SEARCH

SEARCH BY CITATION

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Background

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a systemic disorder that predominantly affects the bowels but is also associated with venous thromboembolism (VTE).

Aim

To provide a quantitative assessment of the association of IBD with venous thromboembolism risk and to explore the possible sources of heterogeneity in the current literature, a meta-analysis of case–control and cohort studies was conducted.

Methods

Studies were identified by a literature search of the PubMed and Scopus databases (from inception inclusive 31 December 2012) for English language studies. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with fixed- and random-effects models. Several subgroup analyses were performed to explore potential study heterogeneity and bias.

Results

Eleven studies met our inclusion criteria. The summary RR for deep venous thromboembolism (DVT) and pulmonary embolism (PE) comparing subjects both with and without IBD was 2.20 (95% CI 1.83–2.65). After adjusting for obesity and smoking, summary relative risks near 2.0 were seen for venous thromboembolism in both UC and CD patients.

Conclusion

This meta-analysis showed that inflammatory bowel disease is associated with an approximately two-fold increase in the risk of venous thromboembolism.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Venous thromboembolism (VTE) affects between 0.5 and 2 persons per thousand in the general community and is a major cause of death in hospitalised patients.[1-3] Thrombosis can start with the formation of a venous clot (thrombosis), often occurring in the deep veins of the legs, thighs, or pelvis, and can often be asymptomatic. The risk factors for venous thrombosis are primarily related to hypercoagulability, which can be either genetic (i.e. procoagulant proteins, protein C anticoagulant pathway, fibrinolytic proteins, homocysteine) or acquired as a result of immobilisation and venous stasis.[4] Acquired risk factors for venous thromboembolism include surgery, trauma, pregnancy, puerperium, lupus anticoagulants, malignant disease, oral contraceptives, long-haul travel, obesity, myeloproliferative disorders and polycythemia vera.[4, 5] Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most common types of thromboembolism, but thromboses are also reported in unusual sites such as cerebral, innominate, retinal, hepatic and mesenteric veins.[6-9]

Inflammatory bowel disease (IBD), which includes Crohn' s disease (CD) and ulcerative colitis (UC), is a systemic disorder that predominantly affects the bowels, but is also associated with a number of extraintestinal manifestations, some of which may be more debilitating than the bowel symptoms. The possible association between IBD and VTE was first reported in 1936 by Bargen and Barker, who described 18 patients with thromboembolic disease (predominantly venous) from among more than 1000 patients treated for IBD at the Mayo Clinic.[10] Since that time, several recent publications have suggested that patients with IBD have an increased risk of VTE[11], although some heterogeneity can be seen in the literature.[12-28] For example, while Nguyen et al.[17] reported that IBD patients may have a more than sevenfold increase in the risk of VTE, Saleh et al.[21] identified a much lower risk.

We conducted a meta-analysis of case-control and cohort studies to provide a quantitative assessment of the association of IBD with VTE risk, and to explore the possible sources of heterogeneity in the current literature. This topic is important as VTE could be a major cause of morbidity and mortality in people with IBD, and new information on the possible association between IBD and VTE could help raise awareness of this issue and assist in establishing guidelines for improving the health of patients with IBD.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Search strategy

Studies were identified by a literature search of the PubMed (from1961 through 31 December 2012) and Scopus databases (from 1978 inclusive 31 December 2012) for English language studies with the following medical subject heading terms and/or text words: venous thromboembolism, deep vein thrombosis, pulmonary embolism, inflammatory bowel disease, ulcerative colitis and Crohn's disease. We also reviewed the reference lists of the identified publications and relevant review articles for additional pertinent studies.

Inclusion and exclusion criteria

Published reports that met the following criteria were included: (i) evaluated risk of first venous thromboembolism, deep vein thrombosis, or pulmonary embolism among patients with Crohn' s disease and/or ulcerative colitis; (ii) had a case–control or cohort design which included a comparison group that lacked inflammatory bowel disease; (iii) reported an estimate of relative risk (RR), either an odds ratio (for case-control studies) or a rate or risk ratio (for cohort studies), accompanied by a corresponding measure of uncertainty [i.e. 95% confidence interval (CI), standard error, variance, or P value]; (iv) evaluated adult patients (>20 years old); and (v) evaluated age and gender as potential confounders. For multiple reports on the same population or subpopulation, we used either the relative risk estimates from the most recent report or the one containing the most cases. These criteria specifically excluded studies that evaluated cerebral thromboembolism or recurrent VTE and those that had a cross-sectional, ecological, or prevalence design.

