Roberto de Franchis

An Imbalance of Pro- vs Anti-Coagulation Factors in Plasma From Patients With Cirrhosis

BACKGROUND & AIMSnPatients with cirrhosis have an increased tendency to develop thromboses despite the longer coagulation times of their plasma, compared with that of healthy individuals. We investigated whether plasma from cirrhotic patients has an imbalance of pro- vs anti-coagulation factors.nnnMETHODSnWe analyzed blood samples from 134 cirrhotic patients and 131 healthy subjects (controls) for levels of pro- and anti-coagulants and for thrombin generation in the presence or absence of thrombomodulin (the main physiologic activator of the protein C anticoagulant pathway).nnnRESULTSnThe median ratio of thrombin generation (with/without thrombomodulin) was higher in patients (0.80; range, 0.51-1.06) than controls (0.66; range, 0.17-0.95), indicating that cirrhotic patients are resistant to the action of thrombomodulin. This resistance resulted in greater hypercoagulability of plasma from patients of Child-Pugh class C than of class A or B. The hypercoagulability of plasma from patients of Child-Pugh class C (0.86; range, 0.70-1.06) was slightly greater than that observed under the same conditions in patients with congenital protein C deficiency (0.76; range, 0.60-0.93). Levels of factor VIII, a potent pro-coagulant involved in thrombin generation, increased progressively with Child-Pugh score (from Child-Pugh class A to C). Levels of protein C, one of the most potent naturally occurring anti-coagulants, showed the opposite trend.nnnCONCLUSIONSnThe hypercoagulability of plasma from patients with cirrhosis appears to result from increased levels of factor VIII and decreased levels of protein C-typical features of patients with cirrhosis. These findings might explain the risk for venous thromboembolism in patients with chronic liver disease.

Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: A randomized, controlled trial

A beneficial effect of recombinant activated factor VII (rFVIIa) in Child‐Pugh class B and C patients with cirrhosis who have variceal bleeding has been suggested. This randomized controlled trial assessed the efficacy and safety of rFVIIa in patients with advanced cirrhosis and active variceal bleeding. At 31 hospitals in an emergency setting, 256 patients (Child‐Pugh > 8; Child‐Pugh B = 26%, C = 74%) were randomized equally to: placebo; 600 μg/kg rFVIIa (200 + 4× 100 μg/kg); or 300 μg/kg rFVIIa (200 + 100 μg/kg). Dosing was intravenous at 0, 2, 8, 14, and 20 hours after endoscopy, in addition to standard vasoactive, prophylactic antibiotic, and endoscopic treatment. The primary composite endpoint consisted of failure to control 24‐hour bleeding, or failure to prevent rebleeding or death at day 5. Secondary endpoints included adverse events and 42‐day mortality. Baseline characteristics were comparable between groups. Administration of rFVIIa had no significant effect on the composite endpoint compared with placebo (P = 0.37). There was no significant difference in 5‐day mortality between groups; however, 42‐day mortality was significantly lower with 600 μg/kg rFVIIa compared with placebo (odds ratio 0.31, 95% confidence interval = 0.13–0.74), and bleeding‐related deaths were reduced from 12% (placebo) to 2% (600 μg/kg). A marked heterogeneity in the failure rate in all treatment groups was observed across participating centers. Adverse events, including overall thromboembolic events, were comparable between groups. Conclusion: Treatment with rFVIIa had no significant effect on the primary composite endpoint compared with placebo. Therefore, decision on the use of this hemostatic agent in acute variceal bleeding should be carefully considered, because results of this study do not support the routine use of rFVIIa in this setting. Adverse events were comparable across groups. (HEPATOLOGY 2008.)

