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Luo X, Yao L, Chen Y, Song Y. Ischemic Stroke May Increase the Risk of Crohn's Disease and Ulcerative Colitis: Evidence from a Bidirectional Mendelian Randomization Study. World Neurosurg 2025; 196:123718. [PMID: 39929265 DOI: 10.1016/j.wneu.2025.123718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 01/18/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND The bidirectional causal relationship between ischemic stroke (IS) and inflammatory bowel disease (IBD) remains unclear, prompting us to propose a bidirectional Mendelian randomization (MR) study to investigate this relationship further. METHODS We obtained IS data from the MEGASTROKE consortium and IBD data, including its subtypes ulcerative colitis (UC) and Crohn's disease (CD), from the International Inflammatory Bowel Disease Genetics Consortium. In this study, we utilized IBD and its subtypes as exposure variables and IS as the outcome variable, and vice versa, to explore the bidirectional relationship between them. We used the IBD genetic data from the FinnGen database as replication data to further explore the causality. In this study, we employed the inverse variance weighting method as our primary approach. For sensitivity analyses, we utilized additional methods including MR-Egger regression, weighted median estimation, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-Robust adjusted profile score. Furthermore, we conducted a random effects meta-analysis to combine the causal relationships derived from both the International Inflammatory Bowel Disease Genetics Consortium and FinnGen datasets, aiming to ascertain more robust causal associations. RESULTS The initial phase of the bidirectional MR study revealed a causal relationship between IS and the risk of CD (odds ratio [OR] = 1.56, 95% confidence interval [CI]: 1.20-2.02, P = 0.0008) and UC (OR = 1.33, 95% CI: 1.05-1.69, P = 0.0179), but did not find a causal relationship between IBD as a whole and the risk of IS, nor between IBD subtypes and the risk of IS. During the replication phase, the FinnGen database did not reveal any significant correlation between IS and the risk of IBD, including its subtypes CD and UC. However, additional meta-analysis of the combined data from both databases indicated that IS is significantly associated with an increased risk of CD (OR inverse-variance weighted (IVW) = 1.38, 95% CI: 1.07-1.69, P < 0.05) and UC (ORIVW = 1.27, 95% CI: 1.04-1.50, P < 0.05), but not with the overall risk of IBD (ORIVW = 1.05, 95% CI: 0.87-1.16, P > 0.05). No significant effects were observed between IBD and IS risk, nor were there significant effects between IS and the risks of IBD, CD, or UC. To ensure the robustness of these findings, heterogeneity and pleiotropy tests were conducted. CONCLUSIONS IBD and its subtypes were not found to be causally associated with the risk of IS, whereas IS was found to be causally associated with the risk of CD and UC. This suggests that the risks of CD and UC should be closely monitored in patients with IS.
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Affiliation(s)
- Xin Luo
- The Third Hospital of Changsha (Changsha Hospital Affiliated to Hunan University), Changsha City, Hunan Province, People's Republic of China
| | - Liping Yao
- The Third Hospital of Changsha (Changsha Hospital Affiliated to Hunan University), Changsha City, Hunan Province, People's Republic of China
| | - Yinchao Chen
- The Third Hospital of Changsha (Changsha Hospital Affiliated to Hunan University), Changsha City, Hunan Province, People's Republic of China
| | - Yanju Song
- The Third Hospital of Changsha (Changsha Hospital Affiliated to Hunan University), Changsha City, Hunan Province, People's Republic of China.
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2
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Khanmirzaei A, Jazi K, Azarinoush G, Shirmohammadi M, Karimtabar H, Pezeshgi Modarres M, Masoumi M. Spontaneous bilateral avascular necrosis of knees and hip leading to early bilateral total hip arthroplasty: a case report of an 18-year-old man recently diagnosed with Crohn's disease. Clin J Gastroenterol 2024; 17:663-670. [PMID: 38796798 DOI: 10.1007/s12328-024-01987-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 05/15/2024] [Indexed: 05/29/2024]
Abstract
Avascular necrosis (AVN) is linked to considerable morbidity, resulting in severe pain and functional impairment. Herein, for the first time, we reported an 18-year-old patient with Crohn's disease during the remission phase under Azathioprine therapy who presented with articular pain. Although no underlying risk factors, the patient was diagnosed with severe AVN of the bilateral femoral head and both knees simultaneously following pain in involved areas. This case highlights the importance of demand multidisciplinary approach to chronic disease. Moreover, clinicians should be aware of articular manifestations in IBD patients to diagnose and treat these conditions as soon as possible. Patients should be evaluated for their psychologic, gastrointestinal, and extra-gastrointestinal comorbidities during each follow-up visit.
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Affiliation(s)
- Amir Khanmirzaei
- Faculty of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Kimia Jazi
- Clinical Research of Development Unit, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran
- Student Research Committee, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Gelareh Azarinoush
- Clinical Research of Development Unit, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran
| | - Maryam Shirmohammadi
- Clinical Research of Development Unit, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran
- Student Research Committee, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Hajar Karimtabar
- Student Research Committee, Faculty of Nursing and Midwifery, Qom University of Medical Sciences, Qom, Iran
| | - Mehdi Pezeshgi Modarres
- Gastroenterology and Hepatology Diseases Research Center, Qom University of Medical Sciences, Qom, Iran.
| | - Maryam Masoumi
- Faculty of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.
- Clinical Research of Development Unit, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran.
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Kumarapperuma H, Wang R, Little PJ, Kamato D. Mechanistic insight: Linking cardiovascular complications of inflammatory bowel disease. Trends Cardiovasc Med 2024; 34:203-211. [PMID: 36702388 DOI: 10.1016/j.tcm.2023.01.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 01/13/2023] [Accepted: 01/13/2023] [Indexed: 01/25/2023]
Abstract
Cardiovascular diseases (CVD) are the leading cause of mortality worldwide despite an aggressive reduction of traditional cardiovascular risk factors. Underlying inflammatory conditions such as inflammatory bowel disease (IBD) increase the risk of developing CVD. A broad understanding of the underlying pathophysiological processes between IBD and CVD is required to treat and prevent cardiovascular events in patients with IBD. This review highlights the commonality between IBD and CVD, including dysregulated immune response, genetics, environmental risk factors, altered gut microbiome, stress, endothelial dysfunction and abnormalities, to shed light on an essential area of modern medicine.
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Affiliation(s)
- Hirushi Kumarapperuma
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
| | - Ran Wang
- Mater Research Institute, The University of Queensland, Translational Research Institute, Queensland 4102, Australia
| | - Peter J Little
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou 510520, China
| | - Danielle Kamato
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102, Australia; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia; School of Environment and Science, Griffith University, Nathan, Queensland 4111, Australia.
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4
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Boccatonda A, Balletta M, Vicari S, Hoxha A, Simioni P, Campello E. The Journey Through the Pathogenesis and Treatment of Venous Thromboembolism in Inflammatory Bowel Diseases: A Narrative Review. Semin Thromb Hemost 2023; 49:744-755. [PMID: 36455617 DOI: 10.1055/s-0042-1758869] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract including Crohn's disease and ulcerative colitis, which may result in several extraintestinal complications (∼20-30% of cases), such as increased risk of venous thromboembolism (VTE). The main pathophysiological mechanism of VTE is an inflammation-induced hypercoagulable state, and recent data have shown that endothelial dysregulation due to gut and systemic inflammation may also lead to a prothrombotic state. Several prothrombotic alterations have been described, such as the activation of the coagulation system, platelet abnormalities, and dysregulation of fibrinolysis. Furthermore, the dysregulation of the gut microbiome seems to play a vital role in increasing systemic inflammation and thus inducing a procoagulant state. Our review aims to examine the main correlations between IBD and VTE, the underlying pathophysiology, and current therapeutic options.
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Affiliation(s)
- Andrea Boccatonda
- Department of Internal Medicine, Bentivoglio Hospital, AUSL Bologna, Bologna, Italy
| | - Marco Balletta
- Department of Internal Medicine, Bologna University, Bologna, Italy
| | - Susanna Vicari
- Department of Internal Medicine, Bentivoglio Hospital, AUSL Bologna, Bologna, Italy
| | - Ariela Hoxha
- Hemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), Padova University Hospital, Padova, Italy
| | - Paolo Simioni
- Hemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), Padova University Hospital, Padova, Italy
| | - Elena Campello
- Hemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), Padova University Hospital, Padova, Italy
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Stadnicki A, Stadnicka I. Venous and arterial thromboembolism in patients with inflammatory bowel diseases. World J Gastroenterol 2021; 27:6757-6774. [PMID: 34790006 PMCID: PMC8567469 DOI: 10.3748/wjg.v27.i40.6757] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/22/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023] Open
Abstract
The risk of thromboembolism (TE) is increased in patients with inflammatory bowel disease (IBD), mainly due to an increased risk of venous TE (VTE). The risk of arterial TE (ATE) is less pronounced, but an increased risk of cardiovascular diseases needs to be addressed in IBD patients. IBD predisposes to arterial and venous thrombosis through similar prothrombotic mechanisms, including triggering activation of coagulation, in part mediated by impairment of the intestinal barrier and released bacterial components. VTE in IBD has clinical specificities, i.e., an earlier first episode in life, high rates during both active and remission stages, higher recurrence rates, and poor prognosis. The increased likelihood of VTE in IBD patients may be related to surgery, the use of medications such as corticosteroids or tofacitinib, whereas infliximab is antithrombotic. Long-term complications of VTE can include post-thrombotic syndrome and high recurrence rate during post-hospital discharge. A global clot lysis assay may be useful in identifying patients with IBD who are at risk for TE. Many VTEs occur in IBD outpatients; therefore, outpatient prophylaxis in high-risk patients is recommended. It is crucial to continue focusing on prevention and adequate treatment of VTE in patients with IBD.
