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De Laffolie J, Ballauff A, Wirth S, Blueml C, Rommel FR, Claßen M, Laaß M, Lang T, Hauer AC. Occurrence of Thromboembolism in Paediatric Patients With Inflammatory Bowel Disease: Data From the CEDATA-GPGE Registry. Front Pediatr 2022; 10:883183. [PMID: 35722497 PMCID: PMC9204097 DOI: 10.3389/fped.2022.883183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/14/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE Among patients with inflammatory bowel disease (IBD), the risk of thromboembolism (TE) is increased, representing a relevant cause of morbidity and mortality. In contrast to other extraintestinal IBD manifestations, TE receives much less attention because of its low incidence, estimated at merely 0.4-0.9% in hospitalised children with IBD. METHODS Cases with TE, as documented in the German-Austrian Paediatric IBD registry gesellschaft für pädiatrische gastroenterologie und ernährung - large paediatric patient registry (CEDATA-GPGE), were analyzed retrospectively. For all patients with signs of TE, a questionnaire was filled in by the treating paediatric gastroenterologist. RESULTS Over 10 years, 4,153 paediatric patients with IBD (0-18 years) were registered in the registry, and 12 of them identified with TE. Eight patients were diagnosed with ulcerative colitis (UC), three with Crohn's disease (CD), and one with IBD-unclassified. The median age at IBD diagnosis was 10 years and at the manifestation of TE 13 years, respectively, with a median latency to TE of 2 years. Prevalence of TE was 0.3%, with a significantly higher risk for patients with UC than CD (OR 5.9, CI 1.56-22.33, p = 0.008). More girls than boys were affected (f:m = 7:5) without reaching significance. Approximately 90% of patients experienced TE during active disease, with relevant cerebral and limb involvement in 6/12 patients. Various risk factors, e.g., hospitalisation, coagulopathy, or anaemia were identified. TE management included intensive care and surgery. Among the 12 patients, 11 recovered fully, in which one patient has focal epilepsy as a sequela. CONCLUSION Paediatric patients with IBD have a substantially increased risk for TE. Risk factors, such as those identified should be considered when managing paediatric IBD and preventive measures for those hospitalised taken routinely. Initiating pharmacological thromboprophylaxis is challenging for the lack of published trials on efficacy and safety in paediatric IBD but should be considered carefully in each case.
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Affiliation(s)
- Jan De Laffolie
- Department of General Pediatrics and Neonatology, University of Giessen, Giessen, Germany
| | | | - Stefan Wirth
- Kinderklinik, Helios Klinikum Wuppertal, Wuppertal, Germany
| | - Carolin Blueml
- Department of Paediatrics, Philipps-University Marburg, Marburg, Germany
| | - Frank Risto Rommel
- Department of General Pediatrics and Neonatology, University of Giessen, Giessen, Germany
| | | | - Martin Laaß
- Children's Hospital, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Thomas Lang
- Kinderklinik Regensburg, Regensburg, Germany
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Yang P, Wang L, Tang X, Liang Y. The methylenetetrahydrofolate reductase 1298 A>C polymorphism is associated with an increased risk of inflammatory bowel disease: evidence from a meta-analysis. Expert Rev Clin Immunol 2021; 17:1221-1229. [PMID: 34528870 DOI: 10.1080/1744666x.2021.1982384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE The association between genetic variants in methylenetetrahydrofolate reductase (MTHFR) and risk for inflammatory bowel disease (IBD) has been widely studied. However, the results are equivocal. In this meta-analysis, we aimed to determine the association between MTHFR polymorphisms and susceptibility to IBD. METHODS We retrieved studies from the PubMed, Web of Science, Ovid, and China National Knowledge Infrastructure databases. Data were analyzed using STATA software; odds ratios (OR) and confidence intervals (CI) were calculated using fixed or random effects models. RESULTS A marginally significant association of the MTHFR 677 C > T polymorphism and patients' IBD risk was observed in the overall analysis (OR = 1.11, 95% CI, 1.01-1.23), but not in the analysis of high-quality studies. However, for the MTHFR 1298 A > C polymorphism, a significant association was found between the MTHFR 1298 AC/CC genotypes and IBD risk in the overall analysis (OR = 1.26, 95% CI, 1.10-1.44), in the high-quality studies (OR = 1.20, 95% CI, 1.02-1.41), and in patients with ulcerative colitis (OR = 1.28, 95% CI, 1.10-1.48). CONCLUSIONS Evidence from this meta-analysis indicates that the MTHFR 1298 A > C polymorphism may be responsible for susceptibility to IBD and ulcerative colitis.
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Affiliation(s)
- Pingliang Yang
- Department of Anesthesiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, P.R. China
| | - Li Wang
- Department of Anesthesiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, P.R. China
| | - Xingming Tang
- Department of Anesthesiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, P.R. China
| | - Yundan Liang
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, P.R. China
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Sleutjes JAM, van Lennep JER, van der Woude CJ, de Vries AC. Thromboembolic and atherosclerotic cardiovascular events in inflammatory bowel disease: epidemiology, pathogenesis and clinical management. Therap Adv Gastroenterol 2021; 14:17562848211032126. [PMID: 34377149 PMCID: PMC8323448 DOI: 10.1177/17562848211032126] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 05/27/2021] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is associated with an increased risk of cardiovascular disease (CVD). The increased risk of CVD concerns an increased risk of venous thromboembolism (VTE), atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF), at corresponding relative risks of 2.5, 1.2 and 2.0, respectively, as compared with the general population. Especially young patients under the age of 40 years run a relatively high risk of these complications when compared with the general population. Chronic systemic inflammation causes a hypercoagulable state leading to the prothrombotic tendency characteristic of VTE, and accelerates all stages involved during atherogenesis in ASCVD. Increased awareness of VTE risk is warranted in patients with extensive colonic disease in both ulcerative colitis and Crohn's disease, as well as during hospitalization, especially when patients are scheduled for surgery. Similarly, critical periods for ASCVD events are the 3 months prior to and 3 months after an IBD-related hospital admission. The increased ASCVD risk is not fully explained by an increased prevalence of traditional risk factors and includes pro-atherogenc lipid profiles with high levels of small dense low-density lipoprotein cholesterol particles and dysfunctional high-density lipoprotein cholesterol. Risk factors associated with HF are location and extent of inflammation, female sex, and age exceeding 40 years. A dose-dependent increase of overall CVD risk has been reported for corticosteroids. Immunomodulating maintenance therapy might reduce CVD risk in IBD, not only by a direct reduction of chronic systemic inflammation but possibly also by a direct effect of IBD medication on platelet aggregation, endothelial function and lipid and glucose metabolism. More data are needed to define these effects accurately. Despite accumulating evidence on the increased CVD risk in IBD, congruent recommendations to develop preventive strategies are lacking. This literature review provides an overview of current knowledge and identifies gaps in evidence regarding CVD risk in IBD, by discussing epidemiology, pathogenesis, and clinical management.
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Affiliation(s)
- Jasmijn A. M. Sleutjes
- Department of Gastroenterology and Hepatology,
Erasmus Medical Center, Rotterdam, the Netherlands
| | | | - C. Janneke van der Woude
- Department of Gastroenterology and Hepatology,
Erasmus Medical Center, Rotterdam, the Netherlands
| | - Annemarie C. de Vries
- Department of Gastroenterology and Hepatology,
Erasmus Medical Center, Dr. Molewaterplein 40, Room Na-618, Rotterdam
3015GD, The Netherlands
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Lagrange J, Lacolley P, Wahl D, Peyrin-Biroulet L, Regnault V. Shedding Light on Hemostasis in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2021; 19:1088-1097.e6. [PMID: 31972287 DOI: 10.1016/j.cgh.2019.12.043] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 12/19/2019] [Accepted: 12/31/2019] [Indexed: 02/07/2023]
Abstract
Patients with inflammatory bowel diseases (IBD) have an increased risk of thrombosis, possibly due to changes in blood cells and molecules involved in hemostasis. They have increased platelet counts and reactivity as well as increased platelet-derived large extracellular vesicles. Coagulation is continuously activated in patients with IBD, based on measured markers of thrombin generation, and the anticoagulant functions of endothelial cells are damaged. Furthermore, fibrinogen is increased and fibrin clots are denser. However, pathogenesis of thrombosis in patients with IBD appears to differ from that of patients without IBD. Patients with IBD also take drugs that might contribute to risk of thrombosis, complicating the picture. We review the features of homeostasis that are altered in patients with IBD and possible mechanisms of this relationship.
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Affiliation(s)
- Jeremy Lagrange
- INSERM U1116, Faculté de Médecine, Université de Lorraine, Vandœuvre-lès-Nancy, France; Université de Lorraine, Nancy, France; Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.
| | - Patrick Lacolley
- INSERM U1116, Faculté de Médecine, Université de Lorraine, Vandœuvre-lès-Nancy, France; Université de Lorraine, Nancy, France; Centre Hospitalier Régionale Universitaire de Nancy, Vandœuvre-lès-Nancy, France
| | - Denis Wahl
- INSERM U1116, Faculté de Médecine, Université de Lorraine, Vandœuvre-lès-Nancy, France; Université de Lorraine, Nancy, France; Division of Vascular Medicine, Centre Hospitalier Régionale Universitaire de Nancy, Vandœuvre-lès-Nancy, France
| | - Laurent Peyrin-Biroulet
- Université de Lorraine, Nancy, France; INSERM U1256, Faculté de Médecine, Université de Lorraine, Vandœuvre-lès-Nancy, France; Department of Gastroenterology, Centre Hospitalier Régionale Universitaire de Nancy, Vandœuvre-lès-Nancy, France
| | - Véronique Regnault
- INSERM U1116, Faculté de Médecine, Université de Lorraine, Vandœuvre-lès-Nancy, France; Université de Lorraine, Nancy, France; Centre Hospitalier Régionale Universitaire de Nancy, Vandœuvre-lès-Nancy, France
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5
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Reply. Clin Gastroenterol Hepatol 2020; 18:3059-3060. [PMID: 33190747 DOI: 10.1016/j.cgh.2019.08.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 08/16/2019] [Indexed: 02/07/2023]
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Zhu L, Cheng J, Gu P, Liu Y, Liu J, Wang J, Shen H. Therapeutic strategies of thromboembolic events in patients with inflammatory bowel diseases: Two case reports. Medicine (Baltimore) 2019; 98:e14622. [PMID: 30817579 PMCID: PMC6831449 DOI: 10.1097/md.0000000000014622] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
RATIONALE Inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammatory condition and immunological abnormalities, which probably develop into venous thromboembolic events (VTEs). VTE in IBD patients mostly occurs at deep venous thrombosis (DVT) and pulmonary embolism (PE). The complications are extremely important in clinical practice considering the high mortality rate. Hence, an early diagnosis of IBD and the control of complications play an important role in therapy of thromboembolic events (TEEs). PATIENT CONCERNS Case 1 was a 31-year-old man with chronic UC who presented with signs of thromboembolism. Case 2 was a 43-year-old woman with CD complicated by fistulas. DIAGNOSES Computed tomography (CT) and digital subtraction angiography (DSA) of the patient (case 1) suggested a thrombus in cerebral vein. The patient (case 2) developed acute ischemia of her right arm; B ultrasonography revealed a thrombus in the distal of the right subclavian artery accompanied by stenosis. INTERVENTIONS To lower blood viscosity and overcome the risk of deep thrombosis, the patient (case 1) was treated with a combination of low-molecular-weight heparin and dextran as anticoagulation. For the patient (case 2), anticoagulation treatment with 75 mg qd clopidogrel (plavix) and 1.25 mg qd warfarin was performed. OUTCOMES In both patients, no further TEE occurred during follow-up 1 year and one and a half years, respectively. LESSONS It is important to pay attention to IBD patients especially those with high coagulation state.
