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1.
Cell Mol Biol Lett ; 27(1): 6, 2022 Jan 11.
Article in English | MEDLINE | ID: covidwho-1622208

ABSTRACT

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with a high mortality rate. The majority of deaths in this disease are caused by ARDS (acute respiratory distress syndrome) followed by cytokine storm and coagulation complications. Although alterations in the level of the number of coagulation factors have been detected in samples from COVID-19 patients, the direct molecular mechanism which has been involved in this pathologic process has not been explored yet. The PI3K/AKT signaling pathway is an intracellular pathway which plays a central role in cell survival. Also, in recent years the association between this pathway and coagulopathies has been well clarified. Therefore, based on the evidence on over-activity of the PI3K/AKT signaling pathway in SARS-CoV-2 infection, in the current review, the probable role of this cellular pathway as a therapeutic target for the prevention of coagulation complications in patients with COVID-19 is discussed.


Subject(s)
Blood Coagulation Disorders/etiology , Blood Coagulation , COVID-19/complications , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Animals , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/metabolism , COVID-19/blood , COVID-19/metabolism , Humans , Inflammation/blood , Inflammation/etiology , Inflammation/metabolism , Molecular Targeted Therapy , SARS-CoV-2/physiology
2.
Front Immunol ; 12: 762782, 2021.
Article in English | MEDLINE | ID: covidwho-1593084

ABSTRACT

Coagulopathy is a frequently reported finding in the pathology of coronavirus disease 2019 (COVID-19); however, the molecular mechanism, the involved coagulation factors, and the role of regulatory proteins in homeostasis are not fully investigated. We explored the dynamic changes of nine coagulation tests in patients and controls to propose a molecular mechanism for COVID-19-associated coagulopathy. Coagulation tests including prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (FIB), lupus anticoagulant (LAC), proteins C and S, antithrombin III (ATIII), D-dimer, and fibrin degradation products (FDPs) were performed on plasma collected from 105 individuals (35 critical patients, 35 severe patients, and 35 healthy controls). There was a statically significant difference when the results of the critical (CRT) and/or severe (SVR) group for the following tests were compared to the control (CRL) group: PTCRT (15.014) and PTSVR (13.846) (PTCRL = 13.383, p < 0.001), PTTCRT (42.923) and PTTSVR (37.8) (PTTCRL = 36.494, p < 0.001), LACCRT (49.414) and LACSVR (47.046) (LACCRL = 40.763, p < 0.001), FIBCRT (537.66) and FIBSVR (480.29) (FIBCRL = 283.57, p < 0.001), ProCCRT (85.57%) and ProCSVR (99.34%) (ProCCRL = 94.31%, p = 0.04), ProSCRT (62.91%) and ProSSVR (65.06%) (ProSCRL = 75.03%, p < 0.001), D-dimer (p < 0.0001, χ 2 = 34.812), and FDP (p < 0.002, χ 2 = 15.205). No significant association was found in the ATIII results in groups (ATIIICRT = 95.71% and ATIIISVR = 99.63%; ATIIICRL = 98.74%, p = 0.321). D-dimer, FIB, PT, PTT, LAC, protein S, FDP, and protein C (ordered according to p-values) have significance in the prognosis of patients. Disruptions in homeostasis in protein C (and S), VIII/VIIIa and V/Va axes, probably play a role in COVID-19-associated coagulopathy.


Subject(s)
Blood Coagulation Disorders/blood , Blood Coagulation Tests/methods , Blood Coagulation , COVID-19/complications , Adult , Aged , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/diagnosis , Blood Coagulation Factors/metabolism , COVID-19/virology , Female , Fibrin/metabolism , Fibrin Fibrinogen Degradation Products/metabolism , Homeostasis , Humans , Male , Middle Aged , Partial Thromboplastin Time , Prognosis , Protein C/metabolism , Prothrombin Time , SARS-CoV-2/genetics , SARS-CoV-2/physiology
3.
Front Immunol ; 12: 738093, 2021.
Article in English | MEDLINE | ID: covidwho-1518484

