{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T12:28:41Z","timestamp":1787228921465,"version":"build-2736575974"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":68,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Pharm Health Care Sci"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Acquired polycystic kidney disease is associated with an increased risk of developing renal cell carcinoma (RCC), which is commonly observed in patients on dialysis and may present with inferior vena cava tumor thrombus. However, there are no prior reports on the use of warfarin for inferior vena cava tumor thrombus in patients on dialysis with RCC receiving combination therapy with lenvatinib and pembrolizumab.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>We describe a 64-year-old Japanese man with RCC complicated by tumor thrombus extending into the renal vein and inferior vena cava who was undergoing hemodialysis. Warfarin was initiated at 2\u00a0mg\/day due to the risk of thrombus progression. His baseline prothrombin time-international normalized ratio (PT-INR) was 1.80 before the initiation of combination therapy with lenvatinib and pembrolizumab. After 8 days of warfarin administration, combination therapy with lenvatinib (10\u00a0mg\/day) and pembrolizumab (200\u00a0mg every 3 weeks) was initiated. Nine days later, the PT-INR elevated to 3.02 despite no change in warfarin dose. The patient remained asymptomatic. Adjusting warfarin to 2\u20132.5\u00a0mg\/day and close PT-INR monitoring successfully restored values to the therapeutic range of 1.6\u20132.6 by day 80, without reducing the lenvatinib dose.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Neither warfarin nor lenvatinib is eliminated by dialysis; therefore, potential pharmacokinetic interactions should be managed with the same caution as in non-dialysis patients. Concomitant use of warfarin and combination therapy with lenvatinib and pembrolizumab in patients with RCC undergoing hemodialysis may enhance anticoagulant effects via multiple interacting factors, including cytochrome P-450-related interactions, systemic inflammation, and hypoalbuminemia. Therefore, careful follow-up, including shorter intervals between outpatient visits (e.g., weekly monitoring), is essential for safe PT-INR management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40780-026-00598-8","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T08:34:12Z","timestamp":1781339652000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prolongation of prothrombin time-international normalized ratio by concomitant use of warfarin and combination therapy with lenvatinib and pembrolizumab in a patient with renal cell carcinoma on dialysis: a case report"],"prefix":"10.1186","volume":"12","author":[{"given":"Shota","family":"Torii","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Narita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Torii-Goto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takamasa","family":"Homma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Esaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Sakakibara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuya","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Takimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"598_CR1","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1111\/j.1464-410x.1991.tb15158.x","volume":"67","author":"JF Brennan","year":"1991","unstructured":"Brennan JF, Stilmant MM, Babayan RK, Siroky MB. Acquired renal cystic disease: Implications for the urologist. Br J Urol. 1991;67:342\u20138. https:\/\/doi.org\/10.1111\/j.1464-410x.1991.tb15158.x.","journal-title":"Br J Urol"},{"key":"598_CR2","doi-asserted-by":"publisher","first-page":"45","DOI":"10.2147\/ijnrd.s75916","volume":"9","author":"M Terris","year":"2016","unstructured":"Terris M, Klaassen Z, Kabaria R. Renal cell carcinoma: Links and risks. Int J Nephrol Renovasc Dis. 2016;9:45\u201352. https:\/\/doi.org\/10.2147\/ijnrd.s75916.","journal-title":"Int J Nephrol Renovasc Dis"},{"key":"598_CR3","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/j.eururo.2009.06.009","volume":"57","author":"G Ciancio","year":"2010","unstructured":"Ciancio G, Manoharan M, Katkoori D, De Los Santos R, Soloway MS. Long-term survival in patients undergoing radical nephrectomy and inferior vena cava thrombectomy: Single-center experience. Eur