To study the predictive value of elevated serum D-dimer on short-term prognosis in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) and the correlation between serum D-dimer level and the clinical data of these patients, a single center retrospective study was conducted to collect the clinical data and 28 and 90-day survival rates of 201 patients. Logistic regression analysis and receiver operating characteristic curves were used to determine the factors affecting short-term prognosis. A Kaplan-Meier curve was used to compare the difference in survival rate between the two groups with elevated D-dimer and normal D-dimer levels. Correlation analysis was used to determine the correlation between serum D-dimer level and the clinical data of the patients. The results showed that international normalized ratio (INR) >2.3 and age >53 years were independent risk factors affecting the 28-day survival rate of the patients (P<0.05). INR >2.3, serum total bilirubin >358.2 µmol/l, age >49 years and elevated serum D-dimer (>550 ng/ml) were independent risk factors affecting the 90-day survival rate of the patients (P<0.05). There were significant differences in the 90-day survival rate and the survival time between the patients with elevated D-dimer and normal D-dimer levels (P<0.05). Serum D-dimer level was positively associated with age, combined spontaneous peritonitis, albumin, INR and the model for end-stage liver disease sodium (MELD-Na) scores, and negatively associated with male sex, red blood cell count, and serum sodium and fibrinogen levels. It was concluded that elevated serum D-dimer (>550 ng/ml) is an independent risk factor affecting the 90-day survival rate of patients with HBV-ACLF. The 90-day survival rate and the survival time of patients with HBV-ACLF and elevated D-dimer levels are significantly lower than those with normal D-dimer levels. Overall, serum D-dimer is associated the short-term prognosis of patients with HBV-ACLF, and the detection of serum D-dimer level at admission can help predict the short-term prognosis of patients with HBV-ACLF, especially the 90-day prognosis.
Acute-on-chronic liver failure (ACLF) refers to acute liver injury that occurs on the basis of underlying liver disease, with jaundice and coagulation disorders as the main manifestations, short-term complications of ascites and hepatic encephalopathy, often combined with multiple organ failure, and high short-term mortality rates (
The reconstituted hemostasis pattern in the disturbed internal environment of patients with ACLF is a subtle balanced hemostasis characterized by the coexistence of hypocoagulability and hypercoagulation, which may lead to the occurrence of hemorrhagic or prothrombotic states (
A single center retrospective study was conducted to screen patients who were hospitalized in The Second Affiliated Hospital of Chongqing Medical University (Chongqing, China) between August 2017 and May 2021. The inclusion criteria included: i) met the diagnostic criteria of APASL ACLF; ii) a diagnosis of ACLF combined with HBV infection; and iii) age within 12-80 years old. The exclusion criteria included: i) a diagnosis of ACLF combined with deep vein thrombosis or portal vein thrombosis; ii) a diagnosis of ACLF combined with liver cancer or other malignant tumors; iii) a diagnosis of ACLF combined with severe chronic extrahepatic diseases; iv) a diagnosis of ACLF combined with atrial fibrillation, coronary heart disease or acute aortic dissection; v) a diagnosis of ACLF combined with human immunodeficiency virus infection; vi) major surgery or trauma within the last 6 months; vii) received anticoagulation therapy within the past month; viii) received immunosuppressive therapy; and ix) pregnant women. A total of 201 patients with HBV-ACLF were included. All patients received standardized medical treatment [according to the Diagnostic and Treatment Guideline for Liver Failure 2018(
Patient data, including age, sex, comorbidities, laboratory test results and prognostic scores, were collected via electronic medical records, and 28 and 90-day survival rates were collated using electronic medical record review and/or standardized telephone interviews. Serum D-dimer level was detected as part of the initial patient tests during the hospitalization period and it was detected by the immunofluorescence method. This method is based on immunofluorescence technology and adopts the double-antibody sandwich method. The sample to be tested is mixed with the detection buffer, and the immunolabeled detection antibody in the buffer will bind to the D-dimer antigen. The intensity of the fluorescent antibody signal is proportional to the concentration of the captured D-dimer, and the concentration of the antigen in the sample can be calculated after being analyzed by an immunoassay analyzer. The type of the analyzer was Jet-iStar3000 produced by Joinstar company, and the D-dimer detection kit produced by Joinstar company was used. The analyzer and kit was used to test the serum samples from 160 healthy individuals and the normal reference range of D-dimer was confirmed to be <550 ng/ml. According to whether the serum D-dimer level was increased (>550 ng/ml), the patients were divided into the elevated D-dimer group and the normal D-dimer group.