ABSTRACT

Disease caused by SARS-CoV-2 coronavirus (COVID-19) led to significant morbidity and mortality worldwide. A systemic hyper-inflammation characterizes severe COVID-19 disease, often associated with acute respiratory distress syndrome (ARDS). Blood biomarkers capable of risk stratification are of great importance in effective triage and critical care of severe COVID-19 patients. Flow cytometry and next-generation sequencing were done on peripheral blood cells and urokinase-type plasminogen activator receptor (suPAR), and cytokines were measured from and mass spectrometry-based proteomics was done on plasma samples from an Indian cohort of COVID-19 patients. Publicly available single-cell RNA sequencing data were analyzed for validation of primary data. Statistical analyses were performed to validate risk stratification. We report here higher plasma abundance of suPAR, expressed by an abnormally expanded myeloid cell population, in severe COVID-19 patients with ARDS. The plasma suPAR level was found to be linked to a characteristic plasma proteome, associated with coagulation disorders and complement activation. Receiver operator characteristic curve analysis to predict mortality identified a cutoff value of suPAR at 1,996.809 pg/ml (odds ratio: 2.9286, 95% confidence interval 1.0427-8.2257). Lower-than-cutoff suPAR levels were associated with a differential expression of the immune transcriptome as well as favorable clinical outcomes, in terms of both survival benefit (hazard ratio: 0.3615, 95% confidence interval 0.1433-0.912) and faster disease remission in our patient cohort. Thus, we identified suPAR as a key pathogenic circulating molecule linking systemic hyperinflammation to the hypercoagulable state and stratifying clinical outcomes in severe COVID-19 patients with ARDS.


Subject(s)
COVID-19/blood , Receptors, Urokinase Plasminogen Activator/blood , SARS-CoV-2 , Adult , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/immunology , Blood Proteins/analysis , COVID-19/immunology , Cytokines/blood , Humans , Inflammation/blood , Inflammation/immunology , Middle Aged , Myeloid Cells/immunology , Proteome/analysis , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/immunology , Severity of Illness Index , Young Adult
4.
Hamostaseologie ; 41(5): 387-396, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1483190

ABSTRACT

Hypercoagulability and vascular injury, which characterize morbidity in COVID-19 disease, are frequently observed in the skin. Several pathomechanisms, such as inflammation caused by angiotensin-converting enzyme 2-mediated uptake into endothelial cells or SARS-CoV-2-initiated host immune responses, contribute to microthrombus formation and the appearance of vascular skin lesions. Besides pathophysiologic mechanisms observed in the skin, this review describes the clinical appearance of cutaneous vascular lesions and their association with COVID-19 disease, including acro-ischemia, reticular lesions, and cutaneous small vessel vasculitis. Clinicians need to be aware that skin manifestations may be the only symptom in SARS-CoV-2 infection, and that inflammatory and thrombotic SARS-CoV-2-driven processes observed in multiple organs and tissues appear identically in the skin as well.


Subject(s)
COVID-19/complications , SARS-CoV-2 , Skin/blood supply , Angiotensin-Converting Enzyme 2/physiology , Antibodies, Antiphospholipid/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/pathology , COVID-19/pathology , COVID-19/physiopathology , Complement Activation , Cytokines/metabolism , Host Microbial Interactions/immunology , Host Microbial Interactions/physiology , Humans , Microvessels/immunology , Microvessels/pathology , Microvessels/physiopathology , Pandemics , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Skin/immunology , Vasculitis/etiology , Vasculitis/pathology , Vasculitis/physiopathology , Virus Internalization
5.
Int J Biol Macromol ; 193(Pt A): 948-955, 2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1471998

ABSTRACT

The severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) keeps on destroying normal social integrity worldwide, bringing about extraordinary medical services, cultural and financial interruption. Individuals with diabetes have been demonstrated to be at higher risk of complications and even death when exposed to SARS-CoV-2. Regardless of pandemic scale infection, there is presently limited comprehension on the potential impact of SARS-CoV-2 on individuals with diabetes. Human serum albumin (HSA) is the most abundant circulating plasma protein in human serum and attracted more interest from researchers because most susceptible to non-enzymatic glycation reactions. Albumin down-regulates the expression of ACE2 that is the target receptor of COVID-19. Hypoalbuminemia, coagulopathy, and vascular disease have been connected in COVID-19 and appear to predict outcomes independent of age and morbidity. This review discusses the most recent evidence that the ACE/ACE2 ratio could influence by human serum albumin both the susceptibility of individuals to SARS-CoV-2 infection and the outcome of the COVID-19 disease.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , COVID-19 , SARS-CoV-2/metabolism , Serum Albumin, Human/metabolism , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/therapy , COVID-19/blood , COVID-19/diagnosis , COVID-19/therapy , Disease Susceptibility , Humans , Vascular Diseases/blood , Vascular Diseases/diagnosis , Vascular Diseases/therapy
6.
Dtsch Med Wochenschr ; 146(15): 944-949, 2021 Aug.
Article in German | MEDLINE | ID: covidwho-1338575

