Raffaele Landolfi

Vascular and Neoplastic Risk in a Large Cohort of Patients With Polycythemia Vera

PURPOSE The clinical course of polycythemia vera is often complicated by thrombosis as well as by the possible transition to myeloid metaplasia with myelofibrosis or acute myeloid leukemia. The aim of this study was to assess the rate of these complications in subjects receiving currently recommended treatments. PATIENTS AND METHODS Overall, 1,638 patients from 12 countries were enrolled onto a large, prospective multicenter project aimed at describing the clinical history of polycythemia vera for the following outcomes: survival, the cumulative rate of cardiovascular death and thrombosis, the cumulative rate of leukemia, myelodysplasia, and myelofibrosis. The mean duration of the disease at entry and the duration of the follow-up were 4.9 and 2.7 years, respectively. RESULTS The overall mortality rate of 3.7 deaths per 100 persons per year resulted from a moderate risk of cardiovascular death and a high risk of death from noncardiovascular causes (mainly hematologic transformations). Age older than 65 years and a positive history of thrombosis were the most important predictors of cardiovascular events. Antiplatelet therapy, but not cytoreductive treatment, was significantly associated with a lower risk of cardiovascular events. We found a consistent association between age and risk of leukemia, and between duration of the disease with risk of myelofibrosis. CONCLUSION The European Collaboration on Low-Dose Aspirin in Polycythemia Vera study documents that large international collaborative studies are feasible in this field, in which few epidemiologic data are available. The persistently high mortality rate from hematologic malignancies characterizes the unmet therapeutic need of polycythemic patients and suggests a priority for future studies in this disease.

Regression of autoimmune thrombocytopenia after eradication of Helicobacter pylori

1 Negrini R, Savio A, Poiesi C, et al. Antigenic minicry between H pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastreonterology 1996; 111: 655–65. 2 Ko GH, Part HB, Shin MK, et al. Monoclonal antibodies against Helicobacter pylori cross-react with human tissue. Helicobacter 1997; 4: 210–15. 3 Nagachima R, Maeda K, Yuda F, Kudo K, Saitoh M, Takahashi T. Helicobacter pylori antigen in the glomeruli of patients with membranous nephropathy. Virchows Arch 1997; 431: 235–39. 4 Machet L, Vaillant L, Machet MC, Buchler M, Lorette G. SchonleinHenoch purpura associated with gastric Helicobacter pylori infection. Dermatology 1997; 194: 86. 5 Francois B, Trimoreau F, Vignon P, Fixe P, Praloran V, Gastinne H. Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor. Am J Med 1997; 103: 114–20.

Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development.

BACKGROUND/AIMS Prognostic scores currently used in cirrhotic patients do not include thrombotic risk factors (TRFs). Predicting factors of portal vein thrombosis (PVT) development are still unknown. We wanted to describe TRFs as a function of liver disease severity using the MELD score and assess the role of local and systemic TRFs as predictors of PVT development in cirrhotic patients. METHODS One hundred consecutive patients with liver cirrhosis were included in the study. TRFs, D-dimers, MELD score, portal vein patency and flow velocity were evaluated in all subjects at baseline and every 6 months thereafter. Variables able to predict PVT development within 1 year were identified by means of multiple logistic regression. RESULTS The plasma levels of protein C and antithrombin were lower and the concentration of D-dimers was higher in patients with advanced disease. Plasma levels of antithrombin, protein C and protein S resulted significantly lower in PVT group at univariate analysis, but reduced portal vein flow velocity was the only variable independently associated with PVT development. CONCLUSIONS Lower concentrations of natural coagulation inhibitors are frequently detected in patients with liver cirrhosis. A reduced portal flow velocity seems to be the most important predictive variable for PVT development in patients with cirrhosis.

