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1.
Cell Mol Life Sci ; 79(2): 94, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1653404

ABSTRACT

Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalysed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metabolism and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochemical nature of arginine citrullination, the enzymatic machinery behind it and also provide information on the pathological consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clinical trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.


Subject(s)
Autoimmune Diseases/pathology , Citrullination/physiology , Inflammation/pathology , Protein Processing, Post-Translational/physiology , Protein-Arginine Deiminases/metabolism , COVID-19/pathology , Citrulline/biosynthesis , Energy Metabolism/physiology , Extracellular Traps/immunology , Gene Expression Regulation/genetics , Humans , Neoplasms/pathology , SARS-CoV-2/immunology , Thromboembolism/pathology
2.
J Intern Med ; 290(3): 655-665, 2021 09.
Article in English | MEDLINE | ID: covidwho-1297793

ABSTRACT

IMPORTANCE: Assessment of the causative association between the COVID-19 and cause of death has been hampered by limited availability of systematically performed autopsies. We aimed to present autopsy-confirmed causes of death in patients who died with COVID-19 and to assess the association between thrombosis and diffuse alveolar damage consistent with COVID-19 (DAD). METHODS: Consecutive forensic (n = 60) and clinical (n = 42) autopsies with positive post-mortem SARS-CoV-2 PCR in lungs (age 73 ± 14 years, 50% men) were included. The cause of death analysis was based on a review of medical records and histological reports. Thrombotic phenomena in lungs were defined as pulmonary thromboembolism (PE), thrombosis in pulmonary artery branches or microangiopathy in capillary vessels. RESULTS: COVID-19 caused or contributed to death in 71% of clinical and 83% of forensic autopsies, in whom significant DAD was observed. Of the patients with COVID-19 as the primary cause of death, only 19% had no thrombotic phenomena in the lungs, as opposed to 38% amongst those with COVID-19 as a contributing cause of death and 54% amongst patients whose death was not related to COVID-19 (p = 0.002). PE was observed in 5 patients. Two patients fulfilled the criteria for lymphocyte myocarditis. CONCLUSIONS: Vast majority of all PCR-positive fatalities, including out-of-hospital deaths, during the SARS-CoV-2 pandemic were related to DAD caused by COVID-19. Pulmonary artery thrombosis and microangiopathy in pulmonary tissue were common and associated with the presence of DAD, whilst venous PE was rarely observed. Histology-confirmed lymphocyte myocarditis was a rare finding.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Cause of Death , Pulmonary Alveoli/pathology , Pulmonary Embolism/pathology , Thromboembolism/pathology , Aged , Autopsy , Capillaries/pathology , Female , Humans , Lymphocytes , Male , Middle Aged , Myocarditis/pathology , Pandemics , Polymerase Chain Reaction , Pulmonary Artery/pathology , SARS-CoV-2 , Thrombotic Microangiopathies/pathology
3.
Sci Rep ; 11(1): 13325, 2021 06 25.
Article in English | MEDLINE | ID: covidwho-1281739

ABSTRACT

COVID 19 is associated with a hypercoagulable state and frequent thromboembolic complications. For how long this acquired abnormality lasts potentially requiring preventive measures, such as anticoagulation remains to be delineated. We used viscoelastic rotational thrombelastometry (ROTEM) in a single center cohort of 13 critical ill patients and performed follow up examinations three months after discharge from ICU. We found clear signs of a hypercoagulable state due to severe hypofibrinolysis and a high rate of thromboembolic complications during the phase of acute illness. Three month follow up revealed normalization of the initial coagulation abnormality and no evidence of venous thrombosis in all thirteen patients. In our cohort the coagulation profile was completely normalized three months after COVID-19. Based on these findings, discontinuation of anticoagulation can be discussed in patients with complete venous reperfusion.


