Simone Saibeni

Inflammation and Coagulation in Inflammatory Bowel Disease: The Clot Thickens

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. Crohns 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.

Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients

Background: The CD40/CD40L system, a key regulator and amplifier of immune reactivity, is activated in inflammatory bowel disease (IBD) mucosa. Aims: To determine whether plasma levels of sCD40L are elevated in Crohn’s disease (CD) and ulcerative colitis (UC) patients compared with normal controls, to investigate the cellular source of sCD40L, and to explore CD40L induction mechanisms. Patients: CD, UC, and normal control subjects were studied. Methods: The concentration of sCD40L in plasma and supernatants of freshly isolated platelets and autologous peripheral blood T cells (PBT) was measured by ELISA. Surface CD40L expression level was measured by flow cytometry in resting and thrombin activated platelets, and unstimulated and CD3/CD28 stimulated PBT before and after coculture with human intestinal microvascular endothelial cells (HIMEC). Results: Compared with normal controls, plasma sCD40L levels were significantly higher in both CD and UC patients and proportional to the extent of mucosal inflammation. Platelets from IBD patients displayed a significantly higher surface CD40L expression than those from control subjects, and released greater amounts of sCD40L than autologous PBT. Contact with IL-1β activated HIMEC induced significant upregulation of CD40L surface expression and release by platelets. Conclusions: Elevated levels of sCD40L in the circulation of IBD patients reflect enhanced surface expression and release of CD40L by platelets. This phenomenon translates to an increased platelet activation state apparently induced by passage through an inflamed mucosal microvascular bed, a conclusion supported by the positive correlation of plasma sCD40L levels with the extent of anatomical involvement by IBD. These results suggest that platelet-endothelial interactions critically contribute to activation of the CD40 pathway in IBD.

Low vitamin B6 plasma levels, a risk factor for thrombosis, in inflammatory bowel disease: Role of inflammation and correlation with acute phase reactants

OBJECTIVES:Individuals with inflammatory bowel disease (IBD) are at increased risk for thrombosis and vitamin deficiencies. Low plasma levels of vitamin B6 are an independent risk factor for thrombosis and may cause hyperhomocysteinemia, another recognized risk factor for thrombosis. The aim of this study was to evaluate vitamin B6 plasma levels in IBD patients.METHODS:We studied 61 IBD patients: 32 with Crohn’s disease and 29 with ulcerative colitis. For each patient, three sex- and age-matched healthy control subjects were studied.RESULTS:Median vitamin B6 levels were significantly lower in IBD patients (22.0 pmol/L, range 3.6–231.0) than in controls (31.1 pmol/L, 3.7–363.4; p < 0.01). In all, 13.1% IBD patients and 5.5% controls had plasma vitamin B6 levels lower than the 5th percentile of distribution in normal controls (p < 0.05). Low vitamin B6 levels were significantly more frequent in patients with active disease than in patients with quiescent disease (seven of 26, 26.9%, vs one of 35, 2.9%; p < 0.001). Moreover, patients with active disease had significantly lower median vitamin B6 levels (13.4 pmol/L, range 3.6–124.0) than patients in a quiescent phase (27.0 pmol/L, 7.8–231.0; p < 0.001). Low vitamin B6 levels were significantly correlated with serum concentrations of C-reactive protein (r = −0.36, 95% CI = −0.59 to −0.09, p < 0.01) and α1-acid-glycoprotein (r = −0.37, 95% CI = −0.59 to −0.10, p < 0.01). Hyperhomocysteinemia was more frequent in patients with low vitamin B6 levels (three of eight, 37.5%) than in patients with normal levels (nine of 53, 17.0%; p = 0.18). There was no statistically significant correlation between vitamin B6 and homocysteine plasma levels (r = −0.13, 95% CI = −0.37 to +0.14, p = 0.33).CONCLUSIONS:Low vitamin B6 plasma levels, an independent risk factor for thrombosis, are frequent in patients with IBD, especially those with active disease.

Prognostic Significance of Endoscopic Remission in Patients with Active Ulcerative Colitis Treated with Oral and Topical Mesalazine: A Prospective, Multicenter Study

