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Britzen-Laurent N, Weidinger C, Stürzl M. Contribution of Blood Vessel Activation, Remodeling and Barrier Function to Inflammatory Bowel Diseases. Int J Mol Sci 2023; 24:ijms24065517. [PMID: 36982601 PMCID: PMC10051397 DOI: 10.3390/ijms24065517] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) consist of a group of chronic inflammatory disorders with a complex etiology, which represent a clinical challenge due to their often therapy-refractory nature. In IBD, inflammation of the intestinal mucosa is characterized by strong and sustained leukocyte infiltration, resulting in the loss of epithelial barrier function and subsequent tissue destruction. This is accompanied by the activation and the massive remodeling of mucosal micro-vessels. The role of the gut vasculature in the induction and perpetuation of mucosal inflammation is receiving increasing recognition. While the vascular barrier is considered to offer protection against bacterial translocation and sepsis after the breakdown of the epithelial barrier, endothelium activation and angiogenesis are thought to promote inflammation. The present review examines the respective pathological contributions of the different phenotypical changes observed in the microvascular endothelium during IBD, and provides an overview of potential vessel-specific targeted therapy options for the treatment of IBD.
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Affiliation(s)
- Nathalie Britzen-Laurent
- Division of Surgical Research, Department of Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
- Correspondence:
| | - Carl Weidinger
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Michael Stürzl
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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Ashour RH, Hazem NM, AbdElfattah AA, El-Kady RA, Elmasry A. Pentosan Polysulfate Sodium augments the therapeutic effect of 5-Aminosalicylic Acid in DSS colitis model; the role of IL-35 expression. Int Immunopharmacol 2022; 106:108620. [PMID: 35247859 DOI: 10.1016/j.intimp.2022.108620] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 01/31/2022] [Accepted: 02/09/2022] [Indexed: 12/19/2022]
Abstract
Ulcerative colitis (UC) primarily affects the mucosa of the distal colon. Dysregulated immune response in genetically-prone persons is claimed to be responsible for chronic intestinal inflammation. This study aimed to explore the efficacy and the hematological effects of pentosan polysulfate sodium (PPS) in a dextran sulfate sodium (DSS)-induced colitis model. Forty C57BL/6 female mice were equally divided into five groups: control group, DSS-colitis group, DSS-colitis treated with 5-aminosalicylic acid, DSS-colitis treated with PPS, and DSS-colitis treated with both drugs. Disease activity index (DAI) and colon length were calculated. Colonic IL-6 and IL-35 levels were assayed by ELISA. IL-35 gene expression was evaluated by qRT-PCR. Colon tissue samples were examined by H&E stain and immunohistochemistry (IHC) of Ki67. The colitis group subjected to combined treatment showed the best outcome with significant improvement of DAI and increased colon length. Colonic IL-6 was significantly lower in both PPS- and combination-treated groups accompanied by a significantly higher IL-35 level and its EBI3 subunit mRNA expression. However, the PPS-treated colitis group showed higher gene expression of IL-35 EBI3 subunit by 1.5-fold compared with the combined group. The colon mucosa and crypts were significantly preserved in mice treated with both drugs with the best Ki67 positive cell density. PPS is a safe and promising drug in the treatment of UC as it exerted the best positive effect on the anti-inflammatory IL-35 level and gene expression. However, superior improvement of DAI was seen when PPS was added to ASA with a greater mucosal proliferation and repair.
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Affiliation(s)
- Rehab H Ashour
- Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.; Pharmacology and Toxicology Department, Al-Qunfudah Medical College, Umm Al-Qura University, KSA
| | - Noha M Hazem
- Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.; Medical Experimental Research Centre, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Department of Pathological Sciences, Fakeeh College for Medical Sciences, Jeddah, KSA
| | - Amany A AbdElfattah
- Medical Histology and Cell Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.; Department of Basic Medical Sciences, Faculty of Medicine, King Salman International University, South Sinai, Egypt
| | - Rania A El-Kady
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.; Department of Pathological Sciences, Fakeeh College for Medical Sciences, Jeddah, KSA
| | - Ahlam Elmasry
- Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt..
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Zhang S, Cho WJ, Jin AT, Kok LY, Shi Y, Heller DE, Lee YAL, Zhou Y, Xie X, Korzenik JR, Lennerz JK, Traverso G. Heparin-Coated Albumin Nanoparticles for Drug Combination in Targeting Inflamed Intestine. Adv Healthc Mater 2020; 9:e2000536. [PMID: 32597571 PMCID: PMC7482138 DOI: 10.1002/adhm.202000536] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/12/2020] [Indexed: 12/18/2022]
Abstract
Targeting areas of inflammation offers potential therapeutic and diagnostic benefits by maximizing drug and imaging marker on-target effects while minimizing systemic exposure that can be associated with adverse side effects. This strategy is particularly beneficial in the management of inflammatory bowel disease (IBD). Here an inflammation-targeting (IT) approach based on heparin-coated human serum albumin nanoparticles (HEP-HSA NPs) that utilize the increased intestinal permeability and changes in electrostatic interaction at the site of intestinal inflammation is described. Using small-molecule and biologic drugs as a model for drug combination, the HEP-HSA NPs demonstrate the capacity to load both drugs simultaneously; the dual-drug loaded HEP-HSA NPs exhibit a higher anti-inflammatory effect than both of the single-drug loaded NPs in vitro and selectively bind to inflamed intestine after enema administration in vivo in a murine model of colitis. Importantly, analyses of the physicochemical characteristics and targeting capacities of these NPs indicate that HEP coating modulates NP binding to the inflamed intestine, providing a foundation for future IT-NP formulation development.
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Affiliation(s)
- Sufeng Zhang
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Won Joon Cho
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Amy T. Jin
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Lie Yun Kok
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Yunhua Shi
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - David E. Heller
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Young-Ah Lucy Lee
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Yixuan Zhou
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Xi Xie
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Joshua R. Korzenik
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Jochen K. Lennerz
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Giovanni Traverso
- Dr. S. Zhang, A. T. Jin, Prof. J. R. Korzenik, Prof. G. Traverso Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. Dr. S. Zhang, W. J. Woo, A. T. Jin, L. Y. Kok, Dr. Y. Shi, D. E. Heller, Y.-A. L. Lee, Y. Zhou, Dr. X. Xie Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Dr. S. Zhang, Prof. J. R. Korzenik, Prof. J. K. Lennerz, Prof. G. Traverso Harvard Medical School, Boston, MA 02115, USA. Prof. J. K. Lennerz Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Prof. G. Traverso Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Coeliac Disease and Mast Cells. Int J Mol Sci 2019; 20:ijms20143400. [PMID: 31373285 PMCID: PMC6678566 DOI: 10.3390/ijms20143400] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 07/05/2019] [Accepted: 07/08/2019] [Indexed: 01/01/2023] Open
Abstract
Over the last decades, there has been an impressive progress in our understanding of coeliac disease pathogenesis and it has become clear that the disorder is the final result of complex interactions of environmental, genetic, and immunological factors. Coeliac disease is now considered a prototype of T-cell-mediated disease characterized by loss of tolerance to dietary gluten and the targeted killing of enterocytes by T-cell receptor αβ intraepithelial lymphocytes. Accumulating evidence, however, indicates that the induction of a gluten-specific T helper-1 response must be preceded by the activation of the innate immune system. Mast cells are key players of the innate immune response and contribute to the pathogenesis of a multitude of diseases. Here, we review the results of studies aimed at investigating the role of mast cells in the pathogenesis of coeliac disease, showing that these cells increase in number during the progression of the disease and contribute to define a pro-inflammatory microenvironment.
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Kothari HG, Gupta SJ, Gaikwad NR. Utility of Carotid Intima-Media Thickness as an Auxiliary Vascular Parameter of Structural Alteration in Ulcerative Colitis. Inflamm Intest Dis 2019; 4:27-34. [PMID: 31172010 PMCID: PMC6537465 DOI: 10.1159/000499199] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 02/27/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is characterized by chronic relapsing-remitting inflammation of the gastrointestinal tract. The chronic inflammatory process may predispose to atherosclerosis. The aim of the study was to assess the carotid intima-media thickness (CIMT) and its relation to subclinical atherosclerosis and to follow up cardiovascular complications in patients with UC. METHODS 83 patients with proven UC in remission were enrolled in the study. 42 age- and sex-matched healthy controls were taken. Patients with known risk factors for atherosclerosis were excluded from the study. Baseline blood investigations along with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fasting lipid profile were done. CIMT was measured using B-mode Doppler imaging study. RESULTS The mean age of the UC patients was 37.06 ± 14.87 years. Left-sided colitis (45.8%) was the commonest type of presentation according to the extent of the disease. Mean CIMT (0.55 ± 0.17) was significantly higher in UC patients when compared to mean CIMT (0.46 ± 0.13) in the control group (p = 0.002). In Pearson correlation analysis, age, ESR, and CRP were positive and significantly correlated with CIMT. Multiple linear regression analysis (R2 = 0.18, p = 0.0026) revealed that age and CRP were significant independent predictors of mean CIMT. On following up for 6 months, 4 patients with UC had complications in the form of venous thrombosis. CONCLUSION CIMT is a simple, noninvasive, reliable and objective auxiliary vascular parameter of structural alteration in UC patients.