ABSTRACT

COVID-19, primarily a respiratory disease, is considered a multi-systemic disease as symptom severity increases. Blood coagulation abnormalities are key features of patients with severe symptoms and indicative of the high risk of both venous and arterial thromboembolism in COVID-19. This prothrombotic condition caused by an interplay of the infectious agent, inflammation, and the blood coagulation system is referred to as COVID-19-associated coagulopathy and characterized by greatly increased D-dimer, high fibrinogen, an extended prothrombin time, and a reduced number of platelets. Due to this high thrombotic potential, prophylactic anticoagulation is recommended in all hospitalized patients. However, the optimal dosage of anticoagulation is still debated. In this article, we provide an overview of the current state of knowledge about COVID-19-associated coagulopathy and discuss clinical therapeutic consequences.


Subject(s)
Blood Coagulation Disorders/complications , COVID-19/complications , Thromboembolism/prevention & control , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/prevention & control , Blood Coagulation Disorders/therapy , COVID-19/blood , Humans , Severity of Illness Index , Thromboembolism/etiology
7.
Int J Mol Sci ; 22(15)2021 Jul 26.
Article in English | MEDLINE | ID: covidwho-1325684

ABSTRACT

In severe COVID-19, which is characterized by blood clots and neutrophil-platelet aggregates in the circulating blood and different tissues, an increased incidence of cardiovascular complications and venous thrombotic events has been reported. The inflammatory storm that characterizes severe infections may act as a driver capable of profoundly disrupting the complex interplay between platelets, endothelium, and leukocytes, thus contributing to the definition of COVID-19-associated coagulopathy. In this frame, P-selectin represents a key molecule expressed on endothelial cells and on activated platelets, and contributes to endothelial activation, leucocyte recruitment, rolling, and tissue migration. Briefly, we describe the current state of knowledge about P-selectin involvement in COVID-19 pathogenesis, its possible use as a severity marker and as a target for host-directed therapeutic intervention.


Subject(s)
Blood Coagulation Disorders/blood , COVID-19/complications , P-Selectin/blood , Blood Coagulation Disorders/etiology , Blood Platelets/metabolism , Endothelial Cells/metabolism , Humans , Leukocytes/metabolism
8.
J Thromb Haemost ; 18(7): 1747-1751, 2020 07.
Article in English | MEDLINE | ID: covidwho-1317985

ABSTRACT

BACKGROUND: Few observations exist with respect to the pro-coagulant profile of patients with COVID-19 acute respiratory distress syndrome (ARDS). Reports of thromboembolic complications are scarce but suggestive for a clinical relevance of the problem. OBJECTIVES: Prospective observational study aimed to characterize the coagulation profile of COVID-19 ARDS patients with standard and viscoelastic coagulation tests and to evaluate their changes after establishment of an aggressive thromboprophylaxis. METHODS: Sixteen patients with COVID-19 ARDS received a complete coagulation profile at the admission in the intensive care unit. Ten patients were followed in the subsequent 7 days, after increasing the dose of low molecular weight heparin, antithrombin levels correction, and clopidogrel in selected cases. RESULTS: At baseline, the patients showed a pro-coagulant profile characterized by an increased clot strength (CS, median 55 hPa, 95% interquartile range 35-63), platelet contribution to CS (PCS, 43 hPa; interquartile range 24-45), fibrinogen contribution to CS (FCS, 12 hPa; interquartile range 6-13.5) elevated D-dimer levels (5.5 µg/mL, interquartile range 2.5-6.5), and hyperfibrinogenemia (794 mg/dL, interquartile range 583-933). Fibrinogen levels were associated (R2  = .506, P = .003) with interleukin-6 values. After increasing the thromboprophylaxis, there was a significant (P = .001) time-related decrease of fibrinogen levels, D-dimers (P = .017), CS (P = .013), PCS (P = .035), and FCS (P = .038). CONCLUSION: The pro-coagulant pattern of these patients may justify the clinical reports of thromboembolic complications (pulmonary embolism) during the course of the disease. Further studies are needed to assess the best prophylaxis and treatment of this condition.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation Disorders/blood , Blood Coagulation , Coronavirus Infections/blood , Pneumonia, Viral/blood , Aged , Anticoagulants/administration & dosage , Biomarkers/blood , Blood Coagulation/drug effects , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/virology , Blood Coagulation Tests , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Female , Fibrinolytic Agents/administration & dosage , Host-Pathogen Interactions , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Prospective Studies , SARS-CoV-2 , Treatment Outcome
9.
J Thromb Haemost ; 18(7): 1752-1755, 2020 07.
Article in English | MEDLINE | ID: covidwho-1317980