Urol. 2010;57:667\u201372. https:\/\/doi.org\/10.1016\/j.eururo.2009.06.009.","journal-title":"Eur Urol"},{"key":"598_CR4","doi-asserted-by":"publisher","first-page":"1166","DOI":"10.1016\/s0022-5347(17)42848-5","volume":"139","author":"FF Marshall","year":"1988","unstructured":"Marshall FF, Dietrick DD, Baumgartner WA, Reitz BA. Surgical management of renal cell carcinoma with intracaval neoplastic extension above the hepatic veins. J Urol. 1988;139:1166\u201371. https:\/\/doi.org\/10.1016\/s0022-5347(17)42848-5.","journal-title":"J Urol"},{"key":"598_CR5","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1053\/j.semvascsurg.2014.06.015","volume":"26","author":"A Calero","year":"2013","unstructured":"Calero A, Armstrong PA. Renal cell carcinoma accompanied by venous invasion and inferior vena cava thrombus: Classification and operative strategies for the vascular surgeon. Semin Vasc Surg. 2013;26:219\u201325. https:\/\/doi.org\/10.1053\/j.semvascsurg.2014.06.015.","journal-title":"Semin Vasc Surg"},{"key":"598_CR6","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1177\/1756287215576443","volume":"7","author":"SP Psutka","year":"2015","unstructured":"Psutka SP, Leibovich BC. Management of inferior vena cava tumor thrombus in locally advanced renal cell carcinoma. Ther Adv Urol. 2015;7:216\u201329. https:\/\/doi.org\/10.1177\/1756287215576443.","journal-title":"Ther Adv Urol"},{"key":"598_CR7","doi-asserted-by":"publisher","first-page":"2276","DOI":"10.1093\/eurheartj\/ehn310","volume":"29","author":"A Torbicki","year":"2008","unstructured":"Torbicki A, Perrier A, Konstantinides S, Agnelli G, Gali\u00e8 N, Pruszczyk P, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008;29:2276\u2013315. https:\/\/doi.org\/10.1093\/eurheartj\/ehn310.","journal-title":"Eur Heart J"},{"key":"598_CR8","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.chest.2024.03.003","volume":"166","author":"SM Stevens","year":"2024","unstructured":"Stevens SM, Woller SC, Baumann Kreuziger L, Doerschug K, Geersing GJ, Klok FA, et al. Antithrombotic therapy for VTE disease: Compendium and review of CHEST guidelines 2012\u20132021. Chest. 2024;166:388\u2013404. https:\/\/doi.org\/10.1016\/j.chest.2024.03.003.","journal-title":"Chest"},{"key":"598_CR9","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.ekir.2024.10.016","volume":"10","author":"NW Lange","year":"2024","unstructured":"Lange NW, Muir J, Salerno DM. Direct oral anticoagulants in patients with ESRD and kidney transplantation. Kidney Int Rep. 2024;10:40\u201353. https:\/\/doi.org\/10.1016\/j.ekir.2024.10.016.","journal-title":"Kidney Int Rep"},{"key":"598_CR10","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/s0163-7258(96)00140-4","volume":"73","author":"LS Kaminsky","year":"1997","unstructured":"Kaminsky LS, Zhang Z-Y. Human P450 metabolism of warfarin. Pharmacol Ther. 1997;73:67\u201374. https:\/\/doi.org\/10.1016\/s0163-7258(96)00140-4.","journal-title":"Pharmacol Ther"},{"key":"598_CR11","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1016\/S0090-9556(25)07750-5","volume":"12","author":"LS Kaminsky","year":"1984","unstructured":"Kaminsky LS, Dunbar DA, Wang PP, Beaune P, Larrey D, Guengerich FP, et al. Human hepatic cytochrome P-450 composition as probed by in vitro microsomal metabolism of warfarin. Drug Metab Dispos. 1984;12:470\u20137. PMID: 6148215.","journal-title":"Drug Metab Dispos"},{"key":"598_CR12","doi-asserted-by":"publisher","first-page":"33","DOI":"10.2165\/00003088-198611010-00003","volume":"11","author":"NH Holford","year":"1986","unstructured":"Holford NH. Clinical pharmacokinetic considerations in the control of oral anticoagulant therapy. Clin Pharmacokinet. 1986;11:33\u201360. https:\/\/doi.org\/10.2165\/00003088-198611010-00003.","journal-title":"Clin Pharmacokinet"},{"issue":"5 Pt 1","key":"598_CR13","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1002\/cpt1976195part1552","volume":"19","author":"A Yacobi","year":"1976","unstructured":"Yacobi A, Udall JA, Levy G. Serum protein binding as a determinant of warfarin body clearance and anticoagulant effect. Clin Pharmacol Ther. 1976;19(5 Pt 1):552\u20138. https:\/\/doi.org\/10.1002\/cpt1976195part1552.","journal-title":"Clin Pharmacol Ther"},{"key":"598_CR14","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.abb.2019.108123","volume":"143","author":"M Ilic","year":"2020","unstructured":"Ilic M, Milanovic M, Poljarevic N, et al. Warfarin increases thermal resistance of albumin through stabilization of the protein lobe that includes its binding site. Int J Biol Macromol. 