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1.
Int J Mol Sci ; 23(3)2022 Feb 05.
Article in English | MEDLINE | ID: covidwho-1674671

ABSTRACT

Inflammation and thrombosis are closely intertwined in numerous disorders, including ischemic events and sepsis, as well as coronavirus disease 2019 (COVID-19). Thrombotic complications are markers of disease severity in both sepsis and COVID-19 and are associated with multiorgan failure and increased mortality. Immunothrombosis is driven by the complement/tissue factor/neutrophil axis, as well as by activated platelets, which can trigger the release of neutrophil extracellular traps (NETs) and release further effectors of immunothrombosis, including platelet factor 4 (PF4/CXCL4) and high-mobility box 1 protein (HMGB1). Many of the central effectors of deregulated immunothrombosis, including activated platelets and platelet-derived extracellular vesicles (pEVs) expressing PF4, soluble PF4, HMGB1, histones, as well as histone-decorated NETs, are positively charged and thus bind to heparin. Here, we provide evidence that adsorbents functionalized with endpoint-attached heparin efficiently deplete activated platelets, pEVs, PF4, HMGB1 and histones/nucleosomes. We propose that this elimination of central effectors of immunothrombosis, rather than direct binding of pathogens, could be of clinical relevance for mitigating thrombotic complications in sepsis or COVID-19 using heparin-functionalized adsorbents.


Subject(s)
Blood Proteins/isolation & purification , Heparin/pharmacology , /drug therapy , Blood Coagulation/physiology , Blood Platelets/metabolism , Blood Proteins/metabolism , COVID-19/metabolism , Extracellular Traps/immunology , Extracellular Traps/metabolism , HMGB Proteins/isolation & purification , HMGB Proteins/metabolism , HMGB1 Protein/isolation & purification , HMGB1 Protein/metabolism , Heparin/metabolism , Histones/isolation & purification , Histones/metabolism , Humans , Neutrophils/metabolism , Platelet Activation/immunology , Platelet Factor 4/isolation & purification , Platelet Factor 4/metabolism , SARS-CoV-2/pathogenicity , Sepsis/blood , Sepsis/metabolism , Thromboplastin/metabolism , Thrombosis/drug therapy
2.
Biomed Res Int ; 2021: 7073348, 2021.
Article in English | MEDLINE | ID: covidwho-1560583

ABSTRACT

Coronavirus disease 2019 (COVID-19) may lead to acute respiratory disease; cardiovascular, gastrointestinal, and coagulation complications; and even death. One of the major complications is cardiovascular disorders, including arrhythmias, myocarditis, pericarditis, and acute coronary artery disease. The aim of this study was to evaluate the frequency of cardiovascular complications and to determine its association with the prognosis of COVID-19 patients. In a prospective analytic study, 137 hospitalized COVID-19 patients were enrolled. During hospitalization, an electrocardiogram (ECG) was performed every other day, and laboratory tests such as cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) were done 0, 6, and 12 hours after admission. These tests were repeated for patients with chest pain or ECG changes. Patients were categorized into three groups (improved, complicated, and expired patients) and assessed for the rate and type of arrhythmias, cardiac complications, lab tests, and outcomes of treatments. There was no significant relationship among the three groups related to primary arrhythmia and arrhythmias during treatment. The most common arrhythmia during hospitalization and after treatment was ST-T fragment changes. There was a significant age difference between the three groups (P = 0.001). There was a significant difference among the three groups for some underlying diseases, including diabetes mellitus (P = 0.003) and hyperlipidemia (P = 0.004). In our study, different types of arrhythmias had no association with patients' outcomes but age over 60 years, diabetes mellitus, and hyperlipidemia played an important role in the prognosis of COVID-19 cases.


Subject(s)
COVID-19/complications , COVID-19/pathology , Cardiovascular Diseases/etiology , Cardiovascular Diseases/pathology , Adult , Aged , Blood Coagulation/physiology , COVID-19/metabolism , Cardiovascular Diseases/metabolism , Creatine Kinase/metabolism , Electrocardiography/methods , Female , Heart/physiopathology , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Troponin I/metabolism , Young Adult
3.
Indian J Pathol Microbiol ; 64(4): 735-740, 2021.
Article in English | MEDLINE | ID: covidwho-1485280

