SpringerLink
Log in

Von Willebrand Factor Antigen Improves Risk Stratification for Patients with a Diagnosis of Resectable Hepatocellular Carcinoma

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Posthepatectomy liver failure (PHLF), complications of portal hypertension, and disease recurrence determine the outcome for hepatocellular carcinoma (HCC) patients undergoing liver resection. This study aimed to evaluate the von Willebrand factor antigen (vWF-Ag) as a non-invasive test for clinically significant portal hypertension (CSPH) and a predictive biomarker for time to recurrence (TTR) and overall survival (OS).

Methods

The study recruited 72 HCC patients with detailed preoperative workup from a prospective trial (NCT02118545) and followed for complications, TTR, and OS. Additionally, 163 compensated patients with resectable HCC were recruited to evaluate vWF-Ag cutoffs for ruling out or ruling in CSPH. Finally, vWF-Ag cutoffs were prospectively evaluated in an external validation cohort of 34 HCC patients undergoing liver resection.

Results

In receiver operating characteristic (ROC) analyses, vWF-Ag (area under the curve [AUC], 0.828) was similarly predictive of PHLF as indocyanine green clearance (disappearance rate: AUC, 0.880; retention rate: AUC, 0.894), whereas computation of future liver remnant was inferior (AUC, 0.756). Cox-regression showed an association of vWF-Ag with TTR (per 10%: hazard ratio [HR], 1.056; 95% confidence interval [CI] 1.017–1.097) and OS (per 10%: HR, 1.067; 95% CI 1.022–1.113). In the analyses, VWF-Ag yielded an AUC of 0.824 for diagnosing CSPH, with a vWF-Ag of 182% or lower ruling out and higher than 291% ruling in CSPH. Therefore, a highest-risk group (> 291%, 9.7% of patients) with a 57.1% incidence of PHLF was identified, whereas no patient with a vWF-Ag of 182% or lower (52.7%) experienced PHLF. The predictive value of vWF-Ag for PHLF and OS was externally validated.

Conclusion

For patients with resectable HCC, VWF-Ag allows for simplified preoperative risk stratification. Patients with vWF-Ag levels higher than 291% might be considered for alternative treatments, whereas vWF-Ag levels of 182% or lower identify patients best suited for surgery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022;76:681–93.

    Article  PubMed  Google Scholar 

  2. van Mierlo KM, Schaap FG, Dejong CH, Olde Damink SW. Liver resection for cancer: new developments in prediction, prevention, and management of postresectional liver failure. J Hepatol. 2016;65:1217–31.

    Article  PubMed  Google Scholar 

  3. Gilg S, Sandstrom P, Rizell M, et al. The impact of post-hepatectomy liver failure on mortality: a population-based study. Scand J Gastroenterol. 2018;53:1335–9.

    Article  PubMed  Google Scholar 

  4. Mandorfer M, Simbrunner B. Prevention of first decompensation in advanced chronic liver disease. Clin Liver Dis. 2021;25:291–310.

    Article  PubMed  Google Scholar 

  5. European Association for the Study of the Liver. European Association for the Study of the L EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.

    Article  Google Scholar 

  6. Kokudo T, Hasegawa K, Shirata C, et al. Assessment of preoperative liver function for surgical decision-making in patients with hepatocellular carcinoma. Liver Canc. 2019;8:447–56.

    Article  Google Scholar 

  7. Procopet B, Fischer P, Horhat A, et al. Good performance of liver stiffness measurement in the prediction of postoperative hepatic decompensation in patients with cirrhosis complicated with hepatocellular carcinoma. Med Ultrasonogr. 2018;20:272–7.

    Article  Google Scholar 

  8. Itoh S, Yoshizumi T, Shirabe K, et al. Functional remnant liver assessment predicts liver-related morbidity after hepatic resection in patients with hepatocellular carcinoma. Hepatol Res. 2017;47:398–404.

    Article  PubMed  Google Scholar 

  9. Cucchetti A, Cescon M, Golfieri R, et al. Hepatic venous pressure gradient in the preoperative assessment of patients with resectable hepatocellular carcinoma. J Hepatol. 2016;64:79–86.

