Venous Thromboembolism in Patients with Inflammatory Bowel Disease: The Role of Pharmacological Therapy and Surgery
Abstract
:1. Introduction
2. Pharmacological Therapies
2.1. Mesalazine
2.2. Azathioprine and 6-Mercaptopurine (6-MP)
2.3. Corticosteroids (CSs)
2.4. Methotrexate (MTX)
2.5. Thalidomide
2.6. Infliximab (and Other Anti-Tumor Necrosis Factor (TNF)-α Agents)
2.7. Vedolizumab (VDZ)
2.8. Ustekinumab (UST)
2.9. Tofacitinib (TOF)
2.10. Upadacitinib
2.11. Filgotinib
3. Surgery
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Murthy, S.K.; Nguyen, G.C. Venous thromboembolism in Inflammatory Bowel Disease: An Epidemiological Review. Am. J. Gastroenterol. 2011, 106, 713–718. [Google Scholar] [CrossRef]
- Papa, A.; Scaldaferri, F.; Danese, S.; Guglielmo, S.; Roberto, I.; Bonizzi, M.; Mocci, G.; Felice, C.; Ricci, C.; Andrisani, G.; et al. Vascular involvement in inflammatory bowel disease: Pathogenesis and clinical aspects. Dig. Dis. 2008, 26, 149–155. [Google Scholar] [CrossRef] [PubMed]
- Solem, C.A.; Loftus, E.V.; Tremaine, W.J.; Sandborn, W.J. Venous thromboembolism in inflammatory bowel disease. Am. J. Gastroenterol. 2004, 99, 97–101. [Google Scholar] [CrossRef] [PubMed]
- Fumery, M.; Xiaocang, C.; Dauchet, L.; Gower-Rousseau, C.; Peyrin-Biroulet, L.; Colombel, J.F. Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: A meta-analysis of observational studies. J. Crohn’s Colitis 2014, 8, 469–479. [Google Scholar] [CrossRef] [PubMed]
- Yuhara, H.; Steinmaus, C.; Corley, D.; Koike, J.; Igarashi, M.; Suzuki, T.; Mine, T. Meta-analysis: The risk of venous thromboembolism in patients with inflammatory bowel disease. Aliment. Pharmacol. Ther. 2013, 37, 953–962. [Google Scholar] [CrossRef]
- Bernstein, C.N.; Blanchard, J.F.; Houston, D.S.; Wajda, A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: A population- based cohort study. Thromb. Haemost. 2001, 85, 430–434. [Google Scholar]
- Kappelmann, M.D.; Horvath-Puho, E.; Sandler, R.S.; Rubin, D.T.; Ullman, T.A.; Pedersen, L.; Sørensen, H.T. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: A population-based nationwide study. Gut 2011, 60, 937–943. [Google Scholar] [CrossRef]
- Nylund, C.M.; Goudie, A.; Garza, J.M.; Crouch, G.; Denson, L.A. Venous thrombotic events in hospitalized children and adolescents with inflammatory bowel disease. JPGN 2013, 56, 485–491. [Google Scholar] [CrossRef]
- Nguyen, G.C.; Sam, J. Rising prevalence of venous thromboembolism and its impact on mortality among hospitalized inflammatory bowel disease patients. Am. J. Gastroenterol. 2008, 103, 2272–2280. [Google Scholar] [CrossRef]
- Papa, A.; Danese, S.; Grillo, A.; Gasbarrini, A. Review article: Inherited thrombophilia in inflammatory bowel disease. Am. J. Gastroenterol. 2003, 98, 1247–1251. [Google Scholar] [CrossRef]
- Danese, S.; Papa, A.; Saibeni, S.; Repici, A.; Malesci, A.; Vecchi, M. Inflammation and coagulation in inflammatory bowel disease: The clot thickens. Am. J. Gastroenterol. 2007, 102, 174–186. [Google Scholar] [CrossRef] [PubMed]
- Grainge, M.J.; West, J.; Card, T.R. Venous thromboembolism during active disease and remission in inflammatory bowel disease: A cohort study. Lancet 2010, 375, 657–663. [Google Scholar] [CrossRef]
