Portal vein thrombosis (PVT) is a relatively frequent event in patients with cirrhosis. While different risk factors for PVT have been reported, such as decreased portal blood flow velocity (PBFV) ...and parameters related with severity of portal hypertension, these are based on retrospective studies assessing only a discrete number of parameters. The aim of the current study was to evaluate the incidence and risks factors for non-tumoral PVT development in a large prospective cohort of patients with cirrhosis.
We performed an exhaustive evaluation of clinical, biochemical, inflammatory and acquired/hereditary hemostatic profiles in 369 patients with cirrhosis without PVT who were prospectively followed-up. Doppler ultrasound was performed at baseline and every 6 months or whenever clinically indicated. PVT development was always confirmed by computed tomography.
Twenty-nine patients developed non-tumoral PVT, with an incidence of 1.6%, 6% and 8.4% at 1, 3 and 5 years, respectively. Low platelet count, PBFV <15 cm/sec and history of variceal bleeding were factors independently associated with a high PVT risk. No relationship between PVT development and any other clinical biochemical, inflammatory and acquired or hereditary hemostatic parameter was found.
In patients with cirrhosis, the factors predictive of PVT development were mainly those related to the severity of portal hypertension. Our results do not support the role of hemostatic alterations (inherited or acquired) and inflammatory markers in the prediction of PVT in patients with cirrhosis.
Patients with cirrhosis and more severe portal hypertension are at higher risk of non-tumoral portal vein thrombosis development. Acquired or inherited hemostatic disorders, as well as inflammatory status, do not seem to predict the development of portal vein thrombosis in patients with cirrhosis.
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•Factors related to more severe portal hypertension are associated with higher risk of PVT in cirrhosis.•Acquired and inherited alterations of coagulation do not predict PVT development during follow-up.•Cirrhosis-associated inflammation or generation of NETs are not relevant factors predicting PVT development.
Endothelial dysfunction is a major determinant of the increased hepatic vascular tone of cirrhotic livers. Von Willebrand factor (vWF), P-selectin and 8-iso-PGF2α (isoprostanes), surrogate markers of ...endothelial dysfunction, are increased in patients with cirrhosis. This study was aimed at exploring in patients with cirrhosis and portal hypertension the relation of these endothelial factors with systemic and hepatic haemodynamics and their possible clinical prognostic value.
42 consecutive patients with cirrhosis and portal hypertension had measurement of the hepatic venous pressure gradient (HVPG), cardiopulmonary pressures and vWF, P-selectin and isoprostane levels in blood samples from hepatic and peripheral veins. Patients were followed up to 2 years, death or liver transplantation and any clinical event were recorded.
vWF, P-selectin and isoprostanes were increased in patients with cirrhosis compared with controls (p<0.001). vWF levels significantly correlated with HVPG, Child-Pugh score and MELD. Cox model analysis disclosed an independent indirect association of peripheral vWF with survival free of portal hypertension-related events and of transplantation. The vWF cut-off value of 216 U/dl (Youden index) disclosed two different populations of patients with cirrhosis with a highly different probability of survival free of portal hypertension-related events and transplantation (87% vs 22%, p=0.001). The prognostic role of vWF persisted after adjusting for parameters of liver dysfunction and for HVPG.
In patients with cirrhosis and portal hypertension vWF levels correlate with liver function and HVPG and independently predict clinical outcome.
Background & Aims Increased hepatic vascular resistance due to fibrosis and elevated hepatic vascular tone is the primary factor in the development of portal hypertension. Heparin may decrease ...fibrosis by inhibiting intrahepatic microthrombosis and thrombin-mediated hepatic stellate cell activation. In addition, heparin enhances eNOS activity, which may reduce hepatic vascular tone. Our study aimed at evaluating the effects of acute, short-, long-term and preventive enoxaparin administration on hepatic and systemic hemodynamics, liver fibrosis and nitric oxide availability in cirrhotic rats. Methods Enoxaparin (1.8 mg/kg subcutaneously), or its vehicle, was administered to CCl4 -cirrhotic rats 24 h and 1 h before the study (acute), daily for 1 week (short-term) or daily for 3 weeks (long-term) and to thioacetamide-cirrhotic rats daily for 3 weeks with/without thioacetamide (preventive/long-term, respectively). Mean arterial pressure, portal pressure, portal blood flow, hepatic vascular resistance and molecular/cellular mechanisms were evaluated. Results No significant changes in hemodynamic parameters were observed in acute administration. However, one-week, three-week and preventive treatments significantly decreased portal pressure mainly due to a decrease in hepatic vascular resistance without significant changes in mean arterial pressure. These findings were associated with significant reductions in liver fibrosis, hepatic stellate cell activation, and desmin expression. Moreover, a reduction in fibrin deposition was observed in enoxaparin-treated rats, suggesting reduced intrahepatic microthrombosis. Conclusion Enoxaparin reduces portal pressure in cirrhotic rats by improving the structural component of increased liver resistance. These findings describe the potentially beneficial effects of enoxaparin beyond the treatment/prevention of portal vein thrombosis in cirrhosis, which deserve further investigation.
