Checkpoint Inhibitors, CAR T Cells, and the Hemostatic System: What Do We Know So Far?

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 - cancer

Introduction

Fig. 1 Proposed pathomechanisms contributing to thromboembolic and hemorrhagic complications in patients receiving checkpoint inhibitors and CAR T cells. Left side: Checkpoint blockade leads to hyperactive T cells secreting inflammatory cytokines and chemokines, activating other immune cells, inducing thromboinflammatory monocytes, and facilitating endothelial cell activation and plaque progression. Right side: CAR T cell therapy induces CRS and ICANS due to excessive immune activation. Rapidly proliferating CAR T cells release large amounts of proinflammatory cytokines, resulting in hypofibrinogenemia, hemostatic alterations, and – together with prior lymphodepletion therapy – reduced platelet counts. [rerif]Abbreviations: ATE, arterial thromboembolism; CRS, cytokine release syndcrom; ICAM1, intercellular adhesion molecule-1; ICANS, immune effector cell-associated neurotoxicity syndrome; NETS, neutrophil extracellular traps; TE, thromboembolism; TF, tissue factor; VCAM1, vascular cell adhesion molecule-1; VTE, venous thromboembolism.

The discovery that the human immune system can be switched toward an inflammatory cell-based anticancer environment has significantly changed the outcome of many cancer entities that had previously been associated with very poor prognoses. Immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells are both therapies that induce a hyperinflammatory milieu in the treated patient. ICIs exert their effect by enabling “dormant” T cells to become fully reactivated and regain their antitumoral immune effects. CAR T cells are autologous T cells that have been genetically modified before being retransfused into circulation with the aim to recognize and kill cancer cells.

A hyperactive immune system, however, comes with a downside: Inflammatory T cells without breaks can directly or indirectly lead to the activation of other blood cells of the innate and adapted immune system. In particular, proinflammatory myeloid cells such as monocytes and macrophages in combination with hyperactive T cells result in an overabundance of inflammatory cytokines and chemokines. An exacerbated immune response not only triggers autoimmune-like adverse events such as thyroiditis or pneumonitis as observed under ICIs but also provides the basis for potentially severe thromboembolic complications.

In this review, we will discuss potential underlying pathophysiologic mechanisms of thromboinflammation under ICIs and CAR T cells. We will look at observed venous and arterial thromboembolic events (VTE, ATE) and analyze proposed clinical and laboratory markers that may be useful in predicting thromboembolic complications under immune therapies. To assess the current studies and publications on these topics, the following keywords were used for our PubMed search: “immune checkpoint inhibitors,” “CAR T,” “CAR T cells,” “thrombosis,” ”coagulation,” “venous thromboembolism,” “arterial thromboembolism,” and “cardiovascular adverse events.”

Cancer-Associated Thromboembolism

Cancer patients have a four- to nine-fold increased risk of VTE, and a two-fold increased risk of ATE compared with the general population. Importantly, the development of thrombosis in these patients is associated with elevated morbidity and mortality.[1] [2] [3] [4] Various clinical risk factors including immobility, cachexia, compression of blood vessels, and type and stage of cancer enhance the risk of developing cancer-associated thrombosis. At the molecular and cellular level, increased expression of procoagulant tissue factor (TF) on cancer cells, shedding of TF-bearing microvesicles (MVs) into circulation, endothelial cell and platelet activation, and release of neutrophil extracellular traps (NETs) by activated neutrophils have been shown to promote a procoagulant plasma milieu in cancer patients.[5] Importantly, several cancer treatments might increase the thrombotic risk, either directly through the pharmacodynamic characteristics of cytotoxic drugs that induce cancer cell apoptosis with cellular TF expression and/or release of proinflammatory cytokines or through constitutional factors (e.g., hospitalization, application via central venous catheters).[6] [7] Among the different types of systemic anticancer therapeutics, immunotherapy was found to have one of the highest 12-month VTE incidence rates when assessing Danish population-based health registries.[3]

ICIs and CAR T cells both represent a novel mechanistic approach to cancer treatment, where the patient's own anticancer immunity is artificially enhanced. A prolonged hyperinflammatory milieu, caused by repeated administration of immune-enhancing medication or the persistent presence of activated T cells, may promote coagulation and atherosclerosis, similar to what is observed in chronic inflammatory conditions.[8] [9] With the emerging and increasingly widespread use of these therapeutics, the question arises whether enhanced immunity will predispose cancer patients to an elevated risk of coagulopathies.