ABSTRACT

A prothrombotic coagulopathy is commonly found in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID-19 respiratory failure is a relatively preserved lung compliance and high Alveolar-arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low-compliance in ARDS. The COVID-19 pandemic is overwhelming the world's medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID-19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation Disorders/drug therapy , Coronavirus Infections/drug therapy , Fibrinolysis/drug effects , Fibrinolytic Agents/administration & dosage , Pneumonia, Viral/drug therapy , Thrombolytic Therapy , Tissue Plasminogen Activator/administration & dosage , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/virology , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Fatal Outcome , Female , Fibrinolytic Agents/adverse effects , Host-Pathogen Interactions , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Recovery of Function , SARS-CoV-2 , Thrombolytic Therapy/adverse effects , Tissue Plasminogen Activator/adverse effects , Treatment Outcome
10.
JCI Insight ; 6(9)2021 05 10.
Article in English | MEDLINE | ID: covidwho-1228934

ABSTRACT

SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16Int) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16Int LDN subset contributes to COVID-19-associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.


Subject(s)
Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , COVID-19/blood , COVID-19/complications , Neutrophils/immunology , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Blood Coagulation Disorders/immunology , COVID-19/immunology , Cytokines/blood , Female , GPI-Linked Proteins/blood , Hospitalization , Humans , Inflammation Mediators/blood , Male , Middle Aged , Neutrophils/classification , Pandemics , Phagocytosis , Platelet Activation , Receptors, IgG/blood , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/immunology , Severity of Illness Index
11.
Oxid Med Cell Longev ; 2021: 6648199, 2021.
Article in English | MEDLINE | ID: covidwho-1211620

ABSTRACT

Introduction: Mortality among critically ill COVID-19 patients remains relatively high despite different potential therapeutic modalities being introduced recently. The treatment of critically ill patients is a challenging task, without identified credible predictors of mortality. Methods: We performed an analysis of 160 consecutive patients with confirmed COVID-19 infection admitted to the Respiratory Intensive Care Unit between June 23, 2020, and October 2, 2020, in University Hospital Center Bezanijska kosa, Belgrade, Serbia. Patients on invasive, noninvasive ventilation and high flow oxygen therapy with moderate to severe ARDS, according to the Berlin definition of ARDS, were selected for the study. Demographic data, past medical history, laboratory values, and CT severity score were analyzed to identify predictors of mortality. Univariate and multivariate logistic regression models were used to assess potential predictors of mortality in critically ill COVID-19 patients. Results: The mean patient age was 65.6 years (range, 29-92 years), predominantly men, 68.8%. 107 (66.9%) patients were on invasive mechanical ventilation, 31 (19.3%) on noninvasive, and 22 (13.8%) on high flow oxygen therapy machine. The median total number of ICU days was 10 (25th to 75th percentile: 6-18), while the median total number of hospital stay was 18 (25th to 75th percentile: 12-28). The mortality rate was 60% (96/160). Univariate logistic regression analysis confirmed the significance of age, CRP, and lymphocytes at admission to hospital, serum albumin, D-dimer, and IL-6 at admission to ICU, and CT score. Serum albumin, D-dimer, and IL-6 at admission to ICU were independently associated with mortality in the final multivariate analysis. Conclusion: In the present study of 160 consecutive critically ill COVID-19 patients with moderate to severe ARDS, IL-6, serum albumin, and D-dimer at admission to ICU, accompanied by chest CT severity score, were marked as independent predictors of mortality.