The data extracted included the year of publication, country of the population studied, study design, number of cases, number of exposed and unexposed subjects (cohort studies), number of controls, source of the controls (case-control studies), follow-up period (for cohort studies), type of IBD (UC or CD), RR estimates with their corresponding confidence intervals (CIs) and variables controlled for by matching or in the multivariable models. The data were abstracted separately by two authors (HY and CS); discordant results were resolved by consensus.

Statistical analysis

Summary RR estimates were calculated using both the fixed-effects (inverse-variance weighted) method[29] and the random-effects method.[30] Odds ratios were assumed to provide estimates of RR. Statistical heterogeneity between studies was evaluated with Cochran's Q-test and the I2-statistic.[31] I2 describes the percentage of total variation across studies due to heterogeneity rather than chance.[32] I2 can be readily calculated from basic results obtained from a typical meta-analysis as follows:

  • display math

where Q is Cochran's heterogeneity statistic and df is the degrees of freedom. Publication bias was assessed by constructing a funnel plot and using Egger and Begg tests.[33, 34] In addition, to further evaluate the possibility of publication bias, and due to the fact that publication bias primarily affects smaller, less precise studies, reports were divided into two groups based on their sample size and precision.[33] Owing to the fact that the funnel plot showed a clear distinction in precision at this point, the five least precise studies were able to be compared to the other studies. All statistical analyses were carried out with STATA, version 11.0 (Stata Corp, College Station, TX, USA). P values < 0.05 were considered statistically significant. All statistical tests were two-sided. The analysis and reporting is consistent with the guidelines recommended for meta-analyses of observational studies.[4]

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Study characteristics

Detailed search steps are described in Figure 1. The electronic search identified 403 abstracts for review. From among these, 38 articles potentially met inclusion criteria and were retrieved for detailed review. The bibliographies of all 38 studies were reviewed and three additional studies were identified, providing 41 articles for full review. We excluded one candidate study[27] due to overlapping publications and one study[28] because it reported relative risks that were not adjusted by age. Eleven studies[12-22] met our predefined inclusion criteria and were thus included in the final analyses, the details of which can be seen in Table 1.

Table 1. Characteristics of IBD, DVT, and/or PE studies
Case-control studies of IBD and DVT and/or PE incidence
Author, year (Ref. No), countryNo. of case patients by subsitesNo. of control subjects (source of controls)Type of IBDRR (95% CI) thrombosis subsiteControlled variables
  1. CD, Crohn' s disease; DVT, deep vein thrombosis; IBD, inflammatory bowel disease; PE, pulmonary embolism; UC, ulcerative colitis.

  2. a

     RR and 95%CIs were calculated from raw data reported in the article.

  3. b

     Brain tumour, steroid use, any dyspnoea, chemotherapy, metastatic cancer, weight loss, operation within last 30 days.

  4. c

     Out-patient procedure, total length of stay, emergency surgery, total works relative value units, American Society of Anesthesiologists score of 1 or 2, white blood cell count >12 000/μL, post-operative organ space infection, post-operative sepsis, post-operative septic shock, dehiscence, failure to wean from ventilator, post-operative reintubation, post-operative neurological deficit, post-operative cerebrovascular accident, post-operative myocardial infarction, post-operative cardiac arrest, post-operative urinary tract infection.

