We found that patients with IBD have a 3.6-fold higher risk of TE compared with controls matched for age and sex. This represents a relevant extraintestinal complication of IBD, including life threatening pulmonary embolism.
This increased risk of TE in IBD has long been proposed, with wide variation in the reported prevalences of between 1.2% and 6.1% in database queries and chart reviews and even reaching 39% in necropsy studies.1–6
There are limitations concerning the weight of these studies in view of their methodological shortcomings—mainly the lack of representative matched control groups—making their interpretation difficult. This shortcoming, the lack of a control group, was recently overcome in a database query that yielded a relative risk of three for TE in IBD, similar to our results.5
However, in this study, patients were not subject to stringent diagnostic criteria. Subjects were considered IBD patients if the diagnosis “IBD” was noted several times in a “physician claim”. In fact, it is possible that diagnostic misclassification of IBD could have influenced the reliability of an association between IBD and TE which has in analogy already been shown for genetic linkage studies.21
To avoid distortion of the data by diagnostic misclassification, we only enrolled patients in the care of IBD centres as these patients reliably fulfilled stringent diagnostic criteria for IBD.22,23
As back up questions, every item on the clinical risk factors for TE was followed by the repeat question of whether TE had occurred in relation to the respective item. Furthermore, patients were asked if they had ever received anticoagulant therapy and for which indication and duration this was taken. Thus the design of our questionnaire increased the probability that all thromboembolic events that had occurred in our outpatient population were recorded.
The second important result of our study is the fact that the prevalence of TE was not increased in rheumatoid arthritis and coeliac disease, indicating that TE is a specific feature of IBD. On the one hand, one would expect an increased prevalence of TE in rheumatoid arthritis due to arthroplasty, a common procedure in patients with rheumatoid arthritis and an association with antiphospholipid antibody syndrome. However, in the present study there was no increased prevalence of TE in rheumatoid arthritis. To our knowledge only one retrospective study has mentioned the prevalence of TE in rheumatoid arthritis although it has to be interpreted cautiously as the data were generated only from chart review and there was no control group.24
However, the reported prevalence of TE in rheumatoid arthritis was 3.8%, being higher than in our data, which can be explained by the fact that in this study TE was also accepted on the basis of a clinical diagnosis alone. The prevalence of TE in coeliac disease was 1%, the same as in the control group. Given the fact that coeliac disease occurs independently of socioeconomic status, the coeliac disease group may be seen as an ideal representative sample of the background population, underscoring the validity of our control group. However, we have provided the first data on the prevalence of TE in coeliac disease. However, TE has also been described as the initial symptom in coeliac disease which has been attributed to acquired hyperhomocysteinaemia as a consequence of folic acid and vitamin B12 deficiency.9,10
Hyperhomocysteinaemia has been recognised as an independent risk factor for arterial and venous TE which may occur secondary to folate and vitamin B12 deficiencies due to malabsorbtion as, for example, in the case of coeliac disease.25
Since the risk of TE is substantially higher in patients with IBD compared with rheumatoid arthritis and coeliac disease, the question then is why. Was it an ascertainment bias in favour of the IBD group as one could argue that IBD patients were more likely to have been subjected to imaging procedures required to make the diagnosis? For two reasons it is unlikely that a significant ascertainment bias occurred. Firstly, comparable intensity of medical care was provided in all three patient groups and, secondly, a considerable number of TEs in all groups were diagnosed and treated in primary and secondary care institutions in a standard fashion, irrespective of whether or not subjects had IBD. The second question in view of this increased risk is the certainly as to whether or not there is a simple explanation for this result based on the higher prevalence of one of the known clinical risk factors for TE in IBD. On average, patients with IBD have had a higher number of operations, longer duration of oral contraceptive use, more pregnancies, higher proportion of smokers,26
and a lower BMI. However, it appears that these factors are not of major relevance for the development of TE in IBD as the relative risk for TE in IBD still remained high after adjustment for these confounding variables in our logistic regression model. Furthermore, only five of 47 TEs in the IBD group occurred postoperatively, five TEs during oral contraceptive use, and none in relation to pregnancies. Thus these risk factors may have only marginally contributed to thromboembolic events in our IBD patients. Finally, we could not elaborate on an association between occurrence of TE and intake of IBD specific medications.
This assumption consequently gives rise to the question of which specific IBD factors might promote the development of TE. It is noteworthy that in the present study, 60% of TEs in IBD occurred during disease activity or in the presence of complications such as stricture, fistulisation, or abscess. In this respect, the role of endotoxins is highly interesting as endotoxins, with interaction of interleukin 1 and tumour necrosis factor α (TNF-α), can activate the coagulation cascade27
and systemic endotoxinaemia has been detected in active and fistulising CD and can obviously be assumed in the presence of abscesses.28,29
Furthermore, adding endotoxin to blood samples of patients with IBD induces formation of microclots.30
Interestingly, such clot formation cannot be induced in healthy subjects, which suggests that the procoagulatory effect of endotoxins might be enhanced by an IBD specific factor. In fact, it has been suggested that in IBD, activation of the coagulation cascade is more pronounced in active disease.31
Additionally, examination of the fibrinolytic system,32
platelet count, platelet function, and platelet factors,33,34
and rheological parameters35
have revealed significant abnormalities, which indicate that prothrombotic factors in IBD are more pronounced in active disease. The role of disease activity in promoting TE is further underscored by the report that administration of anti-TNF-α antibodies (infliximab) not only induces clinical remission but also leads to a decrease in activity markers of coagulation.36
However, there still remain some thromboembolic events in obviously quiescent IBD, which gives rise to the question of whether IBDs are associated with thrombophilic disorders. Several trials have been performed on the prevalence of resistance to activated protein C and factor V Leiden, respectively, factor II polymorphism (20210 G to A), and deficiencies of protein C, protein S, and antithrombin among patients with IBD.1,37–41
None of these studies was able to prove a specific role for one of these disorders in IBD. In contrast, IBD patients were shown to have higher levels of homocystein more frequently, which was attributed to folate deficiencies secondary to malabsorbtion.42,43
Conflicting data have been published on the prevalence of antiphospholipid antibodies in IBD, the majority suggesting an increased frequency in IBD.37,38,44,45
Finally, CD but not UC patients were shown to have higher levels of liporotein (a) more often compared with controls.46
It is known that lipoprotein (a) acts as an acute phase reactant47
and it was not reported if lipoprotein (a) was principally increased in these patients or only associated with flares. In summary, many studies have been performed evaluating the role of almost all of the known prothrombotic states in IBD, with none definitively proving any causal relation to the development of TE in IBD.
In conclusion, patients with IBD are at increased risk of developing TE, which seems to be a specific feature of IBD and was not observed in rheumatoid arthritis and coeliac disease. Although there are no data proving a causal relation of any procoagulative state in the promotion of TE in IBD, it is noteworthy that many thromboembolic events occurred during active disease or in the presence of complications such as stricture, fistulisation, or abscess.