Tissue factor-bearing extracellular vesicles, procoagulant phospholipids and D-dimer as potential biomarkers for venous thromboembolism in patients with newly diagnosed multiple myeloma: A comprehensive analysis.
[en] BACKGROUND: Candidate biomarkers to improve venous thromboembolism (VTE) risk prediction in patients with newly diagnosed multiple myeloma (MM) undergoing anti-myeloma therapy include tissue factor-bearing microvesicles (MV-TF), procoagulant phospholipids (procoag-PPL), and D-dimer.
OBJECTIVE: We aimed to determine the levels of MV-TF, procoag-PPL, and D-dimer at baseline and during initial anti-myeloma therapy and their association with the risk of VTE.
METHODS: This prospective, longitudinal, observational study included 71 patients with newly diagnosed MM who were eligible for anti-myeloma therapy. Circulating MV-TF levels were measured using a functional method adapted from the Chapel Hill TF-dependent Factor Xa generation assay, and PPL and D-dimer levels with commercially available assays. The three biomarkers were measured at baseline and throughout treatment.
RESULTS: Baseline and on-treatment MV-TF levels were higher in patients who developed VTE compared to those who did not (4.25 versus 2.75 fM at baseline, p = 0.047 and 6.5 versus 1.5 fM during treatment, p = 0.001). Baseline and on-treatment Procoag-PPL clotting times did not differ between the groups. Baseline D-dimer levels tended to be higher in patients who developed VTE than in those who did not (1.38 versus 0.7 μg/mL, p = 0.08). During treatment, D-dimer levels were significantly higher in the VTE group than in the non-VTE group (1.08 versus 0.44 μg/mL, p = 0.008).
CONCLUSION: Our results suggest that MV-TF and D-dimer levels may help to refine VTE risk prediction in nMM patients undergoing anti-myeloma therapy. Adequately sized studies including patients receiving new MM therapies are needed to confirm this hypothesis.
Disciplines :
Hematology
Author, co-author :
Charles, Sébastien ; Université de Liège - ULiège > GIGA > GIGA Immunobiology - Hematology ; Clinical Investigation Center CIC-EC 1408, University Hospital of Saint-Etienne, France ; SAINBIOSE, UMR 1059, INSERM, Jean Monnet University, Saint-Etienne, France
Fatrara, T; SAINBIOSE, UMR 1059, INSERM, Jean Monnet University, Saint-Etienne, France, Division of Clinical Hematology, University Hospital of Saint-Etienne, France
Bouriche, T; BioCytex, Research and Technology Department, Marseille, France
Bonifay, A; C2VN, INSERM, INRAE, Aix Marseille University Marseille, France, Department of Hematology, Biogénopôle, CHU La Timone, APHM, Marseille, France
Lecompte, T; Faculty of Medicine, University of Lorraine, Nancy, France, Vascular Medicine Division, University Hospital, Nancy, France
Dignat-George, F; C2VN, INSERM, INRAE, Aix Marseille University Marseille, France, Department of Hematology, Biogénopôle, CHU La Timone, APHM, Marseille, France
Tardy, B; Clinical Investigation Center CIC-EC 1408, University Hospital of Saint-Etienne, France
Frere, C; INSERM UMRS-1166, Institute of Cardiometabolism and Nutrition, GRC 27 GRECO, Sorbonne Université, Paris, France, Division of Hematology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Lacroix, R; C2VN, INSERM, INRAE, Aix Marseille University Marseille, France, Department of Hematology, Biogénopôle, CHU La Timone, APHM, Marseille, France
Chalayer, E; Clinical Investigation Center CIC-EC 1408, University Hospital of Saint-Etienne, France, SAINBIOSE, UMR 1059, INSERM, Jean Monnet University, Saint-Etienne, France, Division of Clinical Hematology, University Hospital of Saint-Etienne, France. Electronic address: emilie.chalayer@chu-st-etienne.fr
Language :
English
Title :
Tissue factor-bearing extracellular vesicles, procoagulant phospholipids and D-dimer as potential biomarkers for venous thromboembolism in patients with newly diagnosed multiple myeloma: A comprehensive analysis.
We would like to thank the PARCC-ARA (Clinical Support Platform for Cancer Research Auvergne Rh\u00F4ne Alpes) and the FFRMG (French Foundation for Research against Multiple Myeloma and Monoclonal Gammopathies) for their financial support, Biocytex (Marseille, France) for providing for free the experimental kits for MV-TF activity measurement, and Diagnostica Stago (Asnieres-sur-Seine, France) for providing for free the D-dimer and PPL assays. We also thank \u2018Les amis de R\u00E9mi\u2019 for their financial support for PhD student grant.
Mulder, F.I., Horváth-Puhó, E., van Es, N., van Laarhoven, H.W.M., Pedersen, L., Moik, F., et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood 137:14 (8 avr 2021), 1959–1969.
Carrier, M., Gal, G.L., Tay, J., Wu, C., Lee, A.Y., Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. J. Thromb. Haemost. 9:4 (2011), 653–663.
