Dexrazoxane reduces antithrombin activity: Five case reports

Dexrazoxane reduces antithrombin activity: Five case reports | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Dexrazoxane reduces antithrombin activity: Five case reports Tomohiro Nagano, Kaho Kondo, Akifumi Matsumura, Daigo Niiya, Soichiro Fujii, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4185398/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Dexrazoxane prevents anthracycline-induced cardiotoxicity and treats anthracycline extravasation. Thrombosis is not a major adverse effect of dexrazoxane use but their relationship has been reported. Here, we describe five patients in whom antithrombin activity decreased after dexrazoxane injections. All five patients were prescribed dexrazoxane to protect the soft tissues from anthracycline extravasation during chemotherapy for hematological malignancies. This led to a reduction in antithrombin activity after a median of 4 days from the first dexrazoxane injection. The activity levels recovered several days later, and one of the patients developed deep vein thrombosis. There was no explanation other than dexrazoxane use, prompting us to speculate that dexrazoxane reduces antithrombin activity. We infer that a decrease in antithrombin activity triggers thrombosis after dexrazoxane injection. Based on these cases and a review of previous reports on dexrazoxane and thrombosis, it is recommended that clinicians monitor antithrombin decline and thrombosis development in patients undergoing dexrazoxane treatment. dexrazoxane thrombosis antithrombin case report Figures Figure 1 1. Introduction Dexrazoxane is a clinically approved drug that has been used for over 20 years to prevent anthracycline-associated cardiotoxicity and treat anthracycline extravasation [ 1 ]. Here, we describe five patients whose antithrombin levels were followed after dexrazoxane administration; all exhibited decreased antithrombin activity. Although the underlying mechanism remains unclear, it has been reported that dexrazoxane can trigger clinical thrombosis; we speculate that this is attributable to reduced antithrombin activity. 2. Case presentation Case 1 (Figure S1 ). An 80-year-old man with an intravascular large B cell lymphoma was treated with rituximab and prednisolone, as well as continuous injection of etoposide, vincristine, and doxorubicin (R-EPOCH). He was in the sixth cycle of treatment when a peripherally inserted central venous catheter (PICC) in the right upper arm, serving as the injection route, broke between the skin and vein at the puncture site; this resulted in leakage of etoposide, vincristine, and doxorubicin. We immediately prescribed dexrazoxane 1,000 mg/m 2 , with a repeat dose 24 h later and 500 mg/m 2 at 24 h after that; this is the recommended dexrazoxane course when treating extravasation. At the last sampling time before extravasation, the antithrombin activity was 104% whereas the fibrinogen/fibrin degradation product (FDP) and d -dimer levels were 2.6 and 1.5 µg/mL, respectively. The antithrombin activity fell to 35% at 6 days after extravasation; the FDP and d -dimer levels slightly increased to 3.5 and 2.1 µg/dL, respectively. Echography of the lower-limb veins revealed a thrombus that was not very bright (i.e., possibly fresh) in the right soleal vein. We injected antithrombin concentrates, and the antithrombin level recovered by 8 days after extravasation. The patient’s FDP and d -dimer levels decreased immediately after injection, and the thrombus did not increase in size. A small nodule formed on the right upper arm, but the patient had no residual symptoms. Antithrombin levels may be depressed by infection, disseminated intravascular coagulation (DIC), liver dysfunction, nephrotic syndrome, or certain drugs; none of these factors was involved. Thus, we speculate that dexrazoxane caused the observed decrease. Case 2 (Figure S2). An 81-year-old woman with a diffuse large B cell lymphoma (DLBCL) began her initial chemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone (R-THP-COP). A peripheral injection catheter in the left antebrachium leaked pirarubicin, and she received dexrazoxane treatment as recommended. Four days after extravasation, the antithrombin activity had fallen from 111–52%; the FDP level had increased from < 2.5 to 11.9 µg/mL; and the d -dimer level had risen from 0.5 to 3.9 µg/mL. Echography of the lower limbs and heart did not reveal any thrombus. Following prescription of antithrombin concentrates, the antithrombin activity, FDP level, and d -dimer level recovered by 8 days after extravasation. The leakage site became erythematous but gradually recovered. Case 3 (Figure S3). Case 3 refers to the same patient as Case 2 . During the sixth course of