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Affiliation(s)
- Antoni Stadnicki
- Department of Physiology, Faculty of Medicine, University of Technology, Katowice 41-209, Poland
| | - Izabela Stadnicka
- Department of Molecular Medicine, Medical University of Silesia, Faculty of Pharmacy, Sosnowiec 41-200, Poland
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6
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Zhang H, Wang X. Risk Factors of Venous Thromboembolism in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. Front Med (Lausanne) 2021; 8:693927. [PMID: 34262920 PMCID: PMC8273255 DOI: 10.3389/fmed.2021.693927] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/31/2021] [Indexed: 12/13/2022] Open
Abstract
Background: Patients suffering from chronic inflammatory disorders, such as inflammatory bowel disorder, are at higher risk of developing thromboembolism. The chronic inflammatory nature of inflammatory bowel disease has been identified as a predominant reason for a state of Virchow's triad (i.e., endothelial dysfunction, stasis, and general hypercoagulability), eventually leading to the onset of venous thromboembolism. Recent studies show that certain factors, such as demographics, medication history, and history of surgical intervention may increase thromboembolism risk in patients with inflammatory bowel disease. However, to date, no study has attempted to evaluate the effect of different risk factors associated with the development of venous thromboembolism in inflammatory bowel disease patients. Objective: To evaluate the risk factors that can influence the incidence of venous thromboembolism in patients with inflammatory bowel disease. Methods: Academic literature was systematically searched based on the PRISMA guidelines across five databases: Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE. A random-effect meta-analysis was conducted to evaluate the hazard ratio for the risk factors (i.e., aging, gender, steroid therapy, surgery, and ulcerative colitis) that can influence the incidence of venous thromboembolism in patients with inflammatory bowel disease. Results: From a total of 963 studies, 18 eligible studies with 1,062,985 (44.59 ± 10.18 years) patients suffering from inflammatory bowel disease were included in the review. A meta-analysis revealed a higher risk of aging (Hazard's ratio: 2.19), steroids (1.87), surgery (1.48), and ulcerative colitis (2.06) on venous thromboembolism in patients with inflammatory bowel disease. We also found that the female gender (0.92) did not increase the incidence of venous thromboembolism in inflammatory bowel disease patients. Conclusion: The study provides preliminary evidence regarding high risks associated with ulcerative colitis, steroid consumption, and aging for the development of venous thromboembolism in patients with inflammatory bowel disease. The findings from this study may contribute to developing awareness among clinicians, better risk stratification and prevention of venous thromboembolic complications in patients with inflammatory bowel disease.
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Affiliation(s)
- Hua Zhang
- Department of Nursing, Xiangya Second Hospital of Central South University, Changsha, China
| | - Xuehong Wang
- Department of Gastroenterology, Xiangya Second Hospital of Central South University, Changsha, China
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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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8
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Pepe M, Carulli E, Forleo C, Moscarelli M, Di Cillo O, Bortone AS, Nestola PL, Biondi-Zoccai G, Giordano A, Favale S. Inflammatory Bowel Disease and Acute Coronary Syndromes: From Pathogenesis to the Fine Line Between Bleeding and Ischemic Risk. Inflamm Bowel Dis 2021; 27:725-731. [PMID: 32592478 DOI: 10.1093/ibd/izaa160] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Indexed: 02/05/2023]
Abstract
Inflammatory bowel disease (IBD) is a pathological condition that first involves the gastrointestinal wall but can also trigger a systemic inflammatory state and thus extraintestinal manifestations. Systemic inflammation is probably secondary to the passage of bacterial products into the bloodstream because of altered intestinal permeability and the consequent release of proinflammatory mediators. Inflammation, through several diverse pathophysiological pathways, determines both a procoagulative state and systemic endothelial dysfunction, which are both deemed to be responsible for venous and arterial thromboembolic adverse events. The management of systemic thrombotic complications is particularly challenging in this category of patients, who also present a high bleeding risk; what is more, both bleeding and thrombotic risks peak during the active phases of the disease. The literature suggests that treating physicians have been, so far, more heavily influenced by concerns about bleeding than by the thrombotic risk. Despite the absence of data provided by large cohorts or randomized studies, the high risk of arterial and venous atherothrombosis in patients with IBD seems unquestionable. Moreover, several reports suggest that when arterial thromboembolism involves the coronary vessels, causing acute coronary syndromes, ischemic complications from antithrombotic drug undertreatment are frequent and severe. This review aims to shed light on the tricky balance between the ischemic and hemorrhagic risks of patients with IBD and to highlight how difficult it is for clinicians to define a tailored therapy based on a case-by-case, careful, and unprejudiced clinical evaluation.
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Affiliation(s)
- Martino Pepe
- Cardiovascular Diseases Section, Cardiothoracic Department, University of Bari, Bari, Italy
| | - Eugenio Carulli
- Cardiovascular Diseases Section, Cardiothoracic Department, University of Bari, Bari, Italy
| | - Cinzia Forleo
- Cardiovascular Diseases Section, Cardiothoracic Department, University of Bari, Bari, Italy
| | - Marco Moscarelli
- Cardiothoracic and Vascular Department, Maria Cecilia Hospital GVM Care and Research, Cotignola (RA), Italy
| | - Ottavio Di Cillo
- Chest Pain Unit, Cardiology Emergency, University of Bari, Bari, Italy
| | - Alessandro Santo Bortone
- Division of Heart Surgery, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Palma Luisa Nestola
- Cardiovascular Diseases Section, Cardiothoracic Department, University of Bari, Bari, Italy
| | - Giuseppe Biondi-Zoccai
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Napoli, Italy
| | - Arturo Giordano
- Invasive Cardiology Unit, Pineta Grande Hospital, Castel Volturno, Caserta, Italy
| | - Stefano Favale
- Cardiovascular Diseases Section, Cardiothoracic Department, University of Bari, Bari, Italy
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9
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Nuñez P, García Mateo S, Quera R, Gomollón F. Inflammatory bowel disease and the risk of cardiovascular diseases. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 44:236-242. [PMID: 33223261 DOI: 10.1016/j.gastrohep.2020.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/11/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) includes both ulcerative colitis and Crohn's disease, which are well recognised as chronic systemic and immune-mediated conditions that frequently involve extraintestinal manifestations. Although comorbidities have long been the subject of research in other chronic inflammatory diseases, this concept is also emerging in IBD. Many pathologies have been linked to IBD, including cardiovascular disease, which is the main cause of death in developed countries. IBD patients are at increased risk of conditions such as early atherosclerosis and myocardial infarction or venous thrombosis and pulmonary thromboembolism. The aim of this review is to make an approximation of the physiopathology of the different manifestations of cardiovascular disease in patients with IBD and how to prevent them.
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Affiliation(s)
- Paulina Nuñez
- Universidad de Chile, Hospital San Juan de Dios, Sección de Gastroenterología, Santiago, Chile
| | - Sandra García Mateo
- Servicio de Aparato Digestivo. Hospital Clínico Universitario «Lozano-Blesa», IIS Aragón, Zaragoza, España
| | - Rodrigo Quera
- Clínica Las Condes, Departamento de Gastroenterología, Programa de Enfermedad Inflamatoria Intestinal, Santiago, Chile
| | - Fernando Gomollón
- Departamento de Medicina, Facultad de Medicina, IIS Aragón, Zaragoza, España.
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Motta JP, Palese S, Giorgio C, Chapman K, Denadai-Souza A, Rousset P, Sagnat D, Guiraud L, Edir A, Seguy C, Alric L, Bonnet D, Bournet B, Buscail L, Gilletta C, Buret AG, Wallace JL, Hollenberg MD, Oswald E, Barocelli E, Le Grand S, Le Grand B, Deraison C, Vergnolle N. Increased Mucosal Thrombin is Associated with Crohn's Disease and Causes Inflammatory Damage through Protease-activated Receptors Activation. J Crohns Colitis 2020; 15:787-799. [PMID: 33201214 PMCID: PMC8095389 DOI: 10.1093/ecco-jcc/jjaa229] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Thrombin levels in the colon of Crohn's disease patients have recently been found to be elevated 100-fold compared with healthy controls. Our aim was to determine whether and how dysregulated thrombin activity could contribute to local tissue malfunctions associated with Crohn's disease. METHODS Thrombin activity was studied in tissues from Crohn's disease patients and healthy controls. Intracolonic administration of thrombin to wild-type or protease-activated receptor-deficient mice was used to assess the effects and mechanisms of local thrombin upregulation. Colitis was induced in rats and mice by the intracolonic administration of trinitrobenzene sulphonic acid. RESULTS Active forms of thrombin were increased in Crohn's disease patient tissues. Elevated thrombin expression and activity were associated with intestinal epithelial cells. Increased thrombin activity and expression were also a feature of experimental colitis in rats. Colonic exposure to doses of active thrombin comparable to what is found in inflammatory bowel disease tissues caused mucosal damage and tissue dysfunctions in mice, through a mechanism involving both protease-activated receptors -1 and -4. Intracolonic administration of the thrombin inhibitor dabigatran, as well as inhibition of protease-activated receptor-1, prevented trinitrobenzene sulphonic acid-induced colitis in rodent models. CONCLUSIONS Our data demonstrated that increased local thrombin activity, as it occurs in the colon of patients with inflammatory bowel disease, causes mucosal damage and inflammation. Colonic thrombin and protease-activated receptor-1 appear as possible mechanisms involved in mucosal damage and loss of function and therefore represent potential therapeutic targets for treating inflammatory bowel disease.
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Affiliation(s)
- Jean-Paul Motta
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France,CVasThera, Arobase Castres-Mazamet, Castres, France
| | - Simone Palese
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France,Università di Parma, Dipartimento di Scienze degli Alimenti e del Farmaco, Parma, Italia
| | - Carmine Giorgio
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France,Università di Parma, Dipartimento di Scienze degli Alimenti e del Farmaco, Parma, Italia
| | - Kevin Chapman
- Department of Physiology & Pharmacology, and Medicine, University of Calgary Cumming School of Medicine, Calgary, AB, Canada
| | | | - Perrine Rousset
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - David Sagnat
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Laura Guiraud
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Anissa Edir
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Carine Seguy
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Laurent Alric
- Department of Internal Medicine and Digestive Diseases, CHU Toulouse, Toulouse, France,Pole Digestif, CHU Toulouse, Toulouse, France,Faculty of Medicine, Paul Sabatier University, Toulouse, France
| | - Delphine Bonnet
- Department of Internal Medicine and Digestive Diseases, CHU Toulouse, Toulouse, France,Pole Digestif, CHU Toulouse, Toulouse, France
| | - Barbara Bournet
- Pole Digestif, CHU Toulouse, Toulouse, France,Faculty of Medicine, Paul Sabatier University, Toulouse, France
| | - Louis Buscail
- Pole Digestif, CHU Toulouse, Toulouse, France,Faculty of Medicine, Paul Sabatier University, Toulouse, France
| | | | - Andre G Buret
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - John L Wallace
- Department of Physiology & Pharmacology, and Medicine, University of Calgary Cumming School of Medicine, Calgary, AB, Canada
| | - Morley D Hollenberg
- Department of Physiology & Pharmacology, and Medicine, University of Calgary Cumming School of Medicine, Calgary, AB, Canada
| | - Eric Oswald
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Elisabetta Barocelli
- Università di Parma, Dipartimento di Scienze degli Alimenti e del Farmaco, Parma, Italia
| | | | | | - Celine Deraison
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France
| | - Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France,Department of Physiology & Pharmacology, and Medicine, University of Calgary Cumming School of Medicine, Calgary, AB, Canada,Corresponding author: Dr Nathalie Vergnolle, PhD, Institut de Recherche en Santé Digestive [IRSD], INSERM UMR-1220, Purpan Hospital, CS60039, 31024 Toulouse cedex 03, France. Tel.: 33-5-62-74-45-00; fax: 33-5-62-74-45-58;
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Ferreira-Duarte M, Sousa JB, Diniz C, Sousa T, Duarte-Araújo M, Morato M. Experimental and Clinical Evidence of Endothelial Dysfunction in Inflammatory Bowel Disease. Curr Pharm Des 2020; 26:3733-3747. [PMID: 32611296 DOI: 10.2174/1381612826666200701212414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
The endothelium has a crucial role in proper hemodynamics. Inflammatory bowel disease (IBD) is mainly a chronic inflammatory condition of the gastrointestinal tract. However, considerable evidence points to high cardiovascular risk in patients with IBD. This review positions the basic mechanisms of endothelial dysfunction in the IBD setting (both clinical and experimental). Furthermore, we review the main effects of drugs used to treat IBD in endothelial (dys)function. Moreover, we leave challenging points for enlarging the therapeutic arsenal for IBD with new or repurposed drugs that target endothelial dysfunction besides inflammation.
