Increased risk of venous thromboembolism in patients with gastrointestinal disorders

Gastrointestinal diseases such as inflammatory bowel diseases are associated with extraintestinal complications which are associated with significant mortality and morbidity. Venous thromboembolism (VTE) is one such complication associated with inflammatory bowel disease, which is important not only due to its high prevalence but also because it is preventable and treatable.1-3 Identifying patients with gastrointestinal diseases who are at risk of VTE could allow clinicians to better risk stratify for preventative treatment, and maintain a high index of suspicion to investigate and diagnose VTE in a timely manner. Such insights would also aid researchers in understanding associations and mechanisms behind the increased VTE risk and implementing measures to reduce the associated mortality and morbidity. In this issue of the American Journal of Hematology, Yuan et al.4 report a prospective cohort study utilizing the UK Biobank, to examine the associations of gastrointestinal diseases with the risk of incident VTE. In this paper, 21 gastrointestinal diseases were explored in the study, including seven cancers and 14 non-neoplastic diseases. A total of 485 936 patients, after excluding participants with baseline VTE, were included in the final analysis. With a median follow-up of 12 years, the authors found an increased risk of VTE amongst 11 gastrointestinal disorders when compared to patients without gastrointestinal disease, particularly significant for gallbladder and biliary tract cancer (hazard ratio [HR] 3.15, 95% confidence interval [CI], 1.74–5.70), pancreatic cancer (HR 2.84, 95% CI 1.65–4.91), cirrhosis (HR 2.34, 95% CU 1.96–2.79), Crohn's disease (HR 1.61, 95% CI 1.33–1.95), and pancreatitis (HR 1.57, 95% CI 1.31–1.88), conferring greater than 50% higher risk when compared to healthy controls. Hence, the headline that “gastrointestinal disease is associated with VTE” is perhaps an over-simplification, as not all different types of gastrointestinal disease confer similar risks, as illustrated by the data from Yuan et al.4 Patients with gastrointestinal disease, particularly the presence of an ongoing inflammatory process such as Crohn's disease, are also at increased risk of VTE due to the interdependency of inflammation and thrombosis which is consistent with previous literature.5 Similarly, the association of cancer and VTE is well known6-8 and was seen within this analysis. However, cancer is not a single diagnosis, and some variation in VTE risk with types of cancer is well recognized.6 Although liver disease and cirrhosis are more commonly associated with hemorrhagic complications, a meta-analysis by Ambrosino et al. has shown an increase in the risk of VTE in patients with liver cirrhosis,9 possibly explained by the changes in hemostatic balance resulting in a simultaneous decline in both pro- and anti- hemostatic drivers.10 Hence, the study by Yuan et al.4 reaffirms conclusions from previous studies that patients with some gastrointestinal diseases are at increased risk of VTE. Nonetheless, the analysis does not address whether VTE is associated with greater disease severity (for example, localized versus extensive disease) nor the impact of ethnicity, aging, and incident comorbidities or changes in drug therapy over the follow-up period. Also, the impact of initiating antithrombotic therapy, and the sequelae of bleeding complications may differ by type of gastrointestinal disease, ethnicity, and other factors.11, 12 Delving deeper into the data relating to the subgroup studies, the authors found that females and patients with higher body mass index were at increased risk of VTE. These findings are supported by a recent study in Norway which has also shown that nearly a quarter of VTE events were attributed to overweight and obesity13 and a Danish study showing a marginally higher lifetime risk of VTE in women compared to men.14 One counter-intuitive finding study by Yuan et al.4 was that the risk of VTE was higher in patients below 60 years of age, while the risk of VTE increases with age due to physiological changes in coagulation and fibrinolytic systems.15 However, previous studies in patients with gastrointestinal disorders have reported that although the numerical incidence of VTE increases with age, that is, higher absolute risk with older adults, the risk ratio in patients below 60 is higher.2, 3 This observation could be indicative of the presence of gastrointestinal disorder playing a larger contributory role as a risk factor for VTE in the younger population or possibly, the absence of other age-related, undiagnosed comorbidities in the younger “healthy” cohort as opposed to the older “healthy” cohort. Therefore, the comparison of a cohort of patients with gastrointestinal disorders to a truly healthy cohort would emphasize the impact of the disease more than the comparison with a cohort with undiagnosed disorders that would contribute to the risk of developing VTE. In conclusion, this study by Yuan et al.4 confirms previously known risk factors associated with VTE in a cohort of patients with gastrointestinal disorders. It particularly highlighted that a younger age may not be “protective” of VTE risk as previously thought. Therefore, understanding and recognizing other risk factors may be beneficial in identifying patients who are at risk and potentially having a higher index of suspicion in patients presenting with symptoms consistent with VTE, and considering prophylactic treatment of patients at increased risk of VTE. The authors have no conflict of interests to declare.