Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00034925.xml
Download PDF
Hamostaseologie 2025; 45(02): 175-187
DOI: 10.1055/a-2528-5071
DOI: 10.1055/a-2528-5071
Review Article
Checkpoint Inhibitors, CAR T Cells, and the Hemostatic System: What Do We Know So Far?
Funding CCR is supported by the Margarete Clemens Stiftung (Deutsches Stiftungszentrum Essen) and by the Mildred Scheel Nachwuchszentrum (MSNZ) Hamburg.
Abstract
Immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells are novel therapeutic strategies that enhance anticancer immunity by activating or engineering cancer-targeting T cells. The resulting hyperinflammation carries several side effects, ranging from autoimmune-like symptoms to cytokine release syndrome (CRS), with potentially severe consequences. Recent findings indicate that ICIs increase the risk of venous and arterial thromboembolic adverse events. Patients with prior VTE might be at higher risk of developing new events under ICI while other risk factors vary across studies. So far, data on CAR T-linked coagulopathies are limited. Hypofibrinogenemia in the presence of CRS is the most commonly observed dysregulation of hemostatic parameters. A rare but particularly severe adverse event is the development of disseminated intravascular coagulation activation, which can occur in the setting of CRS and may be linked to immune effector cell-associated hemophagocytic lymphohistiocytosis. While the increasing number of studies on thromboembolic complications and coagulation alterations under ICIs and CAR T therapies are concerning, these results might be influenced by the retrospective study design and the heterogeneous patient populations. Importantly, numerous promising new T cell-based immunotherapies are currently under investigation for various cancers and are expected to become very prominent therapy options in the near future. Therefore, coagulopathies and thrombosis under T cell-directed immuno- and anti-cancer therapies is important. Our review provides an overview of the current understanding of ICI- and CAR T-associated thromboembolism. We discuss pathogenic mechanisms of inflammation-associated coagulation activation and explore potential biomarkers for VTE.
Keywords
immune checkpoint inhibitors - CAR T cells - hypercoagulability - thromboinflammation - cancerPublication History
Received: 05 August 2024
Accepted: 27 January 2025
Article published online:
07 May 2025
© 2025. Thieme. All rights reserved.
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
-
References
- 1 Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007; 110 (10) 2339-2346
- 2 Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293 (06) 715-722
- 3 Mulder FI, Horváth-Puhó E, van Es N. et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood 2021; 137 (14) 1959-1969
- 4 Navi BB, Reiner AS, Kamel H. et al. Risk of arterial thromboembolism in patients with cancer. J Am Coll Cardiol 2017; 70 (08) 926-938
- 5 Khorana AA, Mackman N, Falanga A. et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers 2022; 8 (01) 11
- 6 Dicke C, Langer F. Pathophysiology of Trousseau's syndrome. Hamostaseologie 2015; 35 (01) 52-59
- 7 Mahajan A, Brunson A, Adesina O, Keegan THM, Wun T. The incidence of cancer-associated thrombosis is increasing over time. Blood Adv 2022; 6 (01) 307-320
- 8 Stark K, Massberg S. Interplay between inflammation and thrombosis in cardiovascular pathology. Nat Rev Cardiol 2021; 18 (09) 666-682
- 9 Esmon CT. Inflammation and thrombosis. J Thromb Haemost 2003; 1 (07) 1343-1348
- 10 Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018; 359 (6382): 1350-1355
- 11 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12 (04) 252-264
- 12 Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 2018; 18 (03) 153-167
- 13 Gougis P, Jochum F, Abbar B. et al. Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective. EClinicalMedicine 2024; 70: 102536
- 14 Rolling CC, Barrett TJ, Berger JS. Platelet-monocyte aggregates: molecular mediators of thromboinflammation. Front Cardiovasc Med 2023; 10: 960398