Immune Checkpoint Inhibitors—Enhancers of the Anticancer Immune System

Immune checkpoints are immunomodulatory proteins on the surface of T cells, myeloid cells, and cancer cells. Of these, programmed cell death protein 1 (PD-1), its ligand programmed cell death protein ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) expressed by activated T cells, tumor cells, or tumor-associated macrophages are established therapeutic targets to intervene with cancer-induced immunosuppression.[10] [11]

Under chronic inflammatory conditions such as malignancies, activated (tumor-specific) T cells upregulate PD-1 on their surface. Interaction of T cell PD-1 with inhibitory PD-L1 on tumor cells or tumor-associated macrophages will eventually suppress T cell cytokine production and proliferation. Subsequently, the effector function of the involved T cell drastically decreases, resulting in impaired cytotoxicity and cytokine secretion, thereby allowing the tumor cells to escape immune surveillance and disseminate within the body. Thus, while increased PD-1 expression is a physiologic mechanism to counteract enhanced immune responses under infection and inflammation, this protection system is hijacked by various cancers to escape immunity.[12] The unraveling of cancer cell-mediated immunosuppression via immune checkpoints has led to the development of ICIs. By blocking PD-1, PD-L1, or CTLA-4, ICIs disrupt the inhibitory interaction of cancer cells and tumor-associated macrophages with cytotoxic T cells. Consequently, T cells become active again and regain their ability to target and kill cancer cells.[10] Since their introduction in 2011, ICIs have dramatically improved the therapeutic outcome of cancers that had previously been associated with very poor overall survival. Currently, the FDA has approved nine ICIs for the treatment of at least 20 different types of cancer, most notably malignant melanoma, lung cancer, head-and-neck squamous cell carcinoma, and cancers of the urogenital, gastroesophageal, and hepatobiliary systems. ICIs are indicated for primary therapy and for the treatment of recurrence, in (neo)adjuvant settings and as maintenance therapy. They are used as a single agent or in combination with other ICIs, chemotherapy, or targeted therapy. Common side-effects under ICIs are immune-related adverse events (irAEs) which result from the dysregulated, hyperactive immune response and can affect almost every organ, most importantly the liver, thyroid, lungs, and intestines.[13] Hence, does immunotherapy also disrupt normal hemostasis?

What Are Possible Underlying Mechanisms of ICI-Associated Thrombosis?

Mechanistically, thrombosis triggered by ICI-induced inflammation, summarized in the term “thromboinflammation,” is plausible. Thrombosis in both venous and arterial vessels of the extremities and visceral organs as well as within the cardio- and cerebrovascular system stems from (chronic) inflammation and is mainly driven by activated monocytes and platelets.[14] An elevated immune response under ICIs may therefore create a fertile ground to switch both cell types toward a proinflammatory phenotype: Following immune checkpoint blockade, “dormant” T cells regain their ability to target and kill cancer cells. As a result, cytotoxic tumor-specific T cells secrete inflammatory cytokines such as interferon γ (IFN-γ) which may then stimulate and activate other innate and adaptive immune cells.[10] Of these, specifically activated monocytes and macrophages secrete a plethora of inflammatory mediators including interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α).[15] [16] [17] This is demonstrated by enhanced platelet adhesion properties to the endothelium, elevated platelet aggregation, and release of procoagulant mediators (e.g., thromboxane A2) stored in platelet granules under inflammatory conditions.[18] [19] [20] [21] Direct T cell-to-monocyte contact as well as T cell-derived IFN-γ induces upregulation of procoagulant TF, the principal initiator of the extrinsic part of the coagulation cascade, on the monocyte surface resulting in enhanced thrombin generation.[22] Intriguingly, in a murine colon cancer model, ICI enhanced TF expression on tumor cells and tumor-associated immune cells.[23] In the same murine cancer model, ICI also promoted the formation of neutrophil-platelet aggregates and neutrophil-extracellular traps (NETs), both of which play crucial roles in thromboinflammation.[24] NETs are derived from activated neutrophils, comprising chromatin, histones, myeloperoxidase, and elastases. In inflammatory settings and in cancer, NETs contribute to thromboembolic complications, and, hence, may also induce coagulation activation in ICI patients.[25] Additionally, IFN-γ induces monocyte CD40 expression[26] which with its ligand CD40L on T cells initiates and drives atherosclerosis.[27] Next to macrophages, T cells are the predominant immune cell type in atherosclerotic plaques and have been found to express high levels of PD-1 as an exhaustion marker.[28] [29] Hence, ICIs might accelerate plaque progression and rupture by generating (hyper)active T cells. This hypothesis is supported by findings from a clinical study in which patients treated with ICI experienced a faster rate of atherosclerotic plaque progression compared with the rate prior to ICI treatment.[30] Several studies on hyperlipidemic mouse models with knockout or genetic modification of PD-1, PD-L1, or CTLA-4 demonstrated an aggravation of atherosclerosis as shown by faster plaque progression when these immune checkpoints were deficient or inhibited.[31] [32] [33] The resulting murine phenotypes were characterized by higher numbers of circulating CD4⁺ and CD8⁺ cells and macrophages. Experimental mice also showed elevated T cell activity and expressed higher levels of IFN-γ and TNF-α and of endothelial cell activation markers vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1).[31] [32] [33] Vice versa, overexpression of CTLA-4 was associated with reduced atherosclerosis in hyperlipidemic mice.[34]

Based on these preclinical findings, it is tempting to speculate that ICI-associated inflammation might activate platelets, induce thromboinflammatory monocytes, and trigger T cell-driven initiation and progression of plaque lesions, thereby exacerbating atherosclerotic and thromboembolic complications in cancer patients undergoing this type of treatment.

Is There a High Thromboembolic Risk under ICIs?

While phase II and phase III pivotal clinical ICI trials did not report thromboembolic events (TE), most probably due to underreporting since such vascular complications were not specifically listed as adverse events in the respective study protocols, findings from several population-based meta-analyses and retrospective studies now suggest an enhanced risk of VTE in cancer patients treated with ICIs. Most of these studies included patients with non-small cell lung cancer (NSCLC) and malignant melanoma in a metastasized state ([Table 1]).