    Article  PubMed  Google Scholar 

  10. Vauthey JN, Dixon E, Abdalla EK, et al. Pretreatment assessment of hepatocellular carcinoma: expert consensus statement. HPB. 2010;12:289–99.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bosch J, Abraldes JG, Berzigotti A, Garcia-Pagan JC. The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol. 2009;6:573–82.

    Article  CAS  PubMed  Google Scholar 

  12. Stremitzer S, Tamandl D, Kaczirek K, et al. Value of hepatic venous pressure gradient measurement before liver resection for hepatocellular carcinoma. Br J Surg. 2011;98:1752–8.

    Article  CAS  PubMed  Google Scholar 

  13. Boleslawski E, Petrovai G, Truant S, et al. Hepatic venous pressure gradient in the assessment of portal hypertension before liver resection in patients with cirrhosis. Br J Surg. 2012;99:855–63.

    Article  CAS  PubMed  Google Scholar 

  14. Wang YY, Zhao XH, Ma L, et al. Comparison of the ability of Child-Pugh score, MELD score, and ICG-R15 to assess preoperative hepatic functional reserve in patients with hepatocellular carcinoma. J Surg Oncol. 2018;118:440–5.

    Article  CAS  PubMed  Google Scholar 

  15. Berzigotti A, Reig M, Abraldes JG, Bosch J, Bruix J. Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: a systematic review and meta-analysis. Hepatology. 2015;61:526–36.

    Article  PubMed  Google Scholar 

  16. Mandorfer M, Hernández-Gea V, García-Pagán JC, Reiberger T. Noninvasive diagnostics for portal hypertension: a comprehensive review. Semin Liver Dis. 2020;40:240–55.

    Article  PubMed  Google Scholar 

  17. Aliseda D, Zozaya G, Martí-Cruchaga P, et al. The impact of portal hypertension assessment method on the outcomes of hepatocellular carcinoma resection: a meta-analysis of matched cohort and prospective studies. Ann Surg. 2023. https://doi.org/10.1016/j.hpb.2024.03.098.

    Article  PubMed  Google Scholar 

  18. Starlinger P, Pereyra D, Haegele S, et al. Perioperative von Willebrand factor dynamics are associated with liver regeneration and predict outcome after liver resection. Hepatology. 2018;67:1516–30.

    Article  CAS  PubMed  Google Scholar 

  19. Ferro D, Quintarelli C, Lattuada A, et al. High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia. Hepatology. 1996;23:1377–83.

    Article  CAS  PubMed  Google Scholar 

  20. Neubauer K, Zieger B. Endothelial cells and coagulation. Cell Tissue Res. 2021. https://doi.org/10.1007/s00441-021-03471-2.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ferlitsch M, Reiberger T, Hoke M, et al. von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation, and mortality in patients with liver cirrhosis. Hepatology. 2012;56:1439–47.

    Article  CAS  PubMed  Google Scholar 

  22. La Mura V, Reverter JC, Flores-Arroyo A, et al. von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension. Gut. 2011;60:1133–8.

    Article  PubMed  Google Scholar 

  23. Mandorfer M, Schwabl P, Paternostro R, et al. von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity. Aliment Pharmacol Ther. 2018;47:980–8.

    Article  CAS  PubMed  Google Scholar 

  24. Bauer AT, Suckau J, Frank K, et al. von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans. Blood. 2015;125:3153–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Franchini M, Frattini F, Crestani S, Bonfanti C, Lippi G. von Willebrand factor and cancer: a renewed interest. Thromb Res. 2013;131:290–2.

    Article  CAS  PubMed  Google Scholar 

  26. Pereyra D, Starlinger P. Von Willebrand factor for the liver: Friend or foe? Reply Hepatol. 2018;67:2061–2.

    Article  Google Scholar 

  27. Rahbari NN, Garden OJ, Padbury R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011;149:713–24.

    Article  PubMed  Google Scholar 

  28. Goksuluk D, Korkmaz S, Zararsiz G, Karaağaoğlu AE. EasyROC: an interactive web-tool for ROC curve analysis using R language environment. R J. 2016;8:213–30.

