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Schulman S, Makatsariya A, Khizroeva J, Bitsadze V, Kapanadze D. The Basic Principles of Pathophysiology of Venous Thrombosis. Int J Mol Sci 2024; 25:11447. [PMID: 39519000 PMCID: PMC11547114 DOI: 10.3390/ijms252111447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 10/19/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024] Open
Abstract
The past few decades have brought tremendous insight into the molecular and pathophysiological mechanisms responsible for thrombus generation. For a clinician, it is usually sufficient to explain the incident of deep vein thrombosis (DVT) with provoking factors such as trauma with vascular injury, immobilization, hormonal factors, or inherited or acquired coagulation defects. About half of DVTs are, however, lacking such triggers and are called unprovoked. Venous stasis and hypoxia at the valve sinus level may start a chain of reactions. The concept of immunothrombosis has added a new dimension to the old etiological triad of venous stasis, vessel wall injury, and changes in blood components. This is particularly important in COVID-19, where hyperinflammation, cytokines, and neutrophil extracellular traps are associated with the formation of microthrombi in the lungs. To better understand the mechanisms behind DVT and reach beyond the above-mentioned simplifications, animal models and clinical epidemiological studies have brought insight into the complex interplay between leukocytes, platelets, endothelium, cytokines, complements, and coagulation factors and inhibitors. These pathways and the interplay will be reviewed here, as well as the roles of cancer, anticancer drugs, and congenital thrombophilic defects on the molecular level in hypercoagulability and venous thromboembolism.
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Affiliation(s)
- Sam Schulman
- Department of Medicine, Thrombosis and Atherosclerosis Research Institute, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
- Department of Obstetrics, Gynecology and Perinatal Medicine, The I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Str 8-2, 119435 Moscow, Russia; (A.M.); (J.K.); (V.B.)
| | - Alexander Makatsariya
- Department of Obstetrics, Gynecology and Perinatal Medicine, The I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Str 8-2, 119435 Moscow, Russia; (A.M.); (J.K.); (V.B.)
| | - Jamilya Khizroeva
- Department of Obstetrics, Gynecology and Perinatal Medicine, The I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Str 8-2, 119435 Moscow, Russia; (A.M.); (J.K.); (V.B.)
| | - Victoria Bitsadze
- Department of Obstetrics, Gynecology and Perinatal Medicine, The I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya Str 8-2, 119435 Moscow, Russia; (A.M.); (J.K.); (V.B.)
| | - Daredzhan Kapanadze
- Center of Pathology of Pregnancy and Hemostasis «Medlabi», Tbilisi 340112, Georgia;
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2
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Kirkham AM, Candeliere J, Nagpal SK, Stelfox HT, Kubelik D, Hajjar G, MacFadden DR, McIsaac DI, Roberts DJ. A systematic review and meta-analysis of outcomes associated with development of surgical site infection after lower-limb revascularization surgery. Vascular 2024:17085381241290039. [PMID: 39363559 DOI: 10.1177/17085381241290039] [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: 10/05/2024]
Abstract
OBJECTIVES Although surgical site infection (SSI) is a commonly used quality metric after lower-limb revascularization surgery, outcomes associated with development of this complication are poorly characterized. We conducted a systematic review and meta-analysis of studies reporting associations between development of an SSI after these procedures and clinical outcomes and healthcare resource use. METHODS We searched MEDLINE, Embase, CENTRAL, and Evidence-Based Medicine Reviews (inception to April 4th, 2023) for studies examining adjusted associations between development of an SSI after lower-limb revascularization surgery and clinical outcomes and healthcare resource use. Two investigators independently screened abstracts and full-text citations, extracted data, and assessed risk of bias. Data were pooled using random-effects models. Heterogeneity was assessed using I2 statistics. GRADE was used to assess estimate certainty. RESULTS Among 6671 citations identified, we included 11 studies (n = 61,628 total patients) that reported adjusted-associations between development of an SSI and 13 different outcomes. Developing an SSI was associated with an increased adjusted-risk of hospital readmission (pooled adjusted-risk ratio (aRR) = 3.55; 95% CI (confidence interval) = 1.40-8.97; n = 4 studies; n = 13,532 patients; I2 = 99.0%; moderate certainty), bypass graft thrombosis within 30-days (pooled aRR = 2.09; 95% CI = 1.41-3.09; n = 2 studies; n = 23,240 patients; I2 = 51.1%; low certainty), reoperation (pooled aRR = 2.69; 95% CI = 2.67-2.72; n = 2 studies; n = 23,240 patients; I2 = 0.0%; moderate certainty), bleeding requiring a transfusion or secondary procedure (aRR = 1.40; 95% CI = 1.26-1.55; n = 1 study; n = 10,910 patients; low certainty), myocardial infarction or stroke (aRR = 1.21; 95% CI = 1.02-1.43; n = 1 study; n = 10,910 patients; low certainty), and major (i.e., above-ankle) amputation (pooled aRR = 1.93; 95% CI = 1.26-2.95; n = 4 studies; n = 32,859 patients; I2 = 83.0; low certainty). Development of an SSI >30-days after the index operation (aRR = 2.20; 95% CI = 1.16-4.17; n = 3 studies; n = 21,949 patients; low certainty) and prosthetic graft infection (aRR = 6.72; 95% CI = 3.21-12.70; n = 1 study; n = 272 patients; low certainty) were both associated with an increased adjusted-risk of major amputation. Prosthetic graft infection was also associated with an increased adjusted-risk of mortality >30-days after the index procedure (aRR = 6.40; 95% CI = 3.32-12.36; n = 1 study; n = 272 patients; low certainty). CONCLUSIONS This systematic review and meta-analysis suggests that development of an SSI after lower-limb revascularization surgery significantly increases patient morbidity and healthcare resource use. SSI is therefore a valuable quality metric after these surgeries. However, current estimates are based on heterogenous, low-to-moderate certainty evidence and should be confirmed by large, multicenter, cohort studies.
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Affiliation(s)
- Aidan M Kirkham
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- School of Epidemiology & Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Jasmine Candeliere
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Sudhir K Nagpal
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of Ottawa, Ottawa, ON, Canada
| | - Henry T Stelfox
- Department of Critical Care Medicine, Medicine, and Community Health Sciences, University of Calgary, Calgary, AB, Canada
| | - Dalibor Kubelik
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of Ottawa, Ottawa, ON, Canada
| | - George Hajjar
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of Ottawa, Ottawa, ON, Canada
| | - Derek R MacFadden
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- School of Epidemiology & Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Division of Infectious Disease, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Daniel I McIsaac
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- School of Epidemiology & Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Departments of Anesthesiology and Pain Medicine, University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada
- Institute for Clinical Evaluative Sciences, Toronto, ON, Canada
| | - Derek J Roberts
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, The Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- School of Epidemiology & Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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3
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Yong J, Toh CH. The convergent model of coagulation. J Thromb Haemost 2024; 22:2140-2146. [PMID: 38815754 DOI: 10.1016/j.jtha.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 04/18/2024] [Accepted: 05/10/2024] [Indexed: 06/01/2024]
Abstract
It is increasingly apparent that the pathologic interplay between coagulation and innate immunity, ie, immunothrombosis, forms the common basis of many challenges across the boundaries of specialized medicine and cannot be fully explained by the conventional concepts of cascade and cell-based coagulation. To improve our understanding of coagulation, we propose a model of coagulation that converges with inflammation and innate immune activation as a unified response toward vascular injury. Evolutionarily integral to the convergent response are damage-associated molecular patterns, which are released as a consequence of injury. Damage-associated molecular patterns facilitate diverse interactions within and between systems, not only to complement and reinforce cell-based clot formation but also to steer the response toward clot resolution and wound healing. By extending coagulation beyond its current boundaries, the convergent model aims to deliver novel diagnostics and therapeutics for contemporary and unexpected challenges across medicine, as exposed by COVID-19 and vaccine-induced immune thrombotic thrombocytopenia.
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Affiliation(s)
- Jun Yong
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK; The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Cheng-Hock Toh
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK; The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
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4
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Hao S, Wei Y, Wang Y, Muhetaer Y, Zhou C, Qiong S, Jiang P, Zhong M. End-expiratory lung volumes as a potential indicator for COVID-19 associated acute respiratory distress syndrome: a retrospective study. BMC Pulm Med 2024; 24:298. [PMID: 38918752 PMCID: PMC11197326 DOI: 10.1186/s12890-024-03118-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 06/19/2024] [Indexed: 06/27/2024] Open
Abstract
BACKGROUND End-expiratory lung volume (EELV) has been observed to decrease in acute respiratory distress syndrome (ARDS). Yet, research investigating EELV in patients with COVID-19 associated ARDS (CARDS) remains limited. It is unclear whether EELV could serve as a potential metric for monitoring disease progression and identifying patients with ARDS at increased risk of adverse outcomes. STUDY DESIGN AND METHODS This retrospective study included mechanically ventilated patients diagnosed with CARDS during the initial phase of epidemic control in Shanghai. EELV was measured using the nitrogen washout-washin technique within 48 h post-intubation, followed by regular assessments every 3-4 days. Chest CT scans, performed within a 24-hour window around each EELV measurement, were analyzed using AI software. Differences in patient demographics, clinical data, respiratory mechanics, EELV, and chest CT findings were assessed using linear mixed models (LMM). RESULTS Out of the 38 patients enrolled, 26.3% survived until discharge from the ICU. In the survivor group, EELV, EELV/predicted body weight (EELV/PBW) and EELV/predicted functional residual capacity (EELV/preFRC) were significantly higher than those in the non-survivor group (survivor group vs. non-survivor group: EELV: 1455 vs. 1162 ml, P = 0.049; EELV/PBW: 24.1 vs. 18.5 ml/kg, P = 0.011; EELV/preFRC: 0.45 vs. 0.34, P = 0.005). Follow-up assessments showed a sustained elevation of EELV/PBW and EELV/preFRC among the survivors. Additionally, EELV exhibited a positive correlation with total lung volume and residual lung volume, while demonstrating a negative correlation with lesion volume determined through chest CT scans analyzed using AI software. CONCLUSION EELV is a useful indicator for assessing disease severity and monitoring the prognosis of patients with CARDS.
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Affiliation(s)
- Shengyu Hao
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Yilin Wei
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, 130 Dong'an Road, Shanghai, China
| | - Yuxian Wang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Yaxiaerjiang Muhetaer
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Chujun Zhou
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Songjie Qiong
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Pan Jiang
- Department of Nutrition, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China.
| | - Ming Zhong
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China.
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Su XY, Gao F, Wang SY, Li J, Wang ZQ, Zhang X. Annexin gene family in Spirometra mansoni (Cestoda: Diphyllobothriidae) and its phylogenetic pattern among Platyhelminthes of medical interest. Parasite 2024; 31:32. [PMID: 38912916 PMCID: PMC11195529 DOI: 10.1051/parasite/2024034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 06/07/2024] [Indexed: 06/25/2024] Open
Abstract
The plerocercoid larvae of Spirometra mansoni are etiological agents of human and animal sparganosis. Annexins are proteins with important roles in parasites. However, our knowledge of annexins in S. mansoni is still inadequate. In this study, 18 new members of the Annexin (ANX) family were characterized in S. mansoni. The clustering analysis demonstrated that all the SmANXs were divided into two main classes, consistent with the patterns of conserved motif organization. The 18 SmANXs were detected at all developmental stages (plerocercoid, adult, and egg) and displayed ubiquitous but highly variable expression patterns in all tissues/organs studied. The representative member rSmANX18 was successfully cloned and expressed. The protein was immunolocalized in the tegument and parenchyma of the plerocercoid and in the tegument, parenchyma, uterus and egg shell of adult worms. The recombinant protein can bind phospholipids with high affinity in a Ca2+-dependent manner, shows high anticoagulant activity and combines with FITC to recognize apoptotic cells. Annexin gene polymorphism and conservative core motif permutation were found in both cestodes and trematodes. SmANXs also revealed high genetic diversity among Platyhelminthes of medical interest. Our findings lay a foundation for further studies on the biological functions of ANXs in S. mansoni as well as other taxa in which ANXs occur.
