Clinical Validation of Global Coagulation Tests to Guide Blood Component Transfusions in Cirrhosis and ACLF.
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ABSTRACT: Background and aims
Patients with cirrhosis and acute-on-chronic liver failure (ACLF) may have bleeding complications and need for invasive procedures. Point-of-care (POC) coagulation tests like thromboelastography (TEG) and Sonoclot may be better for guiding patient management than the standard coagulation tests (SCTs), like prothrombin time, platelet count and international normalized ratio.Methods
We prospectively compared and validated the POC tests and SCTs in 70 persons with ACLF and 72 persons with decompensated cirrhosis who had clinical bleeding and checked for episodes of re-bleeding and transfusion requirements. We assessed pre-procedure requirement of blood components when correction was done based on an SCT or POC strategy.Results
Episodes of bleeding were seen in 45% and 28% of ACLF and cirrhosis patient, respectively (p=0.036), with the major site of bleeding being gastrointestinal (31% and 16%, respectively). Platelet counts correlated with TEG-maximum amplitude in cirrhosis (p=0.045) and prothrombin time correlated positively with TEG-reaction (R) time (p=0.032), TEG-Clot kinetics (K) time (p=0.042), Son-activated clotting time (p=0.038) and negatively with clot rate (p=0.043) in ACLF, making these correctable target variables in POC transfusion algorithms. Of 223 procedures, transfusion of fresh frozen plasma and platelet concentrate was reduced by 25% (p=0.035) and 20.8% (p=0.045) by using a POC strategy in 76 patients. Correction of deranged Son-activated clotting time and TEG-reaction time was noted in 68% and 72% after 24 h of fresh frozen plasma transfusion in ACLF and 85% and 80% in cirrhosis, respectively.Conclusions
Our study clinically validates that POC tests can better detect coagulation defects and transfusion thresholds in ACLF and cirrhosis, whereas use of conventional tests appear to be less suitable in patients with clinical bleeding.Trial registration
NCT04332484.
SUBMITTER: Premkumar M
PROVIDER: S-EPMC8111111 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundLiver failure patients have traditionally been empirically transfused prior to invasive procedures. Blood transfusion is associated with immunologic and nonimmunologic reactions, increased risk of adverse outcomes and high costs. Scientific evidence supporting empirical transfusion is lacking, and the best approach for blood transfusion prior to invasive procedures in cirrhotic patients has not been established so far. The aim of this study is to compare three transfusion strategies (routine coagulation test-guided - ordinary or restrictive, or thromboelastometry-guided) prior to central venous catheterization in critically ill patients with cirrhosis.Methods/designDesign and setting: a double-blinded, parallel-group, single-center, randomized controlled clinical trial in a tertiary private hospital in São Paulo, Brazil.Inclusion criteriaadults (aged 18 years or older) admitted to the intensive care unit with cirrhosis and an indication for central venous line insertion. Patients will be randomly assigned to three groups for blood transfusion strategy prior to central venous catheterization: standard coagulation tests-based, thromboelastometry-based, or restrictive. The primary efficacy endpoint will be the proportion of patients transfused with any blood product prior to central venous catheterization. The primary safety endpoint will be the incidence of major bleeding. Secondary endpoints will be the proportion of transfusion of fresh frozen plasma, platelets and cryoprecipitate; infused volume of blood products; hemoglobin and hematocrit before and after the procedure; intensive care unit and hospital length of stay; 28-day and hospital mortality; incidence of minor bleeding; transfusion-related adverse reactions; and cost analysis.DiscussionThis study will evaluate three strategies to guide blood transfusion prior to central venous line placement in severely ill patients with cirrhosis. We hypothesized that thromboelastometry-based and/or restrictive protocols are safe and would significantly reduce transfusion of blood products in this population, leading to a reduction in costs and transfusion-related adverse reactions. In this manner, this trial will add evidence in favor of reducing empirical transfusion in severely ill patients with coagulopathy.Trial registrationClinicalTrials.gov, identifier: NCT02311985 . Retrospectively registered on 3 December 2014.
