The metabolic syndrome is a clinical disorder characterized by impairment of glucose metabolism, increased arterial blood pressure, and abdominal obesity. The presence of these clinical features exposes patients to a high risk of atherothrombotic cardiovascular events. The pathogenesis of atherothrombosis in the metabolic syndrome is multifactorial, requiring a close relationship among the main components of the metabolic syndrome, including insulin resistance, alterations of glycaemic and lipid pattern, haemodynamic impairment, and early appearance of endothelial dysfunction. Furthermore, haemostatic alterations involving coagulation balance, fibrinolysis, and platelet function play a relevant role both in the progression of the arterial wall damage and in acute vascular events. The mechanisms linking abdominal obesity with prothrombotic changes in the metabolic syndrome have been identified and partially elucidated on the basis of alterations of each haemostatic variable and defined through the evidence of peculiar dysfunctions in the endocrine activity of adipose tissue responsible of vascular impairment, prothrombotic tendency, and low-grade chronic inflammation. This paper will focus on the direct role of adipose tissue on prothrombotic tendency in patients affected by metabolic syndrome, with adipocytes being able to produce and/or release cytokines and adipokines which deeply influence haemostatic/fibrinolytic balance, platelet function, and proinflammatory state.
The Framingham Heart Study was one of the first epidemiological studies which showed the causal relationship between obesity and cardiovascular disease [
The metabolic syndrome is a complex disorder characterized by the presence of a clustering of metabolic risk factors usually in a single individual associated with the presence of central obesity and a strong association with diabetes and cardiovascular disease morbidity and mortality.
According to the National Cholesterol Education Program (NCEP)’s Adult Treatment Panel III criteria [
According to the International Diabetes Federation (IDF), the diagnosis of metabolic syndrome requires evidence of central obesity with cutoff values of waist circumference depending on gender and ethnic group origin (for instance, cut-off is ≥94 cm for Europid males and ≥80 cm for Europid females) together with the other risk factors as defined in revised NCEP [
A Joint Interim Statement (JIS) by many medical organizations confirmed that waist cut-off values defining high-risk groups are different between populations but criticised the criteria of abdominal obesity measurement as a prerequisite of metabolic syndrome [
Thus, at present, a unifying definition is lacking [
Due to the absence of an unifying definition, the metabolic syndrome can be present in several forms according to the combination of the different components; therefore, the exact evaluation of prevalence of the metabolic syndrome is quite different both in the United States and in Europe. Recent data using the World Health Organization (WHO) definition and data from National Health and Nutrition Examination Survey III (NHANES III) indicated that the age-adjusted prevalence of the metabolic syndrome is estimated at 23.7% and increases with the increasing prevalence of central obesity which affects more than 40% of subjects older than 60 years in the United States. Based on the data from 2000, 47 millions of individuals in the United States have the metabolic syndrome [
As mentioned, the metabolic syndrome is recognized as a pervasive condition related to cardiovascular atherosclerotic ischemic disease due to the presence of a clustering of three or more risk factors, including abdominal obesity, atherogenic dyslipidaemia (hypertriglyceridaemia, low HDL cholesterol), raised blood pressure, insulin resistance with or without impaired glucose tolerance, and proinflammatory state [
The metabolic syndrome is clearly related to central obesity and is associated with the development of atherosclerotic vascular damage and an increased susceptibility to the clinical manifestations of atherothrombosis owing to the presence of a network of pathogenic factors (Figure
Potential mechanisms linking visceral obesity, which characterizes the metabolic syndrome, inflammation, and atherothrombotic vascular disease.
This constellation of disorders indicates that insulin resistance and type 2 diabetes mellitus are a major cause of cardiovascular disease, with consequent disabilities and mortality on a global scale, representing also a relevant cause of financial cost in the different healthcare systems.
Apart from metabolic and haemodynamic alterations, central obesity is characterized by an evident prothrombotic tendency (Figure
Prothrombotic disorders in obesity.
