|
1
|
Ma YN, Ma SR, Yang L, Wu J, Wang YR, Bao LJ, Ma L, Wu QQ, Wang ZH. Diagnostic biomarkers and immune infiltration profiles common to COVID-19, acute myocardial infarction and acute ischaemic stroke using bioinformatics methods and machine learning. BMC Neurol 2025; 25:201. [PMID: 40340571 PMCID: PMC12060493 DOI: 10.1186/s12883-025-04212-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 04/28/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND COVID-19 is a disease that affects people globally. Beyond affecting the respiratory system, COVID-19 patients are at an elevated risk for both venous and arterial thrombosis. This heightened risk contributes to an increased probability of acute complications, including acute myocardial infarction (AMI) and acute ischemic stroke (AIS). Given the unclear relationship between COVID-19, AMI, and AIS, it is crucial to gain a deeper understanding of their associations and potential molecular mechanisms. This study aims to utilize bioinformatics to analyze gene expression data, identify potential therapeutic targets and biomarkers, and explore the role of immune cells in the disease. METHODS This study employed three Gene Expression Omnibus (GEO) datasets for analysis, which included data on COVID-19, AMI and AIS. We performed enrichment analysis on the co-DEGs for these three diseases to clarify gene pathways and functions, and also examined the relationship between co-DEGs and immune infiltration. Machine learning techniques and protein-protein interaction networks (PPI) were used to identify hub genes within the co-DEGs. Finally, we employed a dual validation strategy integrating independent GEO datasets and in vitro experiments with human blood samples to comprehensively assess the reliability of our experimental findings. RESULTS We identified 88 co-DEGs associated with COVID-19, AMI and AIS. Enrichment analysis results indicated that co-DEGs were significantly enriched in immune inflammatory responses related to leukocytes and neutrophils. Immune infiltration analysis revealed significant differences in immune cell populations between the disease group and the normal group. Finally, genes selected through machine learning methods included: CLEC4E, S100A12, and IL1R2. Based on the PPI network, the top ten most influential DEGs were identified as MMP9, TLR2, TLR4, ITGAM, S100A12, FCGR1A, CD163, FCER1G, FPR2, and CLEC4D. The integration of the protein-protein interaction (PPI) network with machine learning techniques facilitated the identification of S100A12 as a potential common biomarker for early diagnosis and a therapeutic target for all three diseases. Ultimately, validation of S100A12 showed that it was consistent with our experimental results, confirming its reliability as a biomarker. Moreover, it demonstrated good diagnostic performance for the three diseases. CONCLUSION We employed bioinformatics methods and machine learning to investigate common diagnostic biomarkers and immune infiltration characteristics of COVID-19, AMI and AIS. Functional and pathway analyses indicated that the co-DEGs were primarily enriched in immune inflammatory responses related to leukocytes and neutrophils. Through two machine learning approaches and the PPI network, and subsequent validation and evaluation, we identified S100A12 as a potential common therapeutic target and biomarker related to immune response that may influence these three diseases.
Collapse
Affiliation(s)
- Ya-Nan Ma
- Department of Geriatrics and Specialty Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Si-Rong Ma
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Li Yang
- Department of Geriatrics and Specialty Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Juan Wu
- Department of Geriatrics and Specialty Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Ya-Rong Wang
- Department of Geriatrics and Specialty Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Li-Jia Bao
- Department of Geriatrics and Specialty Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Li Ma
- Department of Geriatrics and Specialty Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Qing-Qiu Wu
- Department of Geriatrics and Specialty Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
| | - Zhen-Hai Wang
- Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
- Diagnosis and Treatment Engineering Technology Research Center of Nervous System Diseases of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China.
- Neurology Center, Ningxia Medical University General Hospital, Yinchuan, Ningxia, China.
| |
Collapse
|
|
2
|
Ban J, Qian J, Zhang C, Li J. Recent advances in TAM mechanisms in lung diseases. J Transl Med 2025; 23:479. [PMID: 40287707 PMCID: PMC12032715 DOI: 10.1186/s12967-025-06398-2] [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: 02/11/2025] [Accepted: 03/18/2025] [Indexed: 04/29/2025] Open
Abstract
TYRO3, MERTK, and AXL receptor tyrosine kinases, collectively known as TAM receptors, play a vital role in maintaining lung tissue homeostasis by regulating integrity and self-renewal. These receptors activate signalling pathways that inhibit apoptosis, promote cell proliferation and differentiation, mediate cell adhesion and migration, and perform other essential biological functions. Additionally, TAM receptors are implicated in mechanisms that suppress anti-tumor immunity and confer resistance to immune checkpoint inhibitors. Disruption of the homeostatic balances can lead to pathological conditions such as lung inflammation, fibrosis, or tumors. Recent studies highlight their significant role in COVID-19-induced lung injury. However, the exact mechanisms by which TAM receptors contribute to lung diseases remain unclear. This article reviews the potential mechanisms of TAM receptor involvement in disease progression, focusing on lung inflammation, fibrosis, cancer, and COVID-19-induced lung injury. It also explores future research aspects and the therapeutic potentials of targeting TAM receptors, providing a theoretical foundation for understanding lung disease mechanisms and identifying treatment targets.
Collapse
Affiliation(s)
- Jiaqi Ban
- School of Public Health, The key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, No.6 Ankang Road, Guian New Area, Guiyang, 561113, Guizhou, China
| | - Jiayi Qian
- School of Public Health, The key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, No.6 Ankang Road, Guian New Area, Guiyang, 561113, Guizhou, China
| | - Chi Zhang
- School of Clinical Medicine, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, 561113, People's Republic of China
| | - Jun Li
- School of Public Health, The key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, No.6 Ankang Road, Guian New Area, Guiyang, 561113, Guizhou, China.
| |
Collapse
|
|
3
|
Shakhidzhanov S, Filippova A, Bovt E, Gubkin A, Sukhikh G, Tsarenko S, Spiridonov I, Protsenko D, Zateyshchikov D, Vasilieva E, Kalinskaya A, Dukhin O, Novichkova G, Karamzin S, Serebriyskiy I, Lipets E, Kopnenkova D, Morozova D, Melnikova E, Rumyantsev A, Ataullakhanov F. Severely Ill COVID-19 Patients May Exhibit Hypercoagulability Despite Escalated Anticoagulation. J Clin Med 2025; 14:1966. [PMID: 40142778 PMCID: PMC11943368 DOI: 10.3390/jcm14061966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/07/2025] [Accepted: 03/09/2025] [Indexed: 03/28/2025] Open
Abstract
Introduction: Severely ill COVID-19 patients receiving prophylactic-dose anticoagulation exhibit high rates of thrombosis and mortality. The escalation of anticoagulation also does not reduce mortality and has an uncertain impact on thrombosis rates. The reasons why escalated doses fail to outperform prophylactic doses in reducing risks of thrombosis and death in severely ill COVID-19 patients remain unclear. We hypothesized that escalated anticoagulation would not effectively prevent hypercoagulability and, consequently, would not reduce the risk of thrombosis and death in some severely ill patients. Methods: We conducted a prospective multicenter study that enrolled 3860 COVID-19 patients, including 1654 severely ill. They received different doses of low-molecular-weight or unfractionated heparin, and their blood coagulation was monitored with activated partial thromboplastin time, D-dimer, and Thrombodynamics. A primary outcome was hypercoagulability detected by Thrombodynamics. Blood samples were collected at the trough level of anticoagulation. Results: We found that escalated anticoagulation did not prevent hypercoagulability in 28.3% of severely ill patients at the trough level of the pharmacological activity. Severely ill patients with such hypercoagulability had higher levels of inflammation markers and better creatinine clearance compared to severely ill patients without it. Hypercoagulability detected by Thrombodynamics was associated with a 1.68-fold higher hazard rate for death and a 3.19-fold higher hazard rate for thrombosis. Elevated D-dimer levels were also associated with higher hazard rates for thrombosis and death, while shortened APTTs were not. The simultaneous use of Thrombodynamics and D-dimer data enhanced the accuracy for predicting thrombotic events and fatal outcomes in severely ill patients. Conclusions: Thrombodynamics reliably detects hypercoagulability in COVID-19 patients and can be used in conjunction with D-dimer to assess the risk of thrombosis and death in severely ill patients. The pharmacological effect of LMWH at the trough level might be too low to prevent thrombosis in some severely ill patients with severe inflammation and better creatinine clearance, even if escalated doses are used.
Collapse
Affiliation(s)
- Soslan Shakhidzhanov
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, 117997 Moscow, Russia; (A.F.); (E.B.); (G.N.); (D.M.); (A.R.)
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia; (I.S.); (S.K.); (I.S.); (E.L.); (E.M.)
| | - Anna Filippova
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, 117997 Moscow, Russia; (A.F.); (E.B.); (G.N.); (D.M.); (A.R.)
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia; (I.S.); (S.K.); (I.S.); (E.L.); (E.M.)
| | - Elizaveta Bovt
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, 117997 Moscow, Russia; (A.F.); (E.B.); (G.N.); (D.M.); (A.R.)
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia; (I.S.); (S.K.); (I.S.); (E.L.); (E.M.)
| | - Andrew Gubkin
- Central Clinical Hospital No. 2 Named After N.A.Semashko “RZD-Medicine”, 121359 Moscow, Russia;
| | - Gennady Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I.Kulakov, 117997 Moscow, Russia;
| | - Sergey Tsarenko
- City Clinical Hospital No. 52 of Moscow Health Care Department, 123182 Moscow, Russia;
| | - Ilya Spiridonov
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia; (I.S.); (S.K.); (I.S.); (E.L.); (E.M.)
| | - Denis Protsenko
- Moscow Multiprofile Clinical Center “Kommunarka” of Moscow Healthcare Department, 142770 Moscow, Russia; (D.P.); (D.K.)
| | - Dmitriy Zateyshchikov
- City Clinical Hospital No. 51 of Moscow Health Care Department, 121309 Moscow, Russia;
| | - Elena Vasilieva
- City Clinical Hospital No. 23 of Moscow Health Care Department, 109004 Moscow, Russia; (E.V.); (A.K.); (O.D.)
| | - Anna Kalinskaya
- City Clinical Hospital No. 23 of Moscow Health Care Department, 109004 Moscow, Russia; (E.V.); (A.K.); (O.D.)
| | - Oleg Dukhin
- City Clinical Hospital No. 23 of Moscow Health Care Department, 109004 Moscow, Russia; (E.V.); (A.K.); (O.D.)
| | - Galina Novichkova
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, 117997 Moscow, Russia; (A.F.); (E.B.); (G.N.); (D.M.); (A.R.)
| | - Sergey Karamzin
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia; (I.S.); (S.K.); (I.S.); (E.L.); (E.M.)
| | - Ilya Serebriyskiy
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia; (I.S.); (S.K.); (I.S.); (E.L.); (E.M.)
| | - Elena Lipets
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia; (I.S.); (S.K.); (I.S.); (E.L.); (E.M.)
| | - Daria Kopnenkova
- Moscow Multiprofile Clinical Center “Kommunarka” of Moscow Healthcare Department, 142770 Moscow, Russia; (D.P.); (D.K.)
| | - Daria Morozova
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, 117997 Moscow, Russia; (A.F.); (E.B.); (G.N.); (D.M.); (A.R.)
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia; (I.S.); (S.K.); (I.S.); (E.L.); (E.M.)
| | - Evgeniya Melnikova
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia; (I.S.); (S.K.); (I.S.); (E.L.); (E.M.)
| | - Alexander Rumyantsev
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, 117997 Moscow, Russia; (A.F.); (E.B.); (G.N.); (D.M.); (A.R.)
| | - Fazoil Ataullakhanov
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, 117997 Moscow, Russia; (A.F.); (E.B.); (G.N.); (D.M.); (A.R.)
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia; (I.S.); (S.K.); (I.S.); (E.L.); (E.M.)
| |
Collapse
|
|
4
|
Ji W, Xie X, Bai G, Fan Y, He Y, Zhang L, Zhou H, Li L, Qiang D, Li H. Type 2 Diabetes Mellitus Aggravates Complement Dysregulation and Affects Cortisol Response in Patients with Post-COVID-19. Diabetes Metab Syndr Obes 2024; 17:3849-3861. [PMID: 39449862 PMCID: PMC11499617 DOI: 10.2147/dmso.s480457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 10/01/2024] [Indexed: 10/26/2024] Open
Abstract
Purpose COVID-19 viral infection results in dysregulation of the complement system and a decrease in cortisol and adrenocorticotropin hormone (ACTH) levels. This study aimed to explore the complement system, as well as cortisol and ACTH responses in patients with post-COVID-19 conditions (PCC) and type 2 diabetes mellitus (T2DM). Patients and Methods This study recruited 31 patients with PCC and T2DM (PCC-T2DM), 19 patients with PCC (PCC), 10 patients with T2DM (T2DM), and 10 healthy participants (control). Cortisol and ACTH in the PCC and PCC-T2DM groups were assessed using the insulin tolerance test. In the fasting state, serum samples were collected for proteomic analyses. Spearman correlation analysis was performed between proteins and cortisol, as well as between proteins and ACTH. Results Cortisol and ACTH levels were consistently decreased in the PCC and PCC-T2DM groups. Proteomic analyses revealed that most of the differentially abundant proteins (DAPs) in the PCC vs control and PCC-T2DM vs T2DM were involved in the coagulation and complement cascade, and the essential complement C3 was significantly upregulated in the PCC and PCC-T2DM groups when compared to their controls. Additionally, complement-related DAPs in the PCC vs control and PCC-T2DM vs T2DM were significantly correlated with cortisol and ACTH levels. In comparing PCC-T2DM samples with PCC samples, we found that upregulated DAPs were linked to the complement system and other immune system, and most DAPs were negatively correlated with cortisol and ACTH. Conclusion Our study revealed that T2DM exacerbated dysregulation of the complement system in patients with PCC, and significant correlations were present between complement protein levels and those of cortisol and ACTH. These results provide novel insights into the dysregulation of complement and endocrine hormones in patients with PCC and T2DM.
Collapse
Affiliation(s)
- Wenrui Ji
- Department of Endocrinology, the First People’s Hospital of Yinchuan, Yinchuan, 750001, People’s Republic of China
| | - Xiaomin Xie
- Department of Endocrinology, the First People’s Hospital of Yinchuan, Yinchuan, 750001, People’s Republic of China
| | - Guirong Bai
- Department of Endocrinology, the First People’s Hospital of Yinchuan, Yinchuan, 750001, People’s Republic of China
| | - Yalei Fan
- The Second Clinical Medical School of Ningxia Medical University, Yinchuan, 750001, People’s Republic of China
| | - Yanting He
- Department of Endocrinology, the First People’s Hospital of Yinchuan, Yinchuan, 750001, People’s Republic of China
| | - Li Zhang
- Department of Endocrinology, the First People’s Hospital of Yinchuan, Yinchuan, 750001, People’s Republic of China
| | - Haiyan Zhou
- Department of Endocrinology, the First People’s Hospital of Yinchuan, Yinchuan, 750001, People’s Republic of China
| | - Ling Li
- Department of Endocrinology, the First People’s Hospital of Yinchuan, Yinchuan, 750001, People’s Republic of China
| | - Dan Qiang
- Department of Endocrinology, the First People’s Hospital of Yinchuan, Yinchuan, 750001, People’s Republic of China
| | - Huan Li
- Department of Endocrinology, the First People’s Hospital of Yinchuan, Yinchuan, 750001, People’s Republic of China
| |
Collapse
|
|
5
|
Khoshnegah Z, Siyadat P, Rostami M, Sheikhi M, Ghorbani M, Mansouritorghabeh H. Protein C and S activities in COVID-19: A systematic review and meta-analysis. J Thromb Thrombolysis 2024; 57:1018-1030. [PMID: 38722521 DOI: 10.1007/s11239-024-02971-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2024] [Indexed: 08/10/2024]
Abstract
COVID-19 has been associated with alterations in coagulation. Recent reports have shown that protein C and S activities are altered in COVID-19. This may affect the complications and outcome of the disease. However, their exact role in COVID-19 remains uncertain. The aim of the current study was therefore to analyze all papers in the literature on protein C and S activities in COVID-19. We searched three medical electronic databases. Of the 2442 papers, 28 studies were selected for the present meta-analysis. For the meta-analysis, means ± standard deviations with 95% confidence intervals (CI) for protein C and S activities were extracted. Pooled p values were calculated using STATA software. Protein C and S activities were significantly lower in COVID-19 patients than in healthy controls (pooled p values: 0.04 and 0.02, respectively). Similarly, protein C activities were considerably lower in nonsurviving patients (pooled p value = 0.00). There was no association between proteins C or S and thrombosis risk or ICU admission in COVID-19 patients (p value > 0.05). COVID-19 patients may exhibit lower activities of the C and S proteins, which might affect disease outcome; however, additional attention should be given when considering therapeutic strategies for these patients.
Collapse
Affiliation(s)
- Zahra Khoshnegah
- Department of Hematology and Blood Banking, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Payam Siyadat
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Mehrdad Rostami
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Sheikhi
- Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Ghorbani
- PhD Student of Hematology and Transfusion Science, Pathology Department, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Hassan Mansouritorghabeh
- Central Diagnostic Laboratories, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
6
|
Riou M, Coste F, Meyer A, Enache I, Talha S, Charloux A, Reboul C, Geny B. Mechanisms of Pulmonary Vasculopathy in Acute and Long-Term COVID-19: A Review. Int J Mol Sci 2024; 25:4941. [PMID: 38732160 PMCID: PMC11084496 DOI: 10.3390/ijms25094941] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/13/2024] Open
Abstract
Despite the end of the pandemic, coronavirus disease 2019 (COVID-19) remains a major public health concern. The first waves of the virus led to a better understanding of its pathogenesis, highlighting the fact that there is a specific pulmonary vascular disorder. Indeed, COVID-19 may predispose patients to thrombotic disease in both venous and arterial circulation, and many cases of severe acute pulmonary embolism have been reported. The demonstrated presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within the endothelial cells suggests that direct viral effects, in addition to indirect effects of perivascular inflammation and coagulopathy, may contribute to pulmonary vasculopathy in COVID-19. In this review, we discuss the pathological mechanisms leading to pulmonary vascular damage during acute infection, which appear to be mainly related to thromboembolic events, an impaired coagulation cascade, micro- and macrovascular thrombosis, endotheliitis and hypoxic pulmonary vasoconstriction. As many patients develop post-COVID symptoms, including dyspnea, we also discuss the hypothesis of pulmonary vascular damage and pulmonary hypertension as a sequela of the infection, which may be involved in the pathophysiology of long COVID.