Kappelman 2011[12] Denmark

125 963 VTE

(71 367 DVT

54 108 PE)

Population controlsUC and CD

a1.5 (1.2–1.8) VTE

1.5 (1.2–1.9) DVT

1.5 (1.1–2.1) PE

Age, gender, malignancy, surgery, fracture, pregnancy, congestive heart failure, diabetes,

Myocardial infarction, stroke hormone replacement, antipsycholic

Cohort studies of IBD and DVT and/or PE incidence based on incidence rate ratios
Author, year (Ref.No), country, (follow-up-period)Study populationRR (95% CI),thrombosis subsite (number of cases)Controlled variables  
Bernstein 2001[13] Canada (1984–1997)

Manitoba Health administrative

Exposed group: 6027 persons with IBD Comparison group: 5529 matched controls

3.47 (2.94–4.09) VTE (187)

4.10 (3.21–5.25) CD VTE (89)

3.04 (2.43–3.81) UC VTE (98)

3.54 (2.89–4.34) DVT (126)

4.71 (3.53–6.29) CD DVT (67)

2.77 (2.07–3.69) UC DVT (59)

3.32 (2.49–4.32) PE (61)

2.94 (1.83–4.73) CD PE (22)

3.59 (2.49–5.17 UC PE (39)

Age, gender, postal area of residence
Mieshler 2004[14] Austria (N/A)

Three out-patient clinics of Division of Gastroenterology and Hepatology Exposed group: 618 patients with IBD

Comparison group: 618 controls matched by age and gender

3.6 (1.7–7.8) VTE (48)Age, gender, operation, injuries, oral contraceptive use, pregnancy, BMI, smoking
Bernstein 2007[15] Canada(1994–2004)The Statistics Canada's Health Person Oriented Information database

50 years and older

a1.3 (1.23–1.37) VTE (N/A)

1.32 (1.24–1.41) DVT (N/A)

1.26 (1.13–1.39) PE (N/A)

Younger than 50 years

a1.57 (1.42–1.72) VTE (N/A)

1.53 (1.37–1.71) DVT (N/A)

1.67 (1.39–2.01) PE (N/A)

Age, gender
Nguyen 2008[16] USA (1998–2004)

Nationwide Inpatients Sample (NIS) Exposed group: 73197 CD discharges

43645 UC discharges

Comparison group: 1% random sample of non-IBD hospital discharges

a1.66 (1.33–2.06) (N/A)

1.48 (1.35–1.62)CD VTE (N/A)

1.85 (1.70–2.01) UC VTE (N/A)

Age, gender, health insurance carrier, neighbourhood income, respective bowel surgery, calendar year, hospital characteristics
Nguyen 2009[17] USA (2005)

Nationwide Inpatients Sample (NIS)

Exposed group: 694 CD patients and

387 UC patients in obstetric hospitalisation

Comparison group:964392 non-IBD patients in obstetric hospitalisations

a7.07 (4.07–12.3) (N/A)

6.12 (2.91–12.9) CD VTE (N/A)

8.44 (3.71–19.2) UC VTE (N/A)

Maternal age, race/ethnicity, median neighbourhood income, comorbidity, health insurance, geographical region, hospital location and teaching status, Caesarean delivery
Grainge 2010[18] UK (1987–2001)

General Practice Research Database(GPRD) Exposed group: 13 756 IBD patients

Comparison group: 71 672 matched controls

3.4 (2.7–4.3) UC VTE (784)Age, gender, BMI, smoking, cancer diagnosis, history of PE or DVT
Rothberg 2011[19] USA (2004–2005)

Patients discharged from 374 acute care facilities in the United States that participated in Premier's Perspective

Exposed group: 814 IBD patients

Comparison group: 241924 non-IBD patients

3.11 (1.59–6.08) VTE (1052)Age, gender, VTE prophylaxis, length of stay> 6 days, pneumonia, chronic obstructive pulmonary disease, stroke, congestive heart failure, urinary tract infection, respiratory failure, septicaemia, obesity, inherited thrombophilia, cancer, central venous catheter, mechanical ventilation, urinary catheter, chemotherapy, steroids
Merrill 2011[20] USA (2008)

National Surgical Quality Improvement Program Participant Use Data File

Exposed group:2249 IBD patients Comparison group: 269 119 patients without IBD

2.03 (1.52–2.7) VTE (2665)Age, gender, race/ethnicity, admitted from home, smoker, BMI>30, medical historyb, clinical factorc
Saleh 2011[21] USA (1979–2005)The National Hospital Discharge Survey