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Affiliation(s)
| | | | - Carmen Diniz
- LAQV@REQUIMTE, University of Porto, Porto, Portugal
| | - Teresa Sousa
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
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12
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Thrombin Induces Secretion of Multiple Cytokines and Expression of Protease-Activated Receptors in Mouse Mast Cell Line. Mediators Inflamm 2019; 2019:4952131. [PMID: 31814803 PMCID: PMC6878808 DOI: 10.1155/2019/4952131] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 07/18/2019] [Accepted: 10/04/2019] [Indexed: 02/05/2023] Open
Abstract
Background Thrombin could elicit degranulation of mast cells involved in numerous physiologic and pathologic processes; however, the detailed scrutiny of this procedure and further research of possible cell signaling pathways are lacking. Methods P815 mouse mast cells were exposed to various concentrations of thrombin for 16 h. Expression of protease-activated receptor (PAR)1, PAR2, PAR3, and PAR4 mRNA in P815 was analyzed by quantitative real-time PCR (qRT-PCR) and the fittest concentration of thrombin was decided. Then, secretions of mediators from P815 stimulated by thrombin 0.2 U/ml were determined using enzyme-linked immunosorbent assay (ELISA) and Luminex liquichip; the possible cell signaling pathways were measured by immunoblotting. Furthermore, inhibition of thrombin inhibitor (hirudin), PAR1 inhibitor (SCH79797), and MAPK inhibitors (SB203580, PD98059, and SP600125) on the mediator section was evaluated by ELISA and Luminex liquichip. Results Thrombin 0.2 U/ml induced the elevated expression of PAR1, PAR2, PAR3, and PAR4, as well as the increasing level of phospho-IκBα, phospho-SAPK/JNK MAPK, phospho-P38 MAPK (Thr180/Tyr182), and phospho-ERK1/2 MAPK (p44/42) in P815. Secretion of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), interleukin- (IL-) 2, IL-6, chemokine ligand- (CCL-) 2, chemokine (C-X-C motif) ligand- (CXCL-) 1, and CXCL-5 from P815 increased apparently; this effect could be diminished by hirudin, whereas SCH79797 and MAPK inhibitors (SB203580, PD98059, and SP600125) diminish the secretions with weaker effect. Conclusion We found the expression of PAR mRNA in P815, activation of signaling pathways of nuclear factor-kappaB (NF-κB), and mitogen-activated protein kinases (MAPKs) including C-Jun NH2-terminal kinase (JNK), P38, and extracellular signal-regulated kinase 1/2 (ERK1/2), and the release of multiple inflammatory mediators stimulated by thrombin, as well as the inhibition of the inflammatory releases by hirudin, SCH79797, and MAPK inhibitors including SB203580, PD98059, and SP600125.
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Abstract
Inflammation has been shown to play an increasingly important role in the pathogenesis of atherosclerosis and in precipitating thrombotic events. Inflammatory bowel disease (IBD) is a systemic inflammatory disorder with a wide range of extraintestinal manifestations including a clinically significant increase in the risk of venous thromboembolism compared to matched controls in several studies. The data for the association between IBD and ischemic heart disease are less clear; multiple population-based studies have shown both positive and negative associations between the 2 conditions. While the systemic inflammation should theoretically increase the risk for cardiovascular disease, inflammatory bowel also potentially provides a cardioprotective effect in several ways. Patients with IBD typically enter the healthcare system at an earlier age and experience a lower incidence of obesity, hypercholesterolemia, and hyperlipidemia. Given the complex interplay among the proatherogenic, prothrombogenic, and cardioprotective effects, IBD should be taken into consideration as a nontraditional risk factor for cardiovascular disease in specific subsets of patients.
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Tsigkas G, Davlouros P, Despotopoulos S, Assimakopoulos SF, Theocharis G, Hahalis G. Inflammatory Bowel Disease: A Potential Risk Factor for Coronary Artery Disease. Angiology 2017; 68:845-849. [DOI: 10.1177/0003319717690993] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Patients with inflammatory bowel disease (IBD) have a higher incidence of coronary artery disease (CAD) compared with the general population. Left main coronary artery (LMCA) thrombosis constitutes a very rare but catastrophic manifestation of acute coronary syndrome. Case reports describing young patients with IBD and LMCA thrombosis are scarce. Most importantly, patients with a positive family history of thrombotic events and those with significant genetic or acquired risk factors such as the antiphospholipid antibody syndrome, advanced age, immobilization, pregnancy, oral contraceptive use, obesity, diabetes, and cigarette smoking may have a higher risk of thrombosis among those with active IBD. We describe a 28-year-old man who was admitted for coronary angiography (CA) due to ST-segment elevation myocardial infarction. He had a recent exacerbation of ulcerative colitis. The patient was a smoker without a family history of CAD. Proximal total occlusion of the left anterior descending (LAD) artery and left circumflex (LCX) artery with massive thrombus was shown on CA, whereas a normal dominant right coronary artery delivered collaterals to the LAD artery.
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Affiliation(s)
- Grigorios Tsigkas
- Department of Cardiology, Patras University Hospital, Patras, Greece
| | | | | | | | | | - George Hahalis
- Department of Cardiology, Patras University Hospital, Patras, Greece
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15
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Schicho R, Marsche G, Storr M. Cardiovascular complications in inflammatory bowel disease. Curr Drug Targets 2016. [PMID: 25642719 DOI: 10.2174/138945011666650202161500] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Over the past years, a growing number of studies have indicated that patients suffering from inflammatory bowel disease (IBD) have an increased risk of developing cardiovascular disease. Both are chronic inflammatory diseases and share certain pathophysiological mechanisms that may influence each other. High levels of cytokines, C-reactive protein (CRP), and homocysteine in IBD patients may lead to endothelial dysfunction, an early sign of atherosclerosis. IBD patients, in general, do not show the typical risk factors for cardiovascular disease but changes in lipid profiles similar to the ones seen in cardiovascular events have been reported recently. Higher levels of coagulation factors frequently occur in IBD which may predispose to arterial thromboembolic events. Finally, the gut itself may have an impact on atherogenesis during IBD through its microbiota. Microbial products are released from the inflamed mucosa into the circulation through a leaky barrier. The induced rise in proinflammatory cytokines could contribute to endothelial damage, artherosclerosis and cardiovascular events. Although large retrospective studies favor a link between IBD and cardiovascular diseases, the mechanisms behind still remain to be determined.
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Affiliation(s)
| | | | - Martin Storr
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
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16
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Schicho R, Marsche G, Storr M. Cardiovascular complications in inflammatory bowel disease. Curr Drug Targets 2016; 16:181-8. [PMID: 25642719 DOI: 10.2174/1389450116666150202161500] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Revised: 01/08/2015] [Accepted: 01/16/2015] [Indexed: 02/07/2023]
Abstract
Over the past years, a growing number of studies have indicated that patients suffering from inflammatory bowel disease (IBD) have an increased risk of developing cardiovascular disease. Both are chronic inflammatory diseases and share certain pathophysiological mechanisms that may influence each other. High levels of cytokines, C-reactive protein (CRP), and homocysteine in IBD patients may lead to endothelial dysfunction, an early sign of atherosclerosis. IBD patients, in general, do not show the typical risk factors for cardiovascular disease but changes in lipid profiles similar to the ones seen in cardiovascular events have been reported recently. Higher levels of coagulation factors frequently occur in IBD which may predispose to arterial thromboembolic events. Finally, the gut itself may have an impact on atherogenesis during IBD through its microbiota. Microbial products are released from the inflamed mucosa into the circulation through a leaky barrier. The induced rise in proinflammatory cytokines could contribute to endothelial damage, artherosclerosis and cardiovascular events. Although large retrospective studies favor a link between IBD and cardiovascular diseases, the mechanisms behind still remain to be determined.
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Affiliation(s)
| | | | - Martin Storr
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria.