Table 1 Studies suggesting an increased risk for thromboembolism during ICI treatment

No. of patients (cancer types)	Design	VTE	ATE	Risk factors	Reference
• 672 (melanoma, NSCLC, RCC, HNSCC, urothelial cancer)	• Singe-center retrospective cohort study	• CI over median follow-up 8.5 mo: 12.9% • CI over 6 mo: 5%	• CI over median follow-up 8.5 mo: 1.8% • CI over 6 mo: 1%	VTE: • Prior VTE	Moik et al, 2021[35]
• 228 (melanoma)	• Single-center retrospective cohort study	• CI over median follow-up 27.3 mo: 16.2% • CI over 6 mo: 8%	• CI over median follow-up 27.3 mo: 6.1% • CI over 6 mo: 2.2%	VTE: • Combination ICI therapy • KS ≥1 • CAD • Anticoagulants	Sussmann et al, 2021[36]
• 279 (urothelial cancer)	• Singe-center retrospective cohort study	• CI over median follow-up 5.6 mo: 13%	• CI over median follow-up 5.6 mo: 2%	No significant associations	Sheng et al, 2022[37]
• 351 (RCC)	• Singe-center retrospective cohort study	• CI over median follow-up 12.8 mo: 11%	• CI over median follow-up 12.8 mo: 2%	No significant associations	Sheng et al., 2021[38]
• 481 (lung cancer)	• Singe-center retrospective cohort study	• CI over median follow-up 9.8 mo: 9.8%	n.a.	VTE: • Metastatic disease	Alma et al, 2022[39]
• 1,686 (miscellaneous, mostly lung cancer and melanoma)	• Singe-center retrospective cohort study	• CI over median follow-up 438 d: 24% • CI over 6 mo: 7.13%	n.a.	VTE: • Metastatic disease, advanced tumor stage • Younger age • MDSC • IL8 • sVCAM-1	Roopkumar et al, 2021[40]
• 2,854 (miscellaneous, mostly NSCLC and melanoma)	• Singe-center retrospective cohort study	• CI over median follow-up 194 d: 8.5% • CI over 6 mo: 7.4%	n.a.	VTE • Moderately younger age • Prior VTE	Gong et al, 2023[30]
• 508 (NSCLC, different types of anticancer therapy)	• Singe-center retrospective cohort study	• VTE rates higher under ICI therapy: 23.5 vs. 13.8% (p < 0.05)	n.a.	n.a.	Abdel-Razeq et al, 2023[41]
• 665 (lung cancer) • 291 (melanoma)	• Multicenter retrospective cohort study	• CI over median follow-up 14 mo: 6.9% • CI over median follow-up 17 mo: 4.8%	• CI over median follow-up 14 mo: 2% • CI over median follow-up 17 mo: 1%	Lung cancer (VTE/ATE): • Hb < 10.9 g/dL • NLR > 4.55 • Prior TE Melanoma (VTE/ATE): • LDH ≥ 198 U/L • NLR ≥ 3.01	Cánovas et al, 2022[42]
• 122 (miscellaneous)	• Single-center retrospective cohort study	• CI: 8.4% (median follow-up not provided)	n.a.	VTE • Prior TE	Ando et al, 2020[43]
• 374 (melanoma, NSCLC)	• Single-center retrospective cohort study	• CI over median follow-up 15.2 mo: 13.4%	n.a.	• Combined ICI Presence of IrAE	le Sève et al, 2023[44]
• 35,218 (miscellaneous)	• Systematic review, meta-analysis of 63 RCT	n.a.	• Risk for cerebral arterial ischemia: 8.8 per 1,000 patients • Risk for MI: 7.4 per 1,000 patients	n.a.	Dolladille et al, 2021[52]
• 2,842 (miscellaneous, mostly lung cancer and melanoma under ICI therapy) • 2,842 matched controls • Subgroup of 40 patients before and under ICI therapy	• Single-center retrospective matched-cohort study • Case-crossover study	n.a.	• Risk for ATE 3.3-fold higher under ICI therapy (p < 0.001) • 3-fold increased risk in atherosclerotic plaque progression	• No arterial hypertension (HR, 10.7 vs. 3.4)	Drobni et al, 2020[53]

Abbreviations: ATE, arterial thromboembolism; CAD, coronary artery disease; CI, cumulative incidence; HNSCC, head and neck squamous cell carcinoma; IL8, interleukin 8; IrAE, immune-related adverse events; KS, Khorana score; LDH, lactate dehydrogenase; n.a., not assessed; MDSC, myeloid-derived suppressor cells; MI, myocardial infarction; NLR, neutrophil-lymphocyte ratio; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; RCT, randomized controlled trials; sVCAM, soluble vascular cell adhesion molecule 1; TE, thromboembolism; VTE, venous thromboembolism; U/L, units/Liter.