1.64 (1.62–1.66) UC VTE (21 000)

1.08 (1.06–1.09) CD VTE

1.77 (1.74–1.80) UC DVT

1.24 (1.22–1.26) CD DVT

1.40 (1.37–1.44) UC PE

0.74 (0.72–0.76) CD PE

Age, gender

Bröms 2012[22] Sweden

(2006–2009)

The Medical Birth, Patient, and Prescribed Drug Registers of all residents in Sweden

Exposed group:1209 UC patients and 787 CD patients

Comparison group: 10773 patients without IBD

a2.61 (1.24–5.49) VTE

3.78 (1.52–9.38) UC VTE(8)

1.26 (0.35–4.53) CD VTE(3)

Age, parity, year and month of birth,
image

Figure 1. Meta-analysis flowchart.

Download figure to PowerPoint

In total, one case-control and 10 cohort studies. No study received greater than 13% of the total weight in the meta-analysis.

Summary results

The overall results of the meta-analysis are shown in Figure 2 and Table 2. All individual studies had RR estimates above 1.0 with statistical significance. The summary RR for DVT and PE comparing subjects with and without IBD was 2.20 (95% CI, 1.83–2.65) for the 11 studies combined. Evidence of heterogeneity was observed (Q = 243.0 P < 0.01, I2 = 95.9%). A sensitivity analysis identified the study by Saleh et al.[21] as the largest contributor to this heterogeneity. In an analysis performed that excluded this study, the summary RR between IBD and VTE was somewhat higher [summary RR = 2.53, 95% CI (1.79–3.58)], although the test for heterogeneity was still statistically significant (Q = 219.7 P < 0.01, I2 = 95.9%).

Table 2. Summary relative risk (RR) estimates and 95% confidence intervals (CIs) for case-control and cohort studies of the association of inflammatory bowel disease (IBD) with deep vein thrombosis (DVT) and pulmonary embolism (PE) incidence by study size, thrombosis sites, IBD type and confounders [smoking and body mass index (BMI)]
SubgroupNo. of studies Summary RR (95% CI) Fixed effect model Q P-heterogeneity I 2 Statistic% Summary RR (95% CI) Random effect model
All studies111.37 (1.36–1.38)243.0<0.0195.92.20 (1.83–2.65)
Study size
Smaller size54.16 (2.98–5.80)16.1<0.0175.23.29 (1.98–5.47)
Larger size61.37 (1.36–1.38)187.5<0.0197.31.90 (1.55–2.31)
Thrombosis subsites
DVT41.45 (1.37–1.54)82.4<0.0196.41.80 (1.11–2.91)
PE41.42 (1.29–1.55)42.8<0.0193.01.63 (0.98–2.72)
IBD
UC61.65 (1.63–1.67)91.9<0.0194.62.57 (2.02–3.28)
CD51.09 (1.08–1.11)176.9<0.0197.72.12 (1.40–3.20)
Adjust for smoking and BMI
Yes32.81 (2.36–3.35)7.910.0274.72.20 (1.83–2.65)
No81.37 (1.36–1.38)171.4<0.0195.91.99 (1.65–2.41)
image

Figure 2. Association between inflammatory bowel disease (IBD) and venous thromboembolism (VTE) incidence in 11 studies.

Download figure to PowerPoint

Evaluation of Heterogeneity

We used various subgroup analyses to further evaluate several potential sources of heterogeneity. Table 2 shows the results of subgroup meta-analysis by study size, thrombosis sites, IBD type and adjustment for confounding factors [smoking and body mass index (BMI)].

The association between IBD and VTE incidence was significant for deep vein thrombosis [summary RR = 1.80, 95% CI (1.11–2.91); n = 4 studies] but not for PE [summary RR = 1.63, 95% CI (0.98–2.72); n = 4 studies]. The evaluation of differences in the effect size by disease type (i.e. Crohn's disease vs. ulcerative colitis) demonstrated that the association between IBD and VTE incidence was similar in patients with UC [summary RR = 2.57, 95% CI (2.02–3.28); n = 6 studies] and CD [summary RR = 2.12, 95% (CI 1.40–3.200; n = 5 studies]. In the subgroup analysis that was restricted to the three publications that controlled for smoking and obesity, the positive association of IBD with VTE [summary RR = 2.20, 95% CI (1.83–2.65); n = 3 studies] remained.