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Affiliation(s)
| | | | - Nitin Rangrao Gaikwad
- Department of Gastroenterology, Government Medical College and Superspeciality Hospital, Nagpur, India
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Zeeshan M, Ali H, Khan S, Khan SA, Weigmann B. Advances in orally-delivered pH-sensitive nanocarrier systems; an optimistic approach for the treatment of inflammatory bowel disease. Int J Pharm 2019; 558:201-214. [DOI: 10.1016/j.ijpharm.2018.12.074] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/24/2018] [Accepted: 12/27/2018] [Indexed: 02/07/2023]
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Alkim H, Koksal AR, Boga S, Sen I, Alkim C. Etiopathogenesis, Prevention, and Treatment of Thromboembolism in Inflammatory Bowel Disease. Clin Appl Thromb Hemost 2017; 23:501-510. [PMID: 26893444 DOI: 10.1177/1076029616632906] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2025] Open
Abstract
The close relationship between inflammation and thrombosis affects the progression and severity of inflammatory bowel disease (IBD). The prevalence of venous thromboembolism (VTE) varies between 1% and 7% among patients with IBD. The VTE risk in patients with IBD is at least 3 times higher than that in the normal general population. The absolute risk is very high during hospitalization, active disease, and surgery. The IBD-related VTE occurs at younger ages and recurs more frequently. The development of thrombosis in IBD is due to the interaction of many hereditary and acquired risk factors. Each patient diagnosed with IBD should be evaluated for a personal and family history of thrombosis and for prothrombotic drug use. Although procoagulant factors are increased during the natural course of inflammation, natural anticoagulants and fibrinolytic activity are decreased. Although IBD is accepted as a prothrombotic condition, there is no treatment that can remove this risk from daily practice. Patient training is required to control important factors, such as long-term immobilization and smoking. Oral contraceptives and hormone replacement therapy should be avoided. Inducing permanent disease remission must be the key approach for the prevention of thrombosis. Low-molecular-weight heparin (LMWH) is the basis of prophylactic treatment, which reduces the thrombosis risk by 50%. Prophylaxis with LMWH should be administered to all patients with IBD hospitalized due to disease attack or surgery. Long-term or even life-long anticoagulation therapy should be planned if there is insufficient disease control, recurrent VTE attacks, positive thrombophilia tests, or thrombosis in vital veins.
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Affiliation(s)
- Huseyin Alkim
- 1 Department of Gastroenterology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Ali Riza Koksal
- 1 Department of Gastroenterology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Salih Boga
- 1 Department of Gastroenterology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Ilker Sen
- 1 Department of Gastroenterology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Canan Alkim
- 1 Department of Gastroenterology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
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Nardelli S, Pisani LF, Tontini GE, Vecchi M, Pastorelli L. MMX ® technology and its applications in gastrointestinal diseases. Therap Adv Gastroenterol 2017; 10:545-552. [PMID: 28804515 PMCID: PMC5484438 DOI: 10.1177/1756283x17709974] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 04/18/2017] [Indexed: 02/04/2023] Open
Abstract
The Multimatrix® (MMX®) preparation MMX® is a recently obtained drug formulation developed to facilitate release of high concentrations of active drugs into the colon, with a homogeneous distribution along all colonic segments, particularly the most distal ones; the distal colonic tracts, indeed, are the most difficult to reach in significant amounts when a drug is given orally. The MMX® formulation is characterized by a lipophilic matrix dispersed in a hydrophilic structure. Indeed, in the last few years, MMX® technology has been widely used in the development of various drugs for the treatment of inflammatory and infectious gastrointestinal diseases localized in the colon. In particular, MMX® mesalamine, budesonide and parnaparin formulations have been investigated in patients with ulcerative colitis, and the first two have reached worldwide registration for the treatment of this disease. Moreover, MMX®-rifamycin is being positively tested in the treatment of colonic bacterial infections, including traveler's diarrhea. MMX® technology is, thus, proving to be a very effective formulation for the treatment of various colonic diseases. This effectiveness has been related not only to specific colonic delivery, but also to its ability to act in a once-daily dosage, thus favouring patients' adherence to prescribed schedules of treatment. The effective delivery of the active molecule to the site of need in the colon is also associated with very low systemic absorption and very low rates of adverse events (AEs). In this paper, we have reviewed all clinical trials performed with an MMX®-bound drug and all possible real-life reports, in order to give an overall evaluation of MMX®.
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Affiliation(s)
| | - Laura Francesca Pisani
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Gian Eugenio Tontini
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Maurizio Vecchi
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy Department of Biomedical Sciences for Health, Università di Milano, Milan, Italy
| | - Luca Pastorelli
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy Department of Biomedical Sciences for Health, Università di Milano, Milan, Italy
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Abstract
Heparin is one of the oldest drugs, which nevertheless remains in widespread clinical use as an inhibitor of blood coagulation. The history of its identification a century ago unfolded amid one of the most fascinating scientific controversies turning around the distribution of credit for its discovery. The composition, purification and structure-function relationship of this naturally occurring glycosaminoglycan regarding its classical role as anticoagulant will be dealt with before proceeding to discuss its therapeutic potential in, among other, inflammatory and infectious disease, cancer treatment, cystic fibrosis and Alzheimer's disease. The first bibliographic reference hit using the words 'nanomedicine' and 'heparin' is as recent as 2008. Since then, nanomedical applications of heparin have experienced an exponential growth that will be discussed in detail, with particular emphasis on its antimalarial activity. Some of the most intriguing potential applications of heparin nanomedicines will be exposed, such as those contemplating the delivery of drugs to the mosquito stages of malaria parasites.
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Affiliation(s)
| | - Elena Lantero
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, ES-08028 Barcelona, Spain.,Barcelona Institute for Global Health (ISGlobal), Barcelona Center for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain
| | - Xavier Fernàndez-Busquets
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, ES-08028 Barcelona, Spain.,Barcelona Institute for Global Health (ISGlobal), Barcelona Center for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain.,Nanoscience & Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain
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10
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Abstract
Venous thromboembolism (VTE) represents one of the most common and life-threatening extraintestinal complications of inflammatory bowel disease (IBD). Therefore, the prevention of VTE is essential and foremost involves the assessment of individual patient risk factors for VTE and, consequently, the correction of those risk factors that are modifiable. Mechanical and pharmacological prophylaxis are highly effective at preventing VTE in patients hospitalized for acute disease, and they are recommended by the leading guidelines for hospitalized patients with IBD. Unfortunately, several recent surveys reported that prophylaxis against VTE is still poorly implemented because of concerns about its safety and a lack of awareness of the magnitude of thrombotic risk in patients with IBD. Therefore, further efforts are required to increase the thromboprophylaxis rate in these patients to bridge the gap between the best care and standard care and, consequently, to avoid preventable VTE-associated morbidity and mortality. This review provides insight on the critical points that persist on the prevention and treatment of VTE in patients with IBD.