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Alkim H, Koksal AR, Boga S, Sen I, Alkim C. Etiopathogenesis, Prevention, and Treatment of Thromboembolism in Inflammatory Bowel Disease. Clin Appl Thromb Hemost 2017; 23:501-510. [PMID: 26893444 DOI: 10.1177/1076029616632906] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2025] Open
Abstract
The close relationship between inflammation and thrombosis affects the progression and severity of inflammatory bowel disease (IBD). The prevalence of venous thromboembolism (VTE) varies between 1% and 7% among patients with IBD. The VTE risk in patients with IBD is at least 3 times higher than that in the normal general population. The absolute risk is very high during hospitalization, active disease, and surgery. The IBD-related VTE occurs at younger ages and recurs more frequently. The development of thrombosis in IBD is due to the interaction of many hereditary and acquired risk factors. Each patient diagnosed with IBD should be evaluated for a personal and family history of thrombosis and for prothrombotic drug use. Although procoagulant factors are increased during the natural course of inflammation, natural anticoagulants and fibrinolytic activity are decreased. Although IBD is accepted as a prothrombotic condition, there is no treatment that can remove this risk from daily practice. Patient training is required to control important factors, such as long-term immobilization and smoking. Oral contraceptives and hormone replacement therapy should be avoided. Inducing permanent disease remission must be the key approach for the prevention of thrombosis. Low-molecular-weight heparin (LMWH) is the basis of prophylactic treatment, which reduces the thrombosis risk by 50%. Prophylaxis with LMWH should be administered to all patients with IBD hospitalized due to disease attack or surgery. Long-term or even life-long anticoagulation therapy should be planned if there is insufficient disease control, recurrent VTE attacks, positive thrombophilia tests, or thrombosis in vital veins.
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Affiliation(s)
- Huseyin Alkim
- 1 Department of Gastroenterology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Ali Riza Koksal
- 1 Department of Gastroenterology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Salih Boga
- 1 Department of Gastroenterology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Ilker Sen
- 1 Department of Gastroenterology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Canan Alkim
- 1 Department of Gastroenterology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
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Karban A, Feldman T, Waterman M, Leiba R, Efrati E. The association of the MTHFR C677T polymorphism with inflammatory bowel diseases in the Israeli Jewish population: An example of genetic heterogeneity. Medicine (Baltimore) 2016; 95:e5611. [PMID: 28002332 PMCID: PMC5181816 DOI: 10.1097/md.0000000000005611] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
MTHFR C677T is a common gene polymorphism that has been shown to be associated with hyperhomocysteinemia. Studies on the role of MTHFR in inflammatory bowel diseases (IBD) have yielded conflicting results, perhaps due in part to genetic heterogeneity. The prevalence of the MTHFR C677T variant allele varies according to Jewish subpopulations: Ashkenazi vs non-Ashkenazi. The aim of this study was to examine the association between MTHFR C677T genotype and IBD in the different Jewish populations.DNA samples were assessed for the presence of the MTHFR C677T variant allele in 445 Jewish Israeli IBD patients: 338 with Crohn's disease [CD] (214 Ashkenazi and 124 non-Ashkenazi Jews) and 107 with ulcerative colitis [UC] (73 Ashkenazi and 34 non-Ashkenazi Jews), and in 347 healthy controls: 173 Ashkenazi and 174 Non-Ashkenazi Jews. Possible genotype-phenotype associations were investigated.We showed a significantly higher frequency of MTHFR 677T variant genotypes in non-Ashkenazi CD patients: Odds ratio of 1.86 for heterozygotes (CT) and 2.89 for homozygotes (TT) compared to non-Ashkenazi healthy controls. No significant association was found for UC in non-Ashkenazi patients or for CD or UC in Ashkenazi patients.Our findings suggest that the MTHFR 677T variant may contribute to the risk of CD in non-Ashkenazi but not Ashkenazi Jews. This may result from genetic heterogeneity and highlights the complexity of the genetic etiology of IBD.
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Affiliation(s)
- Amir Karban
- Department of Internal Medicine C, Rambam Health Care Campus
- Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology
| | - Tzah Feldman
- Department of Internal Medicine C, Rambam Health Care Campus
- Laboratory of Toxicology, Pharmacology and Pharmacogenetics, Israel Poison Information Center, Rambam Health Care Campus
| | - Matti Waterman
- Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology
- Department of Gastroenterology, Rambam Health Care Campus
| | - Ronit Leiba
- Epidemiologic Unit, Rambam Health Care Campus, Haifa, Israel
| | - Edna Efrati
- Laboratory of Toxicology, Pharmacology and Pharmacogenetics, Israel Poison Information Center, Rambam Health Care Campus
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Varzari A, Deyneko IV, Tudor E, Turcan S. Polymorphisms of glutathione S-transferase and methylenetetrahydrofolate reductase genes in Moldavian patients with ulcerative colitis: Genotype-phenotype correlation. Meta Gene 2015; 7:76-82. [PMID: 26862484 PMCID: PMC4707243 DOI: 10.1016/j.mgene.2015.12.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 12/07/2015] [Accepted: 12/08/2015] [Indexed: 12/14/2022] Open
Abstract
Background Glutathione S-transferases (GSTM1, GSTT1, and GSTP1) and methylenetetrahydrofolate reductase (MTHFR) are important enzymes for protection against oxidative stress. In addition, MTHFR has an essential role in DNA synthesis, repair, and methylation. Their polymorphisms have been implicated in the pathogenesis of ulcerative colitis (UC). The aim of the present study was to investigate the role of selected polymorphisms in these genes in the development of UC in the Moldavian population. Methods In a case-control study including 128 UC patients and 136 healthy individuals, GSTM1 and GSTT1 genotypes (polymorphic deletions) were determined using multiplex polymerase chain reaction (PCR). The GSTP1 rs1695 (Ile105Val), MTHFR rs1801133 (C677T), and MTHFR rs1801131 (A1298C) polymorphisms were studied with restriction fragment length polymorphism (RFLP) analysis. Genotype–phenotype correlations were examined using logistic regression analysis. Results None of the genotypes, either alone or in combination, showed a strong association with UC. The case-only sub-phenotypic association analysis showed an association of the MTHFR rs1801133 polymorphism with the extent of UC under co-dominant (p corrected = 0.040) and recessive (p corrected = 0.020; OR = 0.15; CI = 0.04–0.63) genetic models. Also, an association between the MTHFR rs1801131 polymorphism and the severity of UC was reported for the over-dominant model (p corrected = 0.023; coefficient = 0.32; 95% CI = 0.10–0.54). Conclusion The GST and MTHFR genotypes do not seem to be a relevant risk factor for UC in our sample. There was, however, evidence that variants in MTHFR may influence the clinical features in UC patients. Additional larger studies investigating the relationship between GST and MTHFR polymorphisms and UC are required.
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Key Words
- GST, Glutathione S-transferase
- Genetic polymorphism
- Glutathione S-transferases
- HWE, Hardy–Weinberg equilibrium
- IBD, Inflammatory bowel disease
- MTHFR, Methylenetetrahydrofolate reductase
- Methylenetetrahydrofolate reductase
- Moldavian population
- PCR, Polymerase chain reaction
- RFLP, Restriction fragment length polymorphism
- SAM, S-adenosyl methionine
- SNP, Single nucleotide polymorphism
- Susceptibility
- UC, Ulcerative colitis
- Ulcerative colitis
- n, Total number
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Affiliation(s)
- Alexander Varzari
- Laboratory of Human Genetics, Institute of Phthisiopneumology, Kishinev, Republic of Moldova
| | - Igor V Deyneko
- Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Elena Tudor
- Laboratory of Human Genetics, Institute of Phthisiopneumology, Kishinev, Republic of Moldova
| | - Svetlana Turcan
- Department of Gastroenterology, State University of Medicine and Pharmacy, Kishinev, Republic of Moldova
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Abstract
Thrombosis in inflammatory bowel disease (IBD) is an increasingly noted extraintestinal manifestation with high morbidity and mortality. While controlling the activity of the disease with the appropriate therapy, thromboembolism prophylaxis should be applied to all patients. All common risk factors for thromboembolism are also valid for patients with IBD; however, it is clear that uncontrolled disease and hospitalization are major disease-specific risk factors for venous thromboembolism in patients with IBD. Pharmacological thromboprophylaxis with currently available anticoagulants does not increase the risk of further bleeding in patients with IBD with mild-to-moderate bleeding. In severe bleeding or with increased risk of further bleeding due to other comorbid conditions, thromboprophylaxy with mechanical methods should be the treatment option. Whether thrombosis is the cause or the result of intestinal inflammation remains to be elucidated, and other issues in the etiology, such as the role of intestinal flora in thrombosis pathogenesis, will be the subject of future studies.
