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1.
Medicina intensiva ; 2022.
Article in English | EuropePMC | ID: covidwho-2092460

ABSTRACT

Objective To evaluate the rate of thrombosis, bleeding and mortality comparing anticoagulant doses in critically ill COVID-19 patients. Design Retrospective observational and analytical cohort study. Setting COVID-19 patients admitted to the intensive care unit of a tertiary hospital between March and April 2020. Patients 201 critically ill COVID-19 patients were included. Patients were categorized into three groups according to the highest anticoagulant dose received during hospitalization: prophylactic, intermediate and therapeutic. Interventions The incidence of venous thromboembolism (VTE), bleeding and mortality was compared between groups. We performed two logistic multivariable regressions to test the association between VTE and bleeding and the anticoagulant regimen. Main variables of interest VTE, bleeding and mortality. Results 78 patients received prophylactic, 94 intermediate and 29 therapeutic doses. No differences in VTE and mortality were found, while bleeding events were more frequent in the therapeutic (31%) and intermediate (15%) dose group than in the prophylactic group (5%) (p < 0.001 and p < 0.05 respectively). The anticoagulant dose was the strongest determinant for bleeding (odds ratio 2.4, 95% confidence interval 1.26–4.58, p = 0.008) but had no impact on VTE. Conclusions Intermediate and therapeutic doses appear to have a higher risk of bleeding without a decrease of VTE events and mortality in critically ill COVID-19 patients.

2.
Medicina Intensiva (English Edition) ; 2022.
Article in English | ScienceDirect | ID: covidwho-2086553

ABSTRACT

Objective To evaluate the rate of thrombosis, bleeding and mortality comparing anticoagulant doses in critically ill COVID-19 patients. Design Retrospective observational and analytical cohort study. Setting COVID-19 patients admitted to the intensive care unit of a tertiary hospital between March and April 2020. Patients 201 critically ill COVID-19 patients were included. Patients were categorized into three groups according to the highest anticoagulant dose received during hospitalization: prophylactic, intermediate and therapeutic. Interventions The incidence of venous thromboembolism (VTE), bleeding and mortality was compared between groups. We performed two logistic multivariable regressions to test the association between VTE and bleeding and the anticoagulant regimen. Main variables of interest VTE, bleeding and mortality. Results 78 patients received prophylactic, 94 intermediate and 29 therapeutic doses. No differences in VTE and mortality were found, while bleeding events were more frequent in the therapeutic (31%) and intermediate (15%) dose group than in the prophylactic group (5%) (p<0.001 and p<0.05 respectively). The anticoagulant dose was the strongest determinant for bleeding (odds ratio 2.4, 95% confidence interval 1.26–4.58, p=0.008) but had no impact on VTE. Conclusions Intermediate and therapeutic doses appear to have a higher risk of bleeding without a decrease of VTE events and mortality in critically ill COVID-19 patients. Resumen Objetivo Evaluar la incidencia de eventos trombóticos, sangrado y mortalidad comparando diferentes regímenes de anticoagulación en pacientes ingresados en unidades de Cuidados Intensivos (UCI) por COVID-19. Diseño Estudio de cohortes retrospectivo observacional y analítico. Ámbito Pacientes con COVID-19 ingresados en una UCI de un hospital terciario entre marzo y abril del 2020. Pacientes Se incluyó a un total de 201 pacientes de UCI ingresados por COVID-19. Los pacientes se categorizaron en 3 grupos en función de la dosis de anticoagulación más alta recibida durante el ingreso: profiláctica, intermedia y terapéutica. Intervenciones Se comparó la incidencia de eventos trombóticos, hemorragia y mortalidad entre los grupos. Se realizaron 2 regresiones logísticas multivariables para comprobar la asociación entre los eventos trombóticos y el sangrado con el régimen anticoagulante. Principales variables de interés Eventos trombóticos, sangrado y mortalidad. Resultados De los pacientes incluidos, 78 recibieron dosis profilácticas, 94 intermedias y 29 terapéuticas. No se encontraron diferencias en los eventos trombóticos y la mortalidad entre grupos, mientras que los sangrados fueron más frecuentes en el grupo de dosis terapéutica (31%) e intermedia (15%) que en el grupo de dosis profiláctica (5%) (p <0,001 y p <0,05, respectivamente). El régimen anticoagulante fue el mayor determinante de sangrado (odds ratio 2,4;, intervalo de confianza del 95%, 1,26-4,58;p=0,008) pero no tuvo ningún impacto en los eventos trombóticos. Conclusiones Las dosis intermedias y terapéuticas parecen tener un mayor riesgo de sangrado sin una disminución de los eventos trombóticos ni la mortalidad en pacientes de UCI con COVID-19.