In this paper
Haemostasis is a process initiated when a damage occurs to the wall of a blood vessel and culminates with the formation of a stable clot. This occurs in three stages: vasoconstriction, platelet response (white clot formation), and blood coagulation; the last process depends on the tight balancing between the activation of coagulation and fibrinolytic systems activated for the repair of the blood vessel and determining clot dissolution and restoration of the vessel function [
Alterations of the coagulation cascade and/or fibrinolysis, especially in the presence of a low-grade inflammation, are key pathogenic components of the atherothrombotic process which underlies acute coronary and cerebrovascular events [
Recently, the release of cell fragments known as microvesicles or microparticles (MPs) has been recognized as an integral part of the thrombotic process [
MPs are small, irregularly shaped, phospholipid vesicles (200–1,000 nm) containing procoagulant and proinflammatory mediators, released in blood as a consequence of activation or apoptosis of endothelial cells, leukocytes, and platelets [
MPs have been recognized in blood from healthy individuals, but their number is markedly increased in patients under pathological states, such as disseminated intravascular coagulation, diabetes, immune-mediated thrombosis, acute coronary syndromes, systemic inflammatory diseases, and metabolic syndrome [
The impairment of hemostatic balance identified in subjects with central obesity includes alterations of both intrinsic and extrinsic pathways with increased levels of factor VIII (FVIII) and von Willebrand factor (vWF), TF, FVII, and fibrinogen [
vWF is a multimeric glycoprotein synthesized and secreted by vascular endothelial cells and megakaryocytes [
An elevated circulating level of vWF is a marker of endothelial cell damage [
In the Atherosclerosis Risk in Communities (ARIC) study, both vWF and FVIII were associated with components of the metabolic syndrome including BMI, plasma insulin levels, and triglyceridemia [
TF is the primary
The complex TF-FVIIa catalyzes the conversion of factor IX (FIX) and factor X (FX) into their activated forms, serving as the main cofactor to lead to fibrin formation both in physiological and pathological conditions [
In physiological conditions, TF expression is confined only in cells of the adventitia layer which surrounds blood vessels, forming an envelope that prevents blood extravasation; in pathological states, however, TF is expressed also by activated endothelium and monocytes [
Under stimulation of the proinflammatory cytokine transforming growth factor-
An increased number of circulating MPs containing TF have been detected in patients with central obesity with a positive relationship with components of the metabolic syndrome [
FVII is a 50 kDa vitamin K-dependent serine protease synthesized in the liver which plays a pivotal role in the activation of the extrinsic coagulation cascade together with TF [
An association between FVII levels and coronary events has been shown in several but not all studies [
Circulating FVII:c may bind to triglyceride-rich lipoproteins, and its plasma levels are related to those of chylomicron and very-low density lipoprotein (VLDL) fractions [
Fibrinogen is a heterodimer composed of three pairs of nonidentical polypeptide chains (A
Prospective epidemiological studies in general population constantly found an association between raised plasma levels of fibrinogen and increased risk of cardiovascular events, inducing to consider fibrinogen a strong and independent atherothrombotic risk factor through its effects on blood viscosity, coagulation, platelet function, and inflammation [
Although the relationship between fibrinogen and features of the insulin resistance syndrome is weaker than for other hemostatic factors such as PAI-1 and FVII [
In particular, elevated fibrinogen levels could be explained by the proinflammatory state of central obesity and insulin resistance states, characterized by elevated synthesis and secretion of IL-6 and other proinflammatory cytokines.