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11
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Giannotta M, Tapete G, Emmi G, Silvestri E, Milla M. Thrombosis in inflammatory bowel diseases: what's the link? Thromb J 2015; 13:14. [PMID: 25866483 PMCID: PMC4393581 DOI: 10.1186/s12959-015-0044-2] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 02/26/2015] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease affects more than 2 million people in Europe, with almost 20% of patients being diagnosed in pediatric age. Patients with inflammatory bowel disease are at increased risk of thromboembolic complications which may affect patients’ morbidity and mortality. The risk of the most common thromboembolic events, such as deep venous thrombosis and pulmonary embolism, are estimated to be three-fold increased compared to controls, but many other districts can be affected. Moreover, patients with ulcerative colitis and Crohn’s disease experience thromboembolic events at a younger age compared to general population. Many factors have been investigated as determinants of the pro-thrombotic tendency such as acquired risk factors or genetic and immune abnormalities, but a unique cause has not been found. Many efforts have been focused on the study of abnormalities in the coagulation cascade, its natural inhibitors and the fibrinolytic system components and both quantitative and qualitative alterations have been demonstrated. Recently the role of platelets and microvascular endothelium has been reviewed, as the possible link between the inflammatory and hemostatic process.
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Affiliation(s)
- Martina Giannotta
- Gastroenterology Department, AOU Careggi Regional Referral Center for Inflammatory Bowel Disease, Florence, Italy
| | - Gherardo Tapete
- Gastroenterology Department, AOU Careggi Regional Referral Center for Inflammatory Bowel Disease, Florence, Italy
| | - Giacomo Emmi
- Department of Experimental and Clinical Medicine, University of Florence and Patologia Medica Unit, AOU Careggi, Florence, Italy
| | - Elena Silvestri
- Department of Experimental and Clinical Medicine, University of Florence and Patologia Medica Unit, AOU Careggi, Florence, Italy
| | - Monica Milla
- Gastroenterology Department, AOU Careggi Regional Referral Center for Inflammatory Bowel Disease, Florence, Italy
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12
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Higgins PDR, Skup M, Mulani PM, Lin J, Chao J. Increased risk of venous thromboembolic events with corticosteroid vs biologic therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol 2015; 13:316-21. [PMID: 25038374 DOI: 10.1016/j.cgh.2014.07.017] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 06/10/2014] [Accepted: 07/02/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We investigated whether treatment of active inflammatory bowel disease with biologic agents is associated with a reduced risk of venous thromboembolic events (VTEs) compared with corticosteroid therapy. METHODS We performed a retrospective analysis of 15,100 adults with inflammatory bowel disease who were identified from the Truven Health MarketScan databases. We analyzed data from patients who received 6 months of continuous medical and prescription coverage before and 12 months after their first diagnosis and had no VTE during the 6 months before they first received biologic or corticosteroid therapy. The outcome assessed was any VTE that occurred during the 12-month follow-up period. A multivariate logistic regression model was used to evaluate the effects of biologic, corticosteroid, and combination therapies (biologics and corticosteroids) on VTE risk. RESULTS Three hundred twenty-five VTEs occurred during the study period (in 2.25% of patients receiving only corticosteroids, in 0.44% of patients receiving biologics, and in 2.49% of patients receiving combination therapy). Compared with patients receiving only corticosteroids, the odds ratio for VTE in patients receiving only biologics was 0.21 (95% confidence interval, 0.05-0.87) in the multivariate model, and the odds ratio for VTE in patients on combination therapy was 1.01. CONCLUSIONS Compared with treatment with only a biologic agent, corticosteroid therapy is associated with a nearly 5-fold increase in risk for VTE. Combination therapy with corticosteroids and biologic agents was associated with the same risk for VTE as that of corticosteroids alone. Corticosteroids therefore appear to increase risk for VTE.
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Affiliation(s)
- Peter D R Higgins
- Division of Gastroenterology, Department of Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Martha Skup
- Global Health Economics and Outcomes Research, AbbVie Inc, North Chicago, Illinois
| | - Parvez M Mulani
- Global Health Economics and Outcomes Research, AbbVie Inc, North Chicago, Illinois
| | - Jay Lin
- Novosys Health, Flemington, New Jersey
| | - Jingdong Chao
- Global Health Economics and Outcomes Research, AbbVie Inc, North Chicago, Illinois
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Nguyen GC, Bernstein CN, Bitton A, Chan AK, Griffiths AM, Leontiadis GI, Geerts W, Bressler B, Butzner JD, Carrier M, Chande N, Marshall JK, Williams C, Kearon C. Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology. Gastroenterology 2014; 146:835-848.e6. [PMID: 24462530 DOI: 10.1053/j.gastro.2014.01.042] [Citation(s) in RCA: 240] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Guidelines for the management of venous thromboembolism (VTE) from the American College of Chest Physicians do not address patients with inflammatory bowel disease (IBD), a group with a high risk of both VTE and gastrointestinal bleeding. We present recommendations for the prevention and treatment of VTE in patients with IBD. METHODS A systematic literature search was performed to identify studies on VTE in IBD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Statements were developed through an iterative online platform, then finalized and voted on by a working group of adult and pediatric gastroenterologists and thrombosis specialists. RESULTS IBD patients have an approximately 3-fold higher risk of VTE compared with individuals without IBD, and disease flares further increase this risk. Anticoagulant thromboprophylaxis is recommended for IBD patients who are hospitalized with IBD flares without active bleeding and is suggested when bleeding is nonsevere. Anticoagulant thromboprophylaxis is suggested during moderate-severe IBD flares in outpatients with a history of VTE provoked by an IBD flare or an unprovoked VTE, but not otherwise. The recommended duration of anticoagulation after a first VTE is based on the presence of provoking factors. Specific suggestions are made for the prevention and treatment of VTE in pediatric and pregnant IBD patients. CONCLUSIONS Using the American College of Chest Physicians' guidelines as a foundation, we have integrated evidence from IBD studies to develop specific recommendations for the management of VTE in this high-risk population.
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Affiliation(s)
- Geoffrey C Nguyen
- Mount Sinai Hospital Centre for Inflammatory Bowel Disease, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Charles N Bernstein
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Alain Bitton
- Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Anthony K Chan
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Anne M Griffiths
- Division of Gastroenterology, Hepatology, and Nutrition, Sick Kids Hospital, Toronto, Ontario, Canada
| | | | - William Geerts
- Thromboembolism Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Brian Bressler
- Department of Medicine, Division of Gastroenterology, St Paul's Hospital, Vancouver, British Columbia, Canada
| | - J Decker Butzner
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Marc Carrier
- Clinical Epidemiology Program, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Nilesh Chande
- Division of Gastroenterology, Western University, London, Ontario, Canada
| | | | - Chadwick Williams
- Dalhousie University, Halifax, Nova Scotia; Memorial University, St John's, Newfoundland, Canada
| | - Clive Kearon
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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Bryant RV, Jairath V, Curry N, Travis SPL. Thrombosis in inflammatory bowel disease: are we tailoring prophylaxis to those most at risk? J Crohns Colitis 2014; 8:166-71. [PMID: 24095288 DOI: 10.1016/j.crohns.2013.09.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Accepted: 09/06/2013] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE). The reasons are acquired, multifactorial, and related to prothrombotic aberrations during active disease, although the mechanisms remain incompletely elucidated. VTE represents a potentially life-threatening extraintestinal manifestation of IBD, but the associated morbidity and mortality can be reduced by appropriate use of thromboprophylaxis. Nevertheless, despite international guidelines advocating thromboprophylaxis in hospitalised patients with IBD, practice is highly variable, since 65% of gastroenterologists may not use pharmacological VTE prophylaxis in hospitalised patients with acute severe colitis. Furthermore, there is no guidance on appropriate prophylaxis for ambulatory outpatients with active disease who are at an appreciable risk of VTE. Thus the question: are we tailoring thromboprophylaxis to those patients with IBD who are most at risk?
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Affiliation(s)
- Robert V Bryant
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, United Kingdom.
| | - Vipul Jairath
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, United Kingdom; NHS Blood and Transplant, Oxford University Hospitals NHS Trust, United Kingdom.
| | - Nicola Curry
- Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, United Kingdom.
| | - Simon P L Travis
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, United Kingdom.
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15
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Senhaji N, Serbati N, Diakité B, Arazzakou S, Hamzi K, Badre W, Nadifi S. Methylenetetrahydrofolate reductase C677T variant in Moroccan patients with inflammatory bowel disease. Gene 2013; 521:45-9. [PMID: 23542077 DOI: 10.1016/j.gene.2013.02.046] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 02/06/2013] [Accepted: 02/26/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND The association of genetic polymorphisms related to metabolism of homocysteine and folate with inflammatory bowel disease has been evidenced. Several studies have identified genetic variants of MTHFR as significant susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC). The C677T genetic polymorphism in the MTHFR gene is found to be associated with a thermolabile variant enzyme that shows a reduced activity. Therefore, we investigated whether the C677T variant confers genetic susceptibility to CD or UC and evaluated the genotype-phenotype associations in the Moroccan population. METHODS The present study included 96 inflammatory bowel disease patients (68 patients with CD and 28 with UC) and 182 healthy controls. DNA samples were genotyped for the MTHFR (C677T) mutation by the PCR-RFLP method. Statistical analyzes were performed using MedCalc software, Chi square test and Fisher test. RESULTS The respective odds ratio for CD, UC and control group were, 1.55 (CI 95%: 0.53-4.53, P=0.52); 0.50 (CI 95%: 0.06-4.15, P=0.52) and 0.50 (CI 95%: 0.06-4.15, P=0.52). Thus, no statistically significant association with the disease was observed in frequency of the TT variant in comparison to healthy controls. Stratification of IBD patients on the basis of CD or UC showed that individuals carrying at least one T allele are not protected against Crohn's disease. Furthermore, clinical features of the disease did not show any significant association. CONCLUSION In conclusion, the present study indicates that the genetic risk for IBD is not modulated by MTHFR C677T polymorphism in Moroccan population.
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Affiliation(s)
- Nezha Senhaji
- Laboratory of Genetic and Molecular Pathology (LGPM), Medical School, Hassan II University, Casablanca, Morocco.
