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V. La Mura1,2,∗, S. Braham3, F. Branchi4, M. Moia3, A.L. Fracanzani5, M. Colombo1, A. Tripodi3, M. Primignani1 1 U.O. Gastroenterologia-1, IRCCS-Ca’ Granda, Ospedale Maggiore Policlinico, Universita degli studi di Milano, Milan, Italy 2 U.O. Medicina Interna, IRCCS-San Donato, Dipartimento di Scienze Biomediche per la Salute, Universita degli studi di Milano, Milan, Italy 3 Centro Emofilia e Trombosi Angelo Bianchi Bonomi, IRCCS-Ca’ Granda, Ospedale Maggiore Policlinico, Universita degli studi di Milano, Milan, Italy 4 U.O. Gastroenterologia-2, IRCCS-Ca’ Granda, Ospedale Maggiore Policlinico, Universita degli studi di Milano, Milan, Italy 5 U.O. Medicina Interna, IRCCS-Ca’ Granda, Ospedale Maggiore Policlinico, Universita degli studi di Milano, Milan, Italy

Philadelphia-negative Myeloproliferative Neoplasms (MPN), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), Myelofibrosis (Primary [PMF] and secondary to PV and ET [PPV-, PET-MF] and unclassified MPN (U-MPN), are associated with an increased risk of venous thrombosis in unusual sites, such as splanchnic vessels (SVT). SVT can lead to complications such as portal hypertension, esophageal and gastric varices, ascites,hepatic failure and biliopathy. According to a meta-analysis MPN is the underlying cause of portal vein thrombosis (PVT) in 31.5% and Budd Chiari syndrome (BCS) in 40.9% of cases (Smalberg, 2012); a more in-depth analysis of clinical characteristics and evolution of MPN-associated SVT has been hampered by heterogeneity of cohorts comprising small number of cases. We conducted a retrospective multicenter study in patients (pts) with SVT associated with WHO2008-diagnosed MPN, with the aim to describe patient characteristics, disease course and prognostic factors with potential implications for clinical practice. Data were collected from 16 international hematologic centers in the framework of the Italian AGIMM and the IWG-MRT groups. We collected 519 cases of pts with PVT, splenic or mesenteric vein thrombosis (75.1%) and BCS (24.9%) associated with MPN. We used as comparator a cohort of 1686 controls (Ctr) represented by MPN without (w/o) SVT: 741 ET (43.9%), 684 PV (39.7%), 261 PMF (15.5%). Frequency of MPN associated with SVT was 37.8% ET (n=196), 36.8% PV (n=191), 15.4% MF (n=80), 10% U-MPN (n=52). Median follow-up was 89.9 months (mo) (range 0.5-430). For SVT vs Ctr group females were 54.5% vs 44.4% in PV (P=0.001), 68.4 vs 63.5% (p=0.13) in ET, 63.7% vs 29.1% in PMF (p Disclosures No relevant conflicts of interest to declare.

Scant information exists on the role of thrombophilia in extrahepatic portal vein obstruction (EHPVO). We studied 65 patients with EHPVO, 500 with deep vein thrombosis (DVT) of the lower limbs, and 700 healthy controls referred for thrombophilia screening, including the search for gain-of-function mutations in genes encoding coagulation factor V (factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocysteinemia. At least one abnormality in the thrombophilia screening was found in 40% of patients with either EHPVO or lower limb DVT and in 13% of controls, for odds ratios of 4.0 (95% CI, 2.3-7.0) and 4.4 (95% CI, 3.3-5.9), respectively. Statistically significant associations with EHPVO were observed for the prothrombin G20210A mutation (odds ratio, 8.1; 95% CI, 3.8-17.5) and the deficiencies of antithrombin, protein C, or protein S taken together (odds ratio, 4.5; 95% CI, 1.1-18.0). The odds ratio for the prothrombin G20210A was approximately twice that for lower limb DVT. Patients with factor V Leiden had an odds ratio for EHPVO of 0.8 (95% CI, 0.1-6.4) and for lower limb DVT of 7.5 (95% CI, 4.4-13.0). The odds ratio for EHPVO in patients with hyperhomocysteinemia was 2.0 (95% CI, 0.9-4.9). At variance with lower limb DVT, oral contraceptive use was not associated with an increased risk of EHPVO. Myeloproliferative disorders were diagnosed in 35% of patients with EHPVO. In conclusion, the risk for EHPVO is increased in the presence of thrombophilia resulting from the prothrombin G20210A mutation and from the deficiencies of the naturally occurring anticoagulant proteins, but not from factor V Leiden.