ABSTRACT

BACKGROUND: COVID-19 is a pandemic viral disease that has affected the Indian population very badly with more than 8.46 million cases and > 0.125 million deaths. AIM: Primary objective of the study is to establish the role of hematological, coagulation and inflammatory biomarkers in early identification of clinically severe covid-19 cases. MATERIALS AND METHODS: This study was conducted from July 2020 to August 2020 at a dedicated COVID-19 referral hospital in central India. Only RT-PCR confirmed COVID-19 positive 300 cases admitted in the hospital were included in this study. Based on the clinical assessment, patients were categorised as mild, moderate, and severe groups as per ICMR guidelines. Blood samples of all cases were tested for haematological, coagulation and inflammatory biomarkers and mean values were compared among the three groups of patients. RESULTS: 46% patients belonged to >60 years of age group. Hematological parameters like total leukocyte count, absolute neutrophil count, Neutrophil: Lymphocyte ratio, Platelet: Lymphocyte ratio significantly increased with lymphocytopenia (P=0.001). Coagulation profile(D-dimer and PT) and inflammatory biomarkers like CRP, LDH, ferritin, procalcitonin and NT- Pro BNP, all were significantly increased with severity of patients(p=0.001). ROC plotted for all the parameters between severe v/s non-severe cases showed that CRP, LDH and D-dimer had a good discriminative precision with AUC >0.8. CONCLUSION: We suggest that biochemical markers like CRP, LDH and D-dimer can be used as a screening tool to differentiate severe patients from non-severe patients of Covid-19 disease in order to identify severe disease at early stage for optimal utilization of resources & reducing further morbidity & mortality.


Subject(s)
Biomarkers/blood , Blood Coagulation/physiology , COVID-19/physiopathology , Early Diagnosis , Inflammation/blood , Inflammation/physiopathology , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Female , Humans , India , Male , Middle Aged , Predictive Value of Tests , Prognosis , SARS-CoV-2
4.
Adv Sci (Weinh) ; 8(23): e2103266, 2021 12.
Article in English | MEDLINE | ID: covidwho-1479368

ABSTRACT

Activation of endothelial cells following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be the primary driver for the increasingly recognized thrombotic complications in coronavirus disease 2019 patients, potentially due to the SARS-CoV-2 Spike protein binding to the human angiotensin-converting enzyme 2 (hACE2). Vaccination therapies use the same Spike sequence or protein to boost host immune response as a protective mechanism against SARS-CoV-2 infection. As a result, cases of thrombotic events are reported following vaccination. Although vaccines are generally considered safe, due to genetic heterogeneity, age, or the presence of comorbidities in the population worldwide, the prediction of severe adverse outcome in patients remains a challenge. To elucidate Spike proteins underlying patient-specific-vascular thrombosis, the human microcirculation environment is recapitulated using a novel microfluidic platform coated with human endothelial cells and exposed to patient specific whole blood. Here, the blood coagulation effect is tested after exposure to Spike protein in nanoparticles and Spike variant D614G in viral vectors and the results are corroborated using live SARS-CoV-2. Of note, two potential strategies are also examined to reduce blood clot formation, by using nanoliposome-hACE2 and anti-Interleukin (IL) 6 antibodies.


Subject(s)
Blood Coagulation/physiology , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antibodies/chemistry , Antibodies/immunology , Antibodies/metabolism , COVID-19/diagnosis , COVID-19/virology , Endothelial Cells/chemistry , Endothelial Cells/cytology , Endothelial Cells/metabolism , Fibrin/chemistry , Fibrin/metabolism , Genetic Vectors/genetics , Genetic Vectors/metabolism , Humans , Interleukin-6/immunology , Liposomes/chemistry , Microfluidics/methods , Mutation , Nanoparticles/chemistry , Platelet Aggregation , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/analysis , Spike Glycoprotein, Coronavirus/genetics
5.
Am J Health Syst Pharm ; 79(5): 329-337, 2022 02 18.
Article in English | MEDLINE | ID: covidwho-1450366

ABSTRACT

PURPOSE: To provide an overview of current literature on the pathophysiology of sepsis, with a focus on mediators of endothelial injury and organ dysfunction. SUMMARY: Sepsis is a dysregulated response to infection that triggers cascades of interconnected systems. Sepsis has been a significant cause of mortality worldwide, and the recent viral pandemic that may produce severe sepsis and septic shock has been a major contributor to sepsis-related mortality. Understanding of the pathophysiology of sepsis has changed dramatically over the last several decades. Significant insight into the components of the inflammatory response that contribute to endothelial injury and trigger coagulation pathways has been achieved. Similarly, characterization of anti-inflammatory pathways that may lead to secondary infections and poor outcome has illustrated opportunities for improved therapies. Description of an increasing number of important mediators and pathways has occurred and may point the way to novel therapies to address immune dysregulation. Pharmacists will need a fundamental understanding of the overlapping pathways of the immune response to fully prepare for use of novel treatment options. While pharmacists typically understand coagulation cascade how to utilize anticoagulants, the issues in sepsis related coagulopathy and role of mediators such as cytokines and complement and role of activated platelets and neutrophils require a different perspective. CONCLUSION: Pharmacists can benefit from understanding both the cellular and organ system issues in sepsis to facilitate assessment of potential therapies for risk and benefit.


