ALBERT

Description: Hypercoagulability due to high coagulation factors XI, VIII, IX, II, and fibrinogen is recognized as a risk factor of venous thromboembolism (VTE). These factors are cumulatively explored by the activated partial thromboplastin time (APTT). To test the hypothesis that a short APTT increases the risk of VTE, a case-control study was carried out in 605 patients referred for thrombophilia testing after documented VTE and in 1290 controls. Median APTT ratio (coagulation time of test-to-reference plasma) values were 0.97 (range: 0.75-1.41) for patients and 1.00 (range: 0.72-1.33) for controls (P 〈 .001). In patients who had an APTT ratio smaller than the fifth percentile of the distribution in controls, the odds ratio (OR) for VTE was 2.4 (95% confidence interval [CI]: 1.7-3.6) and was independent of inherited thrombophilic abnormalities. Further statistical analyses in 193 patients and 259 controls for whom factor VIII (FVIII) levels were available showed a decrease of the OR from 2.7 (95% CI: 1.4-5.3) to 2.1 (95% CI: 1.0-4.2), indicating that the risk was only partially mediated by high FVIII levels. In conclusion, hypercoagulability detected by a shortened APTT is independently associated with VTE. This inexpensive and simple test should be considered in the evaluation of the risk of VTE.

Description: We compared the performance of PFA-100® closure time (CT) and the skin bleeding time (BT) in the diagnostic work-up of 128 consecutive patients referred to our Centre from June 2002 through June 2003 to be screened for bleeding disorders, due to the presence of bleeding symptoms or the casual finding of abnormal screening tests of hemostasis. The correlation with the severity of the bleeding symptoms and the sensitivity of BT and PFA-100® CT for known defects of primary hemostasis were evaluated. All patients underwent a careful medical interview and were assigned a “bleeding score”, based on the number, type, frequency and severity (development of anemia, need for blood transfusion and/or surgical or medical intervention) of bleeding symptoms. In addition, all patients underwent a first-line screening, which included prothrombin time, activated partial thromboplastin time (APTT), BT and PFA-100® CT (with both the collagen-ADP and the collagen-epinephrine cartridges). The search for Von Willebrand disease (VWD), platelet function disorders (PFD), clotting factor defects and abnormalities of fibrinolysis was performed according to the results of the first line screening tests and the severity and type of bleeding history. Seven (6%) patients had type-1 VWD, 12 (9%) PFD, 29 (23%) defects of clotting factors, 18 (14%) had prolongations of the APTT due to abnormalities that are not associated with bleeding (factor XII deficiency and lupus anticoagulant), while in 63 (49%) all tests gave normal results. The sensitivity of PFA-100® for VWD was 86% (both cartridges), for PFD 75% (collagen-epinephrine) and 8% (collagen-ADP). The sensitivity of BT for VWD was 29%, for PFD 33%. The CT of the PFA-100® CT collagen-epinephrine cartridge was mildly prolonged in 38% of patients with clotting factor deficiency. After dividing the patient population in four quartiles of distribution, according to the severity of the bleeding score (null, low, intermediate and severe), only the CT of the PFA-100® CT collagen-epinephrine cartridge showed a progressive and significant prolongation from the first to the fourth quartile (p=0.04). No association of BT and collagen-ADP CT with the severity of bleeding history was found. In conclusion: 1) CT of the PFA-100® collagen-epinephrine cartridge was significantly associated with the severity of the bleeding history; 2) PFA-100® CT showed a better sensitivity than BT for VWD and PFD; 3) at variance with the BT, PFA-100® could help to discriminate between VWD (prolongation of CT of both cartridges) and PFD (prolongation of CT of the collagen-epinephrine cartridge only).