- Danese, S.; Papa, A. PAI-1 and TAFI in inflammatory bowel disease: The yin and yang of the fibrinolytic system. Eur. J. Gastroenterol. Hepatol. 2008, 20, 826–828. [Google Scholar] [CrossRef] [PubMed]
- Senchenkova, E.; Seifert, H.; Granger, D.N. Hypercoagulability and Platelet Abnormalities in Inflammatory Bowel Disease. Semin. Thromb. Hemost. 2015, 41, 582–589. [Google Scholar] [CrossRef] [PubMed]
- Carty, E.; MacEy, M.; Rampton, D.S. Inhibition of platelet activation by 5-aminosalicylic acid in inflammatory bowel disease. Aliment. Pharmacol. Ther. 2000, 14, 1169–1179. [Google Scholar] [CrossRef] [PubMed]
- Thomas, G.; Skrinska, V.A.; Lucas, F.V. The influence of glutathione and other thiols on human platelet aggregation. Thromb. Res. 1986, 44, 859–866. [Google Scholar] [CrossRef]
- Peter, M.I.; Irving, L.; Marion, G.; Macey, U.S.; Lee, W.; Louise, L.; David, S. Rampton. Formation of Platelet-Leukocyte Aggregates in Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2004, 10, 361–372. [Google Scholar] [CrossRef]
- Majoor, C.J.; Sneeboer, M.M.; de Kievit, A.; Meijers, J.C.; van der Poll, T.; Lutter, R.; Bel, E.H.; Kamphuisen, P.W. The influence of corticosteroids on hemostasis in healthy subjects. J. Thromb. Haemost. 2016, 14, 716–723. [Google Scholar] [CrossRef][Green Version]
- Johannesdottir, S.A.; Horváth-Puhó, E.; Dekkers, O.M.; Cannegieter, S.C.; Jørgensen, J.O.; Ehrenstein, V.; Vandenbroucke, J.P.; Pedersen, L.; Sørensen, H.T. Use of glucocorticoids and risk of venous thromboembolism: A nationwide population-based case-control study. JAMA Intern. Med. 2013, 173, 743–752. [Google Scholar] [CrossRef][Green Version]
- Waljee, A.K.; Wiitala, W.L.; Govani, S.; Stidham, R.; Saini, S.; Hou, J.; Feagins, L.A.; Khan, N.; Good, C.B.; Vijan, S.; et al. Corticosteroid Use and Complications in a US Inflammatory Bowel Disease Cohort. PLoS ONE 2016, 11, 0158017. [Google Scholar] [CrossRef][Green Version]
- Gangireddy, C.; Rectenwald, J.R.; Upchurch, G.R.; Wakefield, T.W.; Khuri, S.; Henderson, W.G.; Henke, P.K. Risk factors and clinical impact of postoperative symptomatic venous thromboembolism. J. Vasc. Surg. 2007, 45, 335–341. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Sarlos, P.; Szemes, K.; Hegyi, P.; Garami, A.; Szabo, I.; Illes, A.; Solymar, M.; Petervari, E.; Vincze, A.; Par, G.; et al. Steroid but not Biological Therapy Elevates the risk of Venous Thromboembolic Events in Inflammatory Bowel Disease: A Meta-Analysis. J. Crohn’s Colitis 2018, 12, 489–498. [Google Scholar] [CrossRef] [PubMed]
- Papa, A.; Papa, V.; Marzo, M.; Scaldaferri, F.; Sofo, L.; Rapaccini, G.L.; Danese, S.; Gasbarrini, A. Prevention and treatment of venous thromboembolism in patients with IBD: A trail still climbing. Inflamm. Bowel Dis. 2015, 21, 1204–1213. [Google Scholar] [CrossRef] [PubMed]
- Papa, A.; De Stefano, V.; Danese, S.; Chiusolo, P.; Persichilli, S.; Casorelli, I.; Zappacosta, B.; Giardina, B.; Gasbarrini, A.; Leone, G.; et al. Hyperhomocysteinemia and prevalence of polymorphisms of homocysteine metabolism-related enzymes in patients with inflammatory bowel disease. Am. J. Gastroenterol. 2001, 96, 2677–2682. [Google Scholar] [CrossRef]
