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1.
Int J Mol Sci ; 23(7)2022 Mar 31.
Article in English | MEDLINE | ID: covidwho-1776246

ABSTRACT

There is accumulating evidence that platelets play roles beyond their traditional functions in thrombosis and hemostasis, e.g., in inflammatory processes, infection and cancer, and that they interact, stimulate and regulate cells of the innate immune system such as neutrophils, monocytes and macrophages. In this review, we will focus on platelet activation in hemostatic and inflammatory processes, as well as platelet interactions with neutrophils and monocytes/macrophages. We take a closer look at the contributions of major platelet receptors GPIb, αIIbß3, TLT-1, CLEC-2 and Toll-like receptors (TLRs) as well as secretions from platelet granules on platelet-neutrophil aggregate and neutrophil extracellular trap (NET) formation in atherosclerosis, transfusion-related acute lung injury (TRALI) and COVID-19. Further, we will address platelet-monocyte and macrophage interactions during cancer metastasis, infection, sepsis and platelet clearance.


Subject(s)
COVID-19 , Thrombosis , Blood Platelets/pathology , Hemostasis , Humans , Immunity, Innate , Inflammation/pathology , Neutrophils/pathology , Platelet Activation , Thrombosis/pathology
2.
Br J Haematol ; 196(4): 902-922, 2022 02.
Article in English | MEDLINE | ID: covidwho-1566272

ABSTRACT

In 145 previously healthy non-critically ill young adults, coronavirus disease 2019 (COVID-19)-related symptoms, risk factors for thrombosis, coagulation and inflammatory parameters were compared, with 29 patients reporting unusual thrombotic events (UTEs) and 116 not having thrombotic events. The inflammatory indices, coagulation and prothrombotic platelet phenotype (PTPP) were significantly higher in patients with UTEs versus those without. Patients with UTEs were categorised according to detection of thrombophilic genes (TGs), coagulation and inflammatory markers to the non-TG and TG subcohort. A total of 38 UTEs were identified, which included splanchnic vein thrombosis (SVT; 11), stroke (six), cerebral vein thrombosis (five), thrombotic microangiopathy (four), limb ischaemia and inferior vena cava thrombosis (three each), ST-segment elevation myocardial infarction (two), superior vena cava thrombosis (two), upper limb deep venous thrombosis and retinal vein thrombosis, one each. We found a 55% prevalence of TGs mainly heterozygous coagulation factor II, thrombin (FII)-G20210A, Janus kinase 2 (JAK2)-V617F, protein-S, and antithrombin III deficiency with a high (76·9%) prevalence of venous UTEs, multiple vessels thrombosis, and recurrence rate among the TG versus non-TG subcohort. The presence of JAK2-V617F, and FII-G20210A mutations was linked with SVT. Thrombosis in the non-TG subcohort was associated with more haemorrhagic problems, thrombosis progression and a significantly higher level of inflammatory markers, PTPP, mean platelet volume, von Willebrand factor, and factor VIII, which remained high for up to 6 months, as well as elevated D-dimer. Acquired and inherited thrombophilia with endotheliopathy appeared to be a relevant mechanism to explain the occurrence of UTEs that are not correlated to COVID-19 severity.


Subject(s)
COVID-19/complications , Thrombophilia/diagnosis , Thrombosis/diagnosis , Blood Platelets/pathology , COVID-19/diagnosis , Factor VIII/analysis , Female , Humans , Longitudinal Studies , Male , Prospective Studies , Thrombophilia/etiology , Thrombosis/etiology , Thrombotic Microangiopathies/diagnosis , Thrombotic Microangiopathies/etiology , Young Adult , von Willebrand Factor/analysis
3.
Dis Markers ; 2021: 6304189, 2021.
Article in English | MEDLINE | ID: covidwho-1553755

ABSTRACT

Background: Early identification of patients with severe coronavirus disease (COVID-19) at an increased risk of progression may promote more individualized treatment schemes and optimize the use of medical resources. This study is aimed at investigating the utility of the C-reactive protein to albumin (CRP/Alb) ratio for early risk stratification of patients. Methods: We retrospectively reviewed 557 patients with COVID-19 with confirmed outcomes (discharged or deceased) admitted to the West Court of Union Hospital, Wuhan, China, between January 29, 2020 and April 8, 2020. Patients with severe COVID-19 (n = 465) were divided into stable (n = 409) and progressive (n = 56) groups according to whether they progressed to critical illness or death during hospitalization. To predict disease progression, the CRP/Alb ratio was evaluated on admission. Results: The levels of new biomarkers, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, CRP/Alb ratio, and systemic immune-inflammation index, were higher in patients with progressive disease than in those with stable disease. Correlation analysis showed that the CRP/Alb ratio had the strongest positive correlation with the sequential organ failure assessment score and length of hospital stay in survivors. Multivariate logistic regression analysis showed that percutaneous oxygen saturation (SpO2), D-dimer levels, and the CRP/Alb ratio were risk factors for disease progression. To predict clinical progression, the areas under the receiver operating characteristic curves of Alb, CRP, CRP/Alb ratio, SpO2, and D-dimer were 0.769, 0.838, 0.866, 0.107, and 0.748, respectively. Moreover, patients with a high CRP/Alb ratio (≥1.843) had a markedly higher rate of clinical deterioration (log - rank p < 0.001). A higher CRP/Alb ratio (≥1.843) was also closely associated with higher rates of hospital mortality, ICU admission, invasive mechanical ventilation, and a longer hospital stay. Conclusion: The CRP/Alb ratio can predict the risk of progression to critical disease or death early, providing a promising prognostic biomarker for risk stratification and clinical management of patients with severe COVID-19.