Publication bias

Visual inspection of the Begg funnel plot demonstrated the asymmetry typically associated with publication bias (Figure 3). That is, smaller, less precise studies [those with the larger standard errors (S.E.)] appear to have higher RRs than the large, more precise studies. Evidence of publication bias was also seen with the Egger or Begg tests (Egger P = 0.02). On visual inspection of the Begg funnel plot, five outlying studies appeared to be the cause of the asymmetry. After removing these five studies, no evidence of publication bias could be found (Egger P = 0.16).

image

Figure 3. Funnel plot with pseudo 95% confidence limits.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

This meta-analysis showed increased risk of VTE in patients with IBD. Overall, this study had several key findings. First, the elevated summary RRs for all studies combined, as well as those in the subgroup analyses of both venous thrombosis and PE, provide strong evidence that patients with IBD are at increased risk (approximately twofold) for both DVT and PE. Second, the increased RRs are similar, regardless of whether or not the studies were adjusted for major potential confounders like smoking or BMI. The similarity of adjusted and unadjusted RRs suggests that while smoking and BMI may increase the risk of DVT or PE, they did not confound the relationship between IBD and DVT/PE.

Third, both the funnel plots and the Egger test suggest that publication bias in the literature may be artificially inflating the apparent association between VTE and IBD. However, publication bias typically affects studies with smaller sample sizes.[32] Consistent with this finding, the summary RR of the five smallest studies [RR = 3.29, 95% CI (1.83–2.65)] was substantially higher than that of the six largest studies [RR = 1.90, 95% CI (1.55–2.31)]. However, analyses limited to only the six largest studies provided RRs that were only moderately smaller than analyses that contained all the studies (summary RR of 1.90 vs. 2.20, respectively). This suggests that publication bias was not the sole cause of the approximately twofold increase in risk identified here.

Fourth, although our results showed that patients with UC may be at a somewhat greater risk for VTE than those with CD, the difference is small; furthermore, elevated RRs were seen in both groups. The possibility of a greater risk among patients with UC, in which rates of DVT or PE were 50/1000 person-years in UC and 40/1000 person-years in CD, was suggested by Bernstein et al.[13] Bernstein's results and this meta-analysis both suggest that health care providers should be aware of the increased risk for both CD and UC patients.

Data from several sources suggest that the association between IBD and the risk of VTE is biologically plausible. IBD creates localised and systemic inflammation, and activation of the coagulation cascade occurs during inflammation.[35] Proinflammatory cytokines such as IL-6 have been shown to stimulate coagulation without concomitant fibrinolysis.[36] Fibrinolysis is depressed in patients with IBD, with decreased plasma levels of tPA activity and increased plasminogen activator inhibitors reported.[37] Thus, inflammation represents a state of relative hypofibrinolysis, promoting a hypercoagulable state.[38-40] Local and systemic inflammation, together with other required risk factors such as surgery, prolonged immobilisation, central venous catheters, fluid depletion, steroid therapy, smoking, oral contraceptives, high levels of antiphospholipid antibodies and hyperhomocysteinaemia (because of vitamin deficiencies), may induce a hypercoagulable state and prothrombotic conditions in patients with IBD.[14, 41]

Several limitations of this study must be considered. All of the studies that assess the association between IBD and VTE are observational studies, and are thus subject to bias.[42] Although adjustment for smoking or BMI actually increased the strength of the association between IBD and VTE, we were unable to evaluate variables such as diet, alcohol and other health conditions. However, despite the inherent limitations of observational studies, the association we found between IBD and an increased risk of VTE may still be valid for several reasons. First, the strength of the associations identified decrease the possibility that they are due to chance alone. Second, all 11 studies included in this meta-analysis reported a RR above 1.0 with statistically significant results. Although some statistical heterogeneity was identified, which makes the exact magnitude of the association less certain, the consistency of the RRs among the 11 studies, despite different study designs, populations and methods, suggests that the positive direction of the association is also not due to chance alone.