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17
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Chande N, Wang Y, McDonald JWD, MacDonald JK. Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2015; 8:CD006774. [PMID: 35658167 PMCID: PMC9392958 DOI: 10.1002/14651858.cd006774.pub4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND There are a limited number of treatment options for patients with ulcerative colitis (UC). An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC. OBJECTIVES To review randomized trials examining the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis. SEARCH METHODS We searched MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD/FBD group specialized trials register up to June 2014. We also searched review papers on ulcerative colitis and references from identified papers in an effort to identify additional randomized trials studying UFH or LMWH use in patients with ulcerative colitis. We searched abstracts from major gastroenterological meetings to identify research published in abstract form. SELECTION CRITERIA Randomized controlled trials comparing UFH or LMWH to placebo or a control therapy for induction of remission in ulcerative colitis were included. Studies published in abstract form only were included if the authors could be contacted for further information. DATA COLLECTION AND ANALYSIS A data extraction form was developed and used to extract data from included studies. Two authors independently extracted data. Any disagreements were resolved by consensus. The Cochrane Risk of Bias tool was used to assess study quality. Data were analyzed on an intention-to-treat basis. The primary outcome was induction of remission, as defined by the studies. Secondary outcomes measures included: endoscopic remission as defined by the authors; clinical, histological or endoscopic improvement as defined by the authors; the occurrence of adverse events; the occurrence of bleeding; and improvements in quality of life as measured by a validated instrument. We calculated the risk ratio (RR) and corresponding 95% confidence interval for dichotomous outcomes. Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy). The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS Five studies were eligible for inclusion (329 patients). Three studies (270 patients) compared low molecular weight heparin to placebo, one study (34 patients) compared LMWH in addition to standard therapy, and one study (25 patients) compared UFH to corticosteroids. The study comparing UFH to corticosteroids was rated at high risk of bias due to a single-blind design. The study that compared the addition of LMWH to standard therapy to standard therapy alone was rated at high risk of bias due to open-label design. The other three studies were rated as low risk of bias. LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission (very low quality of evidence), and clinical, endoscopic, or histological improvement. High dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (RR 1.39; 95% CI 1.09 to 1.77 ; P = 0.008; very low quality of evidence), clinical improvement (RR 1.28; 95% CI 1.06 to 1.55; P = 0.01; very low quality of evidence), and endoscopic improvement (RR 1.21; 95% CI 1.00 to 1.47 ; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission or endoscopic improvement. LMWH was well-tolerated but provided no significant benefit for quality of life. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event. AUTHORS' CONCLUSIONS There is evidence to suggest that LMWH may be effective for the treatment of active UC. When administered by extended colon-release tablets, LMWH was more effective than placebo for treating outpatients with mild to moderate disease. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. A further trial of UFH in patients with mild disease may also be justified. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC.
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Affiliation(s)
- Nilesh Chande
- London Health Sciences Centre ‐ Victoria HospitalRoom E6‐321A800 Commissioners Road EastLondonONCanadaN6A 5W9
| | - Yongjun Wang
- Robarts Research InstituteRobarts Clinical TrialsP.O. Box 5015100 Perth DriveLondonONCanada
| | - John WD McDonald
- Robarts Research InstituteRobarts Clinical TrialsP.O. Box 5015100 Perth DriveLondonONCanada
| | - John K MacDonald
- Robarts Research InstituteRobarts Clinical TrialsP.O. Box 5015100 Perth DriveLondonONCanada
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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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Kraiem I, Hadhri S, Ben Rejeb M, Ifa L, Jmaa A, Ajmi S, Skouri H. Antiphospholipid Antibodies and Procoagulant Profile in Tunisians With Inflammatory Bowel Diseases. Clin Appl Thromb Hemost 2015; 22:734-742. [PMID: 25878173 DOI: 10.1177/1076029615581364] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The hypercoagulable state accompanying inflammatory bowel diseases (IBDs) is still poorly understood. The aim of this study was to assess antiphospholipid antibodies (APAs) and a large panel of inherited and acquired thrombotic markers simultaneously in a sample of Tunisian patients with IBD. In total, 89 consecutive patients with IBD (mean age 38 ± 15 years; 48 with Crohn disease and 41 with ulcerative colitis) and 129 controls were prospectively evaluated for immunoglobulin (Ig) G, IgM, and IgA antibodies against cardiolipin (aCL), β2glycoprotein I (aβ2GPI), and prothrombin (aPT); IgG and IgM antibodies against phosphatidic acid (aPA), phosphatidylinositol (aPI), and annexin V (aAnnV); lupus anticoagulant (LA); coagulation factors; natural inhibitors; and thrombotic genetic polymorphisms. Levels of fibrinogen, factors II, V, and VIII and von Willebrand factor, antithrombin, and protein C were significantly higher in patients with IBD than in controls (P < .05 for all comparisons). At least 1 APA subset was detected in 54 patients. The frequencies of antibodies against anionic phospholipids-aCL, aPI, and aPA-in patients with IBD were 15.9%, 21.3%, and 14.6%, respectively. The frequencies of antiphospholipid cofactor antibodies were 39.8% for aβ2GPI and 15.7% for both aAnnV and aPT. Isolated aβ2GPI IgA was detected in 22 patients, and 12 (13.5%) patients had LA. The IgA aβ2GPI antibodies were frequently detected in Tunisian patients with IBD. These results are of potential diagnostic, prognostic, and therapeutic interest.
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Affiliation(s)
- Imen Kraiem
- Laboratoire d'Hématologie et Banque du Sang, UR12ES05. CHU Sahloul, Sousse, Tunisie
| | - Samira Hadhri
- Laboratoire d'Hématologie et Banque du Sang, UR12ES05. CHU Sahloul, Sousse, Tunisie
| | | | - Lamia Ifa
- Laboratoire d'Hématologie et Banque du Sang, UR12ES05. CHU Sahloul, Sousse, Tunisie
| | - Ali Jmaa
- Service de Gastroentérologie CHU Sahloul, Sousse, Tunisie
| | - Salem Ajmi
- Service de Gastroentérologie CHU Sahloul, Sousse, Tunisie
| | - Hadef Skouri
- Laboratoire d'Hématologie et Banque du Sang, UR12ES05. CHU Sahloul, Sousse, Tunisie
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20
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Koutroubakis IE. The relationship between coagulation state and inflammatory bowel disease: current understanding and clinical implications. Expert Rev Clin Immunol 2015; 11:479-88. [PMID: 25719625 DOI: 10.1586/1744666x.2015.1019475] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel disease (IBD) is associated with a hypercoagulable state and subsequently with an increased risk for venous thromboembolism (VTE). VTE in IBD is characterized by a high recurrence rate and is associated with the disease activity. Acquired endothelial dysfunction, abnormalities of platelets, activation of coagulation system and impaired fibrinolysis are the main changes in the coagulation state in IBD. The development of VTE in IBD has been considered to be the result of multiple interactions between acquired and inherited risk factors. The treatment of VTE in IBD patients is recommended to be similar and to follow the same protocols as for non-IBD patients. In the clinical practice, the management of IBD patients and especially the hospitalized patients should include thromboprophylaxis.
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Affiliation(s)
- Ioannis E Koutroubakis
- Department of Gastroenterology, University Hospital Heraklion, P.O. Box 1352, 71110 Heraklion, Crete, Greece
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Zezos P, Kouklakis G, Saibil F. Inflammatory bowel disease and thromboembolism. World J Gastroenterol 2014; 20:13863-13878. [PMID: 25320522 PMCID: PMC4194568 DOI: 10.3748/wjg.v20.i38.13863] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/24/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) have an increased risk of vascular complications. Thromboembolic complications, both venous and arterial, are serious extraintestinal manifestations complicating the course of IBD and can lead to significant morbidity and mortality. Patients with IBD are more prone to thromboembolic complications and IBD per se is a risk factor for thromboembolic disease. Data suggest that thrombosis is a specific feature of IBD that can be involved in both the occurrence of thromboembolic events and the pathogenesis of the disease. The exact etiology for this special association between IBD and thromboembolism is as yet unknown, but it is thought that multiple acquired and inherited factors are interacting and producing the increased tendency for thrombosis in the local intestinal microvasculature, as well as in the systemic circulation. Clinicians' awareness of the risks, and their ability to promptly diagnose and manage tromboembolic complications are of vital importance. In this review we discuss how thromboembolic disease is related to IBD, specifically focusing on: (1) the epidemiology and clinical features of thromboembolic complications in IBD; (2) the pathophysiology of thrombosis in IBD; and (3) strategies for the prevention and management of thromboembolic complications in IBD patients.
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22
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Kohoutova D, Pecka M, Cihak M, Cyrany J, Maly J, Bures J. Prevalence of hypercoagulable disorders in inflammatory bowel disease. Scand J Gastroenterol 2014; 49:287-94. [PMID: 24328909 DOI: 10.3109/00365521.2013.870597] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE. Inflammatory bowel disease (IBD) can be associated with hypercoagulable disorders. Aim of this single-center, prospective study was an in-depth evaluation of acquired hypercoagulable states in IBD patients. METHODS. A total of 110 patients with Crohn's disease (CD) (aged 19-69; mean 40.5, median 38.5 years), 43 with ulcerative colitis (UC) (aged 17-72; mean 42, median 36 years), and 30 controls were enrolled. Full blood count, serum C-reactive protein (CRP), proteins C and S, activated protein C (APC) resistance, thrombin-antithrombin complex (TAT), F1+F2 fragments, tissue factor pathway inhibitor (TFPI) total and truncated, TFPI-factor Xa, tissue plasminogen activator (tPA) and PAI-I antigen were investigated in peripheral blood samples. RESULTS. Only 18 of 153 (11.8%) IBD patients had hemocoagulation parameters within normal range. Significant difference between IBD patients and controls was found in thrombocyte volume (p < 0.001), protein C (p = 0.025), protein S (p = 0.003), APC resistance (p < 0.001), F1+F2 fragments (p < 0.001), and tPA (p = 0.002). In CD patients who were divided into two subgroups according to serum CRP values (non-active disease: <5 mg/L; active disease ≥5 mg/L), thrombocyte count was significantly lower (p = 0.001), thrombocyte volume was significantly higher (p = 0.002), F1+F2 fragments were significantly lower (p = 0.007) and tPA was significantly higher (p = 0.038) in the subgroup with CRP <5 mg/L. In UC patients, no significant difference depending on CRP was found. CONCLUSIONS. Acquired hypercoagulable abnormalities in IBD patients are frequent. Patients with active CD, but not UC, displayed significantly different hemocoagulable parameters, when compared to non-active CD/UC subjects. In patients with active CD (with increased serum CRP concentration) and patients with active extensive UC found at endoscopy (despite low CRP values), prophylactic anticoagulation therapy should be considered.
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Affiliation(s)
- Darina Kohoutova
- 2nd Department of Internal Medicine - Gastroenterology, Charles University in Praha, Faculty of Medicine at Hradec Kralove, University Teaching Hospital , Hradec Kralove , Czech Republic
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23
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Ornaghi S, Barnhart KT, Frieling J, Streisand J, Paidas MJ. Clinical syndromes associated with acquired antithrombin deficiency via microvascular leakage and the related risk of thrombosis. Thromb Res 2014; 133:972-84. [PMID: 24593911 DOI: 10.1016/j.thromres.2014.02.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/25/2014] [Accepted: 02/11/2014] [Indexed: 12/17/2022]
Abstract
Antithrombin (AT) is a 65kDa glycoprotein belonging to a group of inhibitory factors known as serpins (serine protease inhibitors). It plays a critical role in the inhibition of coagulation and inflammation processes within the environment of the vascular endothelium. Inadequate levels of functional AT in plasma results in an increased risk of thrombotic events, both venous and arterial. AT deficiency can be inherited or acquired. Congenital AT deficiency is the most severe inherited thrombophilic condition with an odds ratio of 20 for the increased risk of venous thrombosis. Acquired AT deficiency occurs in a variety of physiologic and pathologic medical conditions with similar risks of increased thrombosis. In this article, we review clinical settings characterized by an acquired AT deficiency largely or partly subsequent to protein microvascular leakage. Other different mechanisms of AT depletion are implied in some clinical conditions together with endothelial loss, and, therefore, outlined. In addition, we provide a description of the current knowledge on the specific mechanisms underlying endothelial AT leakage and on the consequences of this protein decrease, specifically looking at thrombosis. We identify potential directions of research that might prove useful in patients with acquired AT deficiency.
