Using robust genetic datasets, our study comprehensively explored the potential causal relationships between 731 immune cell characteristics and VTE. From a strictly statistical perspective, no significant associations were observed after FDR correction. 44 immune traits indicated potential links to VTE risk, while VTE exposure showed possible associations with 51 immune traits. Notably, CD4 regulatory T cells, in their secreting, activated, or resting states, appeared to suggest a protective trend against VTE. Conversely, an increased risk of VTE may be associated with memory B cells expressing CD20 and basophils expressing CD33. In addition, VTE exposure showed potential links to decreased levels of CD33 + HLA-DR + AC and CD33 + HLA-DR + CD14dim AC, alongside increased HLA-DR expression on dendritic cells, including those of the myeloid and plasmacytoid types.

Regulatory T cells (Tregs), a specific subset of T-lymphocytes, are responsible for maintaining immune tolerance. In various immune responses, they can transition into different states, resting, activated, and secreting, depending on the body’s needs. Resting Tregs suppress immune reactions through contact-dependent mechanisms, while activated Tregs appear after exposure to self-antigens. Secreting Tregs release cytokines but do not have suppressive functions. Our exploratory findings suggested that CD4 regulatory T cells, particularly in their secreting and activated forms, may indicate a potential protective trend against VTE. Conversely, VTE may be linked to increased levels of CD3 regulatory T cells. Previous research has demonstrated that in atherosclerosis, platelets enhance the differentiation and cytokine production of CD4 + T cells, promoting the differentiation of Th1/Th17/Tregs [25]. Another study indicated that platelets simultaneously activate Th1, Th17, and Treg cells within 48 h of co-culture, mediated by transforming growth factor β (TGF-β) [26]. The precise mechanisms linking Treg phenotypes and VTE remain unclear, necessitating further laboratory studies to elucidate and assess the therapeutic potential of targeting CD4 Tregs in VTE.

Our analysis also suggested that B cells expressing CD20 may represent a potential risk factor for VTE, with VTE potentially linked to increased levels of CD20 in these cells. CD20 is expressed during B cell maturation but is not present on stem cells or mature plasma cells. In thrombotic thrombocytopenic purpura (TTP), anti-CD20 monoclonal antibodies have been explored as an initial therapy, although it is not yet standard practice [27]. A meta-analysis indicated that anti-CD20 antibodies can reduce relapse rates and mortality in acute immune-mediated TTP [28]. Similarly, for catastrophic antiphospholipid syndrome (CAPS), characterized by widespread thrombosis, anti-CD20 antibodies have shown efficacy in treating refractory cases [29]. The therapeutic mechanisms of anti-CD20 antibodies include inducing apoptosis, antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) [30]. By selectively depleting B cells, these antibodies may mitigate inflammation and a range of antibody-mediated pathological processes in thrombotic diseases. Further research is required to explore the potential role of CD20 expression in VTE and to evaluate the efficacy of CD20-targeted therapies.

CD33 also appeared as a potential risk factor for VTE, although its relationship with VTE remains underexplored. Research on CD33 monoclonal antibodies has primarily focused on acute promyelocytic leukemia (APL), which is associated with high early mortality due to severe coagulopathy [31]. The potential mechanisms through which anti-CD33 antibodies might influence VTE are not yet understood and require further investigation in future studies.

Our exploratory findings suggest that elevated HLA-DR expression on T cells may be associated with a protective trend against VTE. HLA-DR is involved in the regulation of platelet activation, which may influence thrombotic events. A previous study reported that leukocyte-platelet adhesion indices in blood from coronary occlusion sites were higher than those in peripheral blood in acute myocardial infarction (AMI) patients [32]. This increased leukocyte-platelet interaction at plaque rupture sites may contribute to the “no-reflow” phenomenon in myocardial infarction. Further studies are required to explore the relationship between HLA-DR-expressing cell populations and VTE risk, as well as the underlying mechanisms.

Our exploratory findings suggest potential associations between various immune cell traits and VTE, suggesting the complex interplay between immune responses and thrombosis. These associations were identified using diverse statistical approaches and provide preliminary insights into this relationship. While further validation is needed, these observations may contribute to a better understanding of VTE and immune responses, potentially aiding in early clinical diagnosis, risk stratification, and the development of personalized treatment strategies for VTE.

The relationship between cancer and VTE, especially in the context of immunotherapy, requires further exploration. Immunotherapy can induce immune disturbances that may elevate VTE risk [14, 33, 34], emphasizing the need to address this specific risk in cancer patients undergoing such treatments. These observational studies may require methodological approaches, such as stratified analyses, multivariable regression models, or propensity score adjustments, to better control for residual bias and confounding factors. Observational studies exploring these associations could benefit from methodological approaches, such as stratified analyses, multivariable regression models, or propensity score adjustments, to better control for residual bias and confounding factors. Understanding these interactions could help optimize immunotherapy dosing and management, reducing adverse effects and improving outcomes. However, due to the inherent limitations of observational studies, future research using appropriate GWAS datasets for Mendelian Randomization analysis or well-designed randomized controlled trials (RCTs) is necessary to provide more robust evidence and deepen our understanding of these intricate relationships.

Limitations of the Study: The GWAS datasets used were mainly from European populations, which limits the generalizability of our findings. Including data from Asian or African populations would enhance the robustness of the conclusions. While MR offers suggestive evidence of causality, it still requires further experimental validation to confirm these associations. Additionally, MR is designed to assess overall causal effects but cannot detect dynamic changes in immune cell traits across different stages of disease progression.

Diagram illustrating the bidirectional associations between immune cell subsets and venous thromboembolism (VTE) observed in the exploratory analysis