Venous thromboembolism (VTE) is the third most common cardiovascular disorder after ischemic heart attack and stroke [1,2]. It is estimated that VTE occurs among 1 to 2 per 1000 persons annually in the United States [3–5]. VTE imposes a substantial burden on the US health care system. The initial clinical management, recurrence, and long-term complications of VTE including post-thrombotic syndrome (PTS) and other VTE-associated comorbid conditions compromise quality of life and cost about $2 billion to 10 billion annually to the health care system in the United States [6,7].

Obesity is a major public health problem not only in the United States, but also rapidly is becoming a global threat [8]. While obesity can serve as a risk factor for some diseases, it also can affect preexisting diseases or lead to an array of comorbid conditions, including coronary artery disease (CAD), type 2 diabetes mellitus, hypertension, stroke, heart failure, obstructive sleep apnea syndrome, gastrointestinal disorders, depression, malignancies, and VTE [9,10]. In this review, we focus on the association between obesity and VTE, explore possible interactions between obesity and several other risk factors for VTE, discuss limitations of current obesity measurement, identify possible research gaps, and suggest some avenues for prevention of VTE associated with obesity. Although medical interventions are important, the clinical management of VTE is not in the scope of this review.

VTE encompasses two distinct clinical entities: deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT begins with formation of a blood clot in the deep veins of the body, usually in the legs or pelvis. PE occurs if the clot becomes detached and travels to the pulmonary arteries, and can result in death. Development of PTS is a common medical complication of DVT [11], while chronic thromboembolic pulmonary hypertension (CTEPH) can occur following a PE [12]. CTEPH is initiated by the obstruction of pulmonary arteries with thrombi that can lead to cardiac failure and death if left untreated [13]. PTS clinically manifests as persistent or intermittent pain, swelling, ulceration, or cramping in the limb affected [6]. In one longitudinal study, the cumulative incidence of PTS was reported to be 17% and 23% at 1-year and 2-year follow-up post-DVT, respectively, and increased gradually to 29% over a period of 8 years [6]. In addition, approximately 30% of patients experienced recurrent VTE (DVT or PE) within 10 years of an initial VTE event [14]. Consequently, VTE can be considered a chronic rather than an acute disease.

The incidence of VTE varies widely across different racial populations and increases with age and hospitalization. Analysis of the California Patient Discharge Data Set showed that the total annual VTE incidence rate per 100,000 adults was 141 for Blacks or African Americans, 104 for Whites, 55 for Hispanics, and 21 for Asians [5]. Blacks or African Americans not only appeared to have the highest overall VTE incidence rate, but also were found to have a significantly greater PE case-fatality rate [5,15,16]. The incidences of PE and DVT also increase sharply with age [3,17]. Stein et al. investigated the database of the National Hospital Discharge Survey, which consists of data obtained during the period 1979 through 1999 from patients of over 400 nonfederal short-stay hospitals in all 50 states and the District of Columbia [17]. They found that the frequency of PE among patients 70 years of age or older was more than 4-times that among patients younger than 50 years of age [17]. Also, hospitalized patients and recently discharged patients were seen to have a remarkably increased risk for VTE [18]. Different from idiopathic or spontaneous VTE that occurs in the absence of known precipitating factors, VTE associated with hospitalization likely is provoked by multiple risk factors for VTE, including immobilization; surgery; trauma; childbirth; stroke; or the patient’s comorbid medical conditions, such as infection, inflamematory bowel disease, or cancer [19].

The most frequently used indicator of obesity is the body mass index (BMI) [10], with a normal range of 18.5 – 24.9 kilograms per square meter (kg/m²) among adults 20 years of age or older. Someone with a BMI of 25 – 29.9 kg/m² is considered overweight, and someone having a BMI ≥ 30 kg/m² is considered to be obese. According to World Health Organization (WHO) criteria established in 1997 [10], obesity among adults is further classified into three categories: Class I obesity is a BMI of 30 – 34.9 kg/m²; Class II obesity is a BMI of 35 – 39.9 kg/m²; and Class III obesity, or morbid obesity, is a BMI ≥ 40 kg/m². Childhood obesity is defined as a BMI greater than or equal to the 95th percentile of BMI-for-age for children and adolescents of the same sex (2 through 19 years of age) [20]. Wang et al. proposed that severe obesity among the pediatric population (2 through 19 years of age) be defined as BMI-for-age greater than or equal to 120% of the 95th percentile of the Centers for Disease Control and Prevention growth charts [21].

