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Thrombosis Research Dec 2022Evidence of micro- and macro-thrombi in the arteries and veins of critically ill COVID-19 patients and in autopsies highlight the occurrence of COVID-19-associated... (Review)
Review
Evidence of micro- and macro-thrombi in the arteries and veins of critically ill COVID-19 patients and in autopsies highlight the occurrence of COVID-19-associated coagulopathy (CAC). Clinical findings of critically ill COVID-19 patients point to various mechanisms for CAC; however, the definitive underlying cause is unclear. Multiple factors may contribute to the prothrombotic state in patients with COVID-19. Aberrant expression of tissue factor (TF), an initiator of the extrinsic coagulation pathway, leads to thrombotic complications during injury, inflammation, and infections. Clinical evidence suggests that TF-dependent coagulation activation likely plays a role in CAC. Multiple factors could trigger abnormal TF expression and coagulation activation in patients with severe COVID-19 infection. Proinflammatory cytokines that are highly elevated in COVID-19 (IL-1β, IL-6 and TNF-α) are known induce TF expression on leukocytes (e.g. monocytes, macrophages) and non-immune cells (e.g. endothelium, epithelium) in other conditions. Antiphospholipid antibodies, TF-positive extracellular vesicles, pattern recognition receptor (PRR) pathways and complement activation are all candidate factors that could trigger TF-dependent procoagulant activity. In addition, coagulation factors, such as thrombin, may further potentiate the induction of TF via protease-activated receptors on cells. In this systematic review, with other viral infections, we discuss potential mechanisms and cell-type-specific expressions of TF during SARS-CoV-2 infection and its role in the development of CAC.
Topics: Humans; Thromboplastin; COVID-19; Critical Illness; SARS-CoV-2; Blood Coagulation Disorders; Thrombosis
PubMed: 36265412
DOI: 10.1016/j.thromres.2022.09.025 -
PLoS Neglected Tropical Diseases Jun 2022Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease with high case fatality rate. Unfortunately, no vaccine or antiviral... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease with high case fatality rate. Unfortunately, no vaccine or antiviral specifically targeting SFTS virus (SFTSV) are available for the time being. Our objective was to investigate the association between clinical laboratory parameters and fatality of SFTS patients.
METHODS
The systematic review was conducted in accordance with The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. We searched (from inception to 24th February 2022) Web of Science, PubMed, National Knowledge Infrastructure databases and Wan Fang Data for relevant researchers on SFTS. Studies were eligible if they reported on laboratory parameters of SFTS patients and were stratified by clinical outcomes. A modified version of Newcastle-Ottawa scale was used to evaluate the quality of included studies. Standardized mean difference (SMD) was used to evaluate the association between laboratory parameters and outcomes. The between-study heterogeneity was evaluated quantitatively by standard Chi-square and the index of heterogeneity (I2). Heterogeneity was explored by subgroup and sensitivity analyses, and univariable meta-regression. Publication bias was determined using funnel plots and Egger's test.
RESULTS
We identified 34 relevant studies, with over 3300 participants across three countries. The following factors were strongly (SMD>1 or SMD<-0.5) and significantly (P<0.05) associated mortality: thrombin time (TT) (SMD = 1.53), viral load (SMD = 1.47), activated partial-thromboplastin time (APTT) (SMD = 1.37), aspartate aminotransferase (AST) (SMD = 1.19), lactate dehydrogenase (LDH) (SMD = 1.13), platelet count (PLT) (SMD = -0.47), monocyte percentage (MON%) (SMD = -0.47), lymphocyte percentage (LYM%) (SMD = -0.46) and albumin (ALB) (SMD = -0.43). Alanine aminotransferase, AST, creatin phosphokinase, LDH, PLT, partial-thromboplastin time and viral load contributed to the risk of dying of SFTS patients in each subgroup analyses. Sensitivity analysis demonstrated that the results above were robust.
CONCLUSIONS/SIGNIFICANCE
The abnormal levels of viral load, PLT, coagulation function and liver function, significantly increase the risk of SFTS mortality, suggesting that SFTS patients with above symptoms call for special concern.