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Opposing effects of low molecular weight heparins on the release of inflammatory cytokines from peripheral blood mononuclear cells of asthmatics. PLoS One 2015; 10:e0118798. [PMID: 25738575 PMCID: PMC4349593 DOI: 10.1371/journal.pone.0118798] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 01/08/2015] [Indexed: 12/24/2022] Open
Abstract
Background T-cell-mediated inflammatory cytokines, such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF-α), play an important role in the initiation and progression of inflammatory airways diseases. Low-molecular-weight heparins (LMWHs), widely used anticoagulants, possess anti-inflammatory properties making them potential treatment options for inflammatory diseases, including asthma. In the current study, we investigated the modulating effects of two LMWHs (enoxaparin and dalteparin) on the release of cytokines from stimulated peripheral blood mononuclear cells (PBMCs) of asthmatic subjects to identify the specific components responsible for the effects. Methods PBMCs from asthmatic subjects (consist of ~75% of T-cells) were isolated from blood taken from ten asthmatic subjects. The PBMCs were pre-treated in the presence or absence of different concentrations of LMWHs, and were then stimulated by phytohaemagglutinin for the release of IL-4, IL-5, IL-13 and TNF-α. LMWHs were completely or selectively desulfated and their anticoagulant effect, as well as the ability to modulate cytokine release, was determined. LMWHs were chromatographically fractionated and each fraction was tested for molecular weight determination along with an assessment of anticoagulant potency and effect on cytokine release. Results Enoxaparin inhibited cytokine release by more than 48%, whereas dalteparin increased their release by more than 25%. The observed anti-inflammatory effects of enoxaparin were independent of their anticoagulant activities. Smaller fractions, in particular dp4 (four saccharide units), were responsible for the inhibitory effect of enoxaparin. Whereas, the larger fractions, in particular dp22 (twenty two saccharide units), were associated with the stimulatory effect of dalteparin. Conclusion Enoxaparin and dalteparin demonstrated opposing effects on inflammatory markers. These observed effects could be due to the presence of structurally different components in the two LMWHs arising from different methods of depolymerisation. This study provides a platform for further studies investigating the usefulness of enoxaparin in various inflammatory diseases.
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Alvarenga V, Pacheco RG, Esposito CC, Buongusto F, Castelo-Branco MTL, Madi K, Belmiro CR, Pavão MSG, de Souza HSP, Schanaider A. Ascidian (chordate-tunicate) and mammalian heparin enemas attenuate experimental diversion colitis. Surgery 2014; 155:217-227. [PMID: 24287143 DOI: 10.1016/j.surg.2013.06.057] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 06/28/2013] [Indexed: 01/19/2023]
Abstract
AIM We sought to investigate whether mammalian or ascidian Styela plicata heparin enemas could diminish inflammation in experimental diversion colitis. METHODS Wistar-specific pathogen-free rats were submitted to a Hartmann's end colostomy and treated with enemas containing mammalian or Styela plicata heparin, or saline. Enemas were administered 3 times a week in the excluded colon segment from 4 to 8 weeks after operation. The effect of treatment was evaluated using video-endoscopic and histologic scores, measuring the cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and transforming growth factor-β production in organ cultures by enzyme-linked immunosorbent assay, quantifying T cells and macrophages, and investigating nuclear factor-kappa B (NF-κB) and external mitogen-activated protein kinase (pERK) activation. RESULTS Treatment with either mammalian or Styela plicata heparins decreased colonoscopic and histologic scores (P < .02) and restored the densities of collagen fibers and the number of goblet cells (P < .03) in the diverted colon. Both heparin treatments decreased the accumulation of T cells and macrophages (P < .03), and the activation of NF-κB and pERK (P < .04) in the diverted colon. The high levels of cytokines IL-1β, TNF-α, and IL-6 from the diversion colitis explants decreased (P < .05) to near normal values with heparin treatments. CONCLUSION The improvement of experimental diversion colitis with heparin treatments indicates the anti-inflammatory effect of these compounds, even after topical administration. Further studies with the nonhemorrhagic heparin obtained from the invertebrate Styela plicata will be necessary to confirm its efficacy for the treatment of human diversion colitis and possibly other forms of colitis.
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Affiliation(s)
- Valter Alvarenga
- Centro de Cirurgia Experimental, Programa de Pós-Graduação em Ciências Cirúrgicas, Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rodrigo Goulart Pacheco
- Centro de Cirurgia Experimental, Programa de Pós-Graduação em Ciências Cirúrgicas, Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Christiano Costa Esposito
- Centro de Cirurgia Experimental, Programa de Pós-Graduação em Ciências Cirúrgicas, Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Buongusto
- Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Kalil Madi
- Departamento de Patologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Celso R Belmiro
- Instituto de Bioquímica Médica, Programa de Glicobiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Faculdade de Medicina Campus UFRJ-Macaé, da Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mauro Sergio Gonçalves Pavão
- Instituto de Bioquímica Médica, Programa de Glicobiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Heitor Siffert Pereira de Souza
- Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Alberto Schanaider
- Centro de Cirurgia Experimental, Programa de Pós-Graduação em Ciências Cirúrgicas, Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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13
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Abstract
Effects of nadroparin sodium, a low molecular weight heparin, in colitis was investigated by analyzing proteins implicated in nuclear factor E2-related factor-2/heme oxygenase-1 (Nrf2/HO-1) and nuclear factor kappa B (NF-κB) pathways. Twenty-eight rats were used. Colitis was induced by acetic acid (AA). Nadroparin sodium was given to prevention and treatment groups in addition to AA. Colitis was assessed histologically and levels of proteins were analyzed with Western blot. Nadroparin not only prevented and ameliorated the AA-induced colitis histopathologically but also decreased expression of colon NF-κB, activator protein-1, cyclooxygenase-2, tumor necrosis factor-alpha, and IL-6, which were significantly increased in group AA compared to control. The accumulation of Nrf2 in nuclear fraction and HO-1 found low in group AA was increased with nadroparin (p < 0.05). The mean malondialdehyde level increased with AA and was decreased significantly with nadroparin prevention and treatment (p < 0.001). Nadroparin sodium has both protective and therapeutic effects against colonic inflammation via exerting anti-oxidative and anti-inflammatory effects by modulating Nrf2/HO-1 and NF-κB pathways.
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14
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Tezel A, Demir M. Inflammatory bowel disease and thrombosis. Turk J Haematol 2012; 29:111-9. [PMID: 24744641 PMCID: PMC3986948 DOI: 10.5505/tjh.2012.04557] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 05/17/2011] [Indexed: 12/31/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a group of chronic and relapsing inflammatory disorders of the gastrointestinalsystem. In these cases, findings are detected in extraintestinal systems also. There is a tendency for thrombotic eventsin IBD, as in the other inflammatory processes. The pathogenesis of this thrombotic tendency is multidimensional,including lack of natural anticoagulants, prothrombotic media induced via the inflammatory process, long-termsedentary life style, steroid use, surgery, and catheter placement. The aim of this review was to highlight the positiverelationship between IBD and thrombotic events, and the proper treatment of at-risk patients.
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Affiliation(s)
- Ahmet Tezel
- Trakya University, School of Medicine, Department of Gastroenterology, Edirne, Turkey
| | - Muzaffer Demir
- Trakya University, School of Medicine, Department of Hematology, Edirne, Turkey
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15
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Li S, Chen X, Wu T, Zhang M, Zhang X, Ji Z. Role of heparin on serum VEGF levels and local VEGF contents in reducing the severity of experimental severe acute pancreatitis in rats. Scand J Gastroenterol 2012; 47:237-44. [PMID: 22214372 DOI: 10.3109/00365521.2011.647063] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The aims of this study were to examine the effects of prophylactic heparin treatment during taurocholate-induced pancreatitis in rats and its impact on serum VEGF levels and local VEGF contents within the pancreas. METHODS Severe acute pancreatitis (SAP) was induced by injecting 4% sodium taurocholate into the pancreatic duct. Heparin at a dose of 150 IU/kg s.c. was administered 30 min before the operation. The rats were sacrificed 1 h, 3 h, 6 h and 12 h (n = 5 per time point) after the onset of pancreatitis. The severity of pancreatitis, serum VEGF levels and local VEGF contents were evaluated with and without heparin pretreatment. RESULTS The serum VEGF levels increased at an early phase of pancreatitis, and the highest level was found at 12 h after inducing pancreatitis. The gray value of the local VEGF showed a remarkable increase from the onset of the pancreatitis. However, the gray value of VEGF did not show an increase over time but maintained a high level during the entire process. Prophylactic heparin treatment significantly improved the morphologic changes, myeloperoxidase (MPO), TNF-α and malondialdehyde (MDA) activities. Meanwhile, it decreased the serum VEGF levels and the contents of VEGF within the pancreatic tissue. CONCLUSIONS The present study suggests that prophylactic heparin ameliorates the severity of taurocholate-induced pancreatitis via its anti-inflammatory properties. These protective effects may be partly due to decreasing serum VEGF levels and VEGF contents within the pancreas.