The role played by coagulation defects in the occurrence of bleeding in cirrhosis is still unclear. This is partly due to the lack of tests that truly reflect the balance of procoagulant and anticoagulant factors in vivo. Conventional coagulation tests such as prothrombin time and activated partial thromboplastin time are inadequate to explore the physiological mechanism regulating thrombin, because they do not allow full activation of the main anticoagulant factor, protein C, whose levels are considerably reduced in cirrhosis. We used a thrombin generation test to investigate the coagulation function in patients with cirrhosis. Thrombin generation measured without thrombomodulin was impaired, which is consistent with the reduced levels of procoagulant factors typically found in cirrhosis. However, when the test was modified by adding thrombomodulin (i.e., the protein C activator operating in vivo), patients generated as much thrombin as controls. Hence, the reduction of procoagulant factors in patients with cirrhosis is compensated by the reduction of anticoagulant factors, thus leaving the coagulation balance unaltered. These findings help clarify the pathophysiology of hemostasis in cirrhosis, suggesting that bleeding is mainly due to the presence of hemodynamic alterations and that conventional coagulation tests are unlikely to reflect the coagulation status of these patients. In conclusion, generation of thrombin is normal in cirrhosis. For a clinical validation of these findings, a prospective clinical trial is warranted where the results of thrombin generation in the presence of thrombomodulin are related to the occurrence of bleeding.

Peri-anastomotic ulcerations may occur in patients with previous abdominal surgery. They may present only with obscure GI bleeding. We report two cases in whom capsule endoscopy identified postsurgical stenoses with ulcers as the cause of obscure GI bleeding. Case 1. A 57-year-old male operated on in 1970 for a post-traumatic diaphragm hernia followed by displacement of the caecum in the upper left abdominal quadrant. Case 2. A 32-year-old female with a salpingectomy for tuberculosis (1978) followed by segmental ileal resection for intestinal obstruction. Both patients had undergone extensive work-up including bidirectional endoscopies and enteroclysis with negative results. Capsule endoscopy with the GIVEN diagnostic system was done. Ileal stenoses with mucosal ulcers in dilated prestenotic loops were observed in both cases. The capsule was retained at the stenosis site, requiring ileal resection and anastomosis. Pathology reports showed mucosal ulcers. In case 2, tuberculosis was ruled out by tissue and faecal polymerase chain reaction and culture. Ileal stenoses with prestenotic ulcerations causing GI bleeding may occur in patients with previous abdominal surgery. Capsule endoscopy may clarify the diagnosis and shorten the diagnostic work-up. However, these patients should be warned that capsule retention requiring surgery might occur.

Philadelphia-negative Myeloproliferative Neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Myelofibrosis Primary (PMF) and secondary to PV and ET (PPV-, PET-MF); included are also some less characterized entities defined as unclassified MPN (U-MPN). Risk of arterial and venous thrombosis is increased in MPN patients, and thrombosis is one of most important causes of mortality and morbidity. The risk of venous thrombosis in unusual sites, such as splanchnic vessels (SVT), is particularly associated with MPN; SVT can lead to complications such as portal hypertension, esophageal and gastric varices, ascites and hepatic failure. A recent meta-analysis reported that a MPN is the underlying cause of portal vein thrombosis in 31.5% and of Budd Chiari syndrome in 40.9% of cases (Smalberg, 2012). A significant association of SVT with JAK2V617F mutated MPN was reported (Dentali, 2009) but study of other correlations has been hampered by heterogeneity of available patient cohorts comprising relatively small number of cases. We conducted a retrospective multicenter study collecting clinical and biological data of patients (pts) with SVT associated with MPN diagnosed according to WHO2008 criteria, aiming to describe patients’ characteristics, trends and prognostic factors, and their potential implications for clinical practice. Data were collected from 15 international hematology centers in the framework of IWG-MRT. We collected 475 cases of pts with portal, splenic or mesenteric vein thrombosis (75.2%) or Budd Chiari syndrome (24.8%) associated with MPN. In 32% of cases, simultaneous involvement of portal (69.1% of total thrombosis), splenic (30.5%) and mesenteric (25.3%) veins occurred, and in 1.7% they were associated with Budd Chiari syndrome. Frequency of MPN subtype: 38.1% ET (n=181), 34.9% PV (n=166), 16.2% MF (n=77), 10.8% U-MPN (n=51). Median follow-up 87.9 mo (range 0.5-430); female 61.3% (n=292; P MF transformation occurred in 32/166 PV (19%) and in 23/181 ET (13%) pts, with median time to progression of 122.3 mo (range 5.4-377.3) and 125.1 mo (range 39.3-255.3), respectively. Evolution to acute leukemia (AL) occurred in 12 pts (2.7%), of which 2 PMF, 6 PV and 4 ET. In 3 PV and 1 ET pts a PPV and PET-MF transformation occurred before AL. After SVT, 77% of pts received anticoagulation, 23.5% antiaggregant therapy and 1.5% both; 68.8% received cytotoxic drugs, 11.4% of pts were treated with trans jugular porto-systemic shunt. No differences in survival were noted with these approaches. Beta blocker therapy was used in 48.5% of pts and correlated with improved survival (p=0.041) At last follow up 70/473 pts (14.8%) died; causes of death are evolution to AL (16.4%), other cancers (14.5%), disease progression without AL (12.7%), SVT (10.9%), hepatic failure and venous thrombosis other than SVT (9.1% each), heart failure and arterial thrombosis (7.3% each), hemorrhage (5.5%), renal failure and infection (3.6% each). After 10 y follow up 8/166 PV (5%), 14/181 ET (8%), 14/77 PMF (18%) and 1/51 U-MPN (1.96%) pts died (p This large study confirms the strong association between JAK2V617F-mutated MPN and SVT and identifies the category of U-MPN as the prognostically more favorable; thrombosis at sites outside the splanchnic vasculature remains the leading cause of death. Disclosures: No relevant conflicts of interest to declare.