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Affiliation(s)
- Sara Ornaghi
- Yale Women and Children's Center For Blood Disorders, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA; Department of Obstetrics and Gynecology, University of Milan-Bicocca, via Pergolesi 33, Monza, MB, Italy.
| | - Kurt T Barnhart
- Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA
| | - Johan Frieling
- rEVO Biologics 175 Crossing Boulevard, Framingham, MA 01702, USA
| | - James Streisand
- rEVO Biologics 175 Crossing Boulevard, Framingham, MA 01702, USA
| | - Michael J Paidas
- Yale Women and Children's Center For Blood Disorders, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA
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Tan VP, Chung A, Yan BP, Gibson PR. Venous and arterial disease in inflammatory bowel disease. J Gastroenterol Hepatol 2013; 28:1095-113. [PMID: 23662785 DOI: 10.1111/jgh.12260] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/26/2013] [Indexed: 12/13/2022]
Abstract
Awareness is increasing that risk of venous thromboembolism and development of atherosclerosis is elevated in patients with some chronic inflammatory diseases. This review aimed to examine the risk of vascular disease in patients with inflammatory bowel disease (IBD) and to identify potential pathogenic mechanisms and therapeutic approaches. An extensive literature search was conducted using MEDLINE database, Cochrane Library and international conference abstracts for studies pertaining to venous and arterial thromboembolism in adult IBD patients. There is a 1.1-3.6 fold risk of venothromboembolism in IBD, affecting 0.55-6.15% of patients. Risks are increased during a flare or with chronically active inflammation. Evidence is building that there may be a modestly increased risk of arterial disease overall, despite evidence that traditional risk factors may be reduced. Multiple pathogenic factors have been identified including endothelial dysfunction, inflammation-mediated calcium deposition in the media of arteries, hyperhomocysteinemia, platelet activation, and altered coagulation and fibrinolysis. The key to active and preventive therapy is to effectively treat inflammation. Recommendations for prophylaxis of venothromboembolism have followed guidelines where they exist and have been extrapolated from studies of other at-risk conditions, as have those for arterial disease, where screening for risk factors and actively treating abnormalities is encouraged. In conclusion, patients with IBD are at considerably increased risk of venothromboembolism and probably of arterial disease, in particular mesenteric ischemia and ischemic heart disease. Increased penetration of gaps between this knowledge and clinical therapeutic action to prevent thromboembolic events into IBD clinical practice is needed.
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Affiliation(s)
- Victoria P Tan
- Department of Medicine, University of Hong Kong, Hong Kong SAR
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25
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Venous thrombotic events in hospitalized children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2013; 56:485-91. [PMID: 23232326 DOI: 10.1097/mpg.0b013e3182801e43] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Adults with inflammatory bowel disease (IBD) have an increased risk of venous thrombotic events (TEs). We sought to evaluate the risk for TE in children and adolescents with IBD using a large population database. METHODS The triennial Healthcare Cost and Utilization Project Kids' Inpatient Database was used in a retrospective cohort study of hospitalized children in the United States across 1997, 2000, 2003, 2006, and 2009. Billing codes were used to identify discharges with Crohn disease, ulcerative colitis, pulmonary embolism, deep vein thrombosis, thrombophlebitis, thrombosis of intracranial venous sinus, Budd-Chiari syndrome, and portal vein thrombosis. A logistic regression model was fitted to quantify the increased risk of TE in children with IBD, while adjusting for other risk factors of thrombosis. RESULTS The total weighted number of pediatric discharges was 7,448,292, and 68,394 (0.92%) were identified with IBD. The incidence of any TE in a hospitalized child or adolescent with IBD was 117.9/10,000 with a relative risk (95% confidence interval) of 2.36 (2.15-2.58). The adjusted odds ratio for any TE in a patient with IBD without surgery was 1.22 (1.08-1.36). Risk factors for TE among patients with IBD include older age, central venous catheter, parenteral nutrition, and an identified hypercoagulable condition. There is an increasing trend of TE in both the IBD and non-IBD patients. CONCLUSIONS Hospitalized children and adolescents with IBD are at increased risk for TE. Conservative methods of TE prevention including hydration, mobilization, or pneumatic devices should be considered in hospitalized patients with IBD.
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Yuhara H, Steinmaus C, Corley D, Koike J, Igarashi M, Suzuki T, Mine T. Meta-analysis: the risk of venous thromboembolism in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013; 37:953-62. [PMID: 23550660 DOI: 10.1111/apt.12294] [Citation(s) in RCA: 157] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2012] [Revised: 01/26/2013] [Accepted: 03/11/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a systemic disorder that predominantly affects the bowels but is also associated with venous thromboembolism (VTE). AIM To provide a quantitative assessment of the association of IBD with venous thromboembolism risk and to explore the possible sources of heterogeneity in the current literature, a meta-analysis of case-control and cohort studies was conducted. METHODS Studies were identified by a literature search of the PubMed and Scopus databases (from inception inclusive 31 December 2012) for English language studies. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with fixed- and random-effects models. Several subgroup analyses were performed to explore potential study heterogeneity and bias. RESULTS Eleven studies met our inclusion criteria. The summary RR for deep venous thromboembolism (DVT) and pulmonary embolism (PE) comparing subjects both with and without IBD was 2.20 (95% CI 1.83-2.65). After adjusting for obesity and smoking, summary relative risks near 2.0 were seen for venous thromboembolism in both UC and CD patients. CONCLUSION This meta-analysis showed that inflammatory bowel disease is associated with an approximately two-fold increase in the risk of venous thromboembolism.
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Affiliation(s)
- H Yuhara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
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Increased procoagulant function of microparticles in pediatric inflammatory bowel disease: role in increased thrombin generation. J Pediatr Gastroenterol Nutr 2013; 56:401-7. [PMID: 23164759 DOI: 10.1097/mpg.0b013e31827daf72] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Patients with inflammatory bowel disease (IBD) have a higher risk for venous thromboembolism compared with non-IBD subjects. The pathogenic mechanisms of the thrombotic events are not fully understood. We investigated levels of circulating microparticles and their influence on thrombin generation in pediatric patients with IBD during active and quiescent disease compared with healthy controls. METHODS Plasma samples were collected from 33 pediatric patients with Crohn disease (CD), 20 pediatric patients with ulcerative colitis (UC), and 60 healthy controls. Microparticles' procoagulant activity was measured by enzyme-linked immunosorbent assay, and the dependency of thrombin generation on microparticles-derived tissue factor was determined by means of calibrated automated thrombography. RESULTS The procoagulant function of microparticles was significantly increased in patients with active and inactive CD, and active UC compared with controls. Endogenous thrombin potential was significantly higher in patients with CD and UC compared with controls. A minor influence of microparticles on thrombin generation was only observed for patients with active UC. CONCLUSIONS Our study shows increased procoagulant function of microparticles in pediatric patients with active and quiescent CD and active UC compared with controls, but demonstrates that they are not a major cause for the higher thrombin generation in pediatric patients with IBD.
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Kim W, Kang B, Kim BW, Kim JS, Lee HM, Lim EJ, Kim JI, Kang BK, Ji JS, Lee BI, Choi H. Crohn's Disease Initially Accompanied by Deep Vein Thrombosis and Ulnar Neuropathy without Metronidazole Exposure. Gut Liver 2013; 7:252-254. [PMID: 23560164 PMCID: PMC3607782 DOI: 10.5009/gnl.2013.7.2.252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Revised: 12/28/2011] [Accepted: 01/09/2012] [Indexed: 01/06/2023] Open
Abstract
Extraintestinal manifestations are not uncommon in Crohn's disease, and a thromboembolic event is a disastrous potential complication. Deep vein thrombosis is the most common manifestation of a thromboembolic event and typically occurs in association with active inflammatory disease. Peripheral neuropathy in Crohn's disease has rarely been reported and is considered an adverse effect of metronidazole therapy. Here, we describe a patient who was initially diagnosed with Crohn's disease complicated with deep vein thrombosis and ulnar neuropathy without metronidazole exposure. The simultaneous occurrence of these complications in the early stage of Crohn's disease has never been reported in the English literature.
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Affiliation(s)
- Woohyeon Kim
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Borami Kang
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Byung-Wook Kim
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Joon Sung Kim
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Hae-Mi Lee
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Eun-Joo Lim
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Jong In Kim
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Bong-Koo Kang
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Jeong-Seon Ji
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Bo-In Lee
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Hwang Choi
- Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
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Chande N, MacDonald JK, Wang JJ, McDonald JWD. Unfractionated or low molecular weight heparin for induction of remission in ulcerative colitis: a Cochrane inflammatory bowel disease and functional bowel disorders systematic review of randomized trials. Inflamm Bowel Dis 2011; 17:1979-86. [PMID: 21618363 DOI: 10.1002/ibd.21776] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2011] [Accepted: 04/19/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND We aimed to systematically review the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis (UC). METHODS A literature search to April 2011 was performed to identify all randomized trials studying UFH or LMWH use in patients with UC. The Cochrane Risk of Bias Tool was used to assess study quality. RESULTS LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission, and clinical, endoscopic, or histological improvement. High-dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (odds ratio [OR] 2.73; 95% confidence interval [CI] 1.32-5.67; P = 0.007), clinical improvement (OR 2.99; 95% CI 1.30-6.87; P = 0.01), and endoscopic improvement (OR 2.25; 95% CI 1.01-5.01; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission, or endoscopic improvement. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event. CONCLUSIONS LMWH administered by extended colon-release tablets may be effective for the treatment of active UC. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC.
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Affiliation(s)
- Nilesh Chande
- Gastroenterology, University of Western Ontario, London, Ontario, Canada.
