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1.
Int J Mol Sci ; 23(9)2022 Apr 29.
Article in English | MEDLINE | ID: covidwho-1820292

ABSTRACT

High prevalence of both criteria and extra-criteria antiphospholipid antibodies (aPL) has been reported in COVID-19 patients. However, the differences in aPL prevalence decreased when an age-matched control group was included. The association of aPL with thrombotic events in COVID-19 is very heterogeneous. This could be influenced by the fact that most of the studies carried out were conducted on small populations enriched with elderly patients in which aPL was measured only at a single point and they were performed with non-standardized assays. The few studies that confirmed aPL in a second measurement showed that aPL levels hardly changed, with the exception of the lupus anticoagulant that commonly reduced. COVID-19 coagulopathy is an aPL-independent phenomenon closely associated with the onset of the disease. Thrombosis occurs later in patients with aPL presence, which is likely an additional prothrombotic factor. B2-glycoprotein deficiency (mainly aPL antigen caused both by low production and consumption) is very common during the SARS-CoV2 infection and has been associated with a greater predisposition to COVID-19 complications. This could be a new prothrombotic mechanism that may be caused by the blockage of its physiological functions, the anticoagulant state being the most important.


Subject(s)
Antiphospholipid Syndrome , Blood Coagulation Disorders , COVID-19 , Thrombosis , Aged , Antibodies, Antiphospholipid , Antiphospholipid Syndrome/complications , Blood Coagulation Disorders/complications , COVID-19/complications , Humans , RNA, Viral , SARS-CoV-2
2.
Anesthesiology ; 137(1): 67-78, 2022 Jul 01.
Article in English | MEDLINE | ID: covidwho-1784403

ABSTRACT

BACKGROUND: COVID-19 causes hypercoagulability, but the association between coagulopathy and hypoxemia in critically ill patients has not been thoroughly explored. This study hypothesized that severity of coagulopathy would be associated with acute respiratory distress syndrome severity, major thrombotic events, and mortality in patients requiring intensive care unit-level care. METHODS: Viscoelastic testing by rotational thromboelastometry and coagulation factor biomarker analyses were performed in this prospective observational cohort study of critically ill COVID-19 patients from April 2020 to October 2020. Statistical analyses were performed to identify significant coagulopathic biomarkers such as fibrinolysis-inhibiting plasminogen activator inhibitor 1 and their associations with clinical outcomes such as mortality, extracorporeal membrane oxygenation requirement, occurrence of major thrombotic events, and severity of hypoxemia (arterial partial pressure of oxygen/fraction of inspired oxygen categorized into mild, moderate, and severe per the Berlin criteria). RESULTS: In total, 53 of 55 (96%) of the cohort required mechanical ventilation and 9 of 55 (16%) required extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation-naïve patients demonstrated lysis indices at 30 min indicative of fibrinolytic suppression on rotational thromboelastometry. Survivors demonstrated fewer procoagulate acute phase reactants, such as microparticle-bound tissue factor levels (odds ratio, 0.14 [0.02, 0.99]; P = 0.049). Those who did not experience significant bleeding events had smaller changes in ADAMTS13 levels compared to those who did (odds ratio, 0.05 [0, 0.7]; P = 0.026). Elevations in plasminogen activator inhibitor 1 (odds ratio, 1.95 [1.21, 3.14]; P = 0.006), d-dimer (odds ratio, 3.52 [0.99, 12.48]; P = 0.05), and factor VIII (no clot, 1.15 ± 0.28 vs. clot, 1.42 ± 0.31; P = 0.003) were also demonstrated in extracorporeal membrane oxygenation-naïve patients who experienced major thrombotic events. Plasminogen activator inhibitor 1 levels were significantly elevated during periods of severe compared to mild and moderate acute respiratory distress syndrome (severe, 44.2 ± 14.9 ng/ml vs. mild, 31.8 ± 14.7 ng/ml and moderate, 33.1 ± 15.9 ng/ml; P = 0.029 and 0.039, respectively). CONCLUSIONS: Increased inflammatory and procoagulant markers such as plasminogen activator inhibitor 1, microparticle-bound tissue factor, and von Willebrand factor levels are associated with severe hypoxemia and major thrombotic events, implicating fibrinolytic suppression in the microcirculatory system and subsequent micro- and macrovascular thrombosis in severe COVID-19.