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Affiliation(s)
- Shunle Li
- First Department of General Surgery, the 2nd Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, PR, China
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16
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Liang J, Wu S, Feng B, Lei S, Luo G, Wang J, Li K, Li X, Xie H, Zhang D, Wang X, Wu K, Miao D, Fan D. Factor V Leiden and inflammatory bowel disease: a systematic review and meta-analysis. J Gastroenterol 2011; 46:1158-66. [PMID: 21805067 DOI: 10.1007/s00535-011-0441-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Accepted: 06/05/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recent studies proved that inflammatory bowel disease (IBD) patients had a higher risk of thromboembolism and a Factor V Leiden mutation that prevents the efficient inactivation of factor V, which leads to thromboembolism and thus contributes to a high potential risk of IBD. However, the relationship between Factor V Leiden mutation and IBD remains controversial. METHODS We conducted a systematic review with meta-analysis of studies assessing the association of Factor V Leiden mutation with the risk of IBD in humans. We extracted the number of IBD and control subjects with or without Factor V Leiden mutation from each study and conducted this analysis using a fixed-effects model. RESULTS Nineteen studies met the inclusion criteria and were included in the meta-analysis. No significant heterogeneity was found in results across the 19 studies (I (2) = 18.8%, P = 0.23), which showed a slight but not significant increase in the risk of IBD with Factor V Leiden mutation in the general population (summary odds ratio [OR] 1.13, 95% confidence interval [CI] 0.87-1.46). Taking into account ethnic differences, further study exhibited a slight but not significant increase in risk of IBD with Factor V Leiden mutation in Europeans (summary OR 1.20, 95% CI 0.88-1.64). However, Factor V Leiden mutation was significantly associated with a higher risk of thromboembolism in IBD patients (summary OR 5.30, 95% CI 2.25-12.48). No publication bias was found in this study. CONCLUSIONS This meta-analysis indicated that although Factor V Leiden mutation was not significantly associated with the risk of IBD, it was significantly associated with a higher risk of thromboembolism in IBD patients.
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Affiliation(s)
- Jie Liang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shannxi, China
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17
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Houissa F, Salem M, Bouzaidi S, Rejeb MB, Mekki H, Debbeche R, Moussa A, Trabelsi S, Said Y, Najjar T. Cerebral thrombosis in inflammatory bowel disease: a report of four cases. J Crohns Colitis 2011; 5:249-52. [PMID: 21575890 DOI: 10.1016/j.crohns.2010.12.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Revised: 12/22/2010] [Accepted: 12/22/2010] [Indexed: 02/08/2023]
Abstract
The risk of thromboembolism is increased in inflammatory bowel disease and its symptoms may be overlooked. The commonest are deep vein thrombosis and pulmonary emboli. Cerebral thrombosis, in a particular stroke, is rare. Furthermore, its treatment can be complex. We present the cases of 4 patients with cerebral vascular involvement.
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Affiliation(s)
- Fatma Houissa
- Gastroenterology department - Charles Nicolle's Hospital, Tunisia.
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18
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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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19
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Scaldaferri F, Lancellotti S, Pizzoferrato M, Cristofaro RD. Haemostatic system in inflammatory bowel diseases: New players in gut inflammation. World J Gastroenterol 2011; 17:594-608. [PMID: 21350708 PMCID: PMC3040331 DOI: 10.3748/wjg.v17.i5.594] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Revised: 03/25/2010] [Accepted: 04/01/2010] [Indexed: 02/06/2023] Open
Abstract
Inflammation and coagulation constantly influence each other and are constantly in balance. Emerging evidence supports this statement in acute inflammatory diseases, such as sepsis, but it also seems to be very important in chronic inflammatory settings, such as inflammatory bowel disease (IBD). Patients with Crohn’s disease and ulcerative colitis have an increased risk of thromboembolic events, and several abnormalities concerning coagulation components occur in the endothelial cells of intestinal vessels, where most severe inflammatory abnormalities occur. The aims of this review are to update and classify the type of coagulation system abnormalities in IBD, and analyze the strict and delicate balance between coagulation and inflammation at the mucosal level. Recent studies on possible therapeutic applications arising from investigations on coagulation abnormalities associated with IBD pathogenesis will also be briefly presented and critically reviewed.
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20
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Simard JM, Schreibman D, Aldrich EF, Stallmeyer B, Le B, James RF, Beaty N. Unfractionated heparin: multitargeted therapy for delayed neurological deficits induced by subarachnoid hemorrhage. Neurocrit Care 2010; 13:439-49. [PMID: 20809188 PMCID: PMC3012204 DOI: 10.1007/s12028-010-9435-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) is associated with numerous "delayed neurological deficits" (DNDs) that have been attributed to multiple pathophysiological mechanisms, including ischemia, microthrombosis, free radical damage, inflammation, and vascular remodeling. To date, effective prophylactic therapy for SAH-induced DNDs has been elusive, due perhaps to the multiplicity of mechanisms involved that render typical, single-agent therapy seemingly futile. We hypothesized that heparin, which has multiple underappreciated salutary effects, might be useful as a multitargeted prophylactic agent against SAH-induced DNDs. We performed a comprehensive review of the literature to evaluate the potential utility of heparin in targeting the multiple pathophysiological mechanisms that have been identified as contributing to SAH-induced DNDs. Our literature review revealed that unfractionated heparin can potentially antagonize essentially all of the pathophysiological mechanisms known to be activated following SAH. Heparin binds >100 proteins, including plasma proteins, proteins released from platelets, cytokines, and chemokines. Also, heparin complexes with oxyhemoglobin, blocks the activity of free radicals including reactive oxygen species, antagonizes endothelin-mediated vasoconstriction, smooth muscle depolarization, and inflammatory, growth and fibrogenic responses. Our review suggests that the use of prophylactic heparin following SAH may warrant formal study.
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Affiliation(s)
- J Marc Simard
- Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD 21201-1595, USA.
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21
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A novel, biodegradable and reversible polyelectrolyte platform for topical-colonic delivery of pentosan polysulphate. Int J Pharm 2010; 404:124-32. [PMID: 21093555 DOI: 10.1016/j.ijpharm.2010.11.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2010] [Revised: 11/01/2010] [Accepted: 11/10/2010] [Indexed: 11/21/2022]
Abstract
The goal of the present work was to develop a swellable hydrogel colonic delivery system, which would maximise the availability of the therapeutic agent at a site of inflammation, especially where the water is scarce. A novel method was developed to manufacture a biodegradable and reversible polyelectrolyte complex (PEC) containing chitosan and poly acrylic-acid (PAA). The PEC was analysed using FTIR and DSC, which confirmed the formation of non-permanent swollen gel-network at an alkaline pH. Pentosan polysulphate (PPS) was incorporated in a PEC and an activated partial thromboplastin time assay was developed to measure the release of PPS from PEC. In vitro studies suggested that the release of PPS was dependent on the initial drug loading and the composition of the PEC. The gel strength of the swollen network, determined using a texture analyser, was dependent on polymer composition and the amount of PPS incorporated. Bacterial enzymes were collected from the rat caecum and colon for the digestion studies and characterised for glucosidase activity, glucuronidase activity and protein content. The digestion of the reversible polyelectrolyte complexes was measured using a dinitro salicylic acid assay and an increased release of drug was also confirmed in the presence of bacterial enzymes.
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22
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Assays and reference materials for current and future applications of heparins. Biologicals 2010; 38:459-66. [DOI: 10.1016/j.biologicals.2010.02.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2010] [Accepted: 02/09/2010] [Indexed: 01/24/2023] Open
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Celasco G, Papa A, Jones R, Moro L, Bozzella R, Surace MM, Naccari GC, Gasbarrini G. Clinical trial: oral colon-release parnaparin sodium tablets (CB-01-05 MMX) for active left-sided ulcerative colitis. Aliment Pharmacol Ther 2010; 31:375-86. [PMID: 19891665 DOI: 10.1111/j.1365-2036.2009.04194.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The administration of parnaparin sodium as oral colon-release tablets (CB-01-05 MMX) has been proposed as a novel approach for the treatment of ulcerative colitis (UC). AIM To assess the efficacy and the tolerability of 8 weeks' oral daily administration of 210 mg of parnaparin sodium compared with placebo in subjects treated with stable-doses of oral aminosalicylates. METHODS This multicenter, randomized, double-blind proof of concept trial compared the efficacy of CB-01-05 MMX 210 mg tablets to placebo in 141 subjects with mild to moderately active left-sided UC treated with stable-doses of aminosalicylates. The efficacy was assessed by clinical activity index (CAI), endoscopic index (EI) and histological score (HS). RESULTS A total of 121 subjects (61 in test group and 60 in control group) formed the per protocol (PP) population. After 8 weeks of treatment, clinical remission was achieved in 83.6% of the CB-01-05 MMX group, and in 63.3% in the comparator group (P = 0.011). This effect was also significantly evident in the test group at week 4 (P = 0.028). A significant difference was also detected in rectal bleeding, (disappeared respectively in 75.4% and 55.0%; P = 0.018), and in mucosal friability (recovered respectively in 80.3% and in 56.7%; P = 0.005). CONCLUSIONS CB-01-05 MMX was safe and significantly effective in treating subjects with mild-to-moderate left-sided UC treated with stable-doses of aminosalicylates.