2020;143:533\u201342. https:\/\/doi.org\/10.1016\/j.abb.2019.108123.","journal-title":"Int J Biol Macromol"},{"key":"598_CR15","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1056\/nejmoa2035716","volume":"384","author":"R Motzer","year":"2021","unstructured":"Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384:1289\u2013300. https:\/\/doi.org\/10.1056\/nejmoa2035716.","journal-title":"N Engl J Med"},{"key":"598_CR16","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1016\/s1470-2045(15)00290-9","volume":"16","author":"RJ Motzer","year":"2015","unstructured":"Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473\u201382. https:\/\/doi.org\/10.1016\/s1470-2045(15)00290-9.","journal-title":"Lancet Oncol"},{"key":"598_CR17","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1007\/s10147-025-02721-5","volume":"30","author":"Y Kato","year":"2025","unstructured":"Kato Y. Lenvatinib enhances antitumor immunity of anti-PD-1 antibody. Int J Clin Oncol. 2025;30:666\u201373. https:\/\/doi.org\/10.1007\/s10147-025-02721-5.","journal-title":"Int J Clin Oncol"},{"key":"598_CR18","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1111\/jcpt.13030","volume":"44","author":"H Yagishita","year":"2019","unstructured":"Yagishita H, Minami S, Akamine Y, Kato S, Iijima K, Miura M. Drug interactions between warfarin and lenvatinib in a patient with the CYP2C9*1\/*3 and VKORC1-1639G\/A genotype. J Clin Pharm Ther. 2019;44:977\u201380. https:\/\/doi.org\/10.1111\/jcpt.13030.","journal-title":"J Clin Pharm Ther"},{"key":"598_CR19","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1002\/bdd.2204","volume":"40","author":"Y Mano","year":"2019","unstructured":"Mano Y, Mizuo H. Minimal impact of hepatic and renal impairment on plasma protein binding of lenvatinib, and identification of its major plasma binding protein. Biopharm Drug Dispos. 2019;40:307\u201311. https:\/\/doi.org\/10.1002\/bdd.2204.","journal-title":"Biopharm Drug Dispos"},{"key":"598_CR20","doi-asserted-by":"publisher","first-page":"103366","DOI":"10.1016\/j.critrevonc.2021.103366","volume":"163","author":"S Fogli","year":"2021","unstructured":"Fogli S, Gianfilippo G, Cucchiara F, Del Re M, Valerio L, Elisei R, et al. Clinical pharmacology and drug-drug interactions of lenvatinib in thyroid cancer. Crit Rev Oncol Hematol. 2021;163:103366. https:\/\/doi.org\/10.1016\/j.critrevonc.2021.103366.","journal-title":"Crit Rev Oncol Hematol"},{"key":"598_CR21","doi-asserted-by":"publisher","first-page":"2528","DOI":"10.1158\/1078-0432.CCR-10-2638","volume":"17","author":"K Yamada","year":"2011","unstructured":"Yamada K, Yamamoto N, Yamanaka T, et al. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res. 2011;17:2528\u201337. https:\/\/doi.org\/10.1158\/1078-0432.CCR-10-2638.","journal-title":"Clin Cancer Res"},{"key":"598_CR22","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1093\/ndt\/gfx212","volume":"33","author":"AO Molnar","year":"2018","unstructured":"Molnar AO, Bota SE, McArthur E, Lam NN, Garg AX, Wald R, et al. Risk and complications of venous thromboembolism in dialysis patients. Nephrol Dial Transpl. 2018;33:874\u201380. https:\/\/doi.org\/10.1093\/ndt\/gfx212.","journal-title":"Nephrol Dial Transpl"},{"key":"598_CR23","doi-asserted-by":"publisher","first-page":"2431149","DOI":"10.1080\/0886022x.2024.2431149","volume":"46","author":"Y Zhan","year":"2024","unstructured":"Zhan Y, Fu X, Bi W, Li G. Risk factors for venous thromboembolism in patients with chronic kidney disease: A systematic review and meta-analysis. Ren Fail. 2024;46:2431149. https:\/\/doi.org\/10.1080\/0886022x.2024.2431149.","journal-title":"Ren Fail"},{"key":"598_CR24","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1111\/j.1525-139x.2007.00381.x","volume":"21","author":"L Willms","year":"2008","unstructured":"Willms L, Vercaigne LM. Does warfarin safely prevent clotting of hemodialysis catheters? Semin Dial. 2008;21:71\u20137. https:\/\/doi.org\/10.1111\/j.1525-139x.2007.00381.x.","journal-title":"Semin Dial"},{"key":"598_CR25","doi-asserted-by":"publisher","first-page":"2123","DOI":"10.2146\/ajhp080436","volume":"66","author":"K Bshury","year":"2009","unstructured":"Bshury K, Shavit-Gevman S, Shteinvil R, Schattner A. Elevated International Normalized Ratio associated with concurrent use of sorafenib and warfarin. Am J Health Syst Pharm. 