| S-EPMC5327508 | biostudies-literature
Project description:Background and aimsPatients with cirrhosis and acute-on-chronic liver failure (ACLF) have immunosuppression, indicated by an increase in circulating immune-deficient monocytes. The aim of this study was to investigate simultaneously the major blood-immune cell subsets in these patients.Material and methodsBlood taken from 67 patients with decompensated cirrhosis (including 35 critically ill with ACLF in the intensive care unit), and 12 healthy subjects, was assigned to either measurements of clinical blood counts and microarray (genomewide) analysis of RNA expression in whole-blood; microarray (genomewide) analysis of RNA expression in blood neutrophils; or assessment of neutrophil antimicrobial functions.ResultsSeveral features were found in patients with ACLF and not in those without ACLF. Indeed, clinical blood count measurements showed that patients with ACLF were characterized by leukocytosis, neutrophilia, and lymphopenia. Using the CIBERSORT method to deconvolute the whole-blood RNA-expression data, revealed that the hallmark of ACLF was the association of neutrophilia with increased proportions of macrophages M0-like monocytes and decreased proportions of memory lymphocytes (of B-cell, CD4 T-cell lineages), CD8 T cells and natural killer cells. Microarray analysis of neutrophil RNA expression revealed that neutrophils from patients with ACLF had a unique phenotype including induction of glycolysis and granule genes, and downregulation of cell-migration and cell-cycle genes. Moreover, neutrophils from these patients had defective production of the antimicrobial superoxide anion.ConclusionsGenomic analysis revealed that, among patients with decompensated cirrhosis, those with ACLF were characterized by dysregulation of blood immune cells, including increases in neutrophils (that had a unique phenotype) and macrophages M0-like monocytes, and depletion of several lymphocyte subsets (including memory lymphocytes). All these lymphocyte alterations, along with defective neutrophil superoxide anion production, may contribute to immunosuppression in ACLF, suggesting targets for future therapies.
| S-EPMC7893087 | biostudies-literature
Project description:Acute-on-chronic liver failure (ACLF) is a recently (re)defined syndrome of acute decompensation of cirrhosis that presents with extrahepatic organ failure(s) and poor outcome. Given the prominent role of inflammation and activation of coagulation in ACLF, we hypothesized that ACLF might be characterized by the generation of neutrophil extracellular traps (NETs), that could drive both activation of coagulation and progression of organ failure.MethodsWe measured markers of circulating DNA, activation of coagulation, inflammation, and oxidative stress in 52 patients with acute decompensation (AD) of cirrhosis and 57 patients with ACLF on admission, and compared levels with 40 healthy controls.ResultsAll analytes were higher in patients compared to controls. Plasma levels of cell-free DNA, but not of the specific NET marker myeloperoxidase-DNA complexes were higher in patients with ACLF compared to AD cirrhosis. In addition, TAT complexes (coagulation), IL-6 (inflammation), and TBARS (oxidative stress) were higher in ACLF compared to AD. Markers for activation of coagulation were not associated with circulating DNA, IL-6, or TBARS. In contrast, levels of circulating DNA, IL-6, and TBARS were higher in patients with more severe disease, higher in patients with organ failure, and higher in patients that died within 30 days of admission. Importantly, myeloperoxidase-DNA levels did not differ between patients with complications and poor outcome.ConclusionsCollectively, we show that cell-free DNA, inflammation, and oxidative stress are associated with outcomes in AD and ACLF, but not with activation of coagulation. Our data argue against a role of NETs in activation of coagulation and in progression of organ failure in patients with AD and ACLF.Lay summaryAcute-on-chronic liver failure is a devastating syndrome that can follow acute decompensation of chronic liver disease. Herein, we demonstrate that these patients accumulate DNA released from dying cells in their blood, and that the quantity of this DNA is related to the outcome of disease. We also show that outcome of disease is not related to recently described neutrophil extracellular traps, which have been shown in animal models to play vital roles in the progression of liver diseases.