VTE incidence rates in ICI-treated patients ranged from 4.4 to 24.4%, with a median time to VTE onset of ∼4 to 5 months ([Table 1]). Studies report varying VTE rates across cancer types including most commonly NSCLC, and malignant melanoma, but also including renal cell carcinoma (RCC), head-and-neck squamous cell carcinoma, and urothelial and gynecological cancer. Higher incidences were typically observed early in treatment and were often associated with poorer outcomes and higher mortality.[30] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44]

Other studies and meta-analyses do not find a difference in VTE risk or even suggest a lower VTE risk under ICI treatment compared with chemotherapy or targeted therapy ([Table 2]).[45] [46] [47] [48] In this regard, a large meta-analysis of 20,273 patients from 68 studies revealed a low VTE incidence rate of 2.7%, mostly related to ICIs targeting PD-1. In this analysis, the majority of studies did not show higher VTE incidences compared with standard treatments.[48] However, it is important to critically comment that this meta-analysis is limited by underreporting of thromboembolic events, as most of the included studies did not evaluate TE as a primary endpoint, along with several other methodological flaws.[49]

Table 2 Studies not suggesting an increased risk for thromboembolism during ICI treatment

No. of patients (cancer types)	Design	VTE	ATE	Risk factors	Reference
• 3,946 (miscellaneous),	• Population-based, retrospective cohort study	• CI over 6 mo: 2.6%	• CI over 6 mo: 1.3%	VTE/any TE: • KS ≥2	Overvad et al, 2022[47]
• 20,273 patients (miscellaneous)	• Systematic review	• Incidence rate: 2.7%	• Incidence rate: 1.1%	VTE: • Advanced disease stage • Cancer type (e.g., genitourinary, pancreatic, and gynecological tumors)	Solinas et al, 2020[48]
• 345 (NSCLC, starting either ICI or platinum-based therapy)	• Singe-center retrospective cohort study	• CI over 6 mo: 4.5% (compared with 7.1% in the chemotherapy cohort)	n.a.	No significant association with KS	Icht et al, 2021[45]
• 730 (NSCLC, different types of anti-cancer therapy)	• Single-center retrospective cohort study	• ICI associated with reduced risk (OR 0.529; p = 0.028)	n.a.	n.a.	He et al, 2023[46]
• 1,215 (miscellaneous) Subgroup analysis: • 159 (NSCLC with platinum-based chemotherapy) • 92 (NSCLC with ICI therapy) • 125 (NSCLC with ICI and chemotherapy)	• Single-center retrospective cohort study	• n.a.	• CI over 6 mo: 2.6% Vascular event rate (chemotherapy vs. ICI vs. ICI and chemotherapy): 4.4 vs. 6.5 vs. 5.6%	ATE: • NSCLC • Prior CVD • Arterial hypertension Dyslipidemia	Bar et al, 2019[50]
• 252 (lung cancer, with or without ICI therapy)	• Single-center retrospective cohort study	n.a.	• CI of MACE over 6 mo (ICI vs. non-ICI therapy): 13.3 vs. 10.3% (HR 1.18; p = 0.66)	ATE: • Troponin I > 0.01 ng/mL • BNP > 100 pg/mL • Combined therapy with anti-VEGF or TKIs	Chitturi et al, 2019[51]

Abbreviations: ATE, arterial thromboembolism; BNP, B-type natriuretic peptide; CI, cumulative incidence; CVD, cardiovascular disease; KS, Khorana score; MACE, major adverse cardiovascular events; n.a., not assessed; NSCLC, non-small cell lung cancer; OR, odds ratio; TE, thromboembolism; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VTE, venous thromboembolism.

Arterial thromboembolism (ATE) and cardiovascular adverse events, including myocardial infarction and ischemic stroke, have been observed under ICI treatment: Overall 6-month incidences of ATE (myocardial infarction, ischemic stroke, or systemic embolism) have been reported to range from 1 to 2.6% in population-based cohort studies on cancer patients receiving ICIs[35] [47] [48] [50] [51] [52] ([Tables 1], [2]). A systematic review and meta-analysis of randomized controlled trials (RCTs) found that IC substantially increased the risk of cerebral arterial ischemia and myocardial infarction.[52] In a matched cohort study on 2,842 patients treated with ICIs and 2,842 age-, cancer type-, and medical history-matched controls, there was a four-fold higher risk of composite cardiovascular events. Within the individual endpoints, ICI therapy was associated with a seven-fold higher risk of myocardial infarction and a four-fold increased risk of ischemic stroke (as estimated by univariate analysis). An elevated cardiovascular risk was confirmed by a case-crossover study design on the ICI cohort when comparing the 2-year interval following ICI therapy with the 2-year interval prior to therapy.[53] In 40 melanoma patients, ICI led to a significant increase in atherosclerotic plaque volume, as seen in CT scans at three timepoints, compared with their measurements before ICI treatment.[53] Similarly, after 4.4 months of ICI treatment, ¹⁸F-FDG/positron emission tomography (PET)-computed tomography (CT) showed an elevated arterial fluorodeoxyglucose (FDG) uptake, especially in non- or mildly calcified arterial regions, pointing toward a mechanistic role for ICIs in very early stages of atherosclerosis.[54]

In contrast, other studies suggest that ICIs carry a similar risk of vascular adverse events as chemo- or targeted therapy: In a retrospective analysis of 1,215 ICI-treated patients, 2.6% developed an acute vascular event within the first 6 months. In this cohort, the 5.2% event rate among lung cancer patients within this cohort was not significantly higher compared with those receiving chemotherapy alone or ICIs combined with chemotherapy[50] [51] ([Table 2]).