Clinical guidelines do not recommend long-term anticoagulation in non-cirrhotic splanchnic vein thrombosis (NC-SVT) without underlying thrombophilia because it is assumed that there is a very low ...risk of recurrent thrombosis (RT). Our first aim was to describe the incidence of RT in people with NC-SVT without an indication for long-term anticoagulation. The second aim was to identify RT risk factors and afterwards verify them in a validation cohort.
This is a multicentre, retrospective observational study evaluating risk factors for RT in 64 people with NC-SVT of idiopathic/local factor aetiology. In a subgroup of 48 individuals, the potential value of additional thrombophilic parameters to predict RT was analysed. Findings were validated in 70 individuals with idiopathic/local factor NC-SVT.
Of the 64 participants in the training cohort, 17 (26%) presented splanchnic and/or extrasplanchnic RT (overall-RT) during follow-up (cumulative incidence: 2, 10, 19, and 34% at 1, 2, 5, and 10 years, respectively). In addition, 53% of people with splanchnic RT were asymptomatic. No clinical or biochemical parameters predicted overall-RT. However, in the 48 people with an additional comprehensive thrombophilic study, factor VIII ≥150% was the only independent factor predicting overall-RT (hazard ratio 7.10, 95% CI 2.17–23.17, p <0.01). In the validation cohort, 19 individuals (27%) presented overall-RT, and it was also independently predicted by factor VIII >150% (hazard ratio 3.71, 95% CI 1.31–10.5, p <0.01). The predictive value of factor VIII was confirmed in both people with idiopathic/local factor aetiology associated NC-SVT.
People with idiopathic/local factor NC-SVT are at risk of overall-RT. Splanchnic RT can be asymptomatic and requires screening for its detection. Values of factor VIII ≥150% may help identify individuals at high risk of overall-RT who could benefit from long-term anticoagulation.
People with idiopathic/isolated local factor non-cirrhotic portal vein thrombosis were previously thought to be at minimal risk of re-thrombosis and therefore did not receive scheduled follow-up. The results of this study are of special interest for hepatologists treating people with non-cirrhotic splanchnic thrombosis, as they show a 25% incidence of re-thrombosis and support the close follow-up of people with factor VIII >150% to ensure the early identification of new thrombotic events.
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•Individuals with non-cirrhotic splanchnic thrombosis without thrombophilia are at risk of re-thrombosis.•Splanchnic re-thrombosis can be asymptomatic and requires screening for its detection.•Factor VIII ≥150% may help identify individuals at higher risk of re-thrombosis.
Balanced hemostasis with hypocoagulable and hypercoagulable features may occur in acute‐on‐chronic liver failure (ACLF). The characteristics and prognostic impact of the coagulation profile in ACLF ...are unknown. Consecutive patients with ACLF (n = 36) and acute decompensation (AD; n = 24) were included. Blood samples for thromboelastometry (TE) were obtained at admission and 72 hours thereafter. The coagulation profile was evaluated in patients with and without ACLF and in those with and without systemic inflammatory response syndrome. The impact of the coagulation profile on transfusion requirements, bleeding events, and short‐term survival was assessed. At admission, patients with ACLF showed more hypocoagulable characteristics compared to AD subjects, with prolonged time to initial fibrin formation and clot formation time and decreased maximum clot firmness and alpha‐angle values. TE parameters worsened at 72 hours in ACLF but improved in patients with AD. Prevalence of a hypocoagulable profile (three or more TE parameters outside range) was significantly higher in patients with ACLF either at admission (61% versus 29% in AD; P = 0.03) or during follow‐up. Hypocoagulability correlated with systemic inflammation and was associated with higher 28‐day (45% versus 16%; P = 0.02) and 90‐day (52% versus 19%; P = 0.01) mortality rates but not with transfusion requirements or bleeding. Prolonged time to initial fibrin formation (extrinsic TE assay >80 seconds) and Model for End‐Stage Liver Disease score at baseline were independent predictors of 28‐day mortality. Conclusion: Patients with ACLF frequently show hypocoagulable features with prolonged time to initial fibrin formation and clot formation time and reduced clot firmness; these alterations worsen after admission, correlate with systemic inflammation, and translate into higher short‐term mortality; hypofibrinolysis could contribute to organ failure in ACLF.