| S-EPMC7001554 | biostudies-literature
Project description:Acute-on-chronic liver failure (ACLF) is a recently (re)defined syndrome of acute decompensation of cirrhosis that presents with extrahepatic organ failure(s) and poor outcome. Given the prominent role of inflammation and activation of coagulation in ACLF, we hypothesized that ACLF might be characterized by the generation of neutrophil extracellular traps (NETs), that could drive both activation of coagulation and progression of organ failure.MethodsWe measured markers of circulating DNA, activation of coagulation, inflammation, and oxidative stress in 52 patients with acute decompensation (AD) of cirrhosis and 57 patients with ACLF on admission, and compared levels with 40 healthy controls.ResultsAll analytes were higher in patients compared to controls. Plasma levels of cell-free DNA, but not of the specific NET marker myeloperoxidase-DNA complexes were higher in patients with ACLF compared to AD cirrhosis. In addition, TAT complexes (coagulation), IL-6 (inflammation), and TBARS (oxidative stress) were higher in ACLF compared to AD. Markers for activation of coagulation were not associated with circulating DNA, IL-6, or TBARS. In contrast, levels of circulating DNA, IL-6, and TBARS were higher in patients with more severe disease, higher in patients with organ failure, and higher in patients that died within 30 days of admission. Importantly, myeloperoxidase-DNA levels did not differ between patients with complications and poor outcome.ConclusionsCollectively, we show that cell-free DNA, inflammation, and oxidative stress are associated with outcomes in AD and ACLF, but not with activation of coagulation. Our data argue against a role of NETs in activation of coagulation and in progression of organ failure in patients with AD and ACLF.Lay summaryAcute-on-chronic liver failure is a devastating syndrome that can follow acute decompensation of chronic liver disease. Herein, we demonstrate that these patients accumulate DNA released from dying cells in their blood, and that the quantity of this DNA is related to the outcome of disease. We also show that outcome of disease is not related to recently described neutrophil extracellular traps, which have been shown in animal models to play vital roles in the progression of liver diseases.
| S-EPMC7001554 | biostudies-literature
Project description:Acute-on-chronic liver failure (ACLF) is a recently (re)defined syndrome of acute decompensation of cirrhosis that presents with extrahepatic organ failure(s) and poor outcome. Given the prominent role of inflammation and activation of coagulation in ACLF, we hypothesized that ACLF might be characterized by the generation of neutrophil extracellular traps (NETs), that could drive both activation of coagulation and progression of organ failure.MethodsWe measured markers of circulating DNA, activation of coagulation, inflammation, and oxidative stress in 52 patients with acute decompensation (AD) of cirrhosis and 57 patients with ACLF on admission, and compared levels with 40 healthy controls.ResultsAll analytes were higher in patients compared to controls. Plasma levels of cell-free DNA, but not of the specific NET marker myeloperoxidase-DNA complexes were higher in patients with ACLF compared to AD cirrhosis. In addition, TAT complexes (coagulation), IL-6 (inflammation), and TBARS (oxidative stress) were higher in ACLF compared to AD. Markers for activation of coagulation were not associated with circulating DNA, IL-6, or TBARS. In contrast, levels of circulating DNA, IL-6, and TBARS were higher in patients with more severe disease, higher in patients with organ failure, and higher in patients that died within 30 days of admission. Importantly, myeloperoxidase-DNA levels did not differ between patients with complications and poor outcome.ConclusionsCollectively, we show that cell-free DNA, inflammation, and oxidative stress are associated with outcomes in AD and ACLF, but not with activation of coagulation. Our data argue against a role of NETs in activation of coagulation and in progression of organ failure in patients with AD and ACLF.Lay summaryAcute-on-chronic liver failure is a devastating syndrome that can follow acute decompensation of chronic liver disease. Herein, we demonstrate that these patients accumulate DNA released from dying cells in their blood, and that the quantity of this DNA is related to the outcome of disease. We also show that outcome of disease is not related to recently described neutrophil extracellular traps, which have been shown in animal models to play vital roles in the progression of liver diseases.
| S-EPMC7001554 | biostudies-literature
Project description:BackgroundPatients with liver cirrhosis typically exhibit abnormal coagulation parameters in conventional coagulation tests (CCTs). Rotational thromboelastometry (ROTEM) is a holistic blood coagulation assay. This method provides an insight into the global hemostatic capabilities and has been suggested to provide a better overview of the coagulation system in liver cirrhosis.MethodsThe goal of this study was to examine hemostasis in patients with stable liver cirrhosis (Non-ACLF) and in acute-on-chronic liver failure (ACLF) by CCT and ROTEM including agreement of both tests and the prospective assessment of test performance based on clinical outcomes in ACLF patients. Therefore, ACLF patients were additionally subgrouped by bleeding events. Fifty-five Non-ACLF patients and twenty-two patients with ACLF were analysed in this prospective cohort study.ResultsCoagulation parameters analysed by CCT were outside the normal range in Non-ACLF and ACLF patients, but were significantly more aberrant in ACLF patients. Non-ACLF patients analysed by ROTEM revealed parameters largely within the normal limits, while significantly more ROTEM parameters in ACLF patients were affected. Maximum clot firmness (MCF) was significantly divergent between both patient groups and correlated well with levels of fibrinogen and platelet count. Using Cohen's Kappa coefficient κ, the strength of agreement between CCT and ROTEM analyses was determined to be fair for Non-ACLF patients and moderate for ACLF patients. Bleeding events occurred significantly more often in ACLF group with significantly reduced A10 and MCF.ConclusionsFor assessing hemostasis in Non-ACLF and ACLF patients the underlying dataset shows advantages of ROTEM over CCT. A10 and MCF represent suitable prognostic parameters in predicting bleeding events in ACLF group.