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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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Gustavsson CG, Svensson PJ, Hertervig E, Sandhall L, Hårdhammar P, Malcevschi-Lind N, Olsson SE. Thrombotic occlusion of all left coronary branches in a young woman with severe ulcerative colitis. ISRN CARDIOLOGY 2011; 2011:134631. [PMID: 22347627 PMCID: PMC3279691 DOI: 10.5402/2011/134631] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Accepted: 04/07/2011] [Indexed: 11/23/2022]
Abstract
Background. The thrombosis risk is increased in active ulcerative colitis. The limited number of reported complications have predominantly been cerebrovascular but other vessel territories may also be affected. Patient. During a severe attack of ulcerative colitis a 37-year-old woman suffered occlusion of all left coronary artery branches. Serial angiographies showed progressive recanalisation of the coronary arteries during anticoagulation, but no atherosclerotic stenosis. The cause of infarction was thus considered to be an extensive coronary thrombosis. However, a large battery of blood tests failed to identify any procoagulant abnormality. Conclusion. Evidence is now accumulating that the increased thrombosis risk also may involve the coronary arteries, even in young patients. To the best of our knowledge this is the third reported case of myocardial infarction despite angiographically normal coronary arteries in a patient with active ulcerative colitis. The extent of affected myocardium was in this case exceptionally large.
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Alkim H, Ayaz S, Alkim C, Ulker A, Sahin B. Continuous active state of coagulation system in patients with nonthrombotic inflammatory bowel disease. Clin Appl Thromb Hemost 2011; 17:600-4. [PMID: 21593018 DOI: 10.1177/1076029611405034] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
This study was planned for searching possible changes of the total coagulation and fibrinolysis system in inflammatory bowel disease (IBD) in order to obtain some clues for explaining the relation between IBD and hypercoagulability. A total of 24 patients with ulcerative colitis, 12 patients with Crohn disease, and 20 healthy controls were studied. Platelets; prothrombin time (PT); partial thromboplastin time (PTT); fibrinogen; D-dimer; fibrinogen degradation products; protein C; protein S; antithrombin; thrombin time; von Willebrand factor; coagulation factors V, VII, VIII, IX, XI, and XIII; plasminogen; antiplasmin; tissue plasminogen activator; plasminogen activator inhibitor 1; and prothrombin fragments 1 + 2 were studied. Most of the procoagulants (platelets, fibrinogen, von Willebrand factor, coagulation factor IX, and plasminogen activator inhibitor 1) were found increased together with decreases in some anticoagulants (protein S and antithrombin) in IBD. Also the activation markers of coagulation (D-dimer, fibrinogen degradation products, and prothrombin fragments 1 + 2) were all increased. The parameters of the total coagulation-fibrinolysis system were increased in IBD, regardless of the form and the activity of the disease.
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Affiliation(s)
- Huseyin Alkim
- Bakırkoy Dr Sadi Konuk Training and Research Hospital, Istanbul, Turkey.
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Wu X, Zhang W, Li JY, Chai BX, Peng J, Wang H, Mulholland MW. Induction of apoptosis by thrombin in the cultured neurons of dorsal motor nucleus of the vagus. Neurogastroenterol Motil 2011; 23:279-85, e123-4. [PMID: 21143557 PMCID: PMC3079207 DOI: 10.1111/j.1365-2982.2010.01641.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND A previous study demonstrated the presence of protease-activated receptor (PAR) 1 and 2 in the dorsal motor nucleus of vagus (DMV). The aim of this study is to characterize the effect of thrombin on the apoptosis of DMV neurons. METHODS The dorsal motor nucleus of vagus neurons were isolated from neonatal rat brainstems using micro-dissection and enzymatic digestion and cultured. Apoptosis of DMV neurons were examined in cultured neurons. Apoptotic neuron was examined by TUNEL and ELISA. Data were analyzed using anova and Student's t-test. KEY RESULTS Exposure of cultured DMV neurons to thrombin (0.1 to 10 U mL(-1)) for 24 h significantly increased apoptosis. Pretreatment of DMV neurons with hirudin attenuated the apoptotic effect of thrombin. Similar induction of apoptosis was observed for the PAR1 receptor agonist SFLLR, but not for the PAR3 agonist TFRGAP, nor for the PAR4 agonist YAPGKF. Protease-activated receptors 1 receptor antagonist Mpr(Cha) abolished the apoptotic effect of thrombin, while YPGKF, a specific antagonist for PAR4, demonstrated no effect. After administration of thrombin, phosphorylation of JNK and P38 occurred as early as 15 min, and remained elevated for up to 45 min. Pretreatment of DMV neurons with SP600125, a specific inhibitor for JNK, or SB203580, a specific inhibitor for P38, significantly inhibited apoptosis induced by thrombin. CONCLUSIONS & INFERENCES Thrombin induces apoptosis in DMV neurons through a mechanism involving the JNK and P38 signaling pathways.
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Affiliation(s)
- Xiaobin Wu
- Department of Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Weizhen Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Ji-Yao Li
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Biao-Xin Chai
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Junsheng Peng
- Department of Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Wang
- Department of Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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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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Broide E, Schopan A, Zaretsky M, Kimchi NA, Shapiro M, Scapa E. Intima-media thickness of the common carotid artery is not significantly higher in Crohn's disease patients compared to healthy population. Dig Dis Sci 2011; 56:197-202. [PMID: 20431949 DOI: 10.1007/s10620-010-1235-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2009] [Accepted: 04/06/2010] [Indexed: 12/14/2022]
Abstract
BACKGROUND Patients with Crohn's disease might have accelerated atherosclerosis due to: chronic systemic inflammation, metabolic changes or prolonged steroid treatment. AIMS The aim of this study was to assess the risk of sub-clinical atherosclerosis in Crohn's disease, by measuring the intima-media thickness and peak systolic velocity of the common carotid artery. METHODS Fifty Crohn's disease patients aged between 20 and 45 years were compared to 25 controls. Patients with a family history of cardiovascular diseases or a known risk for atherosclerosis were excluded. All participants underwent nutritional assessment. Carotid artery ultrasonography was performed and intima-media thickness and peak systolic velocity were measured, proximal to the common carotid bifurcation. Clinical data and laboratory parameters (hemoglobin, highly sensitive C-reactive protein, and plasma homocysteine) were determined. RESULTS No significant differences between the groups were found for intima-media thickness or peak systolic velocity. Multiple regression analysis revealed a positive correlation of intima-media thickness with older age. Peak systolic velocity was negatively associated with age. CONCLUSIONS Crohn's disease patients do not have an increased risk for developing early atherosclerosis.
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Affiliation(s)
- Efrat Broide
- Institute of Gastroenterology, Liver Diseases and Nutrition, Assaf Harofeh Medical Center, 70300, Zerifin, Israel.
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Chande N, McDonald JW, Macdonald JK, Wang JJ. Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2010:CD006774. [PMID: 20927749 DOI: 10.1002/14651858.cd006774.pub3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND There are a limited number of treatment options for patients with ulcerative colitis (UC). An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC. OBJECTIVES To review randomized trials examining the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis. SEARCH STRATEGY The MEDLINE (PUBMED), and EMBASE databases, The Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD group specialized trials register, review papers on ulcerative colitis, and references from identified papers were searched up to June 2010 in an effort to identify all randomized trials studying UFH or LMWH use in patients with ulcerative colitis. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. SELECTION CRITERIA Each author independently reviewed potentially relevant trials to determine their eligibility for inclusion based on the criteria identified above. The Cochrane Risk of Bias tool was used to assess study quality. Studies published in abstract form only were included if the authors could be contacted for further information. DATA COLLECTION AND ANALYSIS A data extraction form was developed and used to extract data from included studies. At least 2 authors independently extracted data. Any disagreements were resolved by consensus. Data were analyzed on an intention-to-treat basis. The primary outcome was induction of remission, as defined by the studies. Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy). MAIN RESULTS LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission, and clinical, endoscopic, or histological improvement. High dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (OR 2.73; 95% CI 1.32 to 5.67; P = 0.007), clinical improvement (OR 2.99; 95% CI 1.30 to 6.87; P = 0.01), and endoscopic improvement (OR 2.25; 95%CI 1.01 to 5.01; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission or endoscopic improvement. LMWH was well-tolerated but provided no significant benefit for quality of life. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event. AUTHORS' CONCLUSIONS There is evidence to suggest that LMWH may be effective for the treatment of active UC. When administered by extended colon-release tablets, LMWH was more effective than placebo for treating outpatients with mild to moderate disease. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. A further trial of UFH in patients with mild disease may also be justified. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC.
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Affiliation(s)
- Nilesh Chande
- LHSC - South Street Hospital, Mailbox 55, 375 South Street, London, Ontario, Canada, N6A 4G5
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Andersohn F, Waring M, Garbe E. Risk of ischemic stroke in patients with Crohn's disease: a population-based nested case-control study. Inflamm Bowel Dis 2010; 16:1387-92. [PMID: 20014016 DOI: 10.1002/ibd.21187] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Observational studies have linked Crohn's disease (CD) to an increased risk of venous thromboembolic complications. Case reports of ischemic stroke in CD patients have raised the question of a similar association, but data from observational studies are lacking. METHODS Using data from the UK General Practice Research Database we conducted a nested case-control analysis within a population-based cohort of 8054 patients with and 161,078 patients without CD. A total of 1748 cases of ischemic stroke were identified to whom 17,348 controls were matched on age, sex, and year of cohort entry. Adjusted odds ratios (ORs) of ischemic stroke associated with CD were calculated by conditional logistic regression. Stratified analyses were performed for age and sex. RESULTS While CD was not associated with an overall increased risk of ischemic stroke (OR 1.10, 95% confidence interval [CI] 0.85-1.43), stratified analyses revealed an increase in risk in younger patients (<50 years: OR 2.93; 95% CI 1.44-5.98) but not in elderly patients (> or =50 years: OR 0.99; 95% CI 0.75-1.30; P for interaction <0.01). The interaction with age remained statistically significant even after changing the cutoff value for the younger and older age group to 45, 55, or 60 years in a sensitivity analysis. There was no interaction with sex (P = 0.79). CONCLUSIONS The study indicates that younger patients with CD may be under an increased risk of ischemic stroke.
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Affiliation(s)
- Frank Andersohn
- Institute for Social Medicine, Epidemiology, and Health Economics, Charité University Medical Center Berlin, Germany.
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Abstract
The Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction involving the hepatic veins, inferior vena cava, or both. BCS has occasionally been reported in the literature as a very rare complication of ulcerative colitis. However, association of Crohn's disease (CD) and BCS is extremely rare with only a single case reported in the world literature to date. We report a case of a young woman with chronically active, therapy-resistant CD who developed massive ascites, elevation of liver enzymes, and coagulopathy in the course of her disease. She was subsequently diagnosed with BCS for which a successful liver transplantation was performed. Chronically active therapy resistant CD and methylenetetrahydrofolate reductase gene mutation have been identified as possible risk factors for development of BCS in this patient.