Subject(s)
C-Reactive Protein/metabolism , COVID-19/diagnosis , Coronary Disease/diagnosis , Hypertension/diagnosis , Pulmonary Disease, Chronic Obstructive/diagnosis , SARS-CoV-2/pathogenicity , Serum Albumin, Human/metabolism , Aged , Area Under Curve , Biomarkers/blood , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/epidemiology , COVID-19/mortality , COVID-19/virology , China/epidemiology , Comorbidity , Coronary Disease/epidemiology , Coronary Disease/mortality , Coronary Disease/virology , Disease Progression , Early Diagnosis , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Hypertension/epidemiology , Hypertension/mortality , Hypertension/virology , Length of Stay/statistics & numerical data , Lymphocytes/pathology , Lymphocytes/virology , Male , Middle Aged , Neutrophils/pathology , Neutrophils/virology , Prognosis , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/mortality , Pulmonary Disease, Chronic Obstructive/virology , ROC Curve , Retrospective Studies , SARS-CoV-2/growth & development , Severity of Illness Index , Survival Analysis
4.
Platelets ; 33(1): 48-53, 2022 Jan 02.
Article in English | MEDLINE | ID: covidwho-1541393

ABSTRACT

Coagulopathy is an evident complication of COVID-19 with predominance of a prothrombotic state. Platelet activation plays a key role. The terms "hyper-reactivity" and "hyperactivity" used in recent literature may not be clear or sufficient to explain the pathological events involved in COVID-related thrombosis (CRT). Inflammation may play a bigger role compared to thrombosis in COVID-related mortality because a smaller percentage of patients with COVID-19 die due to direct effects of thrombosis. Not all COVID-19 patients have thrombocytopenia and a few show thrombocytosis. We believe the platelet pathology is more complex than just activation or hyper-activation, particularly due to the platelets' role in inflammation. Understanding the pathology and consequences of platelets' role may help optimize management strategies and diminish CRT-associated morbidity and mortality. In this viewpoint report, we examine the published evidence of platelet hyper-reactivity in COVID-19 with a focused analysis of the key pathologies, diverse alterations, disease outcomes, and therapeutic targets. We believe that COVID-19 is a disease of inflammation and pathologic platelets, and based on the complexity and diverse pathologies, we propose the term "thrombocytopathy" as a more reflective term of the platelets' involvement in COVID-19. In our opinion, thrombocytopathy is the unpredictable pathologic alterations of platelets in function, morphology and number, caused by different factors with a variety of presentations.


Subject(s)
Blood Platelets/pathology , COVID-19/complications , Cytokine Release Syndrome/complications , Disseminated Intravascular Coagulation/complications , Pulmonary Embolism/complications , SARS-CoV-2/pathogenicity , Abciximab/therapeutic use , Acute Disease , Anticoagulants/therapeutic use , Aspirin/therapeutic use , Blood Platelets/drug effects , Blood Platelets/virology , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/virology , Clopidogrel/therapeutic use , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/drug therapy , Disseminated Intravascular Coagulation/virology , Fibrinolytic Agents/therapeutic use , Humans , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Platelet Activation/drug effects , Pulmonary Embolism/diagnosis , Pulmonary Embolism/drug therapy , Pulmonary Embolism/virology , Treatment Outcome
6.
Med Oncol ; 39(1): 6, 2021 Nov 08.
Article in English | MEDLINE | ID: covidwho-1506526