Background. The reported incidence of post-endoscopic retrograde-cholangiopancreatography/sphincterotomy pancreatitis ranges between 1.3% and 12.8%. This may likely reflect different definitions of pancreatitis and methods of data collection, rather than differences in patient populations, indications and endoscopic expertise. Aims. The present study evaluated the incidence of post-endoscopic retrograde-cholangiopancreatography/sphincterotomy pancreatitis using different definition criteria and different data collection methods. Patients. The 24-hour clinical and enzymatic course of 1185 procedures was recorded. Methods. Pancreatic-like pain and hyperamylasaemia were evaluated either 6 to 8 hours or 24 hours after the procedure; computed tomography scan was performed in those patients with 24-hour pancreatic pain associated with hyperamylasaemia more than three times the upper normal limit. Results. Computed tomography scan findings consistent with pancreatitis were observed in 1.9% of cases, only among those patients with 24-hour pancreatic-like pain and hyperamylasaemia over five times the upper normal limit. The 6–8-hour and 24-hour pancreatic-like pain was associated with serum amylase levels at least three times higher in 11.7% and 6.6% and five times higher or more in 7.4% and 5.1 %, respectively; 6–8 and 24-hour hyperamylasaemia higher than five times the upper normal limit, irrespective of pancreatic-like pain, was reported in 8.3% and in 6.9% of cases. No patients with serum amylase values lower than three times the upper normal limit had clinical symptoms. Conclusions. The incidence of post-procedure pancreatitis ranged from 1.9% to 11.7% depending on the definition criteria adopted.

Abstract 4213 Primary Budd-Chiari syndrome (BCS) is a rare disorder characterized by thrombosis of the hepatic outflow tract anywhere from the level of the hepatic veins to the suprahepatic inferior vena cava. Thrombophilic factors or prothrombotic disorders are found in the majority of patients. However, in around 20% of primary BCS patients still no cause can be identified, which highlights the need to further explore the etiology of this disorder. The fibrinogen γ' variant is a thrombosis risk modifier and may thus contribute to BCS. The aim of this study was to determine the role of fibrinogen γ' levels and common variations in the fibrinogen γ gene (FGG) in the etiology of BCS. Patients were recruited from the EN-Vie cohort, consisting of 163 consecutive BCS patients, enrolled in nine European countries between October 2003 and October 2005. Plasma and/or DNA was available from 118 BCS patients (50 males and 68 females; median age 37.9) and 104 healthy controls (43 males and 61 females; median age 36.8). We measured fibrinogen γ' levels by ELISA and genotyped two haplotype-tagging single nucleotide polymorphisms (SNPs): rs2066865 (10034C>T) tagged FGG H2 and rs1049636 (9340T>C) tagged FGG H3. All statistical analyses were adjusted for differences in age and sex. Fibrinogen γ' (0.50 vs 0.42 g/l; p=0.02) and total fibrinogen levels (3.0 vs. 2.8 g/l, p=0.04) were significantly elevated in BCS patients compared to controls. Also the fibrinogen γ'/total fibrinogen ratio, which adjusts for a potential acute phase induced increase of fibrinogen, was significantly elevated in BCS patients (0.17 vs. 0.15; p=0.03). Logistic regression showed a significant association between an increasing fibrinogen γ'/total fibrinogen ratio and risk of BCS (p=0.03). FGG H2 (OR 0.97; 0.96–0.98) and H3 (OR 1.02; 1.01–1.03) were significantly associated with fibrinogen γ'/total fibrinogen ratios. FGG H2 (OR 0.96; 0.64–1.46) and H3 (OR 0.86; 0.62–1.21) were not associated with BCS. In conclusion, fibrinogen γ' levels and the fibrinogen γ'/total fibrinogen ratio are significantly elevated in BCS patients. Common FGG gene variations determine the fibrinogen γ'/total fibrinogen ratio in these patients. We did not observe an association between FGG gene variations and risk of BCS. This study was carried out on behalf of the European Network for Vascular Disorders of the Liver (EN-Vie). Disclosures: No relevant conflicts of interest to declare.

