Risk of thrombosis and mortality in inflammatory bowel disease.

OBJECTIVES: Patients with inflammatory bowel disease have a higher risk of thrombosis, which is associated with a higher morbidity and mortality. Most data about VTE are related to hospitalized patients with active disease, but several cases happen in the outpatient setting, and are not covered by current prophylaxis recommendation. As the knowledge of VTE in outpatients is still poor, the aim of this study is to evaluate the risk, clinical data and mortality of thrombosis in patients followed in our center, comparing our findings with the current prophylaxis recommendation. METHODS: The medical electronic chart of 1093 inflammatory bowel disease patients and their image exams were actively searched for words related to thrombosis, followed by charts reviewed to collect information about the event and data regarding clinical settings and thrombosis profile. RESULTS: Overall, 654 Crohn's and 439 Colitis patients were included. Thrombosis prevalence was 5.1%,and mortality rate was higher in patients who had suffered thrombosis (10.71% vs. 1.45%, OR 8.0). Half of them developed thrombosis in the outpatient setting, 52% of these had disease activity, 17% had recent hospitalization, and 10% had previous thrombosis. In 27% of cases, diagnosis was done by routine image exams, with no clinical symptoms or previous history of thrombosis. None of them had used thromboprophylaxis. However, a great majority of patients who had thrombosis during hospitalization used heparin prophylaxis. CONCLUSION: Inflammatory bowel disease patients who develop thrombosis have an increased mortality risk. A significant proportion of the events happened in patients without a clear thromboprophylaxis recommendation or in those receiving heparin prophylaxis.

Alterations of mesenchymal and endothelial cells in inflammatory bowel diseases.

The pathogenesis of complex chronic diseases like inflammatory bowel disease (IBD) can no longer be viewed as a one-way street in which classical immune cells have exclusive control over the initiation, duration and outcome of the disease. There is enough experimental evidence to demonstrate that nonimmune cells, among which are mucosal mesenchymal and endothelial cells, also play a decisive role by interacting with immune cells and establishing a two-way reciprocal exchange of signals and responses that dictate the ultimate outcome of inflammation. Smooth muscle cells and fibroblasts/myofibroblasts display a variety of immune functions and modulate the activity and survival of T-cells. Mucosal microvascular cells, through the expression of adhesion molecules and secretion of chemokines, regulate the quantity and quality of leukocytes transmigrating into the interstitial space. A number of receptor-ligand pairs are expressed by immune and nonimmune cells that control their functional interplay, but the CD40/CD40 ligand system may be the most effective because CD40 is expressed by activated muscle and endothelial cells, while the CD40 ligand is expressed by activated T-cells and platelets. The activation of this system in IBD can lead to the establishment of a continuous cycle of nonimmune cell-dependent, antigen-independent interactions that perpetuates gut inflammation.

A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B.

BACKGROUND & AIMS: To elucidate extracellular matrix (ECM) changes underlying intestinal fibrosis, a frequent complication of inflammatory bowel disease, we developed a murine model of chronic colitis associated with intestinal fibrosis. METHODS: Chronic inflammation was established by weekly intrarectal administration of trinitrobenzene sulfonic acid (TNBS). In 2 variations of the model an antisense oligonucleotide for nuclear factor kappa B (NF-kappa B) p65 was given prophylactically or therapeutically to block chronic inflammation-associated fibrosis. Colonic inflammation and fibrosis were determined by histology. Total collagen level was estimated by hydroxyproline quantification. Colonic expression of collagens (Col1a2, Col3a2), ECM remodeling genes (matrix metalloproteinase [MMP]-1, -3, and tissue inhibitor of matrix metalloproteinase [TIMP]-1), and inflammation-modulating cytokines (tumor necrosis factor alpha [TNF-alpha], interferon gamma [IFN-gamma], transforming growth factor beta 1 [TGF-beta 1], and insulin-like growth factor 1 [IGF-1]) were assessed by semiquantitative reverse-transcription polymerase chain reaction. Control and TNBS-treated colonic mesenchymal cells were characterized by morphology, phenotype, and functional response to TNF-alpha and IFN-gamma. RESULTS: Colons of TNBS-treated mice contained acute and chronic inflammatory infiltrates, increased collagen, fibrogenic tissue architecture, and increased expression of TNF-alpha, TGF-beta 1, IGF-1, Col1a2, MMP-1, and TIMP-1. Colonic mesenchymal cells from TNBS-treated mice were also morphologically distinct from those of the control mice, with increased TIMP-1 expression in response to IFN-gamma treatment. Fibrosis persisted for 2-4 weeks after cessation of the TNBS treatment. In mice given NF-kappa B antisense prophylactically, 67% were fibrosis-free, whereas of those treated after establishing chronic inflammation, 43% were free of fibrosis. CONCLUSIONS: Extended TNBS treatment of mice yielded chronic intestinal inflammation-associated fibrosis with extensive fibrogenic ECM changes that could be counteracted by specific blockade of NF-kappa B.