ABSTRACT

To assess the prognostic role of different inflammatory indices on the outcome of cancer patients with COVID-19. Sixty-two adults and 22 pediatric cancer patients with COVID-19 infection were assessed for the prognostic value of certain inflammatory indices including the neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), derived NLR (dNLR), systemic inflammation index (SII), mean platelet volume to platelet ratio (MPR), C-reactive protein to lymphocyte ratio (CRP/L), aggregate index of systemic inflammation (AISI), systemic inflammation response index (SIRI), and neutrophil to lymphocyte, platelet ratio (NLPR). Data were correlated to patients' outcome regarding ICU admission, and incidence of mortality. Increased CRP/L ratio in adult COVID-19 cancer patients was significantly associated with inferior survival [152 (19-2253) in non-survivors, compared to 27.4 (0.8-681) in survivors (P = 0.033)]. It achieved a sensitivity (60%) and a specificity (90.2%) at a cut-off 152, while it achieved a sensitivity of 60% and specificity 95.1% at a cut-off 252 (AUC 0.795, P = 0.033). When combining both CRP/L and NLPR for the prediction of poor outcome in adult cancer patients with COVID19, the sensitivity increased to 80% and the specificity was 70.7% (AUC 0.805, P = 0.027). Increased incidence of ICU admission in pediatric cancer patients associated significantly with the severity of covid19 infection, decreased mean corpuscular hemoglobin (MCH) < 28.3, increased red cell distribution width (RDW) > 16, lymphopenia < 1.04, pseudo Pelger-Huet appearance, and PLR < 196.4 (P = 0.004, P = 0.040, P = 0.029, P = 0. 0.039, P = 0.050, and P = 0.040; respectively). The mean corpuscular volume (MCV), MCH, and RDW could be useful prognostic markers for poor outcome in COVID-19 pediatric cancer patients (P < 0.05 for all). Increased both CRP/L and NLPR associated significantly with poor survival in adult COVID-19 cancer patients, while PLR associated significantly with ICU admission in pediatric COVID-19 cancer patients.


Subject(s)
COVID-19/pathology , Inflammation/pathology , Neoplasms/pathology , Adolescent , Adult , Aged , Blood Platelets/pathology , Child , Child, Preschool , Female , Humans , Inflammation/virology , Leukocyte Count/methods , Lymphocytes/pathology , Male , Middle Aged , Neoplasms/virology , Neutrophils/pathology , Prognosis , Retrospective Studies , SARS-CoV-2/pathogenicity , Sensitivity and Specificity , Young Adult
7.
Am J Pathol ; 192(1): 112-120, 2022 01.
Article in English | MEDLINE | ID: covidwho-1506166

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) increases the risk of myocardial injury that contributes to mortality. This study used multiparameter immunofluorescence to extensively examine heart autopsy tissue of 7 patients who died of COVID-19 compared to 12 control specimens, with or without cardiovascular disease. Consistent with prior reports, no evidence of viral infection or lymphocytic infiltration indicative of myocarditis was found. However, frequent and extensive thrombosis was observed in large and small vessels in the hearts of the COVID-19 cohort, findings that were infrequent in controls. The endothelial lining of thrombosed vessels typically lacked evidence of cytokine-mediated endothelial activation, assessed as nuclear expression of transcription factors p65 (RelA), pSTAT1, or pSTAT3, or evidence of inflammatory activation assessed by expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tissue factor, or von Willebrand factor (VWF). Intimal EC lining was also generally preserved with little evidence of cell death or desquamation. In contrast, there were frequent markers of neutrophil activation within myocardial thrombi in patients with COVID-19, including neutrophil-platelet aggregates, neutrophil-rich clusters within macrothrombi, and evidence of neutrophil extracellular trap (NET) formation. These findings point to alterations in circulating neutrophils rather than in the endothelium as contributors to the increased thrombotic diathesis in the hearts of COVID-19 patients.


Subject(s)
COVID-19 , Coronary Vessels , Myocarditis , Myocardium , SARS-CoV-2/metabolism , Thrombosis , Aged , Aged, 80 and over , Blood Platelets/metabolism , Blood Platelets/pathology , COVID-19/metabolism , COVID-19/pathology , Coronary Vessels/metabolism , Coronary Vessels/pathology , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Female , Gene Expression Regulation , Humans , Male , Middle Aged , Myocarditis/metabolism , Myocarditis/pathology , Myocardium/metabolism , Myocardium/pathology , Neutrophil Activation , Neutrophils/metabolism , Neutrophils/pathology , Platelet Aggregation , Thrombosis/metabolism , Thrombosis/pathology
8.
Blood ; 138(16): 1481-1489, 2021 10 21.
Article in English | MEDLINE | ID: covidwho-1484294

ABSTRACT

A subset of patients with coronavirus disease 2019 (COVID-19) become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in severely ill patients with COVID-19 are still emerging, but the coincidence of critical illness with the timing of the onset of adaptive immunity could implicate an excessive immune response. We hypothesized that platelets might be susceptible to activation by anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies and might contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike immunoglobulin G enhanced platelet-mediated thrombosis on von Willebrand factor in vitro, but only when the glycosylation state of the Fc domain was modified to correspond with the aberrant glycosylation previously identified in patients with severe COVID-19. Furthermore, we found that activation was dependent on FcγRIIA, and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by the therapeutic small molecules R406 (fostamatinib) and ibrutinib, which inhibit tyrosine kinases Syk and Btk, respectively, or by the P2Y12 antagonist cangrelor.


