Y-ECCO Literature Review: Francisco Lopez Romero-Salazar
Hypercoagulation after Hospital Discharge in Acute Severe Ulcerative Colitis: A Prospective Study
Griffiths BH, Desborough MJR, Duijvestein M, et al.
Clin Gastroenterol Hepatol 2024 Dec 16:S1542-3565(24)01085-1.
doi: 10.1016/j.cgh.2024.10.031 [Online ahead of print].
Introduction
Venous thromboembolism (VTE) is a known extraintestinal manifestation of Inflammatory Bowel Disease (IBD), associated with significant morbidity and potentially mortality [1]. Patients with IBD face a higher VTE risk than controls in the general population, with the risk for VTE further increasing during periods of hospitalisation [2]. While current guidelines support pharmacological prophylaxis throughout the duration of a hospital admission [1, 3], the duration of post-discharge thrombotic risk—and thus the indication to continue prophylaxis—remains unclear. To address this gap, Griffiths and colleagues evaluated the hypercoagulability profile of patients with Acute Severe Ulcerative Colitis (ASUC) during hospitalisation and up to 12 weeks post-discharge.
Methods and key findings
The authors conducted a prospective, two-centre study comparing hospitalised patients with ASUC to outpatient controls with known UC on remission. ASUC was defined using modified Truelove and Witts criteria [3]. Patients on anticoagulant or antiplatelet therapy at admission, with haemostatic disorders, with liver cirrhosis or with prior VTE were excluded. Regarding ASUC management, the study collected data on response to intravenous corticosteroids, need for rescue therapy and need for colectomy. To assess hypercoagulability, serial blood samples were analysed, focusing on key coagulation components. In ASUC patients, samples were collected on days 1 and 5 of hospitalisation and at weeks 4 and 8–12 post-discharge. A single blood sample was drawn from control subjects. Parameters included procoagulant factors (fibrinogen and factors II and VIII), natural anticoagulants (proteins C and S, antithrombin) and fibrinolysis markers (D-dimer, plasminogen, clot lysis time and fibrin clot density). Von Willebrand factor (VWF) served as a marker of endothelial activation. Additionally, global functional assays—thrombin generation (TG) and rotational thromboelastometry—captured the overall thrombotic potential at each time point. All patients received in-hospital thromboprophylaxis, without continuation after discharge.
The study included 27 patients hospitalised with ASUC (70% male) and 25 controls (68% male), with 12-week follow-up. At admission, 29.6% of ASUC patients were on prednisolone, 51.9% on mesalazine, 25.9% on immunomodulators and 11.1% on biologics. Median Ulcerative Colitis Endoscopic Index of Severity (UCEIS) at sigmoidoscopy was 6. Among controls, 88% were on mesalazine and 76% on immunomodulators for maintenance. Rescue therapy was required in 44.4% (nine with ciclosporin, three with infliximab). Eight patients underwent colectomy during follow-up. One patient developed cephalic vein thrombosis at one week post-discharge.
When assessing the hypercoagulable state in ASUC patients compared to controls, procoagulant factors, including fibrinogen, VWF and factor VIII, were significantly elevated from admission and remained high throughout follow-up. In contrast, protein C and antithrombin were transiently elevated on day 5 and week 4. Regarding fibrinolysis, D-dimer was elevated during admission and normalised later, while thrombin-activatable fibrinolysis inhibitor (TAFIa) remained significantly increased up to week 12 post-discharge. Regarding global functional assays, the endogenous thrombin potential (ETP) was significantly higher in patients with ASUC and normalised by weeks 8–12. In contrast, clot formation time was significantly shorter and maximum clot firmness (MCF) was consistently higher at all time points compared with controls, indicating persistent hypercoagulability. ETP was the only parameter significantly higher on day 1 and week 4 in patients who required colectomy.
Discussion
This is the first study to provide a prospective, detailed and longitudinal assessment of both specific coagulation markers and global functional assays in patients with ASUC, from admission through post-discharge follow-up. The most striking elevations at admission involved fibrinogen, factor VIII, VWF and TAFIa, which remained high for weeks after discharge, indicating sustained hypercoagulability. These findings align with previous data showing increased post-admission VTE rates in IBD [1]. Interestingly, the hypercoagulable state persisted regardless of ASUC treatment, including surgery—an observation with notable pathophysiological implications.