R-THP-COP, pirarubicin again leaked from the right antebrachium. Before extravasation, the antithrombin activity was 92%; the FDP and d -dimer levels were 8.7 and 7.0 µg/mL, respectively. Dexrazoxane was administered as recommended; the antithrombin activity decreased to 44% at 4 days after extravasation, whereas the FDP and d -dimer levels increased to 54.9 and 13.2 µg/mL, respectively. Antithrombin concentrates were injected at 4 and 6 days after extravasation; all markers recovered to normal levels by approximately 11 days after extravasation. A small nodule formed on the injection site, but this spontaneously recovered. Case 4 (Figure S4). An 80-year-old woman with a DLBCL was receiving her second course of R-THP-COP. On admission, the antithrombin activity was 99%, FDP level was 2.8 µg/mL, and d -dimer level was 1.2 µg/mL. Pirarubicin leaked from the left forearm, and she was treated with dexrazoxane as recommended. On the last day of dexrazoxane administration, the antithrombin activity decreased to 59%; thus, we injected antithrombin concentrates. The FDP and d -dimer levels increased to 4.5 and 2.0 µg/mL, respectively. The antithrombin and FDP levels became nearly normal at 10 days after extravasation. The patient experienced painful erythema, which progressed to purpura and a nodule, but more serious skin damage did not occur. Finally, her symptoms resolved. Case 5 (Figure S5). A 30-year-old man with B lymphoblastic leukemia who was in the fourth cycle of consolidation chemotherapy (i.e., high-dose cytarabine and mitoxantrone, followed by one-time l -asparaginase) experienced mitoxantrone extravasation from a PICC, as described for Case 1 above. He was treated with dexrazoxane as recommended. On day 3 of dexrazoxane, he received 10,000 U/m 2 l -asparaginase in accordance with the treatment protocol. Four days after extravasation, antithrombin activity decreased to 51% and the FDP level increased to 79.6 µg/mL. Before chemotherapy, the antithrombin activity and FDP level were 121% and 5.4 µg/mL, respectively. Contrast-enhanced computed tomography did not reveal pulmonary embolism or deep-vein thrombosis. The patient received antithrombin concentrates three times, on days 4, 5, and 8, after extravasation. Ten days later, the antithrombin activity had recovered to 114% and the FDP level had decreased to 2.4 µg/mL. No skin damage associated with extravasation was observed. l -asparaginase, an antithrombin synthesis inhibitor, may not have caused the decrease in antithrombin activity because the initial consolidation therapy was identical to treatment administered during the fourth cycle; the lowest antithrombin activity at that time was 72%. There was no other obvious cause of antithrombin reduction. Thus, we inferred that dexrazoxane triggered the decrease. Summary (Table 1 ). The average antithrombin activity before dexrazoxane injection was 105%, and the average lowest antithrombin activity thereafter was 48% (Fig. 1 ); this level was reached at 2–6 days after extravasation (median: 4 days). The decreases in activity were temporary; the antithrombin activity recovered approximately 10 days later. The injection of antithrombin concentrates may have affected the recovery period. However, the temporary nature of the effect was clear; the antithrombin concentrates were needed for only a few days in all cases. The decreased antithrombin activity was accompanied by increased FDP (Fig. 1 ) and d -dimer levels. Only one patient (case 5 , treated with l -asparaginase) exhibited a known cause of antithrombin activity decline; potential causes included infection, DIC, liver dysfunction, nephrotic syndrome, and certain drugs. Thrombosis status was evaluated in cases 1 , 2 , and 5 ; thrombosis was detected in only one case. Skin damage was mild in all cases. Table 1 Summary of five cases. Age (years) Sex Disease Chemotherapy AT activity before dexrazoxane injection (%) Lowest AT activity (%) Day of the lowest AT activity * Thrombus Possible reasons of AT decrease Case 1 80 M IVL R-EPOCH 104 35 day6 + none Case 2 81 F DLBCL R-THP-COP 111 52 day4 - none Case 3 81 F DLBCL R-THP-COP 92 44 day4 n.e none Case 4 80 F DLBCL R-THP-COP 99 59 day2 n.e none Case 5 30 M Ph − ALL MIT, HDAC, L-asp 121 51 day4 - L-asp * Day of the lowest antithrombin activity was recorded taking the day of extravasation as day 0. Abbreviations: AT, antithrombin; M, male: F, female; IVL, intravascular large B-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; Ph − ALL, Philadelphia chromosome negative acute lymphoblastic leukemia; MIT, mitoxantrone; HDAC, high dose cytarabine; L-asp, L-asparaginase; n.e, not examined. 