Dose–Response Effect of Baclofen in Reducing Daily Alcohol Intake in Alcohol Dependence: Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Trial

AIMS To explore the effect of baclofen in a dose of 20 mg three times per day, compared with the already studied dose of 10 mg three times per day, in the treatment of alcohol dependence. METHODS We present a secondary analysis of a 12-week double-blind, placebo-controlled, randomized clinical trial with two doses of baclofen, specifically 10 mg t.i.d. and 20 mg t.i.d. Out of 94 subjects consecutively screened, 42 were randomized into the study. Fourteen of the 42 patients were randomly allocated to placebo, 14 to the group treated with baclofen 10 mg t.i.d. (B10 mg) and 14 to the group treated with baclofen 20 mg t.i.d. (B20 mg). RESULTS Compared with patients allocated to placebo, patients allocated to the B10 mg group had a 53% reduction in the number of drinks per day (P < 0.0001) and patients allocated to the B20 mg group had a 68% reduction in the number of drinks per day (P < 0.0001), with respect to the number of drinks per day during the 28 days before randomization. The effect of baclofen 20 mg t.i.d. was greater than that of baclofen 10 mg t.i.d. (P = 0.0214, Wald test) showing a dose-effect relationship. Both doses of baclofen were well tolerated. CONCLUSION This is provisional evidence of a dose-response effect for baclofen in the treatment of alcohol dependence.

The haematocrit and platelet target in polycythemia vera

Polycythemia vera (PV) is a chronic myeloproliferative disorder whose major morbidity and mortality are thrombohaemorragic events and progression to acute leukaemia or myelofibrosis. Whether the haematocrit and platelet count predict such complications remains unclear. The European Collaboration on Low‐dose Aspirin in Polycythemia Vera prospective study included 1638 PV patients. A total of 164 deaths (10%), 145 (8·85%) major thrombosis and 226 (13·8%) total thrombosis were encountered during 4393 person‐years follow‐up (median 2·8 years). In time‐dependent multivariable analysis, a haematocrit in the evaluable range of 40–55% was neither associated with the occurrence of thrombotic events, mortality nor with haematological progression in the studied population. The haematocrit of patients in the highest and lowest deciles at baseline was maintained within a narrow interval of haematocrit values ranging from 40% to 47% throughout follow‐up. High platelet count was associated with a lower progression rate to acute leukaemia/myelofibrosis, whereas it had no significant relationship with thrombotic events or mortality. Our findings do not suggest that the range of haematocrit (<55%) and platelet counts (<600 × 109/l) we encountered in our population had an impact on the outcome of PV patients treated by current therapeutic strategies.

Thrombosis in myeloproliferative disorders: pathogenetic facts and speculation

Thrombophilia, which severely impacts on morbidity and mortality of polycythaemia vera and essential thrombocythaemia, is variably characterized by microcirculatory disturbances, arterial and venous thromboses that often precede disease recognition. Thus, the search for Janus Kinase 2 mutation, the molecular marker of myeloproliferative neoplasms, is becoming increasingly common particularly in patients with vein thromboses at atypical sites. Although the pathogenesis of thrombophilia is still elusive, platelet and leukocyte abnormalities seem particularly critical and likely account for the antithrombotic efficacy of aspirin and hydroxyurea.

Bleeding and thrombosis in myeloproliferative disorders: mechanisms and treatment

2. Thrombohemor rhag ic diathesis of myeloprol i fera t ive disorders: main clinical features . . . . . . . . 204 2. I. Hemorrhag ic diathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 2.2. Thrombot i c diathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 2.2. I. Ar ter ia l th romboses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 2.2.2. Venous thromboses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 2.2.3. Pregnancy compl ica t ions in ET pat ients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 2.3. Prevalence of th rombot ic and hemorrhagic compl ica t ions . . . . . . . . . . . . . . . . . . . . . . . . . . 205 2.3.1. Incidence of hemorrhages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 2.3.2. Mor ta l i ty f rom th rombohemor rhag ic accidents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 2.4. Clinical var iables inf luencing the th rombohemor rhag ic diathesis . . . . . . . . . . . . . . . . . . . . . 209 2.4. I. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 2.4.2. History of pr ior th rombos is . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 2.4.3. Effect of the hematocr i t . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 2.4.4. Effect of white cell count . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 2.4,5. Effect of platelet count . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology.

