Use of Narsoplimab for Eculizumab-Refractory Adult Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

Use of Narsoplimab for Eculizumab-Refractory Adult Transplant-Associated Thrombotic Microangiopathy (TA-TMA) | 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 Use of Narsoplimab for Eculizumab-Refractory Adult Transplant-Associated Thrombotic Microangiopathy (TA-TMA) Sara Young, Indumathy Varadarajan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6940683/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Jan, 2026 Read the published version in Annals of Hematology → Version 1 posted 9 You are reading this latest preprint version Abstract Transplant Associated thrombotic microangiopathy (TA-TMA) is fatal complication associated with hematopoietic stem cell transplant. Endothelial dysfunction and compliment activation causes consumptive thrombocytopenia with intravascular hemolysis, resulting in end organ damage especially to the kidneys and lungs. There are no FDA approved agents for TA-TMA. Eculizumab is the most commonly used agent to treat TA-TMA. Patients who do not respond to Eculizumab have a dismal prognosis with reported mortality up to 80%. Narsoplimab, a mannan-binding lectin-associated serine protease-2 (MASP-2) inhibitor has shown to treat TA-TMA by inhibiting the lectin pathway of the compliment cascade. We report the first adult case with successful management of eculizumab refractory TA- TMA with Narsoplimab. This case highlights the importance of early recognition of TA-TMA and the need to switch therapy to other compliment inhibitors if resistance to Eculizumab is noted. Transplant Associated – Thrombotic Microangiopathy (TA-TMA) Eculizumab Narsoplimab renal failure Diffuse alveolar hemorrhage Figures Figure 1 Introduction Transplant-associated thrombotic microangiopathy (TA-TMA) is a complication from hematopoietic stem cell transplantation (HSCT), resulting in significant mortality and morbidity. 1 TA-TMA has a median onset of 86 days post allogeneic HSCT 2 and occurs due to a combination of microvascular endothelial dysfunction and complement activation. Insults sustained during stem cell transplant can lead to TA-TMA: these include conditioning chemotherapy, calcineurin inhibitors, infections, and graft versus host disease, resulting in microangiopathic hemolytic anemia, thrombocytopenia, and thrombosis. The most common clinical manifestation of TA-TMA is renal failure. However, TA-TMA can also result in posterior reversible encephalopathy (PRES), diffuse alveolar hemorrhage (DAH), serositis, and gastrointestinal bleeding. 3 – 5 Currently, there is no FDA-approved agent for TA-TMA. Eculizumab, a C5 inhibitor, is usually the first line of treatment. However, refractory TA-TMA has a dismal outcome, reporting > 80% mortality in pediatric patients. 10 Here, we report the first adult case of eculizumab-refractory TA-TMA responding to Narsoplimab, an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2). Case Presentation A 24-year-old male received a 10/10 matched unrelated donor allogeneic HSCT marrow product for aplastic anemia. The recipient and donor were IgG positive for EBV; however, the donor was negative for IgG CMV, while the recipient had evidence of prior CMV exposure (CMV D-/R+, EBV D/R+). He received Fludarabine, Cyclophosphamide, ATG and Total body irradiation (2 Gy) for conditioning, GVHD prophylaxis with methotrexate starting on T + 1 and tacrolimus starting on T-3. He had a reactivation of CMV with a viral load of 517 IU/mL on T + 11; hence, he was treated with foscarnet during his admission for transplant. He was placed on letermovir prophylaxis once his viral load decreased to < 50 IU/mL. On T + 46, he developed fevers and diarrhea and was found to have an EBV reactivation with a viral load of 282,000 IU/mL (5.45 log). Colonoscopy with biopsies revealed a lymphoproliferative process. He was treated with four doses of weekly Rituximab with a resolution of the EBV viremia, and the post-treatment PET CT scan did not reveal any evidence of disease. On T + 137, the patient was re-admitted for facial swelling and hypertension. He had progressive thrombocytopenia, hemolytic anemia with LDH of 1046 U/L, plasma-free hemoglobin of 170 mg/dL, haptoglobin < 8 mg/dL, and an absolute reticulocyte count of 0.15 m/uL with multiple schistocytes present in the peripheral smear. His urine protein to creatinine ratio was 6.7 mg/mg, with 24-hour total urine protein of 4.85 g/dL. His C5b-9 complex level was 131 ng/mL (ref < 250ng/ml). The patient was transitioned from sirolimus to mycophenolate