3. Discussion Known adverse events of dexrazoxane administration include myelosuppression, nausea and vomiting, and increased levels of hepatic transaminases. Thrombosis is a rare and thus poorly known side effect, but some authors have suggested that dexrazoxane triggers thrombosis. One randomized controlled trial (RCT) of the cardioprotective effects of dexrazoxane for patients with Hodgkin’s lymphoma demonstrated a statistically significant increase in thrombosis. Four of 106 patients treated with dexrazoxane developed thromboses; this outcome occurred in 1 of 108 patients who did not receive dexrazoxane. Importantly, central nervous system thrombosis developed in one patient in the dexrazoxane arm [ 2 ]. A similar RCT involving patients with advanced breast cancer showed that 1 of 84 patients died of pulmonary embolism [ 3 ]. Another such RCT demonstrated that one patient died of pulmonary embolism and one patient died of deep-vein thrombosis [ 4 ]; this report did not suggest that dexrazoxane caused thrombosis, but no thrombosis-related deaths occurred in the control group. Additionally, one case of deep-vein thrombosis was reported in a phase II/III study of dexrazoxane treatment for extravasation [ 5 ]. In summary, dexrazoxane may cause thromboses that are sometimes critical. Antithrombin (also called antithrombin III) is an endogenous anticoagulant protein; an inherited or acquired deficiency of antithrombin increases the risk of thrombosis [ 6 ]. Here, we have described five patients with reduced antithrombin activity following dexrazoxane administration to protect soft tissues after anthracycline extravasation. We speculate that dexrazoxane caused this decrease because there was no other explanation. No patient exhibited DIC, infection, liver dysfunction, or nephrotic syndrome; no patient, except case 5 , was receiving drugs known to lower antithrombin activity. Additionally, antithrombin activity decreased regardless of clinical thrombosis/tissue damage status. These findings imply that dexrazoxane triggered the observed decrease in antithrombin activity. A limitation of this report is that we lacked information concerning antithrombin levels. Activity and biochemical assays, respectively, reveal whether antithrombin is deactivated or its level has been reduced. We do not know how dexrazoxane decreases antithrombin activity. We have described five patients in whom antithrombin activity levels were decreased by dexrazoxane. This mechanism may explain why dexrazoxane is associated with thrombosis, which is a serious adverse event. To our knowledge, this relationship between dexrazoxane administration and antithrombin levels has not been previously reported. Caution is appropriate when prescribing dexrazoxane; antithrombin levels and thrombosis status should be monitored. Declarations Funding: No funding was received to assist with the preparation of this manuscript. Competing interests: The authors declare no competing financial interests. Ethics approval: Approval was obtained from the ethics committee of Japanese Red Cross Okayama Hospital (No. 2024-105). Consent to publish: Patients signed informed consent regarding publishing their data. Acknowledgments The authors thank Textcheck (http://www.textcheck.com/) for editing the manuscript. Author contributions T.N., K.K, A.M., D.N., S.F. and M.T. collected data and approved the manuscript. T.N. analyzed data and wrote the first draft. D.N. and M.T. edited the manuscript. Data availability statement Data are available from the corresponding author upon reasonable request. References Langer SW (2014) Dexrazoxane for the treatment of chemotherapy-related side effects. Cancer Manage Res 6:357–363. https://doi.org/10.2147/CMAR.S47238 Schwartz CL, Constine LS, Villaluna D, London WB, Hutchison RE, Sposto R et al (2009) A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 114:2051–2059. https://doi.org/10.1182/blood-2008-10-184143 Venturini M, Michelotti A, Mastro LD, Gallo L, Carnino F, Garrone O et al (1996) Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14:3112–3120. https://doi.org/10.1200/JCO.1996.14.12.3112 Marty M, Espié M, Llombart A, Monnier A, Rapoport BL, Stahalova V, Dexrazoxane Study Group (2006) Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane®) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 17:614–622. https://doi.org/10.1093/annonc/mdj134 European Medicines Agency (2006) Savene: EPAR – Scientific Discussion. European Medicines Agency. https://www.ema.europa.eu/en/documents/scientific-discussion/savene-epar-scientific-discussion_en.pdf . Accessed 28 Jan 2024 Ornaghi S, Barnhart KT, Frieling J, Streisand J, Paidas MJ (2014) Clinical syndromes associated with acquired antithrombin deficiency via microvascular leakage and the related risk of thrombosis. Thromb Res 133:972–984. https://doi.org/10.1016/j.thromres.2014.02.014 