Stopping antithrombotic therapy after acute upper gastrointestinal bleeding is associated with reduced survival.

INTRODUCTION: Antithrombotic drugs are often stopped following acute upper gastrointestinal bleeding (AUGIB) and frequently not restarted. The practice of antithrombotic discontinuation on discharge and its impact on outcomes are unclear. OBJECTIVE: To assess whether restarting antithrombotic therapy, prior to hospital discharge for AUGIB, affected clinical outcomes. DESIGN: Retrospective cohort study. SETTING: University hospital between May 2013 and November 2014, with median follow-up of 259 days. PATIENTS: Patients who underwent gastroscopy for AUGIB while on antithrombotic therapy. INTERVENTIONS: Continuation or cessation of antithrombotic(s) at discharge. MAIN OUTCOMES MEASURES: Cause-specific mortality, thrombotic events, rebleeding and serious adverse events (any of the above). RESULTS: Of 118 patients analysed, antithrombotic treatment was stopped in 58 (49.2%). Older age, aspirin monotherapy and peptic ulcer disease were significant predictors of antithrombotic discontinuation, whereas dual antiplatelet use predicted antithrombotic maintenance. The 1-year postdischarge mortality rate was 11.3%, with deaths mainly due to thrombotic causes. Stopping antithrombotic therapy at the time of discharge was associated with increased mortality (HR 3.32; 95% CI 1.07 to 10.31, P=0.027), thrombotic events (HR 5.77; 95% CI 1.26 to 26.35, P=0.010) and overall adverse events (HR 2.98; 95% CI 1.32 to 6.74, P=0.006), with effects persisting after multivariable adjustment for age and peptic ulcer disease. On subgroup analysis, the thromboprotective benefit remained significant with continuation of non-aspirin regimens (P=0.016). There were no significant differences in postdischarge bleeding rates between groups (HR 3.43, 0.36 to 33.04, P=0.255). CONCLUSION: In this hospital-based study, discontinuation of antithrombotic therapy is associated with increased thrombotic events and reduced survival.

Human intrahepatic regulatory T cells are functional, require IL-2 from effector cells for survival, and are susceptible to Fas ligand-mediated apoptosis.

UNLABELLED: Regulatory T cells (Treg ) suppress T effector cell proliferation and maintain immune homeostasis. Autoimmune liver diseases persist despite high frequencies of Treg in the liver, suggesting that the local hepatic microenvironment might affect Treg stability, survival, and function. We hypothesized that interactions between Treg and endothelial cells during recruitment and then with epithelial cells within the liver affect Treg stability, survival, and function. To model this, we explored the function of Treg after migration through human hepatic sinusoidal-endothelium (postendothelial migrated Treg [PEM Treg ]) and the effect of subsequent interactions with cholangiocytes and local proinflammatory cytokines on survival and stability of Treg . Our findings suggest that the intrahepatic microenvironment is highly enriched with proinflammatory cytokines but deficient in the Treg survival cytokine interleukin (IL)-2. Migration through endothelium into a model mimicking the inflamed liver microenvironment did not affect Treg stability; however, functional capacity was reduced. Furthermore, the addition of exogenous IL-2 enhanced PEM Treg phosphorylated STAT5 signaling compared with PEMCD8. CD4 and CD8 T cells are the main source of IL-2 in the inflamed liver. Liver-infiltrating Treg reside close to bile ducts and coculture with cholangiocytes or their supernatants induced preferential apoptosis of Treg compared with CD8 effector cells. Treg from diseased livers expressed high levels of CD95, and their apoptosis was inhibited by IL-2 or blockade of CD95. CONCLUSION: Recruitment through endothelium does not impair Treg stability, but a proinflammatory microenvironment deficient in IL-2 leads to impaired function and increased susceptibility of Treg to epithelial cell-induced Fas-mediated apoptosis. These results provide a mechanism to explain Treg dysfunction in inflamed tissues and suggest that IL-2 supplementation, particularly if used in conjunction with Treg therapy, could restore immune homeostasis in inflammatory and autoimmune liver disease. (Hepatology 2016;64:138-150).