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1.
Int J Mol Med ; 49(3)2022 03.
Article in English | MEDLINE | ID: covidwho-1643663

ABSTRACT

The highly heterogeneous symptomatology and unpredictable progress of COVID­19 triggered unprecedented intensive biomedical research and a number of clinical research projects. Although the pathophysiology of the disease is being progressively clarified, its complexity remains vast. Moreover, some extremely infrequent cases of thrombotic thrombocytopenia following vaccination against SARS­CoV­2 infection have been observed. The present study aimed to map the signaling pathways of thrombocytopenia implicated in COVID­19, as well as in vaccine­induced thrombotic thrombocytopenia (VITT). The biomedical literature database, MEDLINE/PubMed, was thoroughly searched using artificial intelligence techniques for the semantic relations among the top 50 similar words (>0.9) implicated in COVID­19­mediated human infection or VITT. Additionally, STRING, a database of primary and predicted associations among genes and proteins (collected from diverse resources, such as documented pathway knowledge, high­throughput experimental studies, cross­species extrapolated information, automated text mining results, computationally predicted interactions, etc.), was employed, with the confidence threshold set at 0.7. In addition, two interactomes were constructed: i) A network including 119 and 56 nodes relevant to COVID­19 and thrombocytopenia, respectively; and ii) a second network containing 60 nodes relevant to VITT. Although thrombocytopenia is a dominant morbidity in both entities, three nodes were observed that corresponded to genes (AURKA, CD46 and CD19) expressed only in VITT, whilst ADAM10, CDC20, SHC1 and STXBP2 are silenced in VITT, but are commonly expressed in both COVID­19 and thrombocytopenia. The calculated average node degree was immense (11.9 in COVID­19 and 6.43 in VITT), illustrating the complexity of COVID­19 and VITT pathologies and confirming the importance of cytokines, as well as of pathways activated following hypoxic events. In addition, PYCARD, NLP3 and P2RX7 are key potential therapeutic targets for all three morbid entities, meriting further research. This interactome was based on wild­type genes, revealing the predisposition of the body to hypoxia­induced thrombosis, leading to the acute COVID­19 phenotype, the 'long­COVID syndrome', and/or VITT. Thus, common nodes appear to be key players in illness prevention, progression and treatment.


Subject(s)
COVID-19 , Thrombocytopenia , Thrombosis , Vaccines , Artificial Intelligence , COVID-19/complications , COVID-19 Vaccines/adverse effects , Humans , SARS-CoV-2 , Thrombocytopenia/chemically induced , Thrombocytopenia/genetics , Thrombosis/genetics
2.
JCI Insight ; 7(2)2022 01 25.
Article in English | MEDLINE | ID: covidwho-1571524

ABSTRACT

Acute cardiac injury is prevalent in critical COVID-19 and associated with increased mortality. Its etiology remains debated, as initially presumed causes - myocarditis and cardiac necrosis - have proved uncommon. To elucidate the pathophysiology of COVID-19-associated cardiac injury, we conducted a prospective study of the first 69 consecutive COVID-19 decedents at CUIMC in New York City. Of 6 acute cardiac histopathologic features, presence of microthrombi was the most commonly detected among our cohort. We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak erythrocyte sedimentation rate and C-reactive protein were independently associated with increased odds of microthrombi, supporting an immunothrombotic etiology. Using single-nuclei RNA-sequencing analysis on 3 patients with and 4 patients without cardiac microthrombi, we discovered an enrichment of prothrombotic/antifibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling among cardiac fibroblasts in microthrombi-positive, relative to microthrombi-negative, COVID-19 hearts. Non-COVID-19, nonfailing hearts were used as reference controls. Our study identifies a specific transcriptomic signature in cardiac fibroblasts as a salient feature of microthrombi-positive COVID-19 hearts. Our findings warrant further mechanistic study as cardiac fibroblasts may represent a potential therapeutic target for COVID-19-associated cardiac microthrombi.


Subject(s)
COVID-19 , Heart Injuries , RNA-Seq , SARS-CoV-2/metabolism , Thrombosis , Adult , Aged , Aged, 80 and over , COVID-19/genetics , COVID-19/metabolism , COVID-19/pathology , Female , Heart Injuries/genetics , Heart Injuries/metabolism , Heart Injuries/pathology , Humans , Male , Middle Aged , Myocardium/metabolism , Myocardium/pathology , Prospective Studies , Thrombosis/genetics , Thrombosis/metabolism , Thrombosis/pathology
3.
FASEB J ; 35(12): e21969, 2021 12.
Article in English | MEDLINE | ID: covidwho-1532548

ABSTRACT

Several evidence suggests that, in addition to the respiratory tract, also the gastrointestinal tract is a main site of severe acute respiratory syndrome CoronaVirus 2 (SARS-CoV-2) infection, as an example of a multi-organ vascular damage, likely associated with poor prognosis. To assess mechanisms SARS-CoV-2 responsible of tissue infection and vascular injury, correlating with thrombotic damage, specimens of the digestive tract positive for SARS-CoV-2 nucleocapsid protein were analyzed deriving from three patients, negative to naso-oro-pharyngeal swab for SARS-CoV-2. These COVID-19-negative patients came to clinical observation due to urgent abdominal surgery that removed different sections of the digestive tract after thrombotic events. Immunohistochemical for the expression of SARS-CoV-2 combined with a panel of SARS-CoV-2 related proteins angiotensin-converting enzyme 2 receptor, cluster of differentiation 147 (CD147), human leukocyte antigen-G (HLA-G), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 was performed. Tissue samples were also evaluated by electron microscopy for ultrastructural virus localization and cell characterization. The damage of the tissue was assessed by ultrastructural analysis. It has been observed that CD147 expression levels correlate with SARS-CoV-2 infection extent, vascular damage and an increased expression of VEGF and thrombosis. The confirmation of CD147 co-localization with SARS-CoV-2 Spike protein binding on gastrointestinal tissues and the reduction of the infection level in intestinal epithelial cells after CD147 neutralization, suggest CD147 as a possible key factor for viral susceptibility of gastrointestinal tissue. The presence of SARS-CoV-2 infection of gastrointestinal tissue might be consequently implicated in abdominal thrombosis, where VEGF might mediate the vascular damage.


Subject(s)
Basigin/metabolism , COVID-19/complications , Digestive System Diseases/pathology , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , Vascular Endothelial Growth Factor A/metabolism , Aged , Basigin/genetics , COVID-19/virology , Digestive System Diseases/genetics , Digestive System Diseases/metabolism , Digestive System Diseases/virology , Female , Humans , Male , Middle Aged , Prognosis , Spike Glycoprotein, Coronavirus/genetics , Thrombosis/genetics , Thrombosis/metabolism , Thrombosis/virology , Vascular Endothelial Growth Factor A/genetics
4.
Front Immunol ; 12: 752612, 2021.
Article in English | MEDLINE | ID: covidwho-1456293

ABSTRACT

Background: Lymphopenia and the neutrophil/lymphocyte ratio may have prognostic value in COVID-19 severity. Objective: We investigated neutrophil subsets and functions in blood and bronchoalveolar lavage (BAL) of COVID-19 patients on the basis of patients' clinical characteristics. Methods: We used a multiparametric cytometry profiling based to mature and immature neutrophil markers in 146 critical or severe COVID-19 patients. Results: The Discovery study (38 patients, first pandemic wave) showed that 80% of Intensive Care Unit (ICU) patients develop strong myelemia with CD10-CD64+ immature neutrophils (ImNs). Cellular profiling revealed three distinct neutrophil subsets expressing either the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the interleukin-3 receptor alpha (CD123), or programmed death-ligand 1 (PD-L1) overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1- or CD123-expressing ImNs is positively correlated with clinical severity, cytokine storm (IL-1ß, IL-6, IL-8, TNFα), acute respiratory distress syndrome (ARDS), and thrombosis. BALs of patients with ARDS were highly enriched in LOX-1-expressing ImN subsets and in antimicrobial neutrophil factors. A validation study (118 patients, second pandemic wave) confirmed and strengthened the association of the proportion of ImN subsets with disease severity, invasive ventilation, and death. Only high proportions of LOX-1-expressing ImNs remained strongly associated with a high risk of severe thrombosis independently of the plasma antimicrobial neutrophil factors, suggesting an independent association of ImN markers with their functions. Conclusion: LOX-1-expressing ImNs may help identifying COVID-19 patients at high risk of severity and thrombosis complications.


