Clots in colitis: Thromboembolism and beyond

Abstract

Patients with ulcerative colitis (UC) have an increased risk of thromboembolic events, particularly venous thromboembolism (VTE), which encompasses deep vein thrombosis and pulmonary embolism. The incidence of VTE in patients with UC is significantly higher than that in the general population, and a retrospective cohort study found that patients undergoing colectomy had a notable risk of developing VTE, with rates reaching as high as 22% among patients exposed to tofacitinib within a month prior to surgery. The GETAID FOCUS study also reported a high prevalence of self-reported VTE in patients with UC, with a pooled prevalence of approximately 12% across various studies. The risk of thromboembolism in UC is multifactorial and influenced by chronic inflammation, a wide range of medications used, potential surgical interventions, and possibly genetic factors or associations that are yet to be fully defined. Recognizing the various contributing factors is crucial for developing effective preventive strategies and improving patient outcomes.

Key Words: Ulcerative colitis; Venous thromboembolism; Incidence; Risk; Surgery

Core Tip: Patients with ulcerative colitis face a significantly increased risk of thromboembolic events, particularly venous thromboembolism (VTE), compared to the general population. This study emphasizes the multifactorial nature of this risk, influenced by chronic inflammation, medication use, surgical interventions, and potential genetic factors. Additionally, the incidence of VTE varies based on geographical and ethnic/racial factors, highlighting the need for tailored preventive strategies and proactive interventions aimed at reducing morbidity associated with these complications.

INTRODUCTION

Patients with ulcerative colitis (UC) face an increased risk of thromboembolic events, particularly venous thromboembolism (VTE), which encompasses deep vein thrombosis (DVT) and pulmonary embolism. The incidence of VTE in UC patients is significantly higher than in the general population[1]: A retrospective cohort study found that those undergoing colectomy had a notable risk of developing VTE, with rates reaching as high as 22% among patients exposed to tofacitinib within a month prior to surgery[2]. The methodology of this retrospective cohort study involved reviewing patient records who underwent colectomy, tracking their exposure to tofacitinib, and recording VTE events. However, as a single-center study, its generalizability may be limited.

The GETAID FOCUS study also reported a high prevalence of self-reported VTE in UC patients, with a pooled prevalence of approximately 12% across various studies[2]. This study relied on self-reported data from multiple cohorts, which may introduce reporting bias, yet it provides a valuable multinational perspective on VTE prevalence in UC.

The thromboembolism risk in UC is multifactorial, influenced by chronic inflammation, various medications, surgical interventions, and potentially undefined genetic factors.

Recognizing these contributing factors is essential for developing effective preventive strategies and enhancing patient outcomes.

PATHOPHYSIOLOGY OF VTE IN UC

Pathophysiology of VTE in UC patients encompasses a complex interplay of chronic inflammation, endothelial dysfunction, and alterations in coagulation factors. Chronic inflammation leads to the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6, which promote a hypercoagulable state and activate the endothelium, increasing thrombosis risk. Additionally, elevated levels of coagulation factors and platelet activation during inflammatory episodes further contribute to clot formation. Clinical factors such as hospitalization, surgical interventions, and immobilization exacerbate this risk, highlighting the need for targeted prevention strategies in this population[2-4].

RISK PREDICTION AND ESTIMATION OF VTE IN UC: AN INTRIGUING PUZZLE

Predicting and estimating the risk of VTE in patients with UC have been extensively reported over the past decade, through robust findings from randomized controlled trials, systematic reviews, meta-analyses, and population-based studies investigating VTE risk in both adults and pediatric UC populations.

In this context, the retrospective study run by Karim et al[5] at the Aga Khan University Hospital reported an incidence rate of 6.7% among hospitalized UC patients. This study examined hospitalized uc patients over a defined period and monitored for VTE events. Its strength lies in providing insight into real-world VTE risk in a South Asian cohort, though lack of control group and retrospective design limit causal inference.

These results align with a recent systematic review and meta-analysis by Zhang and Wang[6] which indicated that patients with inflammatory bowel disease (IBD), including UC, have a 2-8 fold increased risk of VTE compared to the general population. Specifically, the estimated incidence of VTE in adults with UC ranges from 7.6% to 21.8%. The meta-analysis included numerous studies from varied geographical locations, increasing its generalizability. However, heterogeneity in study design and populations may affect the precision of these estimates.

Interestingly, a monocentric Japanese study retrieved an elevated incidence of silent VTE in UC patients[7], while the GETAID FOCUS study found that self-reported VTE prevalence among UC patients was significantly high, with an odds ratio for developing VTE in those exposed to immunosuppressive therapy like tofacitinib being 4.7 (95%CI: 2.3-9.4) compared to those not exposed[3]. This monocentric study employed imaging screening to identify asymptomatic VTE, underscoring the importance of screening in clinically stable patients, though its limited sample size warrants caution.