Chalayer, E., Talbot, A., Frenzel, L., Karlin, L., Collet, P., Guyotat, D., et al. Prediction of venous thromboembolism in patients with multiple myeloma treated with lenalidomide, bortezomib, dexamethasone, and transplantation: lessons from the substudy of IFM/DFCI 2009 cohort. J. Thromb. Haemost. 20:8 (2022), 1859–1867.
Li, W., Garcia, D., Cornell, R.F., Gailani, D., Laubach, J., Maglio, M.E., et al. Cardiovascular and thrombotic complications of novel multiple myeloma therapies: a review. JAMA Oncol. 3:7 (1 juill 2017), 980–988.
Schoen, M.W., Carson, K.R., Luo, S., Gage, B.F., Li, A., Afzal, A., et al. Venous thromboembolism in multiple myeloma is associated with increased mortality. Res. Pract. Thromb. Haemost. 4:7 (2020), 1203–1210.
Kumar, S.K., Callander, N.S., Adekola, K., Anderson, L., Baljevic, M., Campagnaro, E., et al. Multiple myeloma, version 3.2021, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 18:12 (2 déc 2020), 1685–1717.
Frenzel, L., Decaux, O., Macro, M., Belhadj-Merzoug, K., Manier, S., Touzeau, C., et al. Venous thromboembolism prophylaxis and multiple myeloma patients in real-life: results of a large survey and clinical guidance recommendations from the IFM group. Thromb. Res. 233 (2 déc 2023), 153–164.
Sanfilippo, K.M., Luo, S., Wang, T.F., Fiala, M., Schoen, M., Wildes, T.M., et al. Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score. Am. J. Hematol. 94:11 (nov 2019), 1176–1184.
Li, A., Wu, Q., Luo, S., Warnick, G.S., Zakai, N.A., Libby, E.N., et al. Derivation and validation of a risk assessment model for immunomodulatory drug–associated thrombosis among patients with multiple myeloma. J. Natl. Compr. Cancer Netw. 17:7 (1 juill 2019), 840–847.
Nomura, S., Ito, T., Yoshimura, H., Hotta, M., Nakanishi, T., Fujita, S., et al. Evaluation of thrombosis-related biomarkers before and after therapy in patients with multiple myeloma. J. Blood Med. 9 (janv 2018), 1–7.
Papageorgiou, L., Van Dreden, P., Dimopoulos, M.A., Larsen, A., Mohty, M., Elalamy, I., et al. Procoagulant microparticles derived from myeloma plasma cells have a determinant role in the hypercoagulable state associated with multiple myeloma. A modelization in vitro study. Blood, 134(Supplement_1), 13 nov 2019, 2425.
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. JTH. 20:8 (août 2022), 1766–1777.
Sánchez Prieto, I., Gutiérrez Jomarrón, I., Martínez Vázquez, C., Rodríguez Barquero, P., Gili Herreros, P., García-Suárez, J., Comprehensive evaluation of genetic and acquired thrombophilia markers for an individualized prediction of clinical thrombosis in patients with lymphoma and multiple myeloma. J. Thromb. Thrombolysis 57:6 (27 avr 2024), 984–995.
Chalayer, E., Tardy-Poncet, B., Karlin, L., Chapelle, C., Montmartin, A., Piot, M., et al. Thrombin generation in newly diagnosed multiple myeloma during the first three cycles of treatment: an observational cohort study. Res Pract Thromb Haemost. 3:1 (13 déc 2018), 89–98.
Li, L., Roest, M., Sang, Y., Remijn, J.A., Fijnheer, R., Smit, K., et al. Patients with multiple myeloma have a disbalanced whole blood thrombin generation profile. Front. Cardiovasc. Med., 9, 27 juin 2022, 919495.
Akers, J.C., Gonda, D., Kim, R., Carter, B.S., Chen, C.C., Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J. Neuro-Oncol. 113:1 (mai 2013), 1–11.
Arraud, N., Linares, R., Tan, S., Gounou, C., Pasquet, J.M., Mornet, S., et al. Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J. Thromb. Haemost. 12:5 (2014), 614–627.
Colombo, M., Giannandrea, D., Lesma, E., Basile, A., Chiaramonte, R., Extracellular vesicles enhance multiple myeloma metastatic dissemination. Int. J. Mol. Sci. [Internet], 20(13), 1 juill 2019 [cité 18 janv 2021]. Disponible sur https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650870/.
Saltarella, I., Lamanuzzi, A., Apollonio, B., Desantis, V., Bartoli, G., Vacca, A., et al. Role of extracellular vesicle-based cell-to-cell communication in multiple myeloma progression. Cells, 10(11), 16 nov 2021, 3185.
Giannandrea, D., Platonova, N., Colombo, M., Mazzola, M., Citro, V., Adami, R., et al. Extracellular vesicles mediate the communication between multiple myeloma and bone marrow microenvironment in a NOTCH dependent way. Haematologica 107:9 (1 sept 2022), 2183–2194.
Zarfati, M., Avivi, I., Brenner, B., Katz, T., Aharon, A., Extracellular vesicles of multiple myeloma cells utilize the proteasome inhibitor mechanism to moderate endothelial angiogenesis. Angiogenesis 22:1 (févr 2019), 185–196.
