1 Inflamm Bowel Dis • Volume XX, Number XX, XX 2021 Received for publications April 6, 2020; Editorial Decision December 10, 2020. From the *Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy; † Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy; ‡ Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy; § Department of Pathophysiology and Transplantation, Università degli Studi, Milano, Italy; ¶ Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy Conficts of interest: The authors declare that they have no confict of interest. Author contributions: MV and AT conceived the clinical and laboratory pro- tocol, respectively. LS, LP, and FC managed patients and collected clinical data. LFP and CV conducted laboratory testing. VC conducted data acquisition and statistical analyses. AT reviewed the data and wrote the manuscript. MV and FP reviewed the data and the manuscript. Address correspondence to: Armando Tripodi, Via Pace 9, 20122 Milano, Italy (armando.tripodi@unimi.it). © 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. ORIGINAL RESEARCH ARTICLES - CLINICAL Anti-TNF-α Treatment Reduces the Baseline Procoagulant Imbalance of Patients With Infammatory Bowel Diseases Armando Tripodi, PhD,* ,† Luisa Spina, MD, PhD, ‡ Laura Francesca Pisani, PhD, ‡ Lidia Padovan, PhD,* ,† Flaminia Cavallaro, MD, PhD, ‡ Veena Chantarangkul, PhD,* ,† Carla Valsecchi, PhD,* ,† Flora Peyvandi, MD, PhD,* ,†,§ and Maurizio Vecchi, MD §,¶ Background: Infammatory bowel diseases (IBD) are characterized by an increased thrombosis risk of uncertain etiology. Coagulation derange- ment arising from infammation may be a triggering factor. We hypothesized that strong infammation inhibitors (eg, anti-tumor necrosis factor-α drugs) may affect coagulation. Methods: Forty patients with IBD were compared with 57 control patients for coagulation factors and endogenous thrombin potential (ETP), the latter being the most sensitive marker of in vivo pro- and anticoagulation balance. We measured ETP in the presence and absence of thrombomodulin (the physiologic protein C [PC] activator). Coagulation at different timepoints was also assessed for 28 of these patients during infiximab treatment. Results: The median ETP (nM thrombin × minutes) and range (minimum-maximum) were each higher in patients at baseline than in control patients in both the absence (2120 [1611-3041] vs 1865 [1270-2337]) and the presence (1453 [464-2522] vs 831 [104-1741]) of thrombomodulin. The ETP ratio (with/without thrombomodulin) was high at baseline (0.73 [0.21-0.90] vs 0.45 [0.07-0.85]). The ETP and ETP ratio declined during treatment and were signifcantly lower at the end than at baseline. Factor (F) VIII and fbrinogen, which were high at baseline, decreased during treatment and at the end were signifcantly lower than at baseline. The FVIII/PC ratio, which was high in patients at baseline, declined during treatment and at the end was lower than at baseline. C-reactive protein recorded at the end of treatment was lower than at baseline. Conclusions: Patients with IBD have a procoagulant imbalance as shown by increased ETP at baseline. The ETP decreases during treatment with infiximab, which is related to decreased FVIII and FVIII/PC ratio. This effect is also related to the improvement of infammation as shown by decreased fbrinogen and C-reactive protein. Key Words: hypercoagulability, thrombin generation, factor VIII, protein C, fibrinogen INTRODUCTION The 2 major forms of infammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC), are chronic illnesses characterized by local and systemic infam- mation and by an increased risk of venous thromboembo- lism (VTE) during and after hospitalization. 1-8 Although the etiology and risk factors for VTE are still uncertain, various prothrombotic alterations have been described in patients with IBD. These include quantitative and qualitative derangements of platelets, 9, 10 procoagulant 6, 11 or fbrinolytic proteins, 12, 13 and hyper-homocysteinemia 14 or decreased levels of natu- rally occurring anticoagulants. 15 All these data suggest that a hypercoagulable state does exist in IBD. Hypercoagulability is one of the 3 components of the Virchow triad (the other 2 being reduced blood fow and endothelial dysfunction) historically considered as the major factor responsible for VTE. Hypercoagulability is turn defned by high thrombin generation, representing the fnal step of co- agulation, which is triggered by tissue factor in complex with activated factor VIII (FVIII) and is downregulated by the nat- urally occurring anticoagulants (eg, antithrombin, protein C, and tissue factor pathway inhibitor). 16 Protein C circulates in a zymogenic form and is activated when thrombin binds to its endothelial receptor, thrombomodulin. 17 In normal conditions, the balance between pro- and anticoagulants prevents excessive thrombin formation. Although coagulation can be assessed by measuring indi- vidual pro- or anticoagulants, neither of these approaches can accurately describe the balance between the 2 opposing drivers occurring in vivo. Alternatively, coagulation can be assessed by global tests—prothrombin and activated partial doi: 10.1093/ibd/izaa351 Published online 4 January 2021 Downloaded from https://academic.oup.com/ibdjournal/advance-article/doi/10.1093/ibd/izaa351/6061398 by guest on 24 February 2021