Prognostic role of the vWF/ADAMTS-13 axis in thrombosis risk stratification in gynecologic oncology patients

Aim: to evaluate a prognostic significance for the vWF/ADAMTS-13 (von Willebrand factor/a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) ratio as an integral biomarker for stratifying the risk of venous thromboembolic events and for monitoring the effectiveness of prophylactic anticoagulant therapy (АСТ) in gynecologic oncology patients receiving chemotherapy.

Materials and Methods. This prospective cohort interventional comparative study included 74 patients with ovarian cancer (OC) or cervical canal adenocarcinoma who were undergoing chemotherapy. The patients were divided into groups depending on whether they had experienced thrombotic complications earlier. Levels of vWF, ADAMTS-13, and the vWF/ADAMTS-13 ratio, as well as D-dimer, were assessed. Laboratory parameters were analyzed before chemotherapy, after 1–2 courses, and during prophylactic ACT. Variation statistics, ROC analysis and the Youden criterion were used to determine the threshold values.

Results. Significant disturbances in vWF/ADAMTS-13 axis parameters were detected in patients with pre-chemotherapy thrombotic history, compared to control group: the ratio reached 1.59–1.65 (p < 0.05), compared to 0.65 in control group. During chemotherapy, such alterations worsened (up to 2.04 in OC patients), accompanied by elevated D-dimer level. Administering prophylactic ACT based on low molecular weight heparin normalized the vWF/ADAMTS-13 axis parameters and decreased D-dimer level, reflecting a reduced prothrombotic potential. The incidence of thrombotic complications upon anticoagulant prophylaxis was twice as low as without it (13 % vs. 25 %). ROC analysis confirmed the high diagnostic significance for the vWF/ADAMTS-13 ratio (AUC = 0.87), with an optimal threshold value of ≥ 1.6 for identifying the high-risk group.

Conclusion. The vWF/ADAMTS-13 ratio is a sensitive, integral marker of hypercoagulability. It allows to justify stratification of thrombotic complication risk and monitor the effectiveness of anticoagulant prophylaxis in gynecologic oncology patients receiving chemotherapy. Including vWF/ADAMTS-13 ratio in clinical algorithms can improve the accuracy to select patients for anticoagulant prophylaxis and facilitate treatment personalization.

1. Xu W., Tan X., Li M.L. et al. Von Willebrand factor and hematogenous cancer metastasis under flow. Front Cell Dev Biol. 2024;12:1435718. https://doi.org/10.3389/fcell.2024.1435718.

2. Rayner S.G., Scholl Z., Mandrycky C.J. et al. Endothelial-derived von Willebrand factor accelerates fibrin clotting within engineered microvessels. J Thromb Haemost. 2022;20(7):1627–37. https://doi.org/10.1111/jth.15714.

3. Dong J.F., Moake J.L., Nolasco L. et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood. 20021;100(12):4033–9. https://doi.org/10.1182/blood-2002-05-1401.

4. Muia J., Zhu J., Gupta G. et al. Allosteric activation of ADAMTS13 by von Willebrand factor. Proc Natl Acad Sci U S A. 2014;111(52):18584–9. https://doi.org/10.1073/pnas.1413282112.

5. Obermeier H.L., Riedl J., Ay C. et al. The role of ADAMTS-13 and von Willebrand factor in cancer patients: Results from the Vienna Cancer and Thrombosis Study. Res Pract Thromb Haemost. 2019;3(3):503–14. https://doi.org/10.1002/rth2.12197.

6. Colonne C.K., Favaloro E.J., Pasalic L. The intriguing connections between von Willebrand factor, ADAMTS13 and cancer. Healthcare (Basel). 2022;10(3):557. https://doi.org/10.3390/healthcare10030557.

7. Ayan D., Bozkurt Polat Ş.B., Bayram E. et al. A comparative analysis of the roles of von Willebrand factor and ADAMTS13 in hepatocellular carcinoma: a bioinformatics and microarray-based study. Curr Issues Mol Biol. 202547(4):270. https://doi.org/10.3390/cimb47040270.

8. Guo R., Yang J., Liu X. et al. Increased von Willebrand factor over decreased ADAMTS-13 activity is associated with poor prognosis in patients with advanced non-small-cell lung cancer. J Clin Lab Anal. 2018;32(1):e22219. https://doi.org/10.1002/jcla.22219.

9. Turner N.A., Nolasco L., Ruggeri Z.M., Moake J.L. Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage. Blood. 2009;114(24):5102–11. https://doi.org/10.1182/blood-2009-07-231597.

10. Setiawan B., Permatadewi C.O., de Samakto B. et al. Von Willebrand factor:antigen and ADAMTS-13 level, but not soluble P-selectin, are risk factors for the first asymptomatic deep vein thrombosis in cancer patients undergoing chemotherapy. Thromb J. 2020;18(1):33. https://doi.org/10.1186/s12959-020-00247-6.

11. Pépin M., Kleinjan A., Hajage D. et al. ADAMTS-13 and von Willebrand factor predict venous thromboembolism in patients with cancer. J Thromb Haemost. 2016;14(2):306–15. https://doi.org/10.1111/jth.13205.

12. Feng Y., Li X., Xiao J. et al. ADAMTS13: more than a regulator of thrombosis. Int J Hematol. 2016;104(5):534–9. https://doi.org/10.1007/s12185-016-2091-2.

13. Comerford C., Glavey S., Quinn J., O'Sullivan J.M. The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies. J Thromb Haemost. 2022;20(8):1766–77. https://doi.org/10.1111/jth.15773.

14. Shahidi M. Thrombosis and von Willebrand Factor. Adv Exp Med Biol. 2017;906:285–306. https://doi.org/10.1007/5584_2016_122.

15. Sasano T., Gonzalez-Delgado R., Muñoz N.M. et al. Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer. J Thromb Haemost. 2022;20(1):104–14. https://doi.org/10.1111/jth.15544.

16. Vorobev A., Bitsadze V., Yagubova F. et al. The phenomenon of thrombotic microangiopathy in cancer patients. Int J Mol Sci. 2024;25(16):9055. https://doi.org/10.3390/ijms25169055.

17. Karampinis I., Nowak K., Koett J. et al. Von Willebrand factor in the plasma and in the tumor tissue predicts cancer-associated thrombosis and mortality. Haematologica. 2023;108(1):261–6. https://doi.org/10.3324/haematol.2022.281315.

18. Mulder F.I., Candeloro M., Kamphuisen P.W. et al.; CAT-prediction collaborators. The Khorana score for prediction of venous thromboembolism in cancer patients: a systematic review and meta-analysis. Haematologica. 2019;104(6):1277–87. https://doi.org/10.3324/haematol.2018.209114.

19. Muñoz Martín A.J., Ortega I., Font C. et al. Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer. Br J Cancer. 2018;118(8):1056–61. https://doi.org/10.1038/s41416-018-0027-8.

20. van Es N., Di Nisio M., Cesarman G. et al. Comparison of risk prediction scores for venous thromboembolism in cancer patients: a prospective cohort study. Haematologica. 2017;102(9):1494–501. https://doi.org/10.3324/haematol.2017.169060.

21. Dickson K., Koom-Dadzie K., Brito-Dellan N., Escalante C. Risks, diagnosis, and management of recurrent cancer-associated thrombosis (CAT): a narrative review. Support Care Cancer. 2022;30(10):8539–45. https://doi.org/10.1007/s00520-022-07160-w.