Topics: Antiviral Agents; Bunyaviridae Infections; Humans; Laboratories, Clinical; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Thromboplastin; Viral Load
PubMed: 35714138
DOI: 10.1371/journal.pntd.0010489 -
Annals of the Academy of Medicine,... Apr 2021Coronavirus disease 2019 (COVID-19)-induced coagulopathy (CIC) has been widely reported in the literature. However, the spectrum of abnormalities associated with CIC has... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Coronavirus disease 2019 (COVID-19)-induced coagulopathy (CIC) has been widely reported in the literature. However, the spectrum of abnormalities associated with CIC has been highly variable.
METHODS
We conducted a systematic review of the literature (until 1 June 2020) to assess CIC and disease severity during the early COVID-19 pandemic. Primary outcomes were pooled mean differences in platelet count, D-dimer level, prothrombin time, activated partial thromboplastin time (aPTT) and fibrinogen level between non-severe and severe patients, stratified by degree of hypoxaemia or those who died. The risk factors for CIC were analysed. Random-effects meta-analyses and meta-regression were performed using R version 3.6.1, and certainty of evidence was rated using the Grading of Recommendation, Assessment, Development, and Evaluation approach.
RESULTS
Of the included 5,243 adult COVID-19 patients, patients with severe COVID-19 had a significantly lower platelet count, and higher D-dimer level, prothrombin time and fibrinogen level than non-severe patients. Pooled mean differences in platelet count (-19.7×109/L, 95% confidence interval [CI] -31.7 to -7.6), D-dimer level (0.8μg/mL, 95% CI 0.5-1.1), prothrombin time (0.4 second, 95% CI 0.2-0.6) and fibrinogen level (0.6g/L, 95% CI 0.3-0.8) were significant between the groups. Platelet count and D-dimer level were significant predictors of disease severity on meta-regression analysis. Older men had higher risks of severe coagulopathic disease.
CONCLUSION
Significant variability in CIC exists between non-severe and severe patients, with platelet count and D-dimer level correlating with disease severity. Routine monitoring of all coagulation parameters may help to assess CIC and decide on the appropriate management.
Topics: Adult; Aged; Blood Coagulation Disorders; COVID-19; Humans; Male; Pandemics; Prothrombin Time; SARS-CoV-2
PubMed: 33990820
DOI: 10.47102/annals-acadmedsg.2020420 -
Frontiers in Cardiovascular Medicine 2022Coagulation parameters are important determinants for COVID-19 infection. We conducted meta-analysis to assess the association between early hemostatic parameters and...
INTRODUCTION
Coagulation parameters are important determinants for COVID-19 infection. We conducted meta-analysis to assess the association between early hemostatic parameters and infection severity.
METHODS
Electronic search was made for papers that addressed clinical characteristics of COVID-19 patients and disease severity. Results were filtered using exclusion and inclusion criteria and then pooled into a meta-analysis to estimate the standardized mean difference (SMD) with 95% confidence interval (CI) for D-dimers, fibrinogen, prothrombin time, platelet count (PLT), activated partial thromboplastin time. To explore the heterogeneity and robustness of our fundings, sensitivity and subgroup analyses were conducted. Publication bias was assessed with contour-enhanced funnel plots and Egger's test by linear regression. Coagulation parameters data from retrospective cohort study of 451 patients with COVID-19 at National Research Center for Cardiac Surgery were included in meta-analysis of published studies.
RESULTS
Overall, 41 original studies (17,601 patients) on SARS-CoV-2 were included. For the two groups of patients, stratified by severity, we identified that D-dimers, fibrinogen, activated partial thromboplastin time, and prothrombin time were significantly higher in the severe group [SMD 0.6985 with 95%CI (0.5155; 0.8815); SMD 0.661 with 95%CI (0.3387; 0.9833); SMD 0.2683 with 95%CI (0.1357; 0.4009); SMD 0.284 with 95%CI (0.1472; 0.4208)]. In contrast, PLT was significantly lower in patients with more severe cases of COVID-19 [SMD -0.1684 with 95%CI (-0.2826; -0.0542)]. Neither the analysis by the leave-one-out method nor the influence diagnostic have identified studies that solely cause significant change in the effect size estimates. Subgroup analysis showed no significant difference between articles originated from different countries but revealed that severity assessment criteria might have influence over estimated effect sizes for platelets and D-dimers. Contour-enhanced funnel plots and the Egger's test for D-dimers and fibrinogen revealed significant asymmetry that might be a sign of publication bias.