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Akbulut S, Altiparmak E, Topal F, Ozaslan E, Kucukazman M, Yonem O. Increased levels of homocysteine in patients with ulcerative colitis. World J Gastroenterol 2010; 16:2411-6. [PMID: 20480528 PMCID: PMC2874147 DOI: 10.3748/wjg.v16.i19.2411] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [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
AIM: To investigate serum levels of homocysteine (Hcys) and the risk that altered levels carry for thrombosis development in ulcerative colitis (UC) patients.
METHODS: 55 UC patients and 45 healthy adults were included. Hcys, vitamin B12 and folic acid levels were measured in both groups. Clinical history and thromboembolic events were investigated.
RESULTS: The average Hcys level in the UC patients was 13.3 ± 1.93 μmmol/L (range 4.60-87) and was higher than the average Hcys level of the control group which was 11.2 ± 3.58 μmmol/L (range 4.00-20.8) (P < 0.001). Vitamin B12 and folic acid average values were also lower in the UC group (P < 0.001). When multivariate regression analysis was performed, it was seen that folic acid deficiency was the only risk factor for hyperhomocysteinemia. Frequencies of thromboembolic complications were not statistically significantly different in UC and control groups. When those with and without a thrombosis history in the UC group were compared according to Hcys levels, it was seen that there were no statistically significant differences. A negative linear relationship was found between folic acid levels and Hcys.
CONCLUSION: We could not find any correlations between Hcys levels and history of prior thromboembolic events.
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Erez O, Romero R, Vaisbuch E, Kusanovic JP, Mazaki-Tovi S, Chaiworapongsa T, Gotsch F, Fareed J, Hoppensteadt D, Than NG, Yoon BH, Edwin S, Dong Z, Espinoza J, Mazor M, Hassan SS. High tissue factor activity and low tissue factor pathway inhibitor concentrations in patients with preterm labor. J Matern Fetal Neonatal Med 2010; 23:23-33. [PMID: 19883261 PMCID: PMC3419585 DOI: 10.3109/14767050902994770] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE Preterm labor (PTL) has been associated with an increased thrombin generation in the maternal circulation and amniotic fluid. Tissue factor (TF) is a potent initiator of the coagulation cascade, which can trigger the hemostatic system to generate thrombin. The aims of this study were to determine whether spontaneous PTL with intact membranes is associated with changes in the maternal plasma concentrations and activity of TF as well as tissue factor pathway inhibitor (TFPI). METHODS This cross-sectional study included women in the following groups: (1) normal pregnancies (n = 86); (2) term pregnancies in spontaneous labor (TIL) (n = 67) and not in labor (TNL) (n = 88); and (3) patients with spontaneous PTL and intact membranes (n = 136) that were classified into three sub-groups: (a) PTL without intra-amniotic infection and/or inflammation (IAI) who delivered at term (n = 49); (b) PTL without IAI who delivered preterm (n = 54); and (c) PTL with IAI who delivered preterm (n = 33). Plasma concentrations of TF and TFPI were measured by ELISA, and their activity was measured by chromogenic assays. Non-parametric statistics were used for analysis. RESULTS (1) Among women at term, those with spontaneous labor had a higher median maternal plasma TF and a lower median TFPI concentration than those without labor. (2) Patients with PTL had a significantly lower median maternal plasma TFPI concentration than that of normal pregnant women, regardless of the presence of IAI. (3) There was no significant difference in the median maternal plasma TF concentration between patients with a normal pregnancy and those with PTL. (4) In contrast, the median maternal plasma TF activity was higher among patients with PTL than in women with normal pregnancies, regardless of the presence of IAI or preterm delivery. (5) However, maternal plasma TFPI activity did not differ among the study groups. CONCLUSION Women with preterm parturition, in contrast to those in labor at term, have a higher TF activity and a lower TFPI concentration, without a significant change in the median maternal plasma TF concentration. These observations suggest that the increased thrombin generation reported in patients with PTL may be the result of activation of the extrinsic pathway of the coagulation cascade. In addition, the increased thrombin generation reported in patients with PTL could be due to insufficient anti-coagulation, as reflected by the low maternal plasma TFPI concentration.
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Affiliation(s)
- Offer Erez
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
| | - Roberto Romero
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States
| | - Edi Vaisbuch
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
| | - Juan Pedro Kusanovic
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
| | - Shali Mazaki-Tovi
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
| | - Tinnakorn Chaiworapongsa
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
| | - Francesca Gotsch
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
| | - Jawed Fareed
- Department of Pathology, Loyola University Medical Center, Maywood, IL, United States
| | - Debra Hoppensteadt
- Department of Pathology, Loyola University Medical Center, Maywood, IL, United States
| | - Nandor Gabor Than
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
| | - Bo Hyun Yoon
- Department of Obstetrics and Gynecology, Seoul National University, Seoul, Korea
| | - Sam Edwin
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
| | - Zhong Dong
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
| | - Jimmy Espinoza
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
| | - Moshe Mazor
- Department of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Sonia S. Hassan
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, Detroit, MI, United States
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States
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Miele LF, Turhan A, Lee GS, Lin M, Ravnic D, Tsuda A, Konerding MA, Mentzer SJ. Blood flow patterns spatially associated with platelet aggregates in murine colitis. Anat Rec (Hoboken) 2009; 292:1143-53. [PMID: 19645018 DOI: 10.1002/ar.20954] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
In the normal murine mucosal plexus, blood flow is generally smooth and continuous. In inflammatory conditions, such as chemically-induced murine colitis, the mucosal plexus demonstrates markedly abnormal flow patterns. The inflamed mucosal plexus is associated with widely variable blood flow velocity as well as discontinuous and even bidirectional flow. To investigate the mechanisms responsible for these blood flow patterns, we used intravital microscopic examination of blood flow within the murine mucosal plexus during dextran sodium sulphate-and trinitrobenzenesulfonic acid-induced colitis. The blood flow patterns within the mucosal plexus demonstrated flow exclusion in 18% of the vessel segments (P < 0.01). Associated with these segmental exclusions was significant variation in neighboring flow velocities. Intravascular injection of fluorescent platelets demonstrated platelet incorporation into both fixed and rolling platelet aggregates. Rolling platelet aggregates (mean velocity 113 microm/sec; range, 14-186 microm/sec) were associated with reversible occlusions and flow variations within the mucosal plexus. Gene expression profiles of microdissected mucosal plexus demonstrated enhanced expression of genes for CCL3, CXCL1, CCL2, CXCL5, CCL7, CCL8, and Il-1b (P < 0.01), and decreased expression of CCL6 (P < 0.01). These results suggest that platelet aggregation, activated by the inflammatory mileau, contributes to the complex flow dynamics observed in acute murine colitis.
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Affiliation(s)
- Lino F Miele
- Laboratory of Adaptive and Regenerative Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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Tissue factor pathway inhibitor relates to fibrin degradation in patients with acute deep venous thrombosis. Blood Coagul Fibrinolysis 2009; 19:405-9. [PMID: 18600090 DOI: 10.1097/mbc.0b013e3283049639] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Reduced concentration of tissue factor pathway inhibitor is a risk factor for development of deep venous thrombosis, whereas elevated concentrations of tissue factor pathway inhibitor are observed in patients with acute myocardial infarction and disseminated intravascular coagulation. Presently, we studied the association between inflammation, endothelial cell perturbation, fibrin degradation and the concentration of tissue factor pathway inhibitor in patients suspected for acute deep venous thrombosis. We determined the tissue factor pathway inhibitor -33T/C polymorphism, free and total tissue factor pathway inhibitor, C-reactive protein, von Willebrand factor and D-Dimer in 160 consecutive patients admitted to hospital with a tentative diagnosis of acute deep venous thrombosis. Deep venous thrombosis was identified in 57 patients (18 distal and 39 proximal). The distribution of the tissue factor pathway inhibitor genotypes between patients with and without deep venous thrombosis showed a trend toward significant deviation (P = 0.08). The concentrations of free and total tissue factor pathway inhibitor, C-reactive protein, von Willebrand factor and D-Dimer were significantly higher in patients with deep venous thrombosis than in patients without deep venous thrombosis (P < 0.001 for all quantities). The significant relationship between free and total tissue factor pathway inhibitor and deep venous thrombosis persisted when adjusted for the tissue factor pathway inhibitor -33T/C polymorphism, C-reactive protein, von Willebrand Factor and potentially confounding clinical conditions (P < or = 0.004), but disappeared when adjusted for D-Dimer (P > or = 0.10). We conclude that patients suffering from acute deep venous thrombosis express significantly higher concentrations of tissue factor pathway inhibitor than patients without deep venous thrombosis. The significant relationship is not associated with the -33T/C polymorphism, inflammation or endothelial cell perturbation, but is most likely related to release of tissue factor pathway inhibitor from fibrin deposits.
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Sánchez-Fayos Calabuig P, Martín Relloso MJ, Porres Cubero JC. [Multifactorial etiology and pathogenic factors in inflammatory bowel disease]. GASTROENTEROLOGIA Y HEPATOLOGIA 2009; 32:633-52. [PMID: 19647892 DOI: 10.1016/j.gastrohep.2009.02.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2008] [Accepted: 02/13/2009] [Indexed: 01/06/2023]
Abstract
All the currently available evidence suggests that the two types of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), involve a conflict between the immune system of the intestinal mucosa and intraluminal antigens, mainly the intestinal microflora, which are normally tolerated by the immune system. This conflict is modulated by numerous environmental factors and a clear polygenetic predisposition. The present article reviews the behavior of all the etiologic circumstances (microbial, genetic and environmental) and subsequently analyzes the possible pathogenic factors in which the etiologies can be found, namely: dysfunction of the intestinal epithelium, innate immune system alterations, and distortion of the cellular and humoral arms of the acquired immune system. The role of tissue ischemia in CD and expression of "extraintestinal inflammatory metastases", both in CD and UC, are briefly discussed. Finally, the view that IBD may be a spectrum of pathological processes provoked by distinct etiopathogenic factors and the possible biological significance of the growing incidence of this disease in the western world, coinciding with the decline in infectious diseases in this geographical area, are discussed.
