Factor VIII/protein C ratio independently predicts liver-related events but does not reflect the hypercoagulable state in patients with advanced-chronic liver disease

Background&aims The ratio of procoagulant factor VIII to anticoagulant protein C (FVIII/PC) has been suggested to reflect the haemostatic equilibrium as it correlates with ex-vivo thrombin generation. Moreover, FVIII/PC predicted decompensation and death in a small study not accounting for portal hypertension (PH) severity.

We investigated (i) the prognostic value of FVIII/PC (outcome-cohort) and (ii) whether FVIII/PC reflects the hypercoagulable state (as assessed by thrombomodulin-modified thrombin generation assay; TM-TGA-cohort) in patients undergoing hepatic venous pressure gradient (HVPG)-measurement.

Methods: (i) The outcome-cohort comprised n = 515 patients with evidence of advanced chronic liver disease (ACLD, liver stiffness measurement [LSM]≥10kPa and/or HVPG≥6mmHg) who were stratified according to clinical stage (CS): Probable compensated ACLD (cACLD):LSM≥10kPa-HVPG<6mmHg, CS0:cACLD-HVPG6-9mmHg, CS1:cACLD-HVPG≥10mmHg, CS2:decompensated ACLD (dACLD) with variceal bleeding, CS3:dACLD with non-bleeding decompensation, and CS4:≥2 decompensations.

(ii) TM-TGA-cohort patients (n = 152) had comparable characteristics and were recruited from the prospective VIenna CIrrhosis Study (VICIS;NCT03267615).

Results: (i) FVIII/PC significantly increased across CS (probable cACLD:2.1[IQR:1.7-2.8], CS0:2.4[1.9-3.5], CS1:3.2[2.6-4.7], CS2:3.1[2.7-3.8], CS3:4.0[3.1-5.9], and CS4: 4.1[3.2-6.4]; p<0.001) as well as HVPG (p<0.001) and MELD (p<0.001) strata. Interestingly, FVIII/PC (aHR:1.06[95 %CI:1.01-1.11]; p = 0.010) remained independently associated with decompensation/liver-related mortality, even after extensive multivariable adjustment.

(ii) FVIII/PC showed a weak positive correlation with endogenous thrombin potential in TM-TGA (Spearman’s ρ=0.265; p = 0.001), but this association disappeared after adjusting for severity of liver disease.

Discussion FVIII/PC increases with CS, PH severity, and liver dysfunction. Even after adjusting for these factors, it remained a robust prognostic indicator. This should not be mistaken as evidence for the concept of hypercoagulability as a driver of disease progression, as the correlation between FVIII/PC and thrombin generation is confounded by liver disease severity, and thus, FVIII/PC does not reflect the haemostatic balance.

Publication History

Article published online:
01 September 2021