for immunosuppression on T + 137. Eculizumab weekly at a dose of 900mg was initiated within one week of hospitalization. Despite achieving therapeutic levels (eculizumab plasma level 164 mcg/mL), the patient developed DAH, serositis, and worsening kidney function, leading to intubation on T + 155. Unfortunately, he further deteriorated and required dialysis on T + 166; he received Rituximab, high-dose steroids, and therapeutic plasma exchange in addition to eculizumab. Despite combination therapy, there was no hematologic response, and he required daily platelet and RBC transfusions. Narsoplimab was obtained through a single patient expanded access request from the manufacturer after submission of an Investigation New Drug application (IND) to the FDA, as it has not yet been approved for TA-TMA. Narsoplimab at 370 mg was started on T + 197 and administered twice weekly. He had a detectable haptoglobin of 13 mg/dL on T + 232 and, as of T + 236, no longer required frequent platelet transfusions. After a prolonged complex hospitalization for 4.5 months with a 1-month stay in the intensive care unit, the patient was discharged to a rehabilitation center. The patient continued to respond to Narsoplimab treatment in the outpatient setting and became transfusion-independent on T + 302 (Figs. 1 ). He was given Narsoplimab until 17 months post-transplant by which time he achieved a complete hematological response. At 25 months post-transplant, he is back home living a near normal life with his family but continues to require renal replacement therapy. Discussion TA-TMA has a long-standing challenge in diagnosis due to its spectrum of clinical presentations and lab abnormalities. The Jodele criteria and guidelines on diagnostic and prognostic assessment have helped with early identification and management based on risk stratification of TA-TMA. 6 Elevated C5b-9, random urine protein-to-creatinine ratio >/1 mg/mg, organ dysfunction, LDH >/2-time Upper Limit of Normal, concurrent grade II-IV GVHD, and concurrent infections are noted as poor prognostic factors. Patients with any of these factors are classified as high-risk TA-TMA. 6 Eculizumab has demonstrated efficacy in pediatric patients with high-risk TA-TMA, improving overall survival (OS) to 71% at 6 months and 62% at one year compared to control (18% and 16.7%, respectively). 7 Unfortunately our patient was refractory to Eculizumab despite achieving therapeutic levels. Narsoplimab (Omeros Corporation, Seattle, USA) is a human immunoglobin G4 monoclonal antibody that inhibits mannan-binding lectin-associated serine protease-2 (MASP-2), the effector enzyme of the lectin pathway of complement. 8 In a Phase II study, treatment with Narsoplimab showed promising results in patients with high-risk TA-TMA, with a 61% response rate (defined as improvement of TA-TMA markers and organ dysfunction) and 68% OS at 100 days from the date of diagnosis. However, this study did not include patients who were refractory to eculizumab 9 . Narsoplimab has shown some efficacy in infants and children having eculizumab-refractory TA-TMA.A retrospective study looked at 5 pediatric patients 1 infant and 4 children, presenting with multi-organ dysfunction and a GVHD. This study reported 1 complete response with resolution of Sinusoidal Obstruction syndrome. 2 children had hematopoietic recovery but no organ recovery (partial response). 11 This report demonstrates the effective use of Narsoplimab in treating an adult with TA-TMA, which has been refractory to multiple agents, including Eculizumab, Rituxan, high-dose steroids, and therapeutic plasma exchange. Our case highlights and emphasizes the potential for treatment with Narsoplimab for refractory TA-TMA, which is otherwise fatal. High-risk TA-TMA can also occur without an elevated C5b-9 complex, especially with increased proteinuria. Narsoplimab has also been used successfully to treat high-risk TA-TMA while maintaining GVHD prophylaxis in the first line setting. 