Collapse
Affiliation(s)
- Marianne Riou
- Translational Medicine Federation of Strasbourg (FMTS), University of Strasbourg, CRBS, Team 3072 “Mitochondria, Oxidative Stress and Muscle Protection”, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg, France; (M.R.); (A.M.); (I.E.); (S.T.); (A.C.)
- Physiology and Functional Exploration Service, University Hospital of Strasbourg, 1 Place de l’hôpital, 67091 Strasbourg, France
| | - Florence Coste
- EA4278, Laboratoire de Pharm-Ecologie Cardiovasculaire, UFR Sciences Technologies Santé, Pôle Sport et Recherche, 74 rue Louis Pasteur, 84000 Avignon, France; (F.C.); (C.R.)
| | - Alain Meyer
- Translational Medicine Federation of Strasbourg (FMTS), University of Strasbourg, CRBS, Team 3072 “Mitochondria, Oxidative Stress and Muscle Protection”, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg, France; (M.R.); (A.M.); (I.E.); (S.T.); (A.C.)
- Physiology and Functional Exploration Service, University Hospital of Strasbourg, 1 Place de l’hôpital, 67091 Strasbourg, France
| | - Irina Enache
- Translational Medicine Federation of Strasbourg (FMTS), University of Strasbourg, CRBS, Team 3072 “Mitochondria, Oxidative Stress and Muscle Protection”, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg, France; (M.R.); (A.M.); (I.E.); (S.T.); (A.C.)
- Physiology and Functional Exploration Service, University Hospital of Strasbourg, 1 Place de l’hôpital, 67091 Strasbourg, France
| | - Samy Talha
- Translational Medicine Federation of Strasbourg (FMTS), University of Strasbourg, CRBS, Team 3072 “Mitochondria, Oxidative Stress and Muscle Protection”, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg, France; (M.R.); (A.M.); (I.E.); (S.T.); (A.C.)
- Physiology and Functional Exploration Service, University Hospital of Strasbourg, 1 Place de l’hôpital, 67091 Strasbourg, France
| | - Anne Charloux
- Translational Medicine Federation of Strasbourg (FMTS), University of Strasbourg, CRBS, Team 3072 “Mitochondria, Oxidative Stress and Muscle Protection”, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg, France; (M.R.); (A.M.); (I.E.); (S.T.); (A.C.)
- Physiology and Functional Exploration Service, University Hospital of Strasbourg, 1 Place de l’hôpital, 67091 Strasbourg, France
| | - Cyril Reboul
- EA4278, Laboratoire de Pharm-Ecologie Cardiovasculaire, UFR Sciences Technologies Santé, Pôle Sport et Recherche, 74 rue Louis Pasteur, 84000 Avignon, France; (F.C.); (C.R.)
| | - Bernard Geny
- Translational Medicine Federation of Strasbourg (FMTS), University of Strasbourg, CRBS, Team 3072 “Mitochondria, Oxidative Stress and Muscle Protection”, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg, France; (M.R.); (A.M.); (I.E.); (S.T.); (A.C.)
- Physiology and Functional Exploration Service, University Hospital of Strasbourg, 1 Place de l’hôpital, 67091 Strasbourg, France
| |
Collapse
|
|
7
|
Valencia I, Lumpuy-Castillo J, Magalhaes G, Sánchez-Ferrer CF, Lorenzo Ó, Peiró C. Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus. Cardiovasc Diabetol 2024; 23:75. [PMID: 38378550 PMCID: PMC10880237 DOI: 10.1186/s12933-023-02097-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 12/14/2023] [Indexed: 02/22/2024] Open
Abstract
Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced.
Collapse
Affiliation(s)
- Inés Valencia
- Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, IIS Hospital Universitario de La Princesa, 28009, Madrid, Spain.
| | - Jairo Lumpuy-Castillo
- Laboratory of Diabetes and Vascular Pathology, IIS-Fundación Jiménez Díaz, 28040, Madrid, Spain
- Spanish Biomedical Research Centre On Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, Madrid, Spain
| | - Giselle Magalhaes
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, 28029, Madrid, Spain
| | - Carlos F Sánchez-Ferrer
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, 28029, Madrid, Spain
- Vascular Pharmacology and Metabolism (FARMAVASM), IdiPAZ, Madrid, Spain
| | - Óscar Lorenzo
- Laboratory of Diabetes and Vascular Pathology, IIS-Fundación Jiménez Díaz, 28040, Madrid, Spain.
- Spanish Biomedical Research Centre On Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, Madrid, Spain.
| | - Concepción Peiró
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, 28029, Madrid, Spain.
- Vascular Pharmacology and Metabolism (FARMAVASM), IdiPAZ, Madrid, Spain.
| |
Collapse
|
|
8
|
Apostolo D, Ferreira LL, Di Tizio A, Ruaro B, Patrucco F, Bellan M. A Review: The Potential Involvement of Growth Arrest-Specific 6 and Its Receptors in the Pathogenesis of Lung Damage and in Coronavirus Disease 2019. Microorganisms 2023; 11:2038. [PMID: 37630598 PMCID: PMC10459962 DOI: 10.3390/microorganisms11082038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/31/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
The tyrosine kinase receptors of the TAM family-Tyro3, Axl and Mer-and their main ligand Gas6 (growth arrest-specific 6) have been implicated in several human diseases, having a particularly important role in the regulation of innate immunity and inflammatory response. The Gas6/TAM system is involved in the recognition of apoptotic debris by immune cells and this mechanism has been exploited by viruses for cell entry and infection. Coronavirus disease 2019 (COVID-19) is a multi-systemic disease, but the lungs are particularly affected during the acute phase and some patients may suffer persistent lung damage. Among the manifestations of the disease, fibrotic abnormalities have been observed among the survivors of COVID-19. The mechanisms of COVID-related fibrosis remain elusive, even though some parallels may be drawn with other fibrotic diseases, such as idiopathic pulmonary fibrosis. Due to the still limited number of scientific studies addressing this question, in this review we aimed to integrate the current knowledge of the Gas6/TAM axis with the pathophysiological mechanisms underlying COVID-19, with emphasis on the development of a fibrotic phenotype.
Collapse
Affiliation(s)
- Daria Apostolo
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (L.L.F.); (A.D.T.); (M.B.)
| | - Luciana L. Ferreira
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (L.L.F.); (A.D.T.); (M.B.)
| | - Alice Di Tizio
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (L.L.F.); (A.D.T.); (M.B.)
- Respiratory Diseases Unit, Medical Department, AOU Maggiore della Carità Hospital, 28100 Novara, Italy
| | - Barbara Ruaro
- Pulmonology Department, University of Trieste, 34128 Trieste, Italy;
| | - Filippo Patrucco
- Respiratory Diseases Unit, Medical Department, AOU Maggiore della Carità Hospital, 28100 Novara, Italy
| | - Mattia Bellan
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (L.L.F.); (A.D.T.); (M.B.)
- Division of Internal Medicine, Medical Department, AOU Maggiore della Carità Hospital, 28100 Novara, Italy
| |
Collapse
|
|
9
|
Bhoelan S, Codreanu C, Tichelaar V, Borjas Howard J, Meijer K. Exploring heterogeneity in reported venous thromboembolism risk in COVID-19 and comparison to other viral pneumonias: a systematic review and meta-regression. Res Pract Thromb Haemost 2023; 7:102146. [PMID: 37663366 PMCID: PMC10470259 DOI: 10.1016/j.rpth.2023.102146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 06/18/2023] [Accepted: 06/24/2023] [Indexed: 09/05/2023] Open
Abstract
Background Sources of heterogeneity in venous thromboembolism (VTE) risk in COVID-19 are unclear and comparisons to other viruses are lacking. Objectives To describe VTE risk in patients with COVID-19, explore sources of heterogeneity, and make comparisons with other viral pneumonia. Methods PubMed and Embase data were searched on March 14, 2021, for studies on VTE in adults hospitalized with viral pneumonia. VTE risk estimates were pooled in a random effects meta-analysis stratified by virus type. Heterogeneity in COVID-19 was explored in multivariable meta-regression. Results Seventy studies in COVID-19 (intensive care [ICU] [47] vs ward [23]), 4 studies in seasonal influenza (ICU [3] vs ward [1]), 2 ICU studies in H1N1 and 1 ICU study in SARS-CoV-1 were included. For COVID-19 ICU, pooled VTE risk was 19.6% (95% confidence interval [CI], 16.2%-23.5; I2 = 92.8%) for nonscreening studies and 30.0% (95% CI, 17.9%-45.7%; I2 = 81.9%) for screening studies. For COVID-19 ward, pooled VTE risk was 3.4% (95% CI, 2.4%-4.7%; I2 = 91.3%) and 22.5% (95% CI, 10.2%-42.7%; I2 = 91.6%) for nonscreening and screening studies, respectively. Higher sample size was associated with lower VTE risk. Pooled VTE risk in seasonal influenza and H1N1 at ICU were 9.0% (95% CI, 5.6%-14.2%; I2 = 39.7%) and 29.2% (95% CI, 8.7%-64.2%; I2 = 77.9%), respectively. At ward, VTE risk of seasonal influenza was 2.4% (95% CI, 2.1%-2.7%). In SARS-CoV-1, VTE risk was 47.8% (95% CI, 34.0-62.0). Conclusion Pooled risk estimates in COVID-19 should be interpreted cautiously as a high degree of heterogeneity is present, which hinders comparison to other viral pneumonia. The association of VTE risk in COVID-19 to sample size suggests publication bias.
Collapse
Affiliation(s)
- Soerajja Bhoelan
- Department of Haematology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Catalina Codreanu
- Department of Haematology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Vladimir Tichelaar
- Department of Haematology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Jaime Borjas Howard
- Department of Haematology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Karina Meijer
- Department of Haematology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| |
Collapse
|
|
10
|
Alonso-Beato R, Lago-Rodríguez MO, López-Rubio M, Gómez-Tórtola A, García-Fernández-Bravo I, Oblitas CM, Galeano-Valle F, Demelo-Rodríguez P. [Risk of thrombosis recurrence among patients with COVID-19- and surgery-associated venous thromboembolism]. Rev Clin Esp 2023; 223:255-261. [PMID: 37124998 PMCID: PMC10073585 DOI: 10.1016/j.rce.2023.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/13/2023] [Indexed: 05/02/2023]
Abstract
Introduction Recent surgery is a well-known major transient risk factor for venous thromboembolism (VTE) due to the low risk of VTE recurrence after anticoagulation is discontinued. On the other hand, the risk of VTE recurrence among patients with COVID-19-associated VTE is unknown. This study aimed to compare the risk of VTE recurrence between patients with COVID-19- and surgery-associated VTE. Methods A prospective observational single-center study was performed including consecutive patients diagnosed with VTE in a tertiary hospital from January 2020 to May 2022 and followed up for at least 90 days. Baseline characteristics, clinical presentation, and outcomes were assessed. The incidence of VTE recurrence, bleeding, and death was compared between both groups. Results A total of 344 patients were included in the study: 111 patients with surgery-associated VTE and 233 patients with COVID-19-associated VTE. Patients with COVID-19-associated VTE were more frequently men (65.7% vs 48.6%, p = 0.003). VTE recurrence was 3% among COVID-19 patients and 5.4% among surgical patients, with no significant differences (p = 0.364). The incidence rate of recurrent VTE was 1.25 per 1000 person-months in COVID-19 patients and 2.29 person-months in surgical patients, without significant differences (p = 0.29). In the multivariate analysis, COVID-19 was associated with higher mortality (HR 2.34; 95% CI 1.19-4.58), but not with a higher risk of recurrence (HR 0.52; 95% CI 0.17-1.61). No differences were found in recurrence in the multivariate competing risk analysis (SHR 0.82; 95% CI 0.40 - 2.05). Conclusions In patients with COVID-19 and surgery-associated VTE, the risk of recurrence was low, with no differences between both groups.
Collapse
Affiliation(s)
- R Alonso-Beato
- Unidad de Enfermedad Tromboembólica Venosa, Medicina Interna, Hospital General Universitario Gregorio Marañón, Madrid, España
- Facultad de Medicina, Universidad Complutense de Madrid, Madrid, España
| | - M-O Lago-Rodríguez
- Unidad de Enfermedad Tromboembólica Venosa, Medicina Interna, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - M López-Rubio
- Unidad de Enfermedad Tromboembólica Venosa, Medicina Interna, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - A Gómez-Tórtola
- Unidad de Enfermedad Tromboembólica Venosa, Medicina Interna, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - I García-Fernández-Bravo
- Unidad de Enfermedad Tromboembólica Venosa, Medicina Interna, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - C-M Oblitas
- Unidad de Enfermedad Tromboembólica Venosa, Medicina Interna, Hospital General Universitario Gregorio Marañón, Madrid, España
- Facultad de Medicina, Universidad Complutense de Madrid, Madrid, España
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, España
| | - F Galeano-Valle
- Unidad de Enfermedad Tromboembólica Venosa, Medicina Interna, Hospital General Universitario Gregorio Marañón, Madrid, España
- Facultad de Medicina, Universidad Complutense de Madrid, Madrid, España
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, España
| | - P Demelo-Rodríguez
- Unidad de Enfermedad Tromboembólica Venosa, Medicina Interna, Hospital General Universitario Gregorio Marañón, Madrid, España
- Facultad de Medicina, Universidad Complutense de Madrid, Madrid, España
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, España
| |
Collapse
|
|
11
|
Risk of thrombosis recurrence among patients with COVID-19- and surgery-associated venous thromboembolism. Rev Clin Esp 2023; 223:255-261. [PMID: 36990384 PMCID: PMC10043968 DOI: 10.1016/j.rceng.2023.03.003] [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: 03/29/2023]
Abstract
Introduction Recent surgery is a well-known major transient risk factor for venous thromboembolism (VTE) due to the low risk of VTE recurrence after anticoagulation is discontinued. On the other hand, the risk of VTE recurrence among patients with COVID-19-associated VTE is unknown. This study aimed to compare the risk of VTE recurrence between patients with COVID-19- and surgery-associated VTE. Methods A prospective observational single-center study was performed including consecutive patients diagnosed with VTE in a tertiary hospital from January 2020 to May 2022 and followed up for at least 90 days. Baseline characteristics, clinical presentation, and outcomes were assessed. The incidence of VTE recurrence, bleeding, and death was compared between both groups. Results A total of 344 patients were included in the study: 111 patients with surgery-associated VTE and 233 patients with COVID-19-associated VTE. Patients with COVID-19-associated VTE were more frequently men (65.7% vs 48.6%, p = 0.003). VTE recurrence was 3% among COVID-19 patients and 5.4% among surgical patients, with no significant differences (p = 0.364). The incidence rate of recurrent VTE was 1.25 per 1000 person-months in COVID-19 patients and 2.29 person-months in surgical patients, without significant differences (p = 0.29). In the multivariate analysis, COVID-19 was associated with higher mortality (HR 2.34; 95% CI 1.19–4.58), but not with a higher risk of recurrence (HR 0.52; 95% CI 0.17–1.61). No differences were found in recurrence in the multivariate competing risk analysis (SHR 0.82; 95% CI 0.40–2.05). Conclusions In patients with COVID-19 and surgery-associated VTE, the risk of recurrence was low, with no differences between both groups.
Collapse
|
|
12
|
Shirai K, Ishikawa M, Kobayashi T, Sato K, Murakami H, Kohama K, Manbo N, Hasegawa K, Hirata J. High Plasma tPAPAI-1C Levels May Be Related to a Poor Prognosis in Patients with Severe or Critical COVID-19: A Single-Center Retrospective Study. J Clin Med 2023; 12:jcm12052019. [PMID: 36902805 PMCID: PMC10004413 DOI: 10.3390/jcm12052019] [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: 01/09/2023] [Revised: 02/22/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023] Open
Abstract
Severe novel coronavirus disease 2019 (COVID-19) patients have a high incidence of thrombotic complications and mortality. The pathophysiology of coagulopathy involves fibrinolytic system impairment and vascular endothelial damage. This study examined coagulation and fibrinolytic markers as outcome predictors. In an observational study of 164 COVID-19 patients admitted to our emergency intensive care unit, hematological parameters on days 1, 3, 5, and 7 were retrospectively compared between survivors and nonsurvivors. Nonsurvivors had a higher APACHE II score, SOFA score, and age than survivors. Nonsurvivors also had a significantly lower platelet count and significantly higher plasmin/α2plasmin inhibitor complex (PIC), tissue plasminogen activator/plasminogen activator inhibitor-1 complex (tPAPAI-1C), D-dimer, and fibrin/fibrinogen degradation product (FDP) levels than survivors throughout the measurement period. The 7-day maximum or minimum values of the tPAPAI-1C, FDP, and D-dimer levels were significantly higher in nonsurvivors. A multivariate logistic regression analysis showed that the maximum tPAPAI-1C (OR = 1.034; 95% CI,1.014-1.061; p = 0.0041) was an independent factor affecting mortality, with an area under the curve (AUC) of 0.713 (optimum cut-off of 51 ng/mL; sensitivity, 69.2%; and specificity, 68.4%). COVID-19 patients with poor outcomes exhibit exacerbated coagulopathy with fibrinolysis inhibition and endothelial damage. Consequently, plasma tPAPAI-1C might be a useful predictor of the prognosis in patients with severe or critical COVID-19.