CONCLUSIONS
The hemostatic laboratory parameters, with exception of platelets, are significantly elevated in patients with severe COVID-19. The two variables with strongest association to disease severity were D-dimers and fibrinogen levels. Future research should aim outside conventional coagulation tests and include analysis of clotting formation and platelet/platelet progenitors characteristics.
PubMed: 35360017
DOI: 10.3389/fcvm.2022.794092 -
British Journal of Clinical Pharmacology Nov 2021To identify and critically appraise studies of prediction models, developed using machine learning (ML) methods, for determining the optimal dosing of unfractionated... (Review)
Review
AIM
To identify and critically appraise studies of prediction models, developed using machine learning (ML) methods, for determining the optimal dosing of unfractionated heparin (UFH).
METHODS
Embase, PubMed, CINAHL, Web of Science, International Pharmaceutical Abstracts and IEEE Xplore databases were searched from inception to 31 January 2020 to identify relevant studies using key search terms synonymous with artificial intelligence or ML, 'prediction', 'dose', 'activated partial thromboplastin time (aPTT)' and 'UFH.' Studies had to have used ML methods for developing models that predicted optimal dose of UFH or target therapeutic aPTT levels in the hospital setting. The CHARMS Checklist was used to assess quality and risk of bias of included studies.
RESULTS
Of 8393 retrieved abstracts, 61 underwent full text review and eight studies met inclusion criteria. Four studies described models for predicting aPTT, three studies described models predicting optimal dose of heparin during dialysis and one study described a model that used surrogate outcomes of clotting and bleeding to predict a therapeutic aPTT. Studies varied widely in reporting of study participants, feature characterisation and selection, handling of missing data, sample size calculations and the intended clinical application of the model. Only one study conducted an external validation and no studies evaluated model impacts in clinical practice.
CONCLUSION
Studies of ML models for UFH dosing are few and none report a model ready for routine clinical use. Existing studies are limited by low methodological quality, inadequate reporting of study factors and absence of external validation and impact analysis.
Topics: Anticoagulants; Artificial Intelligence; Heparin; Humans; Machine Learning; Partial Thromboplastin Time
PubMed: 33835524
DOI: 10.1111/bcp.14852 -
Critical Care (London, England) Nov 2023Bacteria are the main pathogens that cause sepsis. The pathogenic mechanisms of sepsis caused by gram-negative and gram-positive bacteria are completely different, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Bacteria are the main pathogens that cause sepsis. The pathogenic mechanisms of sepsis caused by gram-negative and gram-positive bacteria are completely different, and their prognostic differences in sepsis remain unclear.
METHODS
The PubMed, Web of Science, Cochrane Library, and Embase databases were searched for Chinese and English studies (January 2003 to September 2023). Observational studies involving gram-negative (G (-))/gram-positive (G (+)) bacterial infection and the prognosis of sepsis were included. The stability of the results was evaluated by sensitivity analysis. Funnel plots and Egger tests were used to check whether there was publication bias. A meta-regression analysis was conducted on the results with high heterogeneity to identify the source of heterogeneity. A total of 6949 articles were retrieved from the database, and 45 studies involving 5586 subjects were included after screening according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Twenty-seven high-quality studies and 18 moderate-quality studies were identified according to the Newcastle‒Ottawa Scale score. There was no significant difference in the survival rate of sepsis caused by G (-) bacteria and G (+) bacteria (OR 0.95, 95% CI 0.70-1.28). Subgroup analysis according to survival follow-up time showed no significant difference. The serum concentrations of C-reactive protein (CRP) (SMD = 0.39, 95% CI 0.02-0.76), procalcitonin (SMD = 1.95, 95% CI 1.32-2.59) and tumor necrosis factor-alpha (TNF-α) (MD = 0.31, 95% CI 0.25-0.38) in the G (-) bacterial infection group were significantly higher than those in the G (+) bacterial infection group, but there was no significant difference in IL-6 (SMD = 1.33, 95% CI - 0.18-2.84) and WBC count (MD = - 0.15, 95% CI - 0.96-00.66). There were no significant differences between G (-) and G (+) bacteria in D dimer level, activated partial thromboplastin time, thrombin time, international normalized ratio, platelet count, length of stay or length of ICU stay. Sensitivity analysis of the above results indicated that the results were stable.