12 Additionally, our case highlights the importance of timely intervention, as injury induced to the glomeruli from TA-TMA can often be irreversible and patients may require long-term renal replacement therapy. In a disease without any approved therapies and a high morbidity rate, Narsoplimab may be an effective therapy for patients with refractory TA-TMA. Declarations Funding Declaration No funding was received to assist with the preparation of this manuscript. Financial Disclosure Sara Young MD – Does not have any relevant financial disclosure Indumathy Varadarajan MBBS – received consulting fees from Omeros, Kadmon and Kite in the period of 2023-2025. Consent to Publish Declaration No patient identifying data has been used in this case report. The patient has consented to share their HPI, hospital course in this case report. Please review attached consent form. Ethics Declaration Our institution does not require ethics approval for reporting individual cases or case series. Written informed consent was obtained for anonymized patient information to be published in this article. Author Contribution SY collected the information from the electronic medical record and prepared the manuscript. IV created the concept, edited the manuscript, and served as the primary treating clinician. References Postalcioglu M, Kim HT, Obut F et al (2018) Impact of Thrombotic Microangiopathy on Renal Outcomes and Survival after Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transpl 24(11):2344–2353. 10.1016/j.bbmt.2018.05.010 Gavriilaki E, Sakellari I, Batsis I et al (2018) Transplant-associated thrombotic microangiopathy: Incidence, prognostic factors, morbidity, and mortality in allogeneic hematopoietic cell transplantation. Clin Transpl 32(9):e13371. 10.1111/ctr.13371 Dvorak CC, Higham C, Shimano KA (2019) Transplant-Associated Thrombotic Microangiopathy in Pediatric Hematopoietic Cell Transplant Recipients: A Practical Approach to Diagnosis and Management. Front Pediatr 7:133. 10.3389/fped.2019.00133 Young JA, Pallas CR, Knovich MA (2021) Transplant-associated thrombotic microangiopathy: theoretical considerations and a practical approach to an unrefined diagnosis. Bone Marrow Transpl 56(8):1805–1817. 10.1038/s41409-021-01283-0 Jodele S, Laskin BL, Dandoy CE et al (2015) A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev 29(3):191–204. 10.1016/j.blre.2014.11.001 Schoettler ML, Carreras E, Cho B et al (2023) Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research. Transpl Cell Ther 29(3):151–163. 10.1016/j.jtct.2022.11.015 Jodele S, Dandoy CE, Aguayo-Hiraldo P et al (2024) A prospective multi-institutional study of eculizumab to treat high-risk stem cell transplantation-associated TMA. Blood 143(12):1112–1123. 10.1182/blood.2023022526 Castelli M, Micò MC, Grassi A et al (2024) Safety and efficacy of narsoplimab in pediatric and adult patients with transplant-associated thrombotic microangiopathy: a real-world experience. Bone Marrow Transpl 59(8):1161–1168. 10.1038/s41409-024-02305-3 Khaled SK, Claes K, Goh YT et al (2022) Narsoplimab, a Mannan-Binding Lectin-Associated Serine Protease-2 Inhibitor, for the Treatment of Adult Hematopoietic Stem-Cell Transplantation-Associated Thrombotic Microangiopathy. J Clin Oncol 40(22):2447–2457. 10.1200/JCO.21.02389 Jodele S, Dandoy CE, Lane A et al (2020) Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood 135(13):1049–1057. 10.1182/blood.2019004218 Schoettler ML, Patel S, Bryson E et al (2024) Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children. Transpl Cell Ther 30(3):336e. 1-336.e8 Alhomoud M, Scordo M, Perales MA (2024) Successful use of narsoplimab to treat allogeneic transplant-associated thrombotic microangiopathy while maintaining sirolimus. Bone Marrow Transpl 59(6):904–906. 10.1038/s41409-024-02263-w Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 17 Jan, 2026 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 22 Sep, 2025 Reviews received at journal 09 Sep, 2025 Reviews received at journal 07 Sep, 2025 Reviewers agreed at journal 19 Aug, 2025 Reviewers agreed at journal 19 Aug, 2025 Reviewers invited by journal 14 Aug, 2025 Editor assigned by journal 27 Jun, 2025 Submission checks completed at journal 27 Jun, 2025 First submitted to journal 20 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-6940683","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":502582484,"identity":"27709b25-1616-452f-8ba5-fe95bd91e69f","order_by":0,"name":"Sara Young","email":"","orcid":"","institution":"University of Virginia Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Young","suffix":""},{"id":502582485,"identity":"2e315f5d-aea5-4bf7-abb5-1e84cfae0d52","order_by":1,"name":"Indumathy Varadarajan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIiWNgGAWjYBAC+RnJx6R5KoAsCSB+wHCAsBY2ibR06zlnoFoSEojSkmP++28bSVp4jqXdzp13OLF/dvPBD4k/7jDwSx+/QEDL4WO3c7cdTpxx51iyRELCMwbJvpwCImzZdtiY4UaOAVDLYQaDMzwJ+LWw95hJ8845bCx/I//zDxK0NByWM7iRwwa1hf0Afi3MbGnSPMfS5QxvpJlZJKQd5pHs4cGrg0G+mRkYlTXWPHI3kh/f+GBzWI6fh/0Bfj3oAGgFjwFpWoCAVFtGwSgYBaNguAMAABBLuzfBuvYAAAAASUVORK5CYII=","orcid":"","institution":"University of