Subject(s)
Blood Platelets/pathology , COVID-19/complications , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , von Willebrand Factor/metabolism , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antigen-Antibody Complex/immunology , Blood Platelets/immunology , Blood Platelets/metabolism , COVID-19/immunology , COVID-19/virology , Glycosylation , Humans , Platelet Activation/immunology , Thrombosis/immunology , Thrombosis/virology , von Willebrand Factor/genetics
9.
Int J Lab Hematol ; 43(6): 1319-1324, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1416363

ABSTRACT

INTRODUCTION: Health professions are heavily engaged facing the current threat of SARS-CoV-2 (COVID-19). Although there are many diagnostic tools, an accurate and rapid laboratory procedure for diagnosing COVID-19 is recommended. We focused on platelet parameters as the additional biomarkers for clinical diagnosis in patients presenting to the emergency department (ED). MATERIALS AND METHODS: Five hundred and sixty-one patients from February to April 2020 have been recruited. Patients were divided into three groups: (N = 50) COVID-19 positive and (N = 21) COVID-19 negative with molecular testing, (N = 490) as reference population without molecular testing. A Multiplex rRT-PCR from samples collected by nasopharyngeal swabs was performed and the hematological data collected. RESULTS: We detected a mild anemia in COVID-19 group and lymphopenia against reference population: hemoglobin (g/dL) 13.0 (11.5-14.8) versus 13.9 (12.8-15.0) (P = .0135); lymphocytes (109 /L) 1.24 (0.94-1.73) versus 1.99 (1.49-2.64) (P < .0001). In addition, abnormal platelet parameters as follows (COVID group vs reference population): PLT (×109 /L) 209 (160-258) vs 236 (193-279) (P = .0239). IPF (%) 4.05 (2.5-5.9) versus 3.4 (2.2-4.9) (P = .0576); H-IPF (%) 1.25 (0.8-2.2) versus 0.95 (0.6-1.5) (P = .0171) were identified. In particular, COVID positive group had a high H-IPF/IPF Ratio compared to reference population [0.32 (0.29-0.36) versus 0.29 (0.26-0.32), respectively, (P = .0003)]. Finally, a PLT difference of nearly 50 × 109 /L between pre/postCOVID-19 sampling for each patient was found (N = 42) (P = .0194). CONCLUSIONS: COVID-19 group results highlighted higher IPF and H-IPF values, with increased H-IPF/IPF Ratio, associated to PLT count reduction. These findings shall be adopted for a timely diagnosis of patients upon hospital admission.


Subject(s)
COVID-19 Testing/methods , COVID-19/blood , Pandemics , Platelet Count , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Anemia/etiology , Blood Cell Count , Blood Platelets/pathology , COVID-19/diagnosis , Cell Differentiation , Cell Size , Disease Progression , Emergency Service, Hospital , Female , Hemoglobins/analysis , Humans , Italy/epidemiology , Male , Mean Platelet Volume , Middle Aged , Multiplex Polymerase Chain Reaction , Nasopharynx/virology , Pilot Projects , Retrospective Studies , SARS-CoV-2/isolation & purification
10.
Front Immunol ; 12: 728513, 2021.
Article in English | MEDLINE | ID: covidwho-1394762

ABSTRACT

VITT is a rare, life-threatening syndrome characterized by thrombotic symptoms in combination with thrombocytopenia, which may occur in individuals receiving the first administration of adenoviral non replicating vectors (AVV) anti Covid19 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterized by high levels of serum IgG that bind PF4/polyanion complexes, thus triggering platelet activation. Therefore, identification of the fine pathophysiological mechanism by which vaccine components trigger platelet activation is mandatory. Herein, we propose a multistep mechanism involving both the AVV and the neo-synthetized Spike protein. The former can: i) spread rapidly into blood stream, ii), promote the early production of high levels of IL-6, iii) interact with erythrocytes, platelets, mast cells and endothelia, iv) favor the presence of extracellular DNA at the site of injection, v) activate platelets and mast cells to release PF4 and heparin. Moreover, AVV infection of mast cells may trigger aberrant inflammatory and immune responses in people affected by the mast cell activation syndrome (MCAS). The pre-existence of natural antibodies binding PF4/heparin complexes may amplify platelet activation and thrombotic events. Finally, neosynthesized Covid 19 Spike protein interacting with its ACE2 receptor on endothelia, platelets and leucocyte may trigger further thrombotic events unleashing the WITT syndrome.


