Procedural-Related Bleeding in Hospitalized Patients With Liver Disease (PROC-BLeeD): An International, Prospective, Multicenter Observational Study.

BACKGROUND & AIMS: Hospitalized patients with cirrhosis frequently undergo multiple procedures. The risk of procedural-related bleeding remains unclear, and management is not standardized. We conducted an international, prospective, multicenter study of hospitalized patients with cirrhosis undergoing nonsurgical procedures to establish the incidence of procedural-related bleeding and to identify bleeding risk factors. METHODS: Hospitalized patients were prospectively enrolled and monitored until surgery, transplantation, death, or 28 days from admission. The study enrolled 1187 patients undergoing 3006 nonsurgical procedures from 20 centers. RESULTS: A total of 93 procedural-related bleeding events were identified. Bleeding was reported in 6.9% of patient admissions and in 3.0% of the procedures. Major bleeding was reported in 2.3% of patient admissions and in 0.9% of the procedures. Patients with bleeding were more likely to have nonalcoholic steatohepatitis (43.9% vs 30%) and higher body mass index (BMI; 31.2 vs 29.5). Patients with bleeding had a higher Model for End-Stage Liver Disease score at admission (24.5 vs 18.5). A multivariable analysis controlling for center variation found that high-risk procedures (odds ratio [OR], 4.64; 95% confidence interval [CI], 2.44-8.84), Model for End-Stage Liver Disease score (OR, 2.37; 95% CI, 1.46-3.86), and higher BMI (OR, 1.40; 95% CI, 1.10-1.80) independently predicted bleeding. Preprocedure international normalized ratio, platelet level, and antithrombotic use were not predictive of bleeding. Bleeding prophylaxis was used more routinely in patients with bleeding (19.4% vs 7.4%). Patients with bleeding had a significantly higher 28-day risk of death (hazard ratio, 6.91; 95% CI, 4.22-11.31). CONCLUSIONS: Procedural-related bleeding occurs rarely in hospitalized patients with cirrhosis. Patients with elevated BMI and decompensated liver disease who undergo high-risk procedures may be at risk to bleed. Bleeding is not associated with conventional hemostasis tests, preprocedure prophylaxis, or recent antithrombotic therapy.

Safety and efficacy of venous thromboembolism prophylaxis in patients with cirrhosis: A systematic review and meta-analysis.

BACKGROUND & AIMS: Patients with cirrhosis are considered in a haemostatic balance, though weaker than in normal subjects. In these patients, however, the use of pharmacological prophylaxis for venous thromboembolism (VTE) remains controversial. Therefore, in this study, we aimed to assess the safety and efficacy of VTE prophylaxis in patients with cirrhosis. METHODS: We conducted a systematic review of studies reporting the occurrence of bleeding and VTE events in patients with cirrhosis, and controls, undergoing VTE prophylaxis. Meta-regression analysis was conducted to further explore the determinants of heterogeneity in the study of the occurrence of either bleeding or VTE events. RESULTS: In a total of 10 studies, including 5712 patients, of which 2330 undergoing VTE prophylaxis, bleeding (n = 5513) and VTE events occurred in 8.2% and 2.8% patients respectively. A total of 2963 and 3162 patients were included from low-risk of bias studies in bleeding and VTE analysis respectively: while administration of VTE prophylaxis did not seem to reduce VTE (OR = 1.07, CI 0.39-2.96, p = .89), importantly prophylaxis was not associated with increased bleeding risk (OR = 0.56, CI 0.20-1.59, p = .27). Meta-regression analysis showed that no parameter significantly influenced the heterogeneity of data regarding bleeding or VTE events. CONCLUSIONS: In patients with cirrhosis, current evidence is insufficient to advise for or against the use of VTE prophylaxis, mainly due to lack of quality and homogeneity of available data. However, its use does not appear to be associated with a significant bleeding risk. Adequately designed studies are required to provide a measure of its overall utility.

Haemostatic alterations and management of haemostasis in patients with cirrhosis.

Patients with cirrhosis frequently acquire complex changes in their haemostatic system including a decreased platelet count and decreased levels of various haemostatic proteins. Although historically patients with cirrhosis were thought to have a haemostasis-related bleeding tendency, it is now widely accepted that the haemostatic system of patients with cirrhosis remains in balance as a result of simultaneous changes in pro- and anti-haemostatic systems. The concept of rebalanced haemostasis has led to changes in clinical management, although firm evidence from well-designed clinical studies is largely lacking. For example, many invasive procedures in patients with cirrhosis and a prolonged prothrombin time are now performed without prophylaxis with fresh frozen plasma. Conversely, clinicians have become more aware of the need for anti-thrombotic therapy, even in those patients with abnormal routine coagulation tests. This paper will outline recent advances in pathogenesis, prevention and treatment of both bleeding and thrombotic complications in patients with cirrhosis. Among other topics, we will discuss the haemostatic status of acutely ill patients with cirrhosis, the various causes of bleeding in patients with cirrhosis, and how best to prevent or treat bleeding. In addition, we will discuss the hypercoagulable features of patients with cirrhosis, new insights into the pathogenesis of portal vein thrombosis, and how best to prevent or treat thromboses.