- Bramuzzo, M.; Ventura, A.; Martelossi, S.; Lazzerini, M. Thalidomide for inflammatory bowel disease: Systematic review. Medicine (Baltimore) 2016, 95, e4239. [Google Scholar] [CrossRef]
- Robak, M.; Trelinski, J.; Chojnowski, K. Hemostatic changes after 1 month of thalidomide and dexamethasone therapy in patients with multiple myeloma. Med. Oncol. 2012, 29, 3574–3580. [Google Scholar] [CrossRef][Green Version]
- El Accaoui, R.N.; Shamseddeen, W.A.; Taher, A.T. Thalidomide and thrombosis. A meta-analysis. Thromb. Haemost. 2007, 97, 1031–1036. [Google Scholar]
- Davies, R.; Galloway, J.B.; Watson, K.D.; Lunt, M.; Symmons, D.P.M.; Hyrich, K.L. BSRBR Control Centre Consortium, British Society for Rheumatology Biologics Register. Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy: Results from the British Society for Rheumatology Biologics Register. Ann. Rheum. Dis. 2011, 70, 1831–1834. [Google Scholar]
- Higgins, P.D.; Skup, M.; Mulani, P.M.; Lin, J.; Chao, J. Increased risk of venous thromboembolic events with corticosteroid vs biologic therapy for inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 2015, 13, 316–321. [Google Scholar] [CrossRef]
- Desai, R.J.; Gagne, J.J.; Lii, J.; Liu, J.; Friedman, S.; Kim, S.C. Comparative risk of incident venous thromboembolism in patients with inflammatory bowel disease initiating tumor necrosis factor-α inhibitors or nonbiologic agents: A cohort study. CMAJ 2017, 189, E1438–E1447. [Google Scholar] [CrossRef][Green Version]
- Hommes, D.W.; van Dullemen, H.M.; Levi, M.; Van der Ende, A.; Woody, J.; Tytgat, G.N.J.; Van Deventer, S.J.H. Beneficial effect of treatment with a monoclonal anti-tumor necrosis factor-alpha antibody on markers of coagulation and fibrinolysis in patients with active Crohn’s disease. Haemostasis 1997, 27, 269–277. [Google Scholar] [PubMed]
- Danese, S.; Sans, M.; Scaldaferri, F.; Sgambato, A.; Rutella, S.; Cittadini, A.; Piqué, J.A.; Panes, J.; Katz, J.A.; Fiocchi, C.; et al. TNF-alpha blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: A novel anti-inflammatory mechanism of infliximab in Crohn’s disease. J. Immunol. 2006, 176, 2617–2624. [Google Scholar] [CrossRef] [PubMed]
- Bollen, L.; Vande Casteele, N.; Peeters, M.; Bessonov, K.; Van Steen, K.; Rutgeerts, P.; Ferrante, M.; Hoylaerts, M.F.; Vermeire, S.; Gils, A. Short-term effect of infliximab is reflected in the clot lysis profile of patients with inflammatory bowel disease: A prospective study. Inflamm. Bowel. Dis. 2015, 21, 570–578. [Google Scholar] [CrossRef] [PubMed]
- Feagan, B.G.; Rutgeerts, P.; Sands, B.E.; Hanauer, S.; Colombel, J.F.; Sandborn, W.J.; Van Assche, G.; Axler, J.; Kim, H.J.; Danese, S.; et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 2013, 369, 699–710. [Google Scholar] [CrossRef][Green Version]
- Sandborn, W.J.; Feagan, B.G.; Rutgeerts, P.; Hanauer, S.; Colombel, J.F.; Sands, B.E.; Lukas, M.; Fedorak, R.N.; Lee, S.; Bressler, B.; et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N. Engl. J. Med. 2013, 369, 711–721. [Google Scholar] [CrossRef][Green Version]