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Affiliation(s)
- G Celasco
- Cosmo Research and Development Srl, 20020 Lainate, Italy
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24
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Abstract
Inflammatory bowel disease (IBD) is associated with the occurrence of thrombotic complications. They rarely involve cerebrovascular events, manifesting as arterial ischemic strokes or venous thrombosis, more often in patients with ulcerative colitis than Crohn's disease. Pathogenesis of hypercoagulability in IBD contributing to thromboembolic events is not well known. We present a 31-year old man with Crohn's disease complicated with the transverse and sigmoid sinus thrombosis and secondary intracerebral hemorrhage, confirmed in magnetic resonance imaging. Thrombotic complication occurred during the active phase of the disease and treatment with steroids.
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Abstract
Inflammatory bowel diseases (IBDs) are associated with platelet activation and an increased risk for thromboembolism. While the mechanisms that underlie the altered platelet function and hypercoagulable state in IBD remain poorly understood, emerging evidence indicates that inflammation and coagulation are interdependent processes that can initiate a vicious cycle wherein each process propagates and intensifies the other. This review addresses the mechanisms that may account for the mutual activation of coagulation and inflammation during inflammation and summarizes evidence that implicates a role for platelets and the coagulation system in the pathogenesis of human and experimental IBD. The proposed link between inflammation and coagulation raises the possibility of targeting the inflammation-coagulation interface to reduce the morbidity and mortality associated with IBD.
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Affiliation(s)
- Hideo Yoshida
- Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana 71130-3932
- Division of Gastroenterology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan 160-8582
| | - D. Neil Granger
- Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana 71130-3932
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Belmiro CLR, Castelo-Branco MTL, Melim LMC, Schanaider A, Elia C, Madi K, Pavão MSG, de Souza HSP. Unfractionated heparin and new heparin analogues from ascidians (chordate-tunicate) ameliorate colitis in rats. J Biol Chem 2009; 284:11267-11278. [PMID: 19258310 PMCID: PMC2670131 DOI: 10.1074/jbc.m807211200] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2008] [Revised: 02/20/2009] [Indexed: 12/19/2022] Open
Abstract
The anti-inflammatory effect of mammalian heparin analogues, named dermatan sulfate and heparin, isolated from the ascidian Styela plicata was accessed in a TNBS-induced colitis model in rats. Subcutaneous administration of the invertebrate compounds during a 7-day period drastically reduced inflammation as observed by the normalization of the macroscopic and histological characteristics of the colon. At the molecular level, a decrease in the production of TNF-alpha, TGF-beta, and VEGF was observed, as well as a reduction of NF-kappaB and MAPK kinase activation. At the cellular level, the heparin analogues attenuated lymphocyte and macrophage recruitment and epithelial cell apoptosis. A drastic reduction in collagen-mediated fibrosis was also observed. No hemorrhagic events were observed after glycan treatment. These results strongly indicate the potential therapeutic use of these compounds for the treatment of colonic inflammation with a lower risk of hemorrhage when compared with mammalian heparin.
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Affiliation(s)
- Celso L R Belmiro
- Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho (HUCFF) and Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-913, Brazil
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Peterson S, Frick A, Liu J. Design of biologically active heparan sulfate and heparin using an enzyme-based approach. Nat Prod Rep 2009; 26:610-27. [DOI: 10.1039/b803795g] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Celasco G, Moro L, Bozzella R, Mangano K, Quattrocchi C, Aiello C, Donia M, Fagone P, Di Marco R. Efficacy of intracolonic administration of low-molecular-weight heparin CB-01-05, compared to other low-molecular-weight heparins and unfractionated heparin, in experimentally induced colitis in rat. Dig Dis Sci 2008; 53:3170-5. [PMID: 18465235 DOI: 10.1007/s10620-008-0299-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2008] [Accepted: 04/10/2008] [Indexed: 01/19/2023]
Abstract
PURPOSE Parenteral administration of low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH) resulted effective in improving the symptoms of experimental colitis in rat. Today, there is little information about their activity by intracolonic instillation. The scope of this study was to evaluate the ability of CB-01-05 (a LMWH with a mean molecular weight of about 5,700), compared to a series of other LMWHs and to UFH, directly instilled into the distal colon of the rat, to ameliorate dinitrobenzene (DNB)-induced experimental colitis. METHOD Adult male Wistar rats underwent colitis induction by intracolonic instillation of DNB. Starting 24 h after colitis induction, CB-01-05 (0.005-0.9 mg), other LMWHs (0.3-0.6 mg), and UFH (0.6 mg) were instilled, by rectal route, into the distal colon once a day for three consecutive days. On the day following the last administration, the animals were sacrificed and the distal colon was isolated, weighed, macroscopically examined, and processed for histology. Additional experiments in rat splenocytes, performed in order to elucidate the anti-inflammatory mechanisms of CB-01-05, were performed. RESULTS Among the tested items, only CB-01-05 at doses ranging from 0.2 to 0.9 mg was significantly effective in reducing colon weight increase and in improving both the mucosal damaged area and the histological score. The other LMWHs resulted far less effective, showing decreasing activity closely related with the decrease of their molecular weight, thus demonstrating their biological nonequivalence. CB-01-05 resulted also more active than UFH. CB-01-05 was shown to interfere with cytokines production by rat splenocytes, mainly inhibiting interferon (IFN)-gamma expression. CONCLUSIONS CB-01-05 instilled into the colon is well tolerated, has strong anti-inflammatory effect on DNB-induced colitis in rat, and is the most effective agent among other LMWHs and UFH. These results suggest that the anti-inflammatory activity of CB-01-05, together with its topical administration, could represent a new approach in the management of ulcerative colitis.
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Affiliation(s)
- Giuseppe Celasco
- Cosmo Research and Development Srl, Via C. Colombo 1, 20020, Lainate, MI, Italy.
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Pastorelli L, Saibeni S, Spina L, Signorelli C, Celasco G, de Franchis R, Vecchi M. Oral, colonic-release low-molecular-weight heparin: an initial open study of Parnaparin-MMX for the treatment of mild-to-moderate left-sided ulcerative colitis. Aliment Pharmacol Ther 2008; 28:581-8. [PMID: 18700898 DOI: 10.1111/j.1365-2036.2008.03757.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Efficacy of heparin and low-molecular-weight heparins (LMWHs) in inflammatory bowel disease (IBD) treatment has been suggested. The multimatrix oral formulation MMX releases active drugs in the colon, avoiding systemic absorption. Parnaparin sodium is the LMWH chosen to be carried in the MMX formulation. AIM To assess the safety of three different oral dosages (70, 140 and 210 mg once daily) of Parnaparin-MMX (CB-01-05) in left-sided ulcerative colitis (UC). METHODS Left-sided UC patients, with a mild-to-moderate relapse were enrolled. All patients received Parnaparin-MMX for 8 weeks. Clinical Activity Index (CAI), Disease Activity Index (DAI), Endoscopic Activity Index and IBD-QoL were assessed throughout the study. A strict clinical and laboratory follow-up, including assessment of anti-factor Xa activity, was performed. Clinical remission was defined as CAI <4. RESULTS Ten UC patients were enrolled. One patient retired for clinical deterioration. No relevant side effects, including either interference with haemostasis parameters or increased bleeding, were observed. At the end of the treatment, seven patients (70%) were in clinical remission, only one achieving endoscopic healing. Mean final CAI, DAI and IBD-QoL scores were significantly improved from baseline. CONCLUSIONS Parnaparin-MMX appears to be a safe treatment option in mild-to-moderate UC. Controlled studies are warranted.
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Affiliation(s)
- L Pastorelli
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
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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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31
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He G, Ouyang Q, Chen D, Li F, Zhou J. The microvascular thrombi of colonic tissue in ulcerative colitis. Dig Dis Sci 2007; 52:2236-40. [PMID: 17429731 DOI: 10.1007/s10620-006-9158-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2005] [Accepted: 11/15/2005] [Indexed: 01/06/2023]
Abstract
Mucosal microvascular thrombi in rectal biopsies were observed in some ulcerative colitis (UC). Heparin may be effective in steroid resistant UC in some studies, however, the new results of meta-analysis demonstrated a non-significant effect of heparin in controlled clinical trials, differing markedly from observational studies. The objective of this study was to identify colonic microvascular thrombi in larger cases with UC, and analyse its possible risk factors: age, gender, histologic score, extent of lesions and operation or biopsy specimens, and assess the significance of microvascular thrombosis in patients with UC. The microvascular thrombi were identified by immunohistochemical staining with anti-CD61 monoclonal antibody and Martius scarlet blue (MSB) staining in 40 colonic tissue samples of UC (31 biopsy specimens and nine operated cases) and 12 cases of normal colon tissue from operated colonic carcinoma. Logistic regression analysis was used to assess the relationship of age, gender, degree of histology, origin of the specimens, extent of lesions and microvascular thrombi examined. Microvascular thrombi were positive in 14 of 40 UC cases, and none in the controls. The presence of microvascular thrombi was related to operation specimens with odds ratio 11.667, P=0.0179, it might be also related to histologic score (OR=1.350) and extent of lesions (OR=1.619). These results suggest that microvascular thrombosis may be one of the important pathogenesis in some UC, and that the effect of anticoagulant treatment still needs to be assessed.
