There is a discrepancy between the information from clotting tests which have routinely been used in clinical practice and evidence regarding thrombotic and bleeding events in patients with liver ...disease. This discrepancy leads us to rely on other variables which have been shown to be involved in haemostasis in these patients and/or to extrapolate the behaviour of these patients to other settings in order to decide the best clinical approach. The aims of the present review are as follows:(1) to present the information provided by clotting tests in cirrhotic patients;(2) to present the factors that may influence clotting in these patients;(3) to review the clinical evidence; and(4) to put forward a clinical approach based on the first 3 points.
Background
COVID‐19 is associated with a substantial risk of venous thrombotic events, even in the presence of adequate thromboprophylactic therapy.
Objectives
We aimed to better characterize the ...hypercoagulable state of COVID‐19 patients in patients receiving anticoagulant therapy.
Methods
We took plasma samples of 23 patients with COVID‐19 who were on prophylactic or intensified anticoagulant therapy. Twenty healthy volunteers were included to establish reference ranges.
Results
COVID‐19 patients had a mildly prolonged prothrombin time, high von Willebrand factor levels and low ADAMTS13 activity. Most rotational thromboelastometry parameters were normal, with a hypercoagulable maximum clot firmness in part of the patients. Despite detectable anti‐activated factor X activity in the majority of patients, ex vivo thrombin generation was normal, and in vivo thrombin generation elevated as evidenced by elevated levels of thrombin‐antithrombin complexes and D‐dimers. Plasma levels of activated factor VII were lower in patients, and levels of the platelet activation marker soluble CD40 ligand were similar in patients and controls. Plasmin‐antiplasmin complex levels were also increased in patients despite an in vitro hypofibrinolytic profile.
Conclusions
COVID‐19 patients are characterized by normal in vitro thrombin generation and enhanced clot formation and decreased fibrinolytic potential despite the presence of heparin in the sample. Anticoagulated COVID‐19 patients have persistent in vivo activation of coagulation and fibrinolysis, but no evidence of excessive platelet activation. Ongoing activation of coagulation despite normal to intensified anticoagulant therapy indicates studies on alternative antithrombotic strategies are urgently required.
BACKGROUND: Rotation thromboelastometry (TEM) has been proposed as a convenient alternative to standard coagulation tests in guiding the treatment of coagulopathy during orthotopic liver ...transplantation (OLT). This study was aimed at assessing the value of TEM in monitoring blood coagulation and guide transfusion support in OLT.
STUDY DESIGN AND METHODS: Standard coagulation and TEM (EXTEM and FIBTEM) tests were performed at four preestablished intraoperative time points in 236 OLTs and prospectively recorded in a dedicated database together with the main operative and transfusion data. Transfusion thresholds were based on standard coagulation tests. Spearman's rank correlation (ρ), linear regression, and receiver operating characteristic curves were used when appropriate.
RESULTS: EXTEM maximum clot firmness (MCFEXTEM) was the TEM variable that best correlated with the platelet (PLT) and fibrinogen levels (ρ = 0.62 and ρ = 0.69, respectively). MCFFIBTEM correlated with fibrinogen level (ρ = 0.70). EXTEM clot amplitude at 10 minutes (A10EXTEM) was a good linear predictor of MCFEXTEM (R2 = 0.93). The cutoff values that best predicted the transfusion threshold for PLTs and fibrinogen were A10EXTEM = 35 mm and A10FIBTEM = 8 mm. At these values, the negative and positive predictive accuracies of TEM to predict the transfusion thresholds were 95 and 27%, respectively.
CONCLUSION: A10EXTEM is an adequate TEM variable to guide therapeutic decisions during OLT. Patients with A10EXTEM of greater than 35 mm are unlikely to bleed because of coagulation deficiencies, but using A10EXTEM of not more than 35 mm as the sole transfusion criterion can lead to unnecessary utilization of PLTs and fibrinogen‐rich products.