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Affiliation(s)
| | | | | | | | | | - Xi Zhang
- Department of Parasitology, School of Basic Medical Sciences, Zhengzhou University Zhengzhou 450051 PR China
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Suárez-Castillejo C, Calvo N, Preda L, Toledo-Pons N, Millán-Pons AR, Martínez J, Ramón L, Iglesias A, Morell-García D, Bauça JM, Núñez B, Sauleda J, Sala-Llinas E, Alonso-Fernández A. Pulmonary thrombosis associated with COVID-19 pneumonia: Beyond classical pulmonary thromboembolism. Eur J Clin Invest 2024; 54:e14176. [PMID: 38339827 DOI: 10.1111/eci.14176] [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] [Received: 11/02/2023] [Revised: 01/23/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024]
Abstract
BACKGROUND Classical pulmonary thromboembolism (TE) and local pulmonary thrombosis (PT) have been suggested as mechanisms of thrombosis in COVID-19. However, robust evidence is still lacking because this was mainly based on retrospective studies, in which patients were included when TE was suspected. METHODS All patients with COVID-19 pneumonia underwent computed tomography and pulmonary angiography in a prospective study. The main objective was to determine the number and percentage of thrombi surrounded by lung opacification (TSO) in each patient, as well as their relationship with percentage of lung involvement (TLI), to distinguish classical TE (with a random location of thrombi that should correspond to a percentage of TSO equivalent to the TLI) from PT. We determined TLI by artificial intelligence. Analyses at patient level (TLI and percentage of TSO) and at thrombi level (TLI and TSO) were performed. RESULTS We diagnosed TE in 70 out of 184 patients. Three (2-8) thrombi/patient were detected. The percentage of TSO was 100% (75-100) per patient, and TLI was 19.9% (4.6-35.2). Sixty-five patients (92.9%) were above the random scenario with higher percentage of TSO than TLI. Most thrombi were TSO (n = 299, 75.1%). When evaluating by TLI (<10%, 10%-20%, 20%-30% and >30%), percentage of TSO was higher in most groups. Thrombi were mainly in subsegmental/segmental arteries, and percentage of TSO was higher in all locations. CONCLUSIONS Thrombi in COVID-19 were found within lung opacities in a higher percentage than lung involvement, regardless of TLI and clot location, supporting the hypothesis of local PT rather than "classic TE".
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Affiliation(s)
- Carla Suárez-Castillejo
- Servicio de Neumología, Hospital Universitario Son Espases, Palma de Mallorca, Spain
- Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
| | - Néstor Calvo
- Servicio de Radiodiagnostico, Hospital Universitario Son Espases, Palma de Mallorca, Spain
| | - Luminita Preda
- Servicio de Radiodiagnostico, Hospital Universitario Son Espases, Palma de Mallorca, Spain
| | - Nuria Toledo-Pons
- Servicio de Neumología, Hospital Universitario Son Espases, Palma de Mallorca, Spain
- Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
| | | | - Joaquín Martínez
- Servicio de Neumología, Hospital Universitario Son Espases, Palma de Mallorca, Spain
- Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
| | - Luisa Ramón
- Servicio de Neumología, Hospital Universitario Son Espases, Palma de Mallorca, Spain
- Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
| | - Amanda Iglesias
- Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
- CIBER Enfermedades Respiratorias, Madrid, Spain
| | - Daniel Morell-García
- Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
- Servicio de Análisis Clínicos, Hospital Universitario Son Espases, Palma de Mallorca, Spain
| | - Josep Miquel Bauça
- Servicio de Análisis Clínicos, Hospital Universitario Son Espases, Palma de Mallorca, Spain
| | - Belén Núñez
- Servicio de Neumología, Hospital Universitario Son Espases, Palma de Mallorca, Spain
- Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
| | - Jaume Sauleda
- Servicio de Neumología, Hospital Universitario Son Espases, Palma de Mallorca, Spain
- Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
- CIBER Enfermedades Respiratorias, Madrid, Spain
- Facultad de Medicina, Universidad de las Islas Baleares, Palma de Mallorca, Spain
| | - Ernest Sala-Llinas
- Servicio de Neumología, Hospital Universitario Son Espases, Palma de Mallorca, Spain
- Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
- CIBER Enfermedades Respiratorias, Madrid, Spain
- Facultad de Medicina, Universidad de las Islas Baleares, Palma de Mallorca, Spain
| | - Alberto Alonso-Fernández
- Servicio de Neumología, Hospital Universitario Son Espases, Palma de Mallorca, Spain
- Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
- CIBER Enfermedades Respiratorias, Madrid, Spain
- Facultad de Medicina, Universidad de las Islas Baleares, Palma de Mallorca, Spain
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Affiliation(s)
- Guozheng Wang
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom
- Department of Haematology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Simon Timothy Abrams
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom
- Department of Haematology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Cheng-Hock Toh
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom
- Roald Dahl Haemostasis & Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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Kemerley A, Gupta A, Thirunavukkarasu M, Maloney M, Burgwardt S, Maulik N. COVID-19 Associated Cardiovascular Disease-Risks, Prevention and Management: Heart at Risk Due to COVID-19. Curr Issues Mol Biol 2024; 46:1904-1920. [PMID: 38534740 PMCID: PMC10969474 DOI: 10.3390/cimb46030124] [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: 11/28/2023] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 03/28/2024] Open
Abstract
The SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) virus and the resulting COVID-19 pandemic have had devastating and lasting impact on the global population. Although the main target of the disease is the respiratory tract, clinical outcomes, and research have also shown significant effects of infection on other organ systems. Of interest in this review is the effect of the virus on the cardiovascular system. Complications, including hyperinflammatory syndrome, myocarditis, and cardiac failure, have been documented in the context of COVID-19 infection. These complications ultimately contribute to worse patient outcomes, especially in patients with pre-existing conditions such as hypertension, diabetes, or cardiovascular disease (CVD). Importantly and interestingly, reports have demonstrated that COVID-19 also causes myocardial injury in adults without pre-existing conditions and contributes to systemic complications in pediatric populations, such as the development of multisystem inflammatory syndrome in children (MIS-C). Although there is still a debate over the exact mechanisms by which such complications arise, understanding the potential paths by which the virus can influence the cardiovascular system to create an inflammatory environment may clarify how SARS-CoV-2 interacts with human physiology. In addition to describing the mechanisms of disease propagation and patient presentation, this review discusses the diagnostic findings and treatment strategies and the evolution of management for patients presenting with cardiovascular complications, focusing on disease treatment and prevention.
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Affiliation(s)
| | | | | | | | | | - Nilanjana Maulik
- Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut School of Medicine, UConn Health, 263 Farmington Avenue, Farmington, CT 06030, USA; (A.K.); (A.G.); (M.T.); (S.B.)
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9
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Constantinescu-Bercu A, Lobiuc A, Căliman-Sturdza OA, Oiţă RC, Iavorschi M, Pavăl NE, Șoldănescu I, Dimian M, Covasa M. Long COVID: Molecular Mechanisms and Detection Techniques. Int J Mol Sci 2023; 25:408. [PMID: 38203577 PMCID: PMC10778767 DOI: 10.3390/ijms25010408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/25/2023] [Accepted: 12/26/2023] [Indexed: 01/12/2024] Open
Abstract
Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), has emerged as a significant health concern following the COVID-19 pandemic. Molecular mechanisms underlying the occurrence and progression of long COVID include viral persistence, immune dysregulation, endothelial dysfunction, and neurological involvement, and highlight the need for further research to develop targeted therapies for this condition. While a clearer picture of the clinical symptomatology is shaping, many molecular mechanisms are yet to be unraveled, given their complexity and high level of interaction with other metabolic pathways. This review summarizes some of the most important symptoms and associated molecular mechanisms that occur in long COVID, as well as the most relevant molecular techniques that can be used in understanding the viral pathogen, its affinity towards the host, and the possible outcomes of host-pathogen interaction.
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Affiliation(s)
- Adela Constantinescu-Bercu
- Department of Biomedical Sciences, Faculty of Medicine and Biological Sciences, “Ştefan cel Mare” University of Suceava, 720229 Suceava, Romania; (A.C.-B.); (O.A.C.-S.); (M.I.); (N.-E.P.); (M.C.)
| | - Andrei Lobiuc
- Department of Biomedical Sciences, Faculty of Medicine and Biological Sciences, “Ştefan cel Mare” University of Suceava, 720229 Suceava, Romania; (A.C.-B.); (O.A.C.-S.); (M.I.); (N.-E.P.); (M.C.)
| | - Olga Adriana Căliman-Sturdza
- Department of Biomedical Sciences, Faculty of Medicine and Biological Sciences, “Ştefan cel Mare” University of Suceava, 720229 Suceava, Romania; (A.C.-B.); (O.A.C.-S.); (M.I.); (N.-E.P.); (M.C.)
- Suceava Emergency Clinical County Hospital, 720224 Suceava, Romania
| | - Radu Cristian Oiţă
- Integrated Center for Research, Development and Innovation for Advanced Materials, Nanotechnologies, Manufacturing and Control Distributed Systems (MANSiD), Ştefan cel Mare University of Suceava, 720229 Suceava, Romania; (R.C.O.); (I.Ș.); (M.D.)
| | - Monica Iavorschi
- Department of Biomedical Sciences, Faculty of Medicine and Biological Sciences, “Ştefan cel Mare” University of Suceava, 720229 Suceava, Romania; (A.C.-B.); (O.A.C.-S.); (M.I.); (N.-E.P.); (M.C.)
| | - Naomi-Eunicia Pavăl
- Department of Biomedical Sciences, Faculty of Medicine and Biological Sciences, “Ştefan cel Mare” University of Suceava, 720229 Suceava, Romania; (A.C.-B.); (O.A.C.-S.); (M.I.); (N.-E.P.); (M.C.)
| | - Iuliana Șoldănescu
- Integrated Center for Research, Development and Innovation for Advanced Materials, Nanotechnologies, Manufacturing and Control Distributed Systems (MANSiD), Ştefan cel Mare University of Suceava, 720229 Suceava, Romania; (R.C.O.); (I.Ș.); (M.D.)
| | - Mihai Dimian
- Integrated Center for Research, Development and Innovation for Advanced Materials, Nanotechnologies, Manufacturing and Control Distributed Systems (MANSiD), Ştefan cel Mare University of Suceava, 720229 Suceava, Romania; (R.C.O.); (I.Ș.); (M.D.)
- Department of Computers, Electronics and Automation, Ştefan cel Mare University of Suceava, 720229 Suceava, Romania
| | - Mihai Covasa
- Department of Biomedical Sciences, Faculty of Medicine and Biological Sciences, “Ştefan cel Mare” University of Suceava, 720229 Suceava, Romania; (A.C.-B.); (O.A.C.-S.); (M.I.); (N.-E.P.); (M.C.)
