High von Willebrand factor antigen levels and procoagulant imbalance may be involved in both increasing severity of cirrhosis and portal vein thrombosis
Authors: Georgios N. Kalambokis, Aikaterini Oikonomou, Leonidas Christou, Gerasimos Baltayiannis
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. To the Editor: We read with interest the article by Nery et al.1 on the causes and consequences of portal vein thrombosis (PVT) in patients with cirrhosis. The authors demonstrated that advanced cirrhosis is associated with a higher risk of developing PVT but is not causatively related to PVT. Their results are consistent with those of Villa et al.2, who concluded that the progression of cirrhosis and PVT are two separate sequelae of coagulation system activation, considering that both can be prevented by anticoagulant treatment. Consequently, we investigated whether certain hemostatic factors are independently related to both increasing severity of cirrhosis and subsequent development of PVT. A total of 102 patients with cirrhosis (men, n = 81; women, n = 21; mean age, 56.6 ± 7 years; alcoholic/viral/other etiology, n = 71/18/13; Child‐Pugh score, 9 ± 3; Model for End Stage Liver Disease [MELD] score, 12 ± 6) distributed equally for each Child‐Pugh class (A/B/C, n = 34/34/34) were followed up for a mean period of 27.2 months (range, 6‐53 months). Exclusion criteria were intrahepatic/extrahepatic malignancy, thromboembolic disease, and ongoing therapy known to interfere with blood coagulation and platelet function. PVT was defined as complete or partial obstruction of the portal trunk and/or its branches and was diagnosed as in the study by Nery et al. The following biomarkers were evaluated at enrollment: platelet count; factors (F) II, V, VII, and VIII; antithrombin level; protein C (PC) level; FVIII‐to‐PC ratio as an index of procoagulant imbalance; and platelet‐adhesive protein von Willebrand factor antigen (vWF‐Ag) by way of turbidimetric assay. Higher values of vWF‐Ag (P = 0.001), FVIII (P = 0.04), and FVIII‐to‐PC ratio (P = 0.01) were independently related to liver disease severity according to Child‐Pugh class. Fourteen patients (13.7%) developed PVT not related to hepatocellular carcinoma during follow‐up. The occurrence of PVT was independently associated with higher values of vWF‐Ag (P = 0.003) and FVIII‐to‐PC ratio (P = 0.03) but not with Child‐Pugh score or MELD score (Table 1). Table 1 - Univariate and Multivariate Analysis of the Baseline Risk Factors for PVT During Follow‐up Univariate Analysis Multivariate Analysis HR (95% CI) P HR (95% CI) P Platelet count 1.048 (0.980‐1.122) 0.2 — — FII 0.983 (0.962‐1004) 0.1 — — FV 0.984 (0.961‐1007) 0.1 — — FVII 1.219 (0.970‐1.535) 0.09 — — FVIII 1027 (1010‐1043) 0.002 1017 (0.982‐1.051) 0.1 Antithrombin level 0.968 (0.948‐0.992) 0.009 0.990 (0.953‐1.029) 0.3 PC level 0.986 (0.970‐1009) 0.07 — — Factor VIII‐to‐protein C ratio 2.128 (1.518‐2.982) <0.001 1.601 (0.943‐2.717) 0.03 vWF‐Ag 1.008 (1.005‐1.012) <0.001 1.006 (1.002‐1.010) 0.003 Child‐Pugh score 1.004 (0.995‐1.026) 0.06 — — MELD score 1.238 (1107‐1385) 0.006 1.078 (0.927‐1.253) 0.3 Abbreviations: CI, confidence interval; HR, hazard ratio. On the one hand, our findings support the view that increased intrahepatic thrombotic potential may be implicated in the progression of cirrhosis. Indeed, hypercoagulability,3 including increased FVIII‐to‐PC ratio,4 has been correlated with the progression of fibrosis to cirrhosis. Furthermore, elevated vWF‐Ag levels have been closely associated with worsening of portal hypertension and occurrence of decompensation in patients with cirrhosis.5 On the other hand, although the patients who subsequently developed PVT had more severe cirrhosis at baseline (which is in line with the findings by Nery et al.), only higher values of FVIII‐to‐PC ratio and vWF‐Ag but not liver disease severity were significant predictors of development of PVT. Unlike our observations, Tang et al.6 did not find a significant association of procoagulant imbalance with PVT in patients with cirrhosis; however, the authors compared two different patient cohorts—one with and another without PVT—whereas we evaluated the association of hypercoagulability markers with the occurrence of PVT in the same cohort. Consequently, activation of the coagulation system could be the underlying mechanism that, over time, promotes the increase in the severity of cirrhosis and finally the development of PVT, possibly in the face of a deteriorating occlusion of portal venous inflow.