Alternative anthropometric measures that reflect the distribution of body fat have been suggested as being superior to BMI in predicting certain diseases [22,23]. For example, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (W/Hr) that define central obesity appear to be associated more closely with cardiovascular disease (CVD) than BMI [22,24]. WHO reference cutoff points for obesity were introduced in 2008 as a WHR (WC) > 0.9 (102 centimeters (cm)) for males and >0.85 (88 cm) for females [25].

Body fat percentage (BF%) directly calculates an individual’s body composition. It can be measured accurately when using magnetic resonance imaging (MRI) [26] or dual-energy X-ray absorptiometry [27]. In the HERITAGE Family Study, Jackson et al. found that the BF% of females was 10.4% higher than that of males with the same BMI [28]. The American Council on Exercise recommended that cutoff value for obesity was a BF% > 25% for men and >32% for women [29]. In addition, BF% also is subject to change depending on age and race [28,30]. Asian populations generally have a higher BF% and appear to be more sensitive to the metabolic consequences of obesity than Whites of the same age, sex, and BMI [25]. Body fat generally increases and fat-free mass decreases with increasing age [28]. Consequently, older individuals usually have a higher percentage of body fat than younger individuals of the same BMI [30].

VTE results from the complex interactions of genetic and environmental factors that influence the coagulant, inflammatory procoagulant, anticoagulant, and fibrinolytic system, leading to hypercoagulability or hypofibrinolysis, or both. In other words, VTE is a multifactorial chronic disease that most often involves two or more risk factors. Although obesity appears to be a moderate risk factor for VTE [32,49], it can interact with other risk factors in VTE development and recurrence. Here, we have summarized the relationship of obesity with some common weak-to-moderate risk factors for VTE, including genetic factors, use of sex steroid hormones, inflammation, and insulin resistance [50,51].

With the high prevalence of obesity [21,81] and potential interplay of obesity with other risk factors for VTE discussed previously, implementation of effective, safe, and practical prevention strategies is critical in reducing the incidence of VTE associated with obesity and minimizing recurrence of VTE.

Intentional weight loss through diet control and physical activity may modulate risk factors for VTE among the population with obesity. Regular physical activity may reduce risk of VTE through a reduction of the activity of plasminogen activator inhibitor-1 (PAI-1) that was accompanied with body-weight loss [82] and an increase in endothelial release of tissue-type plasminogen activator (t-PA) upon bradykinin stimulation among the individuals who were obese [83]. Lutsey et al. reported that moderate to high intensity physical exercise was associated with reduced risk of VTE compared with low level of physical activity [84]. However, others did not find a significant impact of regular physical exercise on the risk of VTE [85–87]. It is not clear whether increasing intensity and frequency of exercises, or whether exercises in conjunction with diet control to an extent that can result in weight loss may decrease risk of VTE among individuals who are obese. In the NHS and Health Professionals Follow-Up Study (HPFS), Varraso et al. found that a diet intake rich in vitamins E and B6 and fiber was associated with a decreased risk for VTE [88]. These results were corroborated by findings from the WHI study (n = 39,876) [89] and the Longitudinal Investigation of Thromboembolism Etiology (LITE) study (n = 14,962) [90]. However, Lutsey et al. observed no significant association between VTE and food nutrients, including vitamins E and B6 and whole grains, in the Iowa Women’s Health Study (IWHS) [91]. A noticeable difference among these studies was the age of their participants. Lutsey et al. pointed out in the IWHS that the mean age of their study participants at the midpoint of follow-up was 72 years compared a mean age of 60 years among participants in the LITE study [91]. The nurses were 30 through 55 years of age in both the NHS/HPFS and more than 90% of the participants in WHI were younger than 64 years of age [88,89]. A general decline in food-nutrient digestion, absorption, and metabolization among old adults in the IWHS might have contributed in part to the less significant effect of diet on VTE than among younger people in the NHS/HPFS and WHI and LITE studies. Nevertheless, Lutsey et al. found alcohol intake was inversely related to risk of VTE in the IWHS [91]. Moderate wine consumption modulated expression of fibrinolytic proteins, including PAI-1 and t-PA [92,93] and the effects appeared to be alcohol dependent [94]. Although some studies have suggested that alcohol intake conferred a reduced risk of VTE [91,95], the effects have not been confirmed by others [85,96,97]. Given these inconsistent findings about alcohol and VTE, extensive epidemiological investigations are warranted to determine if alcohol consumption might be beneficial in reducing the risk for VTE among individuals who are obese.