Virginia Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Indumathy","middleName":"","lastName":"Varadarajan","suffix":""}],"badges":[],"createdAt":"2025-06-20 16:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6940683/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6940683/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-026-06756-0","type":"published","date":"2026-01-17T16:30:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89641627,"identity":"f63726a1-1d1e-48d6-924d-019891cd0e41","added_by":"auto","created_at":"2025-08-22 08:10:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":73495,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003eTrend in Hemolytic Parameters and CBC\u003c/strong\u003e\u003c/u\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6940683/v1/3a6a2e6e200e4884fa476067.jpg"},{"id":100614687,"identity":"bf97d748-5612-4474-8c58-28c51d94e223","added_by":"auto","created_at":"2026-01-19 17:23:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":377695,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6940683/v1/bae309f0-b615-4fda-8ac3-0b04ce038f7b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Use of Narsoplimab for Eculizumab-Refractory Adult Transplant-Associated Thrombotic Microangiopathy (TA-TMA)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTransplant-associated thrombotic microangiopathy (TA-TMA) is a complication from hematopoietic stem cell transplantation (HSCT), resulting in significant mortality and morbidity.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e TA-TMA has a median onset of 86 days post allogeneic HSCT\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and occurs due to a combination of microvascular endothelial dysfunction and complement activation. Insults sustained during stem cell transplant can lead to TA-TMA: these include conditioning chemotherapy, calcineurin inhibitors, infections, and graft versus host disease, resulting in microangiopathic hemolytic anemia, thrombocytopenia, and thrombosis. The most common clinical manifestation of TA-TMA is renal failure. However, TA-TMA can also result in posterior reversible encephalopathy (PRES), diffuse alveolar hemorrhage (DAH), serositis, and gastrointestinal bleeding.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Currently, there is no FDA-approved agent for TA-TMA. Eculizumab, a C5 inhibitor, is usually the first line of treatment. However, refractory TA-TMA has a dismal outcome, reporting\u0026thinsp;\u0026gt;\u0026thinsp;80% mortality in pediatric patients.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Here, we report the first adult case of eculizumab-refractory TA-TMA responding to Narsoplimab, an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2).\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 24-year-old male received a 10/10 matched unrelated donor allogeneic HSCT marrow product for aplastic anemia. The recipient and donor were IgG positive for EBV; however, the donor was negative for IgG CMV, while the recipient had evidence of prior CMV exposure (CMV D-/R+, EBV D/R+). He received Fludarabine, Cyclophosphamide, ATG and Total body irradiation (2 Gy) for conditioning, GVHD prophylaxis with methotrexate starting on T\u0026thinsp;+\u0026thinsp;1 and tacrolimus starting on T-3. He had a reactivation of CMV with a viral load of 517 IU/mL on T\u0026thinsp;+\u0026thinsp;11; hence, he was treated with foscarnet during his admission for transplant. He was placed on letermovir prophylaxis once his viral load decreased to \u0026lt;\u0026thinsp;50 IU/mL. On T\u0026thinsp;+\u0026thinsp;46, he developed fevers and diarrhea and was found to have an EBV reactivation with a viral load of 282,000 IU/mL (5.45 log). Colonoscopy with biopsies revealed a lymphoproliferative process. He was treated with four doses of weekly Rituximab with a resolution of the EBV viremia, and the post-treatment PET CT scan did not reveal any evidence of disease.\u003c/p\u003e\u003cp\u003eOn T\u0026thinsp;+\u0026thinsp;137, the patient was re-admitted for facial swelling and hypertension. He had progressive thrombocytopenia, hemolytic anemia with LDH of 1046 U/L, plasma-free hemoglobin of 170 mg/dL, haptoglobin\u0026thinsp;\u0026lt;\u0026thinsp;8 mg/dL, and an absolute reticulocyte count of 0.15 m/uL with multiple schistocytes present in the peripheral smear. His urine protein to creatinine ratio was 6.7 mg/mg, with 24-hour total urine protein of 4.85 g/dL. His C5b-9 complex level was 131 ng/mL (ref\u0026thinsp;\u0026lt;\u0026thinsp;250ng/ml). The patient was transitioned from sirolimus to mycophenolate for immunosuppression on T\u0026thinsp;+\u0026thinsp;137. Eculizumab weekly at a dose of 900mg was initiated within one week of hospitalization. Despite achieving therapeutic levels (eculizumab plasma level 164 mcg/mL), the patient developed DAH, serositis, and worsening kidney function, leading to intubation on T\u0026thinsp;+\u0026thinsp;155. Unfortunately, he further deteriorated and required dialysis on\u003c/p\u003e\u003cp\u003eT\u0026thinsp;+\u0026thinsp;166; he received Rituximab, high-dose steroids, and therapeutic plasma exchange in addition to eculizumab. Despite combination therapy, there was no hematologic response, and he required daily platelet and RBC transfusions.