Collapse
Affiliation(s)
- Kunihiro Shirai
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan
- Correspondence: ; Tel.: +81-798-45-6514
| | - Michiko Ishikawa
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Tomoyuki Kobayashi
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Kiyoko Sato
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Hiromoto Murakami
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Keisuke Kohama
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Naomi Manbo
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Kana Hasegawa
- Department of Pediatrics, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Junichi Hirata
- Department of Emergency, Disaster and Critical Care Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan
| |
Collapse
|
|
13
|
Automated SSHHPS Analysis Predicts a Potential Host Protein Target Common to Several Neuroinvasive (+)ssRNA Viruses. Viruses 2023; 15:v15020542. [PMID: 36851756 PMCID: PMC9961674 DOI: 10.3390/v15020542] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/24/2023] [Accepted: 02/01/2023] [Indexed: 02/18/2023] Open
Abstract
Within the viral genome, short stretches of homologous host pathogen sequences (SSHHPS) span the protease cleavage sites. To identify host proteins that may be cleaved during infection, we searched the human proteome for viral protease cleavage sites (~20 amino acids). We developed a sequence-to-symptom tool, automating the search and pairing process. We used the viral protein sequence, PHI-BLAST, and UniProt database for gene ontologies and disease relationships. We applied the tool to nine neuroinvasive viruses: Venezuelan and Eastern Equine encephalitis virus (VEEV, EEEV); severe acute respiratory syndrome (SARS, SARS-CoV-2); Middle East respiratory syndrome (MERS); EV-71; Japanese encephalitis virus (JEV); West Nile (WNV); and Zika (ZIKV). A comparison of the hits identified a protein common to all nine viruses called ADGRA2 (GPR124). ADGRA2 was a predicted hit of the 3CL main protease and papain-like protease (PLpro) of SARS-CoV-2. ADGRA2 is an adhesion G protein-coupled receptor and a key endothelial regulator of brain-specific angiogenesis. It is a Wnt7A/Wnt7B specific coactivator of beta-catenin signaling and is essential for blood-brain barrier (BBB) integrity in central nervous system (CNS) diseases. We show the cleavage of the predicted sequences in MYOM1, VWF by the SARS-CoV-2 PLpro; DNAH8 (dynein) by the MERS PLpro; ADGRA2 by the alphaviral VEEV nsP2 protease; and POT1 by the SARS-CoV-2 and MERS PLpro.
Collapse
|
|
14
|
Meshref M, Hewila IM, Khlidj Y, Korissi R, Shaheen N, Nashwan AJ, Ouerdane Y, Amro Y, Taher KM, Ahmed MG. COVID-19-Associated Cerebrovascular Events: A Case Series Study and a Literature Review of Possible Mechanisms. Case Rep Neurol 2023; 15:11-23. [PMID: 36748059 PMCID: PMC9898811 DOI: 10.1159/000529122] [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: 08/25/2022] [Accepted: 12/29/2022] [Indexed: 02/05/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects multiple body systems, including the nervous system. Cerebrovascular accidents can also occur. Patients with comorbid illnesses have severe manifestations and poor outcomes. Despite the proper mechanism of SARS-CoV-2 infection-associated stroke having not yet been settled, various possible mechanisms have been hypothesized. One possibility is that the virus causes endothelial dysfunction and immune-mediated injury. Another possibility is that the trans-neuronal spread of the virus affects brain tissue. In addition, hypercoagulability caused by SARS-CoV-2 infection could lead to a stroke. A virus-induced dysfunction of the renin-angiotensin system could also lead to a stroke. The immune response and vasculitis resulting from SARS-CoV-2 infection are also possible causes via a cytokine storm, immune dysfunction, and various inflammatory responses. SARS-CoV-2 infection may affect calcitonin gene-related peptides and cerebral blood flow and may lead to stroke. Finally, SARS-CoV-2 may cause hemorrhagic strokes via mechanisms stimulated by its interaction with angiotensin-converting enzyme 2 (ACE2), leading to arterial wall damage and blood pressure changes. In this article, we will present seven cases of stroke-associated SARS-CoV-2 infection.
Collapse
Affiliation(s)
- Mostafa Meshref
- Neurology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ibrahim M. Hewila
- Neurology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
- Neurology Department, Worcestershire Royal Hospital, Worcester, UK
| | - Yahia Khlidj
- Faculty of Medicine, University of Algiers Benyoucef Benkhedda, Algiers, Algeria
| | - Rafik Korissi
- Faculty of Medicine, University of Algiers Benyoucef Benkhedda, Algiers, Algeria
| | - Nour Shaheen
- Alexandria Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | | | | | - Yara Amro
- Pharmacist, Ministry of Health, Cairo, Egypt
| | - Khaled M. Taher
- Neurology Department, King Khaled Hospital, Najran, Saudi Arabia
| | - Mahmoud Galal Ahmed
- Neurology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| |
Collapse
|
|
15
|
History of COVID-19 infection is not associated with increased D-dimer levels and risk of deep-vein thrombosis in total joint arthroplasty. Arch Orthop Trauma Surg 2023; 143:785-789. [PMID: 34546422 PMCID: PMC8453476 DOI: 10.1007/s00402-021-04181-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 09/09/2021] [Indexed: 11/09/2022]
Abstract
INTRODUCTION In the acute phase of COVID-19, elevated D-dimer levels indicate a hypercoagulable state putting the patients at increased risk for venous thromboembolic disease (VTE). It is unclear, if prior COVID-19 disease increases the risk for VTE after total joint arthroplasty (TJA) and if D-dimer levels can be used to identify patients at risk. MATERIALS AND METHODS D-Dimer levels of 313 consecutive SARS-CoV-2 IgG-positive and 2,053 -negative patients undergoing TJA between 05/20 and 12/20 were evaluated. D-Dimer levels were divided into three groups: < 200 ng/ml, 200-400 ng/ml, and > 400 ng/ml D-dimer units (DDU). 277 SARS-CoV-2 IgG-positive patients underwent a Doppler ultrasound to rule out deep-vein thrombosis (DVT) 4-6 weeks after TJA. RESULTS D-Dimer levels did not differ significantly between SARS-CoV-2 IgG-positive and -negative patients (p value 0.53). Among SARS-CoV-2 IgG-negative patients, 1687 (82.17%) had D-dimer levels < 200 ng/ml, 256 (12.47%) between 200 and 400 ng/ml, and 110 (5.36%) > 400 ng/ml. Of the SARS-CoV-2 IgG-positive patients, 257 (83.71%) had D-dimer levels < 200 ng/ml, 34 (11.07%) between 200 and 400 ng/ml, and 16 (5.21%) > 400 ng/ml. A postoperative DVT was detected in nine patients (2.9%) in the SARS-CoV-2 IgG-positive group and a PE in one patient (0.3%). 7/229 patients with < 200 ng/ml (3.1%), 1/28 patients (3.6%) with 200-400 ng/ml and 1/9 patients (11.1%) with D-dimer levels > 400 ng/ml had a DVT or PE (p = 0.43). CONCLUSIONS The findings of this investigation suggest there is no difference in D-dimer levels between SARS-CoV-2 IgG-positive and -negative patients undergoing TJA. Although there is a trend for increased VTE rates with increased D-dimer levels, routine D-dimer testing is not recommended based on the current data. SARS-CoV-2 IgG-positive patients have a low risk of VTE in the current study.
Collapse
|
|
16
|
Rasyid A, Riyanto DL, Harris S, Kurniawan M, Mesiano T, Hidayat R, Wiyarta E. Association of coagulation factors profile with clinical outcome in patient with COVID-19 and acute stroke: A second wave cohort study. Clin Hemorheol Microcirc 2022; 82:371-377. [PMID: 35871324 DOI: 10.3233/ch-221546] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION The second wave of COVID-19 in Indonesia occurred due to delta variant transmission with up to 2266 cases. This variant could cause higher rate of morbidities and mortalities. This study reported coagulation profile of COVID-19 patients with acute stroke and its association with patients' outcome. METHOD This is a cohort-retrospective study conducted during the second wave of COVID-19, June-August 2021 in Cipto Mangunkusumo General Hospital. Inclusion criteria were adult patients with confirmed COVID-19 and diagnosed with acute stroke confirmed by radiological evidences. Exclusion criteria were COVID-19 patients with prior diagnosis of acute stroke. Coagulation factors were analyzed and presented with tables and graphs. RESULTS A total of 33 patients included in this study with majority experienced ischemic stroke (84.8%), followed by ischemic with haemorrhagic transformation (9.1%), and the rest with haemorrhagic stroke. The median of fibrinogen and D-dimer was 487.1(147-8,943)mg/dL and 2,110(250-35,200)ug/L respectively. Prothrombin time (PT) ratio was 0.95(0.82-1.3) and activated partial thromboplastin time (APTT) ratio was 1.01(0.64-2.72). On observation, 33.3% died during hospitalization, D-dimer value in these patients was significantly higher with 9,940ug/L compared to those who survived with 1,160ug/L(p = 0.009). The highest D-dimer value during hospitalization was also significantly higher with the median of 14,395ug/L compared to 3,740 ug/L (p = 0.014). DISCUSSION D-dimer value on initial assessment and its highest value during hospitalization were significantly higher in patient with poor outcome, showing that D-dimer can be one predictor of mortality in COVID-19 patients with acute stroke.
Collapse
Affiliation(s)
- Al Rasyid
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Dinda Larastika Riyanto
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Salim Harris
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Mohammad Kurniawan
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Taufik Mesiano
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Rakhmad Hidayat
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Elvan Wiyarta
- Department of Medical Science, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| |
Collapse
|
|
17
|
Rasyid A, Timan IS, Riyanto DL, Harris S, Kurniawan M, Mesiano T, Hidayat R, Wiyarta E. Coagulation and hemorheology profile of patient with stroke and COVID-19: A case series during second wave pandemic. Clin Hemorheol Microcirc 2022; 82:249-254. [PMID: 35811513 DOI: 10.3233/ch-221504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In 2021 the delta variant was discovered, heralding the start of the second pandemic wave. This case series aims to analyse and compare the coagulation and hemorheology profiles of COVID-19 patients diagnosed with acute stroke during the pandemic's second wave and ascertain the effect on patient outcomes. This case series reports 4 cases with their respective characteristics. Case 1 reports on COVID-19 patients without comorbidities, Case 2 with comorbidities, Case 3 with strokes in young patients, and Case 4 with strokes in elderly patients. All cases had abnormal coagulation and hemorheology factors with mixed outcomes. Coagulation and hemorheology factors tend to be higher in COVID-19 patients with acute stroke. The value of coagulation and hemorheology factors can be a prognostic outcome in COVID-19 patients with severe disease, especially in patients associated with acute stroke.
Collapse
Affiliation(s)
- Al Rasyid
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Ina Susianti Timan
- Department of Clinical Pathology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Dinda Larastika Riyanto
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Salim Harris
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Mohammad Kurniawan
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Taufik Mesiano
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Rakhmad Hidayat
- Department of Neurology, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Elvan Wiyarta
- Department of Medical Science, Faculty of Medicine, Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| |
Collapse
|
|
18
|
Parameters of Coagulation in COVID-19 Patients: A Correlation with Clinical Severity. JOURNAL OF MEDICAL MICROBIOLOGY AND INFECTIOUS DISEASES 2022. [DOI: 10.52547/jommid.10.4.153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
|
|
19
|
Xu X, Feng Y, Jia Y, Zhang X, Li L, Bai X, Jiao L. Prognostic value of von Willebrand factor and ADAMTS13 in patients with COVID-19: A systematic review and meta-analysis. Thromb Res 2022; 218:83-98. [PMID: 36027630 PMCID: PMC9385270 DOI: 10.1016/j.thromres.2022.08.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/14/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND Endotheliopathy and coagulopathy appear to be the main causes for critical illness and death in patients with coronavirus disease 2019 (COVID-19). The adhesive ligand von Willebrand factor (VWF) has been involved in immunothrombosis responding to endothelial injury. Here, we reviewed the current literature and performed meta-analyses on the relationship between both VWF and its cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) with the prognosis of COVID-19. METHODS We searched MEDLINE, Cochrane Library, Web of Science, and EMBASE databases from inception to 4 March 2022 for studies analyzing the relationship between VWF-related variables and composite clinical outcomes of patients with COVID-19. The VWF-related variables analyzed included VWF antigen (VWF:Ag), VWF ristocetin cofactor (VWF:Rco), ADAMTS13 activity (ADAMTS13:Ac), the ratio of VWF:Ag to ADAMTS13:Ac, and coagulation factor VIII (FVIII). The unfavorable outcomes were defined as mortality, intensive care unit (ICU) admission, and severe disease course. We used random or fixed effects models to create summary estimates of risk. Risk of bias was assessed based on the principle of the Newcastle-Ottawa Scale. RESULTS A total of 3764 patients from 40 studies were included. The estimated pooled means indicated increased plasma levels of VWF:Ag, VWF:Rco, and VWF:Ag/ADAMTS13:Ac ratio, and decreased plasma levels of ADAMTS13:Ac in COVID-19 patients with unfavorable outcomes when compared to those with favorable outcomes (composite outcomes or subgroup analyses of non-survivor versus survivor, ICU versus non-ICU, and severe versus non-severe). In addition, FVIII were higher in COVID-19 patients with unfavorable outcomes. Subgroup analyses indicated that FVIII was higher in patients admitting to ICU, while there was no significant difference between non-survivors and survivors. CONCLUSIONS The imbalance of the VWF-ADAMTS13 axis (massive quantitative and qualitative increases of VWF with relative deficiency of ADAMTS13) is associated with poor prognosis of patients with COVID-19.
Collapse
Affiliation(s)
- Xin Xu
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China.
| | - Yao Feng
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China
| | - Yitong Jia
- Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China
| | - Xiao Zhang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China
| | - Long Li
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China
| | - Xuesong Bai
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China
| | - Liqun Jiao
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China; China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, China; Department of Interventional Neuroradiology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China..
| |
Collapse
|
|
20
|
Muñoz-Rivas N, Aibar J, Gabara-Xancó C, Trueba-Vicente Á, Urbelz-Pérez A, Gómez-Del Olmo V, Demelo-Rodríguez P, Rivera-Gallego A, Bosch-Nicolau P, Perez-Pinar M, Rios-Prego M, Madridano-Cobo O, Ramos-Alonso L, Alonso-Carrillo J, Francisco-Albelsa I, Martí-Saez E, Maestre-Peiró A, Méndez-Bailón M, Hernández-Rivas JÁ, Torres-Macho J. Efficacy and Safety of Tinzaparin in Prophylactic, Intermediate and Therapeutic Doses in Non-Critically Ill Patients Hospitalized with COVID-19: The PROTHROMCOVID Randomized Controlled Trial. J Clin Med 2022; 11:5632. [PMID: 36233500 PMCID: PMC9571371 DOI: 10.3390/jcm11195632] [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: 08/12/2022] [Revised: 09/15/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
Hospitalized patients with COVID-19 are at increased risk of thrombosis, acute respiratory distress syndrome and death. The optimal dosage of thromboprophylaxis is unknown. The aim was to evaluate the efficacy and safety of tinzaparin in prophylactic, intermediate, and therapeutic doses in non-critical patients admitted for COVID-19 pneumonia. PROTHROMCOVID is a randomized, unblinded, controlled, multicenter trial enrolling non-critical, hospitalized adult patients with COVID-19 pneumonia. Patients were randomized to prophylactic (4500 IU), intermediate (100 IU/kg), or therapeutic (175 IU/kg) groups. All tinzaparin doses were administered once daily during hospitalization, followed by 7 days of prophylactic tinzaparin at discharge. The primary efficacy outcome was a composite endpoint of symptomatic systemic thrombotic events, need for invasive or non-invasive mechanical ventilation, or death within 30 days. The main safety outcome was major bleeding at 30 days. Of the 311 subjects randomized, 300 were included in the prespecified interim analysis (mean [SD] age, 56.7 [14.6] years; males, 182 [60.7%]). The composite endpoint at 30 days from randomization occurred in 58 patients (19.3%) of the total population; 19 (17.1 %) in the prophylactic group, 20 (22.1%) in the intermediate group, and 19 (18.5%) in the therapeutic dose group (p = 0.72). No major bleeding event was reported; non-major bleeding was observed in 3.7% of patients, with no intergroup differences. Due to these results and the futility analysis, the trial was stopped. In non-critically ill COVID-19 patients, intermediate or full-dose tinzaparin compared to standard prophylactic doses did not appear to affect the risk of thrombotic event, non-invasive ventilation, or mechanical ventilation or death. Trial RegistrationClinicalTrials.gov Identifier (NCT04730856). Edura-CT registration number: 2020-004279-42.