Background and aims
Splanchnic vein thromboses (SVT) are a rare condition that can be life‐threatening. The most severe thrombophilia associated to SVT is antithrombin (AT) deficiency, usually caused ...by SERPINC1 mutations. Although transitory AT deficiencies and congenital disorders of the N‐glycosylation pathways (CDG) have been recently reported as causes of AT deficiency, the current AT clinical screening still only includes anti‐FXa activity. This study aims to (a) improve the detection of AT deficiency in SVT and (b) characterize the features of AT deficiency associated with SVT.
Methods
The study was performed in 2 cohorts: (a) 89 SVT patients with different underlying etiologies but in whom AT deficiency had been ruled out by classical diagnostic methods; and (b) 271 unrelated patients with confirmed AT deficiency and venous thrombosis. AT was evaluated by functional (anti‐FXa and anti‐FIIa) and immunological methods (ELISA, crossed immunoelectrophoresis, western blot), and SERPINC1 sequencing was performed.
Results
In 4/89 patients (4.5%) additional alterations in AT were found (two had SERPINC1 mutations, one had a specific variant causing transient AT deficiency and one patient had CDG). In 11 of the 271 patients (4.1%) with AT deficiency and thrombosis, thrombosis was located at the splanchnic venous territory.
Conclusions
Antithrombin deficiency may be underdiagnosed by current clinical screening techniques. Therefore, a comprehensive AT evaluation should be considered in cases of rethrombosis or doubtful interpretation of anti‐FXa activity levels. SVT is a relatively common localization of the thrombotic event in patients with congenital AT deficiency.
Background and Aims
Data about the prognosis of salvage transjugular intrahepatic portosystemic shunt (TIPS) using covered stents for refractory variceal bleeding caused by portal hypertension are ...scarce. We aimed to assess survival and to identify predictors of mortality in these patients.
Approach and Results
One hundred sixty‐four patients with cirrhosis from five centers treated with salvage TIPS between 2007 and 2017 were retrospectively divided into a derivation cohort (83 patients) and a validation cohort (81 patients). Comparisons were performed using the Mann‐Whitney and Fischer’s exact test. Six‐week overall survival (OS) was correlated with variables on the day of the TIPS using Kaplan‐Meier curves with log‐rank test and univariate/multivariate analyses using the Cox model. Eighty‐three patients were included in the derivation cohort (male, 78%; age, 55 years, alcohol‐associated cirrhosis, 88%; Model for End‐Stage Liver Disease MELD, 19 15‐27; arterial lactate, 3.7 mmol/L 2.0‐8.3). Six‐week OS rate was 58%. At multivariate analysis, the MELD score (OR, 1.064; 95% CI, 1.005‐1.126; P = 0.028) and arterial lactate (OR, 1.063; 95% CI, 1.013‐1.114; P = 0.032) were associated with 6‐week OS. Six‐week OS rates were 100% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15 and 5% in patients with lactate ≥12 mmol/L and/or MELD score ≥ 30. The 81 patients of the validation cohort had similar MELD and arterial lactate level but lower creatinine level (94 vs 106 µmol/L, P = 0.008); 6‐week OS was 67%. Six‐week OS rates were 86% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15 and 10% for patients with lactate ≥12 mmol/L and/or MELD score ≥ 30. In the overall cohort, rebleeding rate was 15.8% at 6 weeks, and the acute‐on‐chronic liver failure grade (OR, 1.699; 95% CI, 1.056‐1.663; P = 0.040) was independently associated with rebleeding.
Conclusions
After salvage TIPS, 6‐week mortality remains high and can be predicted by MELD score and lactate. Survival rate at 6 weeks was >85% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15, while mortality was >90% for lactate ≥12 mmol/L and/or MELD score ≥ 30.