CONCLUSION
The incidence of severe sepsis and the concentrations of inflammatory factors (CRP, PCT, TNF-α) in sepsis caused by G (-) bacteria were higher than those caused by G (+) bacteria. The two groups had no significant difference in survival rate, coagulation function, or hospital stay. The study was registered with PROSPERO (registration number: CRD42023465051).
Topics: Humans; Prognosis; Tumor Necrosis Factor-alpha; Sepsis; Bacterial Infections; Gram-Negative Bacteria; C-Reactive Protein; Bacteria; Gram-Positive Bacteria
PubMed: 38037118
DOI: 10.1186/s13054-023-04750-w -
Journal of Critical Care Oct 2023The initiation of the extracorporeal membrane oxygenation (ECMO) is associated with complex coagulatory and inflammatory processes and consequently needed... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The initiation of the extracorporeal membrane oxygenation (ECMO) is associated with complex coagulatory and inflammatory processes and consequently needed anticoagulation. Systemic anticoagulation bears an additional risk of serious bleeding, and its monitoring is of immense importance. Therefore, our work aims to analyze the association of anticoagulation monitoring with bleeding during ECMO support.
MATERIAL AND METHODS
Systematic literature review and meta-analysis, complying with the PRISMA guidelines (PROSPERO-CRD42022359465).
RESULTS
Seventeen studies comprising 3249 patients were included in the final analysis. Patients experiencing hemorrhage had a longer activated partial thromboplastin time (aPTT), a longer ECMO duration, and higher mortality. We could not find strong evidence of any aPTT threshold association with the bleeding occurrence, as less than half of authors reported a potential relationship. Finally, we identified the acute kidney injury (66%, 233/356) and hemorrhage (46%, 469/1046) to be the most frequent adverse events, while almost one-half of patients did not survive to discharge (47%, 1192/2490).
CONCLUSION
The aPTT-guided anticoagulation is still the standard of care in ECMO patients. We did not find strong evidence supporting the aPTT-guided monitoring during ECMO. Based on the weight of the available evidence, further randomized trials are crucial to clarify the best monitoring strategy.
Topics: Humans; Partial Thromboplastin Time; Anticoagulants; Extracorporeal Membrane Oxygenation; Retrospective Studies; Hemorrhage; Heparin
PubMed: 37244207
DOI: 10.1016/j.jcrc.2023.154332 -
Blood Advances Oct 2023Postpartum hemorrhage (PPH) is a leading cause of maternal morbi-mortality. Although obstetric risk factors are well described, the impact of predelivery hematologic and... (Meta-Analysis)
Meta-Analysis
Postpartum hemorrhage (PPH) is a leading cause of maternal morbi-mortality. Although obstetric risk factors are well described, the impact of predelivery hematologic and hemostatic biomarkers remains incompletely understood. In this systematic review, we aimed to summarize the available literature on the association between predelivery hemostatic biomarkers and PPH/severe PPH. Searching MEDLINE, EMBASE, and CENTRAL databases from inception to October 2022, we included observational studies on unselected pregnant women without bleeding disorder reporting on PPH and on predelivery hemostatic biomarkers. Two review authors independently performed title, abstract and full-text screening, upon which quantitative syntheses of studies reporting on the same hemostatic biomarker were conducted, calculating the mean difference (MD) between women with PPH/severe PPH and controls. A search on 18 October 2022 yielded 81 articles fitting our inclusion criteria. The heterogeneity between studies was considerable. With regard to PPH, the estimated average MD in the investigated biomarkers (platelets, fibrinogen, hemoglobin, Ddimer, activated partial thromboplastin time, and prothrombin time) were not statistically significant. Women who developed severe PPH had lower predelivery platelets than controls (MD = -26.0 109/L; 95% confidence interval, -35.8 to -16.1), whereas differences in predelivery fibrinogen concentration (MD = -0.31 g/L; 95% confidence interval, -0.75 to 0.13) and levels of factor XIII or hemoglobin were not statistically significant in women with and without severe PPH. Predelivery platelet counts were, on average, lower in women with severe PPH compared with controls, suggesting the potential usefulness of this biomarker for predicting severe PPH. This trial was registered at the International Prospective Register of Systematic Reviews as CRD42022368075.
