{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:09:54Z","timestamp":1791266994951,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T00:00:00Z","timestamp":1694649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82100215"],"award-info":[{"award-number":["82100215"]}]},{"name":"National Natural Science Foundation of China","award":["22ZR1411400"],"award-info":[{"award-number":["22ZR1411400"]}]},{"name":"National Natural Science Foundation of China","award":["2023J05291"],"award-info":[{"award-number":["2023J05291"]}]},{"name":"Natural Science Foundation of Shanghai","award":["82100215"],"award-info":[{"award-number":["82100215"]}]},{"name":"Natural Science Foundation of Shanghai","award":["22ZR1411400"],"award-info":[{"award-number":["22ZR1411400"]}]},{"name":"Natural Science Foundation of Shanghai","award":["2023J05291"],"award-info":[{"award-number":["2023J05291"]}]},{"name":"Natural Science Foundation of Fujian province","award":["82100215"],"award-info":[{"award-number":["82100215"]}]},{"name":"Natural Science Foundation of Fujian province","award":["22ZR1411400"],"award-info":[{"award-number":["22ZR1411400"]}]},{"name":"Natural Science Foundation of Fujian province","award":["2023J05291"],"award-info":[{"award-number":["2023J05291"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lenalidomide, a well-established drug for the treatment of multiple myeloma, significantly enhances patients\u2019 survival. Previous clinical studies have demonstrated that its main side effect is an increased risk of thrombotic events. However, the underlying mechanism remains unexplored. Therefore, this study aims to elucidate the mechanism and offer insights into the selection of clinical thrombotic prophylaxis drugs. Firstly, we conducted a retrospective analysis of clinical data from 169 newly diagnosed multiple myeloma patients who received lenalidomide. To confirm the impact of lenalidomide on thrombosis formation, FeCl3-induced thrombosis and deep venous thrombosis models in mice were established. To investigate the effects of lenalidomide on platelet function, both in vivo and in vitro experiments were designed. During the follow-up period, 8 patients developed thrombotic events, including 8 venous and 1 arterial. Further investigation using mice models demonstrated that lenalidomide significantly promoted the formation of venous thrombosis, consistent with clinical findings. To elucidate the underlying mechanism, assays were conducted to assess platelet function and coagulation. We observed that lenalidomide did not have any noticeable impact on platelet function, both in vitro and in vivo, while administration of lenalidomide resulted in significant decreases in prothrombin time, thrombin time, and prothrombin time ratio in patients, as well as a remarkable reduction in tail-bleeding time in mice. The administration of lenalidomide had no significant impact on platelet function, which may affect venous thrombus formation by affecting coagulation. Therefore, anticoagulant drugs may be superior to antiplatelet drugs in the selection of clinical thrombus prophylaxis.<\/jats:p>","DOI":"10.3390\/ijms241814097","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T02:54:13Z","timestamp":1694746453000},"page":"14097","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Lenalidomide Promotes Thrombosis Formation, but Does Not Affect Platelet Activation in Multiple Myeloma"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1341-6115","authenticated-orcid":false,"given":"Panpan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiadai","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"422","DOI":"10.3322\/caac.21252","article-title":"Understanding biology to tackle the disease: Multiple myeloma from bench to bedside, and back: Clinical Aspects and Biology of Myeloma","volume":"64","author":"Bianchi","year":"2014","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1056\/NEJMoa1817249","article-title":"Daratumumab plus Lenalidomide Dexamethasone for Untreated Myeloma","volume":"380","author":"Facon","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1182\/blood.2020005125","article-title":"Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials","volume":"136","author":"Bradbury","year":"2020","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/sj.leu.2405062","article-title":"Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma","volume":"22","author":"Palumbo","year":"2008","journal-title":"Leukemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1007\/s00432-021-03693-5","article-title":"Thromboembolic events thromboprophylaxis associated with immunomodulators in multiple myeloma patients: A real-life study","volume":"148","author":"Leclerc","year":"2022","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Li, P., Xu, B., Xu, J., Wang, Y., Yang, Y., Wang, W., Maihemaiti, A., Li, J., Xu, T., and Ren, L. (2023). Thrombosis events in Chinese patients with newly diagnosed multiple myeloma. Clin. Exp. Med., 1\u201312.","DOI":"10.1007\/s10238-023-01080-7"},{"key":"ref_7","first-page":"785","article-title":"Thrombosis and platelets: An update","volume":"38","author":"Koupenova","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1056\/NEJMra0801082","article-title":"Mechanisms of Thrombus Formation","volume":"359","author":"Furie","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.trsl.2020.06.012","article-title":"Mechanisms and biomarkers of cancer-associated thrombosis","volume":"225","author":"Kim","year":"2020","journal-title":"Transl. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/bjh.16653","article-title":"Primary prevention of venous thromboembolism with apixaban for multiple myeloma patients receiving immunomodulatory agents","volume":"190","author":"Cornell","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1126\/science.1249543","article-title":"How Thalidomide Works Against Cancer","volume":"343","author":"Stewart","year":"2014","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.2174\/156802612801784443","article-title":"TNF Signaling Beholds Thalidomide Saga: A Review of Mechanistic Role of TNF- Signaling under Thalidomide","volume":"12","author":"Majumder","year":"2012","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5713","DOI":"10.1200\/JCO.2009.22.2679","article-title":"Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed\/Refractory Multiple Myeloma","volume":"27","author":"Richardson","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1182\/blood-2018-05-850727","article-title":"IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos","volume":"132","author":"Fedele","year":"2018","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nrclinonc.2012.106","article-title":"Thrombosis and cancer","volume":"9","author":"Young","year":"2012","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3582","DOI":"10.1182\/blood-2008-04-151076","article-title":"Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma","volume":"112","author":"Kristinsson","year":"2008","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/s41569-018-0110-0","article-title":"Platelet biology and functions: New concepts and clinical perspectives","volume":"16","author":"Heemskerk","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1111\/j.1538-7836.2005.01429.x","article-title":"GPVI integrin \u03b1IIb\u03b23 signaling in platelets","volume":"3","author":"Watson","year":"2005","journal-title":"J. Thromb. Haemost."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1182\/blood-2016-03-705681","article-title":"Respective contributions of single and compound granule fusion to secretion by activated platelets","volume":"128","author":"Eckly","year":"2016","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.1161\/ATVBAHA.118.311822","article-title":"Sin1 (Stress-Activated Protein Kinase-Interacting Protein) Regulates Ischemia-Induced Microthrombosis Through Integrin \u03b1IIb\u03b23-Mediated Outside-In Signaling and Hypoxia Responses in Platelets","volume":"38","author":"Xu","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41573-020-0061-0","article-title":"Therapeutic strategies for thrombosis: New targets and approaches","volume":"19","author":"Mackman","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1111\/j.1538-7836.2005.01374.x","article-title":"New anticoagulants","volume":"3","author":"Weitz","year":"2005","journal-title":"J. Thromb. Haemost."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1182\/blood.2019000919","article-title":"Novel antithrombotic strategies for treatment of venous thromboembolism","volume":"135","author":"Weitz","year":"2020","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1111\/jth.12028","article-title":"Venous thromboembolism in cancer clinical trials: Recommendation for standardized reporting and analysis","volume":"10","author":"Carrier","year":"2012","journal-title":"J. Thromb. Haemost."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"H381","DOI":"10.1152\/ajpheart.1977.232.4.H381","article-title":"Androgen-mediated sensitivity in platelet aggregation","volume":"232","author":"Johnson","year":"1977","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1161\/01.ATV.0000110445.95304.91","article-title":"Platelets of Female Mice Are Intrinsically More Sensitive to Agonists Than Are Platelets of Males","volume":"24","author":"Leng","year":"2004","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1600-0609.1985.tb00804.x","article-title":"Platelet count and platelet size in males and females","volume":"35","author":"Bain","year":"2009","journal-title":"Scand. J. Haematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1208\/s12248-012-9401-2","article-title":"Pharmacokinetics and Tissue Disposition of Lenalidomide in Mice","volume":"14","author":"Rozewski","year":"2012","journal-title":"AAPS J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1146\/annurev.me.20.020169.000403","article-title":"Platelet Lifespan","volume":"20","author":"Najean","year":"1969","journal-title":"Annu. Rev. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1182\/blood-2005-04-1667","article-title":"Botrocetin\/VWF-induced signaling through GPIb-IX-V produces TxA2 in an \u03b1IIb\u03b23- and aggregation-independent manner","volume":"106","author":"Liu","year":"2005","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1182\/blood-2008-05-155978","article-title":"Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK\u2013dependent integrin outside-in retractile signaling pathway","volume":"113","author":"Flevaris","year":"2009","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1161\/CIRCULATIONAHA.119.043581","article-title":"Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets","volume":"142","author":"Xu","year":"2020","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1182\/blood-2010-05-287623","article-title":"Willebrand factor\u2013mediated platelet adhesion is critical for deep vein thrombosis in mouse models","volume":"117","author":"Brill","year":"2011","journal-title":"Blood"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14097\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:50:54Z","timestamp":1760129454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14097"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,14]]},"references-count":33,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241814097"],"URL":"https:\/\/doi.org\/10.3390\/ijms241814097","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,14]]}}}