- 15 Norelli M, Camisa B, Barbiera G. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med 2018; 24 (06) 739-748
- 16 Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med 2018; 24 (06) 731-738
- 17 Duan Z, Li Z, Wang Z, Chen C, Luo Y. Chimeric antigen receptor macrophages activated through TLR4 or IFN-γ receptors suppress breast cancer growth by targeting VEGFR2. Cancer Immunol Immunother 2023; 72 (10) 3243-3257
- 18 Speth C, Rambach G, Würzner R. et al. Complement and platelets: mutual interference in the immune network. Mol Immunol 2015; 67 (01) 108-118
- 19 Oleksowicz L, Mrowiec Z, Zuckerman D, Isaacs R, Dutcher J, Puszkin E. Platelet activation induced by interleukin-6: evidence for a mechanism involving arachidonic acid metabolism. Thromb Haemost 1994; 72 (02) 302-308
- 20 Regnault V, de Maistre E, Carteaux JP. et al. Platelet activation induced by human antibodies to interleukin-8. Blood 2003; 101 (04) 1419-1421
- 21 Pignatelli P, De Biase L, Lenti L. et al. Tumor necrosis factor-alpha as trigger of platelet activation in patients with heart failure. Blood 2005; 106 (06) 1992-1994
- 22 Del Prete G, De Carli M, Lammel RM. et al. Th1 and Th2 T-helper cells exert opposite regulatory effects on procoagulant activity and tissue factor production by human monocytes. Blood 1995; 86 (01) 250-257
- 23 Shim YJ, Hisada Y, Swaidani S. et al. Tissue factor (TF) is upregulated in tumor-bearing mice treated with immune checkpoint inhibitor (ICI). The American Society of Hematolgy 2022; 140 (01) 8393-8394
- 24 Shim YJ, Rayman RP, Pavicic P. et al. Immune checkpoint inhibitors (ICI) promote neutrophil-platelet aggregate and NET formation in tumor-bearing mice. The American Society Hematology 2022; 140 (01) 8365-8366
- 25 Middleton EA, He XY, Denorme F. et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020; 136 (10) 1169-1179
- 26 Alderson MR, Armitage RJ, Tough TW, Strockbine L, Fanslow WC, Spriggs MK. CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40. J Exp Med 1993; 178 (02) 669-674
- 27 Lutgens E, Lievens D, Beckers L, Donners M, Daemen M. CD40 and its ligand in atherosclerosis. Trends Cardiovasc Med 2007; 17 (04) 118-123
- 28 Fernandez DM, Rahman AH, Fernandez NF. et al. Single-cell immune landscape of human atherosclerotic plaques. Nat Med 2019; 25 (10) 1576-1588
- 29 Depuydt MAC, Prange KHM, Slenders L. et al. Microanatomy of the human atherosclerotic plaque by single-cell transcriptomics. Circ Res 2020; 127 (11) 1437-1455
- 30 Gong J, Drobni ZD, Alvi RM. et al. Immune checkpoint inhibitors for cancer and venous thromboembolic events. Eur J Cancer 2021; 158: 99-110
- 31 Bu DX, Tarrio M, Maganto-Garcia E. et al. Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler Thromb Vasc Biol 2011; 31 (05) 1100-1107
- 32 Poels K, van Leent MMT, Reiche ME. et al. Antibody-mediated inhibition of CTLA4 aggravates atherosclerotic plaque inflammation and progression in hyperlipidemic mice. Cells 2020; 9 (09) 1987
- 33 Poels K, van Leent MMT, Boutros C. et al. Immune checkpoint inhibitor therapy aggravates T cell-driven plaque inflammation in atherosclerosis. JACC Cardiooncol 2020; 2 (04) 599-610
- 34 Poels K, Neppelenbroek SIM, Kersten MJ, Antoni ML, Lutgens E, Seijkens TTP. Immune checkpoint inhibitor treatment and atherosclerotic cardiovascular disease: an emerging clinical problem. J Immunother Cancer 2021; 9 (06) e002916
- 35 Moik F, Chan WE, Wiedemann S. et al. Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Blood 2021; 137 (12) 1669-1678
- 36 Sussman TA, Li H, Hobbs B, Funchain P, McCrae KR, Khorana AA. Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival. J Immunother Cancer 2021; 9 (01) e001719
- 37 Sheng IY, Gupta S, Reddy CA. et al. Thromboembolism in patients with metastatic renal cell carcinoma treated with immunotherapy. Target Oncol 2021; 16 (06) 813-821
- 38 Sheng IY, Gupta S, Reddy CA. et al. Thromboembolism in patients with metastatic urothelial cancer treated with immune checkpoint inhibitors. Target Oncol 2022; 17 (05) 563-569