| S-EPMC7433140 | biostudies-literature
Project description:BACKGROUND In the intensive care unit (ICU), critically ill patients with cirrhosis and acute-on-chronic liver failure (ACLF) continue to have high mortality rates. The AARC ACLF score is a simple, newly-developed score based on Asian ACLF patients, which performs well in prognosis. The present study attempted to verify the prognostic ability of AARC ACLF in non-Asian critically ill patients with cirrhosis and ACLF. MATERIAL AND METHODS We enrolled 786 patients. Relevant clinical data were collected within 24 h after admission to compare the differences between survivors and non-survivors, and all the patients were followed up for at least 180 days. RESULTS The 28-day, 90-day, and 180-day mortality rates were 28.9% (227/786), 36.4% (286/786), and 40.3% (317/786), respectively. Multivariate Cox regression analysis showed that AARC ACLF score (HR: 1.375, 95% CI: 1.247-1.516, P<0.001) was an independent predictive factor of 28-day mortality, and the AUROC of the predictive ability in 28-day mortality of the AARC ACLF score was 0.754. In addition, the AARC ACLF score was regraded into 3 classes (low risk: AARC ACLF <9, intermediate risk: 9≤ AARC ACLF <12, and high risk: AARC ACLF ≥12). The AARC ACLF score can be used for dynamic assessment by retest at days 4-7. CONCLUSIONS The AARC ACLF score has a good predictive value for 28-day, 90-day, and 180-day mortality in non-Asian critically ill patients with cirrhosis and ACLF, which is not inferior to CLIF-C ACLFsLact and other models. It is easy to use at bedside, and it is dynamic and reliable.
| S-EPMC7526342 | biostudies-literature
Project description:BackgroundPregnancy has major effects that make hematology parameters outside of normal reference ranges. Therefore, we conducted this study to establish reference intervals for Vietnamese pregnant women.MethodsFrom June 2023 to Augst 2023, blood samples from 879 eligible pregnant women were run on DxH 900 hematology analyzer and ACL TOP 550 coagulation analyzer. The tested parameters are prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), white blood cell (WBC) and its differentials (neutrophils, lymphocytes, monocytes, eosinophils and basophils), red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), RBC distribution width (RDW), RBC distribution width standard deviation (RDW-SD), platelet count (PLT), mean platelet volume (MPV). A non-parametric method was used to establish the 2.5th and 97.5th percentile reference intervals.ResultsPT, APTT decrease but fibrinogen increases during pregnancy. Physiological adaptations of pregnancy result in a decrease in RBC count, but an increase in WBC count and no changes in platelet count. The reference intervals for PT (seconds), APTT (seconds), fibrinogen (mg/dL), in the first trimester were 10.30-12.88, 25.40-35.46, 280.28-559.00, in the second trimester were 9.80-11.66, 24.05-33.23, 347.75-593.35, in the third trimester were 9.60-11.40, 23.40-31.80, 330.28-628.56, respectively. The reference intervals for main hematology parameters which are WBC (× 109/L), RBC (× 1012/L), HGB (g/dL), HCT (%), PLT (× 109/L) in the first trimester were 6.33-15.24, 3.73-5.32, 10.33-13.95, 32.22-42.29, 169.66-413.88, in the second trimester were 6.99-15.55, 3.33-4.98, 9.71-13.17, 30.26-40.07, 172.34-372.19, in the third trimester were 6.22-14.14, 3.54-4.98, 9.80-13.97, 31.11-42.70, 151.30-417.14, respectively.ConclusionsMost established referenced intervals from each trimester differ from other trimesters. These trimester-specific reference ranges for Vietnamese pregnant women will aid clinicians in entepreting parameters and help other laboratories adopt these ranges after validating.Trial registrationThis study is registered at www.Clinicaltrialsgov as NCT05929326.
