Deep vein thrombosis (DVT) poses a significant threat, manifesting in localized swelling and pain, and posing a high risk for potentially fatal pulmonary embolism. As part of the diagnostic process, identifying risk factors is paramount. Although most DVT patients undergo anticoagulant therapy, the choice and duration of treatment vary significantly based on individual risk factors [11]. While oral anticoagulation has been established as an effective means to prevent future thromboembolic events, it is not without its risks, including the potential for major bleeding complications. Consequently, it becomes imperative to identify patients at high risk for DVT or bleeding events using readily accessible clinical characteristics. This identification is crucial in facilitating individualized management strategies to mitigate the patient’s risk. The decision to initiate and maintain anticoagulation therapy often hinges on a meticulous evaluation of both thromboembolism and bleeding risks [10].

Prior investigations have demonstrated a link between serum total bile acid (TBA) levels and various chronic illnesses, encompassing liver diseases, dyslipidemia, fatty liver diseases, diabetes, and cardiovascular conditions [6]. Despite this, the specific role of bile acid in the pathogenesis of DVT and its associated bleeding risk remains poorly understood. Our current study aimed to elucidate this role, revealing a strong association between elevated fasting serum TBA levels and a heightened prevalence of DVT, coupled with a reduced bleeding risk. This association persisted even after considering confounding factors such as age, gender, liver diseases, and the MELD (Model for End-Stage Liver Disease) score. Notably, our study is the first large-scale examination to unmask this significant correlation between serum TBA levels and both DVT presence and bleeding risk in patients under suspicion of DVT.

Past research has explored potential mechanisms underlying bile acids’ modulation of coagulation. Bile acids function as signaling molecules, regulating metabolism and inflammation via receptors like the nuclear farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5) [12]. Alongside the classical Virchow’s triad factors (blood flow disturbance, hypercoagulability, and vessel wall changes), inflammation holds a pivotal role in DVT’s pathogenesis. Clinical conditions associated with inflammation, such as sepsis, systemic infections, cancer, trauma, and surgery, are known risk factors for venous thromboembolism (VTE) [13]. Furthermore, previous studies have linked TBA to elevated levels of tumor necrosis factor-α, a marker of inflammation, suggesting that inflammation may serve as a bridge between TBA and DVT. Additionally, immune dysregulation has been identified as a contributory factor in thrombosis, and bile acids have been shown to regulate immune functions. A range of clinical conditions associated with an increased VTE risk, including inflammatory bowel disease, systemic lupus erythematosus, obesity, surgery, cancer, and acute and chronic infections, exhibit deregulated immune networks that intersect with coagulation pathways [14]. Hence, immune dysregulation could potentially moderate the relationship between TBA and DVT.

Platelets are pivotal in the development of venous thrombosis, as recent evidence indicates that they can facilitate thrombus formation by directly activating coagulation pathways. This activation occurs through the release of polyphosphate, which triggers factor XII activation, and protein disulfide isomerase (PDI), which enhances tissue factor (TF) activation [15]. Given that inhibiting platelet activation can safeguard against DVT, which affects a vast population, the role of these cells is particularly significant. Prior studies have established the farnesoid X receptor (FXR) as a crucial factor in the formation of coated platelets, which are preactivated platelets exhibiting increased fibrinogen binding and a prothrombotic phenotype. Bile acids, being natural ligands of FXR, have the potential to induce platelet activation, thus contributing to thrombus formation [16]. Consequently, the correlations between serum total bile acids (TBA) and the presence of DVT as well as bleeding risk may be partially attributed to alterations in platelet function. However, the precise mechanisms underlying these associations remain to be elucidated.

The role of endothelial dysfunction in thrombus formation is pivotal [15]. Notably, bile acids have been linked to endothelial dysfunction [17, 18], which can exacerbate the progression of DVT. Bile acids, through their activation of the farnesoid X receptor (FXR), have been demonstrated to reduce endothelin-1 expression in lung endothelial cells. Additionally, TGR5, another bile acid receptor, is present in aortic endothelial cells that produce nitric oxide. Moreover, bile acids can modulate endothelial cell responses via S1P receptors and Ca2+-dependent K + currents [18]. Furthermore, bile acids’ association with vascular calcification and fibrosis is attributed to their regulation of various signaling pathways [19].

A recent investigation has revealed a novel mechanism in which the nutrient-sensing nuclear receptor FXR regulates coagulation factor synthesis. Malnutrition-induced coagulation dysfunction in mice could be attributed to diminished FXR activation and synthesis resulting from lower bile acid levels [20]. Furthermore, bile acids have the potential to enhance the procoagulant activity of hepatocytes and activate coagulation factors, indicating their relevance in TF-driven coagulation [8]. Consequently, bile acids may exert influence at various stages of thrombus formation, thereby affecting the risk of bleeding events.

Our research revealed an initial steep rise in the correlation between serum TBA levels and DVT events, followed by a gradual decline when TBA concentrations surpassed approximately 6 µmol/L. This pattern suggests a saturation point beyond which an increased risk of DVT events is not observed. The variations in serum TBA levels observed post-inflection point in our study may stem, in part, from potential mild liver irregularities and alterations in the serum TBA profiles among patients with higher TBA levels. To further elucidate the mechanisms underlying TBA’s role in DVT development, studies exploring various serum TBA concentrations and their dynamic changes are warranted.

Our study presents several limitations that merit consideration. Firstly, being a single-center study focused on Chinese patients with suspected DVT, our findings should be cautiously extrapolated to other ethnic groups. Additional studies encompassing diverse ethnic populations are required to validate our observations. Secondly, the cross-sectional nature of our study falls short of establishing a causal link between TBA and DVT. Thirdly, our analysis was confined to fasting TBA levels, without accounting for specific bile acid components. Future prospective investigations are warranted to further explore our preliminary findings.

In summary, our investigation of Chinese patients suspected of having DVT has revealed that fasting serum TBA levels are significantly elevated in those with DVT compared to their non-DVT counterparts. Notably, fasting serum TBA displays a robust and independent association with the presence of DVT and bleeding risk. Consequently, TBA emerges as a clinically valuable and cost-effective biomarker for identifying DVT and assessing bleeding risk. Our findings have the potential to significantly impact nutrition science and practice in the foreseeable future. By understanding this association, nutrition researchers and practitioners can explore dietary interventions or nutritional strategies that may help modulate TBA levels, ultimately contributing to the prevention and management of DVT. Furthermore, incorporating TBA levels into nutritional assessments could provide additional insights into individual bleeding risks, enabling personalized nutrition recommendations for patients.