Topics: Female; Pregnancy; Humans; Postpartum Hemorrhage; Hemostatics; Hemoglobins; Fibrinogen; Biomarkers
PubMed: 37307172
DOI: 10.1182/bloodadvances.2023010143 -
Journal of Medical Virology Feb 2021The outbreak of 2019 novel coronavirus disease (COVID-19) has posed a grave threat to the global public health. The COVID-19-induced infection is closely related to... (Meta-Analysis)
Meta-Analysis
The outbreak of 2019 novel coronavirus disease (COVID-19) has posed a grave threat to the global public health. The COVID-19-induced infection is closely related to coagulation dysfunction in the affected patients. This paper attempts to conduct a meta-analysis and systematically review the blood coagulation indicators in patients with severe COVID-19. A meta-analysis of eligible studies was performed to compare the blood coagulation indicators in patients with severe and nonsevere COVID-19. PubMed, Embase, Web of Science, and the Cochrane Library were searched for studies published between 1 December 2019 and 7 May 2020. A total of 13 studies with 1341 adult patients were enrolled in this analysis. Platelet (weighted mean difference [WMD] = -24.83, 95% confidence interval [CI]: -34.12 to -15.54; P < .001), d-dimer (WMD = 0.19, 95% CI: 0.09-0.29; P < .001), and fibrinogen (WMD = 1.02, 95% CI: 0.50-1.54; P < .001) were significantly associated with the severity in patients with COVID-19. The meta-analysis revealed that no correlation was evident between an increased severity risk of COVID-19 and activated partial thromboplastin time (WMD = -1.56, 95% CI: -5.77 to 2.64; P = .468) or prothrombin time (WMD = 0.19, 95% CI: -0.13 to 0.51; P = .243). The single arm meta-analysis showed that compared with the nonsevere group, the severe group had a lower pooled platelet (165.12 [95% CI: 157.38-172.85] vs 190.09 [95% CI: 179.45-200.74]), higher d-dimer (0.49 [95% CI: 0.33-0.64] vs 0.27 [95% CI: 0.20-0.34]), and higher fibrinogen (4.34 [95% CI: 1.98-6.70] vs 3.19 [95% CI: 1.13-5.24]). Coagulation dysfunction is closely related to the severity of patients with COVID-19, in which low platelet, high d-dimer, and fibrinogen upon admission may serve as risk indicators for increased aggression of the disease. These findings are of great clinical value for timely and effective treatment of the COVID-19 cases.
Topics: Blood Coagulation Disorders; Blood Platelets; COVID-19; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hospitalization; Humans; Partial Thromboplastin Time; Prognosis; Risk Factors; Severity of Illness Index
PubMed: 32706426
DOI: 10.1002/jmv.26346 -
Frontiers in Endocrinology 2022Despite patients with thyroid dysfunction show obvious abnormal hemostatic indicators in the peripheral blood, the current research on whether and how subclinical... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Despite patients with thyroid dysfunction show obvious abnormal hemostatic indicators in the peripheral blood, the current research on whether and how subclinical hypothyroidism (SCH) influence hemostatic function (the coagulation and fibrinolytic system) still remains controversial.
OBJECTIVE
We conducted this study to evaluate how SCH influence on the coagulation and fibrinolytic system in human body.
METHODS
Prior to March 2022, Web of Science, Embase, PubMed, WanFang, CNKI data and reference lists were searched to identify eligible researches. Two of us independently extracted the data and evaluated study quality. The effect size is represented by standard mean difference (SMD). Both fixed and random-effects models were used where appropriate. Review Manager 5.3 and STATA 16.0 were used to analyze the eligible data.
RESULTS
1325 patients from twelve observational studies were involved in our research. Our study revealed that SCH changed the heamostatic balance towards hypercoagulable and hypofibrinolytic conditions accompanied by an increase in tissue fibrinogen, plasminogen activator and plasminogen activator inhibitor-1. By contrast, there was no statistically difference in acivated partial thromboplastin time (APTT) and D-Dimer in SCH group compared with that in control subjects.
CONCLUSIONS
Our study confirmed that SCH is related with a prothrombotic state, as reflected by changes in both coagulation and fibrinolysis. It is highly recommended for screening cardiovascular risk factors in combination with an adequate evaluation of SCH state.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/#recordDetails] PROSPERO [CRD42021275313].
Topics: Blood Coagulation; Fibrinolysis; Hemostatics; Humans; Hypothyroidism; Thyroid Diseases
PubMed: 35574019
DOI: 10.3389/fendo.2022.861746