Subject(s)
Blood Coagulation Disorders , COVID-19 , Respiratory Distress Syndrome , Thrombophilia , Thrombosis , Blood Coagulation Disorders/complications , COVID-19/complications , Critical Illness , Fibrinolysis , Humans , Hypoxia/complications , Microcirculation , Oxygen , Plasminogen Activator Inhibitor 1 , Prospective Studies , Retrospective Studies , Thrombophilia/complications , Thromboplastin
3.
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
4.
Viruses ; 13(12)2021 11 25.
Article in English | MEDLINE | ID: covidwho-1542795

ABSTRACT

Diagnosis of SARS-CoV-2 infections is mostly based on the nasopharyngeal swabs (NPS). However, this collection is invasive and uncomfortable, especially for children and patients with coagulopathies, whose NPS collection often causes bleeding. Thus, the aim of this study was to evaluate the usefulness and accuracy of saliva for the diagnosis of COVID-19 in patients presenting bleeding disorders. Samples of NPS, oropharyngeal swabs (OPS), and saliva were collected simultaneously from 1159 hospitalized patients with hematological diseases and from 524 healthcare workers, both symptomatic and asymptomatic for SARS-CoV-2. All samples were evaluated for SARS-CoV-2 by qRT-PCR. SARS-CoV-2 was detected in NPS, OPS and saliva from 16.9%, 14.4% and 15.6% individuals, respectively. Tests in saliva showed sensitivity, specificity, and overall agreement of 73.3%, 96.9% and 92.7% (=0.74), respectively. Salivary tests had good accuracy (AUC = 0.7) for discriminating negative and positive qRT-PCR for SARS-CoV-2. Higher sensitivity was observed in symptomatic than in non-symptomatic patients, as well as in healthy subjects than in patients with hematological disease, in both OPS and saliva. The mean viral load in NPS was significantly higher than in OPS and in saliva samples (p < 0.001). Saliva is a good diagnostic tool to detect SARS-CoV-2, especially among patients symptomatic for COVID-19, and is a valuable specimen for mass screening of hospitalized patients with hematological diseases, especially for those that with bleeding disorders.


Subject(s)
Blood Coagulation Disorders/complications , COVID-19/complications , COVID-19/diagnosis , Hemorrhagic Disorders/complications , SARS-CoV-2/isolation & purification , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/virology , COVID-19 Testing , Child , Child, Preschool , Cohort Studies , Diagnostic Tests, Routine , Female , Health Personnel , Humans , Infant , Male , Middle Aged , Saliva , Viral Load , Young Adult
5.
Cytokine Growth Factor Rev ; 63: 58-68, 2022 02.
Article in English | MEDLINE | ID: covidwho-1474467

ABSTRACT

Severe COVID-19 patients frequently present thrombotic complications which commonly lead to multiorgan failure and increase the risk of death. Severe SARS-CoV-2 infection induces the cytokine storm and is often associated with coagulation dysfunction. D-dimer, a hallmark of venous thromboembolism (VTE), is observed at a higher level in the majority of hospitalized COVID-19 patients. The precise molecular mechanism of the disproportionate effect of SARS-CoV-2 infection on the coagulation system is largely undefined. SARS-CoV-2 -induced endotheliopathy and, induction of cytokines and growth factors (GFs) most likely play important roles in platelet activation, coagulopathy, and VTE. Generally, viral infections lead to systemic inflammation and induction of numerous cytokines and GFs and many of them are reported to be associated with increased VTE. Most importantly, platelets play key thromboinflammatory roles linking coagulation to immune mediators in a variety of infections including response to viral infection. Since the pathomechanism of coagulopathy and VTE in COVID-19 is largely undefined, herein we highlight the association of dysregulated inflammatory cytokines and GFs with thrombotic complications and coagulopathy in COVID-19.


Subject(s)
Blood Coagulation Disorders , COVID-19 , Venous Thromboembolism , Blood Coagulation Disorders/complications , COVID-19/complications , Cytokines , Humans , SARS-CoV-2 , Venous Thromboembolism/etiology
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.
J Investig Med High Impact Case Rep ; 9: 23247096211019559, 2021.
Article in English | MEDLINE | ID: covidwho-1243797