Subject(s)
Blood Coagulation Disorders/complications , COVID-19/complications , COVID-19/mortality , Cytokine Release Syndrome/complications , Oxygen Inhalation Therapy/methods , Respiratory Distress Syndrome/complications , SARS-CoV-2/genetics , Adult , Aged , Aged, 80 and over , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/virology , COVID-19/epidemiology , COVID-19/therapy , Critical Care , Critical Illness , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/virology , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Intensive Care Units , Interleukin-6/blood , Length of Stay , Male , Middle Aged , Real-Time Polymerase Chain Reaction , Respiration, Artificial , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/virology , Serbia/epidemiology , Serum Albumin, Human/analysis , Severity of Illness Index , Treatment Outcome
12.
Life Sci ; 276: 119376, 2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1157590

ABSTRACT

The severe forms and worsened outcomes of COVID-19 (coronavirus disease 19) are closely associated with hypertension and cardiovascular disease. Endothelial cells express Angiotensin-Converting Enzyme 2 (ACE2), which is the entrance door for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The hallmarks of severe illness caused by SARS-CoV-2 infection are increased levels of IL-6, C-reactive protein, D-dimer, ferritin, neutrophilia and lymphopenia, pulmonary intravascular coagulopathy and microthrombi of alveolar capillaries. The endothelial glycocalyx, a proteoglycan- and glycoprotein-rich layer covering the luminal side of endothelial cells, contributes to vascular homeostasis. It regulates vascular tonus and permeability, prevents thrombosis, and modulates leukocyte adhesion and inflammatory response. We hypothesized that cytokine production and reactive oxygen species (ROS) generation associated with COVID-19 leads to glycocalyx degradation. A cohort of 20 hospitalized patients with a confirmed COVID-19 diagnosis and healthy subjects were enrolled in this study. Mechanisms associated with glycocalyx degradation in COVID-19 were investigated. Increased plasma concentrations of IL-6 and IL1-ß, as well as increased lipid peroxidation and glycocalyx components were detected in plasma from COVID-19 patients compared to plasma from healthy subjects. Plasma from COVID-19 patients induced glycocalyx shedding in cultured human umbilical vein endothelial cells (HUVECs) and disrupted redox balance. Treatment of HUVECs with low molecular weight heparin inhibited the glycocalyx perturbation. In conclusion, plasma from COVID-19 patients promotes glycocalyx shedding and redox imbalance in endothelial cells, and heparin treatment potentially inhibits glycocalyx disruption.


Subject(s)
COVID-19/blood , COVID-19/pathology , Glycocalyx/pathology , Heparin/pharmacology , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/virology , COVID-19/metabolism , COVID-19 Testing , Case-Control Studies , Cell Adhesion/physiology , Endothelium, Vascular/metabolism , Female , Glycocalyx/metabolism , Glycocalyx/virology , Human Umbilical Vein Endothelial Cells , Humans , Interleukin-1beta/blood , Interleukin-6/blood , Male , Middle Aged , Oxidation-Reduction , SARS-CoV-2 , Thrombosis/metabolism
13.
Mol Cell Biochem ; 476(7): 2877-2885, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1141474

ABSTRACT

Coronavirus disease 2019 (COVID-19) induced by SARS-Cov-2 can be related to coagulopathy. Also, the infection-induced inflammatory changes are found in patients with disseminated intravascular coagulopathy (DIC). The lack of previous immunity to COVID-19 has caused infection of a large number of patients worldwide and unpredictability regarding the management of the complications that appear in the course of this viral illness. Lungs are the most important target organ of the SARS-COV-2. In COVID-19 patients, acute lung injury leads to respiratory failure. However, multiorgan failure can also occur in these patients. The primary coagulopathy of COVID-19 is marked by a considerable elevation of D-dimer, ferritin, and fibrinogen degradation products. In comparison, abnormalities in platelet count, prothrombin time, and partial thromboplastin time are partly uncommon in initial presentations. Inflammatory biomarkers including CRP, LDH, and IL-6 are significantly elevated in the early stages of the disease. In this regard, inflammation-associated biomarkers and coagulation test screening, including the assessment of IL-6, CRP, LDH, D-dimer, platelet count, PT&PTT time, ferritin, and fibrinogen levels are suggested for detecting infection by this virus. Overall, COVID-19-associated coagulopathy should be managed like other patients with critical conditions, and supportive care and thromboembolic prophylaxis should be used for severe patients.


Subject(s)
Blood Coagulation , COVID-19/blood , Fibrin Fibrinogen Degradation Products/analysis , Inflammation/blood , Biomarkers/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , COVID-19/complications , COVID-19/physiopathology , Ferritins/blood , Humans , Interleukin-6/blood , L-Lactate Dehydrogenase/blood , Platelet Count , Receptors, Immunologic/blood
14.
Trials ; 22(1): 202, 2021 Mar 10.
Article in English | MEDLINE | ID: covidwho-1127720