Collapse
Affiliation(s)
- Nuria Muñoz-Rivas
- Department of Internal Medicine, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain
- Universidad Complutense, 28040 Madrid, Spain
| | - Jesús Aibar
- Department of Internal Medicine, Hospital Clínic, IDIBAPS, 08036 Barcelona, Spain
- University of Barcelona, 08007 Barcelona, Spain
| | - Cristina Gabara-Xancó
- Department of Internal Medicine, Hospital Clínic, IDIBAPS, 08036 Barcelona, Spain
- University of Barcelona, 08007 Barcelona, Spain
| | - Ángela Trueba-Vicente
- Department of Internal Medicine, Hospital de Emergencias Enfermera Isabel Zendal, 28055 Madrid, Spain
| | - Ana Urbelz-Pérez
- Department of Internal Medicine, Hospital de Emergencias Enfermera Isabel Zendal, 28055 Madrid, Spain
| | - Vicente Gómez-Del Olmo
- Department of Internal Medicine, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Pablo Demelo-Rodríguez
- Department of Internal Medicine, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain
| | | | - Pau Bosch-Nicolau
- Department of Infectious Diseases, Hospital Universitario Vall d’Hebron, 08035 Barcelona, Spain
| | | | - Mónica Rios-Prego
- Department of Internal Medicine, Complexo Hospitalario Universitario de Pontevedra, 36071 Pontevedra, Spain
| | - Olga Madridano-Cobo
- Department of Internal Medicine, Hospital Universitario Infanta Sofía, 28702 San Sebastián de los Reyes, Spain
| | - Laura Ramos-Alonso
- Department of Internal Medicine, Hospital Universitario A Coruña, 15006 A Coruña, Spain
| | - Jesús Alonso-Carrillo
- Department of Internal Medicine, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
| | - Iria Francisco-Albelsa
- Department of Internal Medicine, Hospital Universitari de Girona Dr. Josep Trueta, 17007 Girona, Spain
| | - Edelmira Martí-Saez
- Department of Haematology, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain
| | - Ana Maestre-Peiró
- Department of Internal Medicine, Hospital Universitario de Vinalopó, 03293 Elche, Spain
| | - Manuel Méndez-Bailón
- Universidad Complutense, 28040 Madrid, Spain
- Department of Internal Medicine, Hospital Clinico San Carlos, 28040 Madrid, Spain
| | - José Ángel Hernández-Rivas
- Universidad Complutense, 28040 Madrid, Spain
- Department of Hematology, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain
| | - Juan Torres-Macho
- Department of Internal Medicine, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain
- Universidad Complutense, 28040 Madrid, Spain
| |
Collapse
|
|
21
|
Wettstein L, Immenschuh P, Weil T, Conzelmann C, Almeida‐Hernández Y, Hoffmann M, Kempf A, Nehlmeier I, Lotke R, Petersen M, Stenger S, Kirchhoff F, Sauter D, Pöhlmann S, Sanchez‐Garcia E, Münch J. Native and activated antithrombin inhibits TMPRSS2 activity and SARS-CoV-2 infection. J Med Virol 2022; 95:e28124. [PMID: 36056630 PMCID: PMC9538173 DOI: 10.1002/jmv.28124] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/26/2022] [Accepted: 08/27/2022] [Indexed: 01/11/2023]
Abstract
Host cell proteases such as TMPRSS2 are critical determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, is a broad-spectrum inhibitor of coronavirus infection. Molecular docking and enzyme activity assays demonstrate that AT binds and inhibits TMPRSS2, a serine protease that primes the Spike proteins of coronaviruses for subsequent fusion. Consequently, AT blocks entry driven by the Spikes of SARS-CoV, MERS-CoV, hCoV-229E, SARS-CoV-2 and its variants of concern including Omicron, and suppresses lung cell infection with genuine SARS-CoV-2. Thus, AT is an endogenous inhibitor of SARS-CoV-2 that may be involved in COVID-19 pathogenesis. We further demonstrate that activation of AT by anticoagulants, such as heparin or fondaparinux, increases the anti-TMPRSS2 and anti-SARS-CoV-2 activity of AT, suggesting that repurposing of native and activated AT for COVID-19 treatment should be explored.
Collapse
Affiliation(s)
- Lukas Wettstein
- Institute of Molecular VirologyUlm University Medical CenterUlmGermany
| | | | - Tatjana Weil
- Institute of Molecular VirologyUlm University Medical CenterUlmGermany
| | - Carina Conzelmann
- Institute of Molecular VirologyUlm University Medical CenterUlmGermany
| | - Yasser Almeida‐Hernández
- Computational Biochemistry, Center of Medical BiotechnologyUniversity of Duisburg‐EssenEssenGermany
| | - Markus Hoffmann
- Infection Biology Unit, German Primate Center‐Leibniz Institute for Primate ResearchGöttingenGermany,Faculty of Biology and PsychologyGeorg‐August‐UniversityGöttingenGermany
| | - Amy Kempf
- Infection Biology Unit, German Primate Center‐Leibniz Institute for Primate ResearchGöttingenGermany,Faculty of Biology and PsychologyGeorg‐August‐UniversityGöttingenGermany
| | - Inga Nehlmeier
- Infection Biology Unit, German Primate Center‐Leibniz Institute for Primate ResearchGöttingenGermany
| | - Rishikesh Lotke
- Institute for Medical Virology and Epidemiology of Viral DiseasesUniversity Hospital TübingenTübingenGermany
| | - Moritz Petersen
- Institute for Medical Virology and Epidemiology of Viral DiseasesUniversity Hospital TübingenTübingenGermany
| | - Steffen Stenger
- Institute for Microbiology and HygieneUlm University Medical CenterUlmGermany
| | - Frank Kirchhoff
- Institute of Molecular VirologyUlm University Medical CenterUlmGermany
| | - Daniel Sauter
- Institute for Medical Virology and Epidemiology of Viral DiseasesUniversity Hospital TübingenTübingenGermany
| | - Stefan Pöhlmann
- Infection Biology Unit, German Primate Center‐Leibniz Institute for Primate ResearchGöttingenGermany,Faculty of Biology and PsychologyGeorg‐August‐UniversityGöttingenGermany
| | - Elsa Sanchez‐Garcia
- Computational Biochemistry, Center of Medical BiotechnologyUniversity of Duisburg‐EssenEssenGermany
| | - Jan Münch
- Institute of Molecular VirologyUlm University Medical CenterUlmGermany
| |
Collapse
|
|
22
|
Porembskaya OY, Kravchuk VN, Galchenko MI, Deev RV, Chesnokov MS, Avanesyan AV, Lobastov KV, Tsaplin SN, Laberko LA, Ermakov VS, Pashovkina OV, Schastlivtsev IV, Sayganov SA. Pulmonary Vascular Thrombosis in COVID-19: Clinical and Morphological Parallels. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2022. [DOI: 10.20996/1819-6446-2022-08-01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Aim. We aimed to study the histological and thrombotic changes in lung vessels in patients who died with COVID-19, to access the correlation between anticoagulation therapy (ACT) and thrombotic events (TE), treatment results, clinical and laboratory patients' characteristics.Material and Methods. We retrospectively analyzed treatment results of patients hospitalized with COVID-19 and lung vessel samples of the deceased patients. Dynamic changes and highest levels of D-dimer and fibrinogen were studied in its correlation with the disease severity according to SOFA score, computer tomographic (CT) results, lung, renal and hepatic dysfunction. The association between different doses of ACT and treatment results, laboratory indicators and thrombotic events was accessed. The histological lung vessels examination was performed using Martius Scarlet Blue (MSB)staining.Results. 313 patients were included in the study (61 patients died). The median age of hospitalized patients was 60 years (IQR 51-66 years). The frequency of the intravitallyconfirmed TE was 4,8%. The strong statistical association was revealed between D-dimer level and 3-4 points SOFA score, patients' mortality, oxygen support requirement, CT3-CT4 pneumonia, glomerular filtration rate and TE. There was no mortality in patients with D-dimer normal references, but in cases with three times elevation reached 13%, 48,5% - in cases with 3-6 times elevation and 64,6% - in cases with more than 6 times elevation. The strong statistical association was registered between fibrinogen and SOFA score, CT 3-4 pneumonia, patients' mortality. D-dimer and fibrinogen levels demonstrated weak correlation. There was no statistical correlation between prophylactic, intermediate and therapeutic ACT and D-dimer and fibrinogen levels, CT results, patients' mortality. MSBstaining was used in 36 deceased patients tissue samples. 1394 lung vessels were analyzed. Lung vessels thrombi persisted in samples of all 36 patients (100%). Vessels with the diameter 3,5-30 mm were thrombosed in 7%, with the diameter 0,034-0,84 mm - in 48%, with the diameter 0,85-3,4 mm - in 45%. The frequency of thrombi persisted 06 hours, 6-12 hours, 12-18hours, 18-24 hours and more than 24 hours was12%, 14%, 62%, 5% and 7% respectively.Conclusion. Thrombi of different ages from fresh to organized were observed in one third of lung vessels in all deceased patients. Lung vessels thrombosis plays an important role in pathogenesis and thanatogenesis of COVID-19. The D-dimer level correlates with lung, renal dysfunction, patients' mortality and doesn't show any correlation with ACT and can be accepted as a criterion of lung vessel thrombotic progression.
Collapse
Affiliation(s)
| | | | | | - R. V. Deev
- Mechnikov's North-Western State Medical University
| | | | | | | | - S. N. Tsaplin
- Pirogov Russian National Research Medical University; Clinical hospital no.1 of the Presidents Administration of Russian Federation
| | - L. A. Laberko
- Pirogov Russian National Research Medical University
| | | | - O. V. Pashovkina
- Clinical hospital no.1 of the Presidents Administration of Russian Federation
| | | | | |
Collapse
|
|
23
|
Sim MM, Wood JP. Dysregulation of Protein S in COVID-19. Best Pract Res Clin Haematol 2022; 35:101376. [PMID: 36494145 PMCID: PMC9395234 DOI: 10.1016/j.beha.2022.101376] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/10/2022] [Accepted: 08/15/2022] [Indexed: 12/15/2022]
Abstract
Coronavirus Disease 2019 (COVID-19) has been widely associated with increased thrombotic risk, with many different proposed mechanisms. One such mechanism is acquired deficiency of protein S (PS), a plasma protein that regulates coagulation and inflammatory processes, including complement activation and efferocytosis. Acquired PS deficiency is common in patients with severe viral infections and has been reported in multiple studies of COVID-19. This deficiency may be caused by consumption, degradation, or clearance of the protein, by decreased synthesis, or by binding of PS to other plasma proteins, which block its anticoagulant activity. Here, we review the functions of PS, the evidence of acquired PS deficiency in COVID-19 patients, the potential mechanisms of PS deficiency, and the evidence that those mechanisms may be occurring in COVID-19.
Collapse
Affiliation(s)
- Martha M.S. Sim
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA
| | - Jeremy P. Wood
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA,Gill Heart and Vascular Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Kentucky, Lexington, KY, USA,Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA,Corresponding author. University of Kentucky, 741 S Limestone, BBSRB B359, Lexington, KY, 40536, USA
| |
Collapse
|
|
24
|
Abou-Dakn M. Mikroangiopathien in der Schwangerschaft. DIE GYNÄKOLOGIE 2022. [PMCID: PMC9310689 DOI: 10.1007/s00129-022-04972-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Das Wissen um die Differentialdiagnose der Mikroangiopathien ist auch für Geburtshelfer:innen wichtig. So ist die Kombination aus einer Thrombopenie und Hämolysezeichen wegweisend in der Erkennung der Erkrankung. Es sollten die Differenzialdiagnosen bekannt sein, da diese zu unterschiedlichen Therapienotwendigkeiten führen und Langzeitschäden, beispielsweise für die Niere, vermieden werden müssen. Die Differenzialdiagnosen der Thrombopenie stellen den Einstieg für die weitere Diagnostik dar. In der Kombination mit Hämolysezeichen und Veränderungen der Erythrozytenmorphologie (Fragmentozyten) liegen unterschiedliche Ursachen für die Mikroangiopathie vor. Eine thrombotisch-thrombozytopenische Purpura (TTP) kann während der gesamten Schwangerschaft, aber insbesondere im letzten Trimenon, die Ursache für solche Veränderungen sein. Bei dieser finden sich häufig gastrointestinale oder auch zusätzliche neurologische Symptome. Die Präeklampsie, insbesondere beim HELLP(„hemolysis, elevated liver enzymes, and a low platelet count“)-Syndrom, kann ebenfalls zu einer Mikroangiopathie führen, dieses i.d.R. mit entsprechender Erhöhung des Blutdrucks und insbesondere mit einer deutlichen Erhöhung der Lebertransaminasen, ebenfalls typischerweise im letzten Trimenon kombiniert. Wenn entsprechende Veränderungen nach der Geburt auftreten und diese neben der Hämolyse mit einem Nierenversagen verbunden sind, kann es sich hierbei um ein atypisches hämolytisch-urämisches Syndrom (aHUS) handeln, das spezifisch durch Antikörper therapiert werden sollte. Neben der typischen Gerinnungsaktivierung im Sinne einer Thrombosierung findet sich bei COVID-19 („corona virus disease“) auch das gesamte Bild einer entsprechenden Mikroangiopathie, zum Teil durch entsprechende Aktivierung des Gerinnungssystem, zum Teil durch eine Verstärkung der anderen Mikroangiopathien. Für alle Bereiche werden die Differenzialdiagnosen und mögliche Therapien skizziert.
Collapse
Affiliation(s)
- Michael Abou-Dakn
- Klinik für Gynäkologie und Geburtshilfe, St. Joseph Krankenhaus Berlin-Tempelhof, Wüsthoffstr. 15, 12101 Berlin, Deutschland
| |
Collapse
|
|
25
|
Rostami M, Mansouritorghabeh H. Trend of fluctuations of antithrombin in plasma of patients with COVID-19: a meta-analysis and systematic review. Expert Rev Hematol 2022; 15:747-755. [PMID: 35858633 DOI: 10.1080/17474086.2022.2104708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Antithrombin is considered as one of the accused markers for the development of thrombosis in patients with COVID-19. Because plasma levels of antithrombin vary in patients with COVID-19, a meta-analysis was performed to determine the trend of antithrombin levels in patients with COVID-19. RESEARCH DESIGN AND METHODS A literature search was performed in PubMed, Scopus, and the Web of Science to find papers on antithrombin levels in patients with COVID-19. After removing of duplicate papers, inclusion and exclusion criteria were applied. The full texts of the articles were read to select relevant articles and then to identify the data needed. All meta-analyses were performed using Stata software v16.0. RESULTS Testing for differences between subgroups showed a significant difference between ICU and non-ICU patients. Analysis showed a significant decrease in antithrombin level in patients with severe COVID-19. Analysis showed that the mean value of antithrombin level was 89.65% in all patients. The antithrombin level was significantly lower in the non-survivor group (87.52%) than in the survivor group (92.38%). CONCLUSION : The determination of antithrombin may be useful to determine the susceptibility of COVID-19 patients to hypercoagulability and to indicate the severity of COVID-19 infection.
Collapse
Affiliation(s)
- Mehrdad Rostami
- MSc of Hematology & Blood Banking, Mashhad University of Medical Sciences. Mashhad, Iran
| | - Hassan Mansouritorghabeh
- Central Diagnostic laboratories, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
26
|
Schneider M. The Role of Biomarkers in Hospitalized COVID-19 Patients With Systemic Manifestations. Biomark Insights 2022; 17:11772719221108909. [PMID: 35783222 PMCID: PMC9243490 DOI: 10.1177/11772719221108909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/06/2022] [Indexed: 01/08/2023] Open
Abstract
The following article aims to review COVID-19 biomarkers used in hospital
practice. It is apparent that COVID-19 is not simply a pulmonary disease but has
systemic manifestations. For this reason, biomarkers must be used in the
management of diagnosed patients to provide holistic care. Patients with
COVID-19 have been shown to have pulmonary, hepatobiliary, cardiovascular,
neurologic, and renal injury, along with coagulopathy and a distinct cytokine
storm. Biomarkers can effectively inform clinicians of systemic organ injury due
to COVID-19. Furthermore, biomarkers can be used in predictive models for severe
COVID-19 in admitted patients. The utility of doing so is to allow for risk
stratification and utilization of proper treatment protocols. In addition,
COVID-19 biomarkers in the pediatric population are discussed, specifically in
predicting Multisystem Inflammatory Syndrome. Ultimately, biomarkers can be used
as predictive tools to allow clinicians to identify and adequately manage
patients at increased risk for worse outcomes from COVID-19. Both literature
review and anecdotal evidence has shown that severe COVID-19 is a systemic
disease, and understanding associated biomarkers are crucial for hospitalized
patients’ proper clinical decision-making. For example, the cytokine storm
releases inflammatory markers in different organ systems such as the pulmonary,
hepatobiliary, hematological, cardiac, neurological, and renal systems. This
review summarizes the latest research of COVID-19 that can help inform
healthcare professionals how to better mitigate morbidity and mortality
associated with this disease and provides information about certain systemic
biomarkers that can be incorporated into hospital practice to provide more
comprehensive care for hospitalized COIVD-19 patients.
Collapse
Affiliation(s)
- Michael Schneider
- University of Queensland Ochsner Clinical School, New Orleans, LA, USA
| |
Collapse
|
|
27
|
Abstract
Introduction COVID-19 associated VTE is a new disease entity with high morbidity and mortality. The aim of this paper is to review contemporary emerging literature on the incidence, pathophysiology, predictive prognostic indicators, and management consensus for Covid-19 related thrombotic complications, in particular DVT and PE. Methods A literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All searches were done via PubMed. References of review articles were further screened according to the exclusion criteria. Results In total, 154 records were identified and 20 duplicates were removed. A final 68 articles were included in the qualitative analysis. COVID-19 related thrombosis can affect multiple organs of the body, presenting in the form of arterial or venous thrombosis such as ischemic stroke, myocardial infarction, mesenteric ischemia, limb ischemia, DVT, or PE. DVT and PE has an overall incidence of 6–26%, and severely ill COVID-19 patients have even higher incidence of thromboembolism. On the other hand, incidence of arterial thromboembolism is much lower with incidence of 0.7%–3.7%. D-dimer is found to be an independent risk factor, and IMPROVE score, Caprini score, and Padua score have all been used as predictors. International guidelines suggest the use of low molecular weight heparin (LMWH) or fondaparinux for prophylaxis of VTE, and therapeutic dosage of weight adjusted LMWH for treatment if confirmed diagnosis. Conclusions Contemporary rapidly evolving evidence shows that COVID-19 associated thrombosis was a novel clinical entity, especially in severely ill COVID-19 patients. There are multiple society-driven guidelines only, but without any level 1 evidence for management regimen. The ideal dose for prophylaxis is not established and may vary depending on balance of bleeding and thrombosis risk. The risk of bleeding may be increased in patients in intensive care unit.