Prospective multicenter studies have confirmed the risk of VTE in the UC population and identified specific risk factors. One notable study, part of the ORAL Surveillance trial initiated in 2014 and completed in 2020, enrolled 4362 patients. It revealed two subpopulations of UC patients treated with tofacitinib, highlighting a significant difference in VTE risk compared to those treated with TNF inhibitors. High-risk patients, defined as those aged 65 years or older or with a history of smoking, showed increased VTE incidence, while younger, never-smoking patients did not exhibit a significant increase in risk. These findings underscore the need for individualized benefit-risk assessments for tofacitinib treatment in high-risk UC patients[8]. These results were derived from a robust randomized controlled trial design, strengthening the validity of the findings. However, the specific impact of UC versus other rheumatic diseases in the cohort warrants clarification.

Another multicenter prospective study conducted in Japan found that 11.1% of UC patients developed DVT, and 0.7% experienced pulmonary embolism during surgery, with prolonged hospital stays identified as a significant risk factor[4]. The prospective nature and multicenter design enhance the study’s reliability, although geographical limitations may affect generalizability.

Additionally, a study assessing postoperative VTE risk in UC patients treated with Janus kinase (JAK) inhibitors from 2013 to 2021 aimed to determine if prior JAK inhibitor use increased VTE and complication risks, providing valuable insights for surgical management in this population[9]. This longitudinal study employed surgical outcome data to determine postoperative complication rates. While insightful, control for confounding factors such as underlying disease severity is needed to strengthen conclusions.

Pediatric studies also indicate that, despite the lower overall incidence of VTE compared to adults, thromboembolism risk remains significant in children with UC[10]. A North American population-based study reported an incidence rate of approximately 1.5% among pediatric IBD patients, particularly during acute disease flares[11]. Such population-based approach lends strong external validity to these findings, but the relatively small number of events limits statistical power.

Genetic predispositions may play a role in this thromboembolic over-risk among younger UC patients: Approximately 14% of pediatric patients with IBD carry genetic markers associated with higher rates of thromboembolic events[12]. Exploring these genetic markers may help identify high-risk subgroups for targeted preventive strategies.

GEOGRAPHICAL AND ETHNIC/RACIAL VARIATIONS: RELEVANT PARAMETERS

The incidence and characteristics of VTE in UC vary significantly based on geographical location and ethnic or racial backgrounds, and studies indicate that the prevalence of VTE among IBD patients differs across regions due to variations in healthcare access, genetic predispositions, environmental factors, and lifestyle differences.

For instance, Western populations generally report higher rates of VTE associated with IBD compared to Asian populations. A meta-analysis published in 2021 found that Asian patients had a lower absolute risk of VTE compared to their Western counterparts but still exhibited a two-fold increased risk relative to the general population. This suggests that while the baseline risk may be lower in Asia, the relative increase due to IBD remains significant[13].

Ethnic differences also play a major role in mitigating the thromboembolic risks associated with UC. For example, studies have shown that Black patients may have higher rates of thromboembolic events compared to White patients within similar clinical settings[14]. Additionally, genetic factors such as variations in coagulation factor genes may contribute to differing risks among racial groups. In South Asian populations[13], there is limited data on the prevalence of VTE; however, findings suggest similar trends observed globally, including Pakistan as highlighted by Karim et al[5].

Understanding such variations is essential for tailoring prevention and treatment strategies for thromboembolism in UC patients. Healthcare providers should consider these factors when assessing individual patient risks and implementing prophylactic measures.

CONCLUSION

The intersection of UC and thromboembolism poses a significant clinical challenge that requires heightened awareness among practitioners. The multifactorial nature of thromboembolic risks necessitates a comprehensive approach to patient management.

A personalized management strategy is essential for effectively addressing this risk, necessitating thorough assessment of individual factors such as age, smoking history, and comorbidities. Recognizing the various risk factors associated with VTE—including inherent disease characteristics and external influences like medication regimens—is crucial; for instance, immunosuppressive therapies such as tofacitinib are linked to elevated VTE rates, particularly when administered close to surgical interventions[15].

Preventive strategies should be tailored to each patient's risk profile, for high-risk individuals—such as those with obesity or a history of thromboembolic events—prophylactic anticoagulation should be considered[16].

Preventive strategies should be stratified based on risk factors. For low-risk UC patients, general mobilization and monitoring may be sufficient. For moderate to high-risk patients, especially those with previous VTE events, obesity, or genetic predisposition, the use of Low Molecular Weight Heparin or other anticoagulant prophylaxis should be considered, both in hospitalized settings and perioperatively. Additionally, clinicians and surgeons should reassess VTE risk regularly, especially in contexts of immunosuppressive therapy initiation.

There is a pressing need for more extensive multicenter studies across diverse populations to better understand the epidemiology and pathophysiology of thromboembolism in UC. Such research will not only enhance our knowledge but also guide the development of proactive, targeted interventions aimed at reducing morbidity associated with these complications.