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Risk factors for venous thromboembolism: Smoking, anthropometry, and genetic susceptibility

Marianne Tang Severinsen


Venous thromboembolism (VTE), including deep venous thromboses (DVT) and pulmonary emboli (PE), is a common disease with substantial personal, clinical, and social implications. Venous thromboembolism is thought to start in the calf veins, can progress to the proximal veins, and may break free to cause the potentially fatal condition of PE. VTE is associated with acute symptoms and long-term complications, including post-thrombotic syndrome and chronic pulmonary hypertension. Despite the serious consequences of this disease, 25-50% of VTE events occur in individuals that have no known risk factors. The associations between VTE lifestyle factors like smoking and obesity described by various anthropometric variables have not been established. Furthermore, it is not clear whether there are interactions between lifestyle factors and common genetic risk factors for VTE.
The aims of this thesis were: (1) to evaluate the validity of discharge diagnoses of DVT and PE in the Danish National Patient Registry (study I); (2) to asses the association between smoking and VTE (study II); (3) to assess the association between anthropometry and VTE (study III); and (4) to assess the interactions between genetic risk factors (the Factor V Leiden G1691A mutation and the prothrombin G20210A mutation) and lifestyle factors (smoking and obesity) (study IV).

Study I was a descriptive study that included 1,100 individuals from the Diet, Cancer, and Health cohort that had a record of a VTE discharge diagnosis in the Danish National Patient Registry during a 10 year follow-up period. Medical records and discharge letters were retrieved and reviewed according to a standardised format. We found that VTE discharge diagnoses from wards were reasonably valid, but diagnoses given in emergency departments were largely based on the suspicion of VTE and, therefore, had a low positive predictive value. We also found significant differences between the positive predictive values for DVT and PE, for primary and secondary diagnoses, and for men and women.
In study II, we found that smoking was a risk factor for VTE. The risk of VTE was especially high among women that smoked more than 20 grams of tobacco per day andmen that smoked more than 30 grams of tobacco per day. Former smokers had the same risk as never-smokers for VTE. This underscored the benefits of smoking cessation.
Obesity, measured as body mass index (BMI), was previously found to be associated with VTE. The BMI is a marker of excess weight and correlates well with body fat content in adults; however, it fails to consider the distribution of body fat. In study III, we tested the hypothesis that central obesity might be a better predictor for VTE than peripheral obesity, measured as hip circumference. This hypothesis was valid for the risk of coronary heart disease, but our results showed that both peripheral and central obesity were strong risk factors for VTE. The results indicated a distinction between VTE and coronary heart disease, because no associations have been found between hip circumference and coronary heart disease. Furthermore, this study indicated that the effect of obesity on the risk of VTE was not mediated purely by hypertension, cholesterol levels, or diabetes.
The incidence rate of VTE is highly variable in individuals with the common genetic risk factors, Factor V Leiden (G1691A) and the prothrombin (G20210A) mutation. We evaluated whether the genetic susceptibility to venous thromboses was influenced by obesity and smoking. We found that individuals with one of these mutations seemed to be more susceptible to the unfavourable effects of smoking and obesity. Although genetic risk factors cannot be modified, our study indicated that the risk of VTE might be reduced in genetically disposed individuals by maintaining a healthy body weight and refraining from smoking tobacco.