Description: Abstract 3494 Poster Board III-431 Background von Willebrand disease type 3 (VWD3) is due to virtually complete deficiency of the von Willebrand factor (VWF) and, for this reason, has been also described as “severe VWD”. Although rare (1-5 cases per million population), VWD3 is of major interest because of its severe clinical presentation, the need for replacement therapy with VWF/FVIII concentrates and the risk of occurrence of anti-VWF inhibitors after the infusion of VWF/FVIII concentrates. Aims and design of the study to determine the prevalence and determinants of bleedings requiring therapy with VWF/FVIII concentrates in VWD3 patients, data were collected from the Italian registry on Hemophilia and Allied Disorders organized on behalf of the Italian Association of Hemophilia Centers (AICE). The VWD3 patients included in the registry were then followed up for one year by six Italian Centers and prospective data on number, type and management of bleeding episodes were analyzed. Methods VWD3 patients were diagnosed when VWF antigen was undetectable and factor VIII (FVIII) levels were reduced in plasma. Bleeding severity score (BSS) was calculated at enrollment. Gene deletions and mutations were searched for in all available DNA. Bleeding-free survival was computed with the Kaplan-Meier method and a Cox's proportional hazard model was used to calculate the risk of bleeding (hazard ratio = HR) Results In the Italian registry, 105 VWD3 patients (5.7%) were identified among the 1850 VWD (Italian prevalence=1.75 per million). The entire cohort of VWD3 was characterized by the following demographic, clinical and laboratory parameters (median, range): gender (M/F)= 50/55; age=37 (3-65); BSS=18 (3-35); FVIII= 4 (2-18); anti-VWF inhibitors= 7 cases (6.7%) from 3 families. Molecular diagnosis was available in 65/105 cases with the following gene defects (pt-n): large deletion (7); small deletions and insertions (23); nonsense (9); splice site (8) and missense mutations (17). Mucosal bleedings (64%) were more frequent than hematomas and hemarthrosis (24%). At the time of the enrollment in the registry 95/105 (91%) VWD3 had been already exposed to VWF/FVIII concentrates because of bleeding and/or minor or major surgeries. In the prospective study, 52 VWD3 patients could be enrolled and 46 (88%) were treated in a year for 118 bleeding episodes and 27 minor or major surgeries. BSS〉10 (6.8, 3.8-12.3) and FVIII10U/dL); 64%(BSS〉10&FVIII=5-10U/dL); 59% (BSS=5-10&FVIII10&FVIII

Description: Background: A major complication in severe hemophilia A is the formation of persistent neutralizing antibodies against factor(F) VIII, inhibitors, which render subsequent treatment ineffective. The presence of non-neutralizing anti-FVIII IgG antibodies (NNAs) before FVIII treatment initiation has been associated with subsequent development of inhibitors in previously untreated patients (PUPs) with severe hemophilia A in the frame of the SIPPET cohort (Cannavò A et al, Blood 2017). Up to 30% of PUPs develop neutralizing antibodies (inhibitors) within the first 20-30 exposure days (Eds) to FVIII concentrates, of which one third disappear spontaneously over a course of six months due to endogenous immune tolerance, and two thirds progress into persistent inhibitors that require immunotolerance therapy. The role of each anti-FVIII IgG subclasses (e.g., IgG1, IgG2, IgG3 and IgG4) and their possible prediction of persistent anti-FVIII inhibitors is not known yet. Aims: To investigate the predictive value of anti-FVIII IgG subclasses on persistence of the anti-FVIII inhibitor in PUPs with severe hemophilia A within 60 days from the first development of anti-FVIII inhibitor. Methods: From the 76 patients who developed inhibitors in the SIPPET cohort (Peyvandi et al., N Eng J Med 2016), anti-FVIII IgG subclasses were measured by an ELISA assay in 43 patients according to plasma availability (median age 18 months [IQR: 12-29]), median inhibitor titer: 16 Bethesda IU [IQR: 5-135]). For each IgG subclass, a cutoff of positivity was defined as the mean OD absorbance value + 5 SD, obtained by analyzing the plasma of 150 normal individuals. The association of number of anti-FVIII IgG subclasses and other possible risk factors (age at first treatment, type of FVIII product, number of EDs and type of F8 gene variation) with inhibitor persistence was first estimated by univariate analysis. Predictive associations were assessed by logistic regression, in which inhibitor persistence was the outcome, and number of anti-FVIII IgG subclasses (1= only one [always IgG1], 2 subclasses, 3 subclasses or all 4 subclasses) and age at first treatment with FVIII concentrates were the putative predictors that showed an association with inhibitor persistence. Other risk factors, such as type of FVIII product, number of EDs and type of F8 gene variation, were not associated with inhibitor persistence at univariate analysis. Relative risks (RR) and 95% confidence intervals (95% CI) were recalculated from odds ratios according to Zhang (JAMA, 1998). The predictive capacity was expressed as the area under the receiving operative characteristic (ROC) curve (AUC). Results: Of the 43 patients who developed an inhibitor (31 persistent, 12 transient), 3 had only one IgG subclass (IgG1), 15 two subclasses, 13 three subclasses and 12 were positive for all the four IgG subclasses. The presence of each subclass was associated with an increased risk of inhibitor persistence, both in univariate and multivariate analysis, with relative risks ranging from 1.3 to 1.8. The risk of inhibitor persistence progressively increased with the number of concomitant IgG subclasses. In the model containing also age at first treatment and taking the category with only IgG1 positivity as reference, the RR (95% CI) was 1.7 (0.2 to 2.9) for patients with two IgG subclasses, 2.6 (0.7 to 3.0) for those with three subclasses and 2.8 (1.2 to 3.0) for those with all the four subclasses. The odds of inhibitor persistence increased by 8% for every 1-month increase of age at first treatment (OR 1.08 [0.99 to 1.22]). The AUC of the predictive model was 0.82 (95% CI: 0.68 to 0.96) (Fig 1). Conclusions: The concomitant presence of more than one anti-FVIII IgG subclass within 60 days from the first development of anti-FVIII inhibitor in patients with severe hemophilia A was associated with an increased risk of persistence of the inhibitor. Age at first treatment also predicted inhibitor persistence. In conclusion, this predictive analysis showed a promising discriminative capability for clinicians to select patients with the highest risk of inhibitor persistence who could benefit from immunotolerance therapy. These results need to be confirmed in other cohorts of PUPs with severe hemophilia A. Figure 1. Figure 1. Disclosures Peyvandi: Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Kedrion: Consultancy; Grifols: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Octapharma US: Honoraria; Octapharma US: Honoraria; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau. Palla:Grifols: Other: travel support; Pfizer: Other: travel support. Santagostino:Grifols: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Young:Novo Nordisk: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; Bayer: Consultancy; CSL Behring: Consultancy, Honoraria; Kedrion: Consultancy; Genentech/Roche: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Seth:Shire: Honoraria. Mancuso:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biotest: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Biomarin: Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Bayer: Research Funding; Amgen: Consultancy; Alnylam: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Ewing:Hema Biologics: Honoraria; Novo Nordisk: Honoraria; CSL Behring: Honoraria; Grifols: Honoraria; Bayer: Honoraria; Shire: Honoraria; Genentech: Honoraria; Biogen: Research Funding. Male:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Speakers Bureau; Novo Nordisk: Speakers Bureau; Biotest: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Speakers Bureau; SOBI: Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Majumdar:NIMHD: Research Funding. Manco-Johnson:CSL Behring: Honoraria; Biogentek: Honoraria; Novo Nordisk: Honoraria; Bayer AG: Honoraria, Research Funding; Baxalta, now part of Shire: Honoraria. Mazzucconi:Baxalta-Shire: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novartis,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau. Neme:Shire: Consultancy, Honoraria; Novonordisk: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria. Prezotti:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bioverative: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mannucci:Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta/Shire: Speakers Bureau; Alexion: Speakers Bureau; Novo Nordisk: Speakers Bureau.