The gut is able to maintain tolerance to microbial and food antigens. The intestine minimizes the number of harmful bacteria by shaping the microbiota through a symbiotic relationship. In healthy human intestine, a constant homeostasis is maintained by the perfect regulation of microbial load and the immune response generated against it. Failure of this balance may result in various pathological conditions. Innate immune sensors, such as Toll-like receptors (TLRs), may be considered an interface among intestinal epithelial barrier, microbiota, and immune system. TLRs pathway, activated by pathogens, is involved in the pathogenesis of several infectious and inflammatory diseases. The alteration of the homeostasis between physiologic and pathogenic bacteria of intestinal flora causes a condition called dysbiosis. The breakdown of homeostasis by dysbiosis may increase susceptibility to inflammatory bowel diseases. It is evident that environment, genetics, and host immunity form a highly interactive regulatory triad that controls TLR function. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes, such as in IBD, colitis, and colorectal cancer. The study of interactions between different components of the immune systems and intestinal microbiota will open new horizons in the knowledge of gut inflammation.

Liver Transplantation in Alcoholic Patients: Impact of an Alcohol Addiction Unit Within a Liver Transplant Center

BACKGROUND Many concerns about liver transplantation in alcoholic patients are related to the risk of alcohol recidivism. Starting from 2002, an Alcohol Addiction Unit (AAU) was formed within the liver transplant center for the management of alcoholic patients affected by end-stage liver disease and included in the waiting list for transplantation. We evaluated retrospectively the impact of the AAU on alcohol recidivism after transplantation. The relationship between alcohol recidivism and the duration of alcohol abstinence before transplant was evaluated as well. METHODS Between 1995 and 2010, 92 cirrhotic alcoholic patients underwent liver transplantation. Clinical evaluation and management of alcohol use in these patients was provided by psychiatrists with expertise in addiction medicine not affiliated to the liver transplant center before 2002 (n = 37; group A), or by the clinical staff of the AAU within the liver transplant center starting from 2002 (n = 55; group B). RESULTS Group B, as compared with group A, showed a significantly lower prevalence of alcohol recidivism (16.4 vs. 35.1%; p = 0.038) and a significantly lower mortality (14.5 vs. 37.8%; p = 0.01). Furthermore, an analysis of group B patients with either ≥6 or <6 months of alcohol abstinence before transplantation showed no difference in the rate of alcohol recidivism (21.1 vs. 15.4%; p = ns). CONCLUSIONS The presence of an AAU within a liver transplant center reduces the risk of alcohol recidivism after transplantation. A pretransplant abstinence period <6 months might be considered, at least in selected patients managed by an AAU.

Bleeding and thrombosis in myeloproliferative disorders

Patients with polycythemia vera and essential thrombocythemia have a hemostatic imbalance, the mechanisms of which are still elusive. Hemorrhagic tendency usually manifests in patients with high platelet count and reveals the clinical and laboratory features of acquired von Willebrands disease. In most patients, however, the increased risk of arterial and venous thromboses constitutes the main therapeutic challenge. Data from large retrospective studies have recently allowed us to reassess the clinical epidemiology of these manifestations. Erythromelalgia and other peculiar microcirculatory disturbances are selectively sensitive to aspirin. This finding, and the thromboxane A2 hyperproduction existing in polycythemic and thrombocythemic subjects, provide the rationale for the use of low-dose aspirin in these patients. The efficacy and safety of this treatment in patients with polycythemia vera is being tested in a large scale, randomized trial. Appropriately designed clinical studies are also needed for defining the neoplastic risk of commonly used chemotherapic agents and the antithrombotic efficacy of alternative cytoreductive strategies.