Heparin-like Effect Associated With Risk of Bleeding, Sepsis, and Death in Patients With Severe Alcohol-Associated Hepatitis.

BACKGROUND & AIMS: Endogenous heparinoids or heparin-like effects (HLEs) can cause coagulation failure in patients with cirrhosis and sepsis. We performed a prospective study of the association between HLE and bleeding events, sepsis, and outcomes of patients with severe alcohol-associated hepatitis. METHODS: Our final analysis comprised 78 patients with severe alcohol-associated hepatitis (44.3 ± 11.7 years; all male; discriminant function >32) who presented without sepsis at a single center in India from August 2015 through August 2016. Blood samples were collected at days 0, 3, and 7 after presentation and assessed by a global coagulation assay; by SONOCLOT (global and heparinase treated); and in assays for factor VIII, von Willebrand factor, protein C, and antithrombin. Patients were followed for sepsis, bleeding and outcome. The primary outcome was association of HLE with survival 28 days after presentation. RESULTS: HLEs were observed in 32 patients (41%) at day 0, 27 patients (34.6%) at day 3, and 28 patients (35.9%) patients at day 7. Factors associated with mortality at day 0 were factor VIII activity >160% (hazard ratio [HR], 3.1; 95% CI, 1.4-9.5; P = .026), level of protein C <34% (HR, 0.7; 95% CI, 0.5-0.8; P = .037), antithrombin activity <28% (HR, 0.7; 95% CI, 0.3-1.1; P = .008) and international normalized ratio >2.6 (HR, 2.3; 95% CI, 1.8-9.7; P = .010). In multivariate analyses, only factor VIII activity (HR, 2.3; 95% CI, 1.6-7.8; P = .046), international normalized ratio (1.9; 95% CI, 1.2-4.3; P = .039), level of protein C (HR, 0.9; 95% CI, 0.7-1.1; P = .052) and model for end-stage liver disease score (HR, 3.2; 95% CI, 1.9-10.2; P = .042) were associated with mortality. Episodes of epistaxis, hemorrhoid bleeding, hemoperitoneum, and pulmonary hemorrhage occurred in 10.2%, 12.3%, 3.4%, and 4.5% of patients respectively. The presence of HLE at day 0 increased the risk of sepsis (HR, 2.5; 95% CI, 2.2-4.3; P = .002), bleeding (HR, 1.4; 95% CI, 1.2-5.3; P = .004) and death (HR, 1.2; 95% CI, 1.4-1.7; P = .044). CONCLUSIONS: In a prospective study of patients with severe alcohol-associated hepatitis, we associated HLE with coagulation abnormalities, risk of sepsis, and mortality. Clinicaltrials.govNCT02307409.

Coagulation failure is associated with bleeding events and clinical outcome during systemic inflammatory response and sepsis in acute-on-chronic liver failure: An observational cohort study.

BACKGROUND: Patients with acute-on-chronic liver failure (ACLF) have coagulation failure in the setting of systemic inflammatory syndrome (SIRS), sepsis and extra-hepatic organ failures. METHODS: Consecutive ACLF patients without sepsis at baseline were assessed at days 0, 3 and 7 with thromboelastography (TEG) and specific assays (Factor VIII, von Willebrand factor [vWF], protein C and antithrombin III [ATIII]) and followed for development of sepsis, bleeding and outcome. RESULTS: Of 243 patients, 114 (63% ethanol related; mean age 44.3 ± 11.7 years; 90% male) were recruited. SIRS was noted in 39 (34.2%), 45 (39.5%) and 46 (40%) patients at days 0, 3 and 7 and sepsis in 28 (24%) and 52 (56.1%) patients at days 3 and 7 respectively. The 28- and 90-day survivals were 62% and 51% respectively. A hypocoagulable TEG at baseline was a predictor of bleeding (hazard ratio [HR] 2.1; CI 1.6-4.9; P = 0.050) and mortality (HR 1.9; CI 1.3-7.9; P = 0.043). ACLF patients had increased Factor VIII, vWF, tissue factor levels and tissue plasminogen activator (tPA) activity with reduced protein C and ATIII. Coagulation parameters like Coagulation Index (HR 2.1; CI 1.1-4.5; P = 0.044),clot lysis (HR 3.2; CI 1.9-3.4; P = 0.033), low protein C < 30% (HR 2.1; CI 1.5-2.8; P = 0.017), ATIII (HR 1.4; CI 1.7-3.1; P = 0.052) and tPA (HR 1.5; CI 1.1-2.4; P = 0.052) were predictors of mortality at day 28. Protein C activity <30% (HR 1.3; CI 1.0-2.9; P = 0.042) and tPA >20 ng/mL (HR 1.2; CI 1.1-2.1; P = 0.040) predicted mortality when adjusted for age, gender and baseline MELD. CONCLUSIONS: Dynamic coagulation derangements, measured by TEG, determine the likelihood of bleeding and mortality in ACLF.