Summary

This article describes the complications of venous thromboembolism in children with inflammatory bowel disease.

The incidence of inflammatory bowel disease (IBD) in Oceania has been at a high level. IBD is associated with an increased risk of venous thromboembolism (VTE) events.

Although the incidence of VTE in IBD children is lower than that in adults, current studies show that younger IBD patients may be associated with a higher relative risk of VTE.

Prophylaxis is not standardly used and there is limited high - level evidence-based guidance for VTE prevention in this population. This paper aims to increase the attention of doctors to VTE prevention in IBD children.

Introduction

Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disease of unknown etiology, with the main types being Crohn's disease (CD) and ulcerative colitis (UC). Totally 25% of IBD patients are diagnosed before 18 years of age, and about another quarter of cases are diagnosed before 10 years of age[1].

The incidence of IBD in children is increasing worldwide, with a high level in Oceania[2, 3]. Studies showed that IBD incidence in children in Oceania was 2.9-7.3/100 thousand (person year) between 1971 and 2015[2].

IBD has a prolonged course and is easy to relapse, and parenteral complications such as venous thromboembolism (VTE) are one of the most important reasons for disease recurrence and death.

VTE includes deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE), which result in high mortality.

In addition to the significantly increased mortality associated with VTE, VTE-related events significantly increase social health care cost.

IBD patients constitute a high-risk VTE group, whose risk is 2.85 times that of non-IBD patients [4].

Compared with IBD children without VTE, those with VTE have significantly longer median length of hospital stay (5 vs. 11, P<0.001), increased demand for intensive care (4.8% vs. 30.2%, P < 0.001), elevated adjusted median total cost (32,800 vs. 123,000, P < 0.001), increased hospital-related cost (36,000 vs. 123,000, P < 0.001) and elevated in-hospital mortality (0.2% vs. 1.5%, P < 0.001).

VTE in IBS patients imposes a heavy burden on families and the society[5]. The importance of VTE prevention in adult patients with IBD has attracted full attention.

The guidelines of various countries have proposed the principle of preventive antithrombotic therapy in IBD patients. Recently, more and more studies have focused on VTE complications in IBD children.

1. Mechanism of VTE in IBD patients

The potential etiology and mechanism of VTE in IBD patients are complex. Currently, many mechanisms interact to cause VTE in IBD patients.

The blood of IBD patients is in a hypercoagulable state, with visible acquired endothelial function damage, platelet aggregation, coagulation and impaired fibrinolysis system[6].

Inflammation can promote platelet aggregation and inhibit fibrinolysis by activating the coagulation cascade, which leads to increased risk of VTE.

In addition, studies have shown that children with active and inactive CD and active UC have increased coagulation promoting the function of circulating particles compared with healthy ones [7].

2. Risk factors for VTE in IBD children

The risk of VTE in IBD is related to disease status, and cases in the active stage have the highest risk (HR 8.4; 95% CI 5.5-12.8; P < 0.001)[8].

In addition to disease factors, use of some IBD drugs, including systemic glucocorticoids, can also significantly increase the risk of VTE in IBD patients.

Age is a risk factor for VTE in IBD patients, and young patients have a higher relative risk. Studies have shown that the risks of DVT and PE are significantly higher in IBD patients compared with healthy people, increasing by 6.0 (95% CI 2.5-14.7) and 6.4 (95% CI 2.0-20.3) times, respectively; the relative risk of IBD children is 4 times higher than that of elderly patients [9].

In a cross-sectional study including 44,554 IBD and 28132 CD patients under 21 years of age[10], 456 (1.01%) IBD and 205 (0.72%) CD children developed VTE during hospitalization.

In this study, the risk of VTE in IBD and CD patients undergoing major surgery increased by 1.98 (95% CI 1.54-2.55; P < 0.01) and 2.24 (95% CI 1.55-3.25; P < 0.01) times, respectively. Meanwhile, the risk of VTE in IBD and CD patients with coagulation disorders increased by 7.39 (95% CI 5.34-10.2; P < 0.01) and 6.91 (95% CI 5.34-10.2; P < 0.01) times, respectively.

The risk of VTE was 2.33 (95% CI 1.73-3.12; P < 0.01) and 3.21 (95% CI 2.07-4.98; P < 0.01) times, respectively, in IBD and CD patients administered blood transfusion.

A retrospective analysis including 276 IBD children undergoing colorectal resection showed that 4.3% of the patients developed DVT postoperatively, and median time to DVT diagnosis was 14 days postoperatively[11].

Regression analysis showed that the risk of DVT was significantly increased in children with emergency surgery (HR 18.8; 95% CI 3.18-111; P = 0.001), perioperative blood transfusion (HR 25.1; 95% CI 2.4-259; P = 0.007) and postoperative infection complications (HR 10.5; 95% CI 2.63-41.8; P = 0.001).

In 2021, a new case-control study exploring the risk factors for VTE in IBD children reported that central venous catheter (OR 77.9; 95% CI 6.9-880.6; P < 0.001) and steroid use (or 12.7; 95% CI 1.3-126.4; P = 0.012) are independent risk factors for VTE in children[12]. 

3. Prevention of IBD-related VTE in children

For the prevention of VTE in adult IBD patients, the recommended measures include mechanical and drug approaches[4].

In pediatric IBD patients, there is a lack of high-level evidence-based guidelines to recommend measures. Currently, doctors lack awareness of VTE prevention in IBD children.

In a study aiming to assess the views and practice of pediatric gastroenterologists on VTE prevention in IBD children[13], most of these medical professionals were able to recognize the increased risk of VTE in IBD children; 92% of participants agreed with this statement, and more than 50% strongly agreed.