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16
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Tezel A, Demir M. Inflammatory bowel disease and thrombosis. Turk J Haematol 2012; 29:111-9. [PMID: 24744641 PMCID: PMC3986948 DOI: 10.5505/tjh.2012.04557] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 05/17/2011] [Indexed: 12/31/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a group of chronic and relapsing inflammatory disorders of the gastrointestinalsystem. In these cases, findings are detected in extraintestinal systems also. There is a tendency for thrombotic eventsin IBD, as in the other inflammatory processes. The pathogenesis of this thrombotic tendency is multidimensional,including lack of natural anticoagulants, prothrombotic media induced via the inflammatory process, long-termsedentary life style, steroid use, surgery, and catheter placement. The aim of this review was to highlight the positiverelationship between IBD and thrombotic events, and the proper treatment of at-risk patients.
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Affiliation(s)
- Ahmet Tezel
- Trakya University, School of Medicine, Department of Gastroenterology, Edirne, Turkey
| | - Muzaffer Demir
- Trakya University, School of Medicine, Department of Hematology, Edirne, Turkey
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17
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Novacek G, Papay P, Miehsler W, Reinisch W, Lichtenberger C, Sunder-Plassmann R, Vogelsang H, Gratzer C, Mannhalter C. Are inherited thrombotic risk factors associated with fibrostenosis in Crohn's disease? Inflamm Bowel Dis 2011; 17:2505-11. [PMID: 21351205 DOI: 10.1002/ibd.21648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 01/02/2011] [Indexed: 12/19/2022]
Abstract
BACKGROUND Fibrostenotic lesions are common complications in Crohn's disease (CD) often requiring surgery. Inherited thrombotic risk factors are associated with fibrosis in other chronic inflammatory diseases. The aim of the study was to assess whether inherited thrombotic risk factors are associated with fibrostenosis in CD. METHODS Clinical data on 529 CD patients were collected retrospectively. Subjects were tested for and grouped according to the presence of factor V Leiden (FVL), the prothrombin G20210A, and the methylenetetrahydrofolate reductase C677T mutation (MTHFR). Patients who underwent CD-related intestinal surgery were assessed for the presence of fibrostenosis, which was the primary endpoint. The diagnosis of fibrostenosis was based on surgical, pathological, and histopathological reports. A Cox proportional hazards model was used for statistical analysis. RESULTS Thirty-two (6.1%, heterozygous 30, homozygous 2) patients were carriers of FVL, 19 (3.6%, all heterozygous) carried the prothrombin variant, and 318 (60.1%) the MTHFR variant (243 heterozygous, 75 homozygous). In all, 303 (57.3%) patients underwent intestinal surgery. Fibrostenosis was identified in 219 (72.3%) surgical specimens. The rate of first intestinal surgeries with fibrostenosis tended to be more frequent in patients with the homozygous 677TT MTHFR mutation (hazard ratio, HR 1.39; 95% confidence interval [CI]: 0.98-1.97; P = 0.067). After adjustment for potential confounders homozygous 677TT MTHFR mutation did not remain a risk factor for intestinal surgery with fibrostenosis (HR 1.23; 95% CI: 0.77-1.98; P = 0.387). FVL and the prothrombin variant had no influence on the primary endpoint. CONCLUSIONS The MTHFR 677TT mutation, factor V Leiden, and the prothrombin G20210A mutation are not associated with fibrostenosis in CD.
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Affiliation(s)
- Gottfried Novacek
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology; Vienna, Austria
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18
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Cognat E, Crassard I, Denier C, Vahedi K, Bousser MG. Cerebral venous thrombosis in inflammatory bowel diseases: eight cases and literature review. Int J Stroke 2011; 6:487-92. [PMID: 22017824 DOI: 10.1111/j.1747-4949.2011.00620.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND While the association between inflammatory bowel diseases and thromboembolic events has long been evident, cerebral venous thrombosis in this context remains rare and underreported. METHODS Among 351 consecutive patients with cerebral venous thrombosis collected in two neurology departments between 1997 and 2009, an analysis of patients with inflammatory bowel disease and a review of literature were performed. RESULTS Eight patients had inflammatory bowel disease (6/287, 2/64), Crohn's disease in two, and ulcerative colitis in two. The mean age was 30 · 9 years (18-45). All inflammatory bowel disease-related cerebral venous thrombosis patients had headache, four patients had focal neurological deficits, three had altered consciousness, and two had seizures. Cerebral venous thrombosis occurred between two-months and 17 years after the first inflammatory bowel disease signs. Six patients had other venous prothrombotic risk factors. All patients were treated with heparin or low-molecular-weight heparin. Seven showed a complete recovery (Rankin 0-1) and one a partial recovery (Rankin 2). Compared with the 49 magnetic resonance imaging-confirmed cerebral venous thrombosis patients of the literature, our patients had more frequent associated prothrombotic risk factors. When comparing 57 inflammatory bowel disease-related cerebral venous thrombosis patients with other cerebral venous thrombosis, those with inflammatory bowel disease were younger in age at cerebral venous thrombosis onset, and there was a higher male to female ratio and a lower headache frequency at presentation. CONCLUSION In our cerebral venous thrombosis cohort, inflammatory bowel disease is present in 2 · 3% of cases. As cerebral venous thrombosis has no specific feature and may reveal inflammatory bowel disease, intestinal signs should be systematically looked for. All physicians caring for inflammatory bowel disease patients must consider cerebral venous thrombosis in cases of unusual headache or focal neurological symptoms. Treatment is based on full anticoagulation and specific inflammatory bowel disease treatment.
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Affiliation(s)
- Emmanuel Cognat
- Service de Neurologie AP-HP, Hôpital Lariboisière, Paris Cedex, France
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19
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Liang J, Wu S, Feng B, Lei S, Luo G, Wang J, Li K, Li X, Xie H, Zhang D, Wang X, Wu K, Miao D, Fan D. Factor V Leiden and inflammatory bowel disease: a systematic review and meta-analysis. J Gastroenterol 2011; 46:1158-66. [PMID: 21805067 DOI: 10.1007/s00535-011-0441-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Accepted: 06/05/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recent studies proved that inflammatory bowel disease (IBD) patients had a higher risk of thromboembolism and a Factor V Leiden mutation that prevents the efficient inactivation of factor V, which leads to thromboembolism and thus contributes to a high potential risk of IBD. However, the relationship between Factor V Leiden mutation and IBD remains controversial. METHODS We conducted a systematic review with meta-analysis of studies assessing the association of Factor V Leiden mutation with the risk of IBD in humans. We extracted the number of IBD and control subjects with or without Factor V Leiden mutation from each study and conducted this analysis using a fixed-effects model. RESULTS Nineteen studies met the inclusion criteria and were included in the meta-analysis. No significant heterogeneity was found in results across the 19 studies (I (2) = 18.8%, P = 0.23), which showed a slight but not significant increase in the risk of IBD with Factor V Leiden mutation in the general population (summary odds ratio [OR] 1.13, 95% confidence interval [CI] 0.87-1.46). Taking into account ethnic differences, further study exhibited a slight but not significant increase in risk of IBD with Factor V Leiden mutation in Europeans (summary OR 1.20, 95% CI 0.88-1.64). However, Factor V Leiden mutation was significantly associated with a higher risk of thromboembolism in IBD patients (summary OR 5.30, 95% CI 2.25-12.48). No publication bias was found in this study. CONCLUSIONS This meta-analysis indicated that although Factor V Leiden mutation was not significantly associated with the risk of IBD, it was significantly associated with a higher risk of thromboembolism in IBD patients.
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Affiliation(s)
- Jie Liang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shannxi, China
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20
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Hyperhomocysteinemia and Related Genetic Polymorphisms Correlate with Ulcerative Colitis in Southeast China. Cell Biochem Biophys 2011; 62:203-10. [DOI: 10.1007/s12013-011-9283-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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21
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Cleynen I, Jüni P, Bekkering GE, Nüesch E, Mendes CT, Schmied S, Wyder S, Kellen E, Villiger PM, Rutgeerts P, Vermeire S, Lottaz D. Genetic evidence supporting the association of protease and protease inhibitor genes with inflammatory bowel disease: a systematic review. PLoS One 2011; 6:e24106. [PMID: 21931648 PMCID: PMC3169567 DOI: 10.1371/journal.pone.0024106] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Accepted: 08/04/2011] [Indexed: 12/11/2022] Open
Abstract
As part of the European research consortium IBDase, we addressed the role of proteases and protease inhibitors (P/PIs) in inflammatory bowel disease (IBD), characterized by chronic mucosal inflammation of the gastrointestinal tract, which affects 2.2 million people in Europe and 1.4 million people in North America. We systematically reviewed all published genetic studies on populations of European ancestry (67 studies on Crohn's disease [CD] and 37 studies on ulcerative colitis [UC]) to identify critical genomic regions associated with IBD. We developed a computer algorithm to map the 807 P/PI genes with exact genomic locations listed in the MEROPS database of peptidases onto these critical regions and to rank P/PI genes according to the accumulated evidence for their association with CD and UC. 82 P/PI genes (75 coding for proteases and 7 coding for protease inhibitors) were retained for CD based on the accumulated evidence. The cylindromatosis/turban tumor syndrome gene (CYLD) on chromosome 16 ranked highest, followed by acylaminoacyl-peptidase (APEH), dystroglycan (DAG1), macrophage-stimulating protein (MST1) and ubiquitin-specific peptidase 4 (USP4), all located on chromosome 3. For UC, 18 P/PI genes were retained (14 proteases and 4 protease inhibitors), with a considerably lower amount of accumulated evidence. The ranking of P/PI genes as established in this systematic review is currently used to guide validation studies of candidate P/PI genes, and their functional characterization in interdisciplinary mechanistic studies in vitro and in vivo as part of IBDase. The approach used here overcomes some of the problems encountered when subjectively selecting genes for further evaluation and could be applied to any complex disease and gene family.