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4185398","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":292506749,"identity":"c805a26e-8268-4e21-af2e-20f7c70772e3","order_by":0,"name":"Tomohiro Nagano","email":"","orcid":"","institution":"Japanese Red Cross Okayama Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tomohiro","middleName":"","lastName":"Nagano","suffix":""},{"id":292506750,"identity":"3fc70ed2-f2cc-4f92-983c-af793edbef96","order_by":1,"name":"Kaho Kondo","email":"","orcid":"","institution":"Japanese Red Cross Okayama Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kaho","middleName":"","lastName":"Kondo","suffix":""},{"id":292506751,"identity":"e714381b-b137-4fed-bf75-bfd51171e0be","order_by":2,"name":"Akifumi Matsumura","email":"","orcid":"","institution":"Japanese Red Cross Okayama Hospital","correspondingAuthor":false,"prefix":"","firstName":"Akifumi","middleName":"","lastName":"Matsumura","suffix":""},{"id":292506752,"identity":"fc91c575-4dd6-4142-abc8-4aa41c0bff1b","order_by":3,"name":"Daigo Niiya","email":"","orcid":"","institution":"Japanese Red Cross Okayama Hospital","correspondingAuthor":false,"prefix":"","firstName":"Daigo","middleName":"","lastName":"Niiya","suffix":""},{"id":292506753,"identity":"a8d9e7cb-8750-4b97-a592-a6dce0187c03","order_by":4,"name":"Soichiro Fujii","email":"","orcid":"","institution":"Japanese Red Cross Okayama Hospital","correspondingAuthor":false,"prefix":"","firstName":"Soichiro","middleName":"","lastName":"Fujii","suffix":""},{"id":292506754,"identity":"a830369a-fbc5-48d3-b269-76f66934b681","order_by":5,"name":"Makoto Takeuchi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYFACNgglwcDYcOADiM9OjJYDDAZALcyNB2eA+MzEa2FvPswDEiCkRbf9WOLjDxV/5CXbGxsO2/zaJs/HzMD44WMObi1mZ9IOGxw4Y2A4m+dgw+HcvtuGbcwMzJIzt+HRciC9TeJgmwHjPIlEoJae24xALWzMvPi0nH8O1mI/T/5hw2HLntv2hLXcSDsG0pI4W4Kx4TDDj9uJRGh5lmxw5oxx8syexIaDvQ23k9uYGZvx++V8muGDigo52xnHjz/+8OPPbdv57c0HP3zEowUVMLaByQZi1YPAH1IUj4JRMApGwUgBAJccWbvtFkcrAAAAAElFTkSuQmCC","orcid":"","institution":"Japanese Red Cross Okayama Hospital","correspondingAuthor":true,"prefix":"","firstName":"Makoto","middleName":"","lastName":"Takeuchi","suffix":""}],"badges":[],"createdAt":"2024-03-29 03:29:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4185398/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4185398/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55322450,"identity":"8401b022-2b7f-492d-b577-f6b190aebf18","added_by":"auto","created_at":"2024-04-25 16:27:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":270612,"visible":true,"origin":"","legend":"\u003cp\u003eAntithrombin activities (a) and FDP levels (b) of all patients. Bars are average values and dotted lines are individual levels. “Before dexrazoxane injection” refers to the latest values before dexrazoxane injection. The lowest antithrombin activities and highest FDP values are also shown (“lowest/highest point after extravasation”). “At the end of chemotherapy” refers to the starting point of the next chemotherapy cycle. FDP, fibrinogen/fibrin degradation product.\u003c/p\u003e","description":"","filename":"OnlineFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4185398/v1/d458a7848d885ac68f7d38af.png"},{"id":58333963,"identity":"a3821270-8200-4122-b294-03fd8f8e6375","added_by":"auto","created_at":"2024-06-14 04:46:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":696808,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4185398/v1/2c60820e-79a2-4532-abb9-f816b383e777.pdf"},{"id":55322449,"identity":"3baa29c1-0223-4ac7-ac7f-3a76e330ef43","added_by":"auto","created_at":"2024-04-25 16:27:59","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":484246,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4185398/v1/dda5f5078f2491d2d56c1ca5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Dexrazoxane reduces antithrombin activity: Five case reports","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eDexrazoxane is a clinically approved drug that has been used for over 20 years to prevent anthracycline-associated cardiotoxicity and treat anthracycline extravasation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Here, we describe five patients whose antithrombin levels were followed after dexrazoxane administration; all exhibited decreased antithrombin activity. Although the underlying mechanism remains unclear, it has been reported that dexrazoxane can trigger clinical thrombosis; we speculate that this is attributable to reduced antithrombin activity.