| S-EPMC10638750 | biostudies-literature
Project description:Rivaroxaban and apixaban are both small molecules that reversibly inhibit factor Xa. Compared with rivaroxaban, apixaban has minimal effects on the prothrombin time and activated partial thromboplastin time. To investigate this phenomenon, we used a factor Xa-directed substrate in a buffer system. Although rivaroxaban and apixaban inhibited factor Xa with similar K i values at equilibrium, kinetic measurements revealed that rivaroxaban inhibited factor Xa up to 4-fold faster than apixaban ( p < 0.001). Using a discontinuous chromogenic assay to monitor thrombin production by prothrombinase in a purified system, rivaroxaban was 4-fold more potent than apixaban (K i values of 0.7 ± 0.3 and 2.9 ± 0.5 nM, respectively; p = 0.02). Likewise, in thrombin generation assays in plasma, rivaroxaban prolonged the lag time and suppressed endogenous thrombin potential to a greater extent than apixaban. To characterize how the two inhibitors differ in recognizing factor Xa, inhibition of prothrombinase was monitored in real-time using a fluorescent probe for thrombin. The data were fit using a mixed-inhibition model and the individual association and dissociation rate constants were determined. The association rates for the binding of rivaroxaban to either free factor Xa or factor Xa incorporated into the prothrombinase complex were 10- and 1,193-fold faster than those for apixaban, respectively, whereas dissociation rates were about 3-fold faster. Collectively, these findings suggest that rivaroxaban and apixaban differ in their capacity to inhibit factor Xa and provide a plausible explanation for the observation that rivaroxaban has a greater effect on global tests of coagulation than apixaban.
| S-EPMC6524873 | biostudies-literature
Project description:The insertion of central venous catheters (CVCs) may be associated with peri- and post-procedural bleeding. People who require a central line often have disorders of coagulation as a result of their underlying illness, co-morbidities or the effects of treatment. Clinical practice in some institutions is to mitigate the risk of bleeding in these patients by prophylactically transfusing fresh frozen plasma (FFP) in order to correct clotting factor deficiencies prior to central line insertion. However, FFP transfusion is not without risk, and it remains unclear whether this intervention is associated with reduced rates of bleeding or other clinically-meaningful outcomes.To assess the effect of different prophylactic plasma transfusion regimens prior to central line insertion in people with abnormal coagulation.We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 3), PubMed (e-publications only), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 1 March 2016.We included RCTs involving transfusions of plasma to prevent bleeding in people of any age with abnormal coagulation requiring insertion of a central venous catheter, published in English.We used standard methodological procedures expected by Cochrane.We identified four trials eligible for inclusion, of which three are ongoing. We did not exclude any studies because they were not published in English.The included study randomised 81 adults in intensive care whose INR (International Normalised Ratio) was greater than or equal to 1.5 to no FFP or to a single dose of 12 mL/kg FFP prior to undergoing central venous catheterisation (58 participants) or other invasive procedure (23 participants). It is the subgroup of 58 adults undergoing CVC insertion that were included in this review, the study authors provided unpublished data for this review's outcomes.The quality of the evidence was low or very low across different outcomes according to the GRADE methodology. The included study was at high risk of bias due to lack of blinding of participants and personnel and imbalance in the number of participants who had liver disease between study arms.There was insufficient evidence to determine a difference in major procedure-related bleeding within 24 hours (one RCT; 58 participants; no events in either study arm, very low-quality evidence). We are very uncertain whether FFP reduces minor procedure-related bleeding within 24 hours of the study (one RCT; 58 participants, RR 0.67, 95% CI 0.12 to 3.70, very low-quality evidence).No studies were found that looked at: all-cause mortality; the proportion of participants receiving plasma or red cell transfusions; serious adverse reactions (transfusion or line-related complications); number of days in hospital; change in INR; or quality of life.The three ongoing studies are still recruiting participants (expected recruitment: up to 355 participants in total). and are due to be completed by February 2018.There is only very limited evidence from one RCT to inform the decision whether or not to administer prophylactic plasma prior to central venous catheterisation for people with abnormal coagulation. It is not possible from the current RCT evidence to recommend whether or not prophylactic plasma transfusion is beneficial or harmful in this situation. The three ongoing RCTs will not be able to answer this review's questions, because they are small studies and do not address all of the comparisons included in this review (355 participants in total). To detect an increase in the proportion of participants who had major bleeding from 1 in 100 to 2 in 100 would require a study containing at least 4634 participants (80% power, 5% significance).
| S-EPMC5215106 | biostudies-literature