\u003c/p\u003e\u003cp\u003eNarsoplimab was obtained through a single patient expanded access request from the manufacturer after submission of an Investigation New Drug application (IND) to the FDA, as it has not yet been approved for TA-TMA. Narsoplimab at 370 mg was started on T\u0026thinsp;+\u0026thinsp;197 and administered twice weekly. He had a detectable haptoglobin of 13 mg/dL on T\u0026thinsp;+\u0026thinsp;232 and, as of T\u0026thinsp;+\u0026thinsp;236, no longer required frequent platelet transfusions. After a prolonged complex hospitalization for 4.5 months with a 1-month stay in the intensive care unit, the patient was discharged to a rehabilitation center. The patient continued to respond to Narsoplimab treatment in the outpatient setting and became transfusion-independent on T\u0026thinsp;+\u0026thinsp;302 (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). He was given Narsoplimab until 17 months post-transplant by which time he achieved a complete hematological response. At 25 months post-transplant, he is back home living a near normal life with his family but continues to require renal replacement therapy.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTA-TMA has a long-standing challenge in diagnosis due to its spectrum of clinical presentations and lab abnormalities. The Jodele criteria and guidelines on diagnostic and prognostic assessment have helped with early identification and management based on risk stratification of TA-TMA.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Elevated C5b-9, random urine protein-to-creatinine ratio \u0026gt;/1 mg/mg, organ dysfunction, LDH \u0026gt;/2-time Upper Limit of Normal, concurrent grade II-IV GVHD, and concurrent infections are noted as poor prognostic factors. Patients with any of these factors are classified as high-risk TA-TMA.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eEculizumab has demonstrated efficacy in pediatric patients with high-risk TA-TMA, improving overall survival (OS) to 71% at 6 months and 62% at one year compared to control (18% and 16.7%, respectively).\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Unfortunately our patient was refractory to Eculizumab despite achieving therapeutic levels. Narsoplimab (Omeros Corporation, Seattle, USA) is a human immunoglobin G4 monoclonal antibody that inhibits mannan-binding lectin-associated serine protease-2 (MASP-2), the effector enzyme of the lectin pathway of complement.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e In a Phase II study, treatment with Narsoplimab showed promising results in patients with high-risk TA-TMA, with a 61% response rate (defined as improvement of TA-TMA markers and organ dysfunction) and 68% OS at 100 days from the date of diagnosis. However, this study did not include patients who were refractory to eculizumab\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Narsoplimab has shown some efficacy in infants and children having eculizumab-refractory TA-TMA.A retrospective study looked at 5 pediatric patients 1 infant and 4 children, presenting with multi-organ dysfunction and a GVHD. This study reported 1 complete response with resolution of Sinusoidal Obstruction syndrome. 2 children had hematopoietic recovery but no organ recovery (partial response). \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThis report demonstrates the effective use of Narsoplimab in treating an adult with TA-TMA, which has been refractory to multiple agents, including Eculizumab, Rituxan, high-dose steroids, and therapeutic plasma exchange. Our case highlights and emphasizes the potential for treatment with Narsoplimab for refractory TA-TMA, which is otherwise fatal. High-risk TA-TMA can also occur without an elevated C5b-9 complex, especially with increased proteinuria. Narsoplimab has also been used successfully to treat high-risk TA-TMA while maintaining GVHD prophylaxis in the first line setting.