Familial aggregation of inflammatory bowel disease in northern Italy: A multicenter study

To assess the familial aggregation of inflammatory bowel disease (IBD) in Italy, the family pedigrees of 411 patients with ulcerative colitis (UC) and 241 patients with Crohns disease (CD) seen at 14 participating hospitals were studied. Sufficient information was obtained on 97% of 3752 first-degree relatives, 80% of 8869 second-degree relatives, and 74% of 5791 cousins. Thirty-six propositi (5.52%) had a total of 44 affected relatives (16 CD, 28 UC). The prevalence of IBD was higher in first- than in second-degree relatives and cousins (791, 112, and 163 in 100,000, respectively). A strong intrafamilial disease concordance was observed, with 26 cases of UC and 6 of CD among relatives of UC patients and 10 cases of CD and 2 of UC among relatives of CD patients. The prevalence of UC among first-degree relatives of UC patients and that of CD among first-degree relatives of CD patients was 680 and 531 in 100,000, respectively. In conclusion, there is a high degree of familial aggregation for IBD in Italy, with a strong intrafamilial disease concordance.

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:u2003Forty-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.

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

Background and Aim:u2002 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.

Prophylactic sclerotherapy in high-risk cirrhotics selected by endoscopic criteria: A multicenter randomized controlled trial

Controlled trials of sclerotherapy for the prevention of the first variceal hemorrhage in cirrhotics have given conflicting results. In the present study, 106 cirrhotics were randomized to sclerotherapy (55 patients) or control group (51 patients). Admission criteria were no history of previous variceal bleeding and the presence of high-risk varices, i.e., a variceal score less than or equal to 0 according to Beppu et al. Sclerotherapy sessions were performed at time zero, 7 days, 30 days, and then monthly until eradication. Follow-up endoscopies were performed at 6-month intervals thereafter. Control patients underwent repeat endoscopy at 6-month intervals. Bleeding episodes were treated by sclerotherapy in both groups, whenever possible. Mean follow-up was 24 months. Analysis of the results was performed by the intention-to-treat method. Variceal bleeding occurred in 19 sclerotherapy patients (34.5%) and in 17 controls (35.4%, P = NS). Overall mortality was 34.5% in sclerotherapy patients and 50% in controls (P = NS). Seven of the 19 sclerotherapy patients (36.8%) and 11 of the 17 controls (64.7%) who bled died of hemorrhage (P less than 0.05, log-linear model). It is concluded that prophylactic sclerotherapy does not reduce the incidence of first variceal bleeding in cirrhotics. However, there seems to be a trend toward a lower bleeding-related mortality in sclerotherapy patients than in controls.

The American Society for Gastrointestinal Endoscopy (ASGE) diagnostic algorithm for obscure gastrointestinal bleeding: eight burning questions from everyday clinical practice.

The diagnosis and management of patients with obscure gastrointestinal bleeding are often long and challenging processes. Over the last 10 years the introduction in clinical practice of new diagnostic and therapeutic procedures (i.e. Capsule Endoscopy, Computed Tomographic Enterography, Magnetic Resonance Enterography, and Device Assisted Enteroscopy) has revolutionized the diagnostic/therapeutic work-up of these patients. Based on evidence published in the last 10 years, international scientific societies have proposed new practice guidelines for the management of obscure gastrointestinal bleeding, which include these techniques. However, although these algorithms (the most recent ones are endorsed by the American Society for Gastrointestinal Endoscopy - ASGE) allow the management of the large majority of patients, some issues still remain unsolved. The present paper reports the results of the discussion, based on the literature published up to September 2011, among a panel of experts and gastroenterologists, working with Capsule Endoscopy and with Device Assisted Enteroscopy, attending the 6th annual meeting of the Italian Club for Capsule Endoscopy and Enteroscopy. Eight unresolved issues were selected: each of them is presented as a Burning question and the Answer is the strategy proposed to manage it, according to both the available evidence and the discussion among participants.

Capsule enteroscopy vs. other diagnostic procedures in diagnosing obscure gastrointestinal bleeding: a cost-effectiveness study.

