Obesity and Venous Thromboembolism: Mechanisms, Clinical Implications, and Prevention Strategies With a Focus on Bariatric Surgery

Abstract

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE), constitutes a significant global health concern due to its substantial morbidity and mortality, especially among hospitalized and surgical individuals. DVT commonly presents in the lower extremities with symptoms such as calf pain, swelling potentially spreading to the ankle and foot, localized warmth, and skin discoloration. PTE, arising from acute pulmonary artery obstruction by a thrombus, frequently manifests as sudden dyspnea, chest pain, tachycardia, diaphoresis, hemoptysis, and lightheadedness, posing a life-threatening emergency demanding prompt medical intervention. Obesity stands out as a critical and modifiable risk factor for VTE, elevating its incidence in both the general population and during the perioperative period. Despite its efficacy in weight reduction, bariatric surgery markedly increases VTE risk, establishing it as a primary contributor to postoperative fatalities in surgical patients with obesity. The interplay between obesity and VTE involves a complex network of pathophysiological mechanisms and is further complicated by surgical and postoperative factors, necessitating comprehensive understanding and vigilant preventive strategies, especially within Asian populations, where specific anatomical and clinical factors may influence VTE risk profiles. This review comprehensively examines these pathophysiological links, clinical implications with a focus on bariatric surgery, and current prevention strategies, drawing insights from both Asian and Western guidelines and highlighting the evolving role of direct oral anticoagulants.

INTRODUCTION

Venous thromboembolism (VTE), a collective term for deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE), is a leading cause of morbidity and mortality worldwide, with a significant impact on hospitalized and surgical patients [1,2,3]. DVT primarily affects the lower extremities, characterized by calf pain, swelling that can extend to the ankle and foot, localized warmth, and skin discoloration such as pallor, erythema, or cyanosis. PTE, an acute and life-threatening condition caused by the sudden obstruction of a pulmonary artery by a thrombus, manifests with symptoms including acute dyspnea, chest pain, tachycardia, diaphoresis, hemoptysis, and lightheadedness, demanding immediate medical intervention [4]. Among the multitude of risk factors for VTE, obesity stands out as a crucial and modifiable contributor, significantly elevating VTE risk in both the general populace and the perioperative context, particularly after bariatric surgery [5,6]. The intricate relationship between obesity and VTE is underpinned by a complex interplay of pathophysiological mechanisms, further compounded by surgical and postoperative considerations. This complexity underscores the urgent need for a thorough understanding and diligent preventive strategies, especially within Asian populations, where unique anatomical and clinical characteristics may influence VTE risk profiles. This review aims to comprehensively examine the pathophysiological mechanisms linking obesity to VTE, present clinical evidence of VTE in bariatric surgery patients, discuss VTE prevention guidelines from both Asian and Western perspectives, and explore the emerging role of direct oral anticoagulants (DOACs) in this high-risk group.

PATHOPHYSIOLOGICAL MECHANISMS LINKING OBESITY AND THROMBOSIS

Obesity has been consistently associated with an increased risk of cardiovascular diseases, including coronary heart disease, peripheral arterial disease, stroke, and notably, VTE. Central obesity, characterized by the accumulation of visceral adipose tissue around the trunk, is particularly prevalent among men and Asian populations, and is closely linked to metabolic dysfunctions and an elevated risk of thrombosis [7,8]. The underlying mechanisms connecting obesity and thrombosis are multifactorial, involving several of the key pathophysiological pathways that contribute to a prothrombotic state.

Firstly, leptin, a hormone secreted by adipose tissue in obese individuals, extends beyond its role in appetite regulation to directly influence thrombus formation [2,7,9]. Leptin binds to receptors on platelet surfaces, enhancing platelet aggregation responses, and increases tissue factor (TF) expression in vascular endothelial cells, thereby promoting blood coagulation. This is a key factor contributing to the increased incidence of acute thrombotic events in the obese population. Secondly, obesity is characterized by increased levels of nonesterified fatty acids (NEFAs) and Plasminogen Activator Inhibitor-1 (PAI-1) [10]. Adipocytes in obese individuals release increased levels of NEFAs, which elevate the circulating levels of TF and PAI-1. TF is a crucial initiator of the blood coagulation cascade, while PAI-1 is a primary inhibitor of fibrinolysis. PAI-1 inhibits the activity of tissue plasminogen activator, thereby reducing plasmin formation from plasminogen. Since plasmin is a key enzyme in thrombus degradation, elevated PAI-1 levels impair the body’s ability to break down clots, leading to a prothrombotic state where clots form easily and are less likely to be effectively dissolved, increasing susceptibility to both microvascular and macrovascular thromboses [2,4,11]. Thirdly, obesity leads to increased coagulation factor activity. Obese patients exhibit increased TF-mediated coagulation, with elevated TF expression in adipocytes and monocytes. Furthermore, there is a tendency for increased plasma concentrations of coagulation factors VII and VIII, which play critical roles in the blood coagulation process. These elevated coagulation factors correlate significantly with measures of obesity and an increased risk of coronary heart disease and stroke [1,2,12]. Fourthly, the upregulation of the Renin-Angiotensin System (RAS) is a key mechanism in obesity. Obesity induces activation of the RAS, with angiotensin II, in particular, increasing the production of reactive oxygen species, inflammatory cytokines, and adhesion molecules [2,13,14]. This leads to vasoconstriction, vascular smooth muscle cell proliferation, and destabilization of atherosclerotic plaques, causing vascular damage and inflammation, which further exacerbates the prothrombotic environment. Additionally, chronic inflammation and endothelial dysfunction are key contributors [2,15]. Obesity induces a state of low-grade chronic inflammation, which can lead to dysfunction of vascular endothelial cells [16]. Damaged endothelial cells increase the secretion of pro-thrombotic factors and decrease the release of anti-thrombotic factors, thereby elevating the risk of thrombus formation. These mechanisms collectively contribute to a prothrombotic environment in individuals with obesity, thereby increasing the risk of VTE [2,16]. Thus, obesity acts as a complex factor, influencing the blood coagulation system through various pathways and increasing the likelihood of thrombus formation.

CLINICAL EVIDENCE LINKING OBESITY AND VTE WITH A FOCUS ON BARIATRIC SURGERY

Multiple studies have demonstrated a clear, independent relationship between obesity and idiopathic VTE. Odds ratios of 2.26 and 2.42 have been reported in studies comparing individuals with a body mass index (BMI) over 30 kg/m² to those with a BMI under 25 kg/m², indicating a significant increase in VTE risk associated with obesity, independent of other recognized risk factors [8]. Obese individuals often have chronically elevated intra-abdominal pressure and reduced blood flow velocity in the common femoral veins, which, when combined with factors such as physical inactivity, impaired gait, and comorbid conditions, further impair venous return from the lower limbs and contribute to VTE risk. Bariatric surgery, increasingly performed for the management of morbid obesity, has been associated with a higher incidence of VTE, which remains a leading cause of postoperative mortality in this patient population. Reported rates of DVT following bariatric surgery range up to 5.4%, while the incidence of PTE can reach up to 6.4% [17]. Globally, bariatric patients are considered to be at moderate-to-high risk for VTE, with the majority of VTE events occurring post-discharge, typically within 30 days of surgery [18,19]. Several clinical conditions frequently observed in obese patients can further increase VTE risk, including obesity hypoventilation syndrome, dyspnea at rest, longer operative times or open surgical approaches, and prolonged hospital stays exceeding 3 days [8,18,19]. These evidences strongly suggest that VTE prevention strategies are essential for bariatric surgery patients.

GUIDELINE RECOMMENDATIONS FOR VTE PREVENTION IN ASIAN POPULATIONS UNDERGOING BARIATRIC SURGERY

The only guidelines specifically addressing VTE prevention in the Asian context were published in 2017 through collaboration among experts from South Korea, China, Hong Kong, Singapore, Malaysia, the Philippines, and Taiwan [8]. These guidelines highlight that risk factors for VTE, including advanced age, immobility, malignancy, surgery, and trauma, are largely similar between Asian and Western populations. However, they also recognize that Asians tend to have greater abdominal visceral adiposity compared to Westerners, potentially heightening VTE risk. This is presented as an important anatomical and physiological characteristic to consider when assessing VTE risk and formulating prevention strategies in Asians. The guidelines recommend that pharmacological prophylaxis should be initiated after carefully weighing the risks of bleeding against the risk of thrombosis, and if both risks are high, mechanical prophylaxis using intermittent pneumatic compression should be utilized as a priority. Importantly, there is no evidence suggesting that the risk of bleeding with anticoagulant use is higher in Asian patients than in Caucasian populations. This suggests that aggressive pharmacological prophylaxis can also be applied to Asian patients [8]. Given the absence of validated Asian-specific risk assessment models, the guidelines recommend using the American Society for Metabolic and Bariatric Surgery (ASMBS) advisory and the American College of Chest Physicians risk assessment models [18]. These models advocate early and aggressive postoperative mobilization, mechanical prophylaxis for all bariatric patients, and pharmacological prophylaxis unless contraindicated.

A 2018 survey study of 11 surgeons across 10 Asian countries revealed that most surgeons (63.64%) prefer using both mechanical and chemoprophylaxis, with low molecular weight heparin (LMWH) being the most commonly used chemoprophylactic agent (81.82%) [20]. Most surgeons reported using sequential compression devices routinely and encouraging early ambulation within 4–6 hours postoperatively. The duration of chemoprophylaxis varied, with practices ranging from 3–5 days to up to 2 weeks post-surgery. Notably, 60% of surgeons reported initiating chemoprophylaxis at least one week prior to surgery, while the routine use of inferior vena cava (IVC) filters was not favored, with some surgeons opting for selective use in specific high-risk scenarios. Despite these practices, the study highlighted the lack of unified, evidence-based guidelines for VTE prophylaxis in Asian bariatric surgery patients. This suggests the need for more refined and standardized guidelines that reflect the specific characteristics of the Asian population.

AMERICAN AND EUROPEAN GUIDELINES ON VTE PREVENTION IN BARIATRIC SURGERY

The ASMBS guidelines, updated in 2022, maintain that all bariatric surgery patients should be considered at least at moderate risk for VTE, with the potential to be classified as high or extremely high risk depending on additional factors such as advanced age, higher BMI, and comorbid conditions [18]. These guidelines emphasize early postoperative ambulation, adequate hydration, and the combined use of mechanical and pharmacological prophylaxis throughout hospitalization as key elements of VTE prevention. Notably, given that approximately 80% of postoperative VTE events occur after hospital discharge, extended pharmacoprophylaxis may benefit selected high-risk patients, although current evidence regarding its effectiveness remains limited. This highlights the recognition that VTE risk can persist post-discharge, indicating a need for further research and guidance in this area. In patients with severe renal insufficiency, LMWH dose adjustments or the use of unfractionated heparin (UFH) should be considered, and routine IVC filter use before bariatric surgery is not recommended due to associated complications. Hormonal therapies, including menopausal and contraceptive agents, as well as selective estrogen receptor modulators, are recognized as increasing VTE risk, and perioperative discontinuation should be considered when appropriate. These guidelines are based on Western population data but provide universal prevention principles applicable to bariatric surgery patients.

The 2018 European guidelines provided general recommendations for VTE prophylaxis, but the 2024 update introduced significant, specific changes for obese patients. The existing 2018 guidelines suggested doses of 3,000–4,000 anti-Xa IU of LMWH for patients with a low VTE risk and 4,000–6,000 anti-Xa IU of LMWH for those with a high VTE risk, administered subcutaneously every 12 hours [19]. In contrast, the updated 2024 guidelines recommend LMWH, UFH, or fondaparinux for VTE prevention in high-risk patients with a low bleeding risk (Grade 1B), and specifically state that LMWH should be considered a priority over DOACs (Grade 2C). A key clinical change in the update is the new recommendation to use higher doses of LMWH, UFH, or fondaparinux for patients with a BMI greater than 40 kg/m² or a weight greater than 150 kg (Grade 2B). This further emphasizes the importance of weight-based dose adjustment for obese patients [21,22]. Unlike the ASMBS guidelines, which suggest considering dose adjustment based on Anti-Xa levels, the European guidelines explicitly do not recommend routine monitoring of these levels (Grade 2C) [18,22]. Furthermore, in addition to in-hospital prophylaxis, extended pharmacological prophylaxis for a minimum of 10 days is strongly recommended for high-risk patients, considering the risk of VTE after discharge (Grade 1C). This more refined guideline provides a stronger framework for tailoring VTE prevention strategies to the specific physiological challenges of obesity [21,22]. A comparative summary of these guidelines is provided in Table 1.

Table 1. Comparison of key VTE prevention guidelines.

Recommendations	2022 ASMBS guidelines	2024 European guidelines	2017 Asian guidelines
Recommended prophylaxis	Pharmacological (LMWH, UFH, DOACs) and mechanical prophylaxis are recommended in combination.	Pharmacological (LMWH, UFH, Fondaparinux) prophylaxis is recommended. LMWH is preferred over DOACs. Mechanical prophylaxis is not explicitly mentioned.	Both pharmacological (LMWH is most common) and mechanical prophylaxis (e.g., IPC) are recommended. Mechanical prophylaxis is a priority if bleeding risk is high.
Pharmacological dosage	Enoxaparin 40 mg twice daily, BMI/weight-tiered dosing, or based on anti-Xa levels.	2018: Low risk 3,000–4,000 IU, high risk 4,000–6,000 IU (every 12 hours).	Dosage, frequency, and duration are determined by risk level. No specific figures are provided.
		2024: Higher doses for patients with BMI >40kg/m2 or weight >150 kg.
Extended prophylaxis	Recommended for select high-risk patients.	Strongly recommended for high-risk patients for a minimum of 10 days.	2–4 weeks post-discharge for high-risk patients.
Specific high-risk factors	BMI (≥50 kg/m2), age (≥60 years), prior history of VTE, thrombophilia, etc.	BMI >40 kg/m2 or weight >150 kg, high-risk patients.	BMI (≥50 kg/m2), older age (≥60 years), male gender, immobility, prior history of VTE, thrombophilia, OHS, etc.
Anti-Xa monitoring	Consider dose adjustment based on anti-Xa levels.	Explicitly does not recommend routine monitoring.

