Clinical significance of substantially elevated von Willebrand factor antigen levels in patients with advanced chronic liver disease

Background Von Willebrand factor antigen (VWF) is increasingly used as non-invasive marker for clinically significant portal hypertension (HVPG≥10mmHg) and confers HVPG-independent prognostic information. While quantification of high VWF (i.e.,>420 %) levels is not relevant in the context of von Willebrand disease, substantially elevated VWF may be of clinical significance in ACLD. Thus, we modified our analytical approach to quantify very high VWF levels and investigated their prognostic significance.

Methods Patients with evidence of ACLD and information on VWF undergoing HVPG-measurement at the Vienna Hepatic Hemodynamic Lab were considered. Clinical stages (CS) were defined as follows: probable compensated ACLD (probable cACLD):LSM≥10kPa&HVPG<6mmHg; CS0:cACLD&6-9mmHg; CS1:cACLD&HVPG≥10mmHg; CS2:bleeding; CS3:non-bleeding decompensation; CS4:≥2 decompensations. VWF was measured by an immuno-turbidimetric assay (STA LIATEST VWF:Ag) on a STA-R Evolution (both DIAGNOSTICA STAGO S.A.S., Asnières sur Seine, France) analyzer. Samples were prediluted 1:20 with Owren-Koller buffer, in order to quantify values >420 %.

Results 125(16 %) patients had VWF>420 %. The proportion of VWF>420 % increased with disease severity (probable cACLD-0:5(4 %) vs. 1:22(10 %) vs. 2-4:98(23 %),p≤0.001) and across HVPG (<6mmHg:1(2 %) vs. 6-9:6(6 %) vs. 10-15:17(9 %) vs. ≥16:101(23 %),p≤0.001) and MELD (<10:17(6 %) vs. 10-14:27(10 %) vs. ≥15:80(35 %),p≤0.001) strata. Median VWF was 532(IQR:462-611)% in patients with VWF>420 % and VWF was unrelated to HVPG (Spearman’s ρ=0.140,p = 0.119), but showed direct correlations of weak/moderate strength with MELD (ρ=0.337,p<0.001) and CRP (ρ=0.291,p = 0.001). Among patients with VWF>420 %, VWF was predictive of decompensation/liver-related mortality in univariate analysis (per 10 %; HR:1.02(95 %CI:1.00-1.04),p = 0.025), however, this association did not attain statistical significance after adjusting for MELD.

Conclusion The proportion of patients with substantially elevated VWF steadily increases with disease progression and is particularly high in patients with profound portal hypertension. While VWF

does not reflect HVPG in these patients, it correlates with hepatic dysfunction and systemic inflammation. Quantification of high values provides prognostic information, however the lack of association with clinical outcomes in MELD-adjusted analysis questions their relevance.

Publication History

Article published online:
01 September 2021