Abstract 4212 Primary Budd-Chiari syndrome (BCS) and non-malignant, non-cirrhotic portal vein thrombosis (PVT) are rare disorders with a considerable overlap in etiology. Myeloproliferative neoplasms (MPN) are the most frequent underlying prothrombotic factor in both entities. The JAK2 V617F mutation (VF) has been identified in over half of the individuals with MPN. Recently, a JAK2 haplotype, designated ‘46/1’, has been described. Previous studies suggest that the JAK2 46/1 haplotype represents a disease susceptibility to MPN, independent of VF status. The aim of this study was to determine the role of the JAK2 46/1 haplotype in the etiology of BCS and PVT. Patients were recruited from the EN-Vie cohort, consisting of 163 BCS and 138 PVT patients, consecutively enrolled in nine European countries between October 2003 and October 2005. DNA was available from 116 BCS patients (50 males and 66 females; median age 38.1), 97 PVT patients (47 males and 50 females; median age 49.8) and 104 healthy controls (43 males and 61 females; median age 36.8). The JAK2 46/1 haplotype was tagged by the rs12343867 single nucleotide polymorphism. Frequency of the JAK2 haplotype 46/1 was higher in BCS (36%, p=0.06) compared to controls (27%), while similar in PVT patients (28%, p=0.89). When stratified for VF status, haplotype 46/1 frequency was higher in VF positive BCS (44%, p=0.01) and VF positive PVT patients (40%, p=0.06) compared to controls. Haplotype 46/1 frequency was similar in VF negative BCS (33%, p=0.29) and PVT patients (24%, p=0.47) compared to controls. VF negative BCS patients with a proven MPN also showed increased frequency of the 46/1 haplotype (56%, p=0.07). Logistic regression, adjusted for age and sex, showed an association between the 46/1 haplotype and risk of VF positive BCS (OR: 2.10; 1.16–3.80), VF positive PVT (OR 2.07; 0.95–4.52) and VF negative BCS patients with a proven MPN (OR 3.04; 1.02–9.06). We conclude that the JAK2 46/1 haplotype may be associated with BCS and that this was limited to patients with a proven MPN, independent of VF status. In PVT, the 46/1 haplotype was only associated with patients who were VF positive. This study was carried out on behalf of the European Network for Vascular Disorders of the Liver (EN-Vie). Disclosures: No relevant conflicts of interest to declare.

Response: In response to Spahr et al,[1][1],[2][2] we would like to point out that the “How I treat” Blood articles are meant to feature therapeutic aspects for which evidence from randomized trials is lacking. These articles are based on opinions of experts who have a large clinical experience

The correlation between histological liver abnormalities and fasting serum cholylglycine levels was investigated in 75 chronic asymptomatic HBsAg carriers with normal conventional liver tests, to clarify whether serum CG radioimmunoassay could help in distinguishing the carriers with histological liver damage from those with normal histological findings. Mean (+/- SEM) fasting serum CG levels were 11.6 +/- 1.5 micrograms/dl in 56 carriers with normal liver histology, 14.6 +/- 4.2 micrograms/dl in 16 subjects with CPH and 95.6 +/- 54 micrograms/dl in three carriers with CAH. The incidence of abnormal values (greater than 40 micrograms/dl) among carriers with CAH (66%) was significantly higher than in the other two groups (1.8 and 12.5%, respectively). It is concluded that, among chronic asymptomatic HBsAg carriers with normal conventional liver tests, those who show abnormal serum CG levels are likely to have severe histological damage. This justifies the inclusion of CG radioimmunoassay in the routine follow-up of these subjects. The occurrence of false-positive and false-negative results must be considered if the test is used as an aid in the selection of patients for liver biopsy.