- 39 Alma S, Eloi D, Léa V. et al. Incidence of venous thromboembolism and discriminating capacity of Khorana score in lung cancer patients treated with immune checkpoint inhibitors. J Thromb Thrombolysis 2022; 54 (02) 287-294
- 40 Roopkumar J, Swaidani S, Kim AS. et al. Increased Incidence of Venous Thromboembolism with Cancer Immunotherapy. Med (N Y) 2021; 2 (04) 423-434
- 41 Abdel-Razeq H, Sharaf B, Al-Jaghbeer MJ. et al. COMPASS-CAT versus Khorana risk assessment model for predicting venous thromboembolic events in patients with non-small cell lung cancer on active treatment with chemotherapy and/or immunotherapy, the CK-RAM study. J Thromb Thrombolysis 2023; 56 (03) 447-453
- 42 Cánovas MS, Garay DF, Moran LO. et al. Immune checkpoint inhibitors-associated thrombosis in patients with lung cancer and melanoma: a study of the Spanish society of medical oncology (SEOM) thrombosis and cancer group. Clin Transl Oncol 2022; 24 (10) 2010-2020
- 43 Ando Y, Hayashi T, Sugimoto R. et al. Risk factors for cancer-associated thrombosis in patients undergoing treatment with immune checkpoint inhibitors. Invest New Drugs 2020; 38 (04) 1200-1206
- 44 le Sève JD, Guédon AF, Bordenave S. et al. Risk factors of venous thromboembolic disease in cancer patients treated with immune checkpoint inhibitor. Thromb Haemost 2023; 123 (11) 1049-1056
- 45 Icht O, Darzi N, Shimony S. et al. Venous thromboembolism incidence and risk assessment in lung cancer patients treated with immune checkpoint inhibitors. J Thromb Haemost 2021; 19 (05) 1250-1258
- 46 He X, Wei SN, Qin WW. et al. Evaluating the effect of immune checkpoint inhibitors on venous thromboembolism in non-small cell lung cancer patients. Expert Rev Hematol 2023; 16 (12) 1135-1142
- 47 Overvad TF, Skjøth F, Piazza G. et al. The Khorana score and venous and arterial thrombosis in patients with cancer treated with immune checkpoint inhibitors: a Danish cohort study. J Thromb Haemost 2022; 20 (12) 2921-2929
- 48 Solinas C, Saba L, Sganzerla P, Petrelli F. Venous and arterial thromboembolic events with immune checkpoint inhibitors: a systematic review. Thromb Res 2020; 196: 444-453
- 49 Frere C, Ederhy S, Salem JE. Letter to the editors-in-chief reply to: Solinas et al. Venous and arterial thromboembolic events with immune check point inhibitors: a systematic review. Thromb Res 2021; 208: 214-216
- 50 Bar J, Markel G, Gottfried T. et al. Acute vascular events as a possibly related adverse event of immunotherapy: a single-institute retrospective study. Eur J Cancer 2019; 120: 122-131
- 51 Chitturi KR, Xu J, Araujo-Gutierrez R. et al. Immune checkpoint inhibitor-related adverse cardiovascular events in patients with lung cancer. JACC Cardiooncol 2019; 1 (02) 182-192
- 52 Dolladille C, Akroun J, Morice PM. et al. Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis. Eur Heart J 2021; 42 (48) 4964-4977
- 53 Drobni ZD, Alvi RM, Taron J. et al. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 2020; 142 (24) 2299-2311
- 54 Calabretta R, Hoeller C, Pichler V. et al. Immune checkpoint inhibitor therapy induces inflammatory activity in large arteries. Circulation 2020; 142 (24) 2396-2398
- 55 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111 (10) 4902-4907
- 56 Iwai C, Jo T, Konishi T. et al. Thrombotic risk of platinum combination chemotherapy with and without immune checkpoint inhibitors for advanced non-small cell lung cancer: a nationwide inpatient database study. Cancer Immunol Immunother 2023; 72 (11) 3581-3591
- 57 Key NS, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO guideline update. J Clin Oncol 2023; 41 (16) 3063-3071
- 58 Schneider BJ, Naidoo J, Santomasso BD. et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 2021; 39 (36) 4073-4126
- 59 Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J 2021; 11 (04) 69
- 60 Lee DW, Santomasso BD, Locke FL. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019; 25 (04) 625-638
- 61 Jain MD, Smith M, Shah NN. How I treat refractory CRS and ICANS after CAR T-cell therapy. Blood 2023; 141 (20) 2430-2442