Subject(s)
Blood Coagulation Disorders , Sepsis , Shock, Septic , Anticoagulants , Blood Coagulation/physiology , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/therapy , Humans , Shock, Septic/complications
6.
Clin Immunol ; 232: 108852, 2021 11.
Article in English | MEDLINE | ID: covidwho-1401324

ABSTRACT

BACKGROUND: The majority of the coronavirus disease 2019 (COVID-19) non-survivors meet the criteria for disseminated intravascular coagulation (DIC). Although timely monitoring of clotting hemorrhagic development during the natural course of COVID-19 is critical for understanding pathogenesis, diagnosis, and treatment of the disease, however, limited data are available on the dynamic processes of inflammation/coagulopathy/fibrinolysis (ICF). METHODS: We monitored the dynamic progression of ICF in patients with moderate COVID-19. Out of 694 COVID-19 inpatients from 10 hospitals in Wenzhou, China, we selected 293 adult patients without comorbidities. These patients were divided into different daily cohorts according to the COVID-19 onset-time. Furthermore, data of 223 COVID-19 patients with comorbidities and 22 critical cases were analyzed. Retrospective data were extracted from electronic medical records. RESULTS: The virus-induced damages to pre-hospitalization patients triggered two ICF fluctuations during the 14-day course of the disease. C-reactive protein (CRP), fibrinogen, and D-dimer levels increased and peaked at day 5 (D) 5 and D9 during the 1st and 2nd fluctuations, respectively. The ICF activities were higher during the 2nd fluctuation. Although 12-day medication returned high CRP concentrations to normal and blocked fibrinogen increase, the D-dimer levels remained high on days 17 ±â€¯2 and 23 ±â€¯2 days of the COVID-19 course. Notably, although the oxygenation index, prothrombin time and activated partial thromboplastin time were within the normal range in critical COVID-19 patients at administration, 86% of these patients had a D-dimer level > 500 µg/L. CONCLUSION: COVID-19 is linked with chronic DIC, which could be responsible for the progression of the disease. Understanding and monitoring ICF progression during COVID-19 can help clinicians in identifying the stage of the disease quickly and accurately and administering suitable treatment.


Subject(s)
Blood Coagulation/physiology , COVID-19/complications , Fibrinolysis/physiology , Inflammation/etiology , Inflammation/virology , Adult , Anticoagulants/pharmacology , Blood Coagulation/drug effects , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/metabolism , Blood Coagulation Disorders/pathology , Blood Coagulation Disorders/virology , COVID-19/metabolism , COVID-19/pathology , China , Disease Progression , Disseminated Intravascular Coagulation/etiology , Disseminated Intravascular Coagulation/metabolism , Disseminated Intravascular Coagulation/pathology , Disseminated Intravascular Coagulation/virology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/metabolism , Hemorrhage/etiology , Hemorrhage/pathology , Hemorrhage/virology , Humans , Inflammation/pathology , Male , Middle Aged , Prothrombin Time , SARS-CoV-2/pathogenicity
7.
Diabetes Metab Syndr ; 15(5): 102240, 2021.
Article in English | MEDLINE | ID: covidwho-1347578

ABSTRACT

AIMS: To evaluate calculated total plasma osmolality as a marker of outcome prediction, fluid and metabolic balance, thrombotic risk in severe COVID-19 patients. METHODS: Retrospective data of RT-PCR confirmed hospitalized severe COVID-19 patients (total: n = 175 patients, including diabetic subset: n = 102) were analyzed. Clinically applicable cut-offs were derived using receiver operating characteristic (ROC) curve analysis for calculated total osmolality, eGFR, and D-dimer, and their correlations were studied. RESULTS: Among 175 severe COVID-19 patients, a significant association with mortality was seen with respect to calculated total osmolality (p < 0.001), eGFR (p < 0.001), and D-dimer (p < 0.001). In the total cohort, applicable cut-offs based on ROC curve in predicting outcome were, for total osmolality 299 mosm/kg (area under the curve (AUC)-0.773, odds ratio (OR)-1.09), eGFR 61.5 ml/min/m2 (AUC-0.789, OR-0.96), D-dimer 5.13 (AUC-0.814, OR-2.65) respectively. In diabetic subset, the cut-offs for total osmolality were 298 mosm/kg (AUC-0.794, OR-1.12), eGFR 44.9 ml/min/m2 (AUC-0.774, OR-0.96) and D-dimer 1.59 (AUC-0.769, OR-1.52) respectively. CONCLUSIONS: Applicable cut-offs for calculated total plasma osmolality, eGFR, and D-dimer predicts clinical outcome in severe COVID-19 with and without diabetes. Correlation studies validated calculated total osmolality as a marker of the combined effect of fluid and metabolic imbalance, compromised renal function and hypercoagulability.