Transfusion with Cryoprecipitate for Very Low Fibrinogen Levels Does Not Affect Bleeding or Survival in Critically Ill Cirrhosis Patients.

BACKGROUND: Fibrinogen (FIB) levels less than 150 mg/dL have been associated with increased rates of bleeding and lower survival in critically ill cirrhosis patients. OBJECTIVE: We aimed to determine if treatment with cryoprecipitate (CRYO) for low FIB levels is associated with bleeding outcomes or survival. METHODS: A total of 237 cirrhosis patients admitted to an intensive care unit at a tertiary care liver transplant center with initial FIB levels less than 150 mg/dL were retrospectively assessed for CRYO transfusion, bleeding events, and survival outcomes. RESULTS: The mean MELD score was 27.2 (95% confidence interval [CI]: 26.0-28.3) and CLIF-C acute on chronic liver failure score was 53.4 (51.9-54.8). Ninety-nine (41.8%) were admitted for acute bleeding and the remainder were admitted for nonbleeding illnesses. FIB level on admission correlated strongly with disease severity. After adjusting for disease severity, FIB on admission was not an independent predictor of 30-day survival (hazard ratio [HR]: 0.99, 95% CI: 0.99-1.01, p = 0.68). CRYO transfusion increased FIB levels but had no independent effect on mortality or bleeding complications (HR: 1.10, 95% CI: 0.72-1.70, p = 0.65). CONCLUSION: In cirrhosis patients with critical illness, low FIB levels on presentation reflect severity of illness but are not independently associated with 30-day mortality. Treatment of low FIB with CRYO also does not affect survival or bleeding complications, suggesting FIB is an additional marker of severity of illness but is not itself a direct factor in the pathophysiology of bleeding in critically ill cirrhosis patients.

Rates of Bleeding and Discontinuation of Direct Oral Anticoagulants in Patients With Decompensated Cirrhosis.

BACKGROUND & AIMS: Studies of the effects of direct oral anticoagulants (DOACs) in patients with cirrhosis have been limited by their small sample size, inclusion of patients with well-compensated cirrhosis, short follow-up times, inadequate validation of cirrhosis diagnoses, and non-standard definitions of bleeding. We aimed to systematically determine the characteristics, indications, and outcomes of patients with cirrhosis of all severity classes who received DOACs. METHODS: We performed a retrospective study of 138 patients with confirmed cirrhosis (93 with Child-Turcotte-Pugh scores of B or C) at a single center who started DOAC therapy (58,984 person-days; median, 181 days per patient) from September 2011 through April 2019. We collected data on clinical characteristics, indications for DOAC use, and outcomes. Standardized and validated definitions for bleeding complications were used. RESULTS: Twenty-nine patients (21%) stopped therapy due to a diagnosis of or perceived bleeding. The most common bleeding events were non-variceal upper and lower intestinal bleeding. No pretreatment laboratory parameters were associated with bleeding while patients received treatment, including platelet count (P = .50), international normalized ratio (P = .34), creatinine (P = .27), and model for end-stage liver disease score (P = .22). Frequency of bleeding events related to DOAC did not differ significantly among patients of different Child-Turcotte-Pugh classes (P = .81), DOAC indications (P = .60), or DOAC dosages (P = .10). Higher proportions of patients with hepatocellular carcinoma (P = .01) had major bleeding while receiving. CONCLUSIONS: Patients with decompensated cirrhosis have significant bleeding and rates of discontinuation of DOACs when they take them long term. Pretreatment laboratory parameters, DOAC dose, and Child-Turcotte-Pugh class were not associated with bleeding; hepatocellular carcinoma was associated with major bleeding.

The Spectrum of Disease Severity in Cirrhosis and Its Implications for Hemostasis.

