HEMOSTATIC DERANGEMENTS DURING CAR-T CELL THERAPY

Chimeric Antigen Receptor T-cell (CAR-T) therapy has reshaped the therapeutic landscape of B-cell malignancies, yet coagulopathy—collectively termed CAR-T-associated coagulopathy (CARAC)—is increasingly recognized as a clinically relevant toxicity. Incidence data indicate bleeding in 9-11% of patients (severe in up to 6%), venous thromboembolism in 7-11% within 100 days, and disseminated intravascular coagulation in 14-50% of severe CRS cases.1-4 Events usually cluster in the first 28 days, often correlating with high tumor burden, severe CRS/ICANS, or poor baseline hematologic reserve.2,5 The pathophysiology is multifactorial: cytokine storm (IL-6, IL-1β, TNF-α) triggers endothelial activation with release of von Willebrand factor, angiopoietin-2, and P-selectin, alongside suppression of ADAMTS13 activity and elevation of PAI-1, fostering microvascular thrombosis and impaired fibrinolysis.6-8 Complement activation and glycocalyx shedding add to a thromboinflammatory phenotype,9 while consumption of fibrinogen and platelets drives bleeding.3,8 Importantly, IL-6 blockade, while essential for CRS control, may paradoxically exacerbate hypofibrinogenemia.2 Risk stratification is emerging: elevated pre-infusion Endothelial Activation and Stress Index (EASIX) or its modified version (mEASIX), high IL-10, ferritin, and D-dimer dynamics identify patients at risk for CARAC.6,7 Disease-specific factors (myeloma-related hypercoagulability, bulky lymphoma) and therapy-related features (CD28 costimulation, higher CAR-T dose, lymphodepleting regimen intensity) further shape risk.4,5 Management requires a tailored balance. Prophylactic anticoagulation is reasonable in high-risk, non-thrombocytopenic patients, but evidence-based guidance is lacking.1,3 Supportive strategies include maintaining fibrinogen >150-200 mg/dL, platelet transfusions, cryoprecipitate, and cautious use of antifibrinolytics.2,8 Anti-cytokine therapies (corticosteroids, anakinra) may mitigate endothelial injury and indirectly improve coagulopathy.1,6 Looking ahead, integration of biomarker panels and computational models may enable predictive, personalized risk assessment and targeted supportive interventions.9,10 Embedding such tools in CAR-T care pathways could reduce morbidity and mortality from coagulopathy while preserving antitumor efficacy. References 1. Jiang H, Liu L, Guo T, Wu Y, Ai L, Deng J, Dong J, Mei H, Hu Y. Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy. Ann Hematol. 2019 Jul;98(7):1721-1732. doi: 10.1007/s00277-019-03685-z. 2. Wang Y, Qi K, Cheng H, Cao J, Shi M, Qiao J, Yan Z, Jing G, Pan B, Sang W, Li D, Wang X, Fu C, Zhu F, Zheng J, Li Z, Xu K. Coagulation Disorders after Chimeric Antigen Receptor T Cell Therapy: Analysis of 100 Patients with Relapsed and Refractory Hematologic Malignancies. Biol Blood Marrow Transplant. 2020 May;26(5):865-875. doi: 10.1016/j.bbmt.2019.11.027. 3. Johnsrud A, Craig J, Baird J, Spiegel J, Muffly L, Zehnder J, Tamaresis J, Negrin R, Johnston L, Arai S, Shizuru J, Lowsky R, Meyer E, Weng WK, Shiraz P, Rezvani A, Latchford T, Mackall C, Miklos D, Frank M, Sidana S. Incidence and risk factors associated with bleeding and thrombosis following chimeric antigen receptor T-cell therapy. Blood Adv. 2021 Nov 9;5(21):4465-4475. doi: 10.1182/bloodadvances.2021004716. 4. Parks AL, Kambhampati S, Fakhri B, Andreadis C, Gray L, Wong SW, Shah N, Fang MC. Incidence, management and outcomes of arterial and venous thrombosis after chimeric antigen receptor modified T cells for B cell lymphoma and multiple myeloma. Leuk Lymphoma. 2021 Apr;62(4):1003-1006. doi: 10.1080/10428194.2020.1852474. 5. Schorr C, Forindez J, Espinoza-Gutarra M, Mehta R, Grover N, Perna F. Thrombotic Events Are Unusual Toxicities of Chimeric Antigen Receptor T-Cell Therapies. Int J Mol Sci. 2023 May 6;24(9):8349. doi: 10.3390/ijms24098349. 6. Wang X, Zhang Y, Xue S. Recent progress in chimeric antigen receptor therapy for acute myeloid leukemia. Ann Hematol. 2024 Jun;103(6):1843-1857. doi: 10.1007/s00277-023-05601-y. 7. Galli E, Sorà F, Hohaus S, Fresa A, Pansini I, Autore F, Metafuni E, Innocenti I, Limongiello MA, Giammarco S, Laurenti L, Bacigalupo A, Chiusolo P, De Stefano V, Sica S. Endothelial activation predicts disseminated intravascular coagulopathy, cytokine release syndrome and prognosis in patients treated with anti-CD19 CAR-T cells. Br J Haematol. 2023 Apr;201(1):86-94. doi: 10.1111/bjh.18596. 8. Buechner J, Grupp SA, Hiramatsu H, Teachey DT, Rives S, Laetsch TW, Yanik GA, Wood P, Awasthi R, Yi L, Chassot-Agostinho A, Eldjerou LK, De Moerloose B. Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy. Blood Adv. 2021 Jan 26;5(2):593-601. doi: 10.1182/bloodadvances.2020002757. 9. Moreno-Castaño AB, Fernández S, Ventosa H, Palomo M, Martinez-Sanchez J, Ramos A, Ortiz-Maldonado V, Delgado J, Fernández de Larrea C, Urbano-Ispizua A, Penack O, Nicolás JM, Téllez A, Escolar G, Carreras E, Fernández-Avilés F, Castro P, Diaz-Ricart M. Characterization of the endotheliopathy, innate-immune activation and hemostatic imbalance underlying CAR-T cell toxicities: laboratory tools for an early and differential diagnosis. J Immunother Cancer. 2023 Apr;11(4):e006365. doi: 10.1136/jitc-2022-006365. 10. Demosthenous, C.; Evangelidis, P.; Gatsis, A.; Mitroulis, I.; Vakalopoulou, S.; Vardi, A.; Bountoura, S.; Sakellari, I.; Gavriilaki, E. Endothelial Injury Following CAR-T Cell Immunotherapy for Hematological Malignancies. Cancers 2025, 17, 2876. https://doi.org/10.3390/cancers17172876