3.
Obstetrics, Gynecology and Reproduction ; 16(3):228-243, 2022.
Article in Russian | EMBASE | ID: covidwho-1979784

ABSTRACT

Introduction. Currently, endothelial dysfunction caused by inflammation and immunothrombosisis considered as one of the crucial mechanisms in developing the SARS-CoV-2 virus-mediated coronavirus disease 2019 (COVID-19). A mass endothelial damage followed by release of untypical large quantity of von Willebrand factor (vWF) multimers and subsequent consumption of metalloproteinase ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is described during severe COVID-19. The activation of innate immune cells including neutrophils results in formation of neutrophil extracellular traps (NETs) and myeloperoxidase (MPO) release that, in turn, contributes to spread of inflammation and microvascular thrombosis. Aim: to evaluate a pathogenetic role and predictive significance for serum markers of inflammation, endothelial dysfunction and hemostatis activation such as vWF, ADAMTS-13 and MPO for in-hospital mortality in severe COVID-19 patients requiring mechanical lung ventilation. Materials and Methods. There was performed a single-center observational study with 129 severe COVID-19 patients on mechanical lung ventilation at the intensive care unit, by assessing serum in all subjects vWF, ADAMTS-13 as well as in 79 patients MPO level along with other potential predictors for in-hospital mortality. Results. A multivariate analysis revealed that increased serum level for vWF antigen (vWF:Ag) and MPO antigen (MPO:Ag) were significantly and independently related to high mortality probability: vWF:Ag (IU/ml) - adjusted odds ratio (OR) = 3.360;95 % confidence interval (95 % Cl) = 1.562-7,228 (р = 0,0019);MPO:Ag (ng/ml) - adjusted OR = 1.062;95 % = 1.024-1.101 (p = 0.0011). Such data allowed to obtained a simplified mortality score for categorizing patients as those having a higher or lower score compared with the median score level: a high score was associated with lower cumulative survival rate (p < 0.0001), with 50 % of the cases linked to lethal outcome on day 13 post-hospital admission. Conclusion. Severe COVID-19 patients requiring mechanical lung ventilation were found to have elevated level of serum MPO activity and vWF correlating with poor survival.