Description: Background. von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disorder, no data on the incidence and determinants of bleedings requiring specific treatments have been available thus far. Aims and design of the study: to determine the incidence and determinants of bleedings requiring therapy with DDAVP and/or VWF concentrates in VWD, a national registry was organized by using a database devised to collect detailed retrospective information. Patients included in the registry were followed up for one year and prospective data on number, type and management of bleeding episodes were analyzed. Methods: all patients were diagnosed following recommendations of the ISTH-SSC-SC on VWF with bleeding severity score (BSS) calculated at enrollment. Diagnoses of VWD were confirmed by the coordinating center using also multimeric analysis in plasma and mutations of VWF gene in all types 2 and 3. For different risk categories the incidence of bleeding (mucosal and non-mucosal bleeding) was calculated. Bleeding-free survival was computed with the Kaplan-Meier method and a Cox’s proportional hazard model was used to calculate the risk of bleeding (hazard ratio = HR) Results: In the retrospective study, 1,234/1,529 (81%) cases satisfied the inclusion criteria and were enrolled in the registry as types 1 (54%), 2 (40%) and 3 (6%).VWD diagnosis occurs in young adults (83%), mainly in women (57%). Mucosal bleeding (64%) are more frequent than hematomas or hemarthrosis (15%) but 73% of patients did not require transfusions. In the prospective study based on 814/1,234 (66%) cases of the registry (type 1=47%, 2=47%, 3=6%) 147/815 (18%) were treated in a year for 318 bleeding episodes and 87 minor or major surgeries. BSS 〉10 (6.8, 3.8–12.3), bleeding time 〉20 min (BT = 5.5, 3.1–9.8), VWF:RCo 40 U/dL showed always BSS 30 U/dL and FVIII:C 〉40 U/dL bleeding episodes are very rare, in agreement with their relatively low BSS.