Bleeding and thrombosis are both common complications that patients with advanced liver disease experience. While hemostatic pathways remain largely intact with cirrhosis, this balance can quickly shift in the direction of bleeding or clotting in an unpredictable manner. A growing body of literature is attempting to shed light on difficult scenarios that clinicians often face, ranging from predicting and mitigating bleeding risk in those who need invasive procedures to determining the best strategies to manage both bleeding and thrombotic complications when they occur. Studies examining hemostasis in those with advanced liver disease, however, often include heterogeneous cohorts with varied methodology. While these studies often select a cohort of all types and degrees of cirrhosis, emerging evidence suggests significant differences in underlying systemic inflammation and hemostatic abnormalities among specific phenotypes of liver disease, ranging from compensated cirrhosis to decompensated cirrhosis and acute-on-chronic liver failure. It is paramount that future studies account for these differing disease severities if we hope to address the many critical knowledge gaps in this field.

Clinical Cirrhosis Dilemmas: Survey of Practice from the 7th International Coagulation in Liver Disease Conference.

INTRODUCTION AND AIM: Hemostatic disorders in chronic liver disease and cirrhosis show continued expansion of research efforts. However, clinical decision making is often practiced on an individual patient level as consensus guidelines are lacking. We aimed to better assess individual day-to-day clinical practice through gauging clinicians' responses to common clinical scenarios. MATERIALS AND METHODS: A series of ten clinical scenarios (seven procedural coagulation and three thrombosis management) were posed to conference attendees utilizing real-time polling software (Poll Everywhere). Responses were binomial and were submitted as "Agree" or "Disagree." Results were displayed real time following a standardized response period and an open-forum discussion ensued between conference faculty and attendees following response submission. RESULTS: Twenty conference attendees participated in the clinical scenario plenary session. In general, agreement rates were high. All but one of the ten clinical scenarios had ≥ 70% agreement. Agreement was based both on procedural risk, with greatest agreement seen for low-risk procedures (80-93%), and on peri-procedural coagulation parameters of platelet count and fibrinogen level where > 50,000µ/L and 120 mg/dL were the most agreed upon thresholds, respectively. 75-95% agreement was reached when surveying the need for anticoagulation for mesenteric vein thrombosis in liver transplant candidates; slightly less (71%) agreement was found when deciding to proceed with anticoagulation in non-liver transplant candidates with mesenteric vein thrombosis. CONCLUSIONS: While large-scale, methodologically rigorous randomized controlled trials are lacking to guide clinical decision making in patients with coagulation disorders and chronic liver disease, consensus expert opinion regarding mitigating peri-procedural bleeding risk and treatment of thrombosis appears consistent and strong.

Macrosteatotic Allografts and Obese Recipients Have Nearly Equal Negative Impact on Liver Transplant Survival.

BACKGROUND: Our aim was to evaluate liver transplant outcomes involving donors with high macrosteatosis grafts in the obese modern liver transplant recipient population. METHODS: A high-steatosis graft was defined as donor graft macrosteatosis ≥30% on biopsy. Recipient obesity was defined as body mass index (BMI) >35 adjusted for ascites. Raw and adjusted recipient liver transplant survival were evaluated and compared between 4 cohorts: (1) high-steatosis graft in high-BMI recipient; (2) low-steatosis graft in high-BMI recipient; (3) high-steatosis graft in normal-BMI recipient; and (4) low-steatosis graft in normal-BMI recipient. RESULTS: After adjustment for multiple factors, recipient high-BMI remained an independent predictor of posttransplant mortality at 30 days (P < 0.0001) and persisted at 1 year (P = 0.009). A high-steatosis graft was the strongest independent predictor of mortality at 30 days (hazard ratio 2.05, 1.66-2.53; P < 0.0001) and that effect was diminished but persistent at 1 year (1.27, 1.10-1.46; P = 0.001). CONCLUSIONS: Recipient high-BMI and a high-steatosis graft are both significant independent and equally powerful predictors of mortality after modern liver transplant. High-steatosis grafts transplanted into obese recipients have the highest mortality. The increase in mortality associated with a high-steatosis graft into a normal-BMI recipient is similar in magnitude to a low-steatosis graft placed into a high-BMI recipient.

Overuse of venous thromboembolism prophylaxis among hospitalized patients with liver disease.

INTRODUCTION: Patients with liver disease are at risk of venous thromboembolism (VTE); however, little is understood regarding the safety and efficacy of VTE prophylaxis in patients with cirrhosis. We examined the application of a VTE risk assessment model in VTE prophylaxis decision-making in a closed cohort of hospitalized patients with liver disease. METHODS: Sequential patients admitted to an inpatient hepatology service at a tertiary care center were evaluated for need for VTE prophylaxis. Risk assessment by IMPROVE was compared with current practice patterns of VTE prophylaxis. Rates of bleeding and clotting events were noted. RESULTS: 98 patient encounters were included in our analysis. 76% of patients received VTE prophylaxis in practice. IMPROVE recommended use of VTE prophylaxis in 19% of patients. Patients who received VTE prophylaxis that was not warranted had significantly lower risk of clotting compared with patients in whom VTE prophylaxis was warranted per IMPROVE. CONCLUSIONS: Application of IMPROVE risk assessment would significantly reduce VTE prophylaxis use among hospitalized patients with liver disease. Our findings challenge the "one-size-fits-all" current practice pattern of VTE prophylaxis. Future studies are needed in large cohorts of hospitalized patients with liver disease that include clinical outcomes of bleeding and clotting risk.