ABSTRACT

OBJECTIVES: To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. TRIAL DESIGN: Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial PARTICIPANTS: The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: 1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; 2) Admitted to hospital for COVID-19; 3) One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: a. D-Dimer ≥2 times ULN OR b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4) > 18 years of age; 5) Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: 1) pregnancy; 2) hemoglobin <80 g/L in the last 72 hours; 3) platelet count <50 x 109/L in the last 72 hours; 4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6) patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7) patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; 8) patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11) known history of heparin-induced thrombocytopenia; 12) known allergy to UFH or LMWH; 13) admitted to the intensive care unit at the time of screening; 14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; 15) Imminent death according to the judgement of the most responsible physician; 16) enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. INTERVENTION AND COMPARATOR: Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. MAIN OUTCOMES: The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): 1. All-cause death 2. Composite of ICU admission or all-cause death 3. Composite of mechanical ventilation or all-cause death 4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; 5. Red blood cell transfusion (>1 unit); 6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; 7. Renal replacement therapy; 8. Hospital-free days alive; 9. ICU-free days alive; 10. Ventilator-free days alive; 11. Organ support-free days alive; 12. Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 13. Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 14. Heparin induced thrombocytopenia; 15. Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. RANDOMISATION: Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. BLINDING (MASKING): No blinding involved. This is an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. TRIAL STATUS: Protocol Version Number 1.4. Recruitment began on May 11th, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Anticoagulants/therapeutic use , Blood Coagulation Disorders/drug therapy , COVID-19/drug therapy , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/complications , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , Clinical Trials, Phase III as Topic , Fibrin Fibrinogen Degradation Products/metabolism , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Hospitalization , Humans , Intensive Care Units/statistics & numerical data , Noninvasive Ventilation/statistics & numerical data , Pragmatic Clinical Trials as Topic , Randomized Controlled Trials as Topic , Respiration, Artificial/statistics & numerical data , SARS-CoV-2
15.
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
16.
J Thromb Haemost ; 18(9): 2103-2109, 2020 09.
Article in English | MEDLINE | ID: covidwho-1096903

ABSTRACT

The COVID-19 pandemic has become an urgent issue in every country. Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)-like massive intravascular clot formation is frequently seen in this cohort. Therefore, coagulation tests may be considered useful to discriminate severe cases of COVID-19. The clinical presentation of COVID-19-associated coagulopathy is organ dysfunction primarily, whereas hemorrhagic events are less frequent. Changes in hemostatic biomarkers represented by increase in D-dimer and fibrin/fibrinogen degradation products indicate the essence of coagulopathy is massive fibrin formation. In comparison with bacterial-sepsis-associated coagulopathy/DIC, prolongation of prothrombin time, and activated partial thromboplastin time, and decrease in antithrombin activity is less frequent and thrombocytopenia is relatively uncommon in COVID-19. The mechanisms of the coagulopathy are not fully elucidated, however. It is speculated that the dysregulated immune responses orchestrated by inflammatory cytokines, lymphocyte cell death, hypoxia, and endothelial damage are involved. Bleeding tendency is uncommon, but the incidence of thrombosis in COVID-19 and the adequacy of current recommendations regarding standard venous thromboembolic dosing are uncertain.


Subject(s)
Blood Coagulation Disorders/blood , COVID-19/epidemiology , Disseminated Intravascular Coagulation/blood , Anticoagulants , Blood Coagulation , Blood Coagulation Disorders/complications , Blood Coagulation Tests , COVID-19/complications , Cytokines/metabolism , Disseminated Intravascular Coagulation/complications , Fibrin/chemistry , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/chemistry , Fibrinolysis , Hemorrhage , Hemostasis , Humans , Inflammation , Lung/metabolism , Lung/virology , Lymphocytes/metabolism , Partial Thromboplastin Time , Protease Inhibitors , Prothrombin Time , Sepsis , Thrombosis/metabolism
17.
Med Intensiva (Engl Ed) ; 45(1): 42-55, 2021.
Article in English, Spanish | MEDLINE | ID: covidwho-1065468

ABSTRACT

During the new pandemic caused by SARS-CoV-2, there is short knowledge regarding the management of different disease areas, such as coagulopathy and interpretation of D-dimer levels, its association with disseminated intravascular coagulation (DIC) and controversy about the benefit of anticoagulation. Thus, a systematic review has been performed to define the role of D-dimer in the disease, the prevalence of DIC and the usefulness of anticoagulant treatment in these patients. A literature search was performed to analyze the studies of COVID-19 patients. Four recommendations were drawn based on expert opinion and scientific knowledge, according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The present review suggests the presence of higher levels of D-dimer in those with worse prognosis, there may be an overdiagnosis of DIC in the course of the disease and there is no evidence on the benefit of starting anticoagulant treatment based only on isolated laboratory data.