Background: It has been recommended that the treatment of active ulcerative colitis (UC) should be continued until complete healing of endoscopic lesions. However, the evidence supporting this recommendation is scanty. Aims of the present study were to assess the rate of patients with active UC who achieve clinical but not endoscopic remission after treatment with oral plus topical mesalazine and to compare the rate of relapse in patients with clinical/endoscopic remission and those with only clinical remission. Methods: Patients with active mild or moderate UC were eligible. All patients received mesalazine, 4 g/day orally and 2 g/day per rectum for 6 weeks. Those achieving clinical remission underwent colonoscopy: afterwards, all received maintenance treatment with oral mesalazine, 2 g/day orally for 1 year. Clinical remission was defined as normal frequency of bowel movements with formed stools, no abdominal pain, and no blood in the stools. Endoscopic remission was defined as normal‐appearing mucosa or only mild redness and/or friability, without either ulcers or erosions. Results: In all, 81 patients were enrolled. Sixty‐one (75%) achieved clinical remission. Endoscopic activity was still present in five (8%). The cumulative rate of relapse at 1 year was 23% in patients with clinical and endoscopic remission and 80% in patients with only clinical remission (P < 0.0001). Conclusions: Persistence of endoscopic activity is quite infrequent in patients with active UC achieving clinical remission after a 6‐week treatment with oral plus topical mesalazine, but is a very strong predictor of early relapse. (Inflamm Bowel Dis 2012;)

Inflammatory bowel diseases are not associated with major hereditary conditions predisposing to thrombosis.

Patients with inflammatory bowel diseases (IBD) are at increased risk for thromboembolic complications. Our aim was to evaluate whether the increased risk for thrombosis in IBD could be due to a genetic association of IBD with hereditary prothrombotic conditions. In all, 102 IBD patients (51 with ulcerative colitis and 51 with Crohn’s disease) with no history of thrombosis and 204 matched normal subjects were enrolled. DNA specimens were evaluated by PCR and restriction fragment length polymorphism for factor V Leiden, methylene tetrahydrofolate reductase (MTHFR) and prothrombin gene mutations. In IBD patients and matched controls the observed allele frequencies were similar, being 1.5% and 1.2% for factor V Leiden gene mutation, 1.1% and 0.7% for prothrombin gene mutation, and 45.1% and 47.4% for MTHFR gene mutation, respectively. These rates also were not significantly different when patients were analyzed according to age and sex distribution, diagnosis, and extension and clinical type of disease. In conclusion, our study shows no association between IBD and the most frequent hereditary prothrombotic conditions. Other factors should be evaluated in order to understand the mechanisms underlying the thrombotic risk of IBD.

Thrombosis in inflammatory bowel diseases : Role of inherited thrombophilia

BACKGROUND:Inflammatory bowel diseases (IBD) are characterized by an increased risk for venous and arterial thrombosis. Although the pathogenetic mechanisms of this predisposition are unclear, a possible role of inherited risk factors for thrombosis in determining this predisposition has been suggested.AIM:To evaluate the role of factor V Leiden (G1691A) and G20210A prothrombin gene mutations in determining the occurrence of thrombosis in IBD patients.PATIENTS AND METHODS: Forty-seven IBD patients (30 ulcerative colitis and 17 Crohns disease) with a positive history for thrombosis (9 at arterial sites and 38 at venous sites) were enrolled in the study. For each patient, two non-IBD subjects matched for sex and age, type, and site of thrombosis were used as controls. Peripheral blood DNA specimens were amplified by PCR using appropriate primers and analyzed by restriction analysis on agarose gel electrophoresis. Statistical analysis was performed by means of Fishers exact test.RESULTS:The total number of subjects with one or both mutations was significantly lower in IBD patients with thrombosis than in control subjects (12.8%vs 29.8%, respectively; p= 0.035, OR = 0.34, 95% CI 0.13–0.90). The total frequency of the mutated alleles was also significantly lower in IBD than in controls (7.4%vs 16.5%, respectively; p= 0.041, OR = 0.40, 95% CI 0.17–0.96). Prothrombotic mutations were particularly unfrequent in IBD patients with active disease at the time of thrombosis compared with patients with quiescent disease (8.0%vs 36.4%, respectively; p= 0.057, OR = 0.15, 95% CI 0.02–1.01).CONCLUSIONS:The major inherited risk factors for thrombosis are significantly less frequent in thrombotic IBD patients than in thrombotic non-IBD subjects, suggesting that acquired risk factors play the most relevant role in determining thromboembolic events observed in IBD patients, particularly during active phases of the disease.