- Department of Basic Medical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, CA 91711, USA
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Sekulovski M, Mileva N, Vasilev GV, Miteva D, Gulinac M, Peshevska-Sekulovska M, Chervenkov L, Batselova H, Vasilev GH, Tomov L, Lazova S, Vassilev D, Velikova T. Blood Coagulation and Thrombotic Disorders following SARS-CoV-2 Infection and COVID-19 Vaccination. Biomedicines 2023; 11:2813. [PMID: 37893186 PMCID: PMC10604891 DOI: 10.3390/biomedicines11102813] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/25/2023] [Accepted: 09/29/2023] [Indexed: 10/29/2023] Open
Abstract
Although abundant data confirm the efficacy and safety profile of the developed vaccines against COVID-19, there are still some concerns regarding vaccination in high-risk populations. This is especially valid for patients susceptible to thrombotic or bleeding events and hesitant people due to the fear of thrombotic incidents following vaccination. This narrative review focuses on various inherited and acquired thrombotic and coagulation disorders and the possible pathophysiologic mechanisms interacting with the coagulation system during immunization in view of the currently available safety data regarding COVID-19 vaccines. Inherited blood coagulation disorders and inherited thrombotic disorders in the light of COVID-19, as well as blood coagulation and thrombotic disorders and bleeding complications following COVID-19 vaccines, along with the possible pathogenesis hypotheses, therapeutic interventions, and imaging for diagnosing are discussed in detail. Lastly, the lack of causality between the bleeding and thrombotic events and COVID-19 vaccines is debated, but still emphasizes the importance of vaccination against COVID-19, outweighing the minimal risk of potential rare adverse events associated with coagulation.
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Affiliation(s)
- Metodija Sekulovski
- Department of Anesthesiology and Intensive Care, University Hospital Lozenetz, Kozyak Str., 1407 Sofia, Bulgaria
- Medical Faculty, Sofia University, St. Kliment Ohridski, Kozyak 1 Str., 1407 Sofia, Bulgaria; (G.V.V.); (D.M.); (M.G.); (M.P.-S.); (G.H.V.); (L.T.); (S.L.); (T.V.)
| | - Niya Mileva
- Medical Faculty, Medical University of Sofia, 1 Georgi Sofiiski Str., 1431 Sofia, Bulgaria;
| | - Georgi Vasilev Vasilev
- Medical Faculty, Sofia University, St. Kliment Ohridski, Kozyak 1 Str., 1407 Sofia, Bulgaria; (G.V.V.); (D.M.); (M.G.); (M.P.-S.); (G.H.V.); (L.T.); (S.L.); (T.V.)
- Clinic of Endocrinology and Metabolic Disorders, University Multiprofil Hospital Active Treatement “Sv. Georgi”, 4000 Plovdiv, Bulgaria
| | - Dimitrina Miteva
- Medical Faculty, Sofia University, St. Kliment Ohridski, Kozyak 1 Str., 1407 Sofia, Bulgaria; (G.V.V.); (D.M.); (M.G.); (M.P.-S.); (G.H.V.); (L.T.); (S.L.); (T.V.)
- Department of Genetics, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 8 Dragan Tzankov Str., 1164 Sofia, Bulgaria
| | - Milena Gulinac
- Medical Faculty, Sofia University, St. Kliment Ohridski, Kozyak 1 Str., 1407 Sofia, Bulgaria; (G.V.V.); (D.M.); (M.G.); (M.P.-S.); (G.H.V.); (L.T.); (S.L.); (T.V.)
- Department of General and Clinical Pathology, Medical University of Plovdiv, Bul. Vasil Aprilov 15A, 4000 Plovdiv, Bulgaria
| | - Monika Peshevska-Sekulovska
- Medical Faculty, Sofia University, St. Kliment Ohridski, Kozyak 1 Str., 1407 Sofia, Bulgaria; (G.V.V.); (D.M.); (M.G.); (M.P.-S.); (G.H.V.); (L.T.); (S.L.); (T.V.)
- Department of Gastroenterology, University Hospital Lozenetz, 1407 Sofia, Bulgaria
| | - Lyubomir Chervenkov
- Department of Diagnostic Imaging, Medical University of Plovdiv, Bul. Vasil Aprilov 15A, 4000 Plovdiv, Bulgaria;
| | - Hristiana Batselova
- Department of Epidemiology and Disaster Medicine, Medical University of Plovdiv, University Hospital “St George”, 4000 Plovdiv, Bulgaria;
| | - Georgi Hristov Vasilev
- Medical Faculty, Sofia University, St. Kliment Ohridski, Kozyak 1 Str., 1407 Sofia, Bulgaria; (G.V.V.); (D.M.); (M.G.); (M.P.-S.); (G.H.V.); (L.T.); (S.L.); (T.V.)
- Laboratory of Hematopathology and Immunology, National Specialized Hospital for Active Treatment of Hematological Diseases, 1756 Sofia, Bulgaria
| | - Latchezar Tomov
- Medical Faculty, Sofia University, St. Kliment Ohridski, Kozyak 1 Str., 1407 Sofia, Bulgaria; (G.V.V.); (D.M.); (M.G.); (M.P.-S.); (G.H.V.); (L.T.); (S.L.); (T.V.)
- Department of Informatics, New Bulgarian University, Montevideo 21 Str., 1618 Sofia, Bulgaria
| | - Snezhina Lazova
- Medical Faculty, Sofia University, St. Kliment Ohridski, Kozyak 1 Str., 1407 Sofia, Bulgaria; (G.V.V.); (D.M.); (M.G.); (M.P.-S.); (G.H.V.); (L.T.); (S.L.); (T.V.)
- Pediatric Clinic, University Hospital “N. I. Pirogov”, 21 “General Eduard I. Totleben” Blvd, 1606 Sofia, Bulgaria
- Department of Healthcare, Faculty of Public Health “Prof. Tsekomir Vodenicharov, MD, DSc”, Medical University of Sofia, Bialo More 8 Str., 1527 Sofia, Bulgaria
| | - Dobrin Vassilev
- Faculty of Public Health and Healthcare, Ruse University Angel Kanchev, 7017 Ruse, Bulgaria;
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University, St. Kliment Ohridski, Kozyak 1 Str., 1407 Sofia, Bulgaria; (G.V.V.); (D.M.); (M.G.); (M.P.-S.); (G.H.V.); (L.T.); (S.L.); (T.V.)
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11
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Taha A, Badu I, Sandhyavenu H, Victor V, Duhan S, Atti L, Qureshi HM, Goni TS, Keisham B, Sandhya Venu V, Thyagaturu H, Gonuguntla K, Ullah W, Deshwal H, Balla S. Contemporary outcomes of long-term anticoagulation in COVID-19 patients: a regression matched sensitivity analysis of the national inpatient sample. Expert Rev Cardiovasc Ther 2023; 21:601-608. [PMID: 37409406 DOI: 10.1080/14779072.2023.2234282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 07/05/2023] [Indexed: 07/07/2023]
Abstract
BACKGROUND The role of oral anticoagulation during the COVID-19 pandemic has been debated widely. We studied the clinical outcomes of COVID-19 hospitalizations in patients who were on long-term anticoagulation. RESEARCH DESIGN AND METHODS The Nationwide Inpatient Sample (NIS) database from 2020 was queried to identify COVID-19 patients with and without long-term anticoagulation. Multivariate regression analysis was used to calculate the adjusted odds ratio (aOR) of in-hospital outcomes. RESULTS Of 1,060,925 primary COVID-19 hospitalizations, 102,560 (9.6%) were on long-term anticoagulation. On adjusted analysis, COVID-19 patients on anticoagulation had significantly lower odds of in-hospital mortality (aOR 0.61, 95% CI 0.58-0.64, P < 0.001), acute myocardial infarction (aOR 0.72, 95% CI 0.63-0.83, P < 0.001), stroke (aOR 0.79, 95% CI 0.66-0.95, P < 0.013), ICU admissions, (aOR 0.53, 95% CI 0.49-0.57, P < 0.001) and higher odds of acute pulmonary embolism (aOR 1.47, 95% CI 1.34-1.61, P < 0.001), acute deep vein thrombosis (aOR 1.17, 95% CI 1.05-1.31, P = 0.005) compared to COVID-19 patients who were not on anticoagulation. CONCLUSIONS Compared to COVID-19 patients not on long-term anticoagulation, we observed lower in-hospital mortality, stroke and acute myocardial infarction in COVID-19 patients on long-term anticoagulation. Prospective studies are needed for optimal anticoagulation strategies in hospitalized patients.
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Affiliation(s)
- Amro Taha
- Department of Internal Medicine, Weiss Memorial Hospital, Chicago, IL, USA
| | - Irisha Badu
- Department of Internal Medicine, Onslow Memorial Hospital, Jacksonville, NC, USA
| | | | - Varun Victor
- Department of Internal Medicine, Canton Medical Education Foundation, Canton, Ohio, USA
| | - Sanchit Duhan
- Department of Internal Medicine, Sinai Hospital of Baltimore, Baltimore, MD, USA
| | - Lalitsiri Atti
- Department of Internal Medicine, Sparrow Hospital- Michigan State University, Lansing, MI, USA
| | | | | | - Bijeta Keisham
- Department of Internal Medicine, Sinai Hospital of Baltimore, Baltimore, MD, USA
| | - Vasantha Sandhya Venu
- Department of Computer Science and Engineering, Vardhaman College of Engineering, Hyderabad, India
| | | | | | - Waqas Ullah
- Department of Cardiology, Thomas Jefferson University Hospital, Philadelphia, USA
| | - Himanshu Deshwal
- Department of Medicine, Section of Pulmonary, Critical Care & Sleep Medicine, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Sudarshan Balla
- Department of Cardiology, West Virginia University, Morgantown, WV, USA
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12
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Yamashita Y, Kobayashi T, Mo M. Thrombosis and Anticoagulation Strategies in Patients with COVID-19 Including Japanese Perspective. J Atheroscler Thromb 2023; 30:311-320. [PMID: 36792179 PMCID: PMC10067339 DOI: 10.5551/jat.rv22002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) has become a major health problem worldwide since 2020. Although the main pathophysiology of COVID-19 is a respiratory infectious disease, it could also cause cardiovascular complications, including thrombosis. Thus, anticoagulation therapy has been thought to help prevent thrombosis, leading to improved survival. However, to date, several aspects of the optimal anticoagulation strategies for COVID-19 remain unclear. Considering the status of COVID-19-related thrombosis and some domestic issues in Japan, the optimal anticoagulation strategies for COVID-19 might have to be based on Japanese domestic clinical data considering racial difference. Racial disparities in terms of thromboembolic risk have been well known in the pre-COVID-19 era, and the risk of COVID-19-associated thrombosis depending on race could be an important issue. Considering a potential higher risk of bleeding with anticoagulation therapy in the Asian population, it might be important to maintain a good balance between the risks of thrombosis and bleeding. Latest evidences of COVID-19-related thrombosis and anticoagulation strategies, including some domestic issues in Japan, showed a different status of COVID-19-related thrombosis in Japan from that in Western countries, suggesting the potential benefit of different anticoagulation strategies, specifically for the Japanese population. Although these insights could be useful for the consideration of anticoagulation strategies for the Japanese population, the final decision should be based on balancing the benefits and risks of anticoagulation therapy in each patient.
