
| | - Francesca Rotondo
- Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy
| | - Stefania Serra
- Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy
| | - Monica Vaccari
- Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy
| | | | | | - Miriam Naomi Jacobs
- Department of Toxicology, Centre for Radiation, Chemical and Environmental Hazards Public Health England, Chilton, United Kingdom
| | - Annamaria Colacci
- Department of Experimental, Diagnostic and Specialty Medicine, Section of Cancerology, University of Bologna, Bologna, Italy.,Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy
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Repurposing of Plasminogen: An Orphan Medicinal Product Suitable for SARS-CoV-2 Inhalable Therapeutics. Pharmaceuticals (Basel) 2020; 13:ph13120425. [PMID: 33260813 PMCID: PMC7761183 DOI: 10.3390/ph13120425] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/21/2020] [Accepted: 11/25/2020] [Indexed: 12/13/2022] Open
Abstract
The SARS-CoV-2 infection is associated with pulmonary coagulopathy, which determines the deposition of fibrin in the air spaces and lung parenchyma. The resulting lung lesions compromise patient pulmonary function and increase mortality, or end in permanent lung damage for those who have recovered from the COVID-19 disease. Therefore, local pulmonary fibrinolysis can be efficacious in degrading pre-existing fibrin clots and reducing the conversion of lung lesions into lasting scars. Plasminogen is considered a key player in fibrinolysis processes, and in view of a bench-to-bedside translation, we focused on the aerosolization of an orphan medicinal product (OMP) for ligneous conjunctivitis: human plasminogen (PLG-OMP) eye drops. As such, the sterile and preservative-free solution guarantees the pharmaceutical quality of GMP production and meets the Ph. Eur. requirements of liquid preparations for nebulization. PLG-OMP aerosolization was evaluated both from technological and stability viewpoints, after being submitted to either jet or ultrasonic nebulization. Jet nebulization resulted in a more efficient delivery of an aerosol suitable for pulmonary deposition. The biochemical investigation highlighted substantial protein integrity maintenance with the percentage of native plasminogen band > 90%, in accordance with the quality specifications of PLG-OMP. In a coherent way, the specific activity of plasminogen is maintained within the range 4.8–5.6 IU/mg (PLG-OMP pre-nebulization: 5.0 IU/mg). This is the first study that focuses on the technological and biochemical aspects of aerosolized plasminogen, which could affect both treatment efficacy and clinical dosage delivery. Increasing evidence for the need of local fibrinolytic therapy could merge with the availability of PLG-OMP as an easy handling solution, readily aerosolizable for a fast translation into an extended clinical efficacy assessment in COVID-19 patients.
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COVID-19-associated coagulopathy and disseminated intravascular coagulation. Int J Hematol 2020; 113:45-57. [PMID: 33161508 PMCID: PMC7648664 DOI: 10.1007/s12185-020-03029-y] [Citation(s) in RCA: 256] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 10/15/2020] [Accepted: 10/22/2020] [Indexed: 01/08/2023]
Abstract
The pathology of coronavirus disease 2019 (COVID-19) is exacerbated by the progression of thrombosis, and disseminated intravascular coagulation (DIC), and cytokine storms. The most frequently reported coagulation/fibrinolytic abnormality in COVID-19 is the increase in d-dimer, and its relationship with prognosis has been discussed. However, limits exist to the utility of evaluation by d-dimer alone. In addition, since the coagulation/fibrinolytic condition sometimes fluctuates within a short period of time, regular examinations in recognition of the significance of the examination are desirable. The pathophysiology of disseminated intravascular coagulation (DIC) associated with COVID-19 is very different from that of septic DIC, and both thrombotic and hemorrhagic pathologies should be noted. COVID-19 thrombosis includes macro- and microthrombosis, with diagnosis of the latter depending on markers of coagulation and fibrinolysis. Treatment of COVID-19 is classified into antiviral treatment, cytokine storm treatment, and thrombosis treatment. Rather than providing uniform treatment, the treatment method most suitable for the severity and stage should be selected. Combination therapy with heparin and nafamostat is expected to develop in the future. Fibrinolytic therapy and adsorption therapy require further study
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Managing the pandemic from the radiology department’s point of view. RADIOLOGIA 2020. [PMCID: PMC7749996 DOI: 10.1016/j.rxeng.2020.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The COVID-19 pandemic is forcing our entire society to adopt numerous changes, at least until an effective treatment and/or vaccine becomes widely available. Because COVID-19 is a new disease that has required us to make complex decisions based on scant evidence, the pandemic is having an enormous impact on our health system. Radiology departments play a fundamental role in the management of COVID-19, both in the diagnosis of the disease and in the posterior management of patients. To ensure the safety of patients and healthcare professionals, it is essential to understand the infection so that safe circuits can be implemented. This article summarizes the pathophysiology of COVID-19 infection and explains the measures that radiology departments need to adopt during the pandemic.
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Berhan Y. What immunological and hormonal protective factors lower the risk of COVID-19 related deaths in pregnant women? J Reprod Immunol 2020; 142:103180. [PMID: 32739645 PMCID: PMC7368414 DOI: 10.1016/j.jri.2020.103180] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/09/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023]
Abstract
Despite anticipated increased risk of COVID-19 and increased expression of the SARS CoV-2 receptor (ACE2), the relatively low mortality of pregnant women with COVID-19 has been an area of wonder. The immunological changes predominantly inclining to anti-inflammatory state, which is augmented by placental hormones' immune modulating action, looks against with COVID-19 inflammatory reaction leading to cytokine storm and multiple organ failure. Unlike many other viral infections, the bilateral immune activation of COVID-19 may preferentially make pregnant women at low risk. Taking the physiological advantage of pregnant women, potential clinical trials are proposed. Quite a large number of epidemiological and obstetrics related studies have addressed the cases of women with COVID-19. However, to the best of the author's knowledge, little is done to explore the physiological internal milieu of pregnant women in relation to COVID-19. This review provides an insight into how the hormonal and immunological changes in pregnancy potentially reduce SARS-CoV-2-mediated inflammatory response.
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Affiliation(s)
- Yifru Berhan
- St. Paul's Hospital Millennium Medical College, Ethiopia.
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