We found little evidence that these findings were due to confounding factors. Several of the studies were adjusted for the most likely confounders, including smoking and BMI. The positive association of IBD with VTE risk increased when the meta-analysis was limited to studies that controlled for smoking and BMI [summary RR of studies adjusting for the confounders 2.58, 95% CI (1.89–3.51) and summary RR of studies unadjusted for the confounders 2.10, 95% CI (1.38–3.19)]. This suggests that obesity and smoking do not explain the association between IBD and VTE.

Disease activity seems to be highly associated with thromboembolic risk, as it has been suggested that in IBD, activation of the coagulation cascade is more pronounced in active disease.[43] However, in this meta-analysis, we could not do subgroup analyses based on IBD disease activity. A study by Grainge et al.[18] was the only one to evaluate the association between IBD disease activity and the occurrence of VTE in their population-based study in the United Kingdom.[11] They found a 4.5-fold higher rate of VTE during acute disease flares when compared with periods of remission among IBD patients. The Grainge study selected IBD patients experiencing moderate-to-severe flares, given that a disease flare was defined by the need for corticosteroids. It is possible that corticosteroid therapy may have contributed to an additional risk for the development of VTE in that study. Two studies reported that between 60% and 80% of IBD patients have some component of active disease at the time of VTE diagnosis.[13, 14]

There are several potential reasons for the residual heterogeneity. First, there may have been differences in the anatomical location of IBD between patients. We were not able to do a subgroup analysis based on the anatomical location of IBD because only two studies, one by Miesher et al. and the other by Nguyen et al.[14, 17], in this meta-analysis specified the location of IBD. A study by Solem et al.[26], which was excluded from this meta-analysis due to the RRs of VTE risk among IBD patients being unavailable, showed that CD patients with VTE typically have colonic disease involvement (ileocolonic in 56% and colonic in 23%), and that most UC patients with VTE (76%) have pancolonic disease. This implies that the extent of colonic disease in IBD may correlate with a patient's thromboembolic risk.

Second, because VTE is difficult to diagnose, some degree of differential misclassification is likely to have occurred in the studies included in this meta-analysis. VTE is often clinically silent and in many cases, the first sign of the disease is a sudden fatal PE.[44, 45] Despite modest increases in the antemortem diagnosis of PE over the years, PE diagnosis is confirmed by objective testing in only about 20% of patients.[46]

Third, in this meta-analysis we included a number of very different types of studies of different populations and settings. Some studies are population-based cohorts, some are from referral centres, and others look only at hospitalised patients through discharge databases. This variety could have contributed to the heterogeneity among the studies (>90%).

Fourth, detection bias could lead to artificially increased RRs in this meta-analysis. For example, due to more rigorous medical follow-up of IBD patients, subclinical events may be detected more often in IBD patients than in non-IBD patients. However, given the seriousness of the outcomes assessed, especially PE, it seems unlikely that this bias would account for the entire twofold increased risks identified here.

Our results have important clinical and public health implications. This study showed an increased risk of VTE among IBD patients, which we hope will help increase awareness of this subject. Based on this emerging evidence, several practice guidelines now include recommendations on VTE risk for patients with IBD.[47] For example, the American College of Gastroenterology (ACG), UC practice guidelines state that physicians should consider prophylaxis with heparin in patients hospitalised for a severe disease flare.[48] However, no such recommendations are contained within the current ACG CD guidelines. Guidelines for the treatment of IBD by the British Society of Gastroenterology recommend pharmacological prophylaxis for VTE in hospitalised patients with severe UC.[49] Similar recommendations are included in the latest European Crohn's and Colitis Organization consensus statements on the current management of UC and CD.[50, 51] However, a recent study by Tinsley et al. showed that a total of 29.1% of US gastroenterologists were unaware of any recommendations addressing pharmacological prophylaxis included in the ACG IBD guidelines, and 34.6% would give pharmacological VTE prophylaxis to a hospitalised patient with severe UC.[47]

In conclusion, this study provides evidence of an association between IBD and VTE, and this evidence should be considered in practice guidelines. Future studies involving evaluations of the possible diagnostic bias discussed above, as well as randomised trials evaluating the risks and benefits of both VTE screening and prophylaxis in patients with IBD, could add further clarity to the discussion.