Description: Key Points The bleeding score helps to predict clinical outcomes in adult patients with von Willebrand disease. High bleeding scores correlate with intensive on-demand therapy and may identify cases requiring regular prophylaxis.

Description: Type 2B von Willebrand disease (VWD2B) is caused by an abnormal von Willebrand factor (VWF) with increased affinity for the platelet receptor glycoprotein Ib-α (GPIb-α) that may result in moderate to severe thrombocytopenia. We evaluated the prevalence and clinical and molecular predictors of thrombocytopenia in a cohort of 67 VWD2B patients from 38 unrelated families characterized by VWF mutations. Platelet count, mean platelet volume, and morphologic evaluations of blood smear were obtained at baseline and during physiologic (pregnancy) or pathologic (infections, surgeries) stress conditions. Thrombocytopenia was found in 20 patients (30%) at baseline and in 38 (57%) after stress conditions, whereas platelet counts were always normal in 16 patients (24%) from 5 families carrying the P1266L/Q or R1308L mutations. VWF in its GPIb-α–binding conformation (VWF–GPIb-α/BC) was higher than normal in all except the 16 cases without thrombocytopenia (values up to 6-fold higher than controls). The risk of bleeding was higher in patients with thrombocytopenia (adjusted hazard ratio = 4.57; 95% confidence interval, 1.17-17.90) and in those with the highest tertile of bleeding severity score (5.66; 95% confidence interval, 1.03-31.07). Prediction of possible thrombocytopenia in VWD2B by measuring VWF–GPIb-α/BC is important because a low platelet count is an independent risk factor for bleeding.

Description: INTRODUCTION Platelet function has never been studied systematically in patients with CLL. Novel drugs are now available for CLL treatment that may impact on platelet functions. Fifty per cent of patients treated with Ibrutinib suffered from minor bleedings and only 5% from major bleedings, partly caused by the drug driven inhibition of platelet glycoprotein VI signaling. No data on bleeding tendency has yet emerged on patient treated with Idelalisib, the first specific inhibitor of PI3K δ p110 approved for the treatment of relapsed/refractory CLL or for patients with del17p or TP53 as first line therapy. In animal models a reduction of p110δ on platelets (PLT) does not increase bleeding, causing only a slight reduction of platelet aggregation and activation. Knowledge about potential bleeding complications associated with the use of small molecules may be relevant in older patients and those at increased bleeding risk due to concomitant therapies. PATIENTS AND METHODS Ten patients with CLL (M/F: 6/4; median age: 71 years, range 47-82) who started therapy with Idelalisib were enrolled in a prospective observational pilot study. The Bleeding Severity Score (BSS), a validated questionnaire, was administrated to patients to estimate bleeding before and during idelalisib therapy. All patients underwent coagulation tests and platelet aggregation/secretion studies with different aggregating agents before starting therapy with Idelalisib, after 28 + 7 days and after 3 months. Patients with a platelet count less than 80.000/mm3, in antiplatelet or anticoagulant therapy, with recent use (within 7 days) of NSAIDs and a diagnosis of hereditary thrombocytopenia/pathy were excluded. We defined complete haematological remission (CHR) as Hb more than 11g/dl, PLT more than 100.000/mm3, lymphocyte less than 5.000/mm3 and partial haematological remission (PHR) as a response not fulfilling criteria for CHR. RESULTS No cases of hemorrhagic complications or increased bleeding tendency were observed in patients with CLL and no patients had a pathologic BSS (〉5) at enrolment. All patients had coagulation tests within normal limits at baseline and after 28 days. Platelet count was below 100.000/mm3 in 5 patients. In 9 out of 10 patients platelet aggregation was pathological with at least 2 of the 4 aggregating agents tested. Platelet secretion before initiation of treatment with Idelalisib was particularly impaired with ADP (8/10 patients), while was pathological with collagen, a strong agonist, in only 2 patients. In 8 patients intraplatelet ATP/ADP ratio was pathological, as observed in delta storage pool disease. After 28 days of treatment 4 of 10 patients were in CHR and 3 in PHR. Platelets count was still below 100.000/mm3 in 2 subjects. At 28 days in 5 out of the 9 patients with pathological baseline test, platelet aggregation improved, while 3 remained unchanged and in one worsened. Even ADP secretion normalized in 4 patients. ATP/ADP ratio did not significantly change. At three months 7 patients reached CR and 2 reached PR. At three months platelets count was still below 100000/mm3 in 2 patients. In 3 patients platelet aggregation further ameliorated. CONCLUSIONS In this pilot study, treatment with idelalisib improved platelet aggregation tests in most of the CLL patients who presented a pathological test before starting therapy. It's unlikely that the drug has a direct effect on platelets, given their low expression of PI3Kδ; therefore our results are probably due to the rapid idealisib effect on CLL clone. Based on these preliminary data, Idelalisib seems to be safe in patients with an increased bleeding risk. Disclosures Reda: Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding. Peyvandi:Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; CSL Behring: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Octapharma: Consultancy; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; Grifols: Speakers Bureau; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; SOBI: Speakers Bureau; Bayer: Speakers Bureau.