\u003c/p\u003e"},{"header":"2. Case presentation","content":"\u003cp\u003e \u003cstrong\u003eCase 1\u003c/strong\u003e (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). An 80-year-old man with an intravascular large B cell lymphoma was treated with rituximab and prednisolone, as well as continuous injection of etoposide, vincristine, and doxorubicin (R-EPOCH). He was in the sixth cycle of treatment when a peripherally inserted central venous catheter (PICC) in the right upper arm, serving as the injection route, broke between the skin and vein at the puncture site; this resulted in leakage of etoposide, vincristine, and doxorubicin. We immediately prescribed dexrazoxane 1,000 mg/m\u003csup\u003e2\u003c/sup\u003e, with a repeat dose 24 h later and 500 mg/m\u003csup\u003e2\u003c/sup\u003e at 24 h after that; this is the recommended dexrazoxane course when treating extravasation. At the last sampling time before extravasation, the antithrombin activity was 104% whereas the fibrinogen/fibrin degradation product (FDP) and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-dimer levels were 2.6 and 1.5 \u0026micro;g/mL, respectively. The antithrombin activity fell to 35% at 6 days after extravasation; the FDP and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-dimer levels slightly increased to 3.5 and 2.1 \u0026micro;g/dL, respectively. Echography of the lower-limb veins revealed a thrombus that was not very bright (i.e., possibly fresh) in the right soleal vein. We injected antithrombin concentrates, and the antithrombin level recovered by 8 days after extravasation. The patient\u0026rsquo;s FDP and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-dimer levels decreased immediately after injection, and the thrombus did not increase in size. A small nodule formed on the right upper arm, but the patient had no residual symptoms. Antithrombin levels may be depressed by infection, disseminated intravascular coagulation (DIC), liver dysfunction, nephrotic syndrome, or certain drugs; none of these factors was involved. Thus, we speculate that dexrazoxane caused the observed decrease.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 2\u003c/strong\u003e (Figure S2). An 81-year-old woman with a diffuse large B cell lymphoma (DLBCL) began her initial chemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone (R-THP-COP). A peripheral injection catheter in the left antebrachium leaked pirarubicin, and she received dexrazoxane treatment as recommended. Four days after extravasation, the antithrombin activity had fallen from 111\u0026ndash;52%; the FDP level had increased from \u0026lt;\u0026thinsp;2.5 to 11.9 \u0026micro;g/mL; and the \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-dimer level had risen from 0.5 to 3.9 \u0026micro;g/mL. Echography of the lower limbs and heart did not reveal any thrombus. Following prescription of antithrombin concentrates, the antithrombin activity, FDP level, and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-dimer level recovered by 8 days after extravasation. The leakage site became erythematous but gradually recovered.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 3\u003c/strong\u003e (Figure S3). Case \u003cspan refid=\"FPar3\" class=\"InternalRef\"\u003e3\u003c/span\u003e refers to the same patient as Case \u003cspan refid=\"FPar2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. During the sixth course of R-THP-COP, pirarubicin again leaked from the right antebrachium. Before extravasation, the antithrombin activity was 92%; the FDP and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-dimer levels were 8.7 and 7.0 \u0026micro;g/mL, respectively. Dexrazoxane was administered as recommended; the antithrombin activity decreased to 44% at 4 days after extravasation, whereas the FDP and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-dimer levels increased to 54.9 and 13.2 \u0026micro;g/mL, respectively. Antithrombin concentrates were injected at 4 and 6 days after extravasation; all markers recovered to normal levels by approximately 11 days after extravasation. A small nodule formed on the injection site, but this spontaneously recovered.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 4\u003c/strong\u003e (Figure S4). An 80-year-old woman with a DLBCL was receiving her second course of R-THP-COP. On admission, the antithrombin activity was 99%, FDP level was 2.8 \u0026micro;g/mL, and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-dimer level was 1.2 \u0026micro;g/mL. Pirarubicin leaked from the left forearm, and she was treated with dexrazoxane as recommended. On the last day of dexrazoxane administration, the antithrombin activity decreased to 59%; thus, we injected antithrombin concentrates. The FDP and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-dimer levels increased to 4.5 and 2.0 \u0026micro;g/mL, respectively. The antithrombin and FDP levels became nearly normal at 10 days after extravasation. The patient experienced painful erythema, which progressed to purpura and a nodule, but more serious skin damage did not occur. Finally, her symptoms resolved.