Authorship

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Guarantor of the article: Tetsuya Mine.

Author contributions: H. Yuhara contributed to the study concept and writing of manuscript. J. Koike and M. Igarashi contributed to the data acquisition. H. Yuhara, C. Steinmaus and D. Corley contributed to the analysis and interpretation of data and the drafting of the manuscript. C. Steinmaus, D. Corley, T. Suzuki and T. Mine contributed to the critical revision of the manuscript for important intellectual content. T. Mine supervised the study. All authors approved the final version of the manuscript.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References

Declaration of personal and funding interests: None.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  • 1
    Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008; 28: 3702.
  • 2
    Zhan C, Miller MR. Excess length of stay, charges, and mortality attributable to medical injuries during hospitalization. JAMA 2003; 290: 186874.
  • 3
    Eikelboom JW, Quinlan DJ, O'Donnell M. Major bleeding, mortality, and efficacy of fondaparinux in venous thromboembolism prevention trials. Circulation 2009; 120: 200611.
  • 4
    Longo D, Fauci A, Kasper D, et al. Harrison's Principles of Internal Medicine, 18th edn. McGraw-Hill Professional, pp. 9867.
  • 5
    Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 116773.
  • 6
    Novacek G, Haumer M, Schima W, et al. Aortic mural thrombi in patients with inflammatory bowel disease: report of two cases and review of the literature. Inflamm Bowel Dis 2004; 10: 4305.
  • 7
    Jackson LM, O'Gorman PJ, O'Connell J, et al. Thrombosis in inflammatory bowel disease: clinical setting, procoagulant profile and factor V Leiden. QJM 1997; 90: 1838.
  • 8
    Murata S, Ishikawa N, Oshikawa S, et al. Cerebral sinus thrombosis associated with severe active ulcerative colitis. Intern Med 2004; 43: 4003.
  • 9
    Oldenburg B, Fijnheer R, van der Griend R, et al. Homocysteine in inflammatory bowel disease: a risk factor for thromboembolic complications? Am J Gastroenterol 2000; 95: 282530.
    Direct Link:
  • 10
    Bargen JA, Barker NW. Extensive arterial and venous thrombosis complicating chronic ulcerative colitis. Arch Intern Med 1936; 58: 1731.
  • 11
    Murthy SK, Nguyen GC. Venous thromboembolism in inflammatory bowel disease: an epidemiological review. Am J Gastroenterol 2011; 106: 7138.
  • 12
    Kappelman MD, Horvath-Puho E, Sandler RS, et al. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut 2011; 60: 93743.
  • 13
    Bernstein CN, Blanchard JF, Houston DS, et al. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb Haemost 2001; 85: 4304.
  • 14
    Miehsler W, Reinisch W, Valic E, et al. Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism? Gut 2004; 53: 5428.
  • 15
    Bernstein CN, Nabalamba A. Hospitalization-based major comorbidity of inflammatory bowel disease in Canada. Can J Gastroenterol 2007; 21: 50711.
  • 16
    Nguyen GC, Sam J. Rising prevalence of venous thromboembolism and its impact on mortality among hospitalized inflammatory bowel disease patients. Am J Gastroenterol 2008; 103: 227280.
    Direct Link:
  • 17
    Nguyen GC, Boudreau H, Harris ML, et al. Outcomes of obstetric hospitalizations among women with inflammatory bowel disease in the United States. Clin Gastroenterol Hepatol 2009; 7: 32934.
  • 18
    Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010; 375: 65763.
  • 19
    Rothberg MB, Lindenauer PK, Lahti M, et al. Risk factor model to predict venous thromboembolism in hospitalized medical patients. J Hosp Med 2012; 147: 1204.
  • 20
    Merrill A, Millham F. Increased risk of post-operative deep vein thrombosis and pulmonary embolism in patients with inflammatory bowel disease: a study of national surgical quality improvement program patients. Arch Surg 2012; 147: 1204.
  • 21
    Saleh T, Matta F, Yaekoub AY, et al. Risk of venous thromboembolism with inflammatory bowel disease. Clin Appl Thromb Hemost 2011; 17: 2548.
