Pro-thrombotic State

• Obese, insulin-resistant subjects and type 2 diabetic patients often have a pro-thrombotic state.
• Atherothrombotic complications of the metabolic syndrome are partly due to a dysregulation of hemostasis. This induces a pro-thrombotic state that includes endothelial activation, platelet hyperactivity, hypercoagulability, and hypofibrinolysis.
• Hypofibrinolysis because of elevated PAI-1 levels is a core feature of the metabolic syndrome.
• Weight loss improves all pro-thrombotic factors, indicating that obesity is a modifiable risk factor for thrombosis.

Adipose tissue is much more than an organ that mobilizes energy stored in the form of triglycerides. It is also an endocrine organ that secretes adipokines that contribute to the atherogenic/diabetogenic metabolic risk profile of abdominal obesity [6]. Among the wide variety of bioactive substances called adipokines, several may play a role in thrombosis. A key adipokine is PAI-1. It inhibits plasminogen activator (tPA), which cleaves plasmin from plasminogen and is therefore the primary physiological inhibitor of fibrinolysis in vivo [7] (Figure). Several tissues produce PAI-1, including the liver, spleen, and adipocytes [8]. Elevated PAI-1 concentrations hinder normal clearance of fibrin and promote thrombosis [9], which increases the risk of myocardial infarction and stroke [10]. The link between PAI-1 and the metabolic syndrome was first described by Dr. Irene Juhan-Vague’s group in 1986 and is now well established [11].

Circulating PAI-1 levels are elevated in obese subjects with the metabolic syndrome and in patients with type 2 diabetes. The more severe the metabolic syndrome, the higher plasma PAI-1 levels [12]. PAI-1 levels are associated with high-risk abdominal obesity as established through waist circumference and insulin resistance [13]. Several groups have also reported that increased PAI-1 levels and visceral obesity are closely linked [10,14,15]. For example, changes in plasma PAI-1 levels during a weight-loss program have been shown to be related with changes in visceral fat but not in subcutaneous fat [16]. In addition, treatment with insulin-sensitizing drugs like metformin or troglitazone decreases plasma PAI-1 levels in subjects with type 2 diabetes and in obese subjects [17]. These findings justify the proposal of increased PAI-1 levels (or at least the pro-thrombotic state) as a true component of the metabolic syndrome [5,18].

Leptin is mainly produced and secreted by adipose tissue and acts via the hypothalamus to suppress food intake and increase energy expenditure by modulating glucose and fat metabolism and enhancing thermogenesis [7]. Most obese people have high circulating leptin concentrations, which is a signal sent by adipose tissue to limit caloric intake and restore energy balance by reducing appetite and increasing energy expenditure [19]. It is therefore generally accepted that overweight and obese individuals are resistant to the effects of leptin [20]. The leptin receptor is present in many tissues, including platelets [21]. Leptin promotes human platelet aggregation by increasing normal platelet response to the agonists adenosine diphosphate and thrombin (Figure). This has recently been suggested as one mechanism responsible for acute thrombotic events in obesity [22].

Increased fibrinogen concentrations are a consistent plasma abnormality in obesity. Fibrinogen promotes arterial and venous thrombosis by increasing fibrin formation, platelet aggregation, and plasma viscosity, and it promotes atherosclerosis by fostering the proliferation of vascular smooth muscle and endothelial cells [23] (Figure). Fibrinogen levels are now considered to be more closely related to overall adiposity than insulin resistance [24]. The plasma levels of other clotting factors, such as tissue factor [8] and factor VII and VIII, are also elevated in obese patients [23]. Several studies have shown that weight loss can reverse numerous disturbances in the plasma coagulation cascade [25].

Obesity is a chronic, low-grade inflammatory state, as demonstrated by increased levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) and acute phase proteins such as C-reactive protein (CRP) [26]. Weight loss has a positive impact on this pro-inflammatory state [27]. In addition to its direct effects, inflammation may cause thrombosis indirectly by inducing oxidative stress and endothelial dysfunction [28]. IL-6 may promote thrombosis indirectly by increasing platelet count and aggregation, hepatic synthesis of fibrinogen and CRP, and endothelial adhesion molecule expression, as well as by decreasing adiponectin secretion [29]. TNF-α stimulates leptin production and reduces adiponectin secretion by adipose tissue, induces PAI-1 expression in adipose tissue, and promotes endothelial adhesion molecule expression [7] (Figure).

Oxidative stress is where the normal balance between the body’s pro-oxidant and anti-oxidant systems is disturbed in favour of oxidation [30]. Oxidative stress from the production of reactive oxygen species (ROS) promotes endothelial dysfunction, platelet aggregation, and thrombus formation [31] (Figure). Many obesity-related metabolic abnormalities, such as hyperglycemia, dyslipidemia, and inflammation, all increase ROS production in the endothelium, which promotes oxidative stress [32].

Endothelial dysfunction is a disturbance in the normal balance between vasoconstrictors and vasodilators, growth promoters and inhibitors, pro- and anti-atherogenic processes, and pro- and anti-coagulant factors [33]. Endothelial dysfunction is central to the development and progression of atherosclerosis and enhances the risk of future cardiovascular events [33]. Endothelial dysfunction is present in overweight patients, especially those with visceral obesity and insulin resistance, and weight loss can improve endothelial function [27]. As described above, low levels of adipocyte-derived circulating adiponectin may cause endothelial damage, possibly by lowering nitric oxide (NO) production while increasing ROS [31]. Not only does NO reduce inflammation, platelet aggregation, vascular smooth muscle cell migration and growth, and monocyte and macrophage adhesion, it also encourages vasodilatation [33]. Low NO production may therefore help increase platelet activation, arterial thrombosis (Figure), and atherogenesis.

Several new features have been added to the metabolic syndrome because they frequently accompany the syndrome’s traditional features. A pro-thrombotic state has been found in obese, insulin-resistant subjects likely to have abdominal obesity. Moreover, increased PAI-1 levels, the main hemostatic disorder linked to insulin resistance, is now considered part of the cluster of abnormalities of the metabolic syndrome. In addition, intervention studies have shown that weight loss through a hypocaloric diet and exercise or treatment with insulin-sensitizing agents are effective in reducing this procoagulant state. This evidence lends weight to the notion that obesity is a modifiable risk factor for thrombosis.