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.
Wedge hepatic vein pressure (WHVP) accurately estimates portal pressure (PP) in alcohol- or viral hepatitis-related cirrhosis. Whether this also holds true in cirrhosis caused by non-alcoholic ...steatohepatitis (NASH) is unknown. We aimed to evaluate the agreement between WHVP and PP in patients with NASH cirrhosis in comparison to patients with alcohol- or HCV-related cirrhosis.
All consecutive patients with NASH cirrhosis treated with a transjugular intrahepatic portosystemic shunt (TIPS) in 3 European centres were included (NASH group; n = 40) and matched with 2 controls (1 with alcohol-related and 1 with HCV-related cirrhosis) treated with TIPS contemporaneously (control group; n = 80). Agreement was assessed by Pearson’s correlation (R), intra-class correlation coefficient (ICC), and Bland-Altman method. Disagreement between WHVP and PP occurred when both pressures differed by >10% of PP value. A binary logistic regression analysis was performed to identify factors associated with this disagreement.
Correlation between WHVP and PP was excellent in the control group (R 0.92; p <0.001; ICC 0.96; p <0.001) and moderate in the NASH group (R 0.61; p <0.001; ICC 0.74; p <0.001). Disagreement between WHVP and PP was more frequent in the NASH group (37.5% vs. 14%; p = 0.003) and was mainly because of PP underestimation. In uni- and multivariate analyses, only NASH aetiology was associated with disagreement between WHVP and PP (odds ratio 4.03; 95% CI 1.60–10.15; p = 0.003).
In patients with decompensated NASH cirrhosis, WHVP does not estimate PP as accurately as in patients with alcohol- or HCV-related cirrhosis, mainly because of PP underestimation. Further studies aimed to assess this agreement in patients with compensated NASH cirrhosis are needed.
Portal pressure is usually assessed by measuring wedge hepatic vein pressure because of solid evidence demonstrating their excellent agreement in alcohol- and viral hepatitis-related cirrhosis. Our results show that in patients with decompensated cirrhosis caused by non-alcoholic steatohepatitis, wedge hepatic vein pressure estimates portal pressure with less accuracy than in patients with other aetiologies of cirrhosis, mainly because of portal pressure underestimation.
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•Wedge hepatic vein pressure (WHVP) accurately estimates portal pressure (PP) in patients with alcohol-related or HCV-related cirrhosis.•Agreement between WHVP and PP in decompensated non-alcoholic steatohepatitis (NASH) cirrhosis is worse than in other aetiologies.•WHVP tends to underestimate PP in patients with decompensated NASH cirrhosis.
Background & Aims Patients with cirrhosis and small hepatocellular carcinoma with normal bilirubin and hepatic venous pressure gradient (HVPG) <10 mm Hg have >70% 5-year survival after hepatic ...resection. On the contrary, patients with HVPG ⩾10 mm Hg (clinically significant portal hypertension, CSPH) frequently develop decompensation following surgery, with around 50% 5-year survival. Liver stiffness (LS) evaluation by transient elastography might non-invasively identify CSPH. We investigated the usefulness of LS predicting CSPH in patients with compensated cirrhosis and potentially resectable liver tumors. Methods Ninety-seven consecutive Child-Pugh A patients with potentially resectable liver tumors referred for HVPG measurement were prospectively evaluated. In fasting conditions LS was measured before the hemodynamic study. Results HVPG could be measured in all patients, whereas LS could not be measured in 18 (18.5%) obese patients. In the 79 patients with valid LS, 32 (40.5%) had CSPH; mean HVPG was 8.8 ± 4.7 mm Hg. Mean LS was 18.4 ± 12.3 kPa. LS showed a moderate correlation with HVPG (r = 0.552; p <0.001). LS <13.6 kPa had high sensitivity (91%) but low specificity (57%) excluding CSPH. Conversely, LS >21 kPa had low sensitivity (53%) and high specificity (91%) predicting CSPH. 35% of patients had LS between 13.6 and 21 kPa (“grey zone”). Conclusions These data suggest that in real-life scenarios half of patients with potentially resectable liver nodules can be non-invasively classified as having or not CSPH by LS. However, in the remaining half, LS is either not applicable or inaccurate. In this last population HVPG is still a non replaceable method to detect CSPH.
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