Subject(s)
COVID-19/diagnosis , Glomerular Filtration Rate/physiology , Plasma/chemistry , Biomarkers/blood , Blood Coagulation/physiology , COVID-19/blood , COVID-19/physiopathology , COVID-19/therapy , Cohort Studies , Diabetes Complications/blood , Diabetes Complications/diagnosis , Diabetes Complications/physiopathology , Diabetes Complications/therapy , Female , Fibrin Fibrinogen Degradation Products/analysis , Fibrin Fibrinogen Degradation Products/metabolism , Humans , India , Male , Middle Aged , Osmolar Concentration , Patient Admission/statistics & numerical data , Prognosis , Retrospective Studies , Risk Factors , Severity of Illness Index , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/etiology , Thrombosis/physiopathology , Water-Electrolyte Balance/physiology
8.
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
9.
J Clin Neurosci ; 89: 271-278, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1213386

ABSTRACT

Coronavirus Disease 19 (COVID-19) pandemic affects the worldwide healthcare system and our understanding of this disease grows rapidly. Although COVID-19 is a mainly respiratory disease, neurological manifestations are not uncommon. The aim of this review is to report on the etiology, clinical profile, location, and outcome of patients with intracerebral hemorrhage (ICH) and COVID-19. This review includes 36 studies examining ICH in the clinical presentation of COVID-19. Overall, 217 cases with intracranial hemorrhage, of which 188 ICHs, were reported. Generally, a low incidence of both primary and secondary ICH was found in 8 studies [106 (0.25%) out of 43,137 hospitalized patients with COVID-19]. Available data showed a median age of 58 years (range: 52-68) and male sex 64%, regarding 36 and 102 patients respectively. Furthermore, 75% of the patients were on prior anticoagulation treatment, 52% had a history of arterial hypertension, and 61% were admitted in intensive care unit. Location of ICH in deep structures/basal ganglia was ascertained in only 7 cases making arterial hypertension an improbable etiopathogenetic mechanism. Mortality was calculated at 52.7%. Disease related pathophysiologic mechanisms support the hypothesis that SARS-CoV2 can cause ICH, however typical ICH risk factors such as anticoagulation treatment, or admission to ICU should also be considered as probable causes. Physicians should strongly suspect the possibility of ICH in individuals with severe COVID-19 admitted to ICU and treated with anticoagulants. It is not clear whether ICH is related directly to COVID-19 or reflects expected comorbidity and/or complications observed in severely ill patients.


Subject(s)
COVID-19/diagnostic imaging , COVID-19/epidemiology , Cerebral Hemorrhage/diagnostic imaging , Cerebral Hemorrhage/epidemiology , Adult , Aged , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Blood Coagulation/drug effects , Blood Coagulation/physiology , COVID-19/drug therapy , Cerebral Hemorrhage/drug therapy , Hospitalization/trends , Humans , Hypertension/diagnostic imaging , Hypertension/drug therapy , Hypertension/epidemiology , Intensive Care Units/trends , Male , Middle Aged , Pandemics , Risk Factors , SARS-CoV-2
10.
Lancet Haematol ; 8(7): e524-e533, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1208801

ABSTRACT

COVID-19 is associated with a high incidence of thrombotic complications, which can be explained by the complex and unique interplay between coronaviruses and endothelial cells, the local and systemic inflammatory response, and the coagulation system. Empirically, an intensified dose of thrombosis prophylaxis is being used in patients admitted to hospital with COVID-19 and several guidelines on this topic have been published, although the insufficiency of high quality and direct evidence has led to weak recommendations. In this Viewpoint we summarise the pathophysiology of COVID-19 coagulopathy in the context of patients who are ambulant, admitted to hospital, and critically ill or non-critically ill, and those post-discharge from hospital. We also review data from randomised controlled trials in the past year of antithrombotic therapy in patients who are critically ill. These data provide the first high-quality evidence on optimal use of antithrombotic therapy in patients with COVID-19. Pharmacological thromboprophylaxis is not routinely recommended for patients who are ambulant and post-discharge. A first ever trial in non-critically ill patients who were admitted to hospital has shown that a therapeutic dose of low-molecular-weight heparin might improve clinical outcomes in this population. In critically ill patients, this same treatment does not improve outcomes and prophylactic dose anticoagulant thromboprophylaxis is recommended. In the upcoming months we expect numerous data from the ongoing antithrombotic COVID-19 studies to guide clinicians at different stages of the disease.