- Sands, B.E.; Van Assche, G.; Tudor, D.; Akhundova-Unadkat, G.; Curtis, R.I.; Tan, T. Vedolizumab in Combination With Corticosteroids for Induction Therapy in Crohn’s Disease: A Post Hoc Analysis of GEMINI 2 and 3. Inflamm. Bowel Dis. 2019, 25, 1375–1382. [Google Scholar] [CrossRef][Green Version]
- Vermeire, S.; Loftus, E.V., Jr.; Colombel, J.F.; Feagan, B.G.; Sandborn, W.J.; Sands, B.E.; Danese, S.; D’Haens, G.R.; Kaser, A.; Panaccione, R.; et al. Long-term Efficacy of Vedolizumab for Crohn’s Disease. J. Crohn’s Colitis 2017, 11, 412–424. [Google Scholar] [CrossRef]
- Loftus, E.V., Jr.; Colombel, J.F.; Feagan, B.G.; Vermeire, S.; Sandborn, W.J.; Sands, B.E.; Danese, S.; D’Haens, G.R.; Kaser, A.; Panaccione, R.; et al. Long-term Efficacy of Vedolizumab for Ulcerative Colitis. J. Crohn’s Colitis 2017, 11, 400–411. [Google Scholar] [CrossRef][Green Version]
- Sands, B.E.; Peyrin-Biroulet, L.; Loftus, E.V., Jr.; Danese, S.; Colombel, J.F.; Törüner, M.; Jonaitis, L.; Abhyankar, B.; Chen, J.; Rogers, R.; et al. Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. N. Engl. J. Med. 2019, 381, 1215–1226. [Google Scholar] [CrossRef]
- Cross, R.K.; Chiorean, M.; Vekeman, F.; Xiao, Y.; Wu, E.; Chao, J.; Wang, A.W. Assessment of the real-world safety profile of vedolizumab using the United States Food and Drug Administration adverse event reporting system. PLoS ONE 2019, 14, e0225572. [Google Scholar] [CrossRef][Green Version]
- Feagan, B.G.; Sandborn, W.J.; Gasink, C.; Jacobstein, D.; Lang, Y.; Friedman, J.R.; Blank, M.A.; Johanns, J.; Gao, L.L.; Miao, Y.; et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N. Engl. J. Med. 2016, 375, 1946–1960. [Google Scholar] [CrossRef] [PubMed]
- Sandborn, W.J.; Rutgeerts, P.; Gasink, C.; Jacobstein, D.; Zou, B.; Johanns, J.; Sands, B.E.; Hanauer, S.B.; Targan, S.; Ghosh, S.; et al. Long-term efficacy and safety of ustekinumab for Crohn’s disease through the second year of therapy. Aliment. Pharmacol. Ther. 2018, 48, 65–77. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Hanauer, S.B.; Sandborn, W.J.; Feagan, B.G.; Gasink, C.; Jacobstein, D.; Zou, B.; Johanns, J.; Adedokun, O.J.; Sands, B.E.; Rutgeerts, P.; et al. IM-UNITI: Three-year Efficacy, Safety, and Immunogenicity of Ustekinumab Treatment of Crohn’s Disease. J. Crohn’s Colitis 2020, 14, 23–32. [Google Scholar] [CrossRef]
- Liefferinckx, C.; Verstockt, B.; Gils, A.; Noman, M.; Van Kemseke, C.; Macken, E.; De Vos, M.; Van Moerkercke, W.; Rahier, J.F.; Bossuyt, P.; et al. Long-term Clinical Effectiveness of Ustekinumab in Patients with Crohn’s Disease Who Failed Biologic Therapies: A National Cohort Study. J. Crohn’s Colitis 2019, 13, 1401–1409. [Google Scholar] [CrossRef] [PubMed]
- Xie, W.; Xiao, S.; Huang, Y.; Sun, X.; Zhang, Z. Effect of tofacitinib on cardiovascular events and all-cause mortality in patients with immune-mediated inflammatory diseases: A systematic review and meta-analysis of randomized controlled trials. Ther. Adv. Musculoskelet. Dis. 2019, 11. [Google Scholar] [CrossRef]
- US Food and Drug Administration. Safety Trial Finds Risk of Blood Clots in the Lungs and Death with Higher dose of Tofacitinib (Xeljanz, Xeljanz XR) in Rheumatoid Arthritis Patients; FDA to Investigate. 2019. Available online: https://www.fda.gov/media/120485/download (accessed on 17 October 2019).