2009;66:2123\u20135. https:\/\/doi.org\/10.2146\/ajhp080436.","journal-title":"Am J Health Syst Pharm"},{"key":"598_CR26","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/clpt.2008.302","volume":"85","author":"AE Aitken","year":"2009","unstructured":"Aitken AE, Richardson TA, Morgan ET. Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther. 2009;85:372\u201381. https:\/\/doi.org\/10.1038\/clpt.2008.302.","journal-title":"Clin Pharmacol Ther"},{"key":"598_CR27","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.clgc.2015.09.015","volume":"29","author":"WT Foxx-Lupo","year":"2016","unstructured":"Foxx-Lupo WT, Sing S, Alwan L, Tykodi SS. A drug interaction between cabozantinib and warfarin in a patient with renal cell carcinoma. J Pharm Pract. 2016;29:521\u20133. https:\/\/doi.org\/10.1016\/j.clgc.2015.09.015.","journal-title":"J Pharm Pract"},{"key":"598_CR28","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1007\/s40262-016-0461-9","volume":"56","author":"L Nguyen","year":"2017","unstructured":"Nguyen L, Holland J, Mamelok R, et al. Clinical pharmacokinetics and pharmacodynamics of cabozantinib. Clin Pharmacokinet. 2017;56:431\u201343. https:\/\/doi.org\/10.1007\/s40262-016-0461-9.","journal-title":"Clin Pharmacokinet"},{"key":"598_CR29","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/sj.ki.5002585","volume":"73","author":"D Fouque","year":"2008","unstructured":"Fouque D, Kalantar-Zadeh K, Kopple J, Cano N, Chauveau P, Cuppari L, et al. A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. Kidney Int. 2008;73:391\u20138. https:\/\/doi.org\/10.1038\/sj.ki.5002585.","journal-title":"Kidney Int"},{"key":"598_CR30","doi-asserted-by":"publisher","first-page":"215","DOI":"10.2165\/00003088-200038030-00005","volume":"38","author":"DL Schmucker","year":"2000","unstructured":"Schmucker DL, Vesell ES. Age-related changes in protein binding of drugs: implications for therapy. Clin Pharmacokinet. 2000;38:215\u201324. https:\/\/doi.org\/10.2165\/00003088-200038030-00005.","journal-title":"Clin Pharmacokinet"},{"key":"598_CR31","doi-asserted-by":"publisher","first-page":"144","DOI":"10.2165\/00003088-197803020-00004","volume":"3","author":"JP Tillement","year":"1978","unstructured":"Tillement JP, Lhoste F, Giudicelli JF. Diseases and drug protein binding. Clin Pharmacokinet. 1978;3:144\u201354. https:\/\/doi.org\/10.2165\/00003088-197803020-00004.","journal-title":"Clin Pharmacokinet"},{"key":"598_CR32","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1067\/mcp.2002.121829","volume":"71","author":"LZ Benet","year":"2002","unstructured":"Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002;71:115\u201321. https:\/\/doi.org\/10.1067\/mcp.2002.121829.","journal-title":"Clin Pharmacol Ther"},{"key":"598_CR33","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1160\/TH10-04-0257","volume":"93","author":"E Sconce","year":"2005","unstructured":"Sconce E, Avery P, Wynne H, Kamali F. Dietary vitamin K intake and stability of oral anticoagulant therapy. Thromb Haemost. 2005;93:883\u20138. https:\/\/doi.org\/10.1160\/TH10-04-0257.","journal-title":"Thromb Haemost"}],"container-title":["Journal of Pharmaceutical Health Care and Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40780-026-00598-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40780-026-00598-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40780-026-00598-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T12:03:01Z","timestamp":1787227381000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s40780-026-00598-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,13]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["598"],"URL":"https:\/\/doi.org\/10.1186\/s40780-026-00598-8","relation":{},"ISSN":["2055-0294"],"issn-type":[{"value":"2055-0294","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,13]]},"assertion":[{"value":"16 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study involved human participants. This study was approved by the Ethics Committee of Kariya Toyota General Hospital (approval date: February 13, 2025; registration number: 1097).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Informed consent was obtained from the participant included in this study.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"76"}}