Introduction
Although patients with acute-on-chronic liver failure (ACLF) often demonstrate preserved thrombin generation (TG), they concurrently display hypocoagulable profiles on rotational thromboelastometry (ROTEM) [1]. The extent to which these findings explain the increased bleeding risk in acutely ill cirrhotic patients remains unclear [1–5]. Moreover, most studies do not distinguish between portal hypertensive (PH) and non-PH bleeding, complicating accurate estimation of NPH bleeding prevalence.
Aims & Methods
This is a case-control study, comparing haemostatic profiles of acute decompensation (AD) and ACLF (=cases) to stable cirrhosis (SC) (=controls). Coagulation profiles were evaluated including INR, aPTT, PT, fibrinogen, coagulation factors and inhibitors and advanced global haemostatic tests (ROTEM, TG assay (TGA) ± thrombomodulin (TM)). Secondary objectives focused on identifying associations between coagulation parameters and NPH bleeding and thrombotic events.
Results
A total of 215 patients were included (SC: 122; AD: 53; ACLF: 40). The median Child-Pugh (CP) and MELD-Na scores increased progressively from SC to AD to ACLF (P< 0.001). NPH bleeding occurred in 8,4% (n=18), with higher rates in ACLF (30,8%, P<0,001) and AD (18.9%, P=0.011) than in SC (5.7%). Thrombotic events were observed in 7.0% (n=15).
TGA without TM revealed that ACLF patients had significantly shorter lag time compared to SC, shorter time to peak, reduced peak height and endogenous thrombin potential (ETP) compared to SC/AD; though TM normalized these effects. ETP inhibition by TM was reduced significantly across the three groups. ROTEM parameters showed marked hypocoagulable features in ACLF vs SC/AD, while AD and SC were comparable. Hypocoagulability (≥5 abnormal ROTEM parameters out of 6 parameters) was present in 1.8% of SC, 8.3% of AD, and 22.2% of ACLF patients (P<0.001 for SC vs ACLF); hypercoagulability was rare (2.8% in ACLF). INR and aPTT were significantly prolonged and FVIII elevated, while fibrinogen, PT, and pro- and anticoagulants were reduced in AD/ACLF compared to SC. ROTEM and TGA parameters correlated significantly with MELD-Na and CP scores (P<0,001).
Patients with NPH bleeding had higher CP and MELD-Na scores (P<0,001 and P=0,006), and a greater prevalence of AD (33,3%) and ACLF (38,9%) compared to non-bleeders (22,8% AD; 16,1% ACLF). Hypocoagulability on ROTEM was more frequent among bleeders (31.3% vs 4.5% in non-bleeders, P=0.002). Bleeders also showed greater impairment in INR, aPTT, PT, and most coagulation factors (except FVIII and PS). Multivariate analysis identified ROTEM-defined hypocoagulability as an independent risk factor for NPH bleeding (OR 12.93, 95% CI: 1.13–150.28, P=0.041). No significant differences in coagulation parameters were observed between patients with and without thrombotic complications.
Conclusion
TG demonstrated accelerated initiation and reduced thrombin potential in ACLF vs SC/AD, though TM normalized these effects. ROTEM demonstrated pronounced hypocoagulability in AD/ACLF vs SC. These coagulation abnormalities are paralleling their advanced liver dysfunction.
NPH bleeding events clustered in AD/ACLF cohorts and were associated with ROTEM-defined hypocoagulability. The convergence of ROTEM hypocoagulability as an independent risk factor for NPH bleeding and its prominence in acutely ill cirrhotic patients underscores the heightened NPH bleeding prevalence and ROTEM detected coagulation dysfunction in this patient population.
References
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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.