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Affiliation(s)
- Isabelle Cleynen
- Department of Gastroenterology, Catholic University Leuven, Leuven, Belgium
| | - Peter Jüni
- Clinical Trials Unit Bern, Bern University Hospital, Bern, Switzerland
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | | | - Eveline Nüesch
- Clinical Trials Unit Bern, Bern University Hospital, Bern, Switzerland
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Camila T. Mendes
- Department of Rheumatology, Clinical Immunology and Allergology, University Hospital of Bern, Bern, Switzerland
| | - Stefanie Schmied
- Clinical Trials Unit Bern, Bern University Hospital, Bern, Switzerland
| | - Stefan Wyder
- Department of Rheumatology, Clinical Immunology and Allergology, University Hospital of Bern, Bern, Switzerland
| | - Eliane Kellen
- Leuven Centre for Cancer Prevention, University Hospital Leuven, Leuven, Belgium
| | - Peter M. Villiger
- Department of Rheumatology, Clinical Immunology and Allergology, University Hospital of Bern, Bern, Switzerland
| | - Paul Rutgeerts
- Department of Gastroenterology, Catholic University Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Gastroenterology, Catholic University Leuven, Leuven, Belgium
| | - Daniel Lottaz
- Department of Rheumatology, Clinical Immunology and Allergology, University Hospital of Bern, Bern, Switzerland
- * E-mail:
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22
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Zhong M, Dong XW, Zheng Q, Tong JL, Ran ZH. Factor V Leiden and thrombosis in patients with inflammatory bowel disease (IBD): a meta-analysis. Thromb Res 2011; 128:403-9. [PMID: 21831411 DOI: 10.1016/j.thromres.2011.07.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 06/29/2011] [Accepted: 07/11/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND Testing for genetic risks of Factor V Leiden ( FVL ) in inflammatory bowel disease (IBD) patients with thromboembolism (TE) is common, but the safety and utility of such testing need review. AIM The aim of the present study was to investigate whether the FVL polymorphisms would be one inherited prothrombotic risk factor that could significantly increase the risk of thrombosis in patients with IBD. METHODS We performed an electronic databases search to identify published studies correlating the FVL mutations with four populations including one IBD group with TE complications, one control IBD group without TE complications, one control non-IBD group with TE complications and another healthy control (HC) group. Statistical analysis was performed with Review Manager (RevMan) 5.0. Sub-analysis/sensitivity analysis was also performed. RESULTS We identified 112 titles and included 22 studies in this meta-analysis. The odds ratio (OR) of TE in IBD patients with FVL was higher as compared with IBD patients (OR: 4.00; 95%CI: 2.04, 7.87) and HC (OR: 3.19; 95%CI: 1.38, 7.36). There was a 1.25-fold (95%CI: 0.90-1.74) increase in incidence of FVL gene mutation in IBD patients compared with HC. The FVL mutations were not significantly different between IBD patients with thrombosis and non-IBD patients with thrombosis (OR: 0.79; 95%CI: 0.43, 1.47). CONCLUSION FVL plays a role in IBD-TE, but to no greater extent than it does in the general population with TE.
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Affiliation(s)
- Ming Zhong
- Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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23
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Scaldaferri F, Lancellotti S, Pizzoferrato M, Cristofaro RD. Haemostatic system in inflammatory bowel diseases: New players in gut inflammation. World J Gastroenterol 2011; 17:594-608. [PMID: 21350708 PMCID: PMC3040331 DOI: 10.3748/wjg.v17.i5.594] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Revised: 03/25/2010] [Accepted: 04/01/2010] [Indexed: 02/06/2023] Open
Abstract
Inflammation and coagulation constantly influence each other and are constantly in balance. Emerging evidence supports this statement in acute inflammatory diseases, such as sepsis, but it also seems to be very important in chronic inflammatory settings, such as inflammatory bowel disease (IBD). Patients with Crohn’s disease and ulcerative colitis have an increased risk of thromboembolic events, and several abnormalities concerning coagulation components occur in the endothelial cells of intestinal vessels, where most severe inflammatory abnormalities occur. The aims of this review are to update and classify the type of coagulation system abnormalities in IBD, and analyze the strict and delicate balance between coagulation and inflammation at the mucosal level. Recent studies on possible therapeutic applications arising from investigations on coagulation abnormalities associated with IBD pathogenesis will also be briefly presented and critically reviewed.
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Zitomersky NL, Verhave M, Trenor CC. Thrombosis and inflammatory bowel disease: a call for improved awareness and prevention. Inflamm Bowel Dis 2011; 17:458-70. [PMID: 20848518 DOI: 10.1002/ibd.21334] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Thrombotic complications in patients with inflammatory bowel disease (IBD) are common and require improved awareness and prevention. In this review the interface between IBD and thrombosis is discussed, with emphasis on risk assessment and data to aid clinical decision making. Thromboembolic complications are 3-fold more likely in IBD patients than controls and the relative risk exceeds 15 during disease flares. Improved assessment of thrombosis risk for an individual patient includes thorough personal and family history and awareness of prothrombotic medications and lifestyle choices. Patients with the highest risk of thrombosis are those with active colonic disease, personal or strong family history of thrombosis, and those with significant acquired risk factors. Combined risk factors or hospitalization should prompt mechanical thromboprophylaxis. Indications for prophylactic anticoagulation are not defined currently by clinical studies, especially in pediatric patients, although some groups now advocate prophylactic anticoagulation for all hospitalized IBD patients and even some outpatients with disease flares. Thrombosis management requires a multidisciplinary therapeutic approach to balance anticoagulation and bleeding risk. While bleeding may occur with anticoagulation in IBD, data and experience indicate that therapeutic heparin is safe and bleeding manifestations can be managed supportively in most patients. Until prospective trials of prophylactic anticoagulation are published, management of thrombotic risk and prophylaxis in IBD will remain a clinical challenge.
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Affiliation(s)
- Naamah L Zitomersky
- Division of Gastroenterology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
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25
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Lopez PR, Stewart DW, Smalligan RD. Recurrent deep vein thrombosis despite warfarin therapy in a patient with Crohn's disease. Postgrad Med 2010; 122:181-4. [PMID: 20463427 DOI: 10.3810/pgm.2010.05.2155] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Patients with inflammatory bowel disease (IBD) are known to have an increased propensity for thromboembolic events. Like any patient with a high risk of event recurrence, most of these patients can be managed successfully with long-term warfarin therapy. We present the case of a 66-year-old woman with Crohn's disease who, despite careful attention to the management of her international normalized ratio, developed a new deep vein thrombosis and required inferior vena cava filter placement in addition to ongoing warfarin therapy to prevent recurrent pulmonary emboli. This report serves as a reminder to physicians to have a low threshold for diagnosing thromboembolic events in patients with IBD, even if they are presumed to be adequately anticoagulated. Known and theoretical contributing factors to this increased clotting tendency are also reviewed.
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Affiliation(s)
- Pablo R Lopez
- Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
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26
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Yazici A, Senturk O, Aygun C, Celebi A, Caglayan C, Hulagu S. Thrombophilic Risk Factors in Patients With Inflammatory Bowel Disease. Gastroenterology Res 2010; 3:112-119. [PMID: 27942288 PMCID: PMC5139764 DOI: 10.4021/gr2010.06.209w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/10/2010] [Indexed: 12/26/2022] Open
Abstract
Background Inflammatory bowel disease (IBD) patients have an increased risk for thromboembolism. The aim of this study was to assess the presence of thrombophilic risk factors in IBD patients and to assess the associations of these factors with disease activity. Methods Forty-eight patients with IBD (24 ulcerative colitis, 24 Crohn’s disease) and 40 matched healthy control individuals were enrolled. In addition to routine biochemical analysis, fasting blood samples were studied for prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, protein-C, protein-S, antithrombin III, factor VII, factor VIII, D-dimer, vitamin B12, folic acid and homocysteine. Results Levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, D-dimer and the number of platelets were significantly higher in patients with IBD. When compared to control group, in patients with Crohn’s disease serum homocystein levels were significantly higher (p = 0.025) while serum folic acid levels were significantly lower (p < 0.019). Levels of fibrinogen, D-dimer, protein C, factor VIII, total homocystein and the number of platelets were found to be significantly higher in Crohn’s disease patients who were in active period of the disease. Conclusions Thrombophilic defects are multifactorial and might be frequently seen in IBD patients. They might contribute to thrombotic complications of this disease.
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Affiliation(s)
- Ayten Yazici
- Kocaeli University Medical Faculty Department of Internal Medicine, Kocaeli, Turkey
| | - Omer Senturk
- Kocaeli University Medical Faculty Department of Internal Medicine and Gastroenterology, Kocaeli, Turkey
| | - Cem Aygun
- Kocaeli University Medical Faculty Department of Internal Medicine and Gastroenterology, Kocaeli, Turkey
| | - Altay Celebi
- Kocaeli University Medical Faculty Department of Internal Medicine and Gastroenterology, Kocaeli, Turkey
| | - Cigdem Caglayan
- Kocaeli University Medical Faculty Department of Public Health, Kocaeli, Turkey
| | - Sadettin Hulagu
- Kocaeli University Medical Faculty Department of Internal Medicine and Gastroenterology, Kocaeli, Turkey
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Zintzaras E. Genetic variants of homocysteine/folate metabolism pathway and risk of inflammatory bowel disease: a synopsis and meta-analysis of genetic association studies. Biomarkers 2010; 15:69-79. [PMID: 20085490 DOI: 10.3109/13547500903297184] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
A synopsis and meta-analysis of studies that investigated the association between genetic variants involved in the homocysteine/folate metabolism pathway and risk of inflammatory bowel disease (IBD) were conducted. Four variants (MTHFR C6TTT, MTHFR A1298C, MTR A2756G and MTRR A66G) showed significant associations in individual studies. In meta-analyses, only the variant MTR A2756G indicated an association with the risk of IBD for the allele contrast and the dominant model (odds ratio (OR) 1.48 (1.12-1.97) and OR 1.55 (1.12-2.15), respectively). The effect sizes for Crohn's disease and ulcerative colitis were similar to IBD. Cumulative meta-analysis for C677T indicated a downward trend of association as information accumulates.
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Affiliation(s)
- Elias Zintzaras
- Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
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28
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Natural anticoagulant protein levels in Turkish patients with inflammatory bowel disease. Blood Coagul Fibrinolysis 2010; 21:118-21. [DOI: 10.1097/mbc.0b013e328335d025] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Saibeni S, Saladino V, Chantarangkul V, Villa F, Bruno S, Vecchi M, de Franchis R, Sei C, Tripodi A. Increased thrombin generation in inflammatory bowel diseases. Thromb Res 2010; 125:278-82. [DOI: 10.1016/j.thromres.2009.10.012] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Revised: 10/19/2009] [Accepted: 10/21/2009] [Indexed: 12/19/2022]
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Di Fabio F, Obrand D, Satin R, Gordon PH. Intra-abdominal venous and arterial thromboembolism in inflammatory bowel disease. Dis Colon Rectum 2009; 52:336-42. [PMID: 19279432 DOI: 10.1007/dcr.0b013e31819a235d] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Venous and arterial thromboembolism constitutes a significant cause of morbidity and mortality in patients with inflammatory bowel disease. The most common thrombotic manifestations are lower extremity deep vein thromboses with or without pulmonary embolism. Occasionally, thromboembolic events occur in the main abdominal vessels, such as the portal and superior mesenteric veins, vena cava and hepatic vein, aorta, splanchnic and iliac arteries, or in the limb arteries. The decision-making process for the treatment of these uncommon thromboembolic complications in inflammatory bowel disease may be very challenging for several reasons: 1) no standardized therapies are available; 2) the decision of starting anticoagulant therapy implies the potential risk of intestinal bleeding; 3) thromboembolic events may recur and be life-threatening if inadequately treated. The literature was searched by using MEDLINE, Embase, and the Cochrane library database. Studies published between 1970 and 2007 were reviewed. We discuss the medical and surgical therapeutic options that should be considered to optimize the outcome and reduce the risk of complications in abdominal thromboembolisms associated with inflammatory bowel disease.