Background Capsule enteroscopy is considered the gold standard for evaluating patients with obscure gastrointestinal bleeding. The costs of capsule enteroscopy examination, however, make it uncertain whether the clinically relevant diagnostic gain is also associated with cost savings. Aim To evaluate the incremental cost–effectiveness ratio of capsule enteroscopy in patients with obscure gastrointestinal bleeding. Methods Retrospective study was carried out in nine Italian gastroenterology units from 2003 to 2005. Data on 369 consecutive patients with obscure gastrointestinal bleeding were collected. The diagnostic yield of capsule enteroscopy vs. other imaging procedures was evaluated as a measure of efficacy. The values of Diagnosis Related Group 175 (&U20AC;1884.00 for obscure-occult bleeding and &U20AC;2141.00 for obscure-overt bleeding) were calculated as measures of economic outcomes in the cost analysis. Results Obscure and occult gastrointestinal bleeding was recorded in 177 patients (48%) with a mean duration of anemia history of 17.6±20.7 months. Among patients, 60.9% had had at least one hospital admission, 21.2% at least two, and 1.2% of obscure bleeders up to nine admissions. Overall, 58.4% of patients had positive findings with capsule enteroscopy compared with 28.0% with other imaging procedures (P<0.001). The mean cost of a positive diagnosis with capsule enteroscopy was &U20AC;2090.76 and that of other procedures was &U20AC;3828.83 with a mean cost saving of &U20AC;1738.07 (P<0.001) for one positive diagnosis. Conclusions Capsule enteroscopy is a cost-saving approach in the evaluation of patients with obscure gastrointestinal bleeding.

PERSISTENCE OF CIRCULATING HBsAg/IgM COMPLEXES IN ACUTE VIRAL HEPATITIS, TYPE B: AN EARLY MARKER OF CHRONIC EVOLUTION

Serial serum samples from 110 patients with acute viral hepatitis type B were tested for HBsAg/IgM complexes by a newly developed solid-phase radioimmunoassay. In 102 patients the infection resolved and they recovered from the disease. In these patients, HBsAg/IgM complexes were either absent from the outset of disappeared from serum within four weeks of admission, long before HBsAg had cleared or serum alanine aminotransferase had returned to normal, 8 patients progressed to chronic HBsAg carrier state and chronic liver disease. In these patients, HBsAg/IgM complexes were detectable in the serum on admission, and never disappeared. These results indicate that persistence of circulating complexes containing HBsAg and IgM after the early phase of acute viral hepatitis type B is a predictor of disease chronicity. As early as the fifth week of illness those in whom chronic liver disease developed could be distinguished from those who recovered.

Reduced free protein S levels in patients with inflammatory bowel disease: prevalence, clinical relevance, and role of anti-protein S antibodies.

We evaluated free plasma levels of protein S, a natural anticoagulant factor, the prevalence of anti-protein S antibodies, a possible cause of protein S deficiency, and their correlation with anti-phospholipid antibodies in 53 patients with inflammatory bowel disease (IBD) and 53 age- and sex-matched controls. Mean free plasma protein S levels (± sd) were significantly lower in IBD patients (0.98 ± 0.32 IU/ml) than in controls (1.06 ± 0.28 IU/ml) (P < 0.05); only one patient showed protein S deficiency. Specific antibodies to protein S were found in four IBD patients (7.5%) and in one control (1.9%) (P = NS). Five IBD patients (9.4%) and none of the controls showed anti-phospholipid antibodies (P < 0.06). No correlation was found between free protein S levels and anti-protein S antibodies or between anti-protein S and anti-phospholipid antibodies. In conclusion, free plasma protein S levels are slightly but significantly decreased in IBD patients. The prevalence of anti-protein S and anti-phospholipid antibodies is increased in IBD patients. Anti-protein S antibodies do not appear to determine low protein S levels or to overlap with or belong to anti-phospholipid antibodies.