Introduction
Cirrhotic patients undergo intricate changes in their haemostatic system, resulting in a ‘rebalanced haemostasis’. In patients with acute decompensation (AD) and acute-on-chronic liver failure (ACLF), this delicate balance is particularly susceptible to disruption by external stressors such as infections or acute kidney injury (AKI) rendering them more vulnerable to haemostatic complications than individuals with stable cirrhosis [1,2].
Aims & Methods
This case-control study evaluated coagulation profiles (INR, aPTT, PT, fibrinogen, coagulation factors and inhibitors, rotational thromboelastometry (ROTEM), and thrombin generation assay (TGA) [BleedScreen/ (BS) ThromboScreen (TS) ± thrombomodulin (TM)]) in 215 cirrhotic patients, comparing subgroups with/without AKI or bacterial infection to assess haemostatic impact.
Results
The cohort included 215 patients, with 37 (17.2%) having AKI and 31 (14.4%) bacterial infections. AKI patients had higher median Child-Pugh (11 vs 7, P<0.001) and MELD-Na scores (25 vs 11, P<0.001) than non-AKI patients, with more AD (32.4% vs 23%) and ACLF (59.5% vs 10.1%, P<0.001). Infected patients also showed higher CP (9 vs 7) and MELD-Na scores (33 vs 12, P<0.001), with more ACLF (51.6% vs 13%, P<0.001).
In the overall cohort, AD and ACLF patients have more hypocoagulability on ROTEM than SC. TG was preserved in AD compared to SC but showed more hypocoagulable features in ACLF, which were offset after TM addition. Both TG and ROTEM abnormalities correlated with liver disease severity.
Bacterial infection was linked to increased TG capacity (endogenous thrombin potential (ETP)-TM: 928.15 vs. 770.10 nm·min, P=0.030) and significantly less ETP suppression by TM (11.07% vs. 30.33%, P<0.001). Despite a greater prevalence of ACLF, ROTEM profiles did not differ between infected and non-infected patients. Standard coagulation assays revealed a hypocoagulable state, with lower levels of FII, VII, X, IX, and XI, while fibrinogen and platelet counts remained similar. Hypercoagulable features included increased FVIII and decreased protein S, (PS) and C (PC), and antithrombin (AT).
In the AKI group, TGA showed significantly accelerated TG in BS and TS with reduced TG capacity in TS. After TM addition, no differences in TG speed or total TG capacity were noted. Patients with AKI showed a significantly lower ETP inhibition by TM. ROTEM showed prolonged clotting times in INTEM and EXTEM and reduced maximum clot firmness in FIBTEM, with overall more hypocoagulability (21.2% vs. 4.2%, P=0.003). Standard coagulation assays showed mixed features in AKI, with increased INR, prolonged aPTT and reduced fibrinogen, FII, V, VII, X, IX, and XI levels, along with elevated FVIII and reduced AT and PC. Platelet counts were similar.
Conclusion
Global coagulation assays (TGA and ROTEM) showed similar profiles in infected vs non-infected cirrhotic patients, with some hypercoagulable features on TGA in infection, despite high ACLF prevalence (>50%). In contrast, AKI showed accelerated TG but reduced TG capacity, more hypocoagulable ROTEM features, and lower coagulation factors and inhibitors.
Although ACLF rates were comparable in AKI and infection groups, hypocoagulability was more pronounced in AKI, where in the infection group coagulation status was preserved or showed even some hypercoagulable features. This indicated that these coagulation abnormalities reflect the effects of these destabilizing factors rather than disease severity alone.
References
- Zanetto A, Northup P, Roberts L, Senzolo M. Haemostasis in cirrhosis: Understanding destabilising factors during acute decompensation. Vol. 78, Journal of Hepatology. Elsevier B.V.; 2023. p. 1037–47.
- Intagliata NM, Davis JPE, Lafond J, Erdbruegger U, Greenberg CS, Northup PG, Caldwell SH. Acute kidney injury is associated with low factor XIII in decompensated cirrhosis. Dig Liver Dis. 2019 Oct;51(10):1409-1415.
Disclosure
The reagents for the ROTEM analyses were sponsored by Werfen. This study received a Gilead fellowship, and K.F. received a BSTH-CSL Behring encouragement award.