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Affiliation(s)
- Francesco Di Fabio
- Division of Colon and Rectal Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada
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Chen M, Peyrin-Biroulet L, Xia B, Guéant-Rodriguez RM, Bronowicki JP, Bigard MA, Guéant JL. Methionine synthase A2756G polymorphism may predict ulcerative colitis and methylenetetrahydrofolate reductase C677T pancolitis, in Central China. BMC MEDICAL GENETICS 2008; 9:78. [PMID: 18700049 PMCID: PMC2533647 DOI: 10.1186/1471-2350-9-78] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/24/2007] [Accepted: 08/13/2008] [Indexed: 01/06/2023]
Abstract
Background The association of genetic polymorphisms related to metabolism of homocysteine with inflammatory bowel disease has been evidenced in Crohn disease and remains an open question in ulcerative colitis. We evaluated the association of the polymorphisms of MTHFR, MTR, MTRR and TCN2 genes with ulcerative colitis in Central China. Methods 168 patients were genotyped for these polymorphisms and compared to 219 matched controls. Results Methionine synthase 2756G allele frequency was higher in ulcerative colitis than in controls 0.15 (95% C.I. 0.11–0.19) vs 0.09 (95% C.I. 0.07 – 0.12), (P = 0.0137) and predicted ulcerative colitis risk in logistic regression, with an Odds ratio at 1.8 (95% C.I. 1.15–2.84). Methylenetetrahydrofolate reductase 677TT genotype was 2.7-fold more prevalent in individuals with pancolitis than in those with left colitis or proctitis, with respective percentages of 27.3 (95% C.I.16.4–42.0) and 10.5 (95% C.I. 6.3–17.1) (P = 0.0123). The carriage of 677TT or 677CT/1298AC genotypes of methylenetetrahydrofolate reductase was more frequent in cases with pancolitis than in subjects with left colitis or proctitis (P = 0.0048), with an Odds ratio adjusted by age and sex at 3.3 (95% C.I. 1.4–7.9), P = 0.0084) in logistic regression. Conclusion Methionine synthase and methylenetetrahydrofolate reductase are genes of vitamin B12 and folate cellular metabolism associated respectively with risk and extent of ulcerative colitis, at least in Central China. This finding may open new insights, particularly for the potential interest in treating patients carrying the 677TT MTHFR genetic trait and a deficit in folate.
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Affiliation(s)
- Min Chen
- Inserm, U724, Laboratory of Cellular and Molecular Pathology in Nutrition, Faculty of Medicine, Nancy-Université, Nancy- Vandoeuvre, France.
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Tsiolakidou G, Koutroubakis IE. Thrombosis and inflammatory bowel disease-the role of genetic risk factors. World J Gastroenterol 2008; 14:4440-4. [PMID: 18680221 PMCID: PMC2731268 DOI: 10.3748/wjg.14.4440] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Thromboembolism is a significant cause of morbidity and mortality in patients with inflammatory bowel disease (IBD). Recent data suggest thromboembolism as a disease-specific extraintestinal manifestation of IBD, which is developed as the result of multiple interactions between acquired and genetic risk factors. There is evidence indicating an imbalance of procoagulant, anticoagulant and fibrinolytic factors predisposing in thrombosis in patients with IBD. The genetic factors that have been suggested to interfere in the thrombotic manifestations of IBD include factor V Leiden, factor II (prothrombin, G20210A), methylenetetrahydrofolate reductase gene mutation (MTHFR, 6777T), plasminogen activator inhibitor type 1 (PAI-1) gene mutation and factor XIII (val34leu). In this article we review the current data and future prospects on the role of genetic risk factors in the development of thromboembolism in IBD.
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Peyrin-Biroulet L, Guéant-Rodriguez RM, Chen M, Bronowicki JP, Bigard MA, Guéant JL. Association of MTRR 66A>G polymorphism with superoxide dismutase and disease activity in patients with Crohn's disease. Am J Gastroenterol 2008; 103:399-406. [PMID: 17925002 DOI: 10.1111/j.1572-0241.2007.01573.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The aim of this study was to evaluate the association of nutritional (folate, vitamin B12) and genetic (MTHFR, MTR, MTRR, TCN) determinants of homocysteine metabolism and of superoxide dismutase with Crohn's disease (CD). METHODS One hundred forty patients with CD were compared with 248 matched healthy controls. RESULTS Plasma homocysteine levels were higher in CD patients than controls (11.8 vs 10.4 micromol/L, P= 0.0004). Vitamin B12 and folate levels were lower in CD subjects compared to controls (207 vs 255 pmol/L, P= 0.0082, and 8.6 vs 11 nmol/L, P= 0036, respectively). Patients with a personal history of ileal resection, ileitis, or colectomy had significantly lower vitamin B12 levels. In multivariate analysis, vitamin B12 and MTHFR 677 TT carriers were the two significant independent factors of plasma homocysteine >15 micromol/L in CD patients (P= 0.0187 and 0.0048, respectively). The significant association between homocysteine and vitamin B12 levels remained significant only in patients with the highest superoxide dismutase values (P < 0.0001). The MTRR AA genotype was a significant independent predictor of CD risk (odds ratio 3.7, 95% CI 1.218-11.649, P= 0.0213). The level of superoxide dismutase was significantly higher (P= 0.0143) and was correlated with Crohn's Disease Activity Index (CDAI) scores (P for trend = 0.0276) in patients carrying MTRR AA genotype. CONCLUSIONS Vitamin B12 and MTHFR 677 TT genotype are the main determinants of hyperhomocysteinemia in CD patients. The association of MTRR 66A>G polymorphism with oxidant stress and disease activity provides rationale for screening vitamin deficiencies in these patients.
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Affiliation(s)
- Laurent Peyrin-Biroulet
- Inserm, U724, Laboratory of Cellular and Molecular Pathology in Nutrition, Faculty of Medicine, Vandoeuvre-les-Nancy, France
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He G, Ouyang Q, Chen D, Li F, Zhou J. The microvascular thrombi of colonic tissue in ulcerative colitis. Dig Dis Sci 2007; 52:2236-40. [PMID: 17429731 DOI: 10.1007/s10620-006-9158-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2005] [Accepted: 11/15/2005] [Indexed: 01/06/2023]
Abstract
Mucosal microvascular thrombi in rectal biopsies were observed in some ulcerative colitis (UC). Heparin may be effective in steroid resistant UC in some studies, however, the new results of meta-analysis demonstrated a non-significant effect of heparin in controlled clinical trials, differing markedly from observational studies. The objective of this study was to identify colonic microvascular thrombi in larger cases with UC, and analyse its possible risk factors: age, gender, histologic score, extent of lesions and operation or biopsy specimens, and assess the significance of microvascular thrombosis in patients with UC. The microvascular thrombi were identified by immunohistochemical staining with anti-CD61 monoclonal antibody and Martius scarlet blue (MSB) staining in 40 colonic tissue samples of UC (31 biopsy specimens and nine operated cases) and 12 cases of normal colon tissue from operated colonic carcinoma. Logistic regression analysis was used to assess the relationship of age, gender, degree of histology, origin of the specimens, extent of lesions and microvascular thrombi examined. Microvascular thrombi were positive in 14 of 40 UC cases, and none in the controls. The presence of microvascular thrombi was related to operation specimens with odds ratio 11.667, P=0.0179, it might be also related to histologic score (OR=1.350) and extent of lesions (OR=1.619). These results suggest that microvascular thrombosis may be one of the important pathogenesis in some UC, and that the effect of anticoagulant treatment still needs to be assessed.
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Affiliation(s)
- Guobin He
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China.
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35
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Peyrin-Biroulet L, Rodriguez-Guéant RM, Chamaillard M, Desreumaux P, Xia B, Bronowicki JP, Bigard MA, Guéant JL. Vascular and cellular stress in inflammatory bowel disease: revisiting the role of homocysteine. Am J Gastroenterol 2007; 102:1108-15. [PMID: 17355415 DOI: 10.1111/j.1572-0241.2007.01170.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Moderate hyperhomocysteinemia is a complex trait commonly associated with inflammatory bowel disease (IBD). Nutritional deficiencies and genetic determinants have been identified as risk factors for moderate hyperhomocysteinemia, such as folate and vitamin B(12) deprivation and polymorphisms in the 5,10 methylenetetrahydrofolate reductase (MTHFR) encoding gene, respectively. Homocysteine has a crucial role in cellular stress, epigenetic events, inflammatory processes, and host-microbial interactions. Hyperhomocysteinemia might therefore influence the clinical history of IBD, including disease severity, susceptibility to particular enteric infections, and the risk for the development of colorectal cancer. In contrast, homocysteine metabolism does not seem to contribute to the greater risk of thrombosis in IBD subjects. Herein, we review the evidence linking homocysteine metabolism to the pathophysiology of IBD. Furthermore, we discuss the relevance of screening and treating folate and vitamin B(12) deficiencies in IBD subjects. Given the peculiar frequency of such deficiencies in IBD, normalizing vitamin levels should be an integral part of the management of these patients, especially those with active disease, history of intestinal resection, and/or treated with methotrexate.