Collapse
Affiliation(s)
- Nicole M Cheng
- Division of Vascular & Endovascular Surgery, Department of Surgery, University of Hong Kong Medical Centre, Hong Kong, China
| | - Yiu Che Chan
- Division of Vascular & Endovascular Surgery, Department of Surgery, University of Hong Kong Medical Centre, Hong Kong, China
| | - Stephen W Cheng
- Division of Vascular & Endovascular Surgery, Department of Surgery, University of Hong Kong Medical Centre, Hong Kong, China
| |
Collapse
|
|
28
|
Increased Risk of COVID-19 in Patients with Diabetes Mellitus-Current Challenges in Pathophysiology, Treatment and Prevention. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19116555. [PMID: 35682137 PMCID: PMC9180541 DOI: 10.3390/ijerph19116555] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/10/2022] [Accepted: 05/25/2022] [Indexed: 01/08/2023]
Abstract
Coronavirus disease-COVID-19 (coronavirus disease 2019) has become the cause of the global pandemic in the last three years. Its etiological factor is SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus type 2). Patients with diabetes (DM-diabetes mellitus), in contrast to healthy people not suffering from chronic diseases, are characterised by higher morbidity and mortality due to COVID-19. Patients who test positive for SARCoV-2 are at higher risk of developing hyperglycaemia. In this paper, we present, analyse and summarize the data on possible mechanisms underlying the increased susceptibility and mortality of patients with diabetes mellitus in the case of SARS-CoV-2 infection. However, further research is required to determine the optimal therapeutic management of patients with diabetes and COVID-19.
Collapse
|
|
29
|
Citu C, Burlea B, Gorun F, Motoc A, Gorun OM, Malita D, Ratiu A, Margan R, Grigoras ML, Bratosin F, Citu IM. Predictive Value of Blood Coagulation Parameters in Poor Outcomes in COVID-19 Patients: A Retrospective Observational Study in Romania. J Clin Med 2022; 11:jcm11102831. [PMID: 35628956 PMCID: PMC9146890 DOI: 10.3390/jcm11102831] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 02/01/2023] Open
Abstract
SARS-CoV-2 infection produces alterations in blood clotting, especially in severe cases of COVID-19. Abnormal coagulation parameters in patients with COVID-19 are important prognostic factors of disease severity. The objective of this study was to evaluate the predictive value of aPTT, D-dimer, INR and PT in the mortality of patients with COVID-19. A retrospective, single-center, observational study was conducted on COVID-19 patients admitted to the Municipal Emergency Clinical Hospital in Timisoara, Romania, between August and October 2021. Patients were confirmed as COVID-19 positive by reverse transcription-polymerase chain reaction (RT-PCR) assay. After applying the inclusion/exclusion criteria, a total of 82 patients were included in the analysis. Receiver operating characteristic (ROC) curves of D-Dimer, INR, PT and aPTT were generated to assess whether the baseline of each of these biomarkers was accurately predictive for mortality in patients with COVID-19. Mortality among patients enrolled in this study was 20.7%, associated with older age and presence of heart disease. The areas under the ROC curve (AUC-ROC) of D-Dimer, INR, PT, and aPTT were 0.751, 0.724, 0.706 and 0.753. Differences in survival for patients with coagulation biomarker levels above cut-off values compared to patients below these values were statistically significant. All evaluated parameters had significant differences and good performance in predicting mortality of COVID-19 patients, except fibrinogen, which had no significant difference. Moreover, aPTT and D-dimer were the best performing parameters in predicting mortality in patients with SARS-CoV-2 infection.
Collapse
Affiliation(s)
- Cosmin Citu
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (C.C.); (A.R.)
| | - Bogdan Burlea
- Department of Obstetrics and Gynecology, Municipal Emergency Clinical Hospital Timisoara, 1–3 Alexandru Odobescu Street, 300202 Timisoara, Romania; (B.B.); (O.M.G.)
| | - Florin Gorun
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (C.C.); (A.R.)
- Correspondence:
| | - Andrei Motoc
- Department of Anatomy and Embryology, “Victor Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (A.M.); (M.L.G.)
| | - Oana Maria Gorun
- Department of Obstetrics and Gynecology, Municipal Emergency Clinical Hospital Timisoara, 1–3 Alexandru Odobescu Street, 300202 Timisoara, Romania; (B.B.); (O.M.G.)
| | - Daniel Malita
- Department of Radiology, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square nr. 2, 300041 Timisoara, Romania;
| | - Adrian Ratiu
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (C.C.); (A.R.)
| | - Roxana Margan
- Department 14 Microbiology, Discipline of Hygiene, Center for Studies in Preventive Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Mirela Loredana Grigoras
- Department of Anatomy and Embryology, “Victor Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (A.M.); (M.L.G.)
| | - Felix Bratosin
- Methodological and Infectious Diseases Research Center, Department of Infectious Diseases, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Ioana Mihaela Citu
- Department of Internal Medicine I, “Victor Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania;
| |
Collapse
|
|
30
|
Ceccato A, Camprubí-Rimblas M, Campaña-Duel E, Areny-Balagueró A, Morales-Quinteros L, Artigas A. Anticoagulant Treatment in Severe ARDS COVID-19 Patients. J Clin Med 2022; 11:2695. [PMID: 35628822 PMCID: PMC9148112 DOI: 10.3390/jcm11102695] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/03/2022] [Accepted: 05/06/2022] [Indexed: 02/08/2023] Open
Abstract
Patients with COVID-19 may complicate their evolution with thromboembolic events. Incidence of thromboembolic complications are high and also, patients with the critically-ill disease showed evidence of microthrombi and microangiopathy in the lung probably due to endothelial damage by directly and indirectly injured endothelial and epithelial cells. Pulmonary embolism, deep venous thrombosis and arterial embolism were reported in patients with COVID-19, and several analytical abnormal coagulation parameters have been described as well. D-dimer, longer coagulation times and lower platelet counts have been associated with poor outcomes. The use of anticoagulation or high doses of prophylactic heparin is controversial. Despite the use of anticoagulation or high prophylactic dose of heparin have been associated with better outcomes in observational studies, only in patients with non-critically ill disease benefits for anticoagulation was observed. In critically-ill patient, anticoagulation was not associated with better outcomes. Other measures such as antiplatelet therapy, fibrinolytic therapy or nebulized anticoagulants are being studied in ongoing clinical trials.
Collapse
Affiliation(s)
- Adrian Ceccato
- Critical Care Research Center, Institut d’Investigació i Innovació Parc Taulí I3PT, ParcTaulí, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.A.-B.); (L.M.-Q.); (A.A.)
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 41092 Madrid, Spain
| | - Marta Camprubí-Rimblas
- Critical Care Research Center, Institut d’Investigació i Innovació Parc Taulí I3PT, ParcTaulí, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.A.-B.); (L.M.-Q.); (A.A.)
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 41092 Madrid, Spain
- Bioscience and Medicine Faculty, Universitat Autònoma de Barcelona, Bellaterra, 08193 Catalunya, Spain
| | - Elena Campaña-Duel
- Critical Care Research Center, Institut d’Investigació i Innovació Parc Taulí I3PT, ParcTaulí, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.A.-B.); (L.M.-Q.); (A.A.)
| | - Aina Areny-Balagueró
- Critical Care Research Center, Institut d’Investigació i Innovació Parc Taulí I3PT, ParcTaulí, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.A.-B.); (L.M.-Q.); (A.A.)
| | - Luis Morales-Quinteros
- Critical Care Research Center, Institut d’Investigació i Innovació Parc Taulí I3PT, ParcTaulí, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.A.-B.); (L.M.-Q.); (A.A.)
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 41092 Madrid, Spain
- Bioscience and Medicine Faculty, Universitat Autònoma de Barcelona, Bellaterra, 08193 Catalunya, Spain
- Department of Intensive Care Medicine, Hospital Universitari Sant Pau, 08025 Barcelona, Spain
| | - Antonio Artigas
- Critical Care Research Center, Institut d’Investigació i Innovació Parc Taulí I3PT, ParcTaulí, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.A.-B.); (L.M.-Q.); (A.A.)
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 41092 Madrid, Spain
- Bioscience and Medicine Faculty, Universitat Autònoma de Barcelona, Bellaterra, 08193 Catalunya, Spain
| |
Collapse
|
|
31
|
Feng W, Hou J, Die X, Sun J, Guo Z, Liu W, Wang Y. Application of coagulation parameters at the time of necrotizing enterocolitis diagnosis in surgical intervention and prognosis. BMC Pediatr 2022; 22:259. [PMID: 35538449 PMCID: PMC9086422 DOI: 10.1186/s12887-022-03333-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 05/03/2022] [Indexed: 11/10/2022] Open
Abstract
Purpose It has been shown that abnormalities of coagulation and fibrinolysis system are involved in the pathogenesis of necrotizing enterocolitis (NEC), but not well studied challenge in the context of early detection of disease progression. The present study mainly explores the predictive significance of coagulation parameters at the time of NEC diagnosis in identifying the patients who eventually received surgery and/or NEC-related deaths. Methods The retrospective study of 114 neonates with NEC was conducted with assessments of demographic data, laboratory results at the time of NEC diagnosis, treatment methods and prognosis. According to treatment methods, patients were divided into surgical intervention group and medical treatment group. Predictive factors were put forward and determined by receiver operating characteristic (ROC) curve analysis. An analysis of the surgical intervention and prognosis was performed. Results Of 114 patients, 46 (40.4%) cases received surgical intervention and 14 (12.3%) deaths. prothrombin time (PT), PT international normalized ratio, activated partial thromboplastin time (APTT), fibrinogen and platelet count at the time of NEC diagnosis were independently associated with surgical NEC. The APTT could identify patients at high risk for surgical NEC, with 67.39% sensitivity, 86.76% specificity, better than that of other serological parameters. Coagulopathy was found in 38.6% of all patients. For surgical intervention, the area under the ROC curve (AUC) of coagulopathy was 0.869 (95% confidence interval [CI]: 0.794 ~ 0.944, P < 0.001), with 82.61% sensitivity and 91.18% specificity, outperformed APTT (95% CI: 0.236 ~ 0.173, P = 0.001). Furthermore, the AUC for coagulopathy to predict mortality was 0.809 (95% CI: 0.725 ~ 0.877, P < 0.001), with 92.86% sensitivity and 69.0% specificity. Conclusion Coagulation parameters at the time of NEC diagnosis were conducive to early prediction of surgical NEC and -related deaths, which should be closely monitored in neonates at high risk of NEC and validated as a clinical decision-making tool.
Collapse
Affiliation(s)
- Wei Feng
- Department of General & Neonatal Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Jinping Hou
- Department of General & Neonatal Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Xiaohong Die
- Department of General & Neonatal Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Jing Sun
- Department of General & Neonatal Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Zhenhua Guo
- Department of General & Neonatal Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Wei Liu
- Department of General & Neonatal Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Yi Wang
- Department of General & Neonatal Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China.
| |
Collapse
|
|
32
|
De la Cruz-Cano E, Jiménez-González CDC, Díaz-Gandarilla JA, López-Victorio CJ, Escobar-Ramírez A, Uribe-López SA, Huerta-García E, Ayala-Sumuano JT, Morales-García V, Gútierrez-López L, González-Garrido JA. Comorbidities and laboratory parameters associated with SARS-CoV-2 infection severity in patients from the southeast of Mexico: a cross-sectional study. F1000Res 2022; 11:10. [PMID: 35464048 PMCID: PMC9005987 DOI: 10.12688/f1000research.74023.2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/25/2022] [Indexed: 01/08/2023] Open
Abstract
Background. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic. Among the risk factors associated with the severity of this disease is the presence of several metabolic disorders.
For this reason, the aim of this research was
to identify the comorbidities and laboratory parameters among COVID-19 patients admitted to the intensive care unit (ICU), comparing the patients who required invasive mechanical ventilation (IMV) with those who did not require IMV, in order to determine the clinical characteristics associated with the COVID-19 severity. Methods. We carried out a cross-sectional study among 152 patients who were admitted to the ICU from April 1
st to July 31
st, 2021, in whom the comorbidities and laboratory parameters associated with the SARS-CoV-2 infection severity were identified. The data of these patients was grouped into two main groups: “patients who required IMV” and “patients who did not require IMV”. The nonparametric Mann–Whitney U test for continuous data and the
χ2 test for categorical data were used to compare the variables between both groups. Results. Of the
152 COVID-19 patients who were admitted to the ICU, 66 required IMV and 86 did not require IMV. Regarding the comorbidities found in these patients, a higher prevalence of type 2 diabetes mellitus (T2DM), hypertension and obesity was observed among patients who required IMV vs. those who did not require IMV (
p<0.05). Concerning laboratory parameters, only glucose, Interleukin 6 (IL-6), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were significantly higher among patients who required IMV than in those who did not require IMV (
p<0.05). Conclusion. This study performed in a Mexican population indicates that comorbidities such as: T2DM, hypertension and obesity, as well as elevated levels of glucose, IL-6, LDH and CRP are associated with the COVID-19 severity.
Collapse
Affiliation(s)
- Eduardo De la Cruz-Cano
- División Académica de Ciencias Básicas. CICTAT. Laboratorio de Bioquímica y Biología Molecular., Universidad Juárez Autónoma de Tabasco, Cunduacán,, Tabasco., 86690, Mexico.,Laboratorio de Análisis Clínicos., Secretaría de Salud, Hospital General de Comalcalco., Comalcalco., Tabasco, 86300, Mexico
| | - Cristina Del C Jiménez-González
- División Académica Multidisciplinaria de Comalcalco. Laboratorio de Análisis Clínicos., Universidad Juárez Autónoma de Tabasco., Comalcalco., Tabasco., 86650, Mexico
| | - José A Díaz-Gandarilla
- División Académica Multidisciplinaria de Comalcalco. Laboratorio de Análisis Clínicos., Universidad Juárez Autónoma de Tabasco., Comalcalco., Tabasco., 86650, Mexico
| | - Carlos J López-Victorio
- División Académica de Ciencias Básicas. CICTAT. Laboratorio de Bioquímica y Biología Molecular., Universidad Juárez Autónoma de Tabasco, Cunduacán,, Tabasco., 86690, Mexico
| | - Adelma Escobar-Ramírez
- División Académica de Ciencias Básicas. CICTAT. Laboratorio de Bioquímica y Biología Molecular., Universidad Juárez Autónoma de Tabasco, Cunduacán,, Tabasco., 86690, Mexico
| | - Sheila A Uribe-López
- División Académica Multidisciplinaria de Jalpa de Méndez. Laboratorio de Inmunología y Microbiología Molecular., Universidad Juárez Autónoma de Tabasco, Jalpa de Méndez, Tabasco, 86205, Mexico
| | - Elizabeth Huerta-García
- División Académica Multidisciplinaria de Jalpa de Méndez. Laboratorio de Inmunología y Microbiología Molecular., Universidad Juárez Autónoma de Tabasco, Jalpa de Méndez, Tabasco, 86205, Mexico
| | | | - Vicente Morales-García
- División Académica Multidisciplinaria de Comalcalco. Laboratorio de Análisis Clínicos., Universidad Juárez Autónoma de Tabasco., Comalcalco., Tabasco., 86650, Mexico
| | - Liliana Gútierrez-López
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina., Instituto Politécnico Nacional., Ciudad de México, Ciudad de México, 11340, Mexico
| | - José A González-Garrido
- División Académica de Ciencias Básicas. CICTAT. Laboratorio de Bioquímica y Biología Molecular., Universidad Juárez Autónoma de Tabasco, Cunduacán,, Tabasco., 86690, Mexico
| |
Collapse
|
|
33
|
Al-Mamoori HS, Ahmed MH, Al-Nafie TYS, Al-Attar Z. Assessment of the Level of Protein C in Hospitalized Iraqi Patients with COVID-19 and its Correlation with Hematological and Inflammatory Markers. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.8937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND: COVID-19 coagulopathy manifests by elevation of certain marker of active coagulation as fibrinogen and this increment associated with increased markers of inflammations.
AIM: To measure protein C (PC) level in hospitalized patients with COVID-19 and to find a possible correlation with hematological and inflammatory markers.
PATIENTS AND METHODS: Seventy-five hospitalized Iraqi adult patients with COVID-19 were included in a descriptive cross-sectional research. PC, D-dimer, and erythrocyte sedimentation rate (ESR) blood samples were collected, and further information was received from patient’s records. Statistical analysis was conducted using SPSS version 23 and Microsoft Office Excel 2019.
RESULTS: Mean age of 75 patients included in the study was 60.13 ± 14.65 years. Sixty-two (62.7%) of patients exhibited neutrophilia, whereas 41 had lymphopenia (54.7%). High ratio of neutrophil/lymphocyte (N/L) was seen in 66 (88.0%), eosinopenia was seen in 46 (61.3%), high lactate dehydrogenase level was seen 68 (90.7%), serum ferritin was high in 66 (88.0%), and high level of C-reactive protein was seen in 68 (90.7%), increased ESR was seen in 69 (92.0%) and high level of D-dimer was seen in 56 (74.7%), while low level of PC was seen in 12 (16.0%) patients. PC had significant negative correlation with prothrombin and partial thromboplastin time but no significant correlation with hematological and inflammatory parameters.