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 5\u003c/strong\u003e (Figure S5). A 30-year-old man with B lymphoblastic leukemia who was in the fourth cycle of consolidation chemotherapy (i.e., high-dose cytarabine and mitoxantrone, followed by one-time \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-asparaginase) experienced mitoxantrone extravasation from a PICC, as described for Case \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e1\u003c/span\u003e above. He was treated with dexrazoxane as recommended. On day 3 of dexrazoxane, he received 10,000 U/m\u003csup\u003e2\u003c/sup\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-asparaginase in accordance with the treatment protocol. Four days after extravasation, antithrombin activity decreased to 51% and the FDP level increased to 79.6 \u0026micro;g/mL. Before chemotherapy, the antithrombin activity and FDP level were 121% and 5.4 \u0026micro;g/mL, respectively. Contrast-enhanced computed tomography did not reveal pulmonary embolism or deep-vein thrombosis. The patient received antithrombin concentrates three times, on days 4, 5, and 8, after extravasation. Ten days later, the antithrombin activity had recovered to 114% and the FDP level had decreased to 2.4 \u0026micro;g/mL. No skin damage associated with extravasation was observed. \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-asparaginase, an antithrombin synthesis inhibitor, may not have caused the decrease in antithrombin activity because the initial consolidation therapy was identical to treatment administered during the fourth cycle; the lowest antithrombin activity at that time was 72%. There was no other obvious cause of antithrombin reduction. Thus, we inferred that dexrazoxane triggered the decrease.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eSummary (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The average antithrombin activity before dexrazoxane injection was 105%, and the average lowest antithrombin activity thereafter was 48% (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e); this level was reached at 2\u0026ndash;6 days after extravasation (median: 4 days). The decreases in activity were temporary; the antithrombin activity recovered approximately 10 days later. The injection of antithrombin concentrates may have affected the recovery period. However, the temporary nature of the effect was clear; the antithrombin concentrates were needed for only a few days in all cases. The decreased antithrombin activity was accompanied by increased FDP (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-dimer levels. Only one patient (case \u003cspan refid=\"FPar5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, treated with \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-asparaginase) exhibited a known cause of antithrombin activity decline; potential causes included infection, DIC, liver dysfunction, nephrotic syndrome, and certain drugs. Thrombosis status was evaluated in cases \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cspan refid=\"FPar2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, and \u003cspan refid=\"FPar5\" class=\"InternalRef\"\u003e5\u003c/span\u003e; thrombosis was detected in only one case. Skin damage was mild in all cases.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of five cases.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003cp\u003e(years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDisease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAT activity before dexrazoxane injection (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLowest\u003c/p\u003e \u003cp\u003eAT activity (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDay of the lowest\u003c/p\u003e \u003cp\u003eAT activity *\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eThrombus\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePossible reasons\u003c/p\u003e \u003cp\u003eof AT decrease\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIVL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eR-EPOCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eday6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase \u003cspan refid=\"FPar2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eR-THP-COP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eday4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase \u003cspan refid=\"FPar3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eR-THP-COP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eday4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase \u003cspan refid=\"FPar4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eR-THP-COP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eday2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003enone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase \u003cspan refid=\"FPar5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePh\u003csup\u003e\u0026minus;\u003c/sup\u003eALL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMIT, HDAC, L-asp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eday4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eL-asp\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e* Day of the lowest antithrombin activity was recorded taking the day of extravasation as day 0.