Abstract

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. (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). (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. 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. NCT03267615 (in part). 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.

Highlights

  • As a consequence of abnormal routine coagulation tests and thrombocytopenia, cirrhosis has long been considered an acquired bleeding disorder[1]

  • The imbalance of FVIII/protein C (PC) has even been suggested as a major reason for hypercoagulability in advanced chronic liver disease (ACLD)[7] and predicted hepatic decompensation and death in a small study not accounting for portal hypertension (PH) severity[8]

  • While the probability of remaining free of hepatic decompensation/liver-related death at 1 year was high in q1 (96.1%) and q2 (88.8%) patients, it significantly decreased in patients with a higher FVIII/PC (q3:73.9%,q4:65.8%)

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Summary

Introduction

As a consequence of abnormal routine coagulation tests and thrombocytopenia, cirrhosis has long been considered an acquired bleeding disorder[1]. The liver plays a central role in coagulation and plasma levels of most procoagulant factors are significantly reduced in patients with advanced chronic liver disease (ACLD). These changes are balanced by decreased levels of anticoagulant proteins[2] and highly elevated levels of von Willebrand factor (VWF)(3). As TM-TGA require considerable expertise and are not broadly available, simple laboratory parameters have been suggested as surrogate markers for the hypercoagulable status In this context, the ratio of procoagulant factor VIII to PC (FVIII/PC) has been shown to correlate with the ex-vivo thrombin generation[6]. We (i) investigated the prognostic value of FVIII/PC after adjusting for other relevant variables including the hepatic venous pressure gradient (HVPG), (ii) evaluated whether FVIII/PC reflects the coagulatory balance and the risk of bleeding

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