- Sandborn, W.J.; Panés, J.; Sands, B.E.; Reinisch, W.; Su, C.; Lawendy, N.; Koram, N.; Fan, H.; Jones, T.V.; Modesto, I.; et al. Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme. Aliment. Pharmacol. Ther. 2019, 50, 1068–1076. [Google Scholar] [CrossRef]
- Kotze, P.G.; Teixeira, F.V.; Damião, A.O.M.C. Letter: Thromboembolic and cardiovascular events with tofacitinib in ulcerative colitis-two cases in real world clinical practice. Aliment. Pharmacol. Ther. 2020, 51, 1208–1209. [Google Scholar] [CrossRef]
- Sandborn, W.J.; Ghosh, S.; Panes, J.; Schreiber, S.; D’Haens, G.; Tanida, S.; Siffledeen, J.; Enejosa, J.; Zhou, W.; Othman, A.A.; et al. Efficacy of Upadacitinib in a Randomized Trial of Patients with Active Ulcerative Colitis. Gastroenterology 2020. [Google Scholar] [CrossRef]
- Ma, C.; Lee, J.K.; Mitra, A.R.; Teriaky, A.; Choudhary, D.; Nguyen, T.M.; Vande Casteele, N.; Khanna, R.; Panaccione, R.; Feagan, B.G.; et al. Systematic review with meta-analysis: Efficacy and safety of oral Janus kinase inhibitors for inflammatory bowel disease. Aliment. Pharmacol. Ther. 2019, 50, 5–23. [Google Scholar] [CrossRef][Green Version]
- Olivera, P.A.; Lasa, J.S.; Bonovas, S.; Danese, S.; Peyrin-Biroulet, L. Safety of Janus Kinase Inhibitors in Patients With Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and Meta-Analysis. Gastroenterology 2020, 158, 1554–1573.e12. [Google Scholar] [CrossRef]
- McKechnie, T.; Wang, J.; Springer, J.E.; Gross, P.L.; Forbes, S.; Eskicioglu, C. Extended thromboprophylaxis following colorectal surgery in patients with inflammatory bowel disease: A comprehensive systematic clinical review. Colorectal. Dis. 2019. [Google Scholar] [CrossRef] [PubMed]
- O’Connor, O.J.; Cahill, R.A.; Kirwan, W.O.; Redmond, H.P. The incidence of postoperative venous thrombosis among patients with ulcerative colitis. Ir. J. Med. Sci. 2005, 174, 20–22. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Kayal, M.; Radcliffe, M.; Plietz, M.; Rosman, A.; Greenstein, A.; Khaitov, S.; Sylla, P.; Dubinsky, M.C. Portomesenteric Venous Thrombosis in Patients Undergoing Surgery for Medically Refractory Ulcerative Colitis. Inflamm. Bowel. Dis. 2020, 26, 283–288. [Google Scholar] [CrossRef] [PubMed]
- Wallaert, J.B.; De Martino, R.R.; Marsicovetere, P.S.; Goodney, P.P.; Finlayson, S.R.; Murray, J.J.; Holubar, S.D. Venous thromboembolism after surgery for inflammatory bowel disease: Are there modifiable risk factors? Data from ACS NSQIP. Dis. Colon Rectum. 2012, 55, 1138–1144. [Google Scholar] [CrossRef][Green Version]
- Ali, F.; Al-Kindi, S.G.; Blank, J.J.; Peterson, C.Y.; Ludwig, K.A.; Ridolfi, T.J. Elevated Venous Thromboembolism Risk Following Colectomy for IBD Is Equal to Those for Colorectal Cancer for Ninety Days After Surgery. Dis. Colon Rectum. 2018, 61, 375–381. [Google Scholar] [CrossRef]
- Gross, M.E.; Vogler, S.A.; Mone, M.C.; Sheng, X.; Sklow, B. The importance of extended postoperative venous thromboembolism prophylaxis in IBD: A National Surgical Quality Improvement Program analysis. Dis. Colon Rectum. 2014, 57, 482–489. [Google Scholar] [CrossRef]
- Ramsey, M.; Somashekar, G.K.; Stanich, P.P.; Husain, S.; Levine, E.J.; Conwell, D.; Hinton, A.; Zhang, C. Inflammatory Bowel Disease Adversely Impacts Colorectal Cancer Surgery Short-term Outcomes and Health-Care Resource Utilization. Clin. Transl. Gastroenterol. 2017, 8, e127. [Google Scholar] [CrossRef]
Risk Factor | Prevention/Treatment Modality |
---|---|
Hyperhomocysteinemia | Correction of vitamin deficiency (vitamin B12, vitamin B6, and folic acid) |
Dehydration | Provide adequate hydration |
Prolonged immobilization | Early mobilization, especially after surgery; graduated compression stockings or pneumatic devices |
