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.

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.

Healing gone wrong: convergence of hemostatic pathways and liver fibrosis?

Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellular matrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis - the chronic nature of insult required and the liver's unique ability to regenerate - give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease.

Coagulation testing and management in liver disease patients.

PURPOSE OF REVIEW: The present article aims to provide clinicians with an overview of coagulation testing in individuals with liver disease, to discuss available procoagulants and the rationale for their use, and to provide management strategies in a variety of common clinical scenarios. RECENT FINDINGS: Clinicians and researchers are gaining an increased understanding of the shortfalls of assessing bleeding risk using traditional tests of coagulation. The use of global tests of clot formation, including viscoelastic testing and thrombin generation analysis, continues to evolve and guide the management of these patients. SUMMARY: Abnormal coagulation testing in individuals with cirrhosis leads to a variety of difficult clinical scenarios that can be challenging for practitioners. With advanced liver disease, changes in the traditional tests of hemostasis such as the international normalized ratio reflect decreased synthesis of procoagulant factors but do not capture concomitant decreases in anticoagulant factors. In this setting, transfusion thresholds targeting platelet and fibrinogen goals may provide an effective strategy to optimize clot formation. Global tests of clot formation provide practical information to clinicians and can help guide decision making, although optimal target levels have not been validated.

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.

Coagulation Pathways, Hemostasis, and Thrombosis in Liver Failure.

Achieving hemostasis, preventing and treating thrombosis, and laboratory measurement of the hemostatic pathways constitute the core elements of managing the critically ill patient with liver failure. Uncontrolled bleeding in acutely decompensated cirrhosis and acute-on-chronic liver failure is probably the most familiar clinical challenge to intensivists. Bleeding in these patients can be broadly divided into pressure-driven (portal hypertension-related) bleeding with only limited dependence on hemostatic pathways and intractable mucosal/wound bleeding, which is much more directly related to a severely disturbed hemostatic system with imbalances in the coagulation cascade and the fibrinolytic system. Both types of bleeding can occur simultaneously and may even coexist with inappropriate thrombosis such as portal vein thrombosis or venous thromboembolism. Due to the fundamental role of the liver in coagulation factor synthesis and its direct and indirect regulation of nearly all aspects of the hemostatic system, laboratory measurements of coagulation pathways also constitute key aspects of all prognostic scores that guide clinical decisions and forecast optimal interventions in both acute and chronic forms of liver failure.

Viscoelastic Testing in Liver Disease.

Long thought to be hypocoagulable, new evidence suggests cirrhosis patients have "rebalanced" coagulation in the setting of decreased synthesis of both pro- and anti-coagulant factors. Traditional testing like PT/INR reflects only the decreased synthesis of pro-coagulant factors and thus does not correspond to bleeding or clotting risk in this population. In this review, we discuss the use of viscoelastic testing (VET), an assay of global hemostasis in cirrhosis patients. We describe the technique and interpretation of commercially available VET and assess the application of VET in both transplant and non-transplant cirrhosis populations. VET largely correlates well with traditional testing including platelet count and fibrinogen level, however, is potentially less accurate in patients with low fibrinogen levels. VET may be useful in identifying patients at higher risk of hypercoagulable complications post-transplant and reflects changes in hemostasis in decompensated patients. While VET has been associated with decreased transfusión support in multiple studies, the lack of bleeding in patients who avoided prophylactic transfusion suggests a "rescue" rather than prophylactic approach to transfusion may be ideal and further studies with a "rescue" arm are needed. Additional prospective studies of VET should include clinically relevant endpoints of bleeding and thrombosis.

Extracorporeal photopheresis attenuates murine graft-versus-host disease via bone marrow-derived interleukin-10 and preserves responses to dendritic cell vaccination.

Extracorporeal photopheresis (ECP) is emerging as a therapy for graft-versus-host-disease (GVHD), but the full mechanism of action and the impact on immunity have not been fully established. After murine minor histocompatibility antigen-mismatched bone marrow (BM) transplantation (allo-BMT), coinfusion of ECP-treated splenocytes with T cell-replete BM attenuated GVHD irrespective of the donor strain of the ECP-treated splenocytes, and was associated with increased numbers of regulatory T cells. Coculture of myeloid dendritic cells (DCs) with ECP-treated splenocytes resulted in increased interleukin (IL)-10 production after submaximal stimulation with lipopolysaccharide. Furthermore, male myeloid DCs exposed to ECP-treated splenocytes were less potent at inducing CD8(+) HY responses when used as a vaccine in vivo. The efficacy of ECP-treated splenocytes was enhanced when administered just before delayed donor lymphocyte infusion following T cell-depleted allo-BMT, allowing for the administration of sufficient numbers of T cells to respond to myeloid DC vaccination in the absence of a thymus. Finally, the therapeutic effect of ECP-treated splenocytes was lost in recipients of IL-10-deficient BM. We demonstrate that ECP-treated splenocytes attenuate GVHD irrespective of the source of ECP-treated cells via a mechanism that likely involves modulation of DCs and requires IL-10 produced by BM-derived cells. Importantly, the attenuation of GVHD by ECP-treated splenocytes permits donor lymphocyte infusion-dependent responses to DC vaccines after allo-BMT.

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.

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.

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.

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.

Val-boroPro accelerates T cell priming via modulation of dendritic cell trafficking resulting in complete regression of established murine tumors.

Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine.