Introduction

Thrombosis is the formation of a blood clot within a blood vessel, which restricts the flow of blood. Acute thrombosis, both arterial and venous, is the most common cause of death in developed countries. Obesity, which is the excessive accumulation of fat in the body, is a serious risk factor for the development of arterial thrombosis and venous thromboembolism. Obesity is defined by the body mass index (BMI), which is the calculated measure of weight relative to height. The ability of blood to flow freely through the vessels depends on the balance of various factors such as the blood cells, platelets, plasma proteins, coagulation factors, inflammatory factors and the endothelial lining of the blood vessels. When this balance is disrupted, the risk of clot formation increases significantly.^1,2,3

Pathophysiology of thrombosis

Virchow’s Triad mentions three predisposing factors that contribute to the development of vascular thrombosis:

• Endothelial damage
• Hypercoagulability
• Stasis of blood flow

It is important to understand the factors involved in the formation of thrombus to differentiate the risk, decide the treatment and take preventive measures.^1,4

Endothelial damage 

Endothelium is the inner lining of the blood vessels and the lymphatic system. Healthy endothelium maintains the fluidity of blood and prevents the formation of thrombus through the anticoagulant property and activation and aggregation of platelets. 

Dysfunction of the endothelium leads to the shedding of protective molecules into circulation, which act as biomarkers of damage to the endothelium. Endothelial injury changes the dynamics of the blood flow, leading to turbulence or stenosis, which ultimately increases the risk of clot formation.^4,5,6

Hypercoagulability

Soluble coagulation factors such as fibrinogen and tissue factors, and cells such as platelets, contribute to hypercoagulability. The activation of platelets causes the release of molecules like beta-thromboglobulin that enhance clot formation and inflammation of blood vessels. Plasma fibrinogen increases the viscosity of blood and the aggregation of platelets and leads to clot formation.⁴

Stasis of blood flow

Laminar flow of blood maintains the health of the endothelium, whereas turbulent flow activates the endothelium and increases the prothrombotic factors and attracts platelets and leukocytes. Reduced flow promotes fibrin formation and thrombosis.⁴

Thrombogenesis in obesity

Two important factors predispose to the development of thrombus in obesity:⁷

• Chronic inflammation 
• Impaired fibrinolysis

Chronic inflammation

Obesity is an inflammatory condition characterised by low-grade inflammation due to enlarged fat cells releasing inflammatory substances. This draws macrophages into the fat tissue, especially visceral fat, where they accumulate and become activated. The activated macrophages produce cytokines like TNF-α and IL-6, causing widespread inflammation that affects blood vessels and other body areas. This inflammatory state activates pathways that increase clotting factors, worsening inflammation and promoting blood clot formation, while also raising levels of coagulation factors.⁷

Impaired fibrinolysis 

Fibrinolysis is the process of breaking down fibrin clots by plasmin, aided by tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Plasminogen activator inhibitor-1 (PAI-1) inhibits this process, leading to blood clot persistence. In obesity, increased PAI-1 raises clot risk, linked to TNF-α and chronic inflammation. Thus, the chronic inflammation and impaired fibrinolysis lead to endothelial dysfunction, rupture of atherosclerotic plaques, platelet hyperactivation, hypercoagulability and delayed clot lysis.⁷ 

Modulators of the thrombotic pathway in obesity

Obesity causes dysregulation of factors that act as modulators or fine-tuners of homeostatic balance. The main modulators are adipokines and microRNAs.⁷

Adipokines

Adipose tissue not only stores energy but also acts as an active paracrine and endocrine organ that secretes cytokines, hormones and bioactive substances called adipokines.⁷

Leptin

Leptin is an adipokine derived from fat cells and is found in the endothelial cells, macrophages and platelets in the blood vessels. Leptin increases with obesity and controls the appetite and 

energy expenditure. The association between leptin levels in plasma and vascular thrombosis is proven by numerous studies.

Leptin promotes platelet aggregation and hence thrombosis. Leptin also leads to endothelial dysfunction by increasing the activity of protein kinase and decreasing the production of endothelial nitric oxide (a vasodilator). Along with Leptin, other adipokines have prothrombotic effects, which include resistin and visfatin, and the antifibrinolytic serpin PAI-1.⁷

Adiponectin

Adipose tissue also secretes antithrombotic adipokines such as adiponectin and apelin that have a protective effect.⁷

• Reduce leukocyte cellular interaction
• Inhibit smooth muscle proliferation
• Stimulate nitric oxide production in endothelial cells
• Stimulate the production of anti-inflammatory cytokine IL-10 in macrophages
• Inhibit tissue factor expression

These help improve the vascular function, prevent vascular injury and reduce the risk of coagulation. However, as obesity advances, the plasma level of adiponectin decreases.⁷

Apelin

Apelin is secreted at increased levels in obesity and has several effects:

• Anti-inflammatory effect
• Increase the bioavailability of endothelial nitric oxide
• Reduce atherosclerosis
• Prevents the formation of an aneurysm
• Decrease the expression of PAI-1

MicroRNAs (miRNAs)

MicroRNAs or miRs are small noncoding RNAs that regulate physiological processes by modulating the expression of target genes. miRs have a vital role in the pathogenesis of obesity and thrombosis.⁷

• miR-33 regulates lipid metabolism, and blocking miR-33 reduces atherosclerosis
• miR-421 and miR-30c suppress PAI-1, that can have antithrombotic effect

Prevention and management of thrombosis in obese patients

Weight reduction

Weight loss is the only established approach to treat thrombosis in obesity or prevent thrombosis. It improves endothelial function, lowers inflammatory markers, and restores haemostatic balance.⁷

Pharmacological interventions

The use of anticoagulants and antiplatelet drugs in obese patients is limited, as the efficacy and safety have not been proven in obese patients with increased BMI.

Role of novel therapies

• Novel molecular targets to treat thrombosis in obesity 
• Targeting the pro-inflammatory pathway with anti-inflammatory and antithrombotic drugs like aspirin and statins might help
• PAI-1 is another target for antithrombotic therapy in obesity by inhibiting or limiting its production
• Adipokines targeted therapy
  • Targeting leptin has increased the risk of thrombosis due to its prothrombotic effect
  • Developing leptin receptor antagonists
  • Adiponectin and apelin are potential targets for treating thrombosis in obesity
• Enhancing miRNAs’ action by administering a synthetic miRNA mimic

Need for obesity-specific thrombosis guidelines 

Obesity is a risk factor for the development of venous thromboembolism (VTE), including Deep vein thrombosis (DVT) and pulmonary embolism, considering the multiple comorbidities associated with obesity and the reduced mobility of obese patients. An individualised approach is recommended because anticoagulant therapy in obese patients is still uncertain.⁸

Summary

Thrombosis is the formation of blood clots in blood vessels that hinders blood flow, and it is a leading cause of death in developed countries. Obesity increases the risk of both arterial thrombosis and venous thromboembolism, defined using body mass index (BMI). Proper blood flow relies on a balance of various components, including blood cells and proteins. Disruption of this balance increases the chances of clot formation. Factors contributing to thrombosis include endothelial damage, hypercoagulability, and stasis of blood flow, known as Virchow’s Triad. Endothelial damage affects blood flow and increases clot risk. Hypercoagulability involves factors like platelets that promote clot formation. Stasis occurs when blood flow slows, leading to clotting. In obesity, two main factors increase thrombus development: chronic inflammation and impaired fibrinolysis.

Obesity causes inflammation due to fat cells producing inflammatory substances, activating immune cells, and increasing clotting factors. Impaired fibrinolysis, which involves breaking down clots, is influenced by increased levels of inhibitors like PAI-1, leading to persistent clots. Obesity also disrupts modulators of blood clotting, including adipokines like leptin and adiponectin. Leptin promotes clotting and endothelial dysfunction, while adiponectin offers protective effects against clots. MicroRNAs (miRNAs) also play roles in obesity and thrombosis by regulating gene expression. Preventing and managing thrombosis in obese patients primarily involves weight loss, which can restore overall blood flow and reduce inflammation. Current pharmacological treatments for obesity-related thrombosis are limited, and there is a need for specific guidelines tailored to obese patients to manage venous thromboembolism effectively, considering their unique health challenges. Novel therapies might target inflammatory pathways and antithrombotic agents.