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Affiliation(s)
- Guobin He
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China.
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Pellequer Y, Meissner Y, Ubrich N, Lamprecht A. Epithelial heparin delivery via microspheres mitigates experimental colitis in mice. J Pharmacol Exp Ther 2007; 321:726-33. [PMID: 17322027 DOI: 10.1124/jpet.106.117226] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Low-molecular-weight heparins (LMWH) have been shown to be efficient in the treatment of inflammatory bowel disease (IBD). Parenteral heparin therapy, however, may cause hemorrhagic adverse effects. To reduce this risk, epithelial LMWH delivery in combination with a system ensuring selective drug release to the inflamed tissue was tested here. Enoxaparin loaded microspheres (MS) were administered orally to male BALB mice suffering from a pre-existing experimental colitis, whereas control groups received subcutaneous or rectal LMWH solution. Colon weight/length index and alkaline phosphatase and myeloperoxidase activities were assessed to determine the inflammation. Tissue penetration experiments elucidated the processes involved in the proposed new therapeutic approach. Oral LMWH-MS proved to be equally efficient in mitigating experimental colitis as rectally administered LMWH solution when quantified by myeloperoxidase activity (MS, 10.2+/-1.5 U/mg tissue; rectal, 9.2+/-1.6 U/mg) and to be superior to subcutaneous LMWH (s.c., 21.6+/-5.6 U/mg; untreated colitis control, 30.0+/-3.8 U/mg). Pharmacokinetic studies found a notably low systemic availability of oral LMWH delivered from MS (<5%) indicating a low potential for adverse effects. The tissue permeability was selectively enhanced in the inflamed regions where a 9-fold higher LMWH penetration was found compared with healthy tissue. Epithelial LMWH delivery has been found a promising anti-inflammatory therapeutic approach. The use of LMWH-MS in this context offers a promising tool for IBD therapy by enhancing specifically drug availability at inflamed tissue sites while reducing the risk for systemic adverse effects to a negligibly low level.
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Affiliation(s)
- Yann Pellequer
- Laboratory of Pharmaceutical Engineering, Faculty of Medicine and Pharmacy, University of Franche-Comté, Place Saint Jacques, 25000 Besançon, France
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Danese S, Papa A, Saibeni S, Repici A, Malesci A, Vecchi M. Inflammation and coagulation in inflammatory bowel disease: The clot thickens. Am J Gastroenterol 2007; 102:174-86. [PMID: 17100967 DOI: 10.1111/j.1572-0241.2006.00943.x] [Citation(s) in RCA: 280] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inflammation and coagulation play crucial roles in the pathogenesis of multiple chronic inflammatory disorders. Growing evidence highlights a tight mutual network in which inflammation, coagulation, and fibrinolysis play closely related roles. Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), are chronic inflammatory conditions, characterized by a hypercoagulable state and prothrombotic conditions, and accompanied by abnormalities in coagulation. From a pathophysiological point of view, cells and molecules classically implicated in the physiological process of coagulation have now been shown to behave abnormally in IBD and possibly to also play an active role in disease pathogenesis and/or disease progression. This paper reviews studies performed on the coagulation profile and risk factors for thrombosis in IBD. In particular, an overview is provided of the epidemiology, clinical features, and etiology of thromboembolic complications in IBD. Furthermore, we review hemostatic abnormalities in IBD, as well as the cell types involved in such processes. Finally, we highlight the coagulation system as a dynamic participant in the multifaceted process of chronic intestinal inflammation. Overall, an overview is provided that the coagulation system represents an important, though previously underestimated, component of IBD pathogenesis, and may be a possible target for therapeutic intervention.
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Affiliation(s)
- Silvio Danese
- Division of Gastroenterology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
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Zezos P, Papaioannou G, Nikolaidis N, Patsiaoura K, Papageorgiou A, Vassiliadis T, Giouleme O, Evgenidis N. Low-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treatment of active ulcerative colitis: a randomized, controlled, comparative study. Aliment Pharmacol Ther 2006; 23:1443-53. [PMID: 16669959 DOI: 10.1111/j.1365-2036.2006.02870.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Heparin could be beneficial to the treatment of active ulcerative colitis because of its anticoagulant, anti-inflammatory and immunomodulatory properties. AIM To evaluate the tolerability, safety and efficacy of low-molecular-weight heparin as adjuvant therapy in patients with active ulcerative colitis. METHODS Thirty-four adult patients with active ulcerative colitis were consecutively included in a prospective, randomized, comparative study, and were treated for 12 weeks. Eighteen patients in the 'standard therapy' group were treated with aminosalicylates and weekly tapered corticosteroids. Sixteen patients in the 'heparin therapy' group were treated with standard therapy plus enoxaparin 100 Anti-Xa IU/kg/day subcutaneously. RESULTS Seventeen patients in the 'standard therapy' group and 15 patients in the 'heparin therapy' group completed the study. Tolerability and compliance to therapy were excellent and no withdrawals were noted because of complications. There was a significant improvement in the disease severity in both groups (P<0.001), without any difference between them (P=not significant). Both treatment groups showed similar proportions of disease improvement (65% and 73%, respectively; P=not significant). There were no significant differences in inflammation (fibrinogen, ESR, CRP) and coagulation (thrombin-antithrombin complex, F1+2, D-dimers) parameters during and at the end of the study between treatment groups. CONCLUSION Adjuvant administration of low-molecular heparin in patients with active ulcerative colitis is safe and well tolerated, but no additive benefit over standard therapy for ulcerative colitis was noted.
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Affiliation(s)
- P Zezos
- 2nd Propaedeutic Department of Internal Medicine, Division of Gastroenterology, 'Hippokration' General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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35
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Molina-Infante J, Sanz-García C, Catalina-Rodríguez MV, Nogales-Rincón O, Matilla-Peña A, Núñez-Martínez O, Clemente-Ricote G. Trombosis venosa masiva abdominal con insuficiencia hepática aguda y megacolon tóxico como presentación de colitis ulcerosa. GASTROENTEROLOGIA Y HEPATOLOGIA 2005; 28:551-4. [PMID: 16277962 DOI: 10.1157/13080608] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The prevalence of systemic thromboembolic complications is higher in patients with inflammatory bowel disease than in the general population. This hypercoagulable state is due to an increased production of procoagulant substances proportionally related to the inflammatory activity of the disease, although recent reports have focused on the presence of inherited thrombophilic disorders in this entity. We present the case of a 32-year-old woman with no relevant medical history who presented with massive abdominal vein thrombosis, including suprahepatic, portal, splenic and superior mesenteric veins, and secondary acute liver failure in her first ulcerative colitis flare and who later developed toxic megacolon requiring emergency total colectomy despite steroids and cyclosporine. Anticoagulant therapy achieved complete resolution of suprahepatic thrombosis and partial resolution in the splenic and superior mesenteric veins, with final cavernous transformation of the portal vein.
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Affiliation(s)
- J Molina-Infante
- Sección de Hepatología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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36
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Umit H, Asil T, Celik Y, Tezel A, Dokmeci G, Tuncbilek N, Utku U, Soylu AR. Cerebral sinus thrombosis in patients with inflammatory bowel disease: A case report. World J Gastroenterol 2005; 11:5404-7. [PMID: 16149158 PMCID: PMC4622821 DOI: 10.3748/wjg.v11.i34.5404] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease of the gastrointestinal tract. The pathophysiology of IBD is probably the result of the complex interaction of genetic susceptibility and environmental influences. There is a well-known risk of thrombosis in patients with IBD. We present the case of a 53-year-old man with ulcerative colitis, who spontaneously developed intracranial sinus thrombosis that was treated with low molecular weight heparin. Literature was searched to assess the frequency and characteristics of cerebral sinus thrombosis in IBD and the role of certain etiopathological factors in such thrombotic patients.
