In vivo generation of thrombin in patients with liver disease without apparent evidence of activation of the intrinsic or extrinsic pathway of coagulation

Background: Patients with liver diseases are in a hypercoagulable state, as evidenced by enhanced in vitro thrombin generating capacity and elevated plasma levels of markers of in vivo thrombin generation. However, it is unknown by which mechanism in vivo activation of coagulation occurs. Objectives: We aimed to clarify the mechanisms underlying enhanced in vivo thrombin generation to provide a rationale for targeted anticoagulant therapy. Patients/Methods: Overall, 191 patients diagnosed with stable or acutely decompensated cirrhosis, acute liver failure or injury, acute-on-chronic liver failure, or sepsis without underlying chronic liver disease were recruited from King's College Hospital, London, from 2017 to 2021 and compared with reference values of 41 healthy controls. We measured levels of markers of in vivo activation of coagulation and activation of the intrinsic and extrinsic pathways, their respective zymogens, and natural anticoagulants. Results: Thrombin-antithrombin complexes, prothrombin fragment 1+2 (F1+2), and D-dimer levels were increased in acute and chronic liver disease, proportional to disease severity. Plasma levels of free activated factor XII (FXIIa), C1-esterase-inhibitor (C1inh)-FXIIa, C1inh-factor XI, C1inh-plasma kallikrein, factor-VIIa-antithrombin-complexes, and activated FVII were reduced in acute and chronic liver disease, even after adjusting for zymogen levels, which were also substantially reduced. Natural anticoagulants antithrombin and protein C were profoundly reduced in liver patients. Conclusions: This study provides evidence of enhanced thrombin generation in liver disease without detectable activation of the intrinsic or extrinsic pathway. We propose that defective anticoagulant mechanisms highly amplify the low-grade activation of coagulation by either pathway.</p

Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant

BACKGROUND: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. METHODS: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. RESULTS: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. CONCLUSIONS: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level