As previously reviewed, circulating MPs can contain coagulation factors—TF, in particular—and contribute to the amplification of the thrombotic response [
Several lines of evidence indicate that patients with central obesity, as well as with diabetes mellitus, have increased circulating levels of MPs compared with healthy subjects [
Furthermore,
The fibrinolytic pathway is responsible for the removal of fibrin from the circulation through its degradation within the thrombus; therefore, it plays a pivotal role in disintegrating clots and maintaining vascular patency [
Fibrinolysis is activated by the enzymatic conversion of the proenzyme plasminogen into the active enzyme plasmin which degrades fibrin into soluble fibrin degradation products (FDPs) [
Plasma fibrinolytic activity is tightly regulated by inhibitors, mainly represented by
The primary inhibitor of the fibrinolytic system is PAI-1—a single-chain glycoprotein (379 to 381 amino acids; MW: 48 kDa), member of the superfamily of the serine protease inhibitors—which inhibits plasminogen activation by binding with tPA to form the PAI-1/tPA complex [
Liver, platelets, endothelial cells, and VSMC are the main sources of PAI-1, but other cell types can synthesize and secrete this protein [
TAFI—known as plasma procarboxypeptidases B, R, and U, EC 3.4.17.20—is synthesized in the liver and secreted as a propeptide consisting of 401 amino acids, with a molecular weight of 60 kDa; it is present also in platelets and endothelial cells [
Hypofibrinolysis, that facilitates fibrin deposition in vessel wall, is deeply involved in the increase of atherothrombotic events, especially if associated to a prothrombotic tendency related to high plasma concentrations of vWF/FVIII complex, TF, FVII, and fibrinogen [
Adipocytes synthesize PAI-1 through a mechanism regulated by insulin, glucocorticoids, angiotensin II, and cytokines (Figure
Control of PAI-1 synthesis and release in adipose tissue. It is underlined the role of thrombospondin-1 (TSP1), an adipokine which activates transforming growth factor-
The metabolic syndrome is usually characterized by elevated circulating level of PAI-1 [
There are lines of evidence that a major role in the elevation of PAI-1 in obesity is attributable to upregulated production by adipose tissue itself [
The alteration of the fibrinolytic system related to increased circulating levels of PAI-1 is considered to have a relevant role in the prothrombotic tendency associated with obesity [
A derangement of the endogenous fibrinolytic system could justify, at least in part, clinical observations which evidenced a resistance to intravenous thrombolysis in acute middle cerebral artery ischemic stroke in women with the metabolic syndrome [
Elevated levels of PAI-1 have been also recognized among type 2 diabetic patients [
Studies showed increased circulating levels of TAFI antigen and TAFI activity in obese patients [
As extensively reviewed [
Several defects of platelet function have been identified in insulin-resistant states and central obesity, as recently reviewed [
Mean platelet volume, a parameter directly related to
Furthermore, another index of
Overweight and obese insulin-resistant subjects exhibited also enhanced plasma concentrations of P-selectin—a marker of platelet activation exposed in cell surface and released in circulating blood—in comparison with controls [
The prevalence of activated platelets is usually associated to the increase of other prothrombotic proteins; in particular, some authors found, in patients with severe obesity and insulin resistance, increased levels of soluble CD40 ligand (sCD40L) [
CD40 ligand (CD40L) is a trimeric transmembrane protein structurally related to TNF-
CD40L is stored in the cytoplasm of resting platelets and rapidly exposed on cell surface after activation [
PMPs with a diameter less than 0.1 micron are identified by the presence of glycoprotein CD42b and CD42a [
Recent finding showed that circulating levels of PMPs are elevated in obese nondiabetic subjects in comparison with nonobese controls with a positive correlation with BMI and waist circumference: this fact is related to enhanced
As it will be extensively described in the next part of the paper, several available studies identified as main defect of the platelet function in subjects with central obesity a decreased sensitivity to mediators playing a physiological role in the reduction of platelet sensitivity to proaggregating stimuli, including insulin, NO, and cyclic nucleotides themselves [
Membrane of human platelets expresses insulin receptors, with a density similar to that present in cell types responsive to the metabolic actions of the hormone [