4.
Blood ; 138:1, 2021.
Article in English | EMBASE | ID: covidwho-1582278

ABSTRACT

Severe SARS-CoV-2 infection is complicated by dysregulation of the blood coagulation system and high rates of thrombosis, but virus-intrinsic mechanisms underlying this phenomenon are poorly understood. Increased intracellular calcium concentrations promote externalization of phosphatidylserine (PS), the membrane anionic phospholipid required for assembly and activation of the tenase and prothrombinase complexes to drive blood coagulation. TMEM16F is a ubiquitous phospholipid scramblase that mediates externalization of PS in a calcium-dependent manner. As SARS-CoV-2 ORF3a encodes a presumed cation channel with the ability to transport calcium, we hypothesized that ORF3a expression by infected host cells perturbs the cellular calcium rheostat, driving TMEM16F-dependent externalization of PS and enhancing procoagulant activity. Using a doxycycline-inducible system, synchronized expression of ORF3a in A549 pulmonary epithelial cells resulted in a time-dependent augmentation of tissue factor (TF) procoagulant activity exceeding 9-fold by 48 hours (p < 0.0001), with no change in TF cell-surface expression. This enhancement was dependent upon PS as determined by inhibition with the PS-binding protein lactadherin. Over 2-fold enhancement of prothrombinase activity (p < 0.0001) was also observed by 48 hours. ORF3a increased intracellular calcium levels by 18-fold at 48 hours (p < 0.0001), as determined by the intracellular calcium indicator fluo-4. After 16 hours of ORF3a expression, more than 60% of cells had externalized PS (p < 0.001) without increased cell death, as quantified by flow cytometry following annexin V binding. Immunofluorescence microscopy staining for ORF3a, annexin V, and nuclei confirmed ORF3a expression within internal and cell surface membranes and increased PS externalization. PS externalization was insensitive to the pan-caspase inhibitor z-VAD-FMK, and there was no evidence of apoptotic activation as determined by caspase-3 cleavage. By contrast, ORF3a expression did not augment coagulation in cells deficient in the calcium-dependent phospholipid scramblase TMEM16F. Similarly, ORF3a-enhanced TF procoagulant activity (p < 0.01) and prothrombinase activity (p<0.05) was completely abrogated using TMEM16 inhibitors, including the uricosuric agent benzbromarone that has been registered for human use in over 20 countries. Live SARS-CoV-2 infection of A549-ACE2 cells increased cell surface factor Xa generation at MOI 0.1 (p < 0.01) but not MOI 0.01 or following heat inactivation of the virus, and RNA sequencing confirmed ORF3a induction without increased F3 expression. RNA sequencing of human SARS-CoV-2 infected lung autopsy and control tissue (n= 53) confirmed these findings in vivo. Immunofluorescence staining for ORF3a and KRT8/18 and CD31 in SARS-CoV-2 infected human lung autopsy specimens demonstrated ORF3a expression in pulmonary epithelium and endothelial cells, highlighting the potential pathologic relevance of this mechanism. Here we demonstrate that expression of the SARS-CoV-2 accessory protein ORF3a increases the intracellular calcium concentration and TMEM16F-dependent PS scrambling to augment procoagulant activity of the tenase and prothrombinase complexes. Our studies of human cells and tissues infected with SARS-CoV-2 support the pathologic relevance of this mechanism. We highlight the therapeutic potential to target the ORF3a-TMEM16F axis as with benzbromarone to mitigate dysregulation of coagulation and thrombosis during severe SARS-CoV-2 infection. Disclosures: Schwartz: Miromatrix Inc: Membership on an entity's Board of Directors or advisory committees;Alnylam Inc.: Consultancy, Speakers Bureau. Schulman: CSL Behring: Consultancy, Research Funding.

5.
Research and Practice in Thrombosis and Haemostasis ; 5(SUPPL 2), 2021.
Article in English | EMBASE | ID: covidwho-1509004

ABSTRACT

Background : Previous reports describe high rates of venous thromboembolism (VTE) in critically ill COVID-19 patients. Consequently, intermediate and therapeutic doses anticoagulation have been used in clinical practice, potentially exposing patients to a higher risk of bleeding. Aims : To evaluate the rate of thrombosis, bleeding and mortality comparing prophylactic, intermediate or therapeutic doses in critically ill COVID-19 patients. Methods : All COVID-19 patients admitted to the intensive care unit of a tertiary hospital between March and April 2020 were included. Patients were categorized into three groups according to the highest anticoagulant dose received: prophylactic, intermediate and therapeutic. Incidence of VTE, bleeding and mortality were compared between groups. We performed two logistic multivariable regressions to test the association between VTE and bleeding with clinical characteristics and the anticoagulant regimen. Results : 201 patients were included. 78 (39%) received prophylactic, 94 (47%) intermediate and 29 (14%) therapeutic doses. There were no differences in VTE and mortality between groups. In contrast, bleeding events were more frequent in patients receiving therapeutic (31%) and intermediate (15%) doses than in those receiving prophylactic doses (5%) ( P < 0.001 and P < 0.05 respectively). Major bleedings were also more frequent in patients with anticoagulant doses ( P < 0.01). The anticoagulant dose was the strongest determinant for bleeding (odds ratio [OR] 2.4, 95% confidence interval (CI) 1.26-4.58, P = 0.008) but had no impact on VTE (OR 0.97, 95%CI 0.58-1.68, P = 0.92). Conclusions : Critically ill COVID-19 patients receiving intermediate or therapeutic doses of heparin appear to have a higher risk of bleeding without a decrease of VTE events and mortality.

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