Subject(s)
Antibodies/adverse effects , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/physiopathology , Adenoviridae/genetics , Animals , Blood Platelets/immunology , Blood Platelets/pathology , COVID-19 Vaccines/immunology , Disease Models, Animal , Genetic Vectors , Humans , Mice , Platelet Activation/immunology , Platelet Factor 4 , Rabbits
11.
J Med Virol ; 93(9): 5425-5431, 2021 09.
Article in English | MEDLINE | ID: covidwho-1363680

ABSTRACT

A rapid outbreak of novel coronavirus, coronavirus disease-2019 (COVID-19), has made it a global pandemic. This study focused on the possible association between lymphopenia and computed tomography (CT) scan features and COVID-19 patient mortality. The clinical data of 596 COVID-19 patients were collected from February 2020 to September 2020. The patients' serological survey and CT scan features were retrospectively explored. The median age of the patients was 56.7 ± 16.4 years old. Lung involvement was more than 50% in 214 COVID-19 patients (35.9%). The average blood lymphocyte percentage was 20.35 ± 10.16 (normal range, 20%-50%). Although the levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were high in more than 80% of COVID-19 patients; CRP, ESR, and platelet-to-lymphocyte ratio (PLR) may not indicate the in-hospital mortality of COVID-19. Patients with severe lung involvement and lymphopenia were found to be significantly associated with increased odds of death (odds ratio, 9.24; 95% confidence interval, 4.32-19.78). These results indicated that lymphopenia < 20% along with pulmonary involvement >50% impose a multiplicative effect on the risk of mortality. The in-hospital mortality rate of this group was significantly higher than other COVID-19 hospitalized cases. Furthermore, they meaningfully experienced a prolonged stay in the hospital (p = .00). Lymphocyte count less than 20% and chest CT scan findings with more than 50% involvement might be related to the patient's mortality. These could act as laboratory and clinical indicators of disease severity, mortality, and outcome.


Subject(s)
COVID-19/complications , Lung/pathology , Lymphopenia/complications , Pneumonia/complications , SARS-CoV-2/pathogenicity , Adult , Aged , Biomarkers/blood , Blood Platelets/pathology , Blood Platelets/virology , Blood Sedimentation , C-Reactive Protein , COVID-19/diagnostic imaging , COVID-19/mortality , COVID-19/virology , Female , Hospital Mortality , Humans , Iran , Lung/virology , Lymphocytes/pathology , Lymphocytes/virology , Lymphopenia/diagnostic imaging , Lymphopenia/mortality , Lymphopenia/virology , Male , Middle Aged , Pneumonia/diagnostic imaging , Pneumonia/mortality , Pneumonia/virology , Retrospective Studies , Severity of Illness Index , Survival Analysis , Tomography, X-Ray Computed
12.
J Med Virol ; 93(9): 5390-5395, 2021 09.
Article in English | MEDLINE | ID: covidwho-1363677

ABSTRACT

Hypercoagulability and thrombosis caused by coronavirus disease 2019 (COVID-19) are related to the higher mortality rate. Because of limited data on the antiplatelet effect, we aimed to evaluate the impact of aspirin add-on therapy on the outcome of the patients hospitalized due to severe COVID-19. In this cohort study, patients with a confirmed diagnosis of severe COVID-19 admitted to Imam Hossein Medical Center, Tehran, Iran from March 2019 to July 2020 were included. Demographics and related clinical data during their hospitalization were recorded. The mortality rate of the patients was considered as the primary outcome and its association with aspirin use was assessed. Nine hundred and ninety-one patients were included, of that 336 patients (34%) received aspirin during their hospitalization and 655 ones (66%) did not. Comorbidities were more prevalent in the patients who were receiving aspirin. Results from the multivariate COX proportional model demonstrated a significant independent association between aspirin use and reduction in the risk of in-hospital mortality (0.746 [0.560-0.994], p = 0.046). Aspirin use in hospitalized patients with COVID-19 is associated with a significant decrease in mortality rate. Further prospective randomized controlled trials are needed to assess the efficacy and adverse effects of aspirin administration in this population.


Subject(s)
Aspirin/therapeutic use , COVID-19/drug therapy , Disseminated Intravascular Coagulation/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Pulmonary Embolism/drug therapy , SARS-CoV-2/pathogenicity , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adult , Aged , Alanine/analogs & derivatives , Alanine/therapeutic use , Antiviral Agents/therapeutic use , Blood Platelets/drug effects , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/complications , COVID-19/mortality , COVID-19/virology , Coronary Artery Disease/complications , Coronary Artery Disease/drug therapy , Coronary Artery Disease/mortality , Coronary Artery Disease/virology , Diabetes Mellitus/drug therapy , Diabetes Mellitus/mortality , Diabetes Mellitus/virology , Disseminated Intravascular Coagulation/complications , Disseminated Intravascular Coagulation/mortality , Disseminated Intravascular Coagulation/virology , Drug Combinations , Female , Hospital Mortality , Humans , Hypertension/complications , Hypertension/drug therapy , Hypertension/mortality , Hypertension/virology , Iran , Lopinavir/therapeutic use , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Male , Middle Aged , Pulmonary Embolism/complications , Pulmonary Embolism/mortality , Pulmonary Embolism/virology , Respiration, Artificial/mortality , Respiration, Artificial/statistics & numerical data , Retrospective Studies , Ritonavir/therapeutic use , SARS-CoV-2/drug effects , Severity of Illness Index , Survival Analysis , Treatment Outcome
13.
Int J Mol Sci ; 22(15)2021 Jul 23.
Article in English | MEDLINE | ID: covidwho-1346497