In insulin-sensitive subjects, the hormone exerts an antiaggregating activity recognized by both
The insulin effects are, at least in part, dependent on the activation of ecNOS through an increase of intraplatelet 3′,5′-cyclic guanosine monophosphate (cGMP) mediated by the stimulation of soluble guanylate cyclase activity [
It is known that cGMP and cAMP, acting predominantly via specific protein kinases, block several steps of the agonist-induced elevation of cytosolic calcium, a basic mechanism of platelet activation [
Some
In conditions of insulin resistance, such as central obesity, type 2 diabetes mellitus with obesity, and essential arterial hypertension, a deep reduction of platelet sensitivity to the antiaggregating effects of insulin has been reported [
Also the effects of insulin infusion on platelet deposition to collagen in flowing whole blood perfusion are lost in obese insulin-resistant subjects [
Studies showed that platelets from obese subjects and obese type 2 diabetic patients and individual with the metabolic syndrome are resistant to the antiaggregating effects of NO donors, including glyceryl trinitrate (GTN) and sodium nitroprusside (SNP) [
This impairment of platelet response to NO (defined also as “NO resistance”) is similar to that identified by other authors in platelets of nondiabetic patients affected by coronary ischemic disease [
Obese subjects are also resistant to the antiaggregating effects of both PGI2 and adenosine, which act through the adenylate cyclase/cAMP pathway [
In addition, it was observed that platelets from obese subjects are resistant to the antiaggregating effects of the cyclic nucleotides themselves, as evidenced by experiments with cell permeable analogues of both cGMP and cAMP [
All these observations indicate the occurrence of a multistep resistance to antiaggregation in obesity and in obese type 2 diabetes mellitus, including the ability of insulin to increase NO, the ability of NO to increase cGMP, the ability of cGMP to reduce platelet calcium and consequently aggregation, and, similarly, the ability of PGI2 to increase cAMP and the cAMP ability to reduce platelet function [
Omental adipose tissue is a dynamic endocrine organ which secretes a number of bioactive peptides involved in the control of insulin action, energy homeostasis, inflammation, and cell growth by autocrine, paracrine, and endocrine actions [
Adipokines locally regulate fat mass by modulating adipocyte size/number or angiogenesis [
Cytokines from monocytes and macrophages, such as TNF
Increased fat mass leads to dysregulation of adipose tissue activity with oversecretion of deleterious adipokines and hyposecretion of beneficial ones (adiponectin, in particular) [
In this part of the paper some relevant data concerning several adipokines and cytokines recognized as involved in the derangement of the systemic hemostatic balance in patients with central obesity will be considered: in particular, leptin, ghrelin, adiponectin, and inflammatory cytokines considering their role in hemostatic balance, platelet function, and coagulative alterations characterizing central obesity.
Adipokines are circulating molecules with a central role in the pathophysiology of obesity and its systemic health effects [
Leptin is a 167-amino acid adipokine mainly produced by mature adipocytes, which primarily regulates food intake and energy expenditure [
Leptin influences also angiogenesis, inflammation, arterial pressure, and secretion of other adipokines; in humans, the vascular actions of leptin are considered proatherogenic, and increased circulating levels of leptin are recognized as an independent risk factor for cardiovascular diseases [
At present, evidence indicates that plasma leptin concentrations are independently associated with the intima-media thickness of the common carotid artery [
The prothrombotic actions of leptin are related to an influence on platelet function and coagulation/fibrinolysis balance, resulting in enhanced agonist-induced platelet aggregation and increased stability of arterial thrombi [
Studies
Finally, other mechanisms—such as inflammation, oxidative stress, endothelial dysfunction, and increased sympathetic tone—may contribute to leptin-induced vascular damage [
At present, the role of other adipokines in thrombosis is not fully defined [
The reduced levels of adiponectin, as well as the increased circulating concentrations of TNF-
Recent evidence showed that resistin, an adipokine involved in insulin resistance [
The renin angiotensin system is completely expressed in human adipose tissue, and the synthesis by adipocytes of angiotensinogen—precursor of the major vasoconstrictor hormone angiotensin II—is increased in central obesity [