In summary, the overall incidence remains mixed. The inconclusive findings may be attributed to the diverse patient cohorts, cancer types and stages, variations in study designs and methodologies, as well as lack of comparable cohorts undergoing standard treatment, which complicates drawing definitive conclusions.

Nonetheless, a consistent finding across these studies is that TE tends to occur early, typically within the first 6 months after ICI initiation, and is associated with high mortality and worse treatment outcomes.[30] [35] [36] [39] [40]

Clinical and Laboratory Risk Factors for ICI-Associated Thromboembolism

Several clinical and laboratory risk factors were identified by the studies and analyses discussed above. Traditionally, the Khorana score has been established and validated as a clinical tool to assess the VTE risk in ambulatory cancer patients receiving chemotherapy when ICIs were not yet in use. It integrates both laboratory (hemoglobin level, platelet, and leukocyte counts) and clinical parameters (cancer type, BMI) to perform a comprehensive risk assessment.[55] However, the applicability of the Khorana score for predicting VTE risk in patients under ICI therapy appears limited due to a lack of conclusive evidence. The majority of studies have shown that the Khorana score did not accurately predict VTE risk in various ICI patient cohorts.[35] [39] [42] [45] VTE risk did not differ between types or targets of ICIs.[30] [35] [40] [42] [48] Combination of ICIs such as nivolumab and ipilimumab is particularly associated with a higher probability of irAEs. However, only a few studies so far have observed an increased risk of VTE with ICI combination therapy,[36] [44] while the majority of analyses and publications did not find a significant difference between single ICI and ICIs in combination with other ICIs, chemotherapy, or radiation therapy.[40] [48] In contrast, adding ICIs to platinum-based chemotherapy was associated with an enhanced VTE risk in NSCLC patients in a Japanese database analysis.[56]

History of VTE was a frequent risk factor linked to ICI-associated VTE.[30] [35] [42] [43] Unfortunately, most of these studies do not specify whether patients with prior VTE were under anticoagulant therapy when receiving ICI. Notably, in one study with 228 melanoma patients, anticoagulant therapy, regardless of prior VTE at ICI treatment start, was associated with a higher VTE incidence rate.[36] Intake of anticoagulants was derived from provider prescriptions and it was unclear if patients continued taking these medications during ICI therapy. Additionally, anticoagulants may simply indicate other underlying comorbidities that reflect a higher VTE risk.[36] Importantly, while anticoagulant therapy did not predict an elevated VTE risk under ICI therapy, it attenuated the VTE risk in another retrospective study on 2,854 patients, mostly with NSCLC and melanoma.[30]

Traditional risk factors for CT, such as metastatic disease or older age, have not consistently been shown to increase VTE risk.[39] [40] In contrast, moderately younger age was associated with a higher VTE incidence rate under ICI treatment in three studies.[30] [36] [40] Other solitary risk factors for ICI-associated VTE in NSCLC were a history of antiangiogenic therapy and chronic obstructive pulmonary disease.[46] In patients with NSCLC starting ICI, a neutrophil/lymphocyte ratio (NLR) >4.5 and hemoglobin (Hb) levels <10.9 g/dL have been identified as significant predictors of VTE and ATE. Similarly, in melanoma patients undergoing ICI treatment, an NLR of ≥3.01 or higher and lactate dehydrogenase (LDH) levels ≥ 198 U/L have been found to be predictive of these thromboembolic events. These markers were determined through both univariate and multivariate analyses.[42] Importantly, increase in markers for systemic inflammation (IL-6) and endothelial cell activation (soluble VCAM1), both of which are linked to thromboinflammation and atherosclerosis, or elevated numbers of myeloid-derived suppressor cells (MDSCs) within peripheral blood mononuclear cells (PBMCs) in samples obtained prior to ICI treatment predicted ICI-associated VTE in selected cohorts.[40] While these findings are very interesting, they lack general evidence.

There is conflicting data available on possible clinical or laboratory parameters that might be useful for risk stratification of ICI-associated arterial adverse events. For example, a multivariate analysis on 252 lung cancer patients identified elevated levels of serum troponin I and B-type natriuretic peptide at baseline or during follow-up as indicators of an increased risk for major adverse cardiovascular events (MACE) under ICI treatment. However, the use of ICIs itself was not found to be directly associated with a higher incidence of MACE.[51] In a retrospective study on 1,215 cancer patients, those who experienced cardiovascular adverse events under ICIs had a higher probability of having arterial hypertension, dyslipidemia, or prior cardiovascular disease.[50] In contrast, despite confirming a significantly elevated risk of cardiovascular events with ICI treatment, those patients who experienced a complication did not differ from those without one with respect to age, sex, BMI, history of cardiovascular events, or diabetes.[53]

Given the conflicting data on TE in ICI patients, the question arises as how to handle thromboprophylaxis and VTE treatment in patients receiving ICIs. In this regard, the updated ASCO guidelines on immune-related adverse events in patients treated with ICIs still refer to the Khorana score to estimate the VTE risk before undergoing treatment, as recommended in the ASCO VTE guidelines.[57] [58] In the event of developing a VTE, ICIs may be continued in the cases of uncomplicated thrombosis but should be halted in the presence of PE and only reintroduced after a thorough risk–benefit assessment.[58]

Ultimately, prospective studies, ideally with a matched control group in a randomized clinical trial, are needed to surpass the limitations (risk of bias, methodology, follow-up times, data accessibility, confounders, etc.) of retrospective analyses. However, this is challenging to implement, given the clear indications for ICIs in most cancer settings and the lack of therapeutically equivalent alternatives. What becomes evident so far is that the TE risk is highest within the first 6 months of ICI therapy but appears to continue increasing beyond this period, and that specifically patients with prior TE might need to be strictly monitored for new events.