Subject(s)
Anticoagulants/therapeutic use , Blood Coagulation Disorders , COVID-19 , Thrombelastography , Thromboembolism , Venous Thrombosis , Aged , Blood Coagulation , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/pathology , COVID-19/blood , COVID-19/drug therapy , COVID-19/pathology , Cohort Studies , Female , Humans , Male , Middle Aged , Severity of Illness Index , Thromboembolism/drug therapy , Thromboembolism/pathology , Venous Thrombosis/drug therapy , Venous Thrombosis/pathology
4.
Cytokine ; 143: 155523, 2021 07.
Article in English | MEDLINE | ID: covidwho-1163610

ABSTRACT

Cytokines play pleiotropic, antagonistic, and collaborative in viral disease. The high morbidity and mortality of coronavirus disease 2019 (COVID-19) make it a significant threat to global public health. Elucidating its pathogenesis is essential to finding effective therapy. A retrospective study was conducted on 71 patients hospitalized with COVID-19. Data on cytokines, T lymphocytes, and other clinical and laboratory characteristics were collected from patients with variable disease severity. The effects of cytokines on the overall survival (OS) and event-free survival (EFS) of patients were analyzed. The critically severe and severe patients had higher infection indexes and significant multiple organ function abnormalities than the mild patients (P < 0.05). IL-6 and IL-10 were significantly higher in the critically severe patients than in the severe and mild patients (P < 0.05). IL-6 and IL-10 were closely associated with white blood cells, neutrophils, T lymphocyte subsets, D-D dimer, blood urea nitrogen, complement C1q, procalcitonin C-reactive protein. Moreover, the IL-6 and IL-10 levels were closely correlated to dyspnea and dizziness (P < 0.05). The patients with higher IL-10 levels had shorter OS than the group with lower levels (P < 0.05). The older patients with higher levels of single IL-6 or IL-10 tended to have shorter EFS (P < 0.05), while the patients who had more elevated IL-6 and IL-10 had shorter OS (P < 0.05). The Cox proportional hazard model revealed that IL-6 was the independent factor affecting EFS. IL-6 and IL-10 play crucial roles in COVID-19 prognosis.


Subject(s)
COVID-19/blood , COVID-19/pathology , Interleukin-10/blood , Interleukin-6/blood , T-Lymphocyte Subsets/immunology , Adult , Age Factors , Aged , Aging , Blood Coagulation Factors/analysis , COVID-19/mortality , COVID-19/therapy , Cytokine Release Syndrome/pathology , Female , Humans , Lymphocyte Count , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/immunology , Severity of Illness Index , Survival Analysis , T-Lymphocyte Subsets/cytology , Thromboembolism/pathology , Treatment Outcome
5.
Ann Vasc Surg ; 74: 80-87, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1163382

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) causes thromboembolic complications during or post-infection period despite a lack of conventional risk factors. The study aims to learn fundamental changes in COVID-19 patients who underwent embolectomy in terms of clinical characteristics and clot composition. METHODS: In a retrospective cohort study design, we evaluated 21 patients who underwent embolectomy in our clinic between March 12, 2020, and December 31, 2020. Demographics, characteristics, and laboratory values were abstracted and analyzed. Histopathological assessment was held in the pathology department. RESULTS: Of these 21 patients, 11 (52.3%) were SARS-CoV-2 positive and 10 (47.6%) were SARS-CoV-2 negative. There is no statistical difference in terms of anatomic distribution, diagnostic method, length of hospital stay, amputation or mortality levels. Thromboembolic material of COVID-19 patients include significantly less red blood cell (RBC) (21.2-32.6%; P= 0.01), more lymphocyte (14.1-2.6%; P< 0.001), and more leukocyte (27.1-22.1%; P= 0.05). There was no statistical difference between the fibrin ratio. CONCLUSIONS: Inflammatory cells are prominent in arterial thromboembolic material of COVID-19 patients. A combination of hyperinflammation and prothrombotic status may be responsible for this phenomenon.


Subject(s)
COVID-19/complications , Inflammation/pathology , Peripheral Arterial Disease/pathology , Thromboembolism/pathology , Adult , Aged , Aged, 80 and over , Amputation , COVID-19/diagnosis , COVID-19/mortality , Embolectomy , Female , Humans , Inflammation/etiology , Inflammation/mortality , Inflammation/surgery , Length of Stay , Limb Salvage , Male , Middle Aged , Peripheral Arterial Disease/etiology , Peripheral Arterial Disease/mortality , Peripheral Arterial Disease/surgery , Retrospective Studies , Risk Assessment , Risk Factors , Thromboembolism/etiology , Thromboembolism/mortality , Thromboembolism/surgery , Time Factors , Treatment Outcome
6.
Eur Rev Med Pharmacol Sci ; 25(3): 1670-1679, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1102754