CONCLUSION: COVID-19 coagulopathy is common in majority of patients which include significant changes in WBCs counts, inflammatory markers, PC, and D-dimer levels. Such changes may have a great impact on morbidity and mortality and thus need to be monitored throughout treatment and convalescence.
Collapse
|
|
34
|
Abd El-Lateef AE, Alghamdi S, Ebid G, Khalil K, Kabrah S, Abdel Ghafar MT. Coagulation Profile in COVID-19 Patients and its Relation to Disease Severity and Overall Survival: A Single-Center Study. Br J Biomed Sci 2022; 79:10098. [PMID: 35996516 PMCID: PMC9302539 DOI: 10.3389/bjbs.2022.10098] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 03/18/2022] [Indexed: 01/08/2023]
Abstract
Objectives: This study aims to investigate hemostatic changes in patients with coronavirus disease (COVID-19) and their relationship to disease severity and survival.Methods: This study included 284 patients with COVID-19 who attended the Security Forces Hospital, Makkah, Saudi Arabia between October 2020 and March 2021, and retrospectively reviewed their demographic, radiological, and laboratory findings. The coagulation profile was assayed at the time of diagnosis for platelet counts using an automated hematology analyzer; Sysmex XN2000 while international normalized ratio (INR), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, factor VIII, ristocetin cofactor (RiCoF), and von Willebrand factor antigen (VWF-Ag) were measured by Stago kits on a Stago automated coagulation analyzer (STA Compact Max®).Results: In this study, 32.3% of the cases had severe disease, while 8.8% of the cases died. D-dimer, factor VIII, and RiCoF were the only independent predictors of disease severity, with factor VIII and RiCoF having significantly higher areas under the curve (AUCs) than D-dimer (all p < 0.001). Furthermore, age, aPTT, and factor VIII were associated with an increased risk of mortality in multivariate Cox regression analysis, with factor VIII having a higher AUC of 0.98 than aPTT with an optimal cut-off value of >314 IU/dl in predicting mortality. Cases with factor VIII levels >314 IU/dl, compared to those with factor VIII levels <314 IU/dl, were associated with a significantly shorter mean overall survival time (20.08 vs. 31.35 days, p < 0.001), a lower survival rate (30.3% vs. 99.2%, p < 0.001), and a 16.62-fold increased mortality risk.Conclusion: RiCoF is a novel predictor of disease severity in COVID-19, while factor VIII is confirmed as a predictor of severity and mortality in COVID-19 patients and is associated with lower overall survival and increased mortality risk.
Collapse
Affiliation(s)
- Amal Ezzat Abd El-Lateef
- Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
- Department of Laboratory Medicine, Faculty of Applied Medical Science, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Saad Alghamdi
- Department of Laboratory Medicine, Faculty of Applied Medical Science, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Gamal Ebid
- Department of Laboratory Medicine, Security Forces Hospital, Makkah, Saudi Arabia
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Khalid Khalil
- Department of Internal Medicine, Security Forces Hospital, Makkah, Saudi Arabia
| | - Saeed Kabrah
- Department of Laboratory Medicine, Faculty of Applied Medical Science, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Muhammad Tarek Abdel Ghafar
- Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
- *Correspondence: Muhammad Tarek Abdel Ghafar, , , orcid.org/0000-0002-0621-4291
| |
Collapse
|
|
35
|
Pieri M, Quaggiotti L, Fominskiy E, Landoni G, Calabrò MG, Ajello S, Bonizzoni MA, Scandroglio AM. Anticoagulation strategies in critically-ill SARS-CoV-2 patients: the role of direct thrombin inhibitors. J Cardiothorac Vasc Anesth 2022; 36:2961-2967. [PMID: 35428549 PMCID: PMC8902052 DOI: 10.1053/j.jvca.2022.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 02/28/2022] [Accepted: 03/04/2022] [Indexed: 11/29/2022]
Abstract
Objectives To compare heparin-based anticoagulation and bivalirudin-based anticoagulation within the context of critically ill patients with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Design An observational study. Setting At the intensive care unit of a university hospital. Participants and Interventions Critically ill patients with a SARS-CoV-2 infection receiving full anticoagulation with heparin or bivalirudin. Measurements and Main Results Twenty-three patients received full anticoagulation with bivalirudin and 60 with heparin. Despite patients in the bivalirudin group having higher mortality risk scores (SAPS II 60 ± 16 v 39 ±7, p < 0.001) and a higher need for extracorporeal support compared to the heparin group, hospital mortality was comparable (57% v 45, p = 0.3). No difference in thromboembolic complications was observed, and bleeding events were more frequent in patients treated with bivalirudin (65% v 40%, p = 0.01). Similar results were confirmed in the subgroup analysis of patients undergoing intravenous anticoagulation; in addition to comparable thrombotic complications occurrence and thrombocytopenia rate, however, no difference in the bleeding rate was observed (65% v 35%, p = 0.08). Conclusions Although heparin is the most used anticoagulant in the intensive care setting, bivalirudin-based anticoagulation was safe and effective in a cohort of critically ill patients with SARS-CoV-2. Bivalirudin may be given full consideration as an anticoagulation strategy for critically ill patients with SARS-CoV-2, especially in those with thrombocytopenia and on extracorporeal support.
Collapse
|
|
36
|
Damián-Vázquez G, García-Larragoiti N, Cano-Méndez A, Guzmán-Cancino P, Tiznado-Leyva A, López-Castaneda S, Viveros-Sandoval ME. Recent Findings on Platelet Activation, vWF Multimers and Other Thrombotic Biomarkers Associated with Critical COVID-19. Clin Appl Thromb Hemost 2022. [DOI: 10.1177/10760296221135792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Mortality rate in patients with COVID-19 increases in those admitted to the ICU. Activation of the coagulation system is associated with the worse disease outcomes. The aim of this study was to evaluate platelet activation and thrombotic biomarkers in hospitalized patients with COVID-19 during the second and third infection waves of the pandemic during 2021, following a previous report that included patients from the first wave. Sixty five patients were recruited and classified according to disease outcome; 10 healthy donors were included as a control group. Among prothrombotic biomarkers, t-PA concentrations ( p < .0001), PAI-1 (0.0032) and D dimer ( p = .0011) were higher in patients who developed critical COVID-19. We also found platelet activation via αIIbβIII expression ( p < .0001) and higher presence of vWF-HMWM in severe COVID-19 ( p < .0001). Several prothrombotic biomarkers are found to be increased since hospital admission in patients which lately present a worse disease outcome (ICU admission/death), among these, platelet activation, vWF increased plasma concentration and presence of HMWM seem to be of special interest. New studies regarding the predictive value of thrombotic biomarkers are needed as SARS-CoV-2 variants continue to emerge.
Collapse
Affiliation(s)
- Guadalupe Damián-Vázquez
- Laboratory of Hemostasis and Vascular Biology, Faculty of Medical and Biological Sciences “Dr. Ignacio Chavez”, Universidad Michoacana de San Nicolas de Hidalgo, Morelia, Michoacan, Mexico
| | - Nallely García-Larragoiti
- Laboratory of Hemostasis and Vascular Biology, Faculty of Medical and Biological Sciences “Dr. Ignacio Chavez”, Universidad Michoacana de San Nicolas de Hidalgo, Morelia, Michoacan, Mexico
| | - Alan Cano-Méndez
- Laboratory of Hemostasis and Vascular Biology, Faculty of Medical and Biological Sciences “Dr. Ignacio Chavez”, Universidad Michoacana de San Nicolas de Hidalgo, Morelia, Michoacan, Mexico
| | - Patricia Guzmán-Cancino
- Laboratory of Hemostasis and Vascular Biology, Faculty of Medical and Biological Sciences “Dr. Ignacio Chavez”, Universidad Michoacana de San Nicolas de Hidalgo, Morelia, Michoacan, Mexico
| | - Aidyl Tiznado-Leyva
- Laboratory of Hemostasis and Vascular Biology, Faculty of Medical and Biological Sciences “Dr. Ignacio Chavez”, Universidad Michoacana de San Nicolas de Hidalgo, Morelia, Michoacan, Mexico
| | - Sandra López-Castaneda
- Laboratory of Hemostasis and Vascular Biology, Faculty of Medical and Biological Sciences “Dr. Ignacio Chavez”, Universidad Michoacana de San Nicolas de Hidalgo, Morelia, Michoacan, Mexico
- Epidemiological Surveillance Unit, Hospital General “Dr Miguel Silva,” SSM, Morelia, Michoacan, Mexico
| | - Martha Eva Viveros-Sandoval
- Laboratory of Hemostasis and Vascular Biology, Faculty of Medical and Biological Sciences “Dr. Ignacio Chavez”, Universidad Michoacana de San Nicolas de Hidalgo, Morelia, Michoacan, Mexico
| |
Collapse
|
|
37
|
García de Guadiana-Romualdo L, Morell-García D, Favaloro EJ, Vílchez JA, Bauça JM, Alcaide Martín MJ, Gutiérrez Garcia I, de la Hera Cagigal P, Egea-Caparrós JM, Pérez Sanmartín S, Gutiérrez Revilla JI, Urrechaga E, Álamo JM, Hernando Holgado AM, Lorenzo-Lozano MC, Canalda Campás M, Juncos Tobarra MA, Morales-Indiano C, Vírseda Chamorro I, Pastor Murcia Y, Sahuquillo Frías L, Altimira Queral L, Nuez-Zaragoza E, Adell Ruiz de León J, Ruiz Ripa A, Salas Gómez-Pablos P, Cebreiros López I, Fernández Uriarte A, Larruzea A, López Yepes ML, Sancho-Rodríguez N, Zamorano Andrés MC, Pedregosa Díaz J, Sáenz L, Esparza Del Valle C, Baamonde Calzada MC, García Muñoz S, Vera M, Martín Torres E, Sánchez Fdez-Pacheco S, Vicente Gutiérrez L, Jiménez Añón L, Pérez Martínez A, Pons Castillo A, González Tamayo R, Férriz Vivancos J, Rodríguez-Fraga O, Díaz-Brito V, Aguadero V, García Arévalo MG, Arnaldos Carrillo M, González Morales M, Núñez Gárate M, Ruiz Iruela C, Esteban Torrella P, Vila Pérez M, Acevedo Alcaraz C, Blázquez-Manzanera AL, Galán Ortega A. Harmonized D-dimer levels upon admission for prognosis of COVID-19 severity: Results from a Spanish multicenter registry (BIOCOVID-Spain study). J Thromb Thrombolysis 2022; 53:103-112. [PMID: 34272635 PMCID: PMC8284690 DOI: 10.1007/s11239-021-02527-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/04/2021] [Indexed: 12/20/2022]
Abstract
Coagulopathy is a key feature of COVID-19 and D-dimer has been reported as a predictor of severity. However, because D-dimer test results vary considerably among assays, resolving harmonization issues is fundamental to translate findings into clinical practice. In this retrospective multicenter study (BIOCOVID study), we aimed to analyze the value of harmonized D-dimer levels upon admission for the prediction of in-hospital mortality in COVID-19 patients. All-cause in-hospital mortality was defined as endpoint. For harmonization of D-dimer levels, we designed a model based on the transformation of method-specific regression lines to a reference regression line. The ability of D-dimer for prediction of death was explored by receiver operating characteristic curves analysis and the association with the endpoint by Cox regression analysis. Study population included 2663 patients. In-hospital mortality rate was 14.3%. Harmonized D-dimer upon admission yielded an area under the curve of 0.66, with an optimal cut-off value of 0.945 mg/L FEU. Patients with harmonized D-dimer ≥ 0.945 mg/L FEU had a higher mortality rate (22.4% vs. 9.2%; p < 0.001). D-dimer was an independent predictor of in-hospital mortality, with an adjusted hazard ratio of 1.709. This is the first study in which a harmonization approach was performed to assure comparability of D-dimer levels measured by different assays. Elevated D-dimer levels upon admission were associated with a greater risk of in-hospital mortality among COVID-19 patients, but had limited performance as prognostic test.
Collapse
Affiliation(s)
- Luis García de Guadiana-Romualdo
- Laboratory Medicine Department, Hospital Universitario Santa Lucía, C/ Mezquita, s/n, Paraje Los Arcos, Santa Lucía, 30202, Cartagena, Spain.
| | - Daniel Morell-García
- Laboratory Medicine Department, Hospital Universitario Son Espases, Palma de Mallorca, Spain
| | - Emmanuel J Favaloro
- Haematology, Sydney Centres for Thrombosis and Haemostasis, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia
| | - Juan A Vílchez
- Laboratory Medicine Department, Hospital Universitario Morales Meseguer, Murcia, Spain
| | - Josep M Bauça
- Laboratory Medicine Department, Hospital Universitario Son Espases, Palma de Mallorca, Spain
| | | | | | | | | | - Sonia Pérez Sanmartín
- Laboratory Medicine Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | | | | | - Jose M Álamo
- Biochemical Laboratory, Hospital Marina Baixa, Villajoyosa, Spain
| | | | | | | | - María A Juncos Tobarra
- Laboratory Medicine Department, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
| | - Cristian Morales-Indiano
- Laboratory Medicine Department, Hospital Universitari Germans Trias I Pujol, Badalona, Barcelona, Spain
| | | | - Yolanda Pastor Murcia
- Laboratory Medicine Department, Consorci Hospital General Universitari de València, Valencia, Spain
| | | | - Laura Altimira Queral
- Laboratory Medicine Department, Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain
| | - Elisa Nuez-Zaragoza
- Clinical Laboratory Department, Hospital Universitari Parc Taulí, Sabadell, Spain
| | | | - Alicia Ruiz Ripa
- Laboratory Medicine Department, Laboratori de Referència de Catalunya. Hospital de Mataró, Mataró, Spain
| | | | - Iria Cebreiros López
- Laboratory Medicine Department, Hospital Universitario Virgen de La Arrixaca, Murcia, Spain
| | | | - Alex Larruzea
- Laboratory Medicine Department, Hospital Fundació Sanitària Hospital de Mollet, Barcelona, Spain
| | | | | | | | | | - Luis Sáenz
- Laboratory Medicine Department, Hospital General Universitario Rafael Méndez, Lorca, Spain
| | - Clara Esparza Del Valle
- Laboratory Medicine Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | | | - Sara García Muñoz
- Laboratory Medicine Department, Hospital Universitario de Basurto, Bilbao, Spain
| | - Marina Vera
- Biochemical Laboratory, Hospital Marina Baixa, Villajoyosa, Spain
| | | | | | - Luis Vicente Gutiérrez
- Laboratory Medicine Department, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
| | - Laura Jiménez Añón
- Laboratory Medicine Department, Hospital Universitari Germans Trias I Pujol, Badalona, Barcelona, Spain
| | | | | | - Ruth González Tamayo
- Laboratory Medicine Department, Hospital Universitario de Torrevieja, Torrevieja, Spain
| | - Jorge Férriz Vivancos
- Laboratory Medicine Department, Consorci Hospital General Universitari de València, Valencia, Spain
| | | | - Vicens Díaz-Brito
- Internal Medicine Department, Parc Sanitari Sant Joan de Déu,, Sant Boi de Llobregat, Spain
| | - Vicente Aguadero
- Clinical Laboratory Department, Hospital Universitari Parc Taulí, Sabadell, Spain
| | - M G García Arévalo
- Laboratory Medicine Department, Hospital Universitario Virgen de La Victoria, Málaga, Spain
| | | | - Mercedes González Morales
- Laboratory Medicine Department, Hospital Universitario Santa Lucía, C/ Mezquita, s/n, Paraje Los Arcos, Santa Lucía, 30202, Cartagena, Spain
| | | | - Cristina Ruiz Iruela
- Laboratory Medicine Department, Hospital Fundació Sanitària Hospital de Mollet, Barcelona, Spain
| | | | - Martí Vila Pérez
- Laboratory Medicine Department, Hospital Verge de La Cinta, Tortosa, Spain
| | - Cristina Acevedo Alcaraz
- Laboratory Medicine Department, Hospital Universitario Los Arcos del Mar Menor, San Javier, Spain
| | | | - Amparo Galán Ortega
- Comisión de Magnitudes Biológicas Relacionadas Con La Urgencia Médica, Sociedad Española de Medicina de Laboratorio (SEQC-ML), Barcelona, Spain
| |
Collapse
|
|
38
|
Aydin S, Ugur K, Yalcin H, Sahin İ, Akkoc RF, Yakar B, Yucel D, Aydin S. Overview of COVID-19’s relationship with thrombophilia proteins. TURKISH JOURNAL OF BIOCHEMISTRY 2021; 46:609-622. [DOI: 10.1515/tjb-2021-0183] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Abstract
Abstract
COVID-19 is the most devastating pandemic situation we have experienced in our age, affecting all systems. Although it affects all systems, it shows its most important effect through thrombophilia. Therefore, the possible cause of sudden death due to COVID-19 may be embolism caused by thrombophilia. D-dimer amounts increase due to COVID-19. The thrombosis is associated with sudden death in COVID-19 disease in populations. Since individuals with thrombophilia will be more prone to death due to COVID-19, it may be appropriate to administer low doses of Clexane (Enoxaparin sodium) or low-weight heparin for prophylactic purposes in order to consider these individuals at high risk and to prevent deaths. Moreover, in order not to risk the lives of healthcare professionals with thrombophilia, it would be appropriate to keep them away from individuals with COVID-19 disease and to employ them in different healthcare services according to their fields of expertise. It should also not be forgotten that different symptoms related to COVID-19 appear day by day, these different symptoms probably show that the virus has undergone mutations in order to survive, but no matter what, its effect on thrombophilia has not been eliminated yet. This compilation aims to present the reasons and causes of death due to COVID-19, possible treatment options, and thrombophilia panel tests and new parameters that may have a place in the meticulous interpretation of these tests and possible etiopathology in the light of current information. Therefore, presenting this information in a rational manner and keeping the parameters of the thrombophilia panel under strict control predict that the deaths due to the virus will be partially reduced.