Are CAR T Cells Associated with Coagulation Disorders?

CAR T cell therapy is another revolutionary immune therapy that has significantly shaped the therapeutic landscape for relapsed or refractory multiple myeloma (MM), diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma (PMBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and B cell acute lymphoblastic leukemia (B-ALL). In short, circulating T cells are removed from the patient's blood and engineered ex vivo to express CARs that target CD19 on B cell lymphomas or B cell maturation antigen (BCMA) on plasma cells.[59] Once reinfused into the patient, these CAR T cells will target and specifically kill cancer cells of the respective hematologic malignancy through the induction of apoptosis. Up to date, six CAR T cells have been approved by the FDA and EMA for relapsed or refractory B cell lymphoma (Lisocabtagene maraleucel [Liso-cel], Tisagenlecleucel [Tisa-cel], Axicabtagene ciloleucel [Axi-cel]), MM (Idecabtagene vicleucel [Ide-cel], Ciltacabtagene autoleucel [Cilta-cel]), B-ALL (Tisagenlecleucel, Brexucabtagene autoleucel), and MCL (Brexucabtagene autoleucel).

Similar to ICIs, CAR T cells are characterized by a hyperactive immune response and may therefore be prone to thromboinflammatory complications. Cytokine release syndrome (CRS) is a common and potentially severe adverse event (AE) resulting from the excessive secretion and overabundance of inflammatory cytokines IL-6, IFN-γ, TNF-α, and IL-2 (among others) by active T cells. Subsequently, stimulated monocytes and macrophages accelerate the inflammatory response by producing additional inflammatory mediators, leading to a positive proinflammatory feedback loop. CRS typically manifests within 1 to 7 days after CAR T reinfusion, depending on the specific cell product used. Clinical signs and symptoms are fever, chills, hypotension, and hypoxia that are graded from 1 to 4 (5 for death) and may—when severe—necessitate the patient's admission to the intensive care unit. Another severe CAR T cell-induced complication is immune effector cell-associated neurotoxicity (ICANS) which can lead to aphasia, altered level of consciousness, seizures, and cerebral edema. Proposed pathomechanisms include proinflammatory cytokines, myeloid cells, and T cells passing the blood–brain barrier as well as endothelial cell activation.[60]

To mitigate and manage the inflammatory progression of CRS and ICANS, various treatments are employed according to a specific escalation protocol. These include antipyretic therapy and intravenous hydration, followed by the IL-6 receptor antagonist tocilizumab and/or dexamethasone and, when refractory, may require methylprednisolone or other immune modulators such as the IL-1 receptor antagonist anakinra or the Janus kinase 2 (JAK2) inhibitor ruxolitinib.[61]

The few studies investigating coagulopathies under CAR T cell therapy describe very high incidences of hypofibrinogenemia and prolongation of clotting times, affecting up to >50% of patients.[62] [63] [64] However, these laboratory alterations rarely manifest as bleeding.[62] [63] [65] Importantly, coagulation abnormalities mostly occurred in severe CRS or were accompanied by high levels of IL-6 and C-reactive protein.[62] [63] [66] Endothelial cell activation appears to be involved as shown by elevated markers of FVIII and von Willebrand factor.[66] Prolongation in activated partial thromboplastin time and prothrombin time, increase in international normalized ratio, and rise in D-dimers usually occurred on a median of 6 to 7 days, followed by a decrease in fibrinogen on a median of 10 days. Younger age, lower platelets counts, and a higher number of prior therapies were associated with decreased fibrinogen by univariate analysis, and only younger age by multivariate analyses, while tumor burden, sex, and lymphodepletion regimens had no effect.[62]

Bleeding complications following CAR T cell therapy are mostly minor and mainly attributed to thrombocytopenia: In two retrospective studies, clinically significant bleeding (including gastrointestinal, maxillofacial, and intracerebral hemorrhage) were reported in 10% of patients with B cell lymphoma, MM, and B-ALL, and in 9.5% of 127 patients with DLBCL or B-ALL. All hemorrhagic events coincided with the onset of thrombocytopenia, hypofibrinogenemia, or alterations in global coagulation parameters.[62] [67] In another retrospective study on 56 patients with B cell lymphoma and B-ALL, the cumulative incidence of all types of bleeding events within 1 month after CAR T cell therapy was 32.8%. In this patient group, the severity of thrombocytopenia on day 7 and the rise in D-dimer levels on day 14 were both associated with a high cumulative incidence of bleeding events, and elevation of IL-10 and endothelial cell activation markers were predictive of bleeding complications.[64]

Thrombocytopenia is a very common complication following CAR T cell therapy and prior lymphodepletion chemotherapy, affecting a significant proportion of patients. Prolonged thrombocytopenia can last for up to 180 days or even persist, and may result in an increased frequency of hemorrhagic events. Severe thrombocytopenia (CTCAE-grade 3, defined as platelet counts of less than 50.000/µL) has been reported in 21 to 29% of patients after CT T cell therapy.[68] [69] Baseline risk factors such as disease burden, number of previous (chemo-)therapy lines, type of myeloablative chemotherapy, preexisting cytopenias, and bone marrow infiltration contribute to cytopenias after CAR T cell infusion.[70] In addition, the severity of CRS under CAR T enhances the risk of long-lasting low platelet counts.