ABSTRACT

In this article, we report a case of a 61-year-old male who was diagnosed with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), presenting with acute respiratory distress syndrome requiring intubation and hemodynamic support, marked D-Dimer and troponin I elevation, worsening ST-elevation myocardial infarction on repeat electrocardiograms, and a negative coronary angiogram ruling out a coronary artery thrombosis or occlusion. With worsening diffuse ST-segment elevation on electrocardiograms and reduced ejection fraction on echocardiography in the setting of systemic inflammation, fulminant myocarditis was highly suspected. Despite optimal medical treatment, the patient's condition deteriorated and was complicated by cardiac arrest that failed resuscitation. Although myocarditis was initially suspected, the autopsy revealed no evidence of myocarditis or pericarditis but did demonstrate multiple microscopic sites of myocardial ischemia together with thrombi in the left atrium and pulmonary vasculature. Additionally, scattered microscopic cardiomyocyte necrosis with pathological diagnosis of small vessel micro-thrombotic occlusions. These findings are potentially exacerbated by inflammation-induced coagulopathy, hypoxia, hypotension, and stress, that is, a multifactorial etiology. Further research and an improved understanding are needed to define the precise pathophysiology of the coagulopathic state causing widespread micro-thrombosis with subsequent myocardial and pulmonary injury.


Subject(s)
Blood Coagulation Disorders/complications , COVID-19/epidemiology , Myocarditis/etiology , Pulmonary Embolism/etiology , SARS-CoV-2 , ST Elevation Myocardial Infarction/etiology , COVID-19/complications , Coronary Angiography , Electrocardiography , Fatal Outcome , Humans , Male , Middle Aged , Myocarditis/diagnosis , Myocarditis/virology , Pulmonary Embolism/diagnosis , Radiography, Thoracic
9.
Viruses ; 13(5)2021 05 11.
Article in English | MEDLINE | ID: covidwho-1224259

ABSTRACT

Infection with SARS-CoV-2 leading to COVID-19 induces hyperinflammatory and hypercoagulable states, resulting in arterial and venous thromboembolic events. Deep vein thrombosis (DVT) has been well reported in COVID-19 patients. While most DVTs occur in a lower extremity, involvement of the upper extremity is uncommon. In this report, we describe the first reported patient with an upper extremity DVT recurrence secondary to COVID-19 infection.


Subject(s)
COVID-19/complications , COVID-19/diagnosis , Venous Thrombosis/complications , Venous Thrombosis/diagnosis , Aged, 80 and over , Blood Coagulation Disorders/complications , Humans , Male , Neoplasm Recurrence, Local , Polymerase Chain Reaction , RNA, Viral , Recurrence , Risk Factors , Upper Extremity/blood supply , Venous Thrombosis/therapy
10.
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
11.
A A Pract ; 15(4): e01432, 2021 Mar 30.
Article in English | MEDLINE | ID: covidwho-1158241

ABSTRACT

The role of concurrent illness in coronavirus disease 2019 (COVID-19) is unknown. Patients with leukemia may display altered thromboinflammatory responses. We report a 53-year-old man presenting with acute leukemia and COVID-19 who developed thrombotic complications and acute respiratory distress syndrome. Multiple analyses, including rotational thromboelastometry and flow cytometry on blood and bronchoalveolar lavage, are reported to characterize coagulation and immune profiles. The patient developed chemotherapy-induced neutropenia that may have protected his lungs from granulocyte-driven hyperinflammatory acute lung injury. However, neutropenia also alters viral clearing, potentially enabling ongoing viral propagation. This case depicts a precarious equilibrium between leukemia and COVID-19.


Subject(s)
Acute Lung Injury/complications , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/pathology , COVID-19/complications , COVID-19/pathology , Leukemia, Myeloid, Acute/complications , Acute Lung Injury/diagnosis , Acute Lung Injury/pathology , Blood Coagulation Disorders/diagnosis , Bronchoalveolar Lavage , COVID-19/diagnosis , Flow Cytometry , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Neutropenia/complications , Neutropenia/diagnosis , Neutropenia/pathology , SARS-CoV-2 , Thrombelastography , Virulence Factors
12.
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
13.
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
14.
Int J Environ Res Public Health ; 18(3)2021 01 31.
Article in English | MEDLINE | ID: covidwho-1055064

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease. Bilateral pneumonia, acute respiratory failure, systemic inflammation, endothelial dysfunction and coagulation activation are key features of severe COVID-19. Fibrinogen and D-dimer levels are typically increased. The risk for venous thromboembolism is markedly increased, especially in patients in the intensive care unit despite prophylactic dose anticoagulation. Pulmonary microvascular thrombosis has also been described and the risk for arterial thrombotic diseases also appears to be increased while bleeding is less common than thrombosis, but it can occur. Evaluation for venous thromboembolism may be challenging because symptoms of pulmonary embolism overlap with COVID-19, and imaging studies may not be feasible in all cases. The threshold for evaluation or diagnosis of thromboembolism should be low given the high frequency of these events. Management and treatment are new challenges due to the paucity of high-quality evidence regarding efficacy and safety of different approaches to prevent or treat thromboembolic complications of the disease. All inpatients should receive thromboprophylaxis unless contraindicated. Some institutional protocols provide more aggressive anticoagulation with intermediate or even therapeutic dose anticoagulation for COVID-19 patients admitted to ICU. Therapeutic dose anticoagulation is always appropriate to treat deep venous thrombosis or pulmonary embolism, unless contraindicated. This article reviews evaluation and management of coagulation abnormalities in individuals with COVID-19.


