Evaluation Of Bleeding Events In Acute Exacerbation Of Chronic Liver Disease Patients: A Prospective Observational Study

Background and ObjectionIneffective hemostasis is commonly observed in chronic liver disease and cirrhosis patients,it also has been identified as one of the diagnose criteria of Acute-on-Chronic Liver Failure(ACLF),which characterized as high short-term mortality.In Chinese ACLF patients,coagulation failure is the second most common organ failure,which represents a prevalence of 67.7%.Despite the high prevalence of abnormal coagulation test in patients with chronic liver disease,the view of "rebalance of hemostasis" has become a shared belief as the decrease of anticoagulant factors such as protein C and S was also taken into account.However,some expert holds the opinion that acute decompensation might disturb this"rebalance" and leading to both thrombotic and bleeding complications.In recent ACLF study trials,the occurrence of bleeding complications haven't been described,possible reason could be low incidence of life-threated bleeding event observed during clinical practice.There are trials focus on bleeding in the setting of invasive procedures,gastric variceal bleeding and intracranial bleeding.However,there isn't study describe the minor bleeding events such as skin ecchymosis,gingival bleeding,haematuria,epistaxis,etc.Whether minor bleeding events occur in patients with chronic liver disease and its relationship with the severity of disease are stillunknown.Moreover,there isn't a unified criterion to identify the level of leeding events for cirrhosis patients.Although there are existed bleeding criteria,most of them is developed and used during the research of anti-coagulation drug.Thus,a fine-designed clinical trial is needed to provide evidence of the necessity and the appropriate method to evaluate bleeding events in acute exacerbation of chronic liver disease patients.Here we designed a prospective,observational,cohort trial.The primary objective is to compare the usage of 4 bleeding criteria,which include Thrombolysis In Myocardial Infarction(TIMI),Global Use of Strategies To Open coronary arteries(GUSTO),Bleeding Academic Research Consortium(BARC),the International Society on Thrombosis and Haemostasis(ISTH).Integration degree of clinical character and correlation with outcome are the main consideration.The secondary objective of this study is to evaluate incidence of various kinds of bleeding events,especially minor ones in patients with acute exacerbation of chronic liver disease.Methods and materialsThis study was performed in a single center in Hospital,Southern Medical University,Guangzhou,Guangdong,China from Jun 2017 to Sep 2017.Our study is a prospective,observational,cohort trial.We systematically and consecutively enroll patients with exacerbation of chronic liver disease,patients are divided into 3 groups according to severity of disease:acute on chronic liver injury group(ACLI),pre-Acute-on-Chronic Liver Failure group(pre-ACLF)and ACLF.Pre-ACLF group is defined as reach Asian Pacific Association for the Study of the Liver(APASL)ACLF definition but not reach European Association for the Study of the Liver(EASL)ACLF definition,ACLF group is defined by EASL ACLF definition.The trial is approved by the Biological and Medical Ethics Committee(BMEC)of Nanfang Hospital(NEFC-2017-097).This study has been registered with ClinicalTrials.gov(NCT03281252).All the patients or their legal surrogate is fully informed.Inclusion criteria were:(1)Age?18 years old and<80 years old;(2)Chronic liver disease/cirrhosis;(3)Serum bilirubin higher than 3 mg/dl(51 ?pmol/L)or ALT>10 ULN;(4)Agree to participate in this clinic trial and sign the informed consent.Exclusion criteria were:(1)Any types of malignancies;(2)Pregnancy;(3)Disease lead to disturbance of coagulation;(4)Anti-platelet or anti-coagulation drug used in 4 weeks;(5)Serum or platelet infusion in 4 weeks;(6)Surgeries including splenectomy,subtotal splenectomy,disconnection and liver transplantation;(7)Any other chronic disease leading to organ failure include heart failure(NYHA IV),respiratory failure(PaO2<60mmHg),renal insufficiency(CKD 5)and conscious disturbance(GCS<8).Medical history and physical examination will be recorded by resident after hospitalized,blood routine examinations,biochemical examinations including electrolyte,hepatic and renal function,coagulation test will be performed immediately(if needed)or on the second day of admission.Investigator will estimate the enrollment of patients refer to the medical record.Once a patient is enrolled in the cohort study,he/she or his/her surrogate will be fully informed of this study.Bleeding evaluation will be conducted and record by an investigator during hospitalization for every 3 days in 28 days.The evaluation includes inquiring of epistaxis,stomatorrhagia,gross hemafecia,and gross hematuria.Physical examination will be conducted including visual inspection of hematoma,bruise or petechial of skin.Medical records will be reviewed including clinical record,laboratory test results,surgery record,blood transfusion record,cranial CT scan report.Statistical analysisThe continuous variables are described with mean and standard