Subject(s)
COVID-19/complications , Neutrophils/immunology , Scavenger Receptors, Class E/genetics , Thrombosis/etiology , Adult , Aged , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , Bronchoalveolar Lavage Fluid/immunology , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Critical Illness , Female , Humans , Interleukin-3 Receptor alpha Subunit/genetics , Interleukin-3 Receptor alpha Subunit/immunology , Interleukin-8/genetics , Interleukin-8/immunology , Male , Middle Aged , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/immunology , SARS-CoV-2/physiology , Scavenger Receptors, Class E/immunology , Thrombosis/genetics , Thrombosis/immunology
5.
PLoS One ; 16(9): e0256988, 2021.
Article in English | MEDLINE | ID: covidwho-1394552

ABSTRACT

Epidemiological studies suggest that individuals with comorbid conditions including diabetes, chronic lung, inflammatory and vascular disease, are at higher risk of adverse COVID-19 outcomes. Genome-wide association studies have identified several loci associated with increased susceptibility and severity for COVID-19. However, it is not clear whether these associations are genetically determined or not. We used a Phenome-Wide Association (PheWAS) approach to investigate the role of genetically determined COVID-19 susceptibility on disease related outcomes. PheWAS analyses were performed in order to identify traits and diseases related to COVID-19 susceptibility and severity, evaluated through a predictive COVID-19 risk score. We utilised phenotypic data in up to 400,000 individuals from the UK Biobank, including Hospital Episode Statistics and General Practice data. We identified a spectrum of associations between both genetically determined COVID-19 susceptibility and severity with a number of traits. COVID-19 risk was associated with increased risk for phlebitis and thrombophlebitis (OR = 1.11, p = 5.36e-08). We also identified significant signals between COVID-19 susceptibility with blood clots in the leg (OR = 1.1, p = 1.66e-16) and with increased risk for blood clots in the lung (OR = 1.12, p = 1.45 e-10). Our study identifies significant association of genetically determined COVID-19 with increased blood clot events in leg and lungs. The reported associations between both COVID-19 susceptibility and severity and other diseases adds to the identification and stratification of individuals at increased risk, adverse outcomes and long-term effects.


Subject(s)
COVID-19/genetics , Obesity/genetics , Thrombophlebitis/genetics , Thrombosis/genetics , COVID-19/epidemiology , COVID-19/virology , Cardiovascular Diseases/genetics , Cardiovascular Diseases/pathology , Cardiovascular Diseases/virology , Female , Genetic Predisposition to Disease , Humans , Male , Mendelian Randomization Analysis , Obesity/epidemiology , Obesity/virology , Phenomics , Phenotype , Polymorphism, Single Nucleotide/genetics , SARS-CoV-2/pathogenicity , Thrombophlebitis/epidemiology , Thrombophlebitis/virology , Thrombosis/epidemiology , Thrombosis/virology
6.
J Hematol Oncol ; 14(1): 123, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1365373

ABSTRACT

Thromboembolism is a frequent cause of severity and mortality in COVID-19. However, the etiology of this phenomenon is not well understood. A cohort of 1186 subjects, from the GEN-COVID consortium, infected by SARS-CoV-2 with different severity was stratified by sex and adjusted by age. Then, common coding variants from whole exome sequencing were mined by LASSO logistic regression. The homozygosity of the cell adhesion molecule P-selectin gene (SELP) rs6127 (c.1807G > A; p.Asp603Asn) which has been already associated with thrombotic risk is found to be associated with severity in the male subcohort of 513 subjects (odds ratio = 2.27, 95% Confidence Interval 1.54-3.36). As the SELP gene is downregulated by testosterone, the odd ratio is increased in males older than 50 (OR 2.42, 95% CI 1.53-3.82). Asn/Asn homozygotes have increased D-dimers values especially when associated with poly Q ≥ 23 in the androgen receptor (OR 3.26, 95% CI 1.41-7.52). These results provide a rationale for the repurposing of antibodies against P-selectin as adjuvant therapy in rs6127 male homozygotes especially if older than 50 or with an impaired androgen receptor.


Subject(s)
COVID-19/genetics , P-Selectin/genetics , Thrombosis/genetics , COVID-19/complications , Down-Regulation , Female , Humans , Male , Middle Aged , Point Mutation , SARS-CoV-2/isolation & purification , Thrombosis/etiology
7.
Front Immunol ; 12: 700184, 2021.
Article in English | MEDLINE | ID: covidwho-1365542