Subject(s)
Anticoagulants/therapeutic use , Blood Coagulation Disorders/physiopathology , COVID-19/complications , Heparin, Low-Molecular-Weight/therapeutic use , Aged , Aged, 80 and over , Blood Coagulation/physiology , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/epidemiology , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Critical Illness/therapy , Endothelial Cells/pathology , Endothelial Cells/virology , Hospitalization , Humans , Incidence , Outcome Assessment, Health Care , Patient Discharge/standards , Randomized Controlled Trials as Topic , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Systemic Inflammatory Response Syndrome/physiopathology , Venous Thromboembolism/prevention & control
11.
Sci Rep ; 11(1): 4432, 2021 02 24.
Article in English | MEDLINE | ID: covidwho-1101681

ABSTRACT

Cardiac injury is a common complication of the coronavirus disease 2019 (COVID-19), and is associated with adverse clinical outcomes. In this study, we aimed to reveal the association of cardiac injury with coagulation dysfunction. We enrolled 181 consecutive patients who were hospitalized with COVID-19, and studied the clinical characteristics and outcome of these patients. Cardiac biomarkers high-sensitivity troponin I (hs-cTnI), myohemoglobin and creatine kinase-myocardial band (CK-MB) were assessed in all patients. The clinical outcomes were defined as hospital discharge or death. The median age of the study cohort was 55 (IQR, 46-65) years, and 102 (56.4%) were males. Forty-two of the 181 patients (23.2%) had cardiac injury. Old age, high leukocyte count, and high levels of aspartate transaminase (AST), D-dimer and serum ferritin were significantly associated with cardiac injury. Multivariate regression analysis revealed old age and elevated D-dimer levels as being strong risk predictors of in-hospital mortality. Interleukin 6 (IL6) levels were comparable in patients with or without cardiac injury. Serial observations of coagulation parameters demonstrated highly synchronous alterations of D-dimer along with progression to cardiac injury. Cardiac injury is a common complication of COVID-19 and is an independent risk factor for in-hospital mortality. Old age, high leukocyte count, and high levels of AST, D-dimer and serum ferritin are significantly associated with cardiac injury, whereas IL6 are not. Therefore, the pathogenesis of cardiac injury in COVID-19 may be primarily due to coagulation dysfunction along with microvascular injury.


Subject(s)
Blood Coagulation Disorders/virology , COVID-19/blood , Heart Injuries/virology , Aged , Biomarkers/blood , Blood Coagulation/physiology , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/epidemiology , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19/virology , China/epidemiology , Cohort Studies , Creatine Kinase, MB Form/blood , Female , Fibrin Fibrinogen Degradation Products/analysis , Fibrin Fibrinogen Degradation Products/metabolism , Heart Injuries/blood , Heart Injuries/epidemiology , Heart Injuries/physiopathology , Hemoglobins/metabolism , Hospital Mortality , Humans , Male , Middle Aged , Risk Factors , SARS-CoV-2/isolation & purification , Troponin I/blood
12.
Eur J Intern Med ; 83: 34-38, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065032

ABSTRACT

BACKGROUND: Many COVID-19 patients develop a hyperinflammatory response which activates blood coagulation and may contribute to the occurrence of thromboembolic complications. Blockade of interleukin-6, a key cytokine in COVID-19 pathogenesis, may improve the hypercoagulable state induced by inflammation. The aim of this study was to evaluate the effects of subcutaneous tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 receptor on coagulation parameters. METHODS: Hospitalized adult patients with laboratory-confirmed moderate to critical COVID-19 pneumonia and hyperinflammation, who received a single 324 mg subcutaneous dose of tocilizumab on top of standard of care were enrolled in this analysis. Coagulation parameters were measured before tocilizumab and at day 1, 3, and 7 after treatment. All patients were followed-up for 35 days after admission or until death. RESULTS: 70 patients (mean age 60 years, interquartile range 52-75) were included. Treatment with tocilizumab was associated with a reduction in D-dimer levels (-56%; 95% confidence interval [CI], -68% to -44%), fibrinogen (-48%; 95%CI, -60% to -35%), C-reactive protein (-93%; 95%CI, -99% to -87%), prothrombin time (-4%; 95%CI,-9% to 0.8%), and activated thromboplastin time (-4%; 95%CI,-8.7% to 0.8%), and an increase in platelet count (34%; 95%CI, 23% to 45%). These changes occurred already one day after treatment with sustained reductions throughout day 7. The improvement in coagulation was consistently observed in patients receiving prophylactic or therapeutic dose anticoagulants, and was paralleled by a rapid improvement in respiratory function. CONCLUSIONS: Subcutaneous tocilizumab was associated with significant improvement of blood coagulation parameters independently of thromboprophylaxis dose.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Blood Coagulation/physiology , COVID-19/blood , COVID-19/drug therapy , COVID-19/therapy , Receptors, Interleukin-6/antagonists & inhibitors , Adult , Aged , Blood Cell Count , Blood Coagulation Tests , C-Reactive Protein , Cohort Studies , Combined Modality Therapy , Female , Hospitalization , Humans , Injections, Subcutaneous , Italy , Male , Middle Aged
13.
J Proteome Res ; 19(11): 4417-4427, 2020 11 06.
Article in English | MEDLINE | ID: covidwho-974858