Subject(s)
Blood Coagulation Disorders , COVID-19 , Risk Management , Venous Thromboembolism , Anticoagulants/therapeutic use , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/drug therapy , COVID-19/complications , Humans , Venous Thromboembolism/complications , Venous Thromboembolism/drug therapy
15.
Blood Coagul Fibrinolysis ; 32(3): 225-228, 2021 Apr 01.
Article in English | MEDLINE | ID: covidwho-1028646

ABSTRACT

Coronavirus disease 2019 (COVID-19)-associated coagulopathy is unusual, poorly defined and is linked with significant hypercoagulability and microthrombotic and macrothrombotic complications leading to worse outcomes and higher mortality. Conventional coagulation assays do not always actively reflect these derangements and might fail to detect this coagulopathy. Viscoelastic hemostatic assays (VHA) provide a possible tool that adds to conventional coagulation assays in identifying this hypercoagulable state. VHA has been mostly used in surgery and trauma but it's still not well defined in sepsis patients with lack of large randomized trials. Few studies described VHA findings in patients with COVID-19 showing significant hypercoagulability and fibrinolysis shutdown. Clinicians taking care of these patients might have little experience interpreting VHA results. By reviewing the available literature on the use of VHA in sepsis, and the current knowledge on COVID-19-associated coagulopathy we provide clinicians with a practical guide on VHA utilization in patients with COVID-19.


Subject(s)
Blood Coagulation Disorders/diagnosis , COVID-19/blood , Hemostasis , Thrombelastography , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/virology , COVID-19/complications , COVID-19/physiopathology , Critical Illness , Humans , Sepsis/blood
16.
Int J Mol Sci ; 22(1)2020 Dec 30.
Article in English | MEDLINE | ID: covidwho-1006950

ABSTRACT

Nintedanib is a synthetic orally active tyrosine kinase inhibitor, whose main action is to inhibit the receptors of the platelet-derived growth factor, fibroblast growth factor and vascular endothelial growth factor families. The drug also affects other kinases, including Src, Flt-3, LCK, LYN. Nintedanib is used in the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases and lung cancer. The mechanism of action suggests that nintedanib should be considered one of the potential agents for inhibiting and revising the fibrosis process related to COVID-19 infections. Due to the known induction of coagulation pathways during COVID-19 infections, possible interaction between nintedanib and anticoagulant seems to be an extremely important issue. In theory, nintedanib could increase the bleeding risk, thrombosis and lead to thrombocytopenia. The data from clinical trials on the concomitant use of nintedanib and antithrombotic agents is very limited as this patient group was within the standard exclusion criteria. Nintedanib is an important therapeutic option, despite its interaction with anticoagulants. If anticoagulant therapy is necessary, the more effective and safer option is the concomitant administration of DOACs and nintedanib, especially when drug-monitored therapy will be used in patients at high risk of bleeding complications.


Subject(s)
Anticoagulants/pharmacology , Hemorrhage/etiology , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Anticoagulants/therapeutic use , Antidotes/pharmacology , Antineoplastic Agents/pharmacology , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/drug therapy , COVID-19/complications , COVID-19/drug therapy , COVID-19/metabolism , Drug Interactions , Hemorrhage/epidemiology , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Indoles/adverse effects , Indoles/therapeutic use , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Risk Factors
17.
Eur Rev Med Pharmacol Sci ; 24(24): 13044-13048, 2020 12.
Article in English | MEDLINE | ID: covidwho-1000849

ABSTRACT

As a severe and highly contagious infection, coronavirus disease (COVID-19) affects all aspects of society and has become a global public health problem. Because of the complexity of the pathology of COVID-19, it is difficult to treat. An increasing number of reports have indicated that COVID-19 may have neurological complications, including stroke. The nervous system complications of COVID-19 have gradually attracted research attention. In this review, we summarize the latest findings related to COVID 19, elaborate on the possible mechanism of COVID 19 related onset of stroke, and summarize current treatment options because an improved understanding and appropriate treatments may improve the prognosis of patients with COVID-19-related stroke.