ABSTRACT

Coronavirus disease 2019 (COVID-19), which has high incidence rates with rapid rate of transmission, is a pandemic that spread across the world, resulting in more than 3,000,000 deaths globally. Currently, several drugs have been used for the clinical treatment of COVID-19, such as antivirals (radecivir, baritinib), monoclonal antibodies (tocilizumab), and glucocorticoids (dexamethasone). Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are essential regulators of virus infections and antiviral immune responses including biological processes that are involved in the regulation of COVID-19 and subsequent disease states. Upon viral infections, cellular lncRNAs directly regulate viral genes and influence viral replication and pathology through virus-mediated changes in the host transcriptome. Additionally, several host lncRNAs could help the occurrence of viral immune escape by inhibiting type I interferons (IFN-1), while others could up-regulate IFN-1 production to play an antiviral role. Consequently, understanding the expression and function of lncRNAs during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection will provide insights into the development of lncRNA-based methods. In this review, we summarized the current findings of lncRNAs in the regulation of the strong inflammatory response, immune dysfunction and thrombosis induced by SARS-CoV-2 infection, discussed the underlying mechanisms, and highlighted the therapeutic challenges of COVID-19 treatment and its future research directions.


Subject(s)
COVID-19/immunology , Host Microbial Interactions/genetics , Immunity, Innate/genetics , RNA, Long Noncoding/metabolism , Thrombosis/immunology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Biomarkers/analysis , COVID-19/complications , COVID-19/drug therapy , COVID-19/genetics , COVID-19 Testing/methods , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation, Viral/drug effects , Gene Expression Regulation, Viral/immunology , Host Microbial Interactions/drug effects , Host Microbial Interactions/immunology , Humans , Immune Evasion/genetics , Pandemics/prevention & control , RNA, Long Noncoding/analysis , RNA, Long Noncoding/antagonists & inhibitors , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/genetics , Signal Transduction/immunology , Thrombosis/genetics , Thrombosis/virology , Virus Replication/drug effects , Virus Replication/genetics , Virus Replication/immunology
8.
J Hematol Oncol ; 14(1): 123, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1357037

ABSTRACT

Thromboembolism is a frequent cause of severity and mortality in COVID-19. However, the etiology of this phenomenon is not well understood. A cohort of 1186 subjects, from the GEN-COVID consortium, infected by SARS-CoV-2 with different severity was stratified by sex and adjusted by age. Then, common coding variants from whole exome sequencing were mined by LASSO logistic regression. The homozygosity of the cell adhesion molecule P-selectin gene (SELP) rs6127 (c.1807G > A; p.Asp603Asn) which has been already associated with thrombotic risk is found to be associated with severity in the male subcohort of 513 subjects (odds ratio = 2.27, 95% Confidence Interval 1.54-3.36). As the SELP gene is downregulated by testosterone, the odd ratio is increased in males older than 50 (OR 2.42, 95% CI 1.53-3.82). Asn/Asn homozygotes have increased D-dimers values especially when associated with poly Q ≥ 23 in the androgen receptor (OR 3.26, 95% CI 1.41-7.52). These results provide a rationale for the repurposing of antibodies against P-selectin as adjuvant therapy in rs6127 male homozygotes especially if older than 50 or with an impaired androgen receptor.


Subject(s)
COVID-19/genetics , P-Selectin/genetics , Thrombosis/genetics , COVID-19/complications , Down-Regulation , Female , Humans , Male , Middle Aged , Point Mutation , SARS-CoV-2/isolation & purification , Thrombosis/etiology
9.
Cytokine ; 146: 155634, 2021 10.
Article in English | MEDLINE | ID: covidwho-1293703

ABSTRACT

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


Subject(s)
COVID-19/therapy , Gene Silencing , Inflammation/genetics , Thrombocytosis/genetics , Thrombopoietin/genetics , Thrombosis/genetics , COVID-19/complications , COVID-19/virology , Humans , Inflammation/complications , Inflammation/metabolism , Megakaryocytes/metabolism , SARS-CoV-2/physiology , Thrombocytosis/complications , Thrombocytosis/metabolism , Thrombopoiesis/genetics , Thrombopoietin/metabolism , Thrombosis/complications , Thrombosis/metabolism
10.
Nucleosides Nucleotides Nucleic Acids ; 40(5): 505-517, 2021.
Article in English | MEDLINE | ID: covidwho-1132307

ABSTRACT

COVID-19 has become a major public health problem since December, 2019 and no highly effective drug has been found until now. Numbers of infected people and deaths by COVID-19 are increasing every day worldwide, therefore self-isolation and protection are highly recommended to prevent the spread of the virus and especially to protect major risk groups such as the elderly population and people with comorbidities including diabetes, hypertension, cancer, cardiovascular diseases and metabolic syndrome. On the other hand, young people without any secondary disease have died by COVID-19 as well. In this study we compared two male patients infected by COVID-19 at the same age and one of them was diagnosed with G6PD deficiency. Both COVID-19 and G6PD deficiency enhance the risk of hemolysis and thrombosis. Serum biochemistry, hemogram and immunological parameters showed that risk of hemolysis and thrombosis may increase in the G6PD deficient patient infected by COVID-19.