- 62 Wang Y, Qi K, Cheng H. et al. Coagulation disorders after chimeric antigen receptor T cell therapy: analysis of 100 patients with relapsed and refractory hematologic malignancies. Biol Blood Marrow Transplant 2020; 26 (05) 865-875
- 63 Jiang H, Liu L, Guo T. et al. Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy. Ann Hematol 2019; 98 (07) 1721-1732
- 64 Wang X, Li C, Luo W. et al. IL-10 plus the EASIX score predict bleeding events after anti-CD19 CAR T-cell therapy. Ann Hematol 2023; 102 (12) 3575-3585
- 65 Buechner J, Grupp SA, Hiramatsu H. et al. Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy. Blood Adv 2021; 5 (02) 593-601
- 66 Galli E, Sorà F, Hohaus S. et al. Endothelial activation predicts disseminated intravascular coagulopathy, cytokine release syndrome and prognosis in patients treated with anti-CD19 CAR-T cells. Br J Haematol 2023; 201 (01) 86-94
- 67 Johnsrud A, Craig J, Baird J. et al. Incidence and risk factors associated with bleeding and thrombosis following chimeric antigen receptor T-cell therapy. Blood Adv 2021; 5 (21) 4465-4475
- 68 Juluri KR, Wu QV, Voutsinas J. et al. Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy. Blood Adv 2022; 6 (07) 2055-2068
- 69 Ayuk F, Gagelmann N, von Tresckow B. et al. Real-world results of CAR T-cell therapy for large B-cell lymphoma with CNS involvement: a GLA/DRST study. Blood Adv 2023; 7 (18) 5316-5319
- 70 Rejeski K, Perez A, Sesques P. et al. CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood 2021; 138 (24) 2499-2513
- 71 Hines MR, Knight TE, McNerney KO. et al. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. Transplant Cell Ther 2023; 29 (07) 438.e1-438.e16
- 72 Valade S, Azoulay E, Galicier L. et al. Coagulation disorders and bleedings in critically ill patients with hemophagocytic lymphohistiocytosis. Medicine (Baltimore) 2015; 94 (40) e1692
- 73 Song Z, Tu D, Tang G. et al. Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. Haematologica 2023; 108 (08) 2067-2079
- 74 Mei H, Chen F, Han Y. et al. Chinese expert consensus on the management of chimeric antigen receptor T cell therapy-associated coagulopathy. Chin Med J (Engl) 2022; 135 (14) 1639-1641
- 75 Santomasso BD, Nastoupil LJ, Adkins S. et al. Management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy: ASCO guideline. J Clin Oncol 2021; 39 (35) 3978-3992
- 76 Yang Y, Peng H, Wang J, Li F. New insights into CAR T-cell hematological toxicities: manifestations, mechanisms, and effective management strategies. Exp Hematol Oncol 2024; 13 (01) 110
- 77 Hashmi H, Mirza AS, Darwin A. et al. Venous thromboembolism associated with CD19-directed CAR T-cell therapy in large B-cell lymphoma. Blood Adv 2020; 4 (17) 4086-4090
- 78 Parks AL, Kambhampati S, Fakhri B. et al. 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; 62 (04) 1003-1006
- 79 Melody M, Gandhi S, Saunders H. et al. Incidence of thrombosis in relapsed/refractory B-cell lymphoma treated with axicabtagene ciloleucel: Mayo Clinic experience. Leuk Lymphoma 2022; 63 (06) 1363-1368
- 80 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; 24 (09) 8349
- 81 Bindal P, Patell R, Chiasakul T. et al. A meta-analysis to assess the risk of bleeding and thrombosis following chimeric antigen receptor T-cell therapy: communication from the ISTH SSC Subcommittee on Hemostasis and Malignancy. J Thromb Haemost 2024; 22 (07) 2071-2080
- 82 Moreno-Castaño AB, Fernández S, Ventosa H. et al. 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; 11 (04) e006365
- 83 Friedrich MJ, Neri P, Kehl N. et al. The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients. Cancer Cell 2023; 41 (04) 711-725.e6
- 84 Balendran S, Tam C, Ku M. T-cell engaging antibodies in diffuse large B cell lymphoma - an update. J Clin Med 2023; 12 (21) 6737
- 85 Kantarjian H, Stein A, Gökbuget N. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017; 376 (09) 836-847
- 86 Goebeler ME, Bargou RC. T cell-engaging therapies - BiTEs and beyond. Nat Rev Clin Oncol 2020; 17 (07) 418-434
- 87 Betof Warner A, Corrie PG, Hamid O. Tumor-infiltrating lymphocyte therapy in melanoma: facts to the future. Clin Cancer Res 2023; 29 (10) 1835-1854