Subject(s)
Anosmia/physiopathology , COVID-19/physiopathology , Headache/physiopathology , Stroke/physiopathology , Taste Disorders/physiopathology , Angiotensin-Converting Enzyme 2/metabolism , Anticoagulants/therapeutic use , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/physiopathology , COVID-19/complications , COVID-19/immunology , COVID-19/therapy , Consciousness Disorders/physiopathology , Cytokines/immunology , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Humans , Receptors, Coronavirus/metabolism , Renin-Angiotensin System , SARS-CoV-2 , Stockings, Compression , Stroke/etiology , Stroke/immunology , Stroke/therapy , Thrombolytic Therapy
18.
Med Hypotheses ; 147: 110475, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-988867

ABSTRACT

Coagulopathy has recently been recognized as a recurring complication of COVID-19, most typically associated with critical illness. There are epidemiological, mechanistic and transcriptomic evidence that link Selenium with SARS-CoV-2's intracellular latency. Taking into consideration the vital role of selenoproteins in maintaining an adequate immune response, endothelial homeostasis and a non-prothrombotic platelet activation status, we propose that impairment in selenocysteine synthesis, via perturbations in the aforementioned physiological functions, potentially constitutes a mechanism of coagulopathy in COVID 19 patients other than those developed in critical illness.


Subject(s)
Blood Coagulation Disorders/complications , COVID-19/complications , SARS-CoV-2/pathogenicity , Selenocysteine/biosynthesis , Blood Coagulation Disorders/virology , Blood Platelets/metabolism , Critical Illness , Endothelium, Vascular/metabolism , Homeostasis , Humans , Immune System , Inflammation , Models, Theoretical , Oxidative Stress , Platelet Activation , Selenium/chemistry , Selenocysteine/chemistry , Transcriptome
19.
Phytomedicine ; 81: 153433, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-957350

ABSTRACT

OBJECTIVE: Previous studies mainly reported the clinical characteristics of novel coronavirus 2019 (COVID-19) infections, but the research on clinical characteristics and treatment outcomes of COVID-19 patients with stroke is still rare. METHODS: A multi-center retrospective study was conducted at 11 hospitals in 4 provinces of China, and COVID-19 patients with stroke were enrolled from February 24 to May 4, 2020. We analyzed epidemiological, demographic, and clinical characteristics of cases as well as the laboratory test results, treatment regimens and outcomes, and the clinical characteristics and therapeutic outcomes were compared between severe and nonsevere patients, and by age group, respectively. RESULTS: A total of 27 patients [mean age: 66.41 (SD 12.1) years] were enrolled. Among them, 9 (33.3%) were severe patients and 18 (66.7%) were nonsevere patients; 17 (63.0%) were female; 19 (70.4%) were aged 60 years and above. The most common symptoms were fever [19 (70.4%)], fatigue [12 (44.4%)] and cough [11 (40.7%)], respectively. Abnormal laboratory findings of COVID-19 patients with stroke included high levels of C-reactive protein [19 (73.1%)], D-dimer [14 (58.3%)], blood glucose [14 (53.8%)], fibrinogen [13 (50.0%)], and decreased lymphocytes [12 (44.4%)]. Comparing to nonsevere cases with stroke, severe patients with stroke were likely to be older, susceptible to receiving oxygen inhalation, and had more complications (p < 0.05). In addition, there were significant differences in lymphocytes, neutrophils, lactate dehydrogenase, C-reactive protein, creatine kinase between the severe cases and nonsevere cases (p < 0.05). The older patients had a decreased platelet count and elevated fibrinogen, compared with the younger (p < 0.05). All patients (100%) received antiviral treatment, 12 (44.4%) received antibiotics treatment, 26 (96.3%) received Traditional Chinese Medicine (Lung cleansing & detoxifying decoction), and oxygen inhalation was in 18 (66.7%). The median duration of hospitalization was 16 days. By May 4, 2020, a total of 26 (96.3%) patients were cured and discharged, and 1 (3.7%) patients died. CONCLUSION: COVID-19 patients with stroke had poor indicators of coagulation system, and severe and older patients might have a higher risk of complications and unfavorable coagulation system. However, the overall treatment outcome is favorable.


Subject(s)
COVID-19/complications , COVID-19/therapy , Stroke/complications , Stroke/therapy , Adult , Age Factors , Aged , Aged, 80 and over , Antiviral Agents/therapeutic use , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/therapy , COVID-19/epidemiology , China/epidemiology , Female , Humans , Male , Middle Aged , Oxygen Inhalation Therapy , Retrospective Studies , Stroke/epidemiology , Treatment Outcome
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