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Affiliation(s)
- Yugo Yamashita
- Department of Cardiovascular Medicine, Kyoto University Hospital, Kyoto, Japan
| | | | - Makoto Mo
- Department of Cardiovascular Surgery, Yokohama Minami Kyosai Hospital, Yokohama, Japan
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13
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Tsounis EP, Triantos C, Konstantakis C, Marangos M, Assimakopoulos SF. Intestinal barrier dysfunction as a key driver of severe COVID-19. World J Virol 2023; 12:68-90. [PMID: 37033148 PMCID: PMC10075050 DOI: 10.5501/wjv.v12.i2.68] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/08/2022] [Accepted: 01/16/2023] [Indexed: 03/21/2023] Open
Abstract
The intestinal lumen harbors a diverse consortium of microorganisms that participate in reciprocal crosstalk with intestinal immune cells and with epithelial and endothelial cells, forming a multi-layered barrier that enables the efficient absorption of nutrients without an excessive influx of pathogens. Despite being a lung-centered disease, severe coronavirus disease 2019 (COVID-19) affects multiple systems, including the gastrointestinal tract and the pertinent gut barrier function. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can inflict either direct cytopathic injury to intestinal epithelial and endothelial cells or indirect immune-mediated damage. Alternatively, SARS-CoV-2 undermines the structural integrity of the barrier by modifying the expression of tight junction proteins. In addition, SARS-CoV-2 induces profound alterations to the intestinal microflora at phylogenetic and metabolomic levels (dysbiosis) that are accompanied by disruption of local immune responses. The ensuing dysregulation of the gut-lung axis impairs the ability of the respiratory immune system to elicit robust and timely responses to restrict viral infection. The intestinal vasculature is vulnerable to SARS-CoV-2-induced endothelial injury, which simultaneously triggers the activation of the innate immune and coagulation systems, a condition referred to as “immunothrombosis” that drives severe thrombotic complications. Finally, increased intestinal permeability allows an aberrant dissemination of bacteria, fungi, and endotoxin into the systemic circulation and contributes, to a certain degree, to the over-exuberant immune responses and hyper-inflammation that dictate the severe form of COVID-19. In this review, we aim to elucidate SARS-CoV-2-mediated effects on gut barrier homeostasis and their implications on the progression of the disease.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Patras 26504, Greece
| | - Stelios F Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Patras 26504, Greece
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14
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Lombardi A, De Luca M, Fabiani D, Sabatella F, Del Giudice C, Caputo A, Cante L, Gambardella M, Palermi S, Tavarozzi R, Russo V, D’Andrea A. Ultrasound during the COVID-19 Pandemic: A Global Approach. J Clin Med 2023; 12:1057. [PMID: 36769702 PMCID: PMC9918296 DOI: 10.3390/jcm12031057] [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: 12/28/2022] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 02/03/2023] Open
Abstract
SARS-CoV-2 (severe acute respiratory syndrome Coronavirus-2) rapidly spread worldwide as COVID-19 (Coronavirus disease 2019), causing a costly and deadly pandemic. Different pulmonary manifestations represent this syndrome's most common clinical manifestations, together with the cardiovascular complications frequently observed in these patients. Ultrasound (US) evaluations of the lungs, heart, and lower limbs may be helpful in the diagnosis, follow-up, and prognosis of patients with COVID-19. Moreover, POCUS (point-of-care ultrasound) protocols are particularly useful for patients admitted to intensive care units. The present review aimed to highlight the clinical conditions during the SARS-CoV-2 pandemic in which the US represents a crucial diagnostic tool.
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Affiliation(s)
- Anna Lombardi
- Department of General Medicine, San Leonardo Hospital, 80053 Castellammare di Stabia, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
| | - Mariarosaria De Luca
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
| | - Dario Fabiani
- Department of Cardiology, Luigi Vanvitelli University–Monaldi Hospital, 80131 Naples, Italy
| | - Francesco Sabatella
- Department of Cardiology, Luigi Vanvitelli University–Monaldi Hospital, 80131 Naples, Italy
| | - Carmen Del Giudice
- Department of Cardiology, Luigi Vanvitelli University–Monaldi Hospital, 80131 Naples, Italy
| | - Adriano Caputo
- Department of Cardiology, Luigi Vanvitelli University–Monaldi Hospital, 80131 Naples, Italy
| | - Luigi Cante
- Department of Cardiology, Luigi Vanvitelli University–Monaldi Hospital, 80131 Naples, Italy
| | - Michele Gambardella
- Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy
| | - Stefano Palermi
- Public Health Department, University of Naples Federico II, 80131 Naples, Italy
| | - Rita Tavarozzi
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale, 28100 Novara, Italy
| | - Vincenzo Russo
- Department of Cardiology, Luigi Vanvitelli University–Monaldi Hospital, 80131 Naples, Italy
| | - Antonello D’Andrea
- Department of Cardiology, Luigi Vanvitelli University–Monaldi Hospital, 80131 Naples, Italy
- Department of Cardiology, Umberto I Hospital, 84014 Nocera Inferiore, Italy
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15
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Ali RM, Tharwat AI, Labib HA. Effect of Aspirin Use on clinical Outcome among Critically Ill Patients with COVID- 19. EGYPTIAN JOURNAL OF ANAESTHESIA 2022. [DOI: 10.1080/11101849.2022.2139104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- Rania M. Ali
- Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ayman I. Tharwat
- Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Heba A. Labib
- Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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16
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Bunch CM, Zackariya N, Thomas AV, Langford JH, Aboukhaled M, Thomas SJ, Ansari A, Patel SS, Buckner H, Miller JB, Annis CL, Quate‐Operacz MA, Schmitz LA, Pulvirenti JJ, Konopinski JC, Kelley KM, Hassna S, Nelligan LG, Walsh MM. COVID-associated non-vasculitic thrombotic retiform purpura of the face and extremities: A case report. Clin Case Rep 2022; 10:e6790. [PMID: 36590660 PMCID: PMC9795088 DOI: 10.1002/ccr3.6790] [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: 10/11/2022] [Revised: 11/28/2022] [Accepted: 12/08/2022] [Indexed: 12/29/2022] Open
Abstract
SARS-CoV-2 infection can manifest many rashes. However, thrombotic retiform purpura rarely occurs during COVID-19 illness. Aggressive anti-COVID-19 therapy with a high-dose steroid regimen led to rapid recovery. This immunothrombotic phenomenon likely represents a poor type 1 interferon response and complement activation on the endothelial surface in response to acute infection.
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Affiliation(s)
- Connor M. Bunch
- Departments of Emergency Medicine and Internal MedicineHenry Ford HospitalDetroitMichiganUSA
| | - Nuha Zackariya
- Indiana University School of Medicine—South BendSouth BendIndianaUSA
| | - Anthony V. Thomas
- Indiana University School of Medicine—South BendSouth BendIndianaUSA
| | - Jack H. Langford
- Departments of Emergency Medicine and Internal MedicineSaint Joseph Regional Medical CenterMishawakaIndianaUSA
| | - Michael Aboukhaled
- Departments of Emergency Medicine and Internal MedicineSaint Joseph Regional Medical CenterMishawakaIndianaUSA
| | - Samuel J. Thomas
- Departments of Emergency Medicine and Internal MedicineSaint Joseph Regional Medical CenterMishawakaIndianaUSA
| | - Aida Ansari
- Departments of Emergency Medicine and Internal MedicineSaint Joseph Regional Medical CenterMishawakaIndianaUSA
| | - Shivani S. Patel
- Departments of Emergency Medicine and Internal MedicineSaint Joseph Regional Medical CenterMishawakaIndianaUSA
| | - Hallie Buckner
- Departments of Emergency Medicine and Internal MedicineSaint Joseph Regional Medical CenterMishawakaIndianaUSA
| | - Joseph B. Miller
- Departments of Emergency Medicine and Internal MedicineHenry Ford HospitalDetroitMichiganUSA
| | - Christy L. Annis
- Departments of Emergency Medicine and Internal MedicineSaint Joseph Regional Medical CenterMishawakaIndianaUSA
| | | | | | - Joseph J. Pulvirenti
- Department of Infectious DiseaseSaint Joseph Regional Medical CenterMishawakaIndianaUSA
| | | | | | - Samer Hassna
- Department of Internal MedicineSaint Joseph Regional Medical CenterMishawakaIndianaUSA
| | - Luke G. Nelligan
- Department of Family MedicineMarian University College of Osteopathic MedicineIndianapolisIndianaUSA
| | - Mark M. Walsh
- Departments of Emergency Medicine and Internal MedicineSaint Joseph Regional Medical CenterMishawakaIndianaUSA
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17
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Kanapeckaitė A, Mažeikienė A, Geris L, Burokienė N, Cottrell GS, Widera D. Computational pharmacology: New avenues for COVID-19 therapeutics search and better preparedness for future pandemic crises. Biophys Chem 2022; 290:106891. [PMID: 36137310 PMCID: PMC9464258 DOI: 10.1016/j.bpc.2022.106891] [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: 07/07/2022] [Revised: 09/03/2022] [Accepted: 09/04/2022] [Indexed: 01/07/2023]
Abstract
The COVID-19 pandemic created an unprecedented global healthcare emergency prompting the exploration of new therapeutic avenues, including drug repurposing. A large number of ongoing studies revealed pervasive issues in clinical research, such as the lack of accessible and organised data. Moreover, current shortcomings in clinical studies highlighted the need for a multi-faceted approach to tackle this health crisis. Thus, we set out to explore and develop new strategies for drug repositioning by employing computational pharmacology, data mining, systems biology, and computational chemistry to advance shared efforts in identifying key targets, affected networks, and potential pharmaceutical intervention options. Our study revealed that formulating pharmacological strategies should rely on both therapeutic targets and their networks. We showed how data mining can reveal regulatory patterns, capture novel targets, alert about side-effects, and help identify new therapeutic avenues. We also highlighted the importance of the miRNA regulatory layer and how this information could be used to monitor disease progression or devise treatment strategies. Importantly, our work bridged the interactome with the chemical compound space to better understand the complex landscape of COVID-19 drugs. Machine and deep learning allowed us to showcase limitations in current chemical libraries for COVID-19 suggesting that both in silico and experimental analyses should be combined to retrieve therapeutically valuable compounds. Based on the gathered data, we strongly advocate for taking this opportunity to establish robust practices for treating today's and future infectious diseases by preparing solid analytical frameworks.
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Affiliation(s)
- Austė Kanapeckaitė
- AK Consulting, Laisvės g. 7, LT 12007 Vilnius, Lithuania,Corresponding author
| | - Asta Mažeikienė
- Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, M. K. Čiurlionio g. 21, LT-03101 Vilnius, Lithuania
| | - Liesbet Geris
- Biomechanics Research Unit, GIGA In Silico Medicine, University of Liège, Quartier Hôpital, Avenue de l'Hôpital 11 (B34), Liège 4000, Belgium,Biomechanics Section, Department of Mechanical Engineering, KU Leuven, Celestijnenlaan 300C (2419), Leuven 3001, Belgium,Skeletel Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Herestraat 49 (813), Leuven 3000, Belgium
| | - Neringa Burokienė
- Clinics of Internal Diseases, Family Medicine and Oncology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, M. K. Čiurlionio str. 21/27, LT-03101 Vilnius, Lithuania
| | - Graeme S. Cottrell
- University of Reading, School of Pharmacy, Hopkins Building, Reading RG6 6UB, United Kingdom
| | - Darius Widera
- University of Reading, School of Pharmacy, Hopkins Building, Reading RG6 6UB, United Kingdom
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18
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Dupuy A, Ju LA, Chiu J, Passam FH. Mechano-Redox Control of Integrins in Thromboinflammation. Antioxid Redox Signal 2022; 37:1072-1093. [PMID: 35044225 DOI: 10.1089/ars.2021.0265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Significance: How mechanical forces and biochemical cues are coupled remains a miracle for many biological processes. Integrins, well-known adhesion receptors, sense changes in mechanical forces and reduction-oxidation reactions (redox) in their environment to mediate their adhesive function. The coupling of mechanical and redox function is a new area of investigation. Disturbance of normal mechanical forces and the redox balance occurs in thromboinflammatory conditions; atherosclerotic plaques create changes to the mechanical forces in the circulation. Diabetes induces redox changes in the circulation by the production of reactive oxygen species and vascular inflammation. Recent Advances: Integrins sense changes in the blood flow shear stress at the level of focal adhesions and respond to flow and traction forces by increased signaling. Talin, the integrin-actin linker, is a traction force sensor and adaptor. Oxidation and reduction of integrin disulfide bonds regulate their adhesion. A conserved disulfide bond in integrin αlpha IIb beta 3 (αIIbβ3) is directly reduced by the thiol oxidoreductase endoplasmic reticulum protein 5 (ERp5) under shear stress. Critical Issues: The coordination of mechano-redox events between the extracellular and intracellular compartments is an active area of investigation. Another fundamental issue is to determine the spatiotemporal arrangement of key regulators of integrins' mechanical and redox interactions. How thromboinflammatory conditions lead to mechanoredox uncoupling is relatively unexplored. Future Directions: Integrated approaches, involving disulfide bond biochemistry, microfluidic assays, and dynamic force spectroscopy, will aid in showing that cell adhesion constitutes a crossroad of mechano- and redox biology, within the same molecule, the integrin. Antioxid. Redox Signal. 37, 1072-1093.