Collapse
Affiliation(s)
- Suna Aydin
- Department of Cardiovascular Surgery , Elazig Fethi Sekin City Hospital, Health Science University, Elazig Campus , Elazig , Turkey
| | - Kader Ugur
- Department of Internal Medicine (Endocrinology and Metabolism Diseases) , School of Medicine, Firat University Elazig , Turkey
| | - Hanifi Yalcin
- Department of Histology and Embryology , Faculty of Veterinary Medicine, Firat University Elazig , Turkey
| | - İbrahim Sahin
- Department of Medical Biology , Medical School, Erzincan Binali Yildirim University , Erzincan , Turkey
- Department of Medical Biochemistry and Clinical Biochemistry , (Firat Hormones Research Group), School of Medicine, Firat University , Elazig , Turkey
| | | | - Burkay Yakar
- Department of Medicine , Medical School, Firat University , Elazig , Turkey
| | - Dogan Yucel
- Department of Medical Biochemistry , Faculty of Medicine, Lokman Hekim University , Ankara , Turkey
| | - Suleyman Aydin
- Department of Medical Biochemistry and Clinical Biochemistry , (Firat Hormones Research Group), School of Medicine, Firat University , Elazig , Turkey
| |
Collapse
|
|
39
|
Elieh Ali Komi D, Rahimi Y, Asghari R, Jafari R, Rasouli J, Mohebalizadeh M, Abbasi A, Nejadrahim R, Rezazadeh F, Shafiei-Irannejad V. Investigation of the Molecular Mechanism of Coagulopathy in Severe and Critical Patients With COVID-19. Front Immunol 2021; 12:762782. [PMID: 34975853 PMCID: PMC8716500 DOI: 10.3389/fimmu.2021.762782] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 11/26/2021] [Indexed: 01/22/2023] Open
Abstract
Coagulopathy is a frequently reported finding in the pathology of coronavirus disease 2019 (COVID-19); however, the molecular mechanism, the involved coagulation factors, and the role of regulatory proteins in homeostasis are not fully investigated. We explored the dynamic changes of nine coagulation tests in patients and controls to propose a molecular mechanism for COVID-19-associated coagulopathy. Coagulation tests including prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (FIB), lupus anticoagulant (LAC), proteins C and S, antithrombin III (ATIII), D-dimer, and fibrin degradation products (FDPs) were performed on plasma collected from 105 individuals (35 critical patients, 35 severe patients, and 35 healthy controls). There was a statically significant difference when the results of the critical (CRT) and/or severe (SVR) group for the following tests were compared to the control (CRL) group: PTCRT (15.014) and PTSVR (13.846) (PTCRL = 13.383, p < 0.001), PTTCRT (42.923) and PTTSVR (37.8) (PTTCRL = 36.494, p < 0.001), LACCRT (49.414) and LACSVR (47.046) (LACCRL = 40.763, p < 0.001), FIBCRT (537.66) and FIBSVR (480.29) (FIBCRL = 283.57, p < 0.001), ProCCRT (85.57%) and ProCSVR (99.34%) (ProCCRL = 94.31%, p = 0.04), ProSCRT (62.91%) and ProSSVR (65.06%) (ProSCRL = 75.03%, p < 0.001), D-dimer (p < 0.0001, χ2 = 34.812), and FDP (p < 0.002, χ2 = 15.205). No significant association was found in the ATIII results in groups (ATIIICRT = 95.71% and ATIIISVR = 99.63%; ATIIICRL = 98.74%, p = 0.321). D-dimer, FIB, PT, PTT, LAC, protein S, FDP, and protein C (ordered according to p-values) have significance in the prognosis of patients. Disruptions in homeostasis in protein C (and S), VIII/VIIIa and V/Va axes, probably play a role in COVID-19-associated coagulopathy.
Collapse
Affiliation(s)
- Daniel Elieh Ali Komi
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Yaghoub Rahimi
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Rahim Asghari
- Hematology, Immune Cell Therapy, and Stem Cells Transplantation Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Reza Jafari
- Hematology, Immune Cell Therapy, and Stem Cells Transplantation Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Nephrology and Kidney Transplant Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Javad Rasouli
- Department of Epidemiology and Biostatistics, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mehdi Mohebalizadeh
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Ata Abbasi
- Department of Pathology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Rahim Nejadrahim
- Department of Infectious Diseases, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Farzin Rezazadeh
- Department of Emergency Medicine, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Vahid Shafiei-Irannejad
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| |
Collapse
|
|
40
|
Hosseini SF, Behnam-Roudsari S, Alavinia G, Emami A, Toghyani A, Moradi S, Zadeh MM, Mohseni S, Shafiee MA. Diagnostic and prognostic value of Sepsis-Induced coagulopathy and International Society on Thrombosis and Hemostasis scoring systems in COVID-19-associated disseminated intravascular coagulopathy. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2021; 26:102. [PMID: 34899940 PMCID: PMC8607173 DOI: 10.4103/jrms.jrms_1295_20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 12/30/2020] [Accepted: 03/25/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND The coronavirus disease 2019 (COVID-19) presents various phenotypes from asymptomatic involvement to death. Disseminated intravascular coagulopathy (DIC) is among the poor prognostic complications frequently observed in critical illness. To improve mortality, a timely diagnosis of DIC is essential. The International Society on Thrombosis and Hemostasis (ISTH) introduced a scoring system to detect overt DIC (score ≥5) and another category called sepsis-induced coagulopathy (SIC) to identify the initial stages of DIC (score ≥4). This study aimed to determine whether clinicians used these scoring systems while assessing COVID-19 patients and the role of relevant biomarkers in disease severity and outcome. MATERIALS AND METHODS An exhaustive search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses, using Medline, Embase, Cochrane, CINAHL, and PubMed until August 2020. Studies considering disease severity or outcome with at least two relevant biomarkers were included. For all studies, the definite, maximum, and minimum ISTH/SIC scores were calculated. RESULTS A total of 37 papers and 12,463 cases were reviewed. Studies considering ISTH/SIC criteria to detect DIC suggested a higher rate of ISTH ≥5 and SIC ≥4 in severe cases and nonsurvivors compared with nonsevere cases and survivors. The calculated ISTH scores were dominantly higher in severe infections and nonsurvivors. Elevated D-dimer was the most consistent abnormality on admission. CONCLUSION Higher ISTH and SIC scores positively correlate with disease severity and death. In addition, more patients with severe disease and nonsurvivors met the ISTH and SIC scores for DIC. Given the high prevalence of coagulopathy in COVID-19 infection, dynamic monitoring of relevant biomarkers in the form of ISTH and SIC scoring systems is of great importance to timely detect DIC in suspicious patients.
Collapse
Affiliation(s)
- Sayyideh Forough Hosseini
- Department of Medicine, Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Sahar Behnam-Roudsari
- Department of Medicine, Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Ghazal Alavinia
- Department of Medicine, Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Anahita Emami
- Department of Medicine, Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Arash Toghyani
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sanaz Moradi
- Department of Medicine, Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Mahtab Mojtahed Zadeh
- Department of Medicine, Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Sana Mohseni
- Department of Medicine, Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Mohammad Ali Shafiee
- Department of Medicine, Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| |
Collapse
|
|
41
|
Fenyves BG, Mehta A, MGH COVID‐19 Collection & Processing Team, Kays KR, Beakes C, Margolin J, Goldberg MB, Hacohen N, Filbin MR. Plasma P-selectin is an early marker of thromboembolism in COVID-19. Am J Hematol 2021; 96:E468-E471. [PMID: 34622480 PMCID: PMC8616847 DOI: 10.1002/ajh.26372] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/29/2021] [Accepted: 10/04/2021] [Indexed: 01/18/2023]
Affiliation(s)
- Bánk G. Fenyves
- Department of Emergency MedicineMassachusetts General HospitalBostonMassachusettsUSA
- Department of Molecular BiologySemmelweis UniversityBudapestHungary
- Department of Emergency MedicineSemmelweis UniversityBudapestHungary
| | - Arnav Mehta
- Department of MedicineHarvard Medical SchoolBostonMassachusettsUSA
- Infectious Disease and MicrobiomeBroad Institute of Massachusetts Institute of Technology (MIT) and HarvardCambridgeMassachusettsUSA
- Department of Medical OncologyDana‐Farber Cancer InstituteBostonMassachusettsUSA
- Massachusetts General Hospital Cancer Center, Department of MedicineMassachusetts General HospitalBostonMassachusettsUSA
| | | | - Kyle R. Kays
- Department of Emergency MedicineMassachusetts General HospitalBostonMassachusettsUSA
| | - Caroline Beakes
- Department of Emergency MedicineMassachusetts General HospitalBostonMassachusettsUSA
| | - Justin Margolin
- Department of Emergency MedicineMassachusetts General HospitalBostonMassachusettsUSA
| | - Marcia B. Goldberg
- Department of MedicineHarvard Medical SchoolBostonMassachusettsUSA
- Infectious Disease and MicrobiomeBroad Institute of Massachusetts Institute of Technology (MIT) and HarvardCambridgeMassachusettsUSA
- Center for Bacterial Pathogenesis, Division of Infectious Diseases, Department of MedicineMassachusetts General HospitalBostonMassachusettsUSA
- Department of MicrobiologyHarvard Medical SchoolBostonMassachusettsUSA
- Department of Immunology and Infectious DiseasesHarvard TH Chan School of Public HealthBostonMassachusettsUSA
| | - Nir Hacohen
- Department of MedicineHarvard Medical SchoolBostonMassachusettsUSA
- Infectious Disease and MicrobiomeBroad Institute of Massachusetts Institute of Technology (MIT) and HarvardCambridgeMassachusettsUSA
- Massachusetts General Hospital Cancer Center, Department of MedicineMassachusetts General HospitalBostonMassachusettsUSA
| | - Michael R. Filbin
- Department of Emergency MedicineMassachusetts General HospitalBostonMassachusettsUSA
- Infectious Disease and MicrobiomeBroad Institute of Massachusetts Institute of Technology (MIT) and HarvardCambridgeMassachusettsUSA
- Department of Emergency MedicineHarvard Medical SchoolBostonMassachusettsUSA
| |
Collapse
|
|
42
|
Demelo-Rodriguez P, Galeano-Valle F, Ordieres-Ortega L, Siniscalchi C, Martín Del Pozo M, Fidalgo Á, Gil-Díaz A, Lobo JL, De Ancos C, Monreal M, For the RIETE-Bleeding Investigators. Validation of a Prognostic Score to Identify Hospitalized Patients with COVID-19 at Increased Risk for Bleeding. Viruses 2021; 13:2278. [PMID: 34835085 PMCID: PMC8621368 DOI: 10.3390/v13112278] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Hospitalized patients with COVID-19 are at increased risk for venous thromboembolism (VTE), but also for bleeding. We previously derived a prognostic score including four variables (elevated D-dimer, elevated ferritin, critical illness, and therapeutic-dose anticoagulation) that identified those at increased risk for major bleeding. METHODS We aimed to validate the score in a subsequent cohort of hospitalized patients with COVID-19 receiving standard-, intermediate- or therapeutic doses of VTE prophylaxis. We evaluated its capacity to predict major bleeding, non-major bleeding, and bleeding-related death. RESULTS The cohort included 972 patients from 29 hospitals, of whom 280 (29%) received standard-; 412 (42%) intermediate-, 157 (16%) therapeutic doses of VTE prophylaxis and 123 (13%) other drugs. Median duration of prophylaxis was 14.7 ± 10.3 days. Major bleeding occurred in 65 patients (6.7%) and non-major bleeding in 67 (6.9%). Thirty patients with major bleeding (46%) died within the first 30 days after bleeding. The prognostic score identified 203 patients (21%) at very low risk, 285 (29%) at low risk, 263 (27%) intermediate-risk and 221 (23%) at high risk for bleeding. Major bleeding occurred in 1.0%, 2.1%, 8.7% and 15.4% of the patients, respectively. Non-major bleeding occurred in 0.5%, 3.5%, 9.5% and 14.2%, respectively. The c-statistics was: 0.74 (95% confidence intervals [CI]: 0.68-0.79) for major bleeding, 0.73 (95% CI: 0.67-0.78) for non-major bleeding and 0.82 (95% CI: 0.76-0.87) for bleeding-related death. CONCLUSIONS In hospitalized patients with COVID-19, we validated that a prognostic score including 4 easily available items may identify those at increased risk for bleeding.
Collapse
Affiliation(s)
- Pablo Demelo-Rodriguez
- Department of Internal Medicine, Hospital General Universitario Gregorio Marañón, Doctor Esquerdo 46, 28006 Madrid, Spain; (P.D.-R.); (L.O.-O.)
| | - Francisco Galeano-Valle
- Department of Internal Medicine, Hospital General Universitario Gregorio Marañón, Doctor Esquerdo 46, 28006 Madrid, Spain; (P.D.-R.); (L.O.-O.)
| | - Lucía Ordieres-Ortega
- Department of Internal Medicine, Hospital General Universitario Gregorio Marañón, Doctor Esquerdo 46, 28006 Madrid, Spain; (P.D.-R.); (L.O.-O.)
| | - Carmine Siniscalchi
- Department of Angiology, Azienda Ospedaliera Universitaria, 43126 Parma, Italy;
| | - Mar Martín Del Pozo
- Department of Internal Medicine, Hospital Universitario Infanta Sofía, 28703 Madrid, Spain;
| | - Ángeles Fidalgo
- Department of Internal Medicine, Hospital Universitario de Salamanca, 37007 Salamanca, Spain;
| | - Aída Gil-Díaz
- Department of Internal Medicine, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Spain;
| | - José Luis Lobo
- Department of Pneumonology, Hospital Universitario Araba, 01009 Álava, Spain;
| | - Cristina De Ancos
- Department of Internal Medicine, Hospital Universitario de Fuenlabrada, 28943 Madrid, Spain;
| | - Manuel Monreal
- Department of Internal Medicine, Hospital Germans Trias i Pujol, 08916 Badalona, Spain;
| | | |
Collapse
|
|
43
|
Cumpstey AF, Clark AD, Santolini J, Jackson AA, Feelisch M. COVID-19: A Redox Disease-What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About Its Treatment. Antioxid Redox Signal 2021; 35:1226-1268. [PMID: 33985343 DOI: 10.1089/ars.2021.0017] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Significance: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19), affects every aspect of human life by challenging bodily, socioeconomic, and political systems at unprecedented levels. As vaccines become available, their distribution, safety, and efficacy against emerging variants remain uncertain, and specific treatments are lacking. Recent Advances: Initially affecting the lungs, COVID-19 is a complex multisystems disease that disturbs the whole-body redox balance and can be long-lasting (Long-COVID). Numerous risk factors have been identified, but the reasons for variations in susceptibility to infection, disease severity, and outcome are poorly understood. The reactive species interactome (RSI) was recently introduced as a framework to conceptualize how cells and whole organisms sense, integrate, and accommodate stress. Critical Issues: We here consider COVID-19 as a redox disease, offering a holistic perspective of its effects on the human body, considering the vulnerability of complex interconnected systems with multiorgan/multilevel interdependencies. Host/viral glycan interactions underpin SARS-CoV-2's extraordinary efficiency in gaining cellular access, crossing the epithelial/endothelial barrier to spread along the vascular/lymphatic endothelium, and evading antiviral/antioxidant defences. An inflammation-driven "oxidative storm" alters the redox landscape, eliciting epithelial, endothelial, mitochondrial, metabolic, and immune dysfunction, and coagulopathy. Concomitantly reduced nitric oxide availability renders the sulfur-based redox circuitry vulnerable to oxidation, with eventual catastrophic failure in redox communication/regulation. Host nutrient limitations are crucial determinants of resilience at the individual and population level. Future Directions: While inflicting considerable damage to health and well-being, COVID-19 may provide the ultimate testing ground to improve the diagnosis and treatment of redox-related stress diseases. "Redox phenotyping" of patients to characterize whole-body RSI status as the disease progresses may inform new therapeutic approaches to regain redox balance, reduce mortality in COVID-19 and other redox diseases, and provide opportunities to tackle Long-COVID. Antioxid. Redox Signal. 35, 1226-1268.
Collapse
Affiliation(s)
- Andrew F Cumpstey
- Respiratory and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.,Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Anna D Clark
- Respiratory and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.,Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Jérôme Santolini
- Institute for Integrative Biology of the Cell (I2BC), Biochemistry, Biophysics and Structural Biology, CEA, CNRS, Université Paris-Sud, Universite Paris-Saclay, Gif-sur-Yvette, France
| | - Alan A Jackson
- Human Nutrition, University of Southampton and University Hospital Southampton, Southampton, United Kingdom
| | - Martin Feelisch
- Respiratory and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.,Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| |
Collapse
|
|
44
|
Varikasuvu SR, Varshney S, Dutt N, Munikumar M, Asfahan S, Kulkarni PP, Gupta P. D-dimer, disease severity, and deaths (3D-study) in patients with COVID-19: a systematic review and meta-analysis of 100 studies. Sci Rep 2021; 11:21888. [PMID: 34750495 PMCID: PMC8576016 DOI: 10.1038/s41598-021-01462-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022] Open
Abstract
Hypercoagulability and the need for prioritizing coagulation markers for prognostic abilities have been highlighted in COVID-19. We aimed to quantify the associations of D-dimer with disease progression in patients with COVID-19. This systematic review and meta-analysis was registered with PROSPERO, CRD42020186661.We included 113 studies in our systematic review, of which 100 records (n = 38,310) with D-dimer data) were considered for meta-analysis. Across 68 unadjusted (n = 26,960) and 39 adjusted studies (n = 15,653) reporting initial D-dimer, a significant association was found in patients with higher D-dimer for the risk of overall disease progression (unadjusted odds ratio (uOR) 3.15; adjusted odds ratio (aOR) 1.64). The time-to-event outcomes were pooled across 19 unadjusted (n = 9743) and 21 adjusted studies (n = 13,287); a strong association was found in patients with higher D-dimers for the risk of overall disease progression (unadjusted hazard ratio (uHR) 1.41; adjusted hazard ratio (aHR) 1.10). The prognostic use of higher D-dimer was found to be promising for predicting overall disease progression (studies 68, area under curve 0.75) in COVID-19. Our study showed that higher D-dimer levels provide prognostic information useful for clinicians to early assess COVID-19 patients at risk for disease progression and mortality outcomes. This study, recommends rapid assessment of D-dimer for predicting adverse outcomes in COVID-19.
