Mortality and causes of death in Italian persons with haemophilia, 1990-2007.

Although a number of studies have analysed so far the causes of