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Affiliation(s)
- Alexander Dupuy
- Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.,Charles Perkins Centre, The University of Sydney, Camperdown, Australia.,Heart Research Institute, Newtown, Australia
| | - Lining Arnold Ju
- Charles Perkins Centre, The University of Sydney, Camperdown, Australia.,Heart Research Institute, Newtown, Australia.,School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, Darlington, Australia
| | - Joyce Chiu
- Charles Perkins Centre, The University of Sydney, Camperdown, Australia.,ACRF Centenary Cancer Research Centre, The Centenary Institute, Camperdown, Australia
| | - Freda H Passam
- Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.,Charles Perkins Centre, The University of Sydney, Camperdown, Australia.,Heart Research Institute, Newtown, Australia
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19
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Usefulness of KL-6 for Predicting Clinical Outcomes in Hospitalized COVID-19 Patients. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58101317. [PMID: 36295478 PMCID: PMC9608840 DOI: 10.3390/medicina58101317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/14/2022] [Accepted: 09/19/2022] [Indexed: 12/02/2022]
Abstract
Background: Krebs von den Lungen 6 (KL-6) is a novel biomarker for interstitial lung disease, and it reflects acute lung injury. We explored the usefulness of KL-6 to predict clinical outcomes in hospitalized coronavirus disease 2019 (COVID-19) patients. Methods: In a total of 48 hospitalized COVID-19 patients, KL-6 levels were measured using the HISCL KL-6 assay (Sysmex, Kobe, Japan) with the HISCL 5000 automated analyzer (Sysmex). Clinical outcomes (intensive care unit [ICU] admission, ventilator use, extracorporeal membrane oxygenation [ECMO] use, and 30-day mortality) were analyzed according to KL-6 percentiles. Age, initial KL-6 level, Charlson comorbidity index (CCI), and critical disease were compared using the receiver operating characteristic (ROC) curve and Kaplan-Meier methods for clinical outcomes. Results: KL-6 quartiles were associated with ICU admission, ventilator use, and ECMO use (all p < 0.05), except 30-day mortality (p = 0.187). On ROC curve analysis, initial KL-6 level predicted ICU admission, ventilator use, and ECMO use significantly better than age, CCI, and critical disease (all p < 0.05); age, initial KL-6 level, CCI, and critical disease predicted 30-day mortality comparably. On Kaplan−Meier survival analysis, hazard ratios (95% confidence interval) were 4.8 (1.2−19.3) for age, 4.7 (1.1−21.6) for initial KL-6 level, 3.9 (0.9−16.2) for CCI, and 2.1 (0.5−10.3) for critical disease. Conclusions: This study demonstrated that KL-6 could be a useful biomarker to predict clinical outcomes in hospitalized COVID-19 patients. KL-6 may contribute to identifying COVID-19 patients requiring critical care, including ICU admission and ventilator and/or ECMO use.
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20
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Dix C, Zeller J, Stevens H, Eisenhardt SU, Shing KSCT, Nero TL, Morton CJ, Parker MW, Peter K, McFadyen JD. C-reactive protein, immunothrombosis and venous thromboembolism. Front Immunol 2022; 13:1002652. [PMID: 36177015 PMCID: PMC9513482 DOI: 10.3389/fimmu.2022.1002652] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 08/22/2022] [Indexed: 11/24/2022] Open
Abstract
C-reactive protein (CRP) is a member of the highly conserved pentraxin superfamily of proteins and is often used in clinical practice as a marker of infection and inflammation. There is now increasing evidence that CRP is not only a marker of inflammation, but also that destabilized isoforms of CRP possess pro-inflammatory and pro-thrombotic properties. CRP circulates as a functionally inert pentameric form (pCRP), which relaxes its conformation to pCRP* after binding to phosphocholine-enriched membranes and then dissociates to monomeric CRP (mCRP). with the latter two being destabilized isoforms possessing highly pro-inflammatory features. pCRP* and mCRP have significant biological effects in regulating many of the aspects central to pathogenesis of atherothrombosis and venous thromboembolism (VTE), by directly activating platelets and triggering the classical complement pathway. Importantly, it is now well appreciated that VTE is a consequence of thromboinflammation. Accordingly, acute VTE is known to be associated with classical inflammatory responses and elevations of CRP, and indeed VTE risk is elevated in conditions associated with inflammation, such as inflammatory bowel disease, COVID-19 and sepsis. Although the clinical data regarding the utility of CRP as a biomarker in predicting VTE remains modest, and in some cases conflicting, the clinical utility of CRP appears to be improved in subsets of the population such as in predicting VTE recurrence, in cancer-associated thrombosis and in those with COVID-19. Therefore, given the known biological function of CRP in amplifying inflammation and tissue damage, this raises the prospect that CRP may play a role in promoting VTE formation in the context of concurrent inflammation. However, further investigation is required to unravel whether CRP plays a direct role in the pathogenesis of VTE, the utility of which will be in developing novel prophylactic or therapeutic strategies to target thromboinflammation.
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Affiliation(s)
- Caroline Dix
- Department of Haematology, Alfred Hospital, Melbourne, VIC, Australia
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
| | - Johannes Zeller
- Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, Freiburg, Germany
| | - Hannah Stevens
- Department of Haematology, Alfred Hospital, Melbourne, VIC, Australia
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
- Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Steffen U. Eisenhardt
- Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, Freiburg, Germany
| | - Karen S. Cheung Tung Shing
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC, Australia
| | - Tracy L. Nero
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC, Australia
| | - Craig J. Morton
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC, Australia
- Commonwealth Scientific and Industrial Research Organisation (CSIRO) Biomedical Manufacturing Program, Clayton, VIC, Australia
| | - Michael W. Parker
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC, Australia
- Structural Biology Unit, St. Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
| | - Karlheinz Peter
- Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC, Australia
- Department of Cardiology, Alfred Hospital, Melbourne, VIC, Australia
| | - James D. McFadyen
- Department of Haematology, Alfred Hospital, Melbourne, VIC, Australia
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
- Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC, Australia
- *Correspondence: James D. McFadyen,
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21
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Solimando AG, Marziliano D, Ribatti D. SARS-CoV-2 and Endothelial Cells: Vascular Changes, Intussusceptive Microvascular Growth and Novel Therapeutic Windows. Biomedicines 2022; 10:2242. [PMID: 36140343 PMCID: PMC9496230 DOI: 10.3390/biomedicines10092242] [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: 08/17/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Endothelial activation in infectious diseases plays a crucial role in understanding and predicting the outcomes and future treatments of several clinical conditions. COVID-19 is no exception. Moving from basic principles to novel approaches, an evolving view of endothelial activation provides insights into a better knowledge of the upstream actors in COVID-19 as a crucial future direction for managing SARS-CoV-2 and other infections. Assessing the function of resting and damaged endothelial cells in infection, particularly in COVID-19, five critical processes emerged controlling thrombo-resistance: vascular integrity, blood flow regulation, immune cell trafficking, angiogenesis and intussusceptive microvascular growth. Endothelial cell injury is associated with thrombosis, increased vessel contraction and a crucial phenomenon identified as intussusceptive microvascular growth, an unprecedented event of vessel splitting into two lumens through the integration of circulating pro-angiogenic cells. An essential awareness of endothelial cells and their phenotypic changes in COVID-19 inflammation is pivotal to understanding the vascular biology of infections and may offer crucial new therapeutic windows.
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Affiliation(s)
- Antonio Giovanni Solimando
- Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, 70124 Bari, Italy
| | - Donatello Marziliano
- Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, 70124 Bari, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy
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22
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Zhang H, Lao Q, Zhang J, Zhu J. Coagulopathy in COVID-19 and anticoagulation clinical trials. Best Pract Res Clin Haematol 2022; 35:101377. [PMID: 36494146 PMCID: PMC9395291 DOI: 10.1016/j.beha.2022.101377] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/02/2022] [Accepted: 08/16/2022] [Indexed: 12/15/2022]
Abstract
Severe acute respiratory disease coronavirus 2 (SARS-COV-2) first emerged in Wuhan, China, in December 2019 and has caused a global pandemic of a scale unprecedented in the modern era. People infected with SARS-CoV-2 can be asymptomatic, moderate symptomatic or develop severe COVID-19. Other than the typical acute respiratory distress syndrome (ARDS), patients with moderate or severe COVID-19 also develop a distinctive systemic coagulopathy, known as COVID-19-associated coagulopathy (CAC), which is different from sepsis-related forms of disseminated intravascular coagulation (DIC). Endotheliopathy or endotheliitis are other unique features of CAC. The endothelial cell perturbation can further increase the risk of thrombotic events in COVID-19 patients. In this review, we will summarize the current knowledge on COVID-19 coagulopathy and the possible mechanisms for the condition. We also discuss the results of clinical trials testing methods for mitigating thrombosis events in COVID-19 patients.
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Affiliation(s)
- Heng Zhang
- Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI, USA
| | - Qifang Lao
- Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI, USA; Department of Critical Care Medicine, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Jue Zhang
- Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI, USA
| | - Jieqing Zhu
- Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI, USA; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
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23
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Abstract
The Covid-19 pandemic appeared in China in December 2019 as a cluster of transmissible pneumonia caused by a new betacoronavirus. On March 11, 2020, the World Health Organization (WHO) declared it a pandemic. Covid-19 is a mild infection in 80% of cases, serious in 15% and critical in 5%. Symptomatic forms include a first phase of flu-like viral invasion, and at times a second phase, dysimmune and inflammatory, with acute respiratory distress syndrome, multiorgan failure and thromboembolic complications. Degree of severity is related to age and comorbidities. SARS-CoV-2 is the third highly pathogenic Betacoronavirus to cross the species barrier. Its genome, an RNA of 29,903 nucleotides, shows strong homogeneity with bat coronaviruses from southern China, but the conditions for its passage in humans have yet to be elucidated. Mutations can give rise to variants of concern (VOC) that are more transmissible and able to evade the host's immune response. Several VOCs have succeeded and replaced one another: Alpha in October 2020, Beta and Gamma in December 2020, Delta in spring 2021 and Omicron in November 2021. The Covid-19 pandemic has evolved in five waves of unequal amplitude and severity, with geographical disparities. Worldwide, it has caused 395,000,000 confirmed cases including 5,700,000 deaths. Epidemiological surveillance applies several indicators (incidence rate, test positivity rate, effective R and occupancy rate of intensive care beds) supplemented by genomic monitoring to detect variants by sequencing. Non-pharmacological measures, particularly face mask wearing, have been effective in preventing the transmission of SARS-CoV-2. Few currently available drugs have proven useful, with the exception of dexamethazone for patients requiring oxygen therapy. Development of SARS-CoV-2 vaccines began early on many platforms. Innovation was brought about by the Pfizer-BioNTech and Moderna messenger RNA vaccines, which claim protective efficacy of 95% and 94.1% respectively, far higher than the 70% minimum set by the WHO. Governments have hesitated between two strategies, mitigation and suppression. The second has been favored in critical periods such as April 2020, when 2.5 billion people throughout the world were confined. Vaccination campaigns got underway at the end of December 2020 and progressed without reaching sufficient herd immunity, leading some nations to consider compulsory vaccination or to require a vaccine or health pass, in order for persons to access different activities. Will the pandemic stop with Omicron and become endemic? This part of the Covid-19 story remains to be told.