In summary, both pre-CAR T cell factors and CAR-T-induced CRS contribute to thrombocytopenia and coagulation alterations—most notably, hypofibrinogenemia and elevated D-Dimer levels—that may subsequently lead to bleeding complications, and therefore require close monitoring.

Disseminated intravascular coagulopathy (DIC) is a severe form of coagulopathy with high morbidity and mortality and is characterized by excessive clotting with micro- and macrovascular thromboses. Massive and rapid consumption of coagulation factors due to excessive thrombin generation and fibrin deposition will consequently lead to secondary hyperfibrinolysis and fibrinogen consumption. In CAR T cell studies, the incidence of DIC ranges from 7 to 28%, and DIC mostly occurs in patients with severe CRS.[62] DIC can be linked to hemophagocytic lymphohistiocytosis (HLH), a feared severe and life-threatening complication of CAR T cell-associated CRS, termed immune effector cell-associated HLH-like syndrome (IEC-HS).[71] [72] IEC-HS results from hyperactive and uncontrollable T cells and macrophages that secrete exorbitantly high levels of inflammatory cytokines.[71] In a post-marketing study on CAR T cell-associated hematologic adverse events, HLH (2.7%), coagulopathy (2.5%), and DIC (1.9%) were among the most frequent of 5,112 reported hematologic toxicities reported to the FDA. Importantly, both DIC and HLH had high fatality rates, and must therefore be considered as severe manifestations of inflammation-induced coagulation alterations when treating patients with CAR T cell therapeutics.[73]

Several guidelines and expert consensus recommendations offer strategies for the early detection and management of CAR T cell-associated coagulopathies, including the Chinese expert consensus[74] or the ASCO guidelines.[75] To prevent or reduce the risk of bleeding complications, platelet counts and coagulation parameters should be monitored daily. Platelet counts should be maintained at ≥ 20,000/μL or ≥ 50,000/μL in the presence of bleeding symptoms, and fibrinogen levels should be kept at ≥ 150 mg/dL through appropriate substitution. In cases of developing DIC, the use of IL-6 antagonists, high doses of corticosteroids, and in therapy-refractory cases, intensive immunosuppressive medications are recommended.[74] [75] [76]

In addition to bleeding complications, incidences of VTE in patients treated with CAR T cells for MM and B cell lymphoma have been reported to range from 2.1 to 11%, usually occurring within 3 months after CAR T cell infusion, according to five single-center retrospective studies.[67] [77] [78] [79] [80] A very recently published meta-analysis on 47 studies involving 7,040 patients reported a pooled VTE incidence of 2.4% per patient-month at follow-up until 6 months.[81] The recently published ISTH SSC Subcommittee assessed the risk of VTE to be highest within the first 6 months after CAR T cell infusion.[81] In 148 patients with DLCBL, bulky disease > 10 cm, bridging chemotherapy before receiving CAR T cells, and an Eastern Cooperative Oncology Group (ECOG) status ≥ 2 were significantly associated with a new VTE event following CAR T cell reinsertion in 11% of patients as assessed by univariate analysis. Neither DIC nor bleeding complications were observed in this patient cohort.[77] ICANS ≥ grade 3 and/or severe CRS were predominantly linked to an elevated VTE risk in all studies on thromboembolic complications.[67] [77] [78] [80] Additionally, three of these studies examined the risk of cardiovascular adverse events, finding an incidence of 1% in one of the studies.[67] [78] [80] The association of severe CRS or ICANS and elevated TE risk points to inflammatory mediators secreted by activated adaptive and innate immune cells driving immunothrombosis and endothelial cell activation. In this regard, compared with healthy controls, endothelial cell activation markers including sVCAM-1 as well as NETs as crucial thromboinflammatory drivers were significantly elevated in CAR T cell patients both at baseline (prior to treatment) and following CAR T cell infusion.[82] Hence, it is tempting to speculate that CAR T cell-associated CRS, by inducing endothelial disturbances and coagulation activation, may represent the underlying pathophysiology contributing to TE.

To date, no clear guidelines on thromboprophylaxis or anticoagulant treatment for VTE under CAR T cell therapy have been published. Well-designed clinical trials are needed to determine whether CAR T cell therapy represents a substantial risk factor for thromboembolic complications, and if so, how to address this through appropriate thromboprophylactic strategies.