Continuous variables with normal distribution were expressed as the mean ± standard deviation, non-normally distributed continuous variables were expressed as the median (inter-quartile range) and nominal variables were expressed as n (%). The influencing factors of 28 and 90-day prognosis were determined by univariate and multivariate logistic regression analysis, and the sensitivity and specificity of influencing factors were determined by receiver operating characteristic (ROC) curves. Among the influencing factors, the binary variable was determined by the χ2 test, and its specificity and sensitivity were calculated. Pearson's correlation analysis was performed between the serum D-dimer levels and various baseline data (the point biserial correlation coefficient of continuous variables and dichotomous variables was consistent with the values of Pearson's correlation coefficient). A Kaplan-Meier curve was drawn, and Breslow's test was used to compare the difference in survival between the two groups. All statistical analyses were performed using SPSS v.26.0 (IBM Corp.) and all figures were drawn with GraphPad Prism 9.0 (GraphPad Software, Inc.). P<0.05 was used to indicate a statistically significant difference.
Of the 201 patients, 18 were lost to follow-up. Among the 183 patients, 162 were male and 21 were female, with a mean age of 47.9 years. Overall, 71.6% of patients had underlying cirrhosis, 53.0% had spontaneous peritonitis (SBP) and 61.7% had an elevated serum D-dimer level at baseline (
Multivariate logistic analysis was performed on the patient's baseline data and the 28 and 90-day prognosis of the patients, and the independent risk factors affecting the 28 and 90-day survival rates were obtained. ROC curve was used to analyze the predictive value of these factors on 28 and 90-day survival. The critical value of each indicator was calculated using Jordan index (
The results showed that international normalized ratio (INR) >2.3 and age >53 years were independent risk factors affecting 28-day survival (P<0.05) (
After 90 days of follow-up, 18 of the 201 patients were censored. A Kaplan-Meier curve was drawn, and the Breslow test was used to compare the difference in survival between the elevated D-dimer and normal D-dimer groups. The results showed that there were significant differences in the 90-day survival rate and the survival time between the two groups (P<0.05). The 90-day survival rate and the survival time of patients in the elevated D-dimer group were significantly lower than those in the normal D-dimer group (
Pearson's correlation analysis was performed between the serum D-dimer levels and various baseline data (the point biserial correlation coefficient of continuous variables and dichotomous variables was consistent with the values of Pearson's correlation coefficient). The results showed that serum D-dimer level was negatively associated with male sex (r=-0.146, P=0.049), red blood cell count (r=-0.173, P=0.019), serum sodium (r=-0.158, P=0.033) and fibrinogen (r=-0.273, P<0.001), and positively associated with age (r=0.155, P=0.037), combined SBP (r=0.149, P=0.044), albumin (r=0.160, P=0.031), INR (r=0.149, P=0.044) and MELD-Na score (r=0.174, P=0.018) (
D-dimer is a sensitive marker of coagulation and fibrinolysis, and studies have found that serum D-dimer is elevated in liver failure and portal vein thrombosis (
Infection and sepsis are common in patients with ACLF, and their presence or development is associated with poor outcomes (
Microvascular thrombosis is associated with the activation of the coagulation system and inflammation, which causes multiple organ failure in patients with sepsis (
The study by El Gohary
The limitations of the present study are, first, that all patients included were diagnosed with HBV-ACLF, so the predictive value of serum D-dimer for short-term prognosis in patients with ACLF due to other etiologies remains to be determined. Second, ACLF progresses rapidly, but due to the limitation of retrospective studies, the changes in serum D-dimer levels in the patients with HBV-ACLF could not be dynamically monitored. Whether the short-term increase of serum D-dimer levels has predictive value for the short-term prognosis of HBV-ACLF still needs further research to confirm.
In conclusion, elevated serum D-dimer (>550 ng/ml) was an independent risk factor affecting the 90-day survival rate of the patients with HBV-ACLF (P<0.05). The 90-day survival rate and the survival time of the patients in the elevated D-dimer group were significantly lower compared with those in the normal D-dimer group (P<0.05). Serum D-dimer is associated with the short-term prognosis of patients with HBV-ACLF, and the detection of serum D-dimer at admission can help predict the short-term prognosis of these patients, especially the 90-day prognosis.
Not applicable.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
QC and ZM confirm the authenticity of all the raw data. QC is responsible for data collection, data analysis and writing the paper. ZM and QC designed and performed the study together. All authors have read and approved the final manuscript.
The study was approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China (approval no. 2022032).
All patients in this study provided oral consent for the publication of their data.
The authors declare that they have no competing interests.
Forest plot of 28-day prognostic factors. INR, international normalized ratio.
ROC curve of 28-day prognostic factors. ROC, receiver operating characteristic; INR, international normalized ratio.
Forest plot of 90-day prognostic factors. INR, international normalized ratio; TBil, total bilirubin.
ROC curve of 90-day prognostic factors. ROC, receiver operating characteristic; INR, international normalized ratio; TBil, total bilirubin.
Kaplan-Meier survival curve of the elevated D-dimer and normal D-dimer groups.
Baseline data of patients (n=183).