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Affiliation(s)
- Yves Buisson
- Académie nationale de médecine, 4ème division, 16, rue Bonaparte, 75272 Paris Cedex06, France.
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24
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Butt A, Erkan D, Lee AI. COVID-19 and antiphospholipid antibodies. Best Pract Res Clin Haematol 2022; 35:101402. [PMID: 36494152 PMCID: PMC9568270 DOI: 10.1016/j.beha.2022.101402] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/07/2022] [Accepted: 10/11/2022] [Indexed: 12/14/2022]
Abstract
Antiphospholipid syndrome and the coagulopathy of COVID-19 share many pathophysiologic features, including endotheliopathy, hypercoagulability, and activation of platelets, complement pathways, and neutrophil extracellular traps, all acting in concert via a model of immunothrombosis. Antiphospholipid antibody production in COVID-19 is common, with 50% of COVID-19 patients being positive for lupus anticoagulant in some studies, and with non-Sapporo criteria antiphospholipid antibodies being prevalent as well. The biological significance of antiphospholipid antibodies in COVID-19 is uncertain, as such antibodies are usually transient, and studies examining clinical outcomes in COVID-19 patients with and without antiphospholipid antibodies have yielded conflicting results. In this review, we explore the biology of antiphospholipid antibodies in COVID-19 and other infections and discuss mechanisms of thrombogenesis in antiphospholipid syndrome and parallels with COVID-19 coagulopathy. In addition, we review the existing literature on safety of COVID-19 vaccination in patients with antiphospholipid antibodies and antiphospholipid syndrome.
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Affiliation(s)
- Ayesha Butt
- Section of Hematology, Department of Medicine, Yale School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA.
| | - Doruk Erkan
- Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery and Weill Cornell Medicine, 535 E. 70th St., 6th floor, New York, NY, 10021, USA.
| | - Alfred Ian Lee
- Section of Hematology, Department of Medicine, Yale School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA.
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25
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Voci D, Zbinden S, Micieli E, Kucher N, Barco S. Fixed-Dose Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Pulmonary Embolism Associated with COVID-19. Viruses 2022; 14:1606. [PMID: 35893672 PMCID: PMC9394471 DOI: 10.3390/v14081606] [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: 06/27/2022] [Revised: 11/30/2022] [Accepted: 07/20/2022] [Indexed: 12/07/2022] Open
Abstract
Background. Fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT) rapidly improves hemodynamic parameters and reverses right ventricular dysfunction caused by acute pulmonary embolism (PE). The effectiveness of USAT for acute PE associated with coronavirus disease 2019 (COVID-19) is unknown. Methods and results. The study population of this cohort study consisted of 36 patients with an intermediate-high- or high-risk acute PE treated with a fixed low-dose USAT protocol (r-tPA 10-20 mg/15 h). Of these, 9 patients tested positive for COVID-19 and were age-sex-matched to 27 patients without COVID-19. The USAT protocol included, beyond the infusion of recombinant tissue plasminogen activator, anti-Xa-activity-adjusted unfractionated heparin therapy (target 0.3-0.7 U/mL). The study outcomes were the invasively measured mean pulmonary arterial pressure (mPAP) before and at completion of USAT, and the National Early Warning Score (NEWS), according to which more points indicate more severe hemodynamic impairment. Twenty-four (66.7%) patients were men; the mean age was 67 ± 14 years. Mean ± standard deviation mPAP decreased from 32.3 ± 8.3 to 22.4 ± 7.0 mmHg among COVID-19 patients and from 35.4 ± 9.7 to 24.6 ± 7.0 mmHg among unexposed, with no difference in the relative improvement between groups (p = 0.84). Within 12 h of USAT start, the median NEWS decreased from six (Q1-Q3: 4-8) to three (Q1-Q3: 2-4) points among COVID-19 patients and from four (Q1-Q3: 2-6) to two (Q1-Q3: 2-3) points among unexposed (p = 0.29). One COVID-19 patient died due to COVID-19-related complications 14 days after acute PE. No major bleeding events occurred. Conclusions. Among patients with COVID-19-associated acute PE, mPAP rapidly decreased during USAT with a concomitant progressive improvement of the NEWS. The magnitude of mPAP reduction was similar in patients with and without COVID-19.
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Affiliation(s)
- Davide Voci
- Department of Angiology, University Hospital Zurich, 8091 Zurich, Switzerland; (D.V.); (S.Z.); (E.M.); (N.K.)
| | - Stéphanie Zbinden
- Department of Angiology, University Hospital Zurich, 8091 Zurich, Switzerland; (D.V.); (S.Z.); (E.M.); (N.K.)
| | - Evy Micieli
- Department of Angiology, University Hospital Zurich, 8091 Zurich, Switzerland; (D.V.); (S.Z.); (E.M.); (N.K.)
| | - Nils Kucher
- Department of Angiology, University Hospital Zurich, 8091 Zurich, Switzerland; (D.V.); (S.Z.); (E.M.); (N.K.)
| | - Stefano Barco
- Department of Angiology, University Hospital Zurich, 8091 Zurich, Switzerland; (D.V.); (S.Z.); (E.M.); (N.K.)
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
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26
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Moisa E, Corneci D, Negutu MI, Filimon CR, Serbu A, Popescu M, Negoita S, Grintescu IM. Development and Internal Validation of a New Prognostic Model Powered to Predict 28-Day All-Cause Mortality in ICU COVID-19 Patients-The COVID-SOFA Score. J Clin Med 2022; 11:jcm11144160. [PMID: 35887924 PMCID: PMC9323813 DOI: 10.3390/jcm11144160] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/12/2022] [Accepted: 07/15/2022] [Indexed: 02/04/2023] Open
Abstract
Background: The sequential organ failure assessment (SOFA) score has poor discriminative ability for death in severely or critically ill patients with Coronavirus disease 2019 (COVID-19) requiring intensive care unit (ICU) admission. Our aim was to create a new score powered to predict 28-day mortality. Methods: Retrospective, observational, bicentric cohort study including 425 patients with COVID-19 pneumonia, acute respiratory failure and SOFA score ≥ 2 requiring ICU admission for ≥72 h. Factors with independent predictive value for 28-day mortality were identified after stepwise Cox proportional hazards (PH) regression. Based on the regression coefficients, an equation was computed representing the COVID-SOFA score. Discriminative ability was tested using receiver operating characteristic (ROC) analysis, concordance statistics and precision-recall curves. This score was internally validated. Results: Median (Q1−Q3) age for the whole sample was 64 [55−72], with 290 (68.2%) of patients being male. The 28-day mortality was 54.58%. After stepwise Cox PH regression, age, neutrophil-to-lymphocyte ratio (NLR) and SOFA score remained in the final model. The following equation was computed: COVID-SOFA score = 10 × [0.037 × Age + 0.347 × ln(NLR) + 0.16 × SOFA]. Harrell’s C-index for the COVID-SOFA score was higher than the SOFA score alone for 28-day mortality (0.697 [95% CI; 0.662−0.731] versus 0.639 [95% CI: 0.605−0.672]). Subsequently, the prediction error rate was improved up to 16.06%. Area under the ROC (AUROC) was significantly higher for the COVID-SOFA score compared with the SOFA score for 28-day mortality: 0.796 [95% CI: 0.755−0.833] versus 0.699 [95% CI: 0.653−0.742, p < 0.001]. Better predictive value was observed with repeated measurement at 48 h after ICU admission. Conclusions: The COVID-SOFA score is better than the SOFA score alone for 28-day mortality prediction. Improvement in predictive value seen with measurements at 48 h after ICU admission suggests that the COVID-SOFA score can be used in a repetitive manner. External validation is required to support these results.
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Affiliation(s)
- Emanuel Moisa
- Department of Anaesthesia and Intensive Care Medicine, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.C.); (M.P.); (S.N.); (I.M.G.)
- Clinic of Anaesthesia and Intensive Care Medicine, Elias Emergency University Hospital, 011461 Bucharest, Romania;
- Correspondence: or ; Tel.: +40-753021128
| | - Dan Corneci
- Department of Anaesthesia and Intensive Care Medicine, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.C.); (M.P.); (S.N.); (I.M.G.)
- Clinic of Anaesthesia and Intensive Care Medicine, Dr. Carol Davila Central Military Emergency University Hospital, 010825 Bucharest, Romania; (C.R.F.); (A.S.)
| | - Mihai Ionut Negutu
- Clinic of Anaesthesia and Intensive Care Medicine, Elias Emergency University Hospital, 011461 Bucharest, Romania;
| | - Cristina Raluca Filimon
- Clinic of Anaesthesia and Intensive Care Medicine, Dr. Carol Davila Central Military Emergency University Hospital, 010825 Bucharest, Romania; (C.R.F.); (A.S.)
| | - Andreea Serbu
- Clinic of Anaesthesia and Intensive Care Medicine, Dr. Carol Davila Central Military Emergency University Hospital, 010825 Bucharest, Romania; (C.R.F.); (A.S.)
| | - Mihai Popescu
- Department of Anaesthesia and Intensive Care Medicine, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.C.); (M.P.); (S.N.); (I.M.G.)
- Clinic of Anaesthesia and Intensive Care Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Silvius Negoita
- Department of Anaesthesia and Intensive Care Medicine, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.C.); (M.P.); (S.N.); (I.M.G.)
- Clinic of Anaesthesia and Intensive Care Medicine, Elias Emergency University Hospital, 011461 Bucharest, Romania;
| | - Ioana Marina Grintescu
- Department of Anaesthesia and Intensive Care Medicine, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (D.C.); (M.P.); (S.N.); (I.M.G.)
- Clinic of Anaesthesia and Intensive Care Medicine, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
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27
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Park M, Hur M, Kim H, Lee CH, Lee JH, Kim HW, Nam M. Prognostic Utility of Procalcitonin, Presepsin, and the VACO Index for Predicting 30-day Mortality in Hospitalized COVID-19 Patients. Ann Lab Med 2022; 42:406-414. [PMID: 35177561 PMCID: PMC8859553 DOI: 10.3343/alm.2022.42.4.406] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/16/2021] [Accepted: 12/27/2021] [Indexed: 11/19/2022] Open
Abstract
Background Biomarkers and clinical indices have been investigated for predicting mortality in patients with coronavirus disease (COVID-19). We explored the prognostic utility of procalcitonin (PCT), presepsin, and the Veterans Health Administration COVID-19 (VACO) index for predicting 30-day-mortality in COVID-19 patients. Methods In total, 54 hospitalized COVID-19 patients were enrolled. PCT and presepsin levels were measured using the Elecsys BRAHMS PCT assay (Roche Diagnostics GmbH, Mannheim, Germany) and HISCL Presepsin assay (Sysmex, Kobe, Japan), respectively. The VACO index was calculated based on age, sex, and comorbidities. PCT and presepsin levels and the VACO index were compared using ROC curve, Kaplan-Meier method, and reclassification analysis for the 30-day mortality. Results ROC curve analysis was used to measure PCT and presepsin levels and the VACO index to predict 30-day mortality; the optimal cut-off values were 0.138 ng/mL for PCT, 717 pg/mL for presepsin, and 12.1% for the VACO index. On Kaplan-Meier survival analysis, hazard ratios (95% confidence interval) were 15.9 (4.1-61.3) for PCT, 26.3 (6.4-108.0) for presepsin, and 6.0 (1.7-21.1) for the VACO index. On reclassification analysis, PCT and presepsin in addition to the VACO index significantly improved the prognostic value of the index. Conclusions This study demonstrated the prognostic utility of measuring PCT and presepsin levels and the VACO index in COVID-19 patients. The biomarkers in addition to the clinical index were more useful than the index alone for predicting clinical outcomes in COVID-19 patients.