Segmental colitis associated with diverticula : A prospective study

OBJECTIVE: Little is known about the clinical features and natural history of segmental colitis associated with diverticula. Our aim was to evaluate the incidence of segmental colitis associated with diverticula in patients undergoing colonoscopy, its clinical picture, and its outcome. METHODS: This was a multicenter, prospective study. Patients with inflammatory bowel disease (IBD)-like lesions limited to colonic segments with diverticula were enrolled. Patients were treated with oral and topical 5-aminosalicylic (5-ASA) until remission was achieved; clinical and endoscopic follow-up was planned at 6 wk and 12 months. RESULTS: A total of 5457 consecutive colonoscopies were recorded at five participating institutions; 20 patients (0.36%) met the endoscopic criteria for segmental colitis associated with diverticula. All had lesions in the left colon, and one also had lesions in the right colon. In six cases, a specific diagnosis was made thereafter. The remaining 14 patients (0.25% of colonoscopies; eight men; age range, 49–80 yr) were in clinical and endoscopic remission at the first follow-up visit. At onset, 13/14 had hematochezia, seven had diarrhea, and five had abdominal pain; only one had weight loss. No subject had fever. In all but one case, blood chemistries were normal. Five patients had had similar symptoms previously. Thirteen of 14 patients were in clinical and endoscopic remission at 12 months. CONCLUSIONS: This endoscopic picture is not an exceptional finding. Hematochezia was the main clinical feature, and no relation with gender, age, or smoking habit was found. Blood chemistries were generally normal and the rectum was spared. The histological features were not diagnostic and most patients did not complain of any abdominal symptoms 12 months after enrolment.

Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: Role of B12, folate, and genetics

BACKGROUND & AIMS Hyperhomocysteinemia, a risk factor for thrombosis, recurrent miscarriages, and osteoporosis, might derive from acquired folate and vitamin B 12 deficiencies and from a C677T mutation in methylene-tetrahydrofolate reductase (MTHFR) gene. Undiagnosed gluten-sensitive enteropathy (GSE) is associated with vitamin deficiencies, osteoporosis, and recurrent miscarriages. We evaluated the prevalence and the risk factors for hyperhomocysteinemia in patients with newly diagnosed GSE. METHODS In this prospective study performed in a tertiary care setting, 40 consecutive subjects with newly diagnosed GSE were evaluated for homocysteine, folate, and vitamin B 12 levels and for C677T polymorphism. One hundred twenty sex- and age-matched healthy control subjects were studied. Nonparametric tests and multiple regression analysis were used to evaluate the risk factors in inducing hyperhomocysteinemia in the GSE population. RESULTS Hyperhomocysteinemia was more frequent in GSE patients than in control subjects (8/40, 20.0% vs 7/120, 5.8%) (relative risk, 3.4; 95% confidence interval, 1.3-8.9), as well as folate deficiency (17/40, 42.5% vs 10/120, 8.3%) (relative risk, 5.1; 95% confidence interval, 2.5-10.2). Multiple regression analysis showed that folate and B 12 levels were independently and inversely associated with homocysteine levels, whereas homozygosity for the MTHFR thermolabile variant was not. The prevalence of MTHFR variant in GSE population was not different from that reported in racially comparable control groups. Gluten-free diet was able to normalize folate, vitamin B 12 , and homocysteine levels. CONCLUSIONS Hyperhomocysteinemia is frequent in newly diagnosed GSE. Vitamin deficiencies caused by malabsorption are the most important determinants of this condition. Hyperhomocysteinemia might contribute to the occurrence of common complications of undiagnosed GSE.

Clinical and laboratory aspects of Ro/SSA-52 autoantibodies

Anti-Ro/SSA antibodies, which were described for the first time in systemic lupus erythematosus (SLE) and Sjögrens syndrome (SS), are the most prevalent extractable nuclear antigen (ENA) specificity identified in laboratories. Two types of anti-Ro/SSA antibodies have been described, anti-SSA-52 kDa (aSSA52) and anti-SSA-60 kDa (aSSA60), each specific to different antigens. Anti-Ro/SSA52 autoantibodies are more frequent than other autoantibodies possibly because of the antigens accessible and ubiquitous nature. The sites involved and the symptoms associated with these autoantibodies depend on the antigens structural variability. Isolated congenital complete atrioventricular block (CAVB) shows a close association with maternal anti-Ro/SSA and anti-La/SSB antibodies; the highest relative risks of CAVB are seen in offspring of mothers with antibodies against 52-kDa Ro and 48-kDa La proteins. Anti-Ro/SSA52 antibodies have little impact on adult rheumatic autoimmune diseases or adult cardiac arrhythmias, but the course of autoimmune liver diseases is greatly worsened by their presence, and solid tumours tend to relapse. Their diagnostic role in rheumatic diseases is controversial, although a significant association between isolated anti-Ro/SSA52-kDa positivity and myositis and to a lesser extent with systemic sclerosis (SSc) has been described. However, the majority of the specific diagnosis is mostly based on the simultaneous presence of other autoantibodies that seems diagnostically more relevant.

Pregnancy before and after the diagnosis of inflammatory bowel diseases: Retrospective case–control study

Background and Aim:  Inflammatory bowel diseases (IBD) commonly affect women during the reproductive years. The aim of the present study was to evaluate the reproductive histories of patients with ulcerative colitis (UC) and Crohns disease (CD) considering pregnancies occurring before and after the diagnosis.