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eAbbreviations: AT, antithrombin; M, male: F, female; IVL, intravascular large B-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; Ph\u003csup\u003e\u0026minus;\u003c/sup\u003e ALL, Philadelphia chromosome negative acute lymphoblastic leukemia; MIT, mitoxantrone; HDAC, high dose cytarabine; L-asp, L-asparaginase; n.e, not examined.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eKnown adverse events of dexrazoxane administration include myelosuppression, nausea and vomiting, and increased levels of hepatic transaminases. Thrombosis is a rare and thus poorly known side effect, but some authors have suggested that dexrazoxane triggers thrombosis. One randomized controlled trial (RCT) of the cardioprotective effects of dexrazoxane for patients with Hodgkin\u0026rsquo;s lymphoma demonstrated a statistically significant increase in thrombosis. Four of 106 patients treated with dexrazoxane developed thromboses; this outcome occurred in 1 of 108 patients who did not receive dexrazoxane. Importantly, central nervous system thrombosis developed in one patient in the dexrazoxane arm [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A similar RCT involving patients with advanced breast cancer showed that 1 of 84 patients died of pulmonary embolism [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Another such RCT demonstrated that one patient died of pulmonary embolism and one patient died of deep-vein thrombosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]; this report did not suggest that dexrazoxane caused thrombosis, but no thrombosis-related deaths occurred in the control group. Additionally, one case of deep-vein thrombosis was reported in a phase II/III study of dexrazoxane treatment for extravasation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In summary, dexrazoxane may cause thromboses that are sometimes critical.\u003c/p\u003e \u003cp\u003eAntithrombin (also called antithrombin III) is an endogenous anticoagulant protein; an inherited or acquired deficiency of antithrombin increases the risk of thrombosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Here, we have described five patients with reduced antithrombin activity following dexrazoxane administration to protect soft tissues after anthracycline extravasation. We speculate that dexrazoxane caused this decrease because there was no other explanation. No patient exhibited DIC, infection, liver dysfunction, or nephrotic syndrome; no patient, except case \u003cspan refid=\"FPar5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, was receiving drugs known to lower antithrombin activity. Additionally, antithrombin activity decreased regardless of clinical thrombosis/tissue damage status. These findings imply that dexrazoxane triggered the observed decrease in antithrombin activity.\u003c/p\u003e \u003cp\u003eA limitation of this report is that we lacked information concerning antithrombin levels. Activity and biochemical assays, respectively, reveal whether antithrombin is deactivated or its level has been reduced. We do not know how dexrazoxane decreases antithrombin activity.\u003c/p\u003e \u003cp\u003eWe have described five patients in whom antithrombin activity levels were decreased by dexrazoxane. This mechanism may explain why dexrazoxane is associated with thrombosis, which is a serious adverse event. To our knowledge, this relationship between dexrazoxane administration and antithrombin levels has not been previously reported. Caution is appropriate when prescribing dexrazoxane; antithrombin levels and thrombosis status should be monitored.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding: No funding was received to assist with the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare no competing financial interests.\u003c/p\u003e\n\u003cp\u003eEthics approval: Approval was obtained from the ethics committee of Japanese Red Cross Okayama Hospital (No. 2024-105).\u003c/p\u003e\n\u003cp\u003eConsent to publish: Patients signed informed consent regarding publishing their data.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eThe authors thank Textcheck (http://www.textcheck.com/) for editing the manuscript.