Infections | Timely diagnosis and treatment of infections |
Indwelling catheters | Limit the use of venous catheters; when possible, administer oral and enteral nutrition |
Obesity | Encourage weight loss (diet and exercise) |
Hospitalization | VTE prophylaxis also for IBD patients admitted for non-IBD related reasons |
Smoking | Programs for smoking cessation |
Oral contraceptive use | Advise alternative methods of contraception |
Previous VTE | Search for genetic and acquired risk factors for VTE and administer prophylaxis if necessary |
Abnormalities of Coagulation |
↑ Fibrinogen |
↑ Factors V, VIII, IX |
↑ Prothrombin fragment 1 + 2, fibrinopeptide A and B, TAT complex |
↓ Factor XIII/subunit A factor XIII |
↓ Protein C, protein S, antithrombin |
↓ TFPI |
Abnormalities of Platelets |
↑ Number, activation, aggregation |
Abnormalities of Fibrinolysis |
↓ tPA |
↑ PAI, TAFI |
↑ D-dimer, FDP, FgDP |
Endothelial Abnormalities |
↑ Circulating thrombomodulin, ECPR, and von Willebrand factor |
↓ Tissue thrombomodulin and EPCR |
Nutritional Abnormalities |
↑ Homocysteinemia, lipoprotein A |
↓ Vitamin B6, Vitamin B12, folates |
Immunological Abnormalities |
Antibodies: antiphospholipid, antiprotein S, antiendothelial cells, anti-tPA |
Drug | Route of Administration | Therapeutic Indication | Risk of VTE | Comments |
---|---|---|---|---|
Mesalazine | Oral and topical | Mild-to moderate UC Prevention of postoperative recurrence of CD | Reduced | Specially designed studies are not available |
Azathioprine/6-mercaptopurine | Oral | UC and CD maintenance of remission | Reduced | Specially designed studies are not available |
CSs | Oral, intramuscular, intravenous, topical | Moderately to severely active UC or CD | Increased | Increased VTE risk also for intestinal acting steroids |
MTX | Subcutaneous or intramuscular | CD maintenance of remission | Unclear | MTX needs folate supplementation to reduce hyperhomocysteinemia |
Thalidomide | Oral | Steroid-resistant or steroid-dependent CD | Increased | VTE risk significantly increased when associated with CSs; VTE prophylaxis should be considered |
Infliximab (and other anti-TNF-α) | Intravenous (IFX)Subcutaneous (ADA and GOL) | Steroid-resistant or steroid-dependent UC and CD | Reduced | Increased when IFX is associated with CS |
Vedolizumab | Intravenous | Steroid-resistant or steroid-dependent UC and CD | Reduced | Paucity of data. Association with CS does not increase the risk |
Ustekinumab | Intravenous (induction) followed by subcutaneous (maintenance) | Steroid-resistant or steroid-dependent CD | Reduced | Paucity of data |
Tofacitinib | Oral | Moderately to severely active UC refractory to standard treatments | Unclear | Data from RCTs and observational studies are not sufficient to provide conclusive advice |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Papa, A.; Tursi, A.; Danese, S.; Rapaccini, G.; Gasbarrini, A.; Papa, V. Venous Thromboembolism in Patients with Inflammatory Bowel Disease: The Role of Pharmacological Therapy and Surgery. J. Clin. Med. 2020, 9, 2115. https://doi.org/10.3390/jcm9072115
Papa A, Tursi A, Danese S, Rapaccini G, Gasbarrini A, Papa V. Venous Thromboembolism in Patients with Inflammatory Bowel Disease: The Role of Pharmacological Therapy and Surgery. Journal of Clinical Medicine. 2020; 9(7):2115. https://doi.org/10.3390/jcm9072115
Chicago/Turabian StylePapa, Alfredo, Antonio Tursi, Silvio Danese, Gianludovico Rapaccini, Antonio Gasbarrini, and Valerio Papa. 2020. "Venous Thromboembolism in Patients with Inflammatory Bowel Disease: The Role of Pharmacological Therapy and Surgery" Journal of Clinical Medicine 9, no. 7: 2115. https://doi.org/10.3390/jcm9072115