Variable | Value | Normal range |
---|---|---|
Age, years | 47.9±11.3 | |
Male sex | 162 (88.5%) | |
Cirrhosis | 131 (71.6%) | |
SBP | 97 (53.0%) | |
Red blood cell count (x1012/l) | 4.1±0.7 | 4.3-5.8 |
Hemoglobin, g/l | 131.9±20.8 | 130-175 |
Leucocyte count (x109/l) | 6.4 (4.9-8.6) | 3.5-9.5 |
Neutrophil percentage | 72.0 (66.8-80.7) | 45-75% |
Platelet count (x109/l) | 94 (68.0-125.0) | 100-300 |
Alanine aminotransferase, U/l | 578 (193.0-1,222.0) | 9-50 |
Aspartate aminotransferase, U/l | 385 (150.0-931.0) | 15-40 |
Serum total bilirubin, µmol/l | 298.3 (236.7-373.7) | 5.1-28 |
Albumin, g/l | 31.1±4.1 | 40-55 |
Serum creatinine, µmol/l | 57.7 (49.5-71.0) | 57-97 |
Serum sodium, mmol/l | 134.9±4.0 | 137-147 |
INR | 2.2 (1.9-2.9) | 0.7-1.3 |
Fibrinogen, g/l | 1.5 (1.2-1.9) | 2-4 |
MELD-Na score | 24.8 (21.0-28.8) | |
Log10HBV-DNA | 5.0 (3.8-6.7) | |
Serum D-dimer, ng/ml | 902 (345.2-1,634.6) | 0-550 |
Elevated D-dimer group | 113 (61.7%) | |
28-day mortality | 50 (27.3%) | |
90-day mortality | 89 (48.6%) |
Continuous variables with normally distribution are expressed as the mean ± standard deviation, non-normally distributed continuous variables are expressed as the median values (inter-quartile range) and nominal variables are expressed as n (%). INR, international normalized ratio; SBP, spontaneous peritonitis; HBV, hepatitis B virus; MELD-Na, the model for end-stage liver disease sodium.
Receiver operating characteristic curve analysis of 28-day prognostic factors.
Factor | AUC | 95% Confidence interval | P-value | Specificity, % | Sensitivity, % | Associated criterion |
---|---|---|---|---|---|---|
INR | 0.688 | 0.616-0.754 | <0.0001 | 60.15 | 70.00 | >2.3 |
Age | 0.668 | 0.595-0.736 | 0.0005 | 81.95 | 50.00 | >53 years |
INR, international normalized ratio; AUC, area under the curve.
Receiver operating characteristic curve analysis of 90-day prognostic factors.
Factor | AUC | 95% Confidence interval | P-value | Specificity, % | Sensitivity, % | Associated criterion |
---|---|---|---|---|---|---|
INR | 0.696 | 0.624-0.762 | <0.0001 | 68.09 | 65.17 | >2.3 |
TBil | 0.656 | 0.582-0.724 | 0.0001 | 82.98 | 43.82 | >358.2 µmol/l |
Age | 0.655 | 0.581-0.724 | 0.0001 | 70.21 | 53.93 | >49 years |
INR, international normalized ratio; TBil, total bilirubin; AUC, area under the curve.
χ2 test of elevated serum D-dimer and 90-day survival.
90-Day survival, n (%) | ||||||
---|---|---|---|---|---|---|
Patient group | Died | Survived | χ2 | P-value | Specificity, % | Sensitivity, % |
Elevated D-dimer | 66 (36.07) | 47 (25.68) | 11.295 | 0.001 | 50.00 | 74.16 |
Normal D-dimer | 23 (12.57) | 47 (25.68) |
Elevated serum D-dimer as a binary variable is not suitable for ROC curve analysis, thus, a χ2 test was performed for elevated serum D-dimer and 90-day survival, and its specificity and sensitivity were calculated.
Correlation analysis of serum D-dimer with baseline data.
Variable | Correlation coefficient (r) | P-value |
---|---|---|
Age, years | 0.155 | 0.037 |
Male sex | -0.146 | 0.049 |
Cirrhosis | 0.030 | 0.688 |
SBP | 0.149 | 0.044 |
Red blood cell count (x1012/l) | -0.173 | 0.019 |
Hemoglobin, g/l | -0.119 | 0.109 |
Leucocyte count (x109/l) | 0.050 | 0.501 |
Neutrophil percentage | 0.040 | 0.586 |
Platelet count (x109/l) | 0.047 | 0.527 |
Alanine aminotransferase, U/l | -0.126 | 0.090 |
Aspartate aminotransferase, U/l | -0.013 | 0.857 |
Serum total bilirubin, µmol/l | 0.064 | 0.389 |
Albumin, g/l | 0.160 | 0.031 |
Serum creatinine, µmol/l | -0.081 | 0.278 |
Serum sodium, mmol/l | -0.158 | 0.033 |
INR | 0.149 | 0.044 |
Fibrinogen, g/l | -0.273 | <0.001 |
MELD-Na score | 0.174 | 0.018 |
Log10HBV-DNA | -0.040 | 0.587 |
INR, international normalized ratio; SBP, spontaneous peritonitis; HBV, hepatitis B virus; MELD-Na, the model for end-stage liver disease sodium.