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Affiliation(s)
- Mikyoung Park
- Department of Laboratory Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mina Hur
- Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Hanah Kim
- Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Chae Hoon Lee
- Department of Laboratory Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Jong Ho Lee
- Department of Laboratory Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Hyung Woo Kim
- Department of Laboratory Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Minjeong Nam
- Department of Laboratory Medicine, Korea University Anam Hospital, Seoul, Korea
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28
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Barnes GD, Burnett A, Allen A, Ansell J, Blumenstein M, Clark NP, Crowther M, Dager WE, Deitelzweig SB, Ellsworth S, Garcia D, Kaatz S, Raffini L, Rajasekhar A, Beek AV, Minichiello T. Thromboembolic prevention and anticoagulant therapy during the COVID-19 pandemic: updated clinical guidance from the anticoagulation forum. J Thromb Thrombolysis 2022; 54:197-210. [PMID: 35579732 PMCID: PMC9111941 DOI: 10.1007/s11239-022-02643-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/13/2022] [Indexed: 12/11/2022]
Abstract
Thromboembolism is a common and deadly consequence of COVID-19 infection for hospitalized patients. Based on clinical evidence pre-dating the COVID-19 pandemic and early observational reports, expert consensus and guidance documents have strongly encouraged the use of prophylactic anticoagulation for patients hospitalized for COVID-19 infection. More recently, multiple clinical trials and larger observational studies have provided evidence for tailoring the approach to thromboprophylaxis for patients with COVID-19. This document provides updated guidance for the use of anticoagulant therapies in patients with COVID-19 from the Anticoagulation Forum, the leading North American organization of anticoagulation providers. We discuss ambulatory, in-hospital, and post-hospital thromboprophylaxis strategies as well as provide guidance for patients with thrombotic conditions who are considering COVID-19 vaccination.
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Affiliation(s)
- Geoffrey D Barnes
- University of Michigan, 2800 Plymouth Rd, B14 G214, 48109-2800, Ann Arbor, MI, USA.
| | - Allison Burnett
- University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Arthur Allen
- VA Salt Lake City Health Care System, Salt Lake City, UT, USA
| | - Jack Ansell
- Professor of Medicine, Hofstra/Northwell School of Medicine , New York, USA
| | | | - Nathan P Clark
- Kaiser Permanente Colorado, Colorado University Skaggs School of Pharmacy, Aurora, CO, USA
| | | | | | | | | | | | | | - Leslie Raffini
- University of Pennsylvania Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | | | - Andrea Van Beek
- Kaweah Health Medical Group/Visalia Medical Clinic, Visalia, CA, USA
| | - Tracy Minichiello
- University of California, San Francisco San Francisco VA Medical Center, San Francisco, CA, USA
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29
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Lagrange J, Lecompte T, Knopp T, Lacolley P, Regnault V. Alpha-2-macroglobulin in hemostasis and thrombosis: An underestimated old double-edged sword. J Thromb Haemost 2022; 20:806-815. [PMID: 35037393 DOI: 10.1111/jth.15647] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 01/07/2022] [Accepted: 01/10/2022] [Indexed: 11/27/2022]
Abstract
Antiproteinases such as alpha-2-macroglobulin (A2M) play a role in hemostasis. A2M is highly conserved throughout evolution and is a high molecular weight homo-tetrameric glycoprotein. A2M proteinase inhibitor activity is possible via a unique cage structure leading to proteinase entrapment without direct enzymatic activity inhibition. Following this entrapment, proteinase clearance is possible through A2M binding to the low-density lipoprotein receptor-related protein 1. A2M synthesis is regulated by pro-inflammatory cytokines and increases during several chronic or acute inflammatory diseases and varies with age. For instance, A2M plasma levels are known to be increased in patients with diabetes mellitus, nephrotic syndrome, or sepsis. Concerning hemostasis, A2M can trap many proteinases involved in coagulation and fibrinolysis. Because of its pleiotropic effects A2M can be seen as both anti- and pro-hemostatic. A2M can inhibit thrombin, factor Xa, activated protein C, plasmin, tissue-plasminogen activator, and urokinase. Through its many different functions A2M is generally put apart in the balanced regulation of hemostasis. In addition, the fact that A2M plasma levels are differently regulated during inflammatory-related diseases and that A2M can neutralize cytokines that also modify hemostasis could explain why it is difficult to link common proteins and parameters of hemostasis with the mechanisms of thrombosis in such diseases. Thus, we propose in the present review to summarize known functions of A2M, give a brief overview about diseases, and then to focus on the roles of this antiproteinase in hemostasis and thrombosis.
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Affiliation(s)
- Jeremy Lagrange
- Faculté de Médecine, INSERM U1116, Vandœuvre-lès-Nancy, France
- Université de Lorraine, Nancy, France
- CHRU Nancy, Médecine Vasculaire, Vandœuvre-lès-Nancy, France
| | - Thomas Lecompte
- Université de Lorraine, Nancy, France
- CHRU Nancy, Médecine Vasculaire, Vandœuvre-lès-Nancy, France
- Unité d'hémostase, Département de Médecine, Hôpitaux Universitaires de Genève, Faculté de Médecine - GpG, Université de Genève, Geneva, Switzerland
| | - Tanja Knopp
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
- Institute for Molecular Medicine, University Medical Center Mainz, Mainz, Germany
| | - Patrick Lacolley
- Faculté de Médecine, INSERM U1116, Vandœuvre-lès-Nancy, France
- Université de Lorraine, Nancy, France
- CHRU Nancy, Médecine Vasculaire, Vandœuvre-lès-Nancy, France
| | - Véronique Regnault
- Faculté de Médecine, INSERM U1116, Vandœuvre-lès-Nancy, France
- Université de Lorraine, Nancy, France
- CHRU Nancy, Médecine Vasculaire, Vandœuvre-lès-Nancy, France
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30
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Worku DA. SARS-CoV-2 Associated Immune Dysregulation and COVID-Associated Pulmonary Aspergilliosis (CAPA): A Cautionary Tale. Int J Mol Sci 2022; 23:3228. [PMID: 35328649 PMCID: PMC8953852 DOI: 10.3390/ijms23063228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 02/01/2023] Open
Abstract
As the global SARS-CoV-2 pandemic continues to plague healthcare systems, it has become clear that opportunistic pathogens cause a considerable proportion of SARS-CoV-2-associated mortality and morbidity cases. Of these, Covid-Associated Pulmonary Aspergilliosis (CAPA) is a major concern with evidence that it occurs in the absence of traditional risk factors such as neutropenia and is diagnostically challenging for the attending physician. In this review, we focus on the immunopathology of SARS-CoV-2 and how this potentiates CAPA through dysregulation of local and systemic immunity as well as the unintended consequences of approved COVID treatments including corticosteroids and IL-6 inhibitors. Finally, we will consider how knowledge of the above may aid in the diagnosis of CAPA using current diagnostics and what treatment should be instituted in probable and confirmed cases.
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Affiliation(s)
- Dominic Adam Worku
- Infectious Diseases and Microbiology Department, Morriston Hospital, Swansea University Health Board, Swansea SA6 6NL, UK;
- Public Health Wales, Cardiff CF10 4BZ, UK
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31
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Venous thromboembolism in patients hospitalised with COVID-19 in England. Thromb Res 2022; 213:138-144. [PMID: 35366435 PMCID: PMC8944169 DOI: 10.1016/j.thromres.2022.03.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/11/2022] [Accepted: 03/21/2022] [Indexed: 12/24/2022]
Abstract
Background The aim of this study was to detail the incidence of venous thromboembolism (VTE) in patients hospitalised with COVID-19 in England. Methods This was an exploratory retrospective analysis of observational data from the Hospital Episode Statistics dataset for England. All patients aged ≥18 years in England with a diagnosis of COVID-19 who had a hospital stay that was completed between 1st March 2020 and 31st March 2021 were included. A recorded diagnosis of VTE during the index stay or during a subsequent admission in the six weeks following discharge was the primary outcome in the main analysis. In secondary analysis, VTE diagnosis was the primary exposure and in-hospital mortality the primary outcome. Results Over the 13 months, 374,244 unique patients had a diagnosis of COVID-19 during a hospital stay, of whom 17,346 (4.6%) had a recorded diagnosis of VTE. VTE was more commonly recorded in patients aged 40–79 years, males and in patients of Black ethnicity, even after adjusting for covariates. Recorded VTE diagnosis was associated with longer hospital stay and higher adjusted in-hospital mortality (odds ratio 1.35 (95% confidence interval 1.29 to 1.41)). Conclusions VTE was a common complication of hospitalisation with COVID-19 in England. VTE was associated with both increased length of stay and mortality rate.
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Ji W, Chen L, Yang W, Li K, Zhao J, Yan C, You C, Jiang M, Zhou M, Shen X. Transcriptional landscape of circulating platelets from patients with COVID-19 reveals key subnetworks and regulators underlying SARS-CoV-2 infection: implications for immunothrombosis. Cell Biosci 2022; 12:15. [PMID: 35139909 PMCID: PMC8827164 DOI: 10.1186/s13578-022-00750-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 01/24/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Thrombosis and coagulopathy are pervasive pathological features of coronavirus disease 2019 (COVID-19), and thrombotic complications are a sign of severe COVID-19 disease and are associated with multiple organ failure and increased mortality. Platelets are essential cells that regulate hemostasis, thrombus formation and inflammation; however, the mechanism underlying the interaction between platelets and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. RESULTS The present study performed RNA sequencing on the RNA isolated from platelets obtained from 10 COVID-19 patients and eight healthy donors, and discovered that SARS-CoV-2 not only significantly altered the coding and non-coding transcriptional landscape, but also altered the function of the platelets, promoted thrombus formation and affected energy metabolism of platelets. Integrative network biology analysis identified four key subnetworks and 16 risk regulators underlying SARS-CoV-2 infection, involved in coronavirus disease-COVID-19, platelet activation and immune response pathways. Furthermore, four risk genes (upstream binding transcription factor, RNA polymerase II, I and III subunit L, Y-box binding protein 1 and yippee like 2) were found to be associated with COVID-19 severity. Finally, a significant alteration in the von Willebrand factor/glycoprotein Ib-IX-V axis was revealed to be strongly associated with platelet aggregation and immunothrombosis. CONCLUSIONS The transcriptional landscape and the identification of critical subnetworks and risk genes of platelets provided novel insights into the molecular mechanisms of immunothrombosis in COVID-19 progression, which may pave the way for the development of novel therapeutic strategies for preventing COVID-19-associated thrombosis and improving the clinical outcome of COVID-19 patients.
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Affiliation(s)
- Weiping Ji
- New Coronavirus Infectious Disease Prevention and Control Leadership Office, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325003, People's Republic of China
| | - Lu Chen
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Wei Yang
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, People's Republic of China
| | - Ke Li
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Jingting Zhao
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Congcong Yan
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Cancan You
- New Coronavirus Infectious Disease Prevention and Control Leadership Office, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325003, People's Republic of China
| | - Minghua Jiang
- New Coronavirus Infectious Disease Prevention and Control Leadership Office, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325003, People's Republic of China
| | - Meng Zhou
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China.
| | - Xian Shen
- New Coronavirus Infectious Disease Prevention and Control Leadership Office, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325003, People's Republic of China.