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Shao YL, Zhao WF, Huang XP, Chen LY, Gan JH, Lin M. A case study of acute fulminant ulcerative colitis complicated with idiopathic thrombocytopenic purpura. Shijie Huaren Xiaohua Zazhi 2009; 17:340. [DOI: 10.11569/wcjd.v17.i3.340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Abstract
In both Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), an increased risk of thrombotic events has been demonstrated. Pathogenesis of thrombosis is multifactorial as various primary coagulation system abnormalities other than acquired factors have been reported. The fibrinolytic system has been widely investigated in IBD. Most of the available data report an imbalance in fibrinolytic capacity with a tendency toward a hypofibrinolytic state. Plasma thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 are fundamental inhibitors of the fibrinolytic process and are also considered to be acute-phase reactants. Recent studies have shown an imbalance of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor, suggesting that these molecules might contribute to thromboembolic events in both forms of IBD.
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Deban L, Correale C, Vetrano S, Malesci A, Danese S. Multiple pathogenic roles of microvasculature in inflammatory bowel disease: a Jack of all trades. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 172:1457-66. [PMID: 18458096 DOI: 10.2353/ajpath.2008.070593] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The etiology of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), is still largely unknown. However, it is now clear that the abnormalities underlying pathogenesis of intestinal inflammation are not restricted to those mediated by classic immune cells but also involve nonimmune cells. In particular, advances in vascular biology have outlined a central and multifaceted pathogenic role for the microcirculation in the initiation and perpetuation of IBD. The microcirculation and its endothelial lining play a crucial role in mucosal immune homeostasis through tight regulation of the nature and magnitude of leukocyte migration from the intravascular to the interstitial space. Chronically inflamed IBD microvessels display significant alterations in microvascular physiology and function compared with vessels from healthy and uninvolved IBD intestine. The investigation into human IBD has demonstrated how endothelial activation present in chronically inflamed IBD microvessels results in a functional phenotype that also includes leakiness, chemokine and cytokine expression, procoagulant activity, and angiogenesis. This review contemplates the newly uncovered contribution of intestinal microcirculation to pathogenesis and maintenance of chronic intestinal inflammation. In particular, we assess the multiple roles of the microvascular endothelium in innate immunity, leukocyte recruitment, coagulation and perfusion, and immune-driven angiogenesis in IBD.
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Affiliation(s)
- Livija Deban
- Division of Gastroenterology, Istituto Clinico Humanitas-IRCCS in Gastroenterology, Viale Manzoni, Rozzano, Milan, Italy
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Deban L, Correale C, Vetrano S, Malesci A, Danese S. Multiple pathogenic roles of microvasculature in inflammatory bowel disease: a Jack of all trades. THE AMERICAN JOURNAL OF PATHOLOGY 2008. [PMID: 18458096 DOI: 10.2353/ajpath.2008070593] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The etiology of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), is still largely unknown. However, it is now clear that the abnormalities underlying pathogenesis of intestinal inflammation are not restricted to those mediated by classic immune cells but also involve nonimmune cells. In particular, advances in vascular biology have outlined a central and multifaceted pathogenic role for the microcirculation in the initiation and perpetuation of IBD. The microcirculation and its endothelial lining play a crucial role in mucosal immune homeostasis through tight regulation of the nature and magnitude of leukocyte migration from the intravascular to the interstitial space. Chronically inflamed IBD microvessels display significant alterations in microvascular physiology and function compared with vessels from healthy and uninvolved IBD intestine. The investigation into human IBD has demonstrated how endothelial activation present in chronically inflamed IBD microvessels results in a functional phenotype that also includes leakiness, chemokine and cytokine expression, procoagulant activity, and angiogenesis. This review contemplates the newly uncovered contribution of intestinal microcirculation to pathogenesis and maintenance of chronic intestinal inflammation. In particular, we assess the multiple roles of the microvascular endothelium in innate immunity, leukocyte recruitment, coagulation and perfusion, and immune-driven angiogenesis in IBD.
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Affiliation(s)
- Livija Deban
- Division of Gastroenterology, Istituto Clinico Humanitas-IRCCS in Gastroenterology, Viale Manzoni, Rozzano, Milan, Italy
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Hyperhomocysteinemia in inflammatory bowel disease patients without past intestinal resections: correlations with cobalamin, pyridoxine, folate concentrations, acute phase reactants, disease activity, and prior thromboembolic complications. J Clin Gastroenterol 2008; 42:481-6. [PMID: 18344891 DOI: 10.1097/mcg.0b013e318046eab0] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Homocysteine is a sulfur-containing amino acid formed during the demethylation of methionine and high levels of this amino acid is a known risk factor for both arterial and also venous thromboembolic complications. Deficiencies of cobalamin, folate, and pyridoxine may predispose subjects to hyperhomocysteinemia, a common phenomenon in inflammatory bowel disease (IBD) patients. The aim of this study was to identify the prevalence, risk factors of hyperhomocysteinemia and its correlation with prior thromboembolic events in an IBD cohort without past intestinal resections. METHODS In this prospective study, we studied the concentrations of homocysteine, cobalamin, folate, and pyridoxine in 105 consecutive patients with IBD, of whom 11 had a prior history of thromboembolic complications. Data regarding smoking habits, medication use, disease location, and severity were gathered and patients with past intestinal resections were excluded. Age-matched and sex-matched 85 healthy volunteers served as controls and multivariate regression analysis was performed to find out independent predictors of hyperhomocysteinemia. RESULTS The mean age (+/-SD) in the IBD cohort was 38.69+/-12.13 years, and 51% were male. The mean age in the control group was 37.61+/-10.05 years, and 52% were male. Homocysteine concentrations in patients were higher [16.35 micromol/L (range 6.82 to 48.15) vs. 9.60 micromol/L (range 4.97 to 17.39), P=0.000] and hyperhomocysteinemia had a higher prevalence in patients than in the controls (56.2% vs. 4.7%, chi2=56.179, P=0.000), thus IBD significantly increased the risk of hyperhomocysteinemia [odds ratio=25.973 (95% confidence interval: 8.861-76.128)]. Homocysteine concentrations in patients with a history of thrombosis were not higher than those without a history of thrombosis [16.29 micromol/L (range 8.45 to 34.75) vs. 16.36 micromol/L (range 6.82 to 48.15), not significant]. Hyperhomocysteinemia was found in 54.5% of patients with thrombosis and 56.4% of patients without thrombosis (not significant). On stepwise regression analysis, plasma cobalamin level, albumin concentration, erythrocyte sedimentation rate, and platelet count were found to be independent predictors of elevated homocysteine levels. CONCLUSIONS IBD patients have a higher prevalence of hyperhomocysteinemia than do healthy controls and elevated homocysteine levels are independently associated with lower serum cobalamin, albumin levels and elevated erythrocyte sedimentation rate, and platelet count. There is no correlation between hyperhomocysteinemia and a history of prior thromboembolic events.
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Chande N, McDonald JW, Macdonald JK. Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2008:CD006774. [PMID: 18425969 DOI: 10.1002/14651858.cd006774.pub2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND There are a limited number of treatment options for patients with ulcerative colitis (UC). An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC. OBJECTIVES To review randomized trials examining the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis. SEARCH STRATEGY The MEDLINE (PUBMED), and EMBASE databases, The Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD group specialized trials register, review papers on ulcerative colitis, and references from identified papers were searched in an effort to identify all randomized trials studying UFH or LMWH use in patients with ulcerative colitis. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. SELECTION CRITERIA Each author independently reviewed potentially relevant trials to determine their eligibility for inclusion based on the criteria identified above. The Jadad scale was used to assess study quality. Studies published in abstract form only were included if the authors could be contacted for further information. DATA COLLECTION AND ANALYSIS A data extraction form was developed and used to extract data from included studies. At least 2 authors independently extracted data. Any disagreements were resolved by consensus. Data were analyzed using Review Manager (RevMan 4.2.9). Data were analyzed on an intention-to-treat basis, and treated dichotomously. In cross-over studies, only data from the first arm were included. The primary endpoint was induction of remission, as defined by the studies. Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy). If a comparison was only assessed in a single trial, P-values were derived using the chi-square test. If the comparison was assessed in more than one trial, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals (95% CI). The presence of heterogeneity among studies was assessed using the chi-square test (a P value of 0.10 was regarded as statistically significant). If statistically significant heterogeneity was identified the odds ratio and 95% CI were calculated using a random effects model. MAIN RESULTS There were 2 randomized, double-blind studies assessing LMWH versus placebo for the treatment of mild-moderate active UC. Various outcomes were assessed in the 2 studies. LMWH showed no benefit over placebo in any outcome, including clinical remission (OR 1.09; 95% CI 0.26 to 4.63; P = 0.91), clinical improvement (OR 0.73; 95% CI 0.32 to 1.66; P = 0.45 and OR 1.09; 95% CI 0.18 to 6.58; P = 0.92 in the two studies, respectively), endoscopic improvement (OR 1.35; 95% CI 0.29 to 6.18; P = 0.70), or histological improvement (OR 2.00; 95% CI 0.45 to 8.96; P = 0.37). LMWH was also not beneficial when added to standard therapy in a randomized open-label trial in which the outcome measures included clinical remission (OR 0.71; 95% CI 0.17 to 2.95; P = 0.64), clinical improvement (OR 2.00; 95% CI 0.31 to 12.75; P = 0.46), endoscopic remission (OR 0.71; 95% CI 0.17 to 2.95; P = 0.64), or endoscopic improvement (OR 1.40; 95% CI 0.34 to 5.79; P = 0.64). LMWH was well-tolerated and provided no significant benefit for quality of life. One study examining UFH versus corticosteroids in the treatment of severe UC demonstrated inferiority of UFH in clinical improvement as an outcome measure (OR 0.02; 95% CI 0 to 0.40; P = 0.01). Patients assigned to UFH did not improve clinically. More patients assigned to UFH had rectal hemorrhage as an adverse event. AUTHORS' CONCLUSIONS There is no evidence to support the use of UFH or LMWH for the treatment of active UC. No further trials examining these drugs for patients with UC are warranted, except perhaps a trial of UFH in patients with mild disease. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC.
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Affiliation(s)
- N Chande
- LHSC - South Street Hospital, Mailbox 55, 375 South Street, London, Ontario, Canada, N6A 4G5.
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Abstract
Venous thrombosis and thromboembolism appear to be increased in patients with inflammatory bowel disease. Although several acquired and genetic risk factors are known, about half that develop a thromboembolic event have no identifiable risk factor. Control of the inflammatory process is thought to be the key factor in risk reduction for thrombotic events. Prophylactic use of anticoagulants is not universally recommended, but possible use should be reviewed in an individual patient after evaluation of the risks, such as hemorrhage, compared to potential benefits. Particular consideration should be given if there has been a prior thrombotic event, if hospitalization will require surgery, or if an underlying coagulation disorder is present.
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