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We read with great interest the review article titled “Checkpoint Inhibitors, CAR T Cells, and the Hemostatic System: What Do We Know So Far?” authored by Rolling CC et al.[1] The authors provide a comprehensive and insightful overview of the current understanding of thromboembolic events associated with immune checkpoint inhibitors (ICIs) and Chimeric antigen receptor T (CAR-T) -cell therapies. They further discuss the pathogenic mechanisms linking inflammation to coagulation activation and explore potential biomarkers for venous and arterial thromboembolism (VTE, ATE) in patients treated with ICI or CAR-T.

ICIs and CAR-T-cell therapies represent novel immunotherapeutic strategies that enhance the host's antitumor immune response. However, the resulting hyperinflammatory milieu, whether due to repeated administration of immunomodulatory agents or persistent T-cell activation, may promote coagulation activation. Unrestrained inflammatory T cells can activate other cells of the innate and adaptive immune system. In particular, their interaction with proinflammatory myeloid cells (monocytes and macrophages) drives an excessive release of cytokines and chemokines.[1] This increased immune response not only contributes to autoimmune-like toxicities such as thyroiditis, colitis, hepatitis and pneumonitis seen with ICIs, but also increases the risk of serious thromboembolic complications.[1] This mechanism parallels that observed in chronic inflammatory diseases. Several population-based meta-analyses and retrospective studies support this hypothesis, reporting an increased risk of VTE and ATE in cancer patients treated with ICIs,[1] particularly in those with metastatic non-small cell lung cancer or malignant melanoma.[2]

The authors present several plausible mechanisms underlying ICI-associated thrombosis. As noted in the review, ICI-induced inflammation may trigger thrombosis via a process termed thromboinflammation”.[3] In this context, the contact system (CS), initiated by Factor XII (FXII), plays a central role by bridging coagulation and inflammation ([Fig. 1]). FXII activation leads to thrombin generation via FXI and, concurrently, inflammation via kallikrein-mediated bradykinin release as illustrated in [Fig. 1].[4] [5]

Fig. 1 Contact system. an interface between inflammation, and coagulation. ATIII: antithrombin, BBB: blood-brain barrier, C1INH; C1 esterase inhibitor, cHK: cleaved high molecular weight kininogen, HK: high molecular weight kininogen, KAL: kallikrein, NETs: neutrophil extracellular traps PK:prekallikrein, FXIIa: activated Factor XII, α2M:α2-macroglobulin.

The emerging interest in the CS reflects its potential contribution to cancer-associated thrombosis.[6] CS activation has been documented in several malignancies, including gastrointestinal,[7] lung,[8] breast,[8] prostate,[9] and pancreatic cancers,[10] as well as leukemia.[11] [12] Multiple tumor-derived or associated components, such as polyphosphates,[9] glycosaminoglycans,[8] cell-free DNA,[11] exomes,[9] activated platelets,[9] [13] or neutrophil extracellular traps (NETs)[12] have been implicated in CS activation, thereby contributing to a prothrombotic state.[6] Given that tissue factor (TF) is frequently upregulated in cancers, the simultaneous activation of the extrinsic (TF-mediated) and intrinsic (CS-mediated) pathways may synergistically enhance thrombin generation and drive a hypercoagulable state.[6]

The CS is a component of both the intrinsic coagulation and inflammatory pathways. It is initiated when FXII binds to negatively charged surfaces such as exposed collagen, polyphosphates, nucleic acids, or when FXII is activatey by misfolded proteins leading to its conversion to FXIIa.[14] FXIIa subsequently activates prekallikrein to kallikrein, which in turn further amplifies FXII activation via a positive feedback mechanism. FXIIa also activates FXI, triggering a coagulation cascade that culminates in thrombin formation and fibrin clot generation. Concurrently, FXIIa and kallikrein cleave high molecular weight kininogen to release bradykinin, a potent inflammatory mediator that induces vasodilation and increases vascular permeability. The contact system is primarily regulated by C1 esterase inhibitor, supported by antithrombin and α2-macroglobulin, which together restrain excessive coagulation and inflammation ([Fig. 1]).[4] [5] [14]

It remains unknown whether ICIs can directly activate the CS. However, we speculate that ICI therapy, via persistent T-cell activation, may indirectly promote FXII activation through immune-mediated endothelial injury. Inflammation and vasculitis of the endothelium expose negatively charged extracellular matrix components that might act as potent activators of FXII.[15] ICIs also promote neutrophil–platelet aggregates and NET formation,[16] and NETs have been implicated in activation of the CS, a key driver of thromboinflammation.[11] We therefore also hypothesize that NET-mediated CS activation may contribute to thromboembolic complications in inflammatory and malignant settings and similarly amplify inflammation and coagulation activation in ICI-treated patients ([Fig. 1]). Despite these plausible connections, no studies to date have systematically investigated the role of CS in ICI-treated cancer patients.

In summary, it is plausible that the CS may play a role in ICI-associated inflammation and thromboembolic complications in cancer patients. However, the contribution of the CS to ICI-related thrombosis has yet to be elucidated. Given the inflammatory profile of ICI therapy, further investigation exploring the role of the CS in thromboinflammatory complications is warranted. A deeper understanding of these mechanisms may facilitate personalized therapeutic strategies with improved safety and efficacy compared to current therapeutic approaches.

Author's Contribution

Mustafa Vakur Bor: Conceptualization, Project administration, Writing - original draft, Writing - review & editing. Ida Korfitz Meklenborg: Writing - review & editing. Rasmus Sogaard. Hansen: Writing - review & editing. Christina Ruhlmann: Writing - review & editing. Yaseelan Palarasah: Writing - review & editing.

Publication History

Received: 21 December 2025

Accepted: 12 January 2026

Article published online:
07 May 2026

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