  • 22
    Bröms G, Granath F, Linder M, Stephansson O, Elmberg M, Kieler H. Complications from inflammatory bowel disease during pregnancy and delivery. Clin Gastroenterol Hepatol 2012; 10: 124652.
  • 23
    Grip O, Svensson PJ, Lindgren S. Inflammatory bowel disease promotes venous thrombosis earlier in life. Scand J Gastroenterol 2000; 35: 61923.
  • 24
    Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160: 341520.
  • 25
    Wang JY, Terdiman JP, Vittinghoff E, Minichiello T, Varma MG. Hospitalized ulcerative colitis patients have an elevated risk of thromboembolic events. World J Gastroenterol 2009; 15: 92735.
  • 26
    Solem CA, Loftus EV, Tremaine WJ, et al. Venous thromboembolism in inflammatory bowel disease. Am J Gastroenterol 2004; 99: 97101.
  • 27
    Huerta C, Johansson S, Wallander MA, et al. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med 2007; 167: 93543.
  • 28
    Buchberg B, Masoomi H, Lusby K, et al. Incidence and risk factors of venous thromboembolism in colorectal surgery: does laparoscopy impart an advantage? Arch Surg 2011; 146: 73943.
  • 29
    Greenland S. Meta-analysis. In: Rothman K, Greenland S, eds. Modern Epidemiology. 2nd ed. Philadelphia: Lippincott Raven, 1998; 64373.
  • 30
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 17788.
  • 31
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 153958.
  • 32
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 55760.
  • 33
    Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. Br Med J 1997; 315: 62934.
  • 34
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088101.
  • 35
    Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283: 200812.
  • 36
    Stouthard JM, Levi M, Hack CE, et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76: 73842.
  • 37
    de Jong E, Porte RJ, Knot EA, et al. Disturbed fibrinolysis in patients with inflammatory bowel disease. A study in blood plasma, colon mucosa, and faeces. Gut 1989; 30: 18894.
  • 38
    Zitomersky NL, Verhave M, Trenor CC 3rd. Thrombosis and inflammatory bowel disease: a call for improved awareness and prevention. Inflamm Bowel Dis 2011; 17: 45870.
  • 39
    Levi M, van der Poll T, ten Cate H, et al. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest 1997; 27: 39.
  • 40
    Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation 2003; 107: 398404.
  • 41
    Carter MJ, Lobo AJ, Travis SP, IBD Section, British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004; 53(Suppl 5): V116.
  • 42
    Guyatt GH, Oxman AD, Kunz R, et al. GRADE Working Group. What is “quality of evidence “and why is it important to clinicians? Br Med J 2008; 336: 9958.
  • 43
    Souto J, Martinez E, Roca M, et al. Prothrombotic state and signs of endothelial lesion in plasma of patients with inflammatory bowel disease. Dig Dis Sci 1995; 40: 18839.
  • 44
    Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 1995; 108: 97881.
  • 45
    Heit JA, Silverstein MD, Mohr DN, et al. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med 1999; 159: 44553.
  • 46
    Righini M, Le Gal G, Aujesky D, et al. Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiorit y t rial. Lancet 2008; 371: 134352.
  • 47
    Tinsley A, Naymagon S, Trindade AJ, Sachar DB, Sands BE, Ullman TA. A survey of current practice of venous thromboembolism prophylaxis in hospitalized inflammatory bowel disease patients in the United States. J Clin Gastroenterol 2013; 47: e16.
  • 48
    Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010; 105: 50123.
  • 49
    Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011; 60: 571607.
  • 50
    Travis SP, Stange EF, Lemann M, et al. European evidencebased consensus on the management of ulcerative colitis: current management. J Crohns Colitis 2008; 2: 2462.
  • 51
    Van Assche G, Dignass A, Reinisch W, et al. European Crohn's and Colitis Organisation (ECCO). The second European evidence-based consensus on the diagnosis and management of Crohn's disease: special situations. J Crohns Colitis 2010; 4: 63101.