ABSTRACT

Over 5 million people around the world have tested positive for the beta coronavirus SARS-CoV-2 as of May 29, 2020, a third of which are in the United States alone. These infections are associated with the development of a disease known as COVID-19, which is characterized by several symptoms, including persistent dry cough, shortness of breath, chills, muscle pain, headache, loss of taste or smell, and gastrointestinal distress. COVID-19 has been characterized by elevated mortality (over 100 thousand people have already died in the US alone), mostly due to thromboinflammatory complications that impair lung perfusion and systemic oxygenation in the most severe cases. While the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) have been associated with the severity of the disease, little is known about the impact of IL-6 levels on the proteome of COVID-19 patients. The present study provides the first proteomics analysis of sera from COVID-19 patients, stratified by circulating levels of IL-6, and correlated to markers of inflammation and renal function. As a function of IL-6 levels, we identified significant dysregulation in serum levels of various coagulation factors, accompanied by increased levels of antifibrinolytic components, including several serine protease inhibitors (SERPINs). These were accompanied by up-regulation of the complement cascade and antimicrobial enzymes, especially in subjects with the highest levels of IL-6, which is consistent with an exacerbation of the acute phase response in these subjects. Although our results are observational, they highlight a clear increase in the levels of inhibitory components of the fibrinolytic cascade in severe COVID-19 disease, providing potential clues related to the etiology of coagulopathic complications in COVID-19 and paving the way for potential therapeutic interventions, such as the use of pro-fibrinolytic agents. Raw data for this study are available through ProteomeXchange with identifier PXD020601.


Subject(s)
Blood Proteins/analysis , Complement System Proteins/analysis , Coronavirus Infections , Interleukin-6/blood , Pandemics , Pneumonia, Viral , Proteome/analysis , Adult , Betacoronavirus , Blood Coagulation/physiology , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/physiopathology , Female , Hemolysis , Humans , Male , Middle Aged , Pneumonia, Viral/blood , Pneumonia, Viral/physiopathology , Proteomics , SARS-CoV-2
14.
Exp Biol Med (Maywood) ; 246(6): 688-694, 2021 03.
Article in English | MEDLINE | ID: covidwho-971191

ABSTRACT

Acute respiratory disease caused by a novel coronavirus (SARS-CoV-2) has spread all over the world, since its discovery in 2019, Wuhan, China. This disease is called COVID-19 and already killed over 1 million people worldwide. The clinical symptoms include fever, dry cough, dyspnea, headache, dizziness, generalized weakness, vomiting, and diarrhea. Unfortunately, so far, there is no validated vaccine, and its management consists mainly of supportive care. Venous thrombosis and pulmonary embolism are highly prevalent in patients suffering from severe COVID-19. In fact, a prothrombotic state seems to be present in most fatal cases of the disease. SARS-CoV-2 leads to the production of proinflammatory cytokines, causing immune-mediated tissue damage, disruption of the endothelial barrier, and uncontrolled thrombogenesis. Thrombin is the key regulator of coagulation and fibrin formation. In severe COVID-19, a dysfunctional of physiological anticoagulant mechanisms leads to a progressive increase of thrombin activity, which is associated with acute respiratory distress syndrome development and a poor prognosis. Protease-activated receptor type 1 (PAR1) is the main thrombin receptor and may represent an essential link between coagulation and inflammation in the pathophysiology of COVID-19. In this review, we discuss the potential role of PAR1 inhibition and regulation in COVID-19 treatment.