Subject(s)
COVID-19/genetics , Glucosephosphate Dehydrogenase Deficiency/genetics , Glucosephosphate Dehydrogenase/genetics , Thrombosis/genetics , Adult , COVID-19/blood , COVID-19/complications , COVID-19/virology , Glucosephosphate Dehydrogenase Deficiency/blood , Glucosephosphate Dehydrogenase Deficiency/complications , Glucosephosphate Dehydrogenase Deficiency/pathology , Hemolysis/physiology , Humans , Male , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Thrombosis/blood , Thrombosis/etiology , Thrombosis/virology
11.
PLoS Comput Biol ; 17(3): e1008810, 2021 03.
Article in English | MEDLINE | ID: covidwho-1121603

ABSTRACT

Abnormal coagulation and an increased risk of thrombosis are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis (HLH), a life-threating condition associated with hyperinflammation. The presence of HLH was described in severely ill patients during the H1N1 influenza epidemic, presenting with pulmonary vascular thrombosis. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism to the presence of SARS-CoV-2 using novel network-informed computational algorithms. This approach led to the identification of Neutrophils Extracellular Traps (NETs) as plausible mediators of vascular thrombosis in severe COVID-19 in children and adults. Taken together, the network-informed analysis led us to propose the following model: the release of NETs in response to inflammatory signals acting in concert with SARS-CoV-2 damage the endothelium and direct platelet-activation promoting abnormal coagulation leading to serious complications of COVID-19. The underlying hypothesis is that genetic and/or environmental conditions that favor the release of NETs may predispose individuals to thrombotic complications of COVID-19 due to an increase risk of abnormal coagulation. This would be a common pathogenic mechanism in conditions including autoimmune/infectious diseases, hematologic and metabolic disorders.


Subject(s)
COVID-19/complications , COVID-19/genetics , Extracellular Traps/genetics , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/genetics , Models, Biological , SARS-CoV-2/genetics , Thrombosis/etiology , Thrombosis/genetics , Algorithms , Cell Degranulation/genetics , Computational Biology , Gene Expression Regulation , Gene Regulatory Networks , Genetic Predisposition to Disease , Humans , Pandemics , Protein Interaction Maps , Pulmonary Embolism/etiology , Pulmonary Embolism/genetics , Viral Proteins/genetics
12.
Cell Commun Signal ; 18(1): 190, 2020 12 27.
Article in English | MEDLINE | ID: covidwho-992498

ABSTRACT

The rapid ability of SARS-CoV-2 to spread among humans, along with the clinical complications of coronavirus disease 2019-COVID-19, have represented a significant challenge to the health management systems worldwide. The acute inflammation and coagulation abnormalities appear as the main causes for thousands of deaths worldwide. The intense inflammatory response could be involved with the formation of thrombi. For instance, the presence of uncleaved large multimers of von Willebrand (vWF), due to low ADAMTS13 activity in plasma could be explained by the inhibitory action of pro-inflammatory molecules such as IL-1ß and C reactive protein. In addition, the damage to endothelial cells after viral infection and/or activation of endothelium by pro-inflammatory cytokines, such as IL-1ß, IL-6, IFN-γ, IL-8, and TNF-α induces platelets and monocyte aggregation in the vascular wall and expression of tissue factor (TF). The TF expression may culminate in the formation of thrombi, and activation of cascade by the extrinsic pathway by association with factor VII. In this scenario, the phosphatidylserine-PtdSer exposure on the outer leaflet of the cell membrane as consequence of viral infection emerges as another possible underlying mechanism to acute immune inflammatory response and activation of coagulation cascade. The PtdSer exposure may be an important mechanism related to ADAM17-mediated ACE2, TNF-α, EGFR and IL-6R shedding, and the activation of TF on the surface of infected endothelial cells. In this review, we address the underlying mechanisms involved in the pathophysiology of inflammation and coagulation abnormalities. Moreover, we introduce key biochemical and pathophysiological concepts that support the possible participation of PtdSer exposure on the outer side of the SARS-CoV-2 infected cells membrane, in the pathophysiology of COVID-19. Video Abstract.