Augmented angiotensinogen production by adipose tissue has been directly linked to angiogenesis and new adipose cell formation [
There is evidence that several alterations of hemocoagulative cascade and fibrinolysis in central obesity are closely related to the presence of low-grade inflammation [
TNF-
The contribution of TNF-
TGF-
Finally, TGF-
TSP1 is a multifunctional protein firstly isolated from platelets and megakaryocytes [
Beyond its inhibitory action on angiogenesis, TSP1 regulates cell proliferation, inflammation, and wound healing [
TSP1 expression is increased in obese, insulin-resistant subjects and is positively associated with plasma PAI-1 levels, being one of the regulators of PAI-1 synthesis in adipose tissue [
Abnormal concentrations of lipids and apolipoproteins resulting from changes in the synthesis and catabolism of lipoprotein particles are typically observed in the patients with metabolic syndrome [
Circulating lipoprotein particles interplay with hemostatic factors modifying their expression and with platelets influencing their activation: therefore, mixed dislipidemia characterizing the metabolic syndrome plays a role in the prothrombotic tendency [
The reduction of circulating HDL particles, which are known to exert an antithrombotic activity by decreasing TF expression [
The increased plasma levels of VLDL particles, triglycerides, and free fatty acids and the decrease of circulating HDL particles may enhance the responses of circulating platelets [
Central obesity has a relevant impact on the risk of cardiovascular morbidity and mortality due to atherothrombotic events [
Together with hemodynamic alterations and metabolic impairment, central obesity accelerates the atherosclerotic vascular damage mainly through the presence of prothrombotic tendency and chronic low-grade systemic inflammation [
As extensively reviewed, the prothrombotic tendency in central obesity is the result of a cluster of alterations involving intrinsic and extrinsic coagulation pathways, fibrinolysis and platelet function, each of which cooperates to favour the thrombotic processes [
Growing evidence indicates that adipose tissue of the trunk and/or abdomen has a strong impact on vascular complications, through the production of mediators with paracrine and endocrine actions (adipokines and cytokines) [
As discussed in the second part of this paper, changes in the synthesis and/or release of biologically active molecules as well metabolic alterations have to be considered as fundamental mechanisms involved in the adverse effects of adiposity on the vessel wall and hemostatic balance [
Several mediators synthesized and released by adipose tissue in increased amount cause adverse effects through different mechanisms including the determination of a low-grade inflammatory milieu and oxidative stress; the production of other bioactive molecules with protective vascular effects is downregulated by the increase of the fat mass [
Due to the increasing impact of the central obesity across all ages, including children and adolescents, the prevalence of the metabolic syndrome has reached epidemic proportion both in western and developing countries.
For the high risk of cardiovascular morbidity and mortality, metabolic syndrome represents a relevant problem in the clinical practice which requires an adequate definition of the complex cluster of pathogenetic factors [
Adenosine 5-diphosphate
Atherosclerosis risk in communities
Body mass index
Computed tomography
Endothelial-type constitutive NO synthase
Endothelins
Fibrin degradation products
Factor VII
FVII coagulant activity
Factor VIII
Factor IX
Factor X
Glyceryl trinitrate
Intercellular adhesion molecule-1
Interleukin-6
Low-density lipoproteins
Monocyte chemoattractant protein-1
Magnetic resonance imaging
Macrophage colony-stimulating factor
Microparticles
National Health and Nutrition Examination Survey III
National Cholesterol Education Program Adult Treatment Panel III
Nitric oxide
Superoxide anion
Platelet-activating factor
Plasminogen activator inhibitor-1
Plasminogen activator inhibitor-2
Northwick Park Heart Study
Prostacyclin
Platelet-derived microparticles
Reactive oxygen species
Sodium nitroprusside
Soluble CD40 ligand
Small, dense LDL
Thrombin-activatable fibrinolysis inhibitor
Tissue factor
Tissue-type plasminogen activator
Transforming growth factor-
Tumor necrosis factor-
Thrombospondin-1
Thromboxane A2
Urokinase-type plasminogen activator
Verylow-density lipoproteins
Vascular cell adhesion molecule-1
Von Willebrand factor
Vascular smooth muscle cells
Waist-to-hip ratio
World Health Organization.
The author declares no conflict of interests.
This paper has been conceived, written and completed in memory of Professor Giovanni Anfossi.