ABSTRACT

Platelets are hematopoietic cells whose main function has for a long time been considered to be the maintenance of vascular integrity. They have an essential role in the hemostatic response, but they also have functional capabilities that go far beyond it. This review will provide an overview of platelet functions. Indeed, stress signals may induce platelet apoptosis through proapoptotis or hemostasis receptors, necrosis, and even autophagy. Platelets also interact with immune cells and modulate immune responses in terms of activation, maturation, recruitment and cytokine secretion. This review will also show that platelets, thanks to their wide range of innate immune receptors, and in particular toll-like receptors, and can be considered sentinels actively participating in the immuno-surveillance of the body. We will discuss the diversity of platelet responses following the engagement of these receptors as well as the signaling pathways involved. Finally, we will show that while platelets contribute significantly, via their TLRs, to immune response and inflammation, these receptors also participate in the pathophysiological processes associated with various pathogens and diseases, including cancer and atherosclerosis.


Subject(s)
Atherosclerosis/pathology , Blood Platelets/pathology , Immunity, Innate/immunology , Neoplasms/pathology , Platelet Activation , Receptors, Immunologic/metabolism , Toll-Like Receptors/metabolism , Animals , Atherosclerosis/immunology , Atherosclerosis/metabolism , Blood Platelets/immunology , Blood Platelets/metabolism , Humans , Neoplasms/immunology , Neoplasms/metabolism
14.
Int J Mol Sci ; 21(21)2020 Nov 03.
Article in English | MEDLINE | ID: covidwho-1344351

ABSTRACT

Progressive respiratory failure is seen as a major cause of death in severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection. Relatively little is known about the associated morphologic and molecular changes in the circulation of these patients. In particular, platelet and erythrocyte pathology might result in severe vascular issues, and the manifestations may include thrombotic complications. These thrombotic pathologies may be both extrapulmonary and intrapulmonary and may be central to respiratory failure. Previously, we reported the presence of amyloid microclots in the circulation of patients with coronavirus disease 2019 (COVID-19). Here, we investigate the presence of related circulating biomarkers, including C-reactive protein (CRP), serum ferritin, and P-selectin. These biomarkers are well-known to interact with, and cause pathology to, platelets and erythrocytes. We also study the structure of platelets and erythrocytes using fluorescence microscopy (using the markers PAC-1 and CD62PE) and scanning electron microscopy. Thromboelastography and viscometry were also used to study coagulation parameters and plasma viscosity. We conclude that structural pathologies found in platelets and erythrocytes, together with spontaneously formed amyloid microclots, may be central to vascular changes observed during COVID-19 progression, including thrombotic microangiopathy, diffuse intravascular coagulation, and large-vessel thrombosis, as well as ground-glass opacities in the lungs. Consequently, this clinical snapshot of COVID-19 strongly suggests that it is also a true vascular disease and considering it as such should form an essential part of a clinical treatment regime.


Subject(s)
Blood Platelets/pathology , Cardiovascular Diseases/virology , Coronavirus Infections/blood , Coronavirus Infections/pathology , Erythrocytes/pathology , Ferritins/blood , P-Selectin/blood , Pneumonia, Viral/blood , Pneumonia, Viral/pathology , Betacoronavirus/isolation & purification , Blood Coagulation/physiology , Blood Platelets/virology , COVID-19 , Cardiovascular Diseases/blood , Cardiovascular Diseases/pathology , Coronavirus Infections/virology , Erythrocytes/virology , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Thrombosis/pathology , Thrombosis/virology
15.
Thromb Haemost ; 122(1): 113-122, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1324456