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Affiliation(s)
- Hasan Umit
- Trakya Universitesi Typ Fakültesi, Gastroenteroloji BD, Gullapoglu Yerleskesi, Edirne 22030, Turkey.
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37
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Abstract
Interaction between thrombosis and inflammation is increasingly recognized. With this, interest has arisen in the role of thrombosis in inflammatory conditions, including the inflammatory bowel diseases. Although the association between active inflammatory bowel disease and thromboembolic complications has long been known, there has been a resurgence in research into the role of thrombosis and the hemostatic system in the pathogenesis of both ulcerative colitis and Crohn's disease. Here we review the increased frequency of thromboembolic complications occurring in patients with inflammatory bowel disease; whether thrombosis might play a part in the initiation and maintenance of inflammation in inflammatory bowel disease; abnormalities of the coagulation system found in patients with inflammatory bowel disease; platelet dysfunction in inflammatory bowel disease; the mechanisms by which hemostatic processes might be proinflammatory in inflammatory bowel disease; and how these interactions might impact not only on the prevention of complications, but also on the treatment of the underlying inflammation in inflammatory bowel disease.
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Affiliation(s)
- Peter M Irving
- Centre for Gastroenterology, Institute of Cell and Molecular Science, Barts and The London NHS Trust, United Kingdom
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38
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Malhotra S, Bhasin D, Shafiq N, Pandhi P. Drug treatment of ulcerative colitis: unfractionated heparin, low molecular weight heparins and beyond. Expert Opin Pharmacother 2005; 5:329-34. [PMID: 14996629 DOI: 10.1517/14656566.5.2.329] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Ulcerative colitis (UC) is characterised by chronic inflammation of the colon of unknown aetiology. Medical treatment of UC is complex and sometimes unsatisfactory. A total of 75% of patients experience relapses during the course of their illness and 20 - 25% require a colostomy. Recent years have witnessed a paradigm shift in the way UC is medically treated. The focus has now shifted to newer forms of therapy along with the older established drugs such as sulfasalazine and corticosteroids. Unfractionated heparin and low molecular weight heparins have been tested for their efficacy in patients with UC with conflicting results in various studies. Immunosuppressive and immune-based therapies, drugs modifying biological responses, prebiotics, probiotics, symbiotics, melatonin and topical butyrate have all been tested with variable success. The current review delineates the recent therapeutic alternatives in UC with main emphasis on heparins.
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Affiliation(s)
- Samir Malhotra
- Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India.
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39
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40
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Seksik P, Contou JF, Ducrotté P, Faucheron JL, de Parades V. [The treatment of distal ulcerative colitis]. ACTA ACUST UNITED AC 2005; 28:964-73. [PMID: 15672568 DOI: 10.1016/s0399-8320(04)95174-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Philippe Seksik
- Service d'hépato-gastroentérologie, Hôpital Européen Georges Pompidou, 75015 Paris
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41
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Ji SL, Cui HF, Shi F, Chi YQ, Cao JC, Geng MY, Guan HS. Inhibitory effect of heparin-derived oligosaccharides on secretion of interleukin-4 and interleukin-5 from human peripheral blood T lymphocytes. World J Gastroenterol 2004; 10:3490-4. [PMID: 15526371 PMCID: PMC4576233 DOI: 10.3748/wjg.v10.i23.3490] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the inhibitory effect of heparin-derived oligosaccharides (Oligs) on secretion of interleukin-4 (IL-4) and interleukin-5 (IL-5) from human peripheral blood T lymphocytes (PBTLs).
METHODS: Oligs were prepared by three different heparin depolymerization methods and separated by gel filtration chromatography. PBTLs from ten adult patients with allergic eosinophilic gastroenteritis were treated with phytahematoagglutinin (PHA) and Oligs. The supernatants from the cell culture of PBTLs were harvested and subjected to the determination of IL-4 and IL-5 contents by ELISA method.
RESULTS: At the concentration of 5 μg/mL, Oligs with different Mr had different effects on the secretion of IL-4 and IL-5. The tetrasaccharide with Mr of 1142, produced by depolymerizing heparin with hydrogen peroxide, had the strongest inhibitory effect on the secretion of IL-4. It decreased the IL-4 content from 375.6 ± 39.2 ng/L (PHA group) to 12.5 ± 5.7 ng/L (P < 0.01). The hexasaccharide with Mr of 1806, produced by depolymerizing heparin with β -elimination method, had the strongest inhibitory effect on the secretion of IL-5. It decreased the IL-5 content from 289.2 ± 33.4 ng/L (PHA group) to 22.0 ± 5.2 ng/L (P < 0.01).
CONCLUSION: The inhibitory activity of Oligs on the secretion of IL-4 and IL-5 from human PBTLs closely depends on their molecular structure, and there may be an essential structure to act as an inhibitor. The most effective inhibitors of IL-4 and IL-5 secretion are tetrasaccharides and hexasaccharides, respectively.
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Affiliation(s)
- Sheng-Li Ji
- Key Laboratory of Marine Drugs, Marine Drug and Food Institute, Ocean University of China, Qingdao 266003, Shandong Province, China.
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Abstract
Thromboembolism is an extraintestinal manifestation and an important cause of mortality in inflammatory bowel disease (IBD). The risk of thromboembolism appears to be multifactorial and related to mucosal inflammatory activity in most patients. Various laboratory markers such as thrombin activatable fibrinolysis inhibitor (TAFI) levels have been linked with thrombophilia in IBD but no single laboratory marker has emerged with sufficient predictive value to identify patients at particular risk. Prospective multifactorial analyses will be required; in the interim, clinicians must be vigilant and address common risk factors for thromboembolism in all patients with IBD.
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43
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Danese S, Motte Cd CDL, Fiocchi C. Platelets in inflammatory bowel disease: clinical, pathogenic, and therapeutic implications. Am J Gastroenterol 2004; 99:938-45. [PMID: 15128364 DOI: 10.1111/j.1572-0241.2004.04129.x] [Citation(s) in RCA: 176] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Both Crohn's disease (CD) and ulcerative colitis (UC) are associated with abnormalities of platelet number and function. In the peripheral circulation the state of platelet activation is typically increased, and inflammatory bowel disease (IBD)-involved mucosa frequently contains platelet aggregates within mucosal microthrombi. The relevance of platelet dysfunction to IBD pathogenesis is still unclear, but there is solid evidence demonstrating that platelets, in addition to their traditional role in hemostasis, can also function as potent proinflammatory cells. Upon activation, platelets secrete a large number of biologically active molecules able to induce or amplify an inflammatory process through many of the same cellular and molecular pathways conventionally utilized by immune cells mediating IBD. The aim of this article is to review data on the existence of platelet dysfunction in IBD, substantiate platelets' inflammatory potential, discuss the implications of abnormal platelet activity for chronic intestinal inflammation, and consider the potential benefits of platelet modulation for treatment of IBD.
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Xia B, Han H, Zhang KJ, Li J, Guo GS, Gong LL, Zeng XC, Liu JY. Effects of low molecular weight heparin on platelet surface P-selectin expression and serum interleukin-8 production in rats with trinitrobenzene sulphonic acid-induced colitis. World J Gastroenterol 2004; 10:729-32. [PMID: 14991948 PMCID: PMC4716919 DOI: 10.3748/wjg.v10.i5.729] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To observe the effects of low molecular weight heparin (LMWH) on platelet surface P-selectin expression and serum interleukin-8 production in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis.
METHODS: Colitis was induced in female Sprauge-Dawley rats by colonic administration of 2, 4, 6-TNBS. LMWH, a dalteparin (150 U/kg, 300 U/kg) was subcutaneously administrated one hour before induction of colitis and went on once a day for 6 days. Then a half dose was given for the next 7 days. Control animals received the same volume of normal saline once a day for 14 days after treated by TNBS. Animals were sacrificed at 24 h, days 7 and 14 after induction of colitis. The colon was excised for the evaluation of macroscopic and histological findings and TNF-α immunohistochemical assay. Platelet surface P-selectin expression was determined by radioimmunoassay and serum IL-8 production was assayed by ELISA method.
RESULTS: LMWH treatment in a dose of 300 U/kg for 14 days significantly improved colonic inflammation by histological examination. Serum IL-8 production in the 300 U/kg treatment group was more significantly decreased at day 14 than that at 24 h (P < 0.05). However, platelet surface P-selectin expression and TNF-α staining in colonic tissue were not significantly different among the three groups.
CONCLUSION: LMWH has an anti-inflammatory effect on TNBS induced colitis in rats. The effect is possibly related to inhibition of proinflammatory cytokine IL-8, but not involved platelet surface P-selectin expression.