Effective DVT prophylaxis (mechanical and pharmacological) can reduce the morbidity and mortality of VTE among hospitalized patients [98], but studies examining thromboprophylaxis of patients who are obese are limited [99]. The American College of Chest Physicians (ACCP) guidelines do not recommend using mechanical prophylaxis alone for VTE prevention among patients with morbid obesity unless a high bleeding risk precludes the use of pharmacological prophylaxis; however, the ACCP guidelines do suggest weight-based dosing for certain anticoagulation medications for VTE prophylaxis [100]. Several studies have demonstrated the necessity of adjusting the anticoagulant loading dose and dosing interval to achieve optimal anticoagulation among patients who are morbidly obese [99,101]. Suboptimal adherence to prophylaxis schemes or inappropriate prophylaxis (underprophylaxis of patients who are severely obese or overprophylaxis of patients who are of normal weight or who are underweight) has been reported [98, 99,102]. Moreover, both the ACCP and the National Institute for Health and Clinical Excellence underscore the importance of individualized prophylaxis according to the estimated risk of VTE [103]. Therefore, education of at-risk individuals (e.g., people who are obese), VTE patients, and health care providers to improve clinical awareness and knowledge of VTE is essential to ensure proper and timely thromboprophylaxis [99].

The WHO-defined BMI cutoff points for obesity classification have been accepted generally and used widely. However, BMI does not account for the wide variation in body fat distribution and, hence, might not be appropriate for use in all populations to predict accurately disease development as a risk factor. For example, in a cohort study of Italian children recruited from 15 national clinical centers (n = 1479, 5 – 15 years of age), Maffeis et al. reported that children with a normal BMI but with an increased W/Hr were at high risk for metabolic disorders and CVD compared with those with a lower W/Hr (OR > 7, p < 0.001) [24].

Although growing evidence has suggested an association between obesity and VTE, several questions remain to be answered. For instance:

Does the interplay between obesity and other risk factors for VTE additively or synergistically intensify the clinical severity of VTE (besides the frequency of VTE)?

As discussed previously, epidemiological studies have suggested that obesity is associated with a significantly higher frequency of VTE in the context of multiple risk factors than obesity by itself. Dire future efforts should be directed to:

Develop thromboprophylaxis schemes and other prevention strategies suitable for patients of different obesity categories (i.e., Class I obesity, Class II obesity, and morbid obesity). A fixed dose of FDA-approved anticoagulant regimens might not provide optimal VTE prophylaxis among patients who are severely obese. For example, subcutaneous injection of 40 mg of enoxaparin twice daily generated an anti-Xa concentration of 0.14 internation units per milliliter (IU/mL) among patients who were overweight, but only 0.06 IU/mL among patients who were morbidly obese [101].

In future studies, a combination of two or more methods should be considered in obesity measurement [48]. Some individuals with a normal BMI might have excessive adiposity as determined by more sensitive methods, such as BF% [27]. This so-called “normal weight obesity” suggests that exclusively relying on a single measurement for obesity might be of limited value and might result in inconsistent findings regarding excessive body fat as a risk factor for disease. Given WC (positively) and BMI (negatively) were differently associated with mortality [48], the “obesity paradox” phenomenon among patients with PE [31,32] might be reconciled by using WC or WHR in combination with BMI for obesity assessment.

People who are obese are at an increased risk for VTE compared with individuals who are of normal weight. The extent of the effects of obesity on VTE depends not only on total body fat, but also on the distribution of adipose tissue (e.g., central obesity) and the interplay among risk factors for VTE, such as genetic mutations, hospitalizations, and OCP use. The dimension and strength of possible interactions between obesity and these VTE risk factors may vary across different racial populations and can differ by age and sex as well. Therefore, consideration of other proper anthropometric measurements (not relying on BMI solely) for accurate identification of obesity may be needed to understand the etiology of VTE and to assess the need for and effectiveness of interventions to reduce the risk of VTE among individuals of different races who are obese. With the high prevalence of obesity in the United States [21,81,111], it is likely that the incidence of VTE also will increase with time. Commensurate attention is needed to develop effective VTE prevention strategies aimed at the large population who are obese.