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. 2019 Oct 21;19(1):167.
doi: 10.1186/s12876-019-1082-1.

VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma

Hiroaki Takaya  1 , Tadashi Namisaki  2 , Mitsuteru Kitade  1 , Kosuke Kaji  1 , Keisuke Nakanishi  1 , Yuki Tsuji  1 , Naotaka Shimozato  1 , Kei Moriya  1 , Kenichiro Seki  1 , Yasuhiko Sawada  1 , Soichiro Saikawa  1 , Shinya Sato  1 , Hideto Kawaratani  1 , Takemi Akahane  1 , Ryuichi Noguchi  1 , Masanori Matsumoto  3 , Hitoshi Yoshiji  1
Affiliations

VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma

Hiroaki Takaya et al. BMC Gastroenterol. .

Abstract

Background: To investigate the von Willebrand factor to ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma (HCC) in cirrhosis.

Methods: Serum levels of alpha-fetoprotein, des-γ-carboxy prothrombin, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (alpha-fetoprotein-L3%), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2, as well as the plasma levels of von Willebrand factor antigen (von Willebrand factor: Ag) and ADAMTS13 activity (ADAMTS13:AC), were evaluated in 41 cirrhotic patients with HCC undergoing radiofrequency ablation and in 20 cirrhotic patients without HCC. The diagnostic accuracy of each biomarker was evaluated using the receiver operating characteristic curve analysis.

Results: The von Willebrand factor: Ag and von Willebrand factor: Ag/ADAMTS13:AC ratios were significantly higher in cirrhotic patients with HCC than in those without HCC (p < 0.05 and p < 0.01, respectively), whereas ADAMTS13:AC was significantly lower in those with HCC than those without HCC (p < 0.05). However, no relationship was observed between the von Willebrand factor: Ag/ADAMTS13:AC ratio and serum tumor markers such as alpha-fetoprotein, des-γ-carboxy prothrombin, and alpha-fetoprotein-L3%. Multivariate regression analysis identified von Willebrand factor: Ag/ADAMTS13:AC ratio and alpha-fetoprotein-L3% as significant factors of HCC development. Receiver operating characteristic analysis showed that the von Willebrand factor: Ag/ADAMTS13:AC ratio and alpha-fetoprotein-L3% had a better performance than alpha-fetoprotein, des-γ-carboxy prothrombin, alpha-fetoprotein-L3%, vascular endothelial growth factor, and vascular endothelial growth factor receptor-2, von Willebrand factor: Ag, and ADAMTS13:AC. The von Willebrand factor: Ag/ADAMTS13:AC ratio was exclusively correlated with tumor volume and stage as well as serum vascular endothelial growth factor levels.

Conclusions: The von Willebrand factor: Ag/ADAMTS13:AC ratio can potentially serve as a novel biomarker for early diagnosis of HCC in cirrhotic patients.

Keywords: ADAMTS13; Biomarker; Early diagnosis; HCC; VWF.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Comparison of serum biomarkers between cirrhotic patients with HCC and those without HCC. The AFP (a) and DCP (b) levels did not differ significantly between cirrhotic patients with and without HCC. The AFP-L3% (c), VEGF (d), VEGFR-2 (e) levels, as well as the VWF:Ag (g) and VWF:Ag/ADAMTS13:AC ratio (h), were significantly higher in cirrhotic patients with HCC than in those without HCC. The ADAMTS13:AC (f) was significantly lower in patients with HCC than in those without HCC. Asterisks indicate statistically significant differences between the indicated experimental groups (p < 0.05, p < 0.01). VWF, von Willebrand factor; VWF:Ag, VWF antigen; ADAMTS13, a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13; ADAMTS13:AC, ADAMTS13 activity; VEGF, vascular endothelial growth factor; VEGFR-2, VEGF receptor-2; AFP, alpha-fetoprotein; AFP-L3%, Lens culinaris agglutinin-reactive AFP; DCP, des-γ-carboxy prothrombin; HCC: hepatocellular carcinoma; NS, not significant
Fig. 2
Fig. 2
Correlation of the VWF:Ag/ADAMTS13:AC ratio with conventional tumor markers. The VWF:Ag/ADAMTS13:AC ratio is not significantly correlated with the (a) AFP level, (b) DCP level, and (c) AFP-L3%. VWF, von Willebrand factor; VWF:Ag, VWF antigen; ADAMTS13, a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13; ADAMTS13:AC, ADAMTS13 activity; AFP, alpha-fetoprotein; AFP-L3%, Lens culinaris agglutinin-reactive AFP; DCP, des-γ-carboxy prothrombin; NS, not significant
Fig. 3
Fig. 3
Correlation of the VWF:Ag/ADAMTS13:AC ratio with platelet count. The platelet count is significantly higher in cirrhotic patients with HCC and a VWF:Ag/ADAMTS13:AC ratio ≥ 5 than in those with VWF:Ag/ADAMTS13:AC ratio < 5. Asterisks indicate statistically significant differences between the indicated experimental groups (p < 0.05). VWF, von Willebrand factor; VWF:Ag, VWF antigen; ADAMTS13, a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13; ADAMTS13:AC, ADAMTS13 activity; HCC, hepatocellular carcinoma
Fig. 4
Fig. 4
Diagnostic accuracy of serum biomarkers for the early detection of HCC. The diagnostic accuracy of the VWF:Ag/ADAMTS13:AC ratio (Cutoff value 5.5, sensitivity 51%, specificity 95%, and AUC 0.73) is comparable with that of AFP-L3% (Cutoff value 5.7, sensitivity 54%, specificity 93%, and AUC 0.74). VWF, von Willebrand factor; VWF:Ag, VWF antigen; ADAMTS13, a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13; ADAMTS13:AC, ADAMTS13 activity; AUC, area under the curve; AFP-L3%, Lens culinaris agglutinin-reactive alpha-fetoprotein; HCC, hepatocellular carcinoma
Fig. 5
Fig. 5
Correlation of the serum VEGF levels with the VWF:Ag/ADAMTS13:AC ratio and AFP-L3%. The serum VEGF level is significantly correlated with the VWF:Ag/ADAMTS13:AC ratio (a) but not with the AFP-L3% levels (b). VWF, von Willebrand factor; VWF:Ag, VWF antigen; ADAMTS13, a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13; ADAMTS13:AC, ADAMTS13 activity; VEGF, vascular endothelial growth factor; AFP-L3%, Lens culinaris agglutinin-reactive alpha-fetoprotein
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