Factor VIII/protein C ratio independently predicts liver-related events but does not indicate a hypercoagulable state in ACLD

Abstract

Background & aims: It has been suggested that the ratio of procoagulant factor VIII to anticoagulant protein C (FVIII/PC) reflects the hemostatic equilibrium. Moreover, FVIII/PC predicted decompensation/death in a small study not accounting for portal hypertension severity. We investigated (i) the prognostic value of FVIII/PC (outcome-cohort) and (ii) whether FVIII/PC reflects the hypercoagulable state (assessed by thrombomodulin-modified thrombin generation assay [TM-TGA]) or the risk of bleeding/thrombotic events in patients undergoing hepatic venous pressure gradient (HVPG) measurement during follow-up.

Methods: (i) The outcome-cohort comprised 576 patients with evidence of advanced chronic liver disease (liver stiffness measurement ≥10 kPa and/or HVPG ≥6 mmHg). (ii) TM-TGA-cohort patients (n = 142) were recruited from the prospective VIenna CIrrhosis Study (VICIS: NCT03267615).

Results: (i) FVIII/PC significantly increased across clinical stages (p <0.001) as well as HVPG (p <0.001) and MELD score (p <0.001) strata and remained independently associated with decompensation/liver-related death (adjusted hazard ratio 1.06; 95% CI 1.01-1.11; p = 0.013), even after multivariable adjustment. It was also associated with acute-on-chronic liver failure (ACLF) development (adjusted hazard ratio 1.10; 95% CI 1.02-1.19; p = 0.015) in patients with decompensated cirrhosis. (ii) FVIII/PC showed a weak positive correlation with endogenous thrombin potential (Spearman's ρ = 0.255; p = 0.002), but this association disappeared after adjusting for the severity of liver disease. FVIII/PC was not associated with the development of bleeding (p = 0.272) or thrombotic events (p = 0.269). However, FVIII/PC correlated with biomarkers of different pathophysiological mechanisms that promote liver disease progression.

Conclusion: FVIII/PC provides prognostic information regarding hepatic decompensation/death and ACLF, independently of established prognostic indicators. However, this is not evidence that hypercoagulability drives disease progression, as the correlation between FVIII/PC and thrombin generation is confounded by liver disease severity and FVIII/PC was not associated with thrombosis. Therefore, FVIII/PC does not reflect coagulation and results from previous studies on FVIII/PC require re-interpretation.

Clinical trial number: NCT03267615 (in part).

Lay summary: A balanced coagulation system is essential for preventing bleeding episodes and blood clot formation (thrombosis). Blood of patients with advanced liver disease may have increased coagulation potential, possibly promoting the worsening of liver disease via thrombosis in the blood vessels of the liver. The ratio between the results of 2 blood tests (procoagulant factor VIII to anticoagulant protein C) has been suggested to reflect these increases in coagulation potential. Our study demonstrates, on the one hand, that this ratio is a versatile predictor of the development of complications of cirrhosis, yet on the other hand, that it is unrelated to coagulation.

Keywords: Coagulation; cirrhosis; decompensation; hypercoagulability; portal hypertension.

Conflict of interest statement

Conflicts of interest The authors have nothing to disclose regarding the work under consideration for publication. Conflicts of interests outside the submitted work: L.B., R.J.N., J.W., R.P., L.H., M.J., A.F.S., G.S., P.Q., and T.L. have nothing to disclose. Be.Sc. received travel support from AbbVie, Ipsen and Gilead. Be.Si. received travel support from AbbVie and Gilead. D.B. received travel support from AbbVie and Gilead and speaker fees from AbbVie. M.P. served as a speaker and/or consultant and/or advisory board member for Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Lilly, MSD, and Roche and received travel support from Bayer and Bristol-Myers Squibb. C.A. received honoraria for lectures and advisory boards from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer. M.T. received grant support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx, honoraria for consulting from Albireo, Boehringer-Ingelheim, BiomX, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Regulus, and Shire, speaker fees from Bristol-Myers Squibb, Falk, Gilead, Intercept, and MSD, as well as travel support from AbbVie, Falk, Gilead, and Intercept. T.R. received grant support from AbbVie, Boehringer-Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens, and W. L. Gore & Associates; speaking honoraria from AbbVie, Gilead, Gore, Intercept, Roche, and MSD; consulting/advisory board fees from AbbVie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, and Siemens; and travel support from AbbVie, Boehringer-Ingelheim, Gilead, and Roche. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Collective Acumen, Gilead, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details.

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