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eT.N., K.K, A.M., D.N., S.F. and M.T. collected data and approved the manuscript. T.N. analyzed data and wrote the first draft. D.N. and M.T. edited the manuscript.\u003c/p\u003e\n\u003cp\u003eData availability statement\u003c/p\u003e\n\u003cp\u003eData are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLanger SW (2014) Dexrazoxane for the treatment of chemotherapy-related side effects. Cancer Manage Res 6:357\u0026ndash;363. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2147/CMAR.S47238\u003c/span\u003e\u003cspan address=\"10.2147/CMAR.S47238\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwartz CL, Constine LS, Villaluna D, London WB, Hutchison RE, Sposto R et al (2009) A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 114:2051\u0026ndash;2059. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1182/blood-2008-10-184143\u003c/span\u003e\u003cspan address=\"10.1182/blood-2008-10-184143\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVenturini M, Michelotti A, Mastro LD, Gallo L, Carnino F, Garrone O et al (1996) Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14:3112\u0026ndash;3120. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/JCO.1996.14.12.3112\u003c/span\u003e\u003cspan address=\"10.1200/JCO.1996.14.12.3112\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarty M, Espi\u0026eacute; M, Llombart A, Monnier A, Rapoport BL, Stahalova V, Dexrazoxane Study Group (2006) Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane\u0026reg;) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 17:614\u0026ndash;622. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/annonc/mdj134\u003c/span\u003e\u003cspan address=\"10.1093/annonc/mdj134\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEuropean Medicines Agency (2006) Savene: EPAR \u0026ndash; Scientific Discussion. European Medicines Agency. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ema.europa.eu/en/documents/scientific-discussion/savene-epar-scientific-discussion_en.pdf\u003c/span\u003e\u003cspan address=\"https://www.ema.europa.eu/en/documents/scientific-discussion/savene-epar-scientific-discussion_en.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 28 Jan 2024\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrnaghi S, Barnhart KT, Frieling J, Streisand J, Paidas MJ (2014) Clinical syndromes associated with acquired antithrombin deficiency via microvascular leakage and the related risk of thrombosis. Thromb Res 133:972\u0026ndash;984. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.thromres.2014.02.014\u003c/span\u003e\u003cspan address=\"10.1016/j.thromres.2014.02.014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"dexrazoxane, thrombosis, antithrombin, case report","lastPublishedDoi":"10.21203/rs.3.rs-4185398/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4185398/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDexrazoxane prevents anthracycline-induced cardiotoxicity and treats anthracycline extravasation. Thrombosis is not a major adverse effect of dexrazoxane use but their relationship has been reported. Here, we describe five patients in whom antithrombin activity decreased after dexrazoxane injections. All five patients were prescribed dexrazoxane to protect the soft tissues from anthracycline extravasation during chemotherapy for hematological malignancies. This led to a reduction in antithrombin activity after a median of 4 days from the first dexrazoxane injection. The activity levels recovered several days later, and one of the patients developed deep vein thrombosis. There was no explanation other than dexrazoxane use, prompting us to speculate that dexrazoxane reduces antithrombin activity. We infer that a decrease in antithrombin activity triggers thrombosis after dexrazoxane injection. Based on these cases and a review of previous reports on dexrazoxane and thrombosis, it is recommended that clinicians monitor antithrombin decline and thrombosis development in patients undergoing dexrazoxane treatment.\u003c/p\u003e","manuscriptTitle":"Dexrazoxane reduces antithrombin activity: Five case reports","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-25 16:27:54","doi":"10.21203/rs.3.rs-4185398/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0e45c0f3-438b-406a-8b55-7ee70ba070ae","owner":[],"postedDate":"April 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-14T04:38:07+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-25 16:27:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4185398","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4185398","identity":"rs-4185398","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}