Description: Abstract 1413 Hepatitis virus C (HCV) infection is common in patients with inherited bleeding disorders due to the past use of plasma-derived clotting factor concentrates not treated with virucidal methods. The prognosis of the infection and the outcome of antiviral therapy are related to the stage of liver fibrosis. Since liver biopsy, the gold standard to grade fibrosis, is rarely performed in these patients for cost-benefit reasons, it is important to consider non invasive methods to assess fibrosis such as liver stiffness measurement with transient elastography (TE, Fibroscan®), a technique already validated in non hemophilic patients. We measured TE in 170 patients with inherited bleeding disorders and HCV infection (positive serum HCV-RNA). The main characteristics of these patients are reported in the Table. Steatosis was detected by abdominal ultrasound. Cirrhosis was defined by the presence of irregular liver edge, splenomegaly, dilated portal vein and/or esophageal varices combined either with low platelet count and/or reduced albumin/cholinesterase levels. TE was successfully performed in all but 3 patients, 2 of whom for Body Mass Index (BMI) 〉 30 kg/m2. Overall, the median value of liver stiffness was 7.2 kPa (interquartile range, IQR: 5.3–11.1) with a median success rate of 100% (IQR: 91–100) and a median IQR value of 1.0 (IQR: 0.7–1.9). HCV genotype or the presence of steatosis did not influence the TE values, whereas higher values were observed in patients with cirrhosis than in those without (median 19.8 kPa, IQR: 14.3–28.1 vs 6.8 kPa, IQR: 5.1–9.1, respectively; p〈 0.01). In particular, 18/22 (82%) cirrhotic patients had a liver stiffness value ≥ 12.0 kPa, a cut-off previously identified as associated with severe fibrosis in HCV infected patients. Overall, splenomegaly was present in 51 patients (30%), 16 with cirrhosis and 35 without. In 31/35 (89%) of the latter, TE values were 〈 12 kPa. Moreover, among patients without cirrhosis, 12 (8%) had TE values ≥ 12 kPa: those patients had ALT and GGT levels significantly higher than patients with TE values 〈 12 kPa (p1.5 had a 96% specificity and a 93% negative predictive value for the detection of severe fibrosis. Univariate and multivariate linear regression analyses were performed to investigate the relationship between log transformed TE and demographic (age, BMI) or laboratory (ALT, GGT, APRI) variables potentially influencing the TE values. By univariate analysis a linear association was found with age, ALT, GGT, APRI and BMI values (p

Description: There is increasing evidence that neovascularization may play an important role in hematological malignancies (particularly lymphomas, acute leukemia and myelodysplastic syndromes), but only a few studies have been performed in Ph− chronic myeloproliferative disorders (CMPDs). Increased angiogenesis has been reported in chronic idiopathic myelofibrosis (CIMF), whereas high serum levels of vascular endothelial growth factor (VEGF) have been described in Ph− CMPDs. These findings have led to the use of new therapeutic approaches aimed at directly targeting endothelial cells or VEGF. The aim of this study was to evaluate microvessel density (MVD) and immunohistochemical VEGF expression in the different categories of Ph− CMPD. We examined the bone marrow biopsies (BMBs) of 98 Ph− CMPD patients, classified as follows on the basis of the WHO criteria: 29 cases of essential thrombocythaemia (ET), 39 cases of CIMF (11 CIMF-0, 11 CIMF-1, 7 CIMF-2 and 10 CIMF-3) and 30 cases of polycythemia vera (PV) (20 polycythemic phase [pp-PV] and 10 post-polycythemic myelofibrosis [post-PVMF]. We also analysed 20 normal BMBs of subjects not suffering from hematological disease. MVD was analysed using the “hot-spot” method and an anti-CD34 antibody. Immunohistochemical VEGF expression was expressed as a VEGF index based on the formula [VEGF(i) = VEGF(+) cells x BMB cellularity/100]. Data were statistically tested at the 5% significance level (p