Acute kidney injury is associated with low factor XIII in decompensated cirrhosis.

BACKGROUND/AIMS: The coagulation system is known to be rebalanced but fragile in stable cirrhosis. Acute kidney injury (AKI) is common in these patients and associated with an increased bleeding risk. We aimed to assess coagulation parameters in this population. METHODS: We prospectively enrolled 43 hospitalized patients with decompensated cirrhosis with (n = 22) or without (n = 21) AKI. Coagulation factor levels, viscoelastic coagulation assay, and thrombin generation assay were performed and compared between these groups and a healthy reference group. RESULTS: Conventional markers of coagulation were not statistically different between patients with and without AKI. Factor XIII was significantly reduced in all patients with cirrhosis compared to healthy controls (p = <0.0001). In patients with AKI, factor XIII was significantly lower compared to patients without AKI (AKI 38% vs. non-AKI 60% p = 0.002). In patients with cirrhosis, factor XIII had a significantly positive correlation with EXTEM maximal clot firmness (r = 0.5440, p = 0.0002) and FIBTEM maximal clot firmness (r = 0.7397, p = <0.0001) and a negative correlation with EXTEM clot formation time (-0.413, p = 0.0065). CONCLUSIONS: Factor XIII was significantly reduced in decompensated cirrhosis patients with AKI compared to decompensated patients without AKI. These findings suggest that exacerbation of factor XIII deficiency in AKI in decompensated cirrhosis may affect bleeding risk and warrants further study.

Diagnosis, Development, and Treatment of Portal Vein Thrombosis in Patients With and Without Cirrhosis.

Portal vein thrombosis unrelated to solid malignancy is common in patients with cirrhosis, but less frequently observed in patients without cirrhosis. Prompt diagnosis and management of acute symptomatic portal vein thrombosis are essential. Failure to detect and treat thromboses can result in mesenteric ischemia, chronic cavernous transformation, and complications of portal hypertension. In patients with cirrhosis, development of portal vein thrombosis is often insidious and remains undetected until its incidental detection. Management of portal vein thrombosis in patients with cirrhosis is more controversial. However, there are data to support treatment of specific patients with anticoagulation agents. We review the common and distinct features of portal vein thromboses in patients without liver tumors, with and without cirrhosis.

Anticoagulation and Transjugular Intrahepatic Portosystemic Shunting for Treatment of Portal Vein Thrombosis in Cirrhosis: A Systematic Review and Meta-Analysis.

Portal vein thromboses (PVTs) are associated with hepatic decompensation, worse survival, and worse liver transplant outcomes. We evaluated the impact of anticoagulation (AC) and transjugular intrahepatic portosystemic shunting (TIPS) on recanalization and mortality in patients with cirrhosis and PVT. Systematic search of electronic databases was performed. Clinical trials and observational studies that evaluated primary outcomes of recanalization and survival in patients with cirrhosis having PVT treated with AC or TIPS were included. Risk of bias was assessed. Summary odds ratios (ORs) for pooled data from the included studies were generated using a random effects model. A total of 505 studies were screened for inclusion. After review, 7 studies were ultimately included. Data from 327 patients in total were evaluated. Overall, treatment with either AC or TIPS resulted in partial or complete recanalization (OR: 4.56 [95% confidence interval, CI: 2.46-8.47]) but did not significantly impact mortality (OR: 0.57 [95% CI: 0.21-1.57]). The summary OR of AC for recanalization was 6.00 (95% CI: 2.38-15.07). The summary OR of TIPS for recanalization was 3.80 (95% CI: 1.47-9.83). The summary OR of mortality in patients treated with AC for PVT was 0.28 (95% CI: 0.08-0.95). The mortality summary OR was 1.10 (95% CI 0.23-5.16) in patients who underwent TIPS. There was insufficient data to assess complications such as hepatic encephalopathy or bleeding. Both AC and TIPS have a significant effect on recanalization. Anticoagulation appears to have a protective effect on mortality that is not seen with TIPS. More studies with control groups are need.