Zhou, R., Bozbas, E., Allen-Redpath, K., Yaqoob, P., Circulating extracellular vesicles are strongly associated with cardiovascular risk markers. Front. Cardiovasc. Med., 9, 2022, 907457.
Zarà, M., Guidetti, G.F., Camera, M., Canobbio, I., Amadio, P., Torti, M., et al. Biology and role of extracellular vesicles (EVs) in the pathogenesis of thrombosis. Int. J. Mol. Sci., 20(11), 11 juin 2019, 2840.
Cui, C.J., Wang, G.J., Yang, S., Huang, S.K., Qiao, R., Cui, W., Tissue factor-bearing MPs and the risk of venous thrombosis in cancer patients: a meta-analysis. Sci. Rep., 8(1), 26 janv 2018, 1675.
Bonifay, A., Mackman, N., Hisada, Y., Sachetto, A.T.A., Hau, C., Gray, E., et al. Comparison of assays measuring extracellular vesicle-tissue factor in plasma samples: communication from the ISTH SSC Subcommittee on Vascular Biology. J. Thromb. Haemost. JTH. 22:10 (October 2024), 2910–2921.
Mackman, N., Sachetto, A.T.A, Challenges with measuring tissue factor antigen and activity in human plasma. Blood Vessels Thromb. Hemost., 1(4), December 2024, 100022.
Leebeek, F.W.G., Update of thrombosis in multiple myeloma. Thromb. Res. 140 (1 avr 2016), S76–S80.
Sanfilippo, K.M., Fiala, M.A., Tathireddy, H., Feinberg, D., Vij, R., Gage, B.F., D-dimer improves risk prediction of venous thromboembolism in patients with multiple myeloma. Blood 136 (5 nov 2020), 26–27.
Welsh, J.A., Goberdhan, D.C.I., O'Driscoll, L., Buzas, E.I., Blenkiron, C., Bussolati, B., et al. Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J. Extracell. Vesicles, 13(2), févr 2024, e12404.
Khorana, A.A., Francis, C.W., Menzies, K.E., Wang, J.G., Hyrien, O., Hathcock, J., et al. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost JTH. 6:11 (nov 2008), 1983–1985.
Cesarman-Maus, G., Braggio, E., Maldonado, H., Fonseca, R., Absence of tissue factor expression by neoplastic plasma cells in multiple myeloma. Leukemia 26:7 (juill 2012), 1671–1674.
Aharon, A., Tamari, T., Brenner, B., Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells. Thromb. Haemost. 100:05 (2008), 878–885.
Holnthoner, W., Bonstingl, C., Hromada, C., Muehleder, S., Zipperle, J., Stojkovic, S., et al. Endothelial cell-derived extracellular vesicles size-dependently exert procoagulant activity detected by thromboelastometry. Sci. Rep., 7(1), 16 juin 2017, 3707.
Auwerda, J.J.A., Yuana, Y., Osanto, S., de Maat, M.P.M., Sonneveld, P., Bertina, R.M., et al. Microparticle-associated tissue factor activity and venous thrombosis in multiple myeloma. Thromb Haemost. 105:1 (janv 2011), 14–20.
Nielsen, T., Kristensen, S.R., Gregersen, H., Teodorescu, E.M., Pedersen, S., Prothrombotic abnormalities in patients with multiple myeloma and monoclonal gammopathy of undetermined significance. Thromb Res 202 (2021), 108–118.
Faille, D., Bourrienne, M.C., Raucourt, E. de, Chaisemartin, L. de, Granger, V., Lacroix, R., et al. Biomarkers for the risk of thrombosis in pancreatic adenocarcinoma are related to cancer process. Oncotarget 9:41 (29 mai 2018), 26453–26465.
Es, N. van, Hisada, Y., Nisio, M.D., Cesarman, G., Kleinjan, A., Mahé, I., et al. Extracellular vesicles exposing tissue factor for the prediction of venous thromboembolism in patients with cancer: a prospective cohort study. Thromb. Res. 166 (1 juin 2018), 54–59.
Sanfilippo, K.M., Fiala, M.A., Feinberg, D., Tathireddy, H., Girard, T., Vij, R., et al. D-dimer predicts venous thromboembolism in multiple myeloma: a nested case-control study. Res Pract Thromb Haemost., 7(8), 1 nov 2023, 102235.
Ghansah, H., Orbán-Kálmándi, R., Debreceni, I.B., Katona, É., Rejtő, L., Váróczy, L., et al. Low factor XIII levels and altered fibrinolysis in patients with multiple myeloma. Thromb. Res. 234 (févr 2024), 12–20.
Peduzzi, P., Concato, J., Kemper, E., Holford, T.R., Feinstein, A.R., A simulation study of the number of events per variable in logistic regression analysis. J. Clin. Epidemiol. 49:12 (déc 1996), 1373–1379.
Vallier, L., Bouriche, T., Bonifay, A., Judicone, C., Bez, J., Franco, C., et al. Increasing the sensitivity of the human microvesicle tissue factor activity assay. Thromb. Res.(182), 1 oct 2019, 64–74.