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Affiliation(s)
- Laurent Peyrin-Biroulet
- Inserm, U724, Laboratory of Cellular and Molecular Pathology in Nutrition, Faculty of Medicine, Nancy-Universitè Vandoeuvre-les-Nancy, F-54511, France
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36
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Abstract
BACKGROUND Patients with Crohn's disease (CD) and ulcerative colitis (UC) have a three- to fourfold greater risk of venous thrombosis compared with the general population. We aimed to determine if patients with CD and UC had a greater likelihood of mutations in genes that increase clotting risk, in a population-based case-control study. METHODS Subjects were drawn from the University of Manitoba IBD Research Registry and controls were drawn from Manitoba Health's administrative database. Cases (CD, N = 327; UC, N = 165) and controls (N = 412) underwent venipuncture. DNA was purified from whole blood. Genotypes for wild-type and common mutations that have been associated with venous thrombosis for each of Factor II (prothrombin) (G20210A), Factor V (G1691A:'Leiden'), methylenetetrahydrofolate reductase (MTHFR, C677T), and Factor XIII (val34leu) were assessed. RESULTS A total of 1.5% and 6.1% were heterozygous for Factor II and Factor V variants, respectively, without differences among cases and controls. Only one subject was homozygous for Factor V Leiden (and none were homozygous for Factor II mutation). Although some differences were observed among cases and controls in the prevalence of MTHFR C677T (decrease in mutant allele carriership in UC) and FXIII val34leu (increase in double mutant allele carriership in CD), these did not explain an excess risk of thrombosis. Age, sex, or disease phenotypes were not associated with prothrombotic genotypes. CONCLUSIONS While there was a slightly greater prevalence of Factor XIII mutation carriership in CD, we did not find that gene mutations for these four common factors could explain the greater risk of venous thrombosis in CD and UC.
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Affiliation(s)
- Charles N Bernstein
- Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
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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; 102:174-86. [PMID: 17100967 DOI: 10.1111/j.1572-0241.2006.00943.x] [Citation(s) in RCA: 276] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inflammation and coagulation play crucial roles in the pathogenesis of multiple chronic inflammatory disorders. Growing evidence highlights a tight mutual network in which inflammation, coagulation, and fibrinolysis play closely related roles. Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), are chronic inflammatory conditions, characterized by a hypercoagulable state and prothrombotic conditions, and accompanied by abnormalities in coagulation. From a pathophysiological point of view, cells and molecules classically implicated in the physiological process of coagulation have now been shown to behave abnormally in IBD and possibly to also play an active role in disease pathogenesis and/or disease progression. This paper reviews studies performed on the coagulation profile and risk factors for thrombosis in IBD. In particular, an overview is provided of the epidemiology, clinical features, and etiology of thromboembolic complications in IBD. Furthermore, we review hemostatic abnormalities in IBD, as well as the cell types involved in such processes. Finally, we highlight the coagulation system as a dynamic participant in the multifaceted process of chronic intestinal inflammation. Overall, an overview is provided that the coagulation system represents an important, though previously underestimated, component of IBD pathogenesis, and may be a possible target for therapeutic intervention.
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Affiliation(s)
- Silvio Danese
- Division of Gastroenterology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
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38
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Attvall E, Frigyesi A, Sternby B. What is the impact of resistance to activated protein C (Leiden mutation to factor V) in inflammatory bowel disease? Int J Colorectal Dis 2006; 21:705-10. [PMID: 16411113 DOI: 10.1007/s00384-005-0067-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/01/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Resistance to activated protein C (APCR) caused by the Leiden mutation to factor V is the most common cause of inherited thrombosis. Patients with inflammatory bowel disease (IBD) are considered to have an increased risk of thromboembolic complications, and the role of APCR as a cause has previously been investigated. In this study, we investigated if APCR was associated with non-thrombotic morbidities in IBD. PATIENTS/METHODS Of 951 patients asked to participate, 389 agreed by returning a signed informed consent and filled questionnaire and took the blood test for APCR. Self-reported IBD-related surgery was used as a rough indicator for increased morbidity. RESULTS APCR was present in 6.6% of patients with Crohn's disease (CD; 10/152) and in 12.7% of ulcerative colitis (UC) patients (30/237). The difference of 6.1% is significant (p=0.039). Among patients with CD and APCR, 9 out of 10 had had surgery, significantly more than among those without APCR (81/142). In patients with UC and APCR, 10 out of 30 had had surgery, still significantly more than in those without APCR (36/207). For the whole group of IBD patients, APCR is associated with a significantly increased risk for thrombosis (p=0.0018), and for the UC group (8/28) p=0.0029, but not for the CD patients alone (2/9), p=0.2323. No other significant differences could be shown for parameters normally related to increased morbidity. CONCLUSIONS APCR in IBD was associated with an increased frequency of IBD-related surgery, which may warrant screening for APCR in therapy-resistant IBD. In patients with APCR, it may be more difficult and/or important to control inflammation.
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Affiliation(s)
- Emma Attvall
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Lund University Hospital, Lund University, 221 85, Lund, Sweden
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Rothfuss KS, Stange EF, Herrlinger KR. Extraintestinal manifestations and complications in inflammatory bowel diseases. World J Gastroenterol 2006; 12:4819-31. [PMID: 16937463 PMCID: PMC4087615 DOI: 10.3748/wjg.v12.i30.4819] [Citation(s) in RCA: 210] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) that often involve organs other than those of the gastrointestinal tract. These nonintestinal affections are termed extraintestinal symptoms. Differentiating the true extraintestinal manifestations of inflammatory bowel diseases from secondary extraintestinal complications, caused by malnutrition, chronic inflammation or side effects of therapy, may be difficult. This review concentrates on frequency, clinical presentation and therapeutic implications of extraintestinal symptoms in inflammatory bowel diseases. If possible, extraintestinal manifestations are differentiated from extraintestinal complications. Special attention is given to the more recently described sites of involvement; i.e. thromboembolic events, osteoporosis, pulmonary involvement and affection of the central nervous system.
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Affiliation(s)
- Katja S Rothfuss
- Robert-Bosch-Hospital, Department of Gastroenterology, Hepatology and Endocrinology, Auerbachstrasse 110, D-70376 Stuttgart, Germany.
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40
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Abstract
Inflammatory bowel diseases are associated with extraintestinal manifestations involving almost every organ system in the body. They occur in approximately 20% to 40% of patients with inflammatory bowel diseases. Immune-related and genetic mechanisms play an important role in the pathogenesis of these complications. Peripheral arthritis, erythema nodosum, and episcleritis respond to the treatment of the underlying intestinal inflammation, whereas axial arthropathy, pyoderma gangrenosum, and uveitis do not. Immunomodulator therapy, particularly with biologic agents has been shown to be effective in treating some of the extraintestinal manifestations. Early recognition and treatment are crucial in preventing major morbidity.
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Affiliation(s)
- Sripathi R Kethu
- Department of Medicine, Division of Gastroenterology, Brown Medical School, Providence, RI 02912, USA.
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Stocco G, Martelossi S, Sartor F, Toffoli G, Lionetti P, Barabino A, Fontana M, Decorti G, Bartoli F, Giraldi T, Ventura A. Prevalence of methylenetetrahydrofolate reductase polymorphisms in young patients with inflammatory bowel disease. Dig Dis Sci 2006; 51:474-479. [PMID: 16614955 DOI: 10.1007/s10620-006-3158-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2005] [Accepted: 05/04/2005] [Indexed: 12/09/2022]
Abstract
Inflammatory bowel disease (IBD) has been related to mutations of methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in the metabolism of folate and methionine, both of which are important factors in DNA methylation and synthesis. A mutated MTHFR genotype was associated with increased toxicity of methotrexate treatment. The objective of this study was to verify, in a population of young patients with IBD, the presence of an association among mutations in the MTHFR gene, the incidence of IBD, and the risk of adverse events during the treatment with thiopurines azathioprine (AZA) or 6-mercaptopurine (6MP). Ninety-two patients with IBD were enrolled; 63 were treated with thiopurines; patients and 130 controls were genotyped for MTHFR mutations by PCR-based methods. The incidence of mutations in the MTHFR gene was not different between patients with IBD and control subjects; the mutated genotype was not associated with an increased risk of toxicity during thiopurine treatment.
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Affiliation(s)
- Gabriele Stocco
- Department of Biomedical Sciences, University of Trieste, Trieste, Italy.
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O'Connor OJ, Cahill RA, Kirwan WO, Redmond HP. The incidence of postoperative venous thrombosis among patients with ulcerative colitis. Ir J Med Sci 2005; 174:20-2. [PMID: 16285333 DOI: 10.1007/bf03169142] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Patients with Ulcerative Colitis (UC) have inherent prothrombotic tendencies. It is unknown whether this necessitates the use of additional perioperative anti-thrombotic prophylaxis when such patients require major surgery. METHODS The postoperative courses of 79 patients with UC undergoing 180 major abdominal and pelvic operations were examined for clinical and radiological evidence of venous thrombosis. Eighteen patients with Familial Adenomatous Polyposis (FAP) having surgery (35 operations) of similar magnitude were also studied. Standard anti-thrombosis prophylaxis was utilised in all patients. RESULTS Nine patients with UC were clinically suspected of developing postoperative venous thrombosis, but only three (3.8%) had their diagnosis confirmed radiologically (all had a pulmonary embolus). Therefore, the overall postoperative thrombosis rate, on an intention to treat basis, was 1.7% (3/180). No patient with FAP developed significant venous thrombosis. CONCLUSION Standard perioperative antithrombotic modalities are sufficient to maintain any potential increase in postoperative thrombotic risk at an acceptable level in patients with UC undergoing operative intervention.
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Affiliation(s)
- O J O'Connor
- Dept of Academic Surgery, Cork University Hospital, Wilton, Cork
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43
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Koutroubakis IE. Therapy insight: Vascular complications in patients with inflammatory bowel disease. ACTA ACUST UNITED AC 2005; 2:266-72. [PMID: 16265230 DOI: 10.1038/ncpgasthep0190] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2005] [Accepted: 05/03/2005] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD) is associated with an increased risk of vascular complications. The most important of these complications are arterial and venous thromboembolism, which represent a significant cause of morbidity and mortality in IBD patients. Recent data suggest that thromboembolism is a disease-specific extraintestinal manifestation of IBD. The most common thrombotic manifestations in IBD are deep vein thrombosis of the leg and pulmonary emboli. It has been suggested that disease activity and the extent of colonic localization are correlated with the risk of developing thromboembolism. The occurrence of thrombosis in patients with IBD is partially attributed to the existing hypercoagulable state in IBD. Both coagulation and fibrinolysis are activated in patients with IBD; this is especially true for those with active disease. The most common risk factors for thrombophilia in IBD patients with venous thromboembolism are Leiden mutation in the gene encoding factor V, hyperhomocysteinemia, and antiphospholipid antibodies. The main genetic defects that have been established as risk factors for venous thrombosis are rather uncommon in IBD, but when present increase the risk of thromboembolism. Screening for coagulation defects seems justified only in IBD patients with a history of thrombosis or a family history of venous thromboembolic events. Antithrombotic treatment of IBD patients with venous thromboembolism is similar to that of thrombotic non-IBD patients.