Subject(s)
Blood Coagulation/physiology , COVID-19/pathology , Disseminated Intravascular Coagulation/pathology , Receptor, PAR-1/metabolism , Thrombin/metabolism , Anticoagulants/therapeutic use , Blood Coagulation/drug effects , Blood Coagulation Factors/metabolism , COVID-19/drug therapy , Disseminated Intravascular Coagulation/drug therapy , Humans , Pulmonary Embolism/pathology , Pulmonary Embolism/prevention & control , Receptor, PAR-1/antagonists & inhibitors , Receptors, Cell Surface/metabolism , SARS-CoV-2 , Venous Thrombosis/pathology , Venous Thrombosis/prevention & control
15.
Crit Care ; 24(1): 676, 2020 12 07.
Article in English | MEDLINE | ID: covidwho-962957

ABSTRACT

BACKGROUND: There is emerging evidence for enhanced blood coagulation in coronavirus 2019 (COVID-19) patients, with thromboembolic complications contributing to morbidity and mortality. The mechanisms underlying this prothrombotic state remain enigmatic. Further data to guide anticoagulation strategies are urgently required. METHODS: We used viscoelastic rotational thromboelastometry (ROTEM) in a single-center cohort of 40 critically ill COVID-19 patients. RESULTS: Clear signs of a hypercoagulable state due to severe hypofibrinolysis were found. Maximum lysis, especially following stimulation of the extrinsic coagulation system, was inversely associated with an enhanced risk of thromboembolic complications. Combining values for maximum lysis with D-dimer concentrations revealed high sensitivity and specificity of thromboembolic risk prediction. CONCLUSIONS: The study identifies a reduction in fibrinolysis as an important mechanism in COVID-19-associated coagulopathy. The combination of ROTEM and D-dimer concentrations may prove valuable in identifying patients requiring higher intensity anticoagulation.


Subject(s)
COVID-19/complications , Fibrinolysis/physiology , Thrombelastography/methods , Thromboembolism/diagnosis , Blood Coagulation/physiology , Blood Coagulation Tests/methods , Blood Coagulation Tests/standards , COVID-19/diagnostic imaging , COVID-19/physiopathology , Cohort Studies , Critical Illness/epidemiology , Critical Illness/therapy , Female , Humans , Male , Middle Aged , Point-of-Care Systems/standards , Point-of-Care Systems/statistics & numerical data , Thromboembolism/diagnostic imaging , Viscoelastic Substances/analysis , Viscoelastic Substances/therapeutic use
16.
Arterioscler Thromb Vasc Biol ; 41(1): 401-414, 2021 01.
Article in English | MEDLINE | ID: covidwho-945064

ABSTRACT

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with derangement in biomarkers of coagulation and endothelial function and has been likened to the coagulopathy of sepsis. However, clinical laboratory metrics suggest key differences in these pathologies. We sought to determine whether plasma coagulation and fibrinolytic potential in patients with COVID-19 differ compared with healthy donors and critically ill patients with sepsis. Approach and Results: We performed comparative studies on plasmas from a single-center, cross-sectional observational study of 99 hospitalized patients (46 with COVID-19 and 53 with sepsis) and 18 healthy donors. We measured biomarkers of endogenous coagulation and fibrinolytic activity by immunoassays, thrombin, and plasmin generation potential by fluorescence and fibrin formation and lysis by turbidity. Compared with healthy donors, patients with COVID-19 or sepsis both had elevated fibrinogen, d-dimer, soluble TM (thrombomodulin), and plasmin-antiplasmin complexes. Patients with COVID-19 had increased thrombin generation potential despite prophylactic anticoagulation, whereas patients with sepsis did not. Plasma from patients with COVID-19 also had increased endogenous plasmin potential, whereas patients with sepsis showed delayed plasmin generation. The collective perturbations in plasma thrombin and plasmin generation permitted enhanced fibrin formation in both COVID-19 and sepsis. Unexpectedly, the lag times to thrombin, plasmin, and fibrin formation were prolonged with increased disease severity in COVID-19, suggesting a loss of coagulation-initiating mechanisms accompanies severe COVID-19. CONCLUSIONS: Both COVID-19 and sepsis are associated with endogenous activation of coagulation and fibrinolysis, but these diseases differently impact plasma procoagulant and fibrinolytic potential. Dysregulation of procoagulant and fibrinolytic pathways may uniquely contribute to the pathophysiology of COVID-19 and sepsis.