Collapse
Affiliation(s)
| | | | - Naveen Dutt
- Department of Respiratory Medicine, All India Institute of Medical Sciences, Jodhpur, 342005, India
| | - Manne Munikumar
- Department of Bioinformatics, ICMR-National Institute of Nutrition, Hyderabad, 500007, India
| | - Shahir Asfahan
- Department of Respiratory Medicine, All India Institute of Medical Sciences, Jodhpur, 342005, India
| | - Paresh P Kulkarni
- Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Pratima Gupta
- Department of Microbiology, All India Institute of Medical Sciences, Rishikesh, 249203, India
| |
Collapse
|
|
45
|
Lichter Y, Badelbayov T, Shalev I, Schvartz R, Szekely Y, Benisty D, Goldiner I, Kagarlyk M, Asraf K, Doolman R, Luttwak E, Kirgner I, Avivi I, Adi N, Katz BZ. Low FXIII activity levels in intensive care unit hospitalized COVID-19 patients. Thromb J 2021; 19:79. [PMID: 34736472 PMCID: PMC8567130 DOI: 10.1186/s12959-021-00333-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 10/17/2021] [Indexed: 12/26/2022] Open
Abstract
Background COVID-19 infection is associated with a hypercoagulable state. Severe COVID-19 patients present with high plasma fibrinogen levels, continuous deposition of fibrin and the presence of microthrombi in their lungs, accompanied by significant fibrinolysis, resulting in high D-dimer levels. Due to the role of FXIII in fibrin crosslinking and clot stabilization, we analyzed its activity levels and dynamics in COVID-19 patients hospitalized in the intensive care unit (ICU). Methods FXIII levels were measured in thirty four COVID-19 patients hospitalized in the ICU and in fourteen non-severe COVID-19 patients. FVIII levels were measured for comparison. Laboratory data and clinical variables were recorded. Results The average FXIII activity level in 34 ICU hospitalized COVID-19 patients was 69.9±33 %, significantly lower compared to an average of 120±20.9 % FXIII activity in 14 non-severe COVID-19 patients. FXIII activity levels were below the low normal value (< 79 % FXIII activity) in 74 % of the ICU hospitalized COVID-19 patients. In contrast, high FVIII activity was measured among all severe COVID-19 patients. Consecutive measurements, performed in fourteen ICU hospitalized COVID-19 patients, pointed to a significant decrease in FXIII activity from the average of 85.7±28.2 %, (which is in the normal range), to an average of 68.0±20.4 %, below the low normal range, within 6.4±3.4 days of ICU hospitalization. Liver functions did not differentiate between patients with low and normal FXIII activity. No inhibitor to FXIII activity was found in the plasma of severe COVID-19 patients. Levels of FXIII-A antigen correlated with FXIII activity, and were low in severe COVID-19 patients. Conclusions Low FXIII activity levels were found in COVID-19 patients hospitalized in the ICU, with gradual decline during their hospitalization. A mechanism of consumption may account for the low FXIII activity in these patients.
Collapse
Affiliation(s)
- Yael Lichter
- The Intensive Care Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Tanya Badelbayov
- The Hematology Institute, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv, Israel
| | - Irina Shalev
- The Hematology Institute, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv, Israel
| | - Reut Schvartz
- Division of anesthesiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Yishay Szekely
- The Division of cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Dan Benisty
- The Hematology Institute, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv, Israel
| | - Ilana Goldiner
- The Central Laboratory, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Maxim Kagarlyk
- The Dworman Automated-Mega Laboratory, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Keren Asraf
- The Dworman Automated-Mega Laboratory, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Ram Doolman
- The Dworman Automated-Mega Laboratory, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Efrat Luttwak
- The Hematology Institute, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv, Israel
| | - Ilya Kirgner
- The Hematology Institute, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Irit Avivi
- The Hematology Institute, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nimrod Adi
- The Intensive Care Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ben-Zion Katz
- The Hematology Institute, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv, Israel. .,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| |
Collapse
|
|
46
|
Prévention du risque thromboembolique veineux et surveillance de l’hémostase chez les patients hospitalisés pour COVID-19 : propositions réactualisées (avril 2021). Groupe d’intérêt en hémostase périopératoire (GIHP) et groupe d’étude sur l’hémostase et la thrombose (GFHT). ANESTHÉSIE & RÉANIMATION 2021. [PMCID: PMC8516597 DOI: 10.1016/j.anrea.2021.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
|
47
|
Ceballos FC, Ryan P, Blancas R, Martin-Vicente M, Vidal-Alcántara EJ, Peréz-García F, Bartolomé S, Churruca-Sarasqueta J, Virseda-Berdices A, Martínez-González O, Brochado-Kith O, Rava M, Vilches-Medkouri C, Blanca-López N, Ramirez Martinez-Acitores I, Moreira-Escriche P, De Juan C, Resino S, Fernández-Rodríguez A, Jiménez-Sousa MÁ. Are Reduced Levels of Coagulation Proteins Upon Admission Linked to COVID-19 Severity and Mortality? Front Med (Lausanne) 2021; 8:718053. [PMID: 34660629 PMCID: PMC8514618 DOI: 10.3389/fmed.2021.718053] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/03/2021] [Indexed: 12/24/2022] Open
Abstract
Background: The link between coagulation system disorders and COVID-19 has not yet been fully elucidated. Aim: Evaluating the association of non-previously reported coagulation proteins with COVID-19 severity and mortality. Design: Cross-sectional study of 134 COVID-19 patients recruited at admission and classified according to the highest COVID-19 severity reached (asymptomatic/mild, moderate, or severe) and 16 healthy control individuals. Methods: Coagulation proteins levels (antithrombin, prothrombin, factor_XI, factor_XII, and factor_XIII) and CRP were measured in plasma by the ProcartaPlex Panel (Invitrogen) multiplex immunoassay upon diagnosis. Results: We found higher levels of antithrombin, prothrombin, factor XI, factor XII, and factor XIII in asymptomatic/mild and moderate COVID-19 patients compared to healthy individuals. Interestingly, decreased levels of antithrombin and factors XI, XII, and XIII were observed in those patients who eventually developed severe illness. Additionally, survival models showed us that patients with lower levels of these coagulation proteins had an increased risk of death. Conclusion: COVID-19 provokes early increments of some specific coagulation proteins in most patients. However, lower levels of these proteins at diagnosis might “paradoxically” imply a higher risk of progression to severe disease and COVID-19-related mortality.
Collapse
Affiliation(s)
- Francisco C Ceballos
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Madrid, Spain
| | - Pablo Ryan
- Department of Infectious Diseases, Hospital Universitario Infanta Leonor, Madrid, Spain
| | - Rafael Blancas
- Critical Care Department, Hospital Universitario del Tajo, Aranjuez, Spain
| | - María Martin-Vicente
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Madrid, Spain
| | - Erick Joan Vidal-Alcántara
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Madrid, Spain
| | - Felipe Peréz-García
- Clinical Microbiology Department, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain
| | - Sofía Bartolomé
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Madrid, Spain
| | | | - Ana Virseda-Berdices
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Madrid, Spain
| | | | - Oscar Brochado-Kith
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Madrid, Spain
| | - Marta Rava
- Unit AIDS Research Network Cohort (CoRIS), National Center of Epidemiology (CNE), Health Institute Carlos III (ISCIII), Madrid, Spain
| | | | | | | | | | - Carmen De Juan
- Department of Infectious Diseases, Hospital Universitario Severo Ochoa, Madrid, Spain
| | - Salvador Resino
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Madrid, Spain
| | - Amanda Fernández-Rodríguez
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Madrid, Spain
| | - María Ángeles Jiménez-Sousa
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Madrid, Spain
| |
Collapse
|
|
48
|
Mukarramah DA, Rini IS, Sofyan RF, Kiat MI, Iskandar I, Ritana A, Brahma B. Oncologic Head and Neck Reconstructive Microsurgery during the COVID-19 Pandemic in Dharmais Cancer Hospital-National Cancer Center, Jakarta, Indonesia. JOURNAL OF RECONSTRUCTIVE MICROSURGERY OPEN 2021. [DOI: 10.1055/s-0041-1736420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Abstract
Background Head and neck cancer is one of the leading cancers worldwide. Complex head and neck procedures are potentially aerosol-generating and considered high risk for coronavirus disease 2019 (COVID-19) transmission between the patients, surgeons, and other health-care workers (HCWs). Several adjustments in the microsurgery procedure were needed. The COVID-19 protocol was developed and applied to minimize the COVID-19 transmission. The study objectives were to describe the preoperative, intraoperative, and postoperative protocols applied and the characteristics of patients who underwent head and neck reconstructive microsurgery during the COVID-19 pandemic in Dharmais Cancer Hospital-National Cancer Center.
Methods This study was a retrospective descriptive study of patients who underwent head and neck reconstructive microsurgery between March 2020 and December 2020 in the plastic surgery department and surgical oncology department, Dharmais Cancer Hospital-National Cancer Center, Jakarta, Indonesia. The patients' characteristics including sex, age, location of the defects, the flap type, flap survival, and complications were obtained from medical records and analyzed using SPSS version 23.
Results There were 55 patients, 30 (54.54%) patients were female, and 25 (45.45%) patients were male. The mean age at the time of surgery was 51.32 ± 1.85 years. The most common cancer type was squamous cell carcinoma for 49.09% (n = 27/55). The most frequent location was tongue for 25.45% (n = 14/55). Anterolateral thigh flap was also the most used flap in this study for 50.91% (n = 14/55). The overall survival rate of this study was 83.64% (n = 46/55). There were nine patients (16.36%) who were found with postoperative complications. There was no nosocomial infection with COVID-19 for patients, surgeons, and other HCWs.
Conclusion Microsurgery can be performed even in the COVID-19 pandemic as the gold standard for oncologic head and neck reconstruction by applying protocols to protect the patients, surgeons, and other HCWs.
Collapse
Affiliation(s)
- Dewi Aisiyah Mukarramah
- Department of Plastic, Reconstructive, and Aesthetic Surgery, Dharmais Cancer Hospital-National Cancer Center, Jakarta, Indonesia
| | - Irena Sakura Rini
- Department of Plastic, Reconstructive, and Aesthetic Surgery, Dharmais Cancer Hospital-National Cancer Center, Jakarta, Indonesia
| | - Rian Fabian Sofyan
- Department of Surgical Oncology, Dharmais Cancer Hospital-National Cancer Center, Jakarta, Indonesia
| | - Muhammad Irsyad Kiat
- Department of Plastic, Reconstructive, and Aesthetic Surgery, Dharmais Cancer Hospital-National Cancer Center, Jakarta, Indonesia
| | - Iskandar Iskandar
- Department of Surgical Oncology, Dharmais Cancer Hospital-National Cancer Center, Jakarta, Indonesia
| | - Azmi Ritana
- Department of Plastic, Reconstructive, and Aesthetic Surgery, Dharmais Cancer Hospital-National Cancer Center, Jakarta, Indonesia
| | - Bayu Brahma
- Department of Surgical Oncology, Dharmais Cancer Hospital-National Cancer Center, Jakarta, Indonesia
| |
Collapse
|
|
49
|
Martín-Rojas RM, Chasco-Ganuza M, Casanova-Prieto S, Delgado-Pinos VE, Pérez-Rus G, Duque-González P, Sancho M, Díez-Martín JL, Pascual-Izquierdo C. A mild deficiency of ADAMTS13 is associated with severity in COVID-19: comparison of the coagulation profile in critically and noncritically ill patients. Blood Coagul Fibrinolysis 2021; 32:458-467. [PMID: 34310402 PMCID: PMC8527912 DOI: 10.1097/mbc.0000000000001068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 07/09/2021] [Indexed: 11/25/2022]
Abstract
Early descriptions of COVID-19 associated coagulopathy identified it as a disseminated intravascular coagulation (DIC). However, recent studies have highlighted the potential role of endothelial cell injury in its pathogenesis, and other possible underlying mechanisms are being explored. This study aimed to analyse the coagulation parameters of critically and noncritically ill patients with COVID-19 bilateral pneumonia, determine if coagulation factors consumption occurs and explore other potential mechanisms of COVID-19 coagulopathy. Critically and noncritically ill patients with a diagnosis of COVID-19 bilateral pneumonia were recruited. For each patient, we performed basic coagulation tests, quantification of coagulation factors and physiological inhibitor proteins, an evaluation of the fibrinolytic system and determination of von Willebrand Factor (vWF) and ADAMTS13. Laboratory data were compared with clinical data and outcomes. The study involved 62 patients (31 ICU, 31 non-ICU). The coagulation parameters assessment demonstrated normal median prothrombin time (PT), international normalized ratio (INR) and activated partial thromboplastin time (APTT) in our cohort and all coagulation factors were within normal range. PAI-1 median levels were elevated (median 52.6 ng/ml; IQR 37.2-85.7), as well as vWF activity (median 216%; IQR 196-439) and antigen (median 174%; IQR 153.5-174.1). A mild reduction of ADAMTS13 was observed in critically ill patients and nonsurvivors. We demonstrated an inverse correlation between ADAMTS13 levels and inflammatory markers, D-dimer and SOFA score in our cohort. Elevated vWF and PAI-1 levels, and a mild reduction of ADAMTS13 in the most severe patients, suggest that COVID-19 coagulopathy is an endotheliopathy that has shared features with thrombotic microangiopathy.
Collapse
Affiliation(s)
| | | | | | | | | | - Patricia Duque-González
- Department of Anesthesiology and Reanimation
- Instituto de Investigación Sanitaria Gregorio Marañon, Madrid, Spain
| | - Milagros Sancho
- Intensive Care Unit, University General Hospital Gregorio Marañon
- Instituto de Investigación Sanitaria Gregorio Marañon, Madrid, Spain
| | - José Luis Díez-Martín
- Department of Hematology
- Universidad Complutense de Madrid
- Instituto de Investigación Sanitaria Gregorio Marañon, Madrid, Spain
| | | |
Collapse
|
|
50
|
Villar M, Urra JM, Rodríguez-Del-Río FJ, Artigas-Jerónimo S, Jiménez-Collados N, Ferreras-Colino E, Contreras M, de Mera IGF, Estrada-Peña A, Gortázar C, de la Fuente J. Characterization by Quantitative Serum Proteomics of Immune-Related Prognostic Biomarkers for COVID-19 Symptomatology. Front Immunol 2021; 12:730710. [PMID: 34566994 PMCID: PMC8457011 DOI: 10.3389/fimmu.2021.730710] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 08/19/2021] [Indexed: 12/22/2022] Open
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 challenges the understanding of factors affecting disease progression and severity. The identification of prognostic biomarkers and physiological processes associated with disease symptoms is relevant for the development of new diagnostic and therapeutic interventions to contribute to the control of this pandemic. To address this challenge, in this study, we used a quantitative proteomics together with multiple data analysis algorithms to characterize serum protein profiles in five cohorts from healthy to SARS-CoV-2-infected recovered (hospital discharge), nonsevere (hospitalized), and severe [at the intensive care unit (ICU)] cases with increasing systemic inflammation in comparison with healthy individuals sampled prior to the COVID-19 pandemic. The results showed significantly dysregulated proteins and associated biological processes and disorders associated to COVID-19. These results corroborated previous findings in COVID-19 studies and highlighted how the representation of dysregulated serum proteins and associated BPs increases with COVID-19 disease symptomatology from asymptomatic to severe cases. The analysis was then focused on novel disease processes and biomarkers that were correlated with disease symptomatology. To contribute to translational medicine, results corroborated the predictive value of selected immune-related biomarkers for disease recovery [Selenoprotein P (SELENOP) and Serum paraoxonase/arylesterase 1 (PON1)], severity [Carboxypeptidase B2 (CBP2)], and symptomatology [Pregnancy zone protein (PZP)] using protein-specific ELISA tests. Our results contributed to the characterization of SARS-CoV-2–host molecular interactions with potential contributions to the monitoring and control of this pandemic by using immune-related biomarkers associated with disease symptomatology.
Collapse
Affiliation(s)
- Margarita Villar
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ciudad Real, Spain.,Biochemistry Section, Faculty of Science and Chemical Technologies, and Regional Centre for Biomedical Research, University of Castilla-La Mancha, Ciudad Real, Spain
| | - José Miguel Urra
- Immunology, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain.,Medicine School, Universidad de Castilla la Mancha, Ciudad Real, Spain
| | | | - Sara Artigas-Jerónimo
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ciudad Real, Spain
| | | | - Elisa Ferreras-Colino
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ciudad Real, Spain
| | - Marinela Contreras
- Interdisciplinary Laboratory of Clinical Analysis, Interlab-UMU, University of Murcia, Murcia, Spain
| | | | - Agustín Estrada-Peña
- Department of Animal Pathology, Faculty of Veterinary Medicine, University of Zaragoza, Zaragoza, Spain
| | - Christian Gortázar
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ciudad Real, Spain
| | - José de la Fuente
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ciudad Real, Spain.,Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, United States
| |
Collapse
|