ABSTRACT

OBJECTIVES: Pulmonary thrombus formation is a hallmark of coronavirus disease 2019 (COVID-19). A dysregulated immune response culminating in thromboinflammation has been described, but the pathomechanisms remain unclear. METHODS: We studied 41 adult COVID-19 patients with positive results on reverse-transcriptase polymerase-chain-reaction assays and 37 sex- and age-matched healthy controls. Number and surface characteristics of extracellular vesicles (EVs) and citrullinated histone H3 levels were determined in plasma upon inclusion by flow cytometry and immunoassay. RESULTS: In total, 20 patients had severe and 21 nonsevere disease. The number of EV (median [25th, 75th percentile]) was significantly higher in patients compared with controls (658.8 [353.2, 876.6] vs. 435.5 [332.5, 585.3], geometric mean ratio [95% confidence intervals]: 2.6 [1.9, 3.6]; p < 0.001). Patients exhibited significantly higher numbers of EVs derived from platelets, endothelial cells, leukocytes, or neutrophils than controls. EVs from alveolar-macrophages and alveolar-epithelial cells were detectable in plasma and were significantly higher in patients. Intercellular adhesion molecule-1-positive EV levels were higher in patients, while no difference between tissue factor-positive and angiotensin-converting enzyme-positive EV was seen between both groups. Levels of EV did not differ between patients with severe and nonsevere COVID-19. Citrullinated histone H3 levels (ng/mL, median [25th, 75th percentile]) were higher in patients than in controls (1.42 [0.6, 3.4] vs. 0.31 [0.1, 0.6], geometric mean ratio: 4.44 [2.6, 7.7]; p < 0.001), and were significantly lower in patients with nonsevere disease compared with those with severe disease. CONCLUSION: EV and citrullinated histone H3 are associated with COVID-19 and could provide information regarding pathophysiology of the disease.


Subject(s)
COVID-19/blood , Extracellular Vesicles/pathology , Histones/blood , SARS-CoV-2 , Adult , Aged , Biomarkers/blood , Blood Platelets/pathology , COVID-19/complications , Case-Control Studies , Citrullination , Extracellular Traps/metabolism , Female , Histones/chemistry , Humans , Male , Middle Aged , Pandemics , Severity of Illness Index , /etiology
16.
Front Immunol ; 12: 676828, 2021.
Article in English | MEDLINE | ID: covidwho-1320577

ABSTRACT

In coronavirus disease 2019 (COVID-19), ulcerative lesions have been episodically reported in various segments of the gastrointestinal (GI) tract, including the oral cavity, oropharynx, esophagus, stomach and bowel. In this report, we describe an autopsy case of a COVID-19 patient who showed two undiagnosed ulcers at the level of the anterior and posterior walls of the hypopharynx. Molecular testing of viruses involved in pharyngeal ulcers demonstrated the presence of severe acute respiratory syndrome - coronavirus type 2 (SARS-CoV-2) RNA, together with herpes simplex virus 1 DNA. Histopathologic analysis demonstrated full-thickness lympho-monocytic infiltration (mainly composed of CD68-positive cells), with hemorrhagic foci and necrosis of both the mucosal layer and deep skeletal muscle fibers. Fibrin and platelet microthrombi were also found. Cytological signs of HSV-1 induced damage were not found. Cells expressing SARS-CoV-2 spike subunit 1 were immunohistochemically identified in the inflammatory infiltrations. Immunohistochemistry for HSV1 showed general negativity for inflammatory infiltration, although in the presence of some positive cells. Thus, histopathological, immunohistochemical and molecular findings supported a direct role by SARS-CoV-2 in producing local ulcerative damage, although a possible contributory role by HSV-1 reactivation cannot be excluded. From a clinical perspective, this autopsy report of two undiagnosed lesions put the question if ulcers along the GI tract could be more common (but frequently neglected) in COVID-19 patients.


Subject(s)
COVID-19/complications , Hypopharynx/pathology , SARS-CoV-2/isolation & purification , Ulcer/pathology , Aged , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Autopsy , Blood Platelets/metabolism , Blood Platelets/pathology , COVID-19/mortality , COVID-19/pathology , COVID-19/physiopathology , Gastrointestinal Tract/pathology , Herpesvirus 1, Human/genetics , Herpesvirus 1, Human/isolation & purification , Humans , Hypopharynx/virology , Immunohistochemistry , Inflammation/immunology , Inflammation/metabolism , Inflammation/virology , Lymphocytes/metabolism , Monocytes/metabolism , Mucous Membrane/pathology , Muscle, Skeletal/pathology , Necrosis/pathology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , Ulcer/virology
17.
J Immunol Res ; 2021: 9917302, 2021.
Article in English | MEDLINE | ID: covidwho-1311190

ABSTRACT

BACKGROUND: The prognostic nutritional index (PNI) has been reported to significantly correlate with poor survival and postoperative complications in patients with various diseases, but its relationship with mortality in COVID-19 patients has not been addressed. METHOD: A multicenter retrospective study involving patients with severe COVID-19 was conducted to investigate whether malnutrition and other clinical characteristics could be used to stratify the patients based on risk. RESULTS: A total of 395 patients were included in our study, with 236 patients in the training cohort, 59 patients in the internal validation cohort, and 100 patients in the external validation cohort. During hospitalization, 63/236 (26.69%) and 14/59 (23.73%) patients died in the training and validation cohorts, respectively. PNI had the strongest relationships with the neutrophil-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level but was less strongly correlated with the CURB65, APACHE II, and SOFA scores. The baseline PNI score, platelet (PLT) count, LDH level, and PaO2/FiO2 (P/F) ratio were independent predictors of mortality in COVID-19 patients. A nomogram incorporating these four predictors showed good calibration and discrimination in the derivation and validation cohorts. A PNI score less than 33.405 was associated with a higher risk of mortality in severe COVID-19 patients in the Cox regression analysis. CONCLUSION: These findings have implications for predicting the risk of mortality in COVID-19 patients at the time of admission and provide the first direct evidence that a lower PNI is related to a worse prognosis in severe COVID-19 patients.