deviation;categorical variables are described as numbers(%).Comparison of continuous variables will be analyzed by t-test(2 groups)or one-way ANOVA(more than 2 groups).Categorical frequency comparison will be analyzed by chi-square test.To assess the relationship between bleeding criteria and mortality,we compare the area under curve of receiver operating curve(AUC)of 4 bleeding criteria by means of compared Z test.Log-rank method is used in Kaplan-Meier survival analyses of each definition.Other analysis includes data comparison between bleeding patients and non-bleeding patients and the comparison of bleeding incidence between different severities of disease.All data will be analyzed by IBM SPSS statistics software,version 21.0(SPSS Inc.,Chicago,IL,USA)and MedCalc17.9 statistics software(MedCalc Software,Belgium).P value<0.05 was taken as statistical significance.ResultsTotally 104 patients with acute decompensation of chronic liver disease were included,10 patients were excluded:taking anti-platelet drug(n=3),diagnosed of cancer(n=1),diagnosed of cholestatic liver disease(n=1),failure of observation(n=1).Eventually 94 patients were included,ACLI group n=56,pre-ACLF group n=26,ACLF group n=12.Significant difference was found in age,Model for End-stage Liver Disease(MELD)score,Chronic Liver Failure Consortium Organ failure(CLIF-C OFs)score,28-days mortality and 90-day mortality,progression rate,white blood cell(WBC),platelet(PLT),prothrombin time(PT),activated partial thromboplastin time(APTT),D-dimer,total bilirubin(TB)between 3 groups(p<0.05).There was no significant difference of etiology,cirrhosis rate,hemoglobin,creatinine,Aspartate aminotransferase,Alanine aminotransferase,between 3 groups.Bleeding events occurred in 57.6%patients.In 42.4%patients haven't discover any bleeding events.Incidence of severe bleeding events diverse according to different criteria:incidence of BARC>Type2 is 3.2%,incidence of TIMI major is 1.1%, incidence of GUSTO severe is 1.1%,incidence of ISTH major is 5.3%.Bleeding patients have higher mortality rate in 28 and 90 days and severer of disease degree.The most common bleeding place is skin ecchymosis after puncture(52/94),skin ecchymosis(9/94),epistaxis(8/94),gingival bleeding(6/94),gastric variceal bleeding(4/94)and intracranial bleeding(1/94),lethal bleeding rate is 1/94,which occurred in intracranial bleeding patient.Patients with bleeding event has higher age,MELD score,CLIF-C-OF score,28-day mortality,90-day mortality,progression rate,TB,PT,APTT,INR,D-Dimer,PLT compare with non-bleeding patients.Relationship between survival and four bleeding criteria is compared.Patients were divided into groups according to different bleeding criteria score,and the survival of each group was compared by Kaplan-Meier survival analysis.The 90-day survival rate of non-bleeding group was 100%,ISTH score had a better ability to distinguish the survival condition.The median survival time for ISTH defined Minor,NMCR and Major was 83.9 days,62.17 days,15.2 days.Respectively,the median survival time for GUSTO defined Mild,Moderate,and Severe was 80.1,12.5,and 13 days.The median survival time of TIMI defined Minimal,Minor,and Major was 79 days,4 days,and 13 days.The median survival time of BARC defined Type 1,Type 2,Type 3,and Type 5 bleeding events were 81.4 days,19 days,12.5 days,and 13 days.With the Logrank test,significant difference of survival was observed in different score in four criteria(p<0.05).In ROC curve analysis of bleeding criteria and 28-day mortality.ISTH have the largest Area Under Curve(AUC),which is 0.95(95%CI:0.861-1),comparing with BARC AUC=0.880(95%CI:0.747-1,p=0.042),TIMI AUC=0.801(95%CI:0.653-0.948,p=0.020).Defining bleeding events fitting ISTH minor and NMCR criteria as small bleeding events,totally 55(58.5%)patients were found minor bleeding during hospitalization,in the ACLI group,pre-ACLF group,EASL-ACLF group,incidence of minor bleeding events was 41.1%,76.9%,100%.Significant difference was found between groups.Defining bleeding fitting ISTH severe criteria as major bleeding event,a total of 5(5.3%)patients in the hospital observed major bleeding events,the incidence in group ACLI,pre-ACLF and EASL-ACLF was 1.8%,11.5%,8.3%.There was no significant difference of major bleeding events between three groups.ConclusionHemorrhagic events are common in patients with chronic liver disease and increase with the severity of disease,but the occurrence of severe bleeding events is rare.In this study,57.6%of the chronic liver disease patients had varying degrees of bleeding during hospitalization.The most common bleeding site was skin ecchymosis after puncture,lethal bleeding incidence was 1/94.According to different definitions,the incidence of severe bleeding events is different.The bleeding population had higher 28-day mortality,90-day mortality,age,MELD score,CLIF-C OFs score,hospital progression rate,TB,PT,APTT,INR,D-Dimer and platelet compared with those without bleeding.In ROC curve analysis of bleeding criteria and 28-day mortality.ISTH have the largest AUC=0.95,comparing with BARC AUC=0.880,TIMI AUC=0.801.The applicability of the ISTH standard is better in the assessment of hemorrhagic events in patients with chronic liver disease.