Totally 36% of doctors provided VTE preventive measures in IBD children, while most doctors took no preventive measures.

For not providing VTE preventive measures, 81.4% of the doctors surveyed pointed to lack of clear guidelines, 56.25% were unwilling to prescribe VTE preventive measures, and 48.72% were worried about the risk of bleeding in children.

There is little evidence for the effectiveness of risk prevention in pediatric IBD combined with VTE. Generally, VTE is considered a postoperative complication, and its risk is higher in colorectal surgery patients.

Among IBD patients, compared with CD cases, UC patients have a higher risk of VTE postoperatively, and corresponding preventive measures are needed[14].

In a retrospective study including 366 children with chronic UC undergoing colectomy [15], 87% of VTE patients had thrombosis of the portal vein.

The time to thrombosis diagnosis was 38.7 days after colectomy. All patients had acute abdominal pain. Totally 93% of children with VTE received anticoagulant therapy, with an average treatment course of 96.3 days.

In case of postoperative abdominal pain in children with chronic UC undergoing colectomy, intra-abdominal VTE should be highly suspected.

In this population, preventive anticoagulation therapy should be considered during the perioperative period. In a study by Bence et al. [11], 15% of children with IBD undergoing colorectal resection received perioperative chemoprevention, and 32% received mechanical prevention.

Due to the low proportion of children receiving VTE preventive measures, this study did not observe a significant difference between perioperative chemical or mechanical prevention and postoperative DVT.

This study suggested that all IBD children undergoing abdominal surgery should benefit from mechanical preventive measures to prevent VTE during the perioperative period, and chemical prevention should be considered on the basis of individualization.

4. Prospects

IBD is associated with an increased risk of VTE events. Although the incidence of VTE in IBD children is lower than that of adults, currently available studies showed that younger IBD patients may have a higher relative risk of VTE.

The current studies support the use of drug or mechanical prophylaxis for VTE prevention in adult IBD patients. However, there is no consensus on VTE prevention in IBD children.

The Canadian Society of Gastroenterology does not recommend anticoagulant prophylaxis for IBD children without a history of VTE, but the grade of this recommendation is low.

The risk and benefit of VTE prevention remain unknown in IBD children. In the future, a specific risk assessment model should be developed for such individuals.

Attention should be paid to preventing and/or correcting risk factors for acquired VTE to reduce the risk of VTE in IBD children. For high-risk IBD children with risk factors for VTE, the individual risk factors should be fully weighed, and VTE prevention should be reasonable and effective.

In addition, in the treatment of IBD, many anti-inflammatory drugs such as infliximab and 5-aminosalicylic acid may reduce the risk of VTE. Whether they are appropriate for IBD children still needs a large-scale prospective study.

Tracy Wang, Medical Affairs Lead, Cordis (Cardinal Heath), China. 

Reference

[1] Däbritz J, Gerner P, Enninger A, et al. Inflammatory Bowel Disease in Childhood and Adolescence. Dtsch Arztebl Int, 2017, 114: 331-338.
[2] Sýkora J, Pomahačová R, Kreslová M, et al. Current global trends in the incidence of pediatric-onset inflammatory bowel disease. World J Gastroenterol, 2018, 24: 2741-2763.
[3] King JA, Underwood FE, Panaccione N, et al. Trends in hospitalisation rates for inflammatory bowel disease in western versus newly industrialised countries: a population-based study of countries in the Organisation for Economic Co-operation and Development. Lancet Gastroenterol Hepatol, 2019, 4: 287-295.
[4] Nguyen GC, Bernstein CN, Bitton A, et al. Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology. Gastroenterology, 2014, 146: 835-848.e836.
[5] Chien KA, Cooley V, Prishtina F, et al. Health and Financial Burdens Associated with Venous Thrombosis in Hospitalized Children with Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr, 2021,
[6] Koutroubakis IE. The relationship between coagulation state and inflammatory bowel disease: current understanding and clinical implications. Expert Rev Clin Immunol, 2015, 11: 479-488.
[7] Deutschmann A, Schlagenhauf A, Leschnik B, et al. Increased procoagulant function of microparticles in pediatric inflammatory bowel disease: role in increased thrombin generation. J Pediatr Gastroenterol Nutr, 2013, 56: 401-407.
[8] Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet, 2010, 375: 657-663.
[9] 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: 937-943.
[10] Mckie K, Mcloughlin RJ, Hirsh MP, et al. Risk Factors for Venous Thromboembolism in Children and Young Adults With Inflammatory Bowel Disease. J Surg Res, 2019, 243: 173-179.
[11] Bence CM, Traynor MD, Jr., Polites SF, et al. The incidence of venous thromboembolism in children following colorectal resection for inflammatory bowel disease: A multi-center study. J Pediatr Surg, 2020, 55: 2387-2392.
[12] Mitchel EB, Rosenbaum S, Gaeta C, et al. Venous Thromboembolism in Pediatric Inflammatory Bowel Disease: A Case-Control Study. J Pediatr Gastroenterol Nutr, 2021,
[13] Chien KA, Hammad HT, Gerber L, et al. Pediatric Gastroenterologists' Approach to Venous Thromboembolism Prophylaxis in Pediatric Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr, 2018, 66: 286-288.
[14] Cheng K, Faye AS. Venous thromboembolism in inflammatory bowel disease. World J Gastroenterol, 2020, 26: 1231-1241.
[15] Antiel RM, Hashim Y, Moir CR, et al. Intra-abdominal venous thrombosis after colectomy in pediatric patients with chronic ulcerative colitis: incidence, treatment, and outcomes. J Pediatr Surg, 2014, 49: 614-617.