Subject(s)
Blood Platelets/pathology , COVID-19/diagnosis , Malnutrition/epidemiology , Nutrition Assessment , SARS-CoV-2/physiology , Aged , COVID-19/epidemiology , COVID-19/mortality , China/epidemiology , Cohort Studies , Female , Humans , Hydro-Lyases/blood , Male , Middle Aged , Predictive Value of Tests , Prognosis , Quinine , Retrospective Studies , Survival Analysis
18.
Br J Haematol ; 194(3): 530-536, 2021 08.
Article in English | MEDLINE | ID: covidwho-1270823

ABSTRACT

COVID-19, caused by SARS-CoV-2, is a contagious life-threatening viral disease that has killed more than three million people worldwide to date. Attempts have been made to identify biomarker(s) to stratify disease severity and improve treatment and resource allocation. Patients with SARS-COV-2 infection manifest with a higher inflammatory response and platelet hyperreactivity; this raises the question of the role of thrombopoiesis in COVID-19 infection. Immature platelet fraction (IPF, %) and immature platelet counts (IPC, ×109 /l) can be used to assess thrombopoiesis. This study investigates whether the level of thrombopoiesis correlates with COVID-19 severity. A large cohort of 678 well-characterized COVID-19 patients was analyzed, including 658 (97%) hospitalized and 139 (21%) admitted to the intensive care unit (ICU). Elevated percentage IPF at presentation was predictive of length of hospitalization (P < 0·01) and ICU admission (P < 0·05). Additionally, percentage IPF at the peak was significantly higher among ICU patients than non-ICU patients (6·9 ± 5·1 vs 5·3 ± 8·4, P < 0·01) and among deceased patients than recovered patients (7·9 ± 6·3 vs 5·4 ± 7·8, P < 0·01). Furthermore, IPC at the peak was significantly higher among ICU patients than non-ICU patients (18·5 ± 16·2 vs. 13·2 ± 8·3, P < 0·05) and among patients on a ventilator than those not (22·1 ± 20·1 vs.13·4 ± 8·4, P < 0·05). Our study demonstrated that elevated initial and peak values of percentage IPF and IPC might serve as prognostic biomarkers for COVID-19 progression to severe conditions.


Subject(s)
Blood Platelets/pathology , COVID-19/pathology , Thrombopoiesis , Aged , Blood Platelets/cytology , COVID-19/blood , COVID-19/mortality , Female , Hospitalization , Humans , Intensive Care Units , Male , Middle Aged , Platelet Count , SARS-CoV-2/isolation & purification , Severity of Illness Index
19.
J Biomed Sci ; 28(1): 46, 2021 Jun 11.
Article in English | MEDLINE | ID: covidwho-1266487

ABSTRACT

Dysregulated formation of neutrophil extracellular traps (NETs) is observed in acute viral infections. Moreover, NETs contribute to the pathogenesis of acute viral infections, including those caused by the dengue virus (DV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Furthermore, excessive NET formation (NETosis) is associated with disease severity in patients suffering from SARS-CoV-2-induced multiple organ injuries. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and other members of C-type lectin family (L-SIGN, LSECtin, CLEC10A) have been reported to interact with viral glycans to facilitate virus spreading and exacerbates inflammatory reactions. Moreover, spleen tyrosine kinase (Syk)-coupled C-type lectin member 5A (CLEC5A) has been shown as the pattern recognition receptor for members of flaviviruses, and is responsible for DV-induced cytokine storm and Japanese encephalomyelitis virus (JEV)-induced neuronal inflammation. Moreover, DV activates platelets via CLEC2 to release extracellular vesicles (EVs), including microvesicles (MVs) and exosomes (EXOs). The DV-activated EXOs (DV-EXOs) and MVs (DV-MVs) stimulate CLEC5A and Toll-like receptor 2 (TLR2), respectively, to enhance NET formation and inflammatory reactions. Thus, EVs from virus-activated platelets (PLT-EVs) are potent endogenous danger signals, and blockade of C-type lectins is a promising strategy to attenuate virus-induced NETosis and intravascular coagulopathy.


Subject(s)
COVID-19/immunology , Encephalitis Virus, Japanese/immunology , Encephalitis, Japanese/immunology , Extracellular Traps/immunology , Lectins, C-Type/immunology , SARS-CoV-2/immunology , Blood Platelets/immunology , Blood Platelets/pathology , COVID-19/pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Encephalitis, Japanese/pathology , Humans , Platelet Activation/immunology , Signal Transduction/immunology
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