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Additionally, our case highlights the importance of timely intervention, as injury induced to the glomeruli from TA-TMA can often be irreversible and patients may require long-term renal replacement therapy. In a disease without any approved therapies and a high morbidity rate, Narsoplimab may be an effective therapy for patients with refractory TA-TMA.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cu\u003eFunding Declaration\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received to assist with the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Disclosure\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSara Young MD – Does not have any relevant financial disclosure\u003c/p\u003e\n\u003cp\u003eIndumathy Varadarajan MBBS – received consulting fees from Omeros, Kadmon and Kite in the period of 2023-2025.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eConsent to Publish Declaration\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo patient identifying data has been used in this case report. The patient has consented to share their HPI, hospital course in this case report. Please review attached consent form.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eEthics Declaration\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur institution does not require ethics approval for reporting individual cases or case series. Written informed consent was obtained for anonymized patient information to be published in this article.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSY collected the information from the electronic medical record and prepared the manuscript. IV created the concept, edited the manuscript, and served as the primary treating clinician.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePostalcioglu M, Kim HT, Obut F et al (2018) Impact of Thrombotic Microangiopathy on Renal Outcomes and Survival after Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transpl 24(11):2344\u0026ndash;2353. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.bbmt.2018.05.010\u003c/span\u003e\u003cspan address=\"10.1016/j.bbmt.2018.05.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGavriilaki E, Sakellari I, Batsis I et al (2018) Transplant-associated thrombotic microangiopathy: Incidence, prognostic factors, morbidity, and mortality in allogeneic hematopoietic cell transplantation. Clin Transpl 32(9):e13371. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/ctr.13371\u003c/span\u003e\u003cspan address=\"10.1111/ctr.13371\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDvorak CC, Higham C, Shimano KA (2019) Transplant-Associated Thrombotic Microangiopathy in Pediatric Hematopoietic Cell Transplant Recipients: A Practical Approach to Diagnosis and Management. Front Pediatr 7:133. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fped.2019.00133\u003c/span\u003e\u003cspan address=\"10.3389/fped.2019.00133\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoung JA, Pallas CR, Knovich MA (2021) Transplant-associated thrombotic microangiopathy: theoretical considerations and a practical approach to an unrefined diagnosis. Bone Marrow Transpl 56(8):1805\u0026ndash;1817. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41409-021-01283-0\u003c/span\u003e\u003cspan address=\"10.1038/s41409-021-01283-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJodele S, Laskin BL, Dandoy CE et al (2015) A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev 29(3):191\u0026ndash;204. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.blre.2014.11.001\u003c/span\u003e\u003cspan address=\"10.1016/j.blre.2014.11.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchoettler ML, Carreras E, Cho B et al (2023) Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research. Transpl Cell Ther 29(3):151\u0026ndash;163. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jtct.2022.11.015\u003c/span\u003e\u003cspan address=\"10.1016/j.jtct.2022.11.015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJodele S, Dandoy CE, Aguayo-Hiraldo P et al (2024) A prospective multi-institutional study of eculizumab to treat high-risk stem cell transplantation-associated TMA. Blood 143(12):1112\u0026ndash;1123. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood.2023022526\u003c/span\u003e\u003cspan address=\"10.1182/blood.2023022526\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCastelli M, Mic\u0026ograve; MC, Grassi A et al (2024) Safety and efficacy of narsoplimab in pediatric and adult patients with transplant-associated thrombotic microangiopathy: a real-world experience. Bone Marrow Transpl 59(8):1161\u0026ndash;1168. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41409-024-02305-3\u003c/span\u003e\u003cspan address=\"10.1038/s41409-024-02305-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKhaled SK, Claes K, Goh YT et al (2022) Narsoplimab, a Mannan-Binding Lectin-Associated Serine Protease-2 Inhibitor, for the Treatment of Adult Hematopoietic Stem-Cell Transplantation-Associated Thrombotic Microangiopathy. J Clin Oncol 40(22):2447\u0026ndash;2457. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.21.02389\u003c/span\u003e\u003cspan address=\"10.1200/JCO.21.02389\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJodele S, Dandoy CE, Lane A et al (2020) Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood 135(13):1049\u0026ndash;1057. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood.2019004218\u003c/span\u003e\u003cspan address=\"10.1182/blood.2019004218\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchoettler ML, Patel S, Bryson E et al (2024) Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children. Transpl Cell Ther 30(3):336e. 1-336.e8\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlhomoud M, Scordo M, Perales MA (2024) Successful use of narsoplimab to treat allogeneic transplant-associated thrombotic microangiopathy while maintaining sirolimus. Bone Marrow Transpl 59(6):904\u0026ndash;906. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41409-024-02263-w\u003c/span\u003e\u003cspan address=\"10.1038/s41409-024-02263-w\" 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":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Transplant Associated – Thrombotic Microangiopathy (TA-TMA), Eculizumab, Narsoplimab, renal failure, Diffuse alveolar hemorrhage","lastPublishedDoi":"10.21203/rs.3.rs-6940683/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6940683/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTransplant Associated thrombotic microangiopathy (TA-TMA) is fatal complication associated with hematopoietic stem cell transplant. Endothelial dysfunction and compliment activation causes consumptive thrombocytopenia with intravascular hemolysis, resulting in end organ damage especially to the kidneys and lungs. There are no FDA approved agents for TA-TMA. Eculizumab is the most commonly used agent to treat TA-TMA. Patients who do not respond to Eculizumab have a dismal prognosis with reported mortality up to 80%. Narsoplimab, a mannan-binding lectin-associated serine protease-2 (MASP-2) inhibitor has shown to treat TA-TMA by inhibiting the lectin pathway of the compliment cascade. We report the first adult case with successful management of eculizumab refractory TA- TMA with Narsoplimab. This case highlights the importance of early recognition of TA-TMA and the need to switch therapy to other compliment inhibitors if resistance to Eculizumab is noted.\u003c/p\u003e","manuscriptTitle":"Use of Narsoplimab for Eculizumab-Refractory Adult Transplant-Associated Thrombotic Microangiopathy (TA-TMA)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-22 08:10:53","doi":"10.21203/rs.3.rs-6940683/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-22T17:24:07+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-09T15:10:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-07T16:29:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"82781025946981991788961965907413154917","date":"2025-08-19T13:05:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"330054290031839882587839476026716243912","date":"2025-08-19T05:55:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-14T08:38:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-27T07:59:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-27T07:57:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2025-06-20T16:40:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bc9fd579-bf70-4e99-bd80-31631c73cde5","owner":[],"postedDate":"August 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T16:47:36+00:00","versionOfRecord":{"articleIdentity":"rs-6940683","link":"https://doi.org/10.1007/s00277-026-06756-0","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2026-01-17 16:30:03","publishedOnDateReadable":"January 17th, 2026"},"versionCreatedAt":"2025-08-22 08:10:53","video":"","vorDoi":"10.1007/s00277-026-06756-0","vorDoiUrl":"https://doi.org/10.1007/s00277-026-06756-0","workflowStages":[]},"version":"v1","identity":"rs-6940683","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6940683","identity":"rs-6940683","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}