    Article  Google Scholar 

  29. Abraldes JG, Bureau C, Stefanescu H, et al. Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the “Anticipate” study. Hepatology. 2016;64:2173–84.

    Article  CAS  PubMed  Google Scholar 

  30. Mandorfer M, Kozbial K, Schwabl P, et al. Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy. Hepatology. 2020;71:1023–36.

    Article  CAS  PubMed  Google Scholar 

  31. Hobeika C, Guyard C, Sartoris R, et al. Performance of non-invasive biomarkers compared with invasive methods for risk prediction of posthepatectomy liver failure in hepatocellular carcinoma. Br J Surg. 2022;109:455–63.

    Article  PubMed  Google Scholar 

  32. Gavriilidis P, Hammond JS, Hidalgo E. A systematic review of the impact of portal vein pressure changes on clinical outcomes following hepatic resection. HPB. 2020;22:1521–9.

    Article  PubMed  Google Scholar 

  33. Starlinger P, Ahn JC, Mullan A, et al. The addition of C-reactive protein and von Willebrand factor to MELD-Na improves prediction of wait-list mortality. Hepatology. 2021. https://doi.org/10.1002/hep.31838.

    Article  PubMed  Google Scholar 

  34. Aryal B, Yamakuchi M, Shimizu T, et al. Bivalent property of intra-platelet VWF in liver regeneration and HCC recurrence: a prospective multicenter study. Cancer Biomark. 2019;26:51–61.

    Article  CAS  PubMed  Google Scholar 

  35. Wang Q, Liu W, Fan J, et al. von Willebrand factor promotes platelet-induced metastasis of osteosarcoma through activation of the VWF-GPIb axis. J Bone Oncol. 2020;25:100325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Feinauer MJ, Schneider SW, Berghoff AS, et al. Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model. Blood. 2020. https://doi.org/10.1016/j.celrep.2021.110027.

    Article  Google Scholar 

  37. Qi Y, Chen W, Liang X, et al. Novel antibodies against GPIbα inhibit pulmonary metastasis by affecting vWF-GPIbα interaction. J Hematol Oncol. 2018;11:117.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kong QF, Lv B, Wang B, Zhang XP, Sun HJ, Liu J. Association of von Willebrand factor (vWF) expression with lymph node metastasis and hemodynamics in papillary thyroid carcinoma. Eur Rev Med Pharmacol Sci. 2020;24:2564–71.

    PubMed  Google Scholar 

  39. Yang AJ, Wang M, Wang Y, et al. Cancer cell-derived von Willebrand factor enhanced metastasis of gastric adenocarcinoma. Oncogenesis. 2018;7:12.

    Article  PubMed  PubMed Central  Google Scholar 

  40. O’Sullivan JM, Preston RJS, Robson T, O’Donnell JS. Emerging roles for von Willebrand factor in cancer cell biology. Semin Thromb Hemost. 2018;44:159–66.

    Article  PubMed  Google Scholar 

  41. Marasco G, Colecchia A, Colli A, et al. Role of liver and spleen stiffness in predicting the recurrence of hepatocellular carcinoma after resection. J Hepatol. 2019;70:440–8.

    Article  PubMed  Google Scholar 

  42. Hugenholtz GC, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT, Lisman T. An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: implications for hemostasis and clinical outcome. Hepatology. 2013;58:752–61.

    Article  CAS  PubMed  Google Scholar 

  43. Llop E, Berzigotti A, Reig M, et al. Assessment of portal hypertension by transient elastography in patients with compensated cirrhosis and potentially resectable liver tumors. J Hepatol. 2012;56:103–8.

    Article  PubMed  Google Scholar 

  44. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C, et al. Renewing consensus in portal hypertension. J Hepatol. 2022;76:959–74.

    Article  PubMed  Google Scholar 

  45. Reiberger T, Schwabl P, Trauner M, Peck-Radosavljevic M, Mandorfer M. Measurement of the hepatic venous pressure gradient and transjugular liver biopsy. J Vis Exp. 2020. https://doi.org/10.3791/58819.