Subject(s)
COVID-19/genetics , Inflammation/genetics , Phosphatidylserines/genetics , Thrombosis/genetics , ADAM17 Protein/genetics , ADAMTS13 Protein/genetics , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Endothelial Cells/virology , Humans , Inflammation/complications , Inflammation/virology , Phosphatidylserines/metabolism , Receptors, Interleukin-6/genetics , SARS-CoV-2/pathogenicity , Thrombosis/pathology , Thrombosis/virology , von Willebrand Factor/genetics
13.
Prostaglandins Leukot Essent Fatty Acids ; 162: 102183, 2020 11.
Article in English | MEDLINE | ID: covidwho-808662

ABSTRACT

COVID-19 symptoms vary from silence to rapid death, the latter mediated by both a cytokine storm and a thrombotic storm. SARS-CoV (2003) induces Cox-2, catalyzing the synthesis, from highly unsaturated fatty acids (HUFA), of eicosanoids and docosanoids that mediate both inflammation and thrombosis. HUFA balance between arachidonic acid (AA) and other HUFA is a likely determinant of net signaling to induce a healthy or runaway physiological response. AA levels are determined by a non-protein coding regulatory polymorphisms that mostly affect the expression of FADS1, located in the FADS gene cluster on chromosome 11. Major and minor haplotypes in Europeans, and a specific functional insertion-deletion (Indel), rs66698963, consistently show major differences in circulating AA (>50%) and in the balance between AA and other HUFA (47-84%) in free living humans; the indel is evolutionarily selective, probably based on diet. The pattern of fatty acid responses is fully consistent with specific genetic modulation of desaturation at the FADS1-mediated 20:3→20:4 step. Well established principles of net tissue HUFA levels indicate that the high linoleic acid and low alpha-linoleic acid in populations drive the net balance of HUFA for any individual. We predict that fast desaturators (insertion allele at rs66698963; major haplotype in Europeans) are predisposed to higher risk and pathological responses to SARS-CoV-2 could be reduced with high dose omega-3 HUFA.


Subject(s)
Coronavirus Infections/complications , Fatty Acids, Unsaturated/biosynthesis , Inflammation/etiology , Lipid Metabolism/genetics , Pneumonia, Viral/complications , Thrombosis/etiology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , Fatty Acids, Unsaturated/genetics , Genetic Predisposition to Disease , Haplotypes , Humans , Individuality , Inflammation/epidemiology , Inflammation/genetics , Inflammation/metabolism , Lipogenesis/genetics , Metabolic Networks and Pathways/genetics , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Pneumonia, Viral/metabolism , Polymorphism, Single Nucleotide , Risk Factors , SARS-CoV-2 , Thrombosis/epidemiology , Thrombosis/genetics , Thrombosis/metabolism
14.
Med Hypotheses ; 144: 110218, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-728777

ABSTRACT

Covid-19, caused by SARS-CoV-2, has major world-wide health-related and socio-economic consequences. There are large disparities in the burden of Covid-19 with an apparent lower risk of poor outcomes in East Asians compared to populations in the West. A recent study suggested that Covid-19 leads to a severe extrahepatic vitamin K insufficiency, which could lead to impaired activation of extrahepatic proteins like endothelial anticoagulant protein S in the presence of normal hepatic procoagulant activity. This would be compatible with the enhanced thrombogenicity in severe Covid-19. The same study showed that vitamin K antagonists (VKA) that inhibit vitamin K recycling, had a greater impact on procoagulant activity than on the activation of extrahepatic vitamin K-dependent proteins during SARS-CoV-2 infections. A genetic polymorphism in the vitamin K epoxide reductase complex 1, VKORC1 -1639A, is particularly prevalent in East Asia and associates with low vitamin K recycling rates. Carriage of the allele may be regarded as bioequivalent to low-dose VKA use. We speculate that VKORC1 -1639A confers protection against thrombotic complications of Covid-19 and that differences in its allele frequency are partially responsible for the differences in Covid-19 severity between East and West.


Subject(s)
COVID-19/genetics , Vitamin K Epoxide Reductases/genetics , Americas/epidemiology , COVID-19/complications , COVID-19/enzymology , Europe/epidemiology , Far East/epidemiology , Gene Frequency , Humans , Models, Biological , Pandemics , Polymorphism, Single Nucleotide , SARS-CoV-2 , Severity of Illness Index , Thrombosis/etiology , Thrombosis/genetics , Thrombosis/prevention & control , Vitamin K/antagonists & inhibitors , Vitamin K Deficiency/etiology
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