The use of global haemostasis assays in this study adds depth to its findings. TG, the end-product of the coagulation cascade, reflects the net balance between procoagulant and anticoagulant forces. Elevated TG levels are clinically relevant as they predict risk of first VTE [4]. In this study, ETP and peak TG remained elevated up to week 4, indicating a hypercoagulable state beyond hospitalisation. These findings were reinforced by rotational thromboelastometry. EXTEM MCF and FIBTEM values remained significantly elevated throughout follow-up compared to controls. As FIBTEM isolates fibrinogen’s role, the results suggest fibrinogen was the main driver of clot stability, consistent with previous studies [5].
The development of VTE relies on Virchow’s triad, highlighting the link between inflammation and haemostasis. In UC, interleukin-6 can be a key driver of inflammation [6] and promotes endothelial release of VWF and hepatic production of fibrinogen and thrombopoietin [7]. Elevated thrombin generation and hyperfibrinogenaemia increase clot strength and are associated with greater VTE risk [7].
Worryingly, despite current guideline recommendations [1, 3], recent data suggest that up to 25% of patients with ASUC do not receive pharmacological thromboprophylaxis during admission [8]. This has been attributed to possible concerns in a patient presenting with rectal bleeding [9]. This current study documents a sustained hypercoagulable state during acute illness and reinforces the rationale for routine in-hospital thromboprophylaxis in patients with ASUC.
However, most VTE events in IBD occur after discharge [1]. While extended prophylaxis appears to reduce VTE in cancer patients with comparable risk [10], it is not currently routinely recommended in IBD [3]. This study shows hypercoagulability up to 12 weeks. Although clinical outcomes should guide clinical decisions, these findings and the favourable risk-benefit may justify extended thromboprophylaxis post-discharge.
Regarding the study's limitations, the small sample size and only one thrombotic event limit clinical interpretation. A 30% colectomy rate, which is higher than would be expected for first presentation with ASUC [3], suggests more severe disease and possible overestimation of hypercoagulability (although no significant differences were observed compared to medication responders).
Finally, this study is relevant not only for highlighting ASUC-associated hypercoagulability but also for its potential clinical implications. Given the study’s findings, the low bleeding risk of prophylactic dosing and the potential severity of VTE, extended thromboprophylaxis should be reconsidered, at least until more individualised data are available. This study also opens important research questions, such as how long thromboprophylaxis should last, whether all patients with ASUC should receive it and whether similar findings apply to flares that do not meet ASUC criteria and are managed in the outpatient/ambulatory setting.
Conclusion
This study confirms that ASUC represents a hypercoagulable disease state that persists for several weeks after hospital discharge, supporting the consideration of standardised extended thromboprophylaxis protocols in this specific clinical scenario.
References
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- 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.
- Spinelli A, Bonovas S, Burisch J, et al. ECCO guidelines on therapeutics in ulcerative colitis: Surgical treatment. J Crohns Colitis 2022;16:179–89.
- Lutsey PL, Folsom AR, Heckbert SR, et al. Peak thrombin generation and subsequent venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study. J Thromb Haemost 2009;7:1639–48.
- Owczarek D, Cibor D, Salapa K, et al. Reduced plasma fibrin clot permeability and susceptibility to lysis in patients with inflammatory bowel disease: a novel prothrombotic mechanism. Inflamm Bowel Dis 2013;19:2616–24.
- Wine E, Mack DR, Hyams J, et al. Interleukin-6 is associated with steroid resistance and reflects disease activity in severe pediatric ulcerative colitis. J Crohns Colitis 2013;7:916–22.
- Kerr R, Stirling D, Ludlam CA. Interleukin 6 and haemostasis. Br J Haematol 2001;115:3–12.
- Vuyyuru S, Alphonsus L, De Silva TA, et al. P550 Short and long-term outcomes after acute severe ulcerative colitis in adults: a 12-year Canadian experience in the post biologic era. J Crohns Colitis 2024;18(Suppl 1):i1082–3.
- Sam JJ, Bernstein CN, Razik R, et al. Physicians’ perceptions of risks and practices in venous thromboembolism prophylaxis in inflammatory bowel disease. Dig Dis Sci 2013;58:46–52.
- Fagarasanu A, Alotaibi GS, Hrimiuc R, et al. Role of extended thromboprophylaxis after abdominal and pelvic surgery in cancer patients: a systematic review and meta-analysis. Ann Surg Oncol 2016;23:1422–30.2.
Profile
Francisco Lopez Romero-Salazar is undertaking an advanced fellowship in gastroenterology and nutrition at Cambridge University Hospitals in Cambridge, United Kingdom. He has particular interests in nutrition and IBD and better understanding the role of dietary interventions in IBD.