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Affiliation(s)
- Bing Xia
- Department of Internal Medicine, Zhongnan Hospital, Wuhan University, Wuhan 430071, Hubei Province, China.
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Abstract
Historically, mast cells were known as a key cell type involved in type I hypersensitivity. Until last two decades, this cell type was recognized to be widely involved in a number of non-allergic diseases including inflammatory bowel disease (IBD). Markedly increased numbers of mast cells were observed in the mucosa of the ileum and colon of patients with IBD, which was accompanied by great changes of the content in mast cells such as dramatically increased expression of TNF-α, IL-16 and substance P. The evidence of mast cell degranulation was found in the wall of intestine from patients with IBD with immunohistochemistry technique. The highly elevated histamine and tryptase levels were detected in mucosa of patients with IBD, strongly suggesting that mast cell degranulation is involved in the pathogenesis of IBD. However, little is known of the actions of histamine, tryptase, chymase and carboxypeptidase in IBD. Over the last decade, heparin has been used to treat IBD in clinical practice. The low molecular weight heparin (LMWH) was effective as adjuvant therapy, and the patients showed good clinical and laboratory response with no serious adverse effects. The roles of PGD2, LTC4, PAF and mast cell cytokines in IBD were also discussed. Recently, a series of experiments with dispersed colon mast cells suggested there should be at least two pathways in man for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner. The hypothesis is that mast cell secretogogues induce mast cell degranulation, release histamine, then stimulate the adjacent mast cells or positively feedback to further stimulate its host mast cells through H1 receptor. Whereas released tryptase acts similarly to histamine, but activates mast cells through its receptor PAR-2. The connections between current anti-IBD therapies or potential therapies for IBD with mast cells were discussed, implicating further that mast cell is a key cell type that is involved in the pathogenesis of IBD. In conclusion, while pathogenesis of IBD remains unclear, the key role of mast cells in this group of diseases demonstrated in the current review implicates strongly that IBD is a mast cell associated disease. Therefore, close attentions should be paid to the role of mast cells in IBD.
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Affiliation(s)
- Shao-Heng He
- Allergy and Inflammation Research Institute, Medical College, Shantou University, Shantou 515031, Guangdong Province, China.
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46
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Abstract
The pathophysiology of inflammatory bowel disease (IBD) is gradually being unravelled and new therapies are being developed to target the disturbed biological processes. This article outlines the clinical features of IBD, its current therapy and pathogenesis. The difficulties for clinical pharmacologists and gastroenterologists associated with designing, executing and interpreting clinical trials in IBD are then discussed. The final section reviews methods that can used to demonstrate the pharmacological actions of new treatments in patients with IBD. It is emphasized that proof of the therapeutic efficacy of a novel agent with a specific mechanism of action yields not only clinical benefit to patients with IBD, but also indicates the importance of the targeted biochemical pathway in the pathogenesis of the disease.
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Affiliation(s)
- E Carty
- Academic Department of Adult and Paediatric Gastroenterology, Barts and The London School of Medicine, Start 1 Building, 2, Newark Street, London E1 2AD, UK
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Papa A, Danese S, Grillo A, Gasbarrini G, Gasbarrini A. Review article: inherited thrombophilia in inflammatory bowel disease. Am J Gastroenterol 2003; 98:1247-51. [PMID: 12818264 DOI: 10.1111/j.1572-0241.2003.07491.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Individuals with inflammatory bowel disease frequently experience increased systemic thromboembolic complications, which represent an important cause of morbidity and mortality. Risk factors for thrombosis can be inherited or acquired. The most common inherited risk factors for thromboembolism are factor V Leiden mutation, G20210A mutation in the prothrombin gene, and homozygous C677T mutation in the methylenetetrahydrofolate reductase gene. In the last few years, a great amount of literature has focused on the prevalence of such genetic mutations and their role in determining thrombosis in IBD patients. In this review, we summarize the results of these studies.
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Affiliation(s)
- Alfredo Papa
- Department of Internal Medicine, Catholic University of Rome, Rome, Italy
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Lindmark E, Siegbahn A. Tissue factor regulation and cytokine expression in monocyte-endothelial cell co-cultures: effects of a statin, an ACE-inhibitor and a low-molecular-weight heparin. Thromb Res 2002; 108:77-84. [PMID: 12586136 DOI: 10.1016/s0049-3848(02)00401-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Mounting evidence implies beneficial properties of statins and angiotensin converting enzyme (ACE)-inhibitors beyond those of their original indications in the treatment of coronary artery disease (CAD). Less is known of the mechanisms by which low-molecular-weight (LMW) heparin, also used in unstable CAD, affects the cellular micro-environment. The effects of these drugs in monocyte-endothelial cell co-culture systems have so far been sparsely investigated. MATERIALS AND METHODS We studied the expression of tissue factor (TF) and the cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-10 in a co-culture model with monocytic, vitamin D(3)(vitD(3))-differentiated U-937 cells and human coronary artery endothelial cells (HCAEC), and the effects of the above-mentioned drugs in this system. Cells were co-cultured for 18 h, with or without pre-stimulation of the HCAEC with interferon (IFN)-gamma, and in the presence or absence of simvastatin, enalapril or dalteparin. Analyses of surface tissue factor and intracellular cytokines were done by flow cytometry. RESULTS Co-culture with activated HCAEC induced tissue factor expression in U-937 cells but not in the endothelial cells. All three drugs significantly reduced tissue factor up-regulation (p<0.001 for each). Co-culture also induced IL-6 expression in U-937 cells and an increase in IL-10 production by HCAEC, none of which was affected by drugs. When cultured separately, both cell types expressed TNF-alpha. This was attenuated in U-937 cells by all three drugs (p<0.001 for each), whereas only enalapril reduced the TNF-alpha content of activated HCAEC (p=0.02). Enalapril also down-regulated the basal expression of IL-6 (p=0.01) and IL-10 (p<0.01) in HCAEC, which simvastatin and dalteparin failed to do. CONCLUSIONS In this study, we demonstrated for the first time that a statin, an ACE-inhibitor and an LMW-heparin all suppress tissue factor up-regulation in monocyte-endothelial cell co-cultures, thus adding new information regarding the cellular effects of these drugs that may be of importance in the treatment of CAD.
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Affiliation(s)
- Eva Lindmark
- Laboratory for Coagulation Research, Department of Medical Sciences, Clinical Chemistry, Uppsala University Hospital, Uppsala S-751 85, Sweden
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van Bodegraven AA, Schoorl M, Linskens RK, Bartels PC, Tuynman HA. Persistent activation of coagulation and fibrinolysis after treatment of active ulcerative colitis. Eur J Gastroenterol Hepatol 2002; 14:413-8. [PMID: 11943956 DOI: 10.1097/00042737-200204000-00014] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Haemostatic changes may be involved in the pathogenesis and progression of ulcerative colitis. We studied longitudinally inflammatory and haemostatic parameters in patients treated for severe ulcerative colitis. DESIGN AND SETTING We carried out a descriptive study of longitudinal blood measurements in patients with severe ulcerative colitis from one large regional hospital. METHODS Nineteen patients with severe ulcerative colitis were assessed by an endoscopic score and a patient score at baseline. Patients were assessed by patient scores during treatment at scheduled intervals. At each visit, inflammatory and haemostatic parameters were determined. RESULTS At baseline, the erythrocyte sedimentation rate, C-reactive protein, leucocyte and granulocyte count, thrombin-antithrombin complexes, prothrombin fragment 1+2, fibrinogen and degradation products of fibrinogen and fibrin were increased in patients when compared with controls, whereas albumin concentration and factor XIII activity were significantly lower. Antithrombin activity was normal. During treatment, the median patient score diminished significantly from 12 to 4.5 points after 2 weeks, decreased further to 4 points after 4 weeks and remained below 4 points throughout the remaining study period. Inflammation parameters returned to within the reference range in two patients after 4 weeks, whereas the coagulation markers prothrombin fragment 1+2 and thrombin-antithrombin complexes returned to normal values after 8 weeks and 24 weeks, respectively. In contrast with markers of inflammation, slightly increased concentrations of the degradation products of both fibrinogen and fibrin were found for almost 1 year, which indicated low-grade activation of coagulation and fibrinolysis. CONCLUSIONS These results are compatible with a condition of persistent hypercoagulation in patients with ulcerative colitis who are in clinical remission. Persistent hypercoagulation may contribute to the clinical course of ulcerative colitis.
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Affiliation(s)
- Ad A van Bodegraven
- Department of Gastroenterology, Academic Hospital Free University, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
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Affiliation(s)
- Sandra Kim
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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