VTE = venous thromboembolism, ASMBS = American Society for Metabolic and Bariatric Surgery, LMWH = low molecular weight heparin, UFH = unfractionated heparin, DOAC = direct oral anticoagulant, IPC = intermittent pneumatic compression, BMI = body mass index, OHS = obesity hypoventilation syndrome.

THE EMERGING ROLE OF DOACS IN VTE PROPHYLAXIS POST-BARIATRIC SURGERY

DOACs provide an attractive alternative for VTE prophylaxis due to their oral administration, minimal drug-drug and food interactions, and fixed dosing regimens [23]. Rivaroxaban, approved for thromboprophylaxis in orthopedic procedures, does not require dose adjustment in patients with extreme obesity [24,25]. Pharmacokinetic and pharmacodynamic studies have shown that significant weight loss and anatomical changes following bariatric surgery, including Roux-en-Y gastric bypass and sleeve gastrectomy, do not meaningfully affect the pharmacokinetics and pharmacodynamics of rivaroxaban, supporting its use in this population [26,27]. However, it is also important to note that the surgical alterations to the gastrointestinal tract in bariatric surgery can significantly reduce the absorption rate of orally administered drugs, making the stability of DOAC pharmacokinetics a critical consideration. This factor is a key reason why the 2024 European guidelines suggest LMWH over oral DOACs for specific high-risk scenarios, implicitly acknowledging the growing consideration of DOACs in the discussion of VTE prophylaxis but also highlighting the need for more definitive evidence regarding their post-surgical efficacy [21].

A recent randomized controlled trial conducted in 2023 evaluated the efficacy and safety of once-daily 10 mg rivaroxaban administered for either 7 or 28 days postoperatively in 272 bariatric surgery patients [28]. The study found a very low incidence of VTE in both groups, indicating that a 7-day course of rivaroxaban may be sufficient for effective VTE prophylaxis in this setting. However, despite promising findings, the routine adoption of DOACs for VTE prophylaxis post-bariatric surgery requires further validation through large-scale studies to establish optimal dosing strategies, safety profiles, and efficacy, particularly in the Asian population where specific considerations such as higher visceral adiposity may influence VTE risk. While the convenience of DOACs is appealing, their use in Asian bariatric surgery patients warrants specific consideration due to population-specific physiological and genetic factors. The average body weight of Asian patients is typically lower than that of Western populations, which may lead to higher drug exposure and a potentially elevated risk of bleeding when using standard DOAC doses. Furthermore, a well-documented genetic predisposition for a higher incidence of intracranial hemorrhage exists in Asian populations when using various anticoagulants, which could be a significant concern [29]. These factors underscore the need for dedicated pharmacokinetic and safety studies in this demographic to establish appropriate weight-based or dose-adjusted regimens. Without this data, the application of general DOAC guidelines to Asian patients may not be optimal and could result in either subtherapeutic drug levels or an increased risk of hemorrhagic complications.

CONCLUSION

Obesity significantly contributes to an increased risk of VTE through a complex network of pathophysiological mechanisms, further exacerbated in the perioperative period, particularly following bariatric surgery. Preventing VTE in bariatric patients requires a multifaceted approach incorporating early ambulation, mechanical prophylaxis, and pharmacological strategies tailored to individual risk profiles. While LMWH remains the standard pharmacological agent for VTE prophylaxis, emerging data on the safety and efficacy of DOACs, including rivaroxaban, offer promising alternatives that warrant further investigation.

Despite the existence of guidelines from Western and Asian authorities, there remains a need for unified, evidence-based, and region-specific guidelines to optimize VTE prevention in bariatric surgery patients, particularly within Asian populations. Asian populations may possess distinct anatomical characteristics (e.g., higher visceral adiposity) and genetic factors compared to Western populations, necessitating the urgent development of Asian-specific VTE risk assessment models that reflect these characteristics. While currently adopting Western models, these may not be optimally tailored for Asian patients.

Furthermore, additional research on optimal pharmacological prophylaxis regimens, especially the role of DOACs, is needed in Asian populations. Although DOACs are appealing due to their convenience, there is a lack of large-scale clinical studies on their pharmacokinetic characteristics, dose response, and long-term safety and efficacy in Asians. Future research should focus on bridging these gaps and establishing optimal dosages and durations of DOACs in this high-risk group to improve patient outcomes while minimizing the risks associated with VTE. Ultimately, the development of tailored prevention strategies that reflect the clinical realities and patient characteristics of the Asian region will play a crucial role in reducing the incidence of VTE and enhancing the safety of bariatric surgery patients.