Abstract
Background
This risk analysis aimed to explore all modifiable factors associated with prolonged mechanical ventilation (lasting > 24 h) after liver transplantation, based on prospectively ...collected data from a clinical trial.
Methods
We evaluated 306 candidates. Ninety-three patients were excluded for low risk for transfusion (preoperative haemoglobin > 130 g.l
−1
), and 31 patients were excluded for anticoagulation therapy, bleeding disorders, familial polyneuropathy, or emergency status. Risk factors were initially identified with a log-binomial regression model. Relative risk was then calculated and adjusted for age, sex, and disease severity (Model for End-Stage Liver Disease MELD score).
Results
Early tracheal extubation was performed in 149 patients (84.7%), and 27 patients (15.3%) required prolonged mechanical ventilation. Reoperations were required for 6.04% of the early extubated patients and 44% of patients who underwent prolonged ventilation (
p
= 0.001). A MELD score > 23 was the main risk factor for prolonged ventilation. Once modifiable risk factors were adjusted for MELD score, sex, and age, three factors were significantly associated with prolonged ventilation: tranexamic acid (
p
= 0.007) and red blood cell (
p
= 0.001) infusion and the occurrence of postreperfusion syndrome (
p
= 0.004). The median (IQR) ICU stay was 3 (2–4) days in the early extubation group vs. 5 (3–10) days in the prolonged ventilation group (
p
= 0.001). The median hospital stay was also significantly shorter after early extubation, at 14 (10–24) days, vs. 25 (14–55) days in the prolonged ventilation group (
p
= 0.001). Eight patients in the early-extubation group (5.52%) were readmitted to the ICU, nearly all for reoperations, with no between-group differences in ICU readmissions (prolonged ventilation group, 3.7%). Conclusion.
We conclude that bleeding and postreperfusion syndrome are the main modifiable factors associated with prolonged mechanical ventilation and length of ICU stay, suggesting that trials should explore vasopressor support strategies and other interventions prior to graft reperfusion that might prevent potential fibrinolysis.
Trial Registration.
European Clinical Trials Database (EudraCT 2018–002510-13,) and on ClinicalTrials.gov (NCT01539057).
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.
We 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.
All 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.
Collectively, 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.
Acute-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.
Thromboelastometry is considered the best method to assesses hemostasis in liver disease. Diagnostic performance could be improved by adding protein C activators such as thrombomodulin or Protac®. We ...assessed changes in ROTEM parameters after the addition of Protac® in patients with acute-on-chronic liver failure (ACLF), acute decompensation (AD), and healthy individuals (HI) to define different hemostasis patterns, considering standard and velocity ROTEM parameters, and assess whether Protac® can improve the definition of the pattern.
Pre-test, we investigated whether diluted EXTEM reagent improved the effect of Protac® on the clotting time (CT)-ratio with and without Protac®. Ten ACLF and 20 AD patients and 21 HI were included in the main study.
Standard EXTEM was used in the main study. INTEM CFT, INTEM A5 (inverse), and INTEM TPI (inverse) were the parameters that best differentiated liver disease from HI (ROC AUC, 0.921, 0.906, and 0.928, respectively; all P-values < 0.001). Combining INTEM CFT with EXTEM LI60-ratio only slightly improved the diagnostic performance (ROC AUC, 0.948; P < 0.001). EXTEM LI60 and INTEM maxV-t were the parameters that best differentiated between ACLF and AD patients (ROC AUC, 0.743, P = 0.033; and 0.723, P = 0.050; respectively). Combining EXTEM LI60 + INTEM maxV-t moderately improved the diagnostic performance (ROC AUC, 0.81, P < 0.001).
ROTEM velocity, fibrinolysis parameters and the indices calculated improve the diagnosis in combination with standard parameters (e.g., CFT and A5). Ratios calculated with and without Protac® (e.g., EXTEM LI60-ratio) only slightly increased the diagnostic performance in discriminating hemostasis patterns.
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