Subject(s)
Anticoagulants/therapeutic use , Blood Coagulation Disorders/blood , COVID-19/blood , Disseminated Intravascular Coagulation/blood , Fibrin Fibrinogen Degradation Products/analysis , SARS-CoV-2 , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/mortality , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/mortality , Critical Illness , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/drug therapy , Disseminated Intravascular Coagulation/epidemiology , Humans , Medical Overuse , Observational Studies as Topic , Pandemics , Prevalence , Prognosis
18.
J Thromb Haemost ; 19(2): 522-530, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1059727

ABSTRACT

BACKGROUND: Multiple investigators have described an increased incidence of thromboembolic events in SARS-CoV-2-infected individuals. Data concerning hemostatic complications in children hospitalized for COVID-19/multisystem inflammatory syndrome in children (MIS-C) are scant. OBJECTIVES: To share our experience in managing SARS-CoV-2-associated pro-coagulant state in hospitalized children. METHODS: D-dimer values were recorded at diagnosis in children hospitalized for SARS-CoV-2-related manifestations. In moderately to critically ill patients and MIS-C cases, coagulation and inflammatory markers were checked at multiple time points and median results were compared. Pro-thrombotic risk factors were appraised for each child and thromboprophylaxis was started in selected cases. RESULTS: Thirty-five patients were prospectively enrolled. D-dimer values did not discriminate COVID-19 of differing severity, whereas were markedly different between the COVID-19 and the MIS-C cohorts. In both cohorts, D-dimer and C-reactive protein levels increased upon clinical worsening but were not accompanied by decreased fibrinogen or platelet values, with all parameters returning to normal upon disease resolution. Six patients had multiple thrombotic risk factors and were started on pharmacological thromboprophylaxis. No deaths or thrombotic or bleeding complications occurred. CONCLUSIONS: COVID-19 pediatric patients show mildly altered coagulation and inflammatory parameters; on the other hand, MIS-C cases showed laboratory signs of an inflammatory driven pro-coagulant status. Universal anticoagulant prophylaxis in hospitalized children with SARS-CoV-2-related manifestations is not warranted, but may be offered to patients with other pro-thrombotic risk factors in the context of a multi-modal therapeutic approach.


Subject(s)
Anticoagulants/therapeutic use , Blood Coagulation Disorders/drug therapy , Blood Coagulation/drug effects , COVID-19/drug therapy , Thromboembolism/prevention & control , Adolescent , Age Factors , Biomarkers/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , COVID-19/blood , COVID-19/complications , Child , Child, Preschool , Clinical Decision-Making , Female , Hospitalization , Humans , Infant , Infant, Newborn , Italy , Male , Prospective Studies , Risk Factors , Thromboembolism/blood , Thromboembolism/etiology , Time Factors , Treatment Outcome , Young Adult
19.
Eur Rev Med Pharmacol Sci ; 25(1): 518-522, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1052578

ABSTRACT

OBJECTIVE: From the beginning of the novel coronavirus infection (COVID-19) pandemic in the world, much efforts have been accomplished to explain a precise clinical feature for the disease and to find the best therapeutic approach for the patients. Although coagulation abnormalities have found in novel coronavirus infection (COVID-19) patients, still little is known about the association between the disease and changes in coagulation parameters. Our purpose is to evaluate the differences between the coagulation parameters between COVID-19 patients and healthy counterparts. PATIENTS AND METHODS: 63 patients with confirmed COVID-19 infection were admitted to the present study. We evaluated coagulation value in these patients and in 40 healthy individuals. RESULTS: We found that although there was no significant difference between PT and PTT values in patients and healthy counterparts, the fibrinogen values in patients were higher than the control group (p < 0.05). Moreover, the values of fibrin/fibrinogen degradation products (FDP) and D-dimer in all COVID-19 cases were considerably higher than those in control people (p < 0.05). Of note, FDP and D-dimer in patients with regular COVID-19 infection were lower than patients with severe forms. CONCLUSIONS: It seems that the conduction of routine blood coagulation test could be a beneficial supplementary approach for early diagnosis of COVID-19. In addition, our study shed more light on the therapeutic value of anti-coagulant-based treatment for COVID-19 patients, especially for those with severe type of the disease.


