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Table 1: Diseases and Conditions Associated with an Increased Risk of Arterial and/or Venous Thrombosis and Inflammation

Disease or Condition Diabetes

Overweight and obesity Metabolic syndrome Chronic obstructive

pulmonary disease Systemic lupus erythematosus

Inflammatory bowel disease HIV infection Sickle cell disease Ageing Type of Thrombosis Arterial and venous Arterial and venous Arterial Arterial and venous Arterial and venous

Arterial and venous Venous

Arterial and venous Estimated Thrombosis Risk

Arterial and venous* HR for AMI: 2.5 (2.45–2.55) in men and 3.73 (3.65–3.82) in women OR for VTE: 1.42 (1.12–1.77) OR for CVD: 1.36 (1.27–1.44)†

HR for VTE: 1.92 (1.05–3.48) in women and 2.78 (1.47–5.27) in men‡ OR for CVD: 3.48 (2.26–5.37) OR for VTE: 1.94 (1.04–3.63)# OR for CVD: 2.7 (2.3–3.2)

IR for arterial VTE: 11.8 events/100 person-years IR for VTE: 12.06 events/100 person-years IRR for ischaemic heart disease: 1.26 (1.11–1.44) HR for acute mesenteric ischaemia: 11.2 OR for VTE: 3.6 (1.7–7.8) RR for CVD: 1.5–2§

OR for PE: 3.9 (2.2–6.9) OR for DVT/PE: 1.8 (1.2–2.9)

IR for CVD: from 3 per 1,000 men 35–44 years of age to 74 per 1,000 men 85–94 years of age; for women,

similar rates occur 10 years later in life For VTE: 10-fold increase in risk from 45–49 to >85 years of age

*A recent large epidemiological study reported that diabetes, after controlling for other variables, is actually not a risk factor for venous thromboembolism (Heit et al., 2009). †In those 45–64 years of age compared with those >65 years of age. ‡For waist circumference ≥85cm in women and ≥95cm in men. #Idiopathic event in men. §Compared with men of the same age. Risk is reported as odds ratio (OR), hazard ratio (HR), incidence rate (IR), incidence rate ratio (IRR) or relative risk (RR), depending on the original study design. Exemplification risk estimates were chosen. Other estimates are available in the medical literature. 95% confidence intervals (CIs) are in brackets. AMI = acute myocardial infarction; CVD = cardiovascular disease; DVT = deep vein thrombosis; HIV = human immunodeficiency virus; PE = pulmonary embolism; VTE = venous thromboembolism. a. Booth GL, et al., Lancet, 2006;368:29–36; b. Ageno W, et al., Circulation, 2008;117:93–102; c. Ye J, et al., Ann Epidemiol, 2009;19:718–23; d. Borch KH, et al., Arterioscler Thromb Vasc Biol, 2010;30:121–7; e. Cabré JJ, et al., BMC Public Health, 2008;8:251; f. Ageno W, et al., J Thromb Haemost, 2006;4:1914–8; g. Finkelstein J, et al., Int J Chron Obstruct Pulmon Dis, 2009;4: 337–49; h. Chang ER, et al., J Rheumatol, 2006;33:1780–4; i. Bernstein CN, et al., Clin Gastroenterol Hepatol, 2008;6:41–5; j. Ha C, et al., Am J Gastroenterol, 2009;104:1445–51. k. Miehsler W, et al. Gut, 2004;53:542; l. Grinspoon SK, et al., Circulation, 2008;118:198–210; m. Tsaras G, et al., Am J Med, 2009;122:507–12; n. Lloyd-Jones D, et al., Circulation, 2009;121(7):e46–e215; o. Silverstein MD, et al., Arch Intern Med, 1998;158:585–93.

required for adaptive immunity, for example antigen-specific antibody production and allograft rejection.6

In inflammatory bowel disease,

CD40L-positive platelets have been shown to adhere to mucosal microvascular endothelium in vivo, where they trigger or amplify a pro-inflammatory response.11

Platelets also secrete soluble CD40L

(sCD40L), which in sickle cell anaemia is elevated in plasma and biologically active. It therefore contributes to the induction of B cells, tissue factor and inter-Cellular adhesion molecule 1 (ICAM-1), suggesting that sCD40L may add to the chronic inflammation and increased thrombotic activity known to occur in this disorder.12 sCD40L interacts with another protein, type I transmembrane receptor CD40, which is expressed on platelet activation but is also present on monocytes/macrophages and endothelial cells. The sCD40L–CD40 interaction in this context promotes monocyte adhesion to vascular endothelium, endothelial activation and expression of leukocyte adhesion molecules.8

Platelets have been shown to activate dendritic cells through the expression of CD40L in both in vitro and in vivo mouse models. Thus, through the co-stimulatory activity of dendritic cells, platelets are able to regulate T- and B-cell responses.13

Although the clinical significance

of these observations has not yet been determined, it is interesting to note that increased expression of platelet activation markers, including CD40L, can be detected in several diseases with T- and B-cell components. These include inflammatory bowel disease, atherosclerosis, diabetes and systemic lupus erythematosus.13

An activating capability of oxidised low-density lipoprotein (LDL) cholesterol on platelets mediated by the platelet receptor CD36 has


Besides hyperlipidemia, two other mechanisms might link obesity or the metabolic syndrome to thrombosis. The first is mediated by leptin, a hormone that regulates energy intake and is structurally and functionally related to cytokines. Leptin can enhance platelet aggregation when present in high concentrations, such as those observed in obese individuals.16,17

recently been described. This is an interesting relationship between platelets and the chronic inflammatory feature of atherosclerosis.14 This activation can be further augmented by endothelial-cell-derived microparticles, which also bind and activate platelets via CD36.15

Lloyd-Jones et al., 2009n Silverstein et al., 1998o


Booth et al., 2006a Ageno et al., 2008b Ye et al., 2009c

Borch et al., 2010d Cabré et al., 2008e Ageno et al., 2006f

Finkelstein et al., 2009g Chang et al., 2006h

Bernstein et al., 2008i Ha et al., 2009j

Miehsler et al., 2004k Grinspoon et al., 2008l Tsaras et al., 2009m

A second mechanism is observed in

This may be why platelets from patients with diabetes or those who are obese are less sensitive to the antiaggregating effects of insulin.19

central obesity and involves insulin resistance. Platelets physiologically express insulin receptors. Insulin decreases the sensitivity of circulating platelets to agonists and platelet deposition under high shear rate conditions.18

Another pathway linking innate immunity, haemostasis and thrombosis is the activation of a complement by platelets or platelet microparticles, supposedly through the expression of the C1q receptor on the platelet surface and the expression of P-selectin.7

The complement-activated

components C3a and C5a are potent pro-inflammatory agents. The terminal complement complex C5b–9 has platelet- and endothelial- activating properties at sublytic concentrations.7

The platelet chemokine platelet factor-4 (PF-4) and beta-thromboglobulins have an important, although diversified, role in innate immunity as well as an established and well-known role in haemostasis.20,21


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