Subject(s)
Blood Coagulation Disorders/blood , Blood Coagulation/physiology , COVID-19/blood , SARS-CoV-2 , Sepsis/blood , Biomarkers/blood , Blood Coagulation Disorders/etiology , COVID-19/complications , COVID-19/epidemiology , Cross-Sectional Studies , Female , Fibrinolysin/metabolism , Humans , Male , Middle Aged , Pandemics , Sepsis/complications
17.
Med Hypotheses ; 146: 110371, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-912499

ABSTRACT

The universal phenomenon of blood clotting is well known to be protective in external cellular/ tissue injury. However, the emergence of unusual thrombotic presentations in COVID-19 patients is the real concern. Interaction of the spike glycoprotein with ACE2 receptor present in the host cell surface mediates the entry of SARS-CoV-2 causing COVID-19 infection. New clinical findings of SARS-CoV-2 pathogenesis are coming out every day, and one such mystery is the formation of mysterious blood clots in the various tissues and organs of COVID-19 patients, which needs critical attention. To address this issue, we hypothesis that, high ACE2 expression in the endothelium of blood vessels facilitates the high-affinity binding of SARS-CoV-2 using spike protein, causing infection and internal injury inside the vascular wall of blood vessels. This viral associated injury may directly/indirectly initiate activation of coagulation and clotting cascades forming internal blood clots. However, the presence of these clots is undesirable as they are responsible for thrombosis and need to be treated with anti-thrombotic intervention.


Subject(s)
COVID-19/complications , Models, Cardiovascular , Pandemics , SARS-CoV-2 , Thrombosis/etiology , Angiotensin-Converting Enzyme 2/physiology , Blood Coagulation/physiology , COVID-19/physiopathology , COVID-19/virology , Endothelium, Vascular/injuries , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Host Microbial Interactions/physiology , Humans , Receptors, Virus/physiology , Spike Glycoprotein, Coronavirus/physiology , Thrombosis/physiopathology , Thrombosis/virology
18.
Clin Appl Thromb Hemost ; 26: 1076029620962853, 2020.
Article in English | MEDLINE | ID: covidwho-873836

ABSTRACT

Thrombotic complications of the novel coronavirus (COVID-19) are a concerning aspect of the disease, due to the high incidence in critically ill patients and poor clinical outcomes. COVID-19 predisposes patients to a hypercoagulable state, however, the pathophysiology behind the thrombotic complications seen in this disease is not well understood. Several mechanisms have been proposed and the pathogenesis likely involves a host immune response contributing to vascular endothelial cell injury, inflammation, activation of the coagulation cascade via tissue factor expression, and shutdown of fibrinolysis. Treatments targeting these pathways may need to be considered to improve clinical outcomes and decrease overall mortality due to thrombotic complications. In this review, we will discuss the proposed pathophysiologic mechanisms for thrombotic complications in COVID-19, as well as treatment strategies for these complications based on the current literature available.


Subject(s)
Betacoronavirus , Blood Coagulation/physiology , Coronavirus Infections/complications , Pandemics , Pneumonia, Viral/complications , Thrombophilia/etiology , COVID-19 , Coronavirus Infections/epidemiology , Global Health , Humans , Incidence , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Thrombophilia/blood , Thrombophilia/epidemiology
20.
Eur Respir Rev ; 29(157)2020 Sep 30.
Article in English | MEDLINE | ID: covidwho-810447

ABSTRACT

Novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has rapidly spread throughout the world, resulting in a pandemic with high mortality. There are no effective treatments for the management of severe COVID-19 and current therapeutic trials are focused on antiviral therapy and attenuation of hyper-inflammation with anti-cytokine therapy. Severe COVID-19 pneumonia shares some pathological similarities with severe bacterial pneumonia and sepsis. In particular, it disrupts the haemostatic balance, which results in a procoagulant state locally in the lungs and systemically. This culminates in the formation of microthrombi, disseminated intravascular coagulation and multi-organ failure. The deleterious effects of exaggerated inflammatory responses and activation of coagulation have been investigated in bacterial pneumonia and sepsis and there is recognition that although these pathways are important for the host immune response to pathogens, they can lead to bystander tissue injury and are negatively associated with survival. In the past two decades, evidence from preclinical studies has led to the emergence of potential anticoagulant therapeutic strategies for the treatment of patients with pneumonia, sepsis and acute respiratory distress syndrome, and some of these anticoagulant approaches have been trialled in humans. Here, we review the evidence from preclinical studies and clinical trials of anticoagulant treatment strategies in bacterial pneumonia and sepsis, and discuss the importance of these findings in the context of COVID-19.


Subject(s)
Anticoagulants/therapeutic use , Betacoronavirus , Blood Coagulation/physiology , Coronavirus Infections/blood , Pneumonia, Bacterial/blood , Pneumonia, Viral/blood , Sepsis/blood , Biomarkers/blood , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Humans , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , SARS-CoV-2
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