Subject(s)
Blood Coagulation Disorders/blood , Blood Coagulation Disorders/prevention & control , COVID-19/blood , Fibrin Fibrinogen Degradation Products/analysis , Anticoagulants/administration & dosage , Anticoagulants/therapeutic use , Blood Coagulation/drug effects , Blood Coagulation Disorders/etiology , Blood Coagulation Tests , COVID-19/complications , Case-Control Studies , Clinical Laboratory Techniques , Female , Humans , Male , Predictive Value of Tests , SARS-CoV-2
20.
Acta Med Port ; 34(1): 44-55, 2021 Jan 04.
Article in English | MEDLINE | ID: covidwho-1049254

ABSTRACT

COVID-19 associated coagulopathy is a dysfunction of severe SARS-CoV-2 infection, characterized by significantly increased fibrinogen, D-dimer and C reactive protein and normal to near-normal prothrombin time, activated partial thromboplastin time and platelet count. Hypercoagulopathy and hypofibrinolysis coexist and are detected by viscoelastic tests. These features, when associated with immobilization and intrinsic risk factors (age, obesity, comorbidities, drugs) of the patient, can trigger thromboembolic events, despite thromboprophylaxis. The lungs are the first and most severely damaged organ. To date, most patients have exhibited hypercoagulability on viscoelastic tests not detected by standard coagulation tests. A high rate of thrombotic events was reported, suggesting that it should be considered as a cause of clinical deterioration in intensive care and potentially other clinical settings. In advanced stage, COVID-19 associated coagulopathy, fibrinogen and platelet count can decrease significantly, depending on the severity of clinical status resembling consumptive coagulopathy. In this stage, bleeding events can occur, especially if the patient is under extracorporeal membrane oxygenation (ECMO). Viscoelastic tests are very useful tools to assess hypercoagulability and hypofibrinolysis (not detectable by standard coagulation tests) in critically ill SARS-CoV-2 patients with COVID-19 associated coagulopathy and look like very promising tools for anticoagulation management. However, further research needs to be carried out to determine whether abnormal viscoelastic tests alone or in combination with other clinical or laboratory findings can identify patients at increased thrombotic risk. Clinical trials to evaluate hypercoagulability using viscoelastic tests and the need for personalized dosage of anticoagulation in SARS-CoV-2 patientsare quickly emerging.


A coagulopatia associada à COVID-19 é uma disfunção associada à infeção SARS-CoV-2 grave, caraterizada por aumento significativo do fibrinogénio, D-dímeros e Proteína C reativa, e por valores normais/muito pouco alterados do tempo de protrombina, tempo de tromboplastina parcial ativado, e número de plaquetas. A hipercoagulabilidade e a hipofibrinólise coexistem e são detetadas por testes viscoelásticos. Quando associadas à imobilização e aos fatores de risco intrínsecos do doente (idade, obesidade, comorbilidades, drogas) potenciam eventos tromboembólicos, apesar da tromboprofilaxia. Os pulmões são o órgão inicialmente e mais gravemente afetado. Até à data, a maioria dos doentes apresentou hipercoagulabilidade nos testes viscoelásticos, não detetada pelos testes de coagulação de rotina, e foi reportada uma elevada taxa de eventos trombóticos, sugerindo que esta deveria ser considerada uma das causas de deterioração clínica, não só em cuidados intensivos. Na coagulopatia associada à COVID-19 avançada, o número de plaquetas e o fibrinogénio podem diminuir significativamente, dependendo da gravidade clínica da infeção, assemelhando-se o quadro a uma coagulopatia de consumo. Nesta fase pode haver hemorragia, especialmente se o doente estiver sob extracorporeal membrane oxygenation. Os testes viscoelásticos afiguram-se muito úteis para avaliar a hipercoagulabilidade e a hipofibrinólise em doentes críticos SARS-CoV-2 com coagulopatia associada à COVID-19, parecendo também promissores para a gestão da anticoagulação. No entanto, é necessária mais investigação para determinar se testes viscoelásticos alterados, individualmente ou quando combinadoscom outros resultados clínicos/laboratoriais, podem identificar os doentes com risco trombótico acrescido. Estão a emergir rapidamente ensaios clínicos para avaliação da hipercoagulabilidade por testes viscoelásticos e da necessidade de personalização da anticoagulação em doentes SARS-CoV-2.


Subject(s)
Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/physiopathology , COVID-19/complications , COVID-19/physiopathology , Hemostasis , Blood Coagulation Disorders/blood , COVID-19/blood , Elasticity , Hematologic Tests , Humans , Viscosity
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