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Umit H, Asil T, Celik Y, Tezel A, Dokmeci G, Tuncbilek N, Utku U, Soylu AR. Cerebral sinus thrombosis in patients with inflammatory bowel disease: A case report. World J Gastroenterol 2005; 11:5404-7. [PMID: 16149158 PMCID: PMC4622821 DOI: 10.3748/wjg.v11.i34.5404] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease of the gastrointestinal tract. The pathophysiology of IBD is probably the result of the complex interaction of genetic susceptibility and environmental influences. There is a well-known risk of thrombosis in patients with IBD. We present the case of a 53-year-old man with ulcerative colitis, who spontaneously developed intracranial sinus thrombosis that was treated with low molecular weight heparin. Literature was searched to assess the frequency and characteristics of cerebral sinus thrombosis in IBD and the role of certain etiopathological factors in such thrombotic patients.
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Affiliation(s)
- Hasan Umit
- Trakya Universitesi Typ Fakültesi, Gastroenteroloji BD, Gullapoglu Yerleskesi, Edirne 22030, Turkey.
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45
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Spina L, Saibeni S, Battaglioli T, Peyvandi F, de Franchis R, Vecchi M. Thrombosis in inflammatory bowel diseases: role of inherited thrombophilia. Am J Gastroenterol 2005; 100:2036-41. [PMID: 16128949 DOI: 10.1111/j.1572-0241.2005.42029.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are characterized by an increased risk for venous and arterial thrombosis. Although the pathogenetic mechanisms of this predisposition are unclear, a possible role of inherited risk factors for thrombosis in determining this predisposition has been suggested. AIM To evaluate the role of factor V Leiden (G1691A) and G20210A prothrombin gene mutations in determining the occurrence of thrombosis in IBD patients. PATIENTS AND METHODS Forty-seven IBD patients (30 ulcerative colitis and 17 Crohn's disease) with a positive history for thrombosis (9 at arterial sites and 38 at venous sites) were enrolled in the study. For each patient, two non-IBD subjects matched for sex and age, type, and site of thrombosis were used as controls. Peripheral blood DNA specimens were amplified by PCR using appropriate primers and analyzed by restriction analysis on agarose gel electrophoresis. Statistical analysis was performed by means of Fisher's exact test. RESULTS The total number of subjects with one or both mutations was significantly lower in IBD patients with thrombosis than in control subjects (12.8%vs 29.8%, respectively; p= 0.035, OR = 0.34, 95% CI 0.13-0.90). The total frequency of the mutated alleles was also significantly lower in IBD than in controls (7.4%vs 16.5%, respectively; p= 0.041, OR = 0.40, 95% CI 0.17-0.96). Prothrombotic mutations were particularly unfrequent in IBD patients with active disease at the time of thrombosis compared with patients with quiescent disease (8.0%vs 36.4%, respectively; p= 0.057, OR = 0.15, 95% CI 0.02-1.01). CONCLUSIONS The major inherited risk factors for thrombosis are significantly less frequent in thrombotic IBD patients than in thrombotic non-IBD subjects, suggesting that acquired risk factors play the most relevant role in determining thromboembolic events observed in IBD patients, particularly during active phases of the disease.
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Affiliation(s)
- Luisa Spina
- Gastroenterology and Gastrointestinal Endoscopy Service, Hepatology Unit, IRCCS Maggiore Hospital, Mangiagalli, Italy
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46
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Siegel CA, Sands BE. Review article: practical management of inflammatory bowel disease patients taking immunomodulators. Aliment Pharmacol Ther 2005; 22:1-16. [PMID: 15963074 DOI: 10.1111/j.1365-2036.2005.02520.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Azathioprine, mercaptopurine, methotrexate, ciclosporin and tacrolimus all have their respective niches in the treatment of inflammatory bowel disease. These immunomodulators are potent and effective medications; however, they potentially have serious toxicity. To maximize benefit and minimize risk, clinicians must understand the mechanism of action, appropriate indications, range of toxicity and proper dosing of these medications. Furthermore, once initiating therapy, patients need to be monitored appropriately for evidence of efficacy and toxicity. This review includes the rationale behind recommendations for the management and monitoring of patients using immunomodulators. For the purine antagonists--azathioprine and mercaptopurine--the evidence for utility of thiopurine methyltransferase testing and mercaptopurine metabolite monitoring is addressed. The roles of liver biopsy and screening for methylenetetrahydrofolate reductase mutations in patients taking methotrexate are reviewed. With appropriate monitoring, the calcineurin inhibitors--ciclosporin and tacrolimus--can be used safely and effectively. Immunomodulators are important agents for the treatment of Crohn's disease and ulcerative colitis, and prescribing clinicians should be comfortable recognizing both their value and their limitations.
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Affiliation(s)
- C A Siegel
- Gastrointestinal Unit and MGH Crohn's and Colitis Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
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47
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Brown RS, Armen S, Padmanabhan A, Hartranft TH, Price PD. A 49-year-old male with acute superior mesenteric artery occlusion during active ulcerative colitis: report of a case. Dis Colon Rectum 2005; 48:572-4. [PMID: 15875297 DOI: 10.1007/s10350-004-0807-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- R Shane Brown
- Department of Surgery, Mount Carmel Health System, Columbus, Ohio 43222, USA.
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48
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Oldenburg B, Van Tuyl BAC, van der Griend R, Fijnheer R, van Berge Henegouwen GP. Risk factors for thromboembolic complications in inflammatory bowel disease: the role of hyperhomocysteinaemia. Dig Dis Sci 2005; 50:235-40. [PMID: 15745078 DOI: 10.1007/s10620-005-1588-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel disease (IBD) is associated with an increased risk for thromboembolic events. Aim of this study was to examine the relationship of hyperhomocysteinemia and thrombosis in IBD patients and to assess the role of this factor in addition to other known prothrombotic abnormalities. IBD patients with a history of thrombosis (n = 22) and sex-, age-, and diagnosis-matched IBD controls (n = 23) were studied. Homocysteine (tHcy) was assessed before and after methionine loading. Plasma levels of protein C, protein S, antithrombin III, and fibrinogen and the presence of anticardiolipin and antiphospholipid antibodies were determined and genetic testing for factor V Leiden and the prothrombin gene mutation was performed. Results showed that fasting homocysteine levels in IBD patients with a history of arterial or venous thrombosis tended to be higher than in IBD controls, although not significantly. The increase in homocysteine levels after methionine loading was significantly higher in IBD patients in the arterial thrombosis group than in IBD controls (40.9 +/- 17.7 vs. 27.2 +/- 9.9 microM; P < 0.05). Among the other prothrombotic factors, only factor V Leiden was significantly associated with a history of venous thrombosis (20 vs. 0%). At least one risk factor was found in 64% of the IBD patients with previous thromboembolic complications. We conclude that there is an association between hyperhomocysteinemia and a history of arterial thrombosis in IBD patients. We confirm the high prevalence of factor V Leiden in IBD patients with a history of venous thrombosis. In the majority of IBD patients with previous thromboembolic complications, at least one prothrombotic risk factor is detected.
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Affiliation(s)
- Bas Oldenburg
- Department of Gastroenterology, University Medical Center, Diakonessenhuis, Utrecht, The Netherlands.
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Novacek G, Haumer M, Schima W, Müller C, Miehsler W, Polterauer P, Vogelsang H. Aortic mural thrombi in patients with inflammatory bowel disease: report of two cases and review of the literature. Inflamm Bowel Dis 2004; 10:430-5. [PMID: 15475753 DOI: 10.1097/00054725-200407000-00016] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Thromboembolic events are a known complication in inflammatory bowel disease (IBD). We report on 2 young women with IBD and aortic mural thrombi as a source of arterioarterial embolization to the lower limbs resulting in significant morbidity. The first case was a 36-year-old woman with severe ulcerative colitis who presented with signs of microembolism into two toes of her right foot. A thrombus in the otherwise normal infrarenal aorta with occlusion of the inferior mesenteric artery was revealed by computed tomography (CT) and intrarterial angiography. The digital ischemia resolved without sequelae. The second case was a 41-year-old woman with Crohn's disease complicated by fistulas. She developed acute ischemia of her right leg. Arteriography and CT revealed infrapopliteal embolic occlusions and a thrombus in the distal otherwise normal abdominal aorta and the left iliac artery. A primarily successful thrombectomy had to be repeated 5 times because of reocclusion. Eventually the leg was exarticulated at the knee. In both patients no further thromboembolic event occurred during follow-up of 4 1/2 years and 5 1/2 years, respectively, and aortic thrombi had resolved at follow-up CT scans. Extensive work up for hypercoagulability was negative in both patients. We consider IBD as the most likely trigger for arterioarterial embolization in the absence of thrombophilia in both patients. Finally we give an overview of the literature of similar cases with aortic mural thrombi in IBD patients.
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Affiliation(s)
- Gottfried Novacek
- Department of Internal Medicine IV, University of Vienna, Vienna, Austria.
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50
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Papa A, Danese S, Grillo A, Gasbarrini G, Gasbarrini A. Review article: inherited thrombophilia in inflammatory bowel disease. Am J Gastroenterol 2003; 98:1247-51. [PMID: 12818264 DOI: 10.1111/j.1572-0241.2003.07491.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Individuals with inflammatory bowel disease frequently experience increased systemic thromboembolic complications, which represent an important cause of morbidity and mortality. Risk factors for thrombosis can be inherited or acquired. The most common inherited risk factors for thromboembolism are factor V Leiden mutation, G20210A mutation in the prothrombin gene, and homozygous C677T mutation in the methylenetetrahydrofolate reductase gene. In the last few years, a great amount of literature has focused on the prevalence of such genetic mutations and their role in determining thrombosis in IBD patients. In this review, we summarize the results of these studies.
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Affiliation(s)
- Alfredo Papa
- Department of Internal Medicine, Catholic University of Rome, Rome, Italy
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