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Vincent JL, Levi M, Hunt BJ. Prevention and management of thrombosis in hospitalised patients with COVID-19 pneumonia. THE LANCET. RESPIRATORY MEDICINE 2022; 10:214-220. [PMID: 34838161 PMCID: PMC8616572 DOI: 10.1016/s2213-2600(21)00455-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/28/2021] [Accepted: 10/07/2021] [Indexed: 12/13/2022]
Abstract
A proportion of people infected with SARS-CoV-2 develop moderate or severe COVID-19, with an increased risk of thromboembolic complications. The inflammatory response to SARS-CoV-2 infection can cause an acute-phase response and endothelial dysfunction, which contribute to COVID-19-associated coagulopathy, the clinical and laboratory features of which differ in some respects from those of classic disseminated intravascular coagulation. Understanding of the pathophysiology of thrombosis in COVID-19 is needed to develop approaches to management and prevention, with implications for short-term and long-term health outcomes. Evidence is emerging to support treatment decisions in patients with COVID-19, but many questions remain about the optimum approach to management. In this Viewpoint, we provide a summary of the pathophysiology of thrombosis and associated laboratory and clinical findings, and highlight key considerations in the management of coagulopathy in hospitalised patients with severe COVID-19, including coagulation assessment, identification of thromboembolic complications, and use of antithrombotic prophylaxis and therapeutic anticoagulation. We await the results of trials that are underway to establish the safety and benefits of prolonged thromboprophylaxis after hospital discharge.
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Affiliation(s)
- Jean-Louis Vincent
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
| | - Marcel Levi
- Department of Medicine and Cardiometabolic Programme-National Institute for Health Research UCLH/UCL Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK; Department of Vascular Medicine, Amsterdam University Medical Center (location Academic Medical Center), Amsterdam, Netherlands
| | - Beverley J Hunt
- Kings Healthcare Partners and Thrombosis & Haemophilia Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK
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34
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Affiliation(s)
- Charlotte A Bradbury
- Bristol Haematology and Oncology Centre, University of Bristol, Bristol BS2 8ED, UK.
| | - Zoe McQuilten
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia; Clinical Haematology, Monash Health, Melbourne, VIC, Australia
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35
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Oba S, Hosoya T, Amamiya M, Mitsumura T, Kawata D, Sasaki H, Kamiya M, Yamamoto A, Ando T, Shimada S, Shirai T, Okamoto T, Tateishi T, Endo A, Aiboshi J, Nosaka N, Yamanouchi H, Ugawa T, Nagaoka E, Oi K, Tao S, Maejima Y, Tanaka Y, Tanimoto K, Takeuchi H, Tohda S, Hirakawa A, Sasano T, Arai H, Otomo Y, Miyazaki Y, Yasuda S. Arterial and Venous Thrombosis Complicated in COVID-19: A Retrospective Single Center Analysis in Japan. Front Cardiovasc Med 2021; 8:767074. [PMID: 34869681 PMCID: PMC8639692 DOI: 10.3389/fcvm.2021.767074] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/18/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Thrombosis is a characteristic complication in coronavirus disease 2019 (COVID-19). Since coagulopathy has been observed over the entire clinical course, thrombosis might be a clue to understanding the specific pathology in COVID-19. Currently, there is limited epidemiological data of COVID-19-associated thrombosis in the Japanese population and none regarding variant strains of SARS-CoV-2. Here, we elucidate the risk factors and the pattern of thrombosis in COVID-19 patients. Methods: The patients consecutively admitted to Tokyo Medical and Dental University Hospital with COVID-19 were retrospectively analyzed. SARS-CoV-2 variants of concern/interest (VOC/VOI) carrying the spike protein mutants E484K, N501Y, or L452R were identified by PCR-based analysis. All thrombotic events were diagnosed by clinical symptoms, ultrasonography, and/or radiological tests. Results: Among the 516 patients, 32 patients experienced 42 thromboembolic events. Advanced age, severe respiratory conditions, and several abnormal laboratory markers were associated with the development of thrombosis. While thrombotic events occurred in 13% of the patients with a severe respiratory condition, those events still occurred in 2.5% of the patients who did not require oxygen therapy. Elevated D-dimer and ferritin levels on admission were independent risk factors of thrombosis (adjusted odds ratio 9.39 and 3.11, 95% confidence interval 2.08-42.3, and 1.06-9.17, respectively). Of the thrombotic events, 22 were venous, whereas 20 were arterial. While patients with thrombosis received anticoagulation and antiinflammatory therapies with a higher proportion, the mortality rate, organ dysfunctions, and bleeding complications in these patients were higher than those without thrombosis. The incidence of thrombosis in COVID-19 became less frequent over time, such as during the replacement of the earlier strains of SARS-CoV-2 by VOC/VOI and during increased use of anticoagulatory therapeutics. Conclusion: This study elucidated that elevated D-dimer and ferritin levels are useful biomarkers of thrombosis in COVID-19 patients. The comparable incidence of arterial thrombosis with venous thrombosis and the development of thrombosis in less severe patients required further considerations for the management of Japanese patients with COVID-19. Further studies would be required to identify high-risk populations and establish appropriate interventions for thrombotic complications in COVID-19.
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Affiliation(s)
- Seiya Oba
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tadashi Hosoya
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Miki Amamiya
- Department of Cardiovascular Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Takahiro Mitsumura
- Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Daisuke Kawata
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hirokazu Sasaki
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Mari Kamiya
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Akio Yamamoto
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Takahiro Ando
- Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Sho Shimada
- Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tsuyoshi Shirai
- Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tsukasa Okamoto
- Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tomoya Tateishi
- Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Akira Endo
- Trauma and Acute Critical Care Medical Center, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Junichi Aiboshi
- Trauma and Acute Critical Care Medical Center, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Nobuyuki Nosaka
- Department of Intensive Care Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hideo Yamanouchi
- Department of Intensive Care Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Toyomu Ugawa
- Department of Intensive Care Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Eiki Nagaoka
- Department of Cardiovascular Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Keiji Oi
- Department of Cardiovascular Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Susumu Tao
- Department of Cardiovascular Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yasuhiro Maejima
- Department of Cardiovascular Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yukie Tanaka
- Research Core, Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kousuke Tanimoto
- Research Core, Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.,Genome Laboratory, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hiroaki Takeuchi
- Department of Molecular Virology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Shuji Tohda
- Clinical Laboratory, Tokyo Medical and Dental University (TMDU) Hospital, Tokyo, Japan
| | - Akihiro Hirakawa
- Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tetsuo Sasano
- Department of Cardiovascular Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hirokuni Arai
- Department of Cardiovascular Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yasuhiro Otomo
- Trauma and Acute Critical Care Medical Center, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yasunari Miyazaki
- Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Shinsuke Yasuda
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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Lu CH, Li KJ, Wu CH, Shen CY, Kuo YM, Hsieh SC, Yu CL. The FcγRIII Engagement Augments PMA-Stimulated Neutrophil Extracellular Traps (NETs) Formation by Granulocytes Partially via Cross-Talk between Syk-ERK-NF-κB and PKC-ROS Signaling Pathways. Biomedicines 2021; 9:biomedicines9091127. [PMID: 34572313 PMCID: PMC8472361 DOI: 10.3390/biomedicines9091127] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/14/2021] [Accepted: 08/30/2021] [Indexed: 12/16/2022] Open
Abstract
Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cell in the circulation capable of neutrophil extracellular traps (NETs) formation after stimulation. Both NADPH oxidase-dependent and -independent pathways are involved in NET formation. The IgG is the most abundant immunoglobulin in human serum. However, the impact of the circulating IgG on NET formation is totally unexplored. In this study, the all-trans retinoic acid (ATRA)-induced mature granulocytes (dHL-60) were pre-treated with monomeric human IgG, papain-digested Fab fragment, crystallizable IgG Fc portion, rituximab (a human IgG1), or IgG2. The NET formation of the dHL-60 in the presence/absence of phorbol 12-myristate 13-acetate (PMA) stimulation was then measured by the fluorescent area after SYTOX green nucleic acid stain. The intracellular reactive oxygen species (ROS) generation was measured by flow cytometry. Total and phosphorylated Syk, SHP-1, and ERK were detected by immunoblot. We found that human monomeric IgG and its subclasses IgG1 and IgG2 per se induced negligible NET formation of dHL-60, but the FcγRIII engagement by these IgG subclasses and Fc portion augment PMA-stimulated dHL-60 NET formation in a dose-dependent manner. Furthermore, we found that increased Syk and ERK phosphorylation, intracellular ROS generation, and pro-inflammatory cytokines, IL-8 and TNF-α, production could be induced after FcγRIII engagement. Blocking FcγRIII engagement by a specific antibody diminished the augmented NET formation. In conclusion, we discovered that cross-talk between FcγRIII engagement-induced Syk-ERK and PMA-induced PKC signaling pathways augment NET formation of dHL-60 via increased ROS generation and pro-inflammatory cytokines, IL-8 and TNF-α, production.
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Affiliation(s)
- Cheng-Hsun Lu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Ko-Jen Li
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
| | - Cheng-Han Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Chieh-Yu Shen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Yu-Min Kuo
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Song-Chou Hsieh
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
| | - Chia-Li Yu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
- Correspondence:
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Kaklamanos A, Belogiannis K, Skendros P, Gorgoulis VG, Vlachoyiannopoulos PG, Tzioufas AG. COVID-19 Immunobiology: Lessons Learned, New Questions Arise. Front Immunol 2021; 12:719023. [PMID: 34512643 PMCID: PMC8427766 DOI: 10.3389/fimmu.2021.719023] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/09/2021] [Indexed: 12/17/2022] Open
Abstract
There is strong evidence that COVID-19 pathophysiology is mainly driven by a spatiotemporal immune deregulation. Both its phenotypic heterogeneity, spanning from asymptomatic to severe disease/death, and its associated mortality, are dictated by and linked to maladaptive innate and adaptive immune responses against SARS-CoV-2, the etiologic factor of the disease. Deregulated interferon and cytokine responses, with the contribution of immune and cellular stress-response mediators (like cellular senescence or uncontrolled inflammatory cell death), result in innate and adaptive immune system malfunction, endothelial activation and inflammation (endothelitis), as well as immunothrombosis (with enhanced platelet activation, NET production/release and complement hyper-activation). All these factors play key roles in the development of severe COVID-19. Interestingly, another consequence of this immune deregulation, is the production of autoantibodies and the subsequent development of autoimmune phenomena observed in some COVID-19 patients with severe disease. These new aspects of the disease that are now emerging (like autoimmunity and cellular senescence), could offer us new opportunities in the field of disease prevention and treatment. Simultaneously, lessons already learned from the immunobiology of COVID-19 could offer new insights, not only for this disease, but also for a variety of chronic inflammatory responses observed in autoimmune and (auto)inflammatory diseases.
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Affiliation(s)
- Aimilios Kaklamanos
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Institute for Autoimmune Systemic and Neurological Diseases, Athens, Greece
| | - Konstantinos Belogiannis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Skendros
- First Department of Internal Medicine and Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Vassilis G. Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
- Basic Research Center, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
- Center for New Biotechnologies and Precision Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Panayiotis G. Vlachoyiannopoulos
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Institute for Autoimmune Systemic and Neurological Diseases, Athens, Greece
| | - Athanasios G. Tzioufas
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Institute for Autoimmune Systemic and Neurological Diseases, Athens, Greece
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38
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Affiliation(s)
- George Goshua
- Section of Hematology, Yale School of Medicine, New Haven, CT, USA.,Department of Health Policy and Management, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Ayesha Butt
- Section of Hematology, Yale School of Medicine, New Haven, CT, USA
| | - Alfred I Lee
- Section of Hematology, Yale School of Medicine, New Haven, CT, USA
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