ABSTRACT

The emergence of Coronavirus Disease 19 (COVID-19) as a pandemic has claimed hundreds of thousands of lives worldwide since its initial breakout. With increasing reports from clinical observations and autopsy findings, it became clear that the disease causes acute respiratory distress syndrome (ARDS), as well as a broad spectrum of systemic and multiorgan pathologies, including angiopathy, endothelialitis, and thrombosis. Coagulopathy is associated with the activity of megakaryocytes, which play crucial roles in modulating the platelet homeostasis. Only a few autopsy reports include findings on thrombosis formation and the presence of megakaryocytes. Here we review and summarize the possible involvement and the pathophysiology of the thromboembolic events in COVID-19 patients based on post-mortem reports. We reviewed post-mortem reports from March 2020 to September 2020. Eleven autopsy reports that demonstrated thromboembolic involvement findings, either macroscopically or microscopically, were included in this review. All studies reported similar pulmonary gross findings. Not all studies described thrombi formation and megakaryocyte findings. Pulmonary embolism, coagulopathy, severe endothelial injury, and widespread thrombosis are frequent in COVID-19 patients, following many patients with high-level D-Dimer, increased fibrinogen, abnormal prothrombic coagulation, and thrombocytopenia. Reports showed that thrombus was also found in the lower extremities' deep veins and the prostatic venous plexus. In conclusion, a complex interaction of SARS-CoV-2 virus invasion with platelets, leukocytes, endothelial cells, inflammation, immune response, and the possible involvement of megakaryocytes may increase the cumulative risk of thrombosis by a yet unclear cellular and humoral interaction.


Subject(s)
COVID-19/mortality , Endothelium, Vascular/pathology , SARS-CoV-2 , Thromboembolism/mortality , Autopsy , Blood Coagulation , COVID-19/complications , COVID-19/pathology , Humans , Lung/blood supply , Lung/pathology , Megakaryocytes/pathology , Pandemics , Thromboembolism/etiology , Thromboembolism/pathology
7.
Am J Forensic Med Pathol ; 42(2): 164-169, 2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-1035550

ABSTRACT

ABSTRACT: As of August 23, 2020, the 2019 novel coronavirus disease (COVID-19) has infected more than 23,518,340 people and caused more than 810,492 deaths worldwide including 4,717 deaths in China. We present a case of a 53-year-old woman who was admitted to the hospital because of dry coughs and high fever on January 26, 2020, in Wuhan, China. She was not tested for SARS-CoV-2 RNA until on hospital day 11 (illness day 21) because of a significant shortage of test kits at the local hospital. Then, her test was positive for COVID-19 on hospital day 20. Despite intensive medical treatments, she developed respiratory failure with secondary bacterial infection and expired on hospital day 23 (3 days after she was tested positive for SARS-CoV-2 RNA). A systemic autopsy examination, including immunohistochemistry and ultrastructural studies, demonstrates that SARS-CoV-2 can infect multiple organs with profound adverse effect on the immune system, and the lung pathology is characterized by diffuse alveolar damage. Extrapulmonary SARS-CoV-2 RNA was detected in several organs postmortem. The detailed pathological features are described. In addition, this report highlights the value of forensic autopsy in studying SARS-CoV-2 infection and the importance of clinicopathological correlation in better understanding the pathogenesis of COVID-19.


Subject(s)
COVID-19/diagnosis , Autopsy , Epiglottitis/pathology , Female , Fibroblasts/pathology , Humans , Infarction/pathology , Intracranial Thrombosis/pathology , Kidney/blood supply , Kidney/pathology , Lung/pathology , Lymph Nodes/pathology , Lymphocytes/pathology , Middle Aged , Myocytes, Cardiac/pathology , Myofibroblasts/pathology , Necrosis , RNA, Viral/analysis , Splenic Infarction/pathology , Subarachnoid Hemorrhage/pathology , Thromboembolism/pathology , Thrombosis/pathology , Thyroiditis, Autoimmune/pathology , Urinary Bladder/pathology
8.
Hum Pathol ; 105: 74-83, 2020 11.
Article in English | MEDLINE | ID: covidwho-933118

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has been declared by the World Health Organization as an emerging public health problem of global importance and classified as a pandemic. SARS-CoV-2 infection can result in diverse, multiorgan pathology, the most significant being in the lungs (diffuse alveolar damage in its different phases, microthrombi, bronchopneumonia, necrotizing bronchiolitis, viral pneumonia), heart (lymphocytic myocarditis), kidney (acute tubular injury), central nervous system (microthrombi, ischemic necrosis, acute hemorrhagic infarction, congestion, and vascular edema), lymph nodes (hemophagocytosis and histiocytosis), bone marrow (hemophagocytosis), and vasculature (deep vein thrombosis). An understanding of the spectrum and frequency of histologic findings in COVID-19 is essential for gaining a better understanding of disease pathophysiology and its ongoing impact on public health. To this end, we conducted a systematic meta-analysis of histopathologic observations to date and review the reported findings.


Subject(s)
COVID-19/pathology , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Autopsy , Biopsy , Blood Vessels/pathology , Central Nervous System/pathology , Female , Humans , Kidney/pathology , Lung/pathology , Lymph Nodes/pathology , Male , Middle Aged , Myocardium/pathology , Thromboembolism/pathology
9.
Int J Mol Med ; 46(3): 903-912, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-750592

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) is a novel ß coronavirus that is the etiological agent of the pandemic coronavirus disease 2019 (COVID­19) that at the time of writing (June 16, 2020) has infected almost 6 million people with some 450,000 deaths. These numbers are still rising daily. Most (some 80%) cases of COVID­19 infection are asymptomatic, a substantial number of cases (15%) require hospitalization and an additional fraction of patients (5%) need recovery in intensive care units. Mortality for COVID­19 infection appears to occur globally between 0.1 and 0.5% of infected patients although the frequency of lethality is significantly augmented in the elderly and in patients with other comorbidities. The development of acute respiratory distress syndrome and episodes of thromboembolism that may lead to disseminated intravascular coagulation (DIC) represent the primary causes of lethality during COVID­19 infection. Increasing evidence suggests that thrombotic diathesis is due to multiple derangements of the coagulation system including marked elevation of D­dimer that correlate negatively with survival. We propose here that the thromboembolic events and eventually the development of DIC provoked by SARS­CoV­2 infection may represent a secondary anti­phospholipid antibody syndrome (APS). We will apply both Baconian inductivism and Cartesian deductivism to prove that secondary APS is likely responsible for coagulopathy during the course of COVID­19 infection. Diagnostic and therapeutic implications of this are also discussed.


Subject(s)
Antiphospholipid Syndrome/pathology , Coronavirus Infections/pathology , Disseminated Intravascular Coagulation/pathology , Pneumonia, Viral/pathology , Thromboembolism/pathology , Thrombosis/pathology , Antiphospholipid Syndrome/immunology , Antiviral Agents/therapeutic use , Betacoronavirus , Blood Coagulation/physiology , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Disseminated Intravascular Coagulation/immunology , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Pandemics , Phospholipids/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , SARS-CoV-2 , Thromboembolism/immunology
10.
J Korean Med Sci ; 35(35): e324, 2020 Sep 07.
Article in English | MEDLINE | ID: covidwho-745662

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic infection associated with high morbidity and mortality. The Korean city of Daegu endured the first large COVID-19 outbreak outside of China. Since the report of the first confirmed case in Daegu on February 18, 2020, a total of 6,880 patients have been reported until May 29, 2020. We experienced five patients with ischemic stroke and COVID-19 during this period in four tertiary hospitals in Daegu. The D-dimer levels were high in all three patients in whom D-dimer blood testing was performed. Multiple embolic infarctions were observed in three patients and suspected in one. The mean time from stroke symptom onset to emergency room arrival was 22 hours. As a result, acute treatment for ischemic stroke was delayed. The present case series report raises the possibility that the coronavirus responsible for COVID-19 causes or worsens stroke, perhaps by inducing inflammation. The control of COVID-19 is very important; however, early and proper management of stroke should not be neglected during the epidemic.


Subject(s)
Coronavirus Infections/pathology , Cytokines/blood , Fibrin Fibrinogen Degradation Products/analysis , Pneumonia, Viral/pathology , Stroke/diagnosis , Stroke/therapy , Aged , Aged, 80 and over , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Coronavirus Infections/therapy , Emergency Medical Services , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/therapy , Republic of Korea/epidemiology , SARS-CoV-2 , Stroke/epidemiology , Thromboembolism/pathology , Thrombolytic Therapy/methods , Time-to-Treatment
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