In conclusion, CAR T cell therapies are frequently linked to thrombocytopenia and coagulopathies, mostly hypofibrinogenemia, in the presence of elevated inflammation. Clinically relevant bleeding and thromboembolic complications following CAR T cell insertion have been reported in a few studies and need to be taken into consideration, particularly when patients develop severe CRS. Since CAR T cells have only very recently been implemented as FDA-approved therapeutic options in selected malignancies, long-term data are still lacking. Many uncertainties remain regarding the duration of CAR T cell persistence and its impact on coagulation abnormalities. Also, the dynamics of CAR T cell toxicities that influence bleeding or thromboembolic complications—or merely result in laboratory hemostatic abnormalities without clinical consequences—remain to be fully elucidated.

Open questions that need to be addressed are as follows: What are clinical and laboratory predictors for TE in CAR T cell therapies, and (how) are they linked to therapeutic outcomes? Is there a risk that hyperreactive T cells could create an inflammatory environment that eventually promotes endothelial cell activation and atherosclerosis (and its severe sequelae such as myocardial infarction)? How can we minimize the risk of CAR T cell-associated thrombohemorrhagic side effects, and, importantly, what is the best acute and long-term management to prevent and treat those complications?

A Look at the Future

Another emerging T cell-associated immunotherapy is bispecific T cell engagers (TCEs) that are designed to recognize tumor-associated antigens and T cell antigens. Combining these two cell epitopes as targets will eventually result in T cell activation and tumor cell lysis.[83] TCEs have been approved for MM, B-ALL, and DLBCL.[83] [84] [85] Importantly, TCEs are associated with hyperinflammation, cytokine release syndrome, and hematologic toxicities.[86] Tumor-infiltrating lymphocyte therapy represents another promising adoptive T cell therapy currently being evaluated in malignant melanoma.[87] Furthermore, multiple phase I–II trials evaluate CAR T cells and TCEs for solid cancers. With the rapid advancement and expanding indications of novel T cell-directed anticancer approaches, there is a growing need to investigate the adverse effects of (chronic) inflammation on coagulation.

Conclusion

In summary, most studies indicate a significant risk of VTE and ATE in patients treated with ICI, and at least coagulation changes are noted in CAR T cell therapy. However, these findings may be biased due to their retrospective nature and heterogeneous study designs. Prospective randomized controlled clinical trials are needed to determine whether immunotherapy further increases the risk of thromboembolic complications in patients already exposed to multiple clinical and cancer-associated risk factors for VTE and ATE. Designing these studies will be challenging since ICI and CAR T cell therapeutics are frequently the primary treatment options in various cancer scenarios and are withheld only in the presence of significant contraindications. Ultimately, since immunotherapy has become an integral part of cancer therapies, clinicians need to pay close attention to coagulation disorders arising from heightened inflammation.

Conflict of Interest

CCR: Grants or contracts from any entity: DFG Research Grant, Roggenbuck-Stiftung, Clemens-Stiftung; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Pfizer; Support for attending meetings and/or travel: Pfizer, LFB, CSL Behring.

SL: has no conflicts of interest

AB-H: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca; Support for attending meetings and/or travel: Octapharma.

LB: Grants or contracts from any entity: Early Career Research Grant of the GTH e.V.; Support for attending meetings and/or travel: CSL Behring, Sobi, Biomarin.

CB: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AOK Germany, Bristol Myers Squipp, med update, Merck Serono, Roche Pharma, Sanofi Aventis; Participation on a Data Safety Monitoring Board or Advisory Board: Astra Zeneca, Bayer Healthcare, BioNTech, Bristol Myers Squipp, Merck Serono, Sanofi Aventis; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: DGHO, Hamburg Cancer Society, National Network of German Cancer Centers, Northern German Society of Internal Medicine; Other financial or non-financial interests: more than 95 clinical trials, Local PI, Institutional, no financial interest, our department is involved in several clinical trials sponsored by industry and cooperative groups where we hold praticipants roles and local PI roles and PI roles.

WA: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Johnson&Johnson, AstraZeneca; Participation on a Data Safety Monitoring Board or Advisory Board: Johnson&Johnson.

MV: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, BeiGene, Pfizer, Bristol-Myers Squibb, Johnson & Johnson; Support for attending meetings and/or travel: Bayer, CSL Behring, LEO Pharma; Participation on a Data Safety Monitoring Board or Advisory Board: BeiGene, Johnson & Johnson.

FL: Consulting fees: Alexion, Aspen, AstraZeneca, Bayer, BioMarin, Bristol Myers Squibb, Chugai, CSL Behring, Daiichi Sankyo, LEO Pharma, Mitsubishi Tanabe Pharma, Novo Nordisk, Pfizer, Roche, SOBI, Takeda, Viatris; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Alexion, Aspen, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, CSL Behring, Daiichi Sankyo, Grifols, Janssen-Cilag, LEO Pharma, Mitsubishi Tanabe Pharma, Novo Nordisk, Pfizer, SOBI, Viatris, Werfen; Participation on a Data Safety Monitoring Board or Advisory Board: Alexion, Aspen, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, CSL Behring, Daiichi Sankyo, Grifols, Janssen-Cilag, LEO Pharma, Mitsubishi Tanabe Pharma, Novo Nordisk, Pfizer, SOBI, Viatris, Werfen; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Secretary of GTH e.V.

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Publication History

Received: 05 August 2024

Accepted: 27 January 2025

Article published online:
07 May 2025