    Article  PubMed  Google Scholar 

  46. Takaya H, Namisaki T, Kitade M, et al. VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma. BMC Gastroenterol. 2019;19:167.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kirschbaum M, Jenne CN, Veldhuis ZJ, et al. Transient von Willebrand factor-mediated platelet influx stimulates liver regeneration after partial hepatectomy in mice. Liver Int. 2017;37:1731–7.

    Article  PubMed  Google Scholar 

Download references

Funding

Dr. Mattias Mandorfer served as a speaker and/or consultant and/or advisory board member for AbbVie, Echosens, Gilead, Ipsen, and W. L. Gore & Associates and received grants/research support from Echosens, as well as travel support from AbbVie and Gilead. Dr. Matthias Pinter Consultatn/Ad Board: AstaZeneca, Bayer, BMS, Eisai, Eli Lilly, Ipsen, MSD, Roche. Lecture Fees: AstaZeneca, Bayer, BMS, Eisai, MSD, Roche. Grant: AstraZeneca, Bayer, Eisai, Roche. Travel: Bayer, BMS, Ipsen, Roche. Dr. Thomas Reiberger received grant support from Abbvie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens and W. L. Gore & Associates; speaking honoraria from Abbvie, Gilead, Intercept/Advanz Pharma, Roche, MSD, W. L. Gore & Associates; consulting/advisory board fee from Abbvie, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics, Siemens; and travel support from Abbvie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead, and Roche. Dr. Dietmar Tamandl Siemens Healthineers: Travel and Research grant, Honoraria, Speaker fees; Roche: Consultant fees; Sanova: Speaker fees; Bristol-Myers Squibb: Speaker fees; Bracco: Speaker fees.

Author information

Author notes

  1. David Pereyra and Mattias Mandorfer have shared first authorship.

Authors and Affiliations

  1. Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, Vienna, Austria

    David Pereyra MD, PhD, Christoph Koeditz MD, Gregor Ortmayr MD, Clara Schuetz MD, Benedikt Rumpf MD, Daphni Ammon MD, Johannes Laengle MD, PhD, Christoph Schwarz MD, PhD & Patrick Starlinger MD, PhD

  2. Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, General Hospital, Vienna, Austria

    Mattias Mandorfer MD, Matthias Pinter MD, PhD & Thomas Reiberger MD

  3. Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, General Hospital, Vienna, Austria

    Mattias Mandorfer MD & Thomas Reiberger MD

  4. Department of Surgery, HPB Center Vienna Health Network and Sigmund Freud Private University, Vienna, Austria

    Jonas Santol MD, Jan Philipp Jonas MD & Thomas Gruenberger MD

  5. Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA

    Jonas Santol MD, Lindsey Gregory PA-C, MS, Cornelius Thiels MD, Susanne Warner MD, Rory Smoot MD, Mark Truty MD, Michael Kendrick MD, David Nagorney MD, Sean Cleary MD & Patrick Starlinger MD, PhD

  6. Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, General Hospital, Vienna, Austria

    Florian Lindenlaub MD & Dietmar Tamandl MD

  7. Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria

    Thomas Reiberger MD

Authors
  1. David Pereyra MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mattias Mandorfer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonas Santol MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lindsey Gregory PA-C, MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christoph Koeditz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gregor Ortmayr MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Clara Schuetz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Benedikt Rumpf MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daphni Ammon MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Johannes Laengle MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christoph Schwarz MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jan Philipp Jonas MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Matthias Pinter MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Florian Lindenlaub MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Dietmar Tamandl MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Cornelius Thiels MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Susanne Warner MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Rory Smoot MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Mark Truty MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Michael Kendrick MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. David Nagorney MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Sean Cleary MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Thomas Gruenberger MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Thomas Reiberger MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Patrick Starlinger MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Starlinger MD, PhD.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 6509 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pereyra, D., Mandorfer, M., Santol, J. et al. Von Willebrand Factor Antigen Improves Risk Stratification for Patients with a Diagnosis of Resectable Hepatocellular Carcinoma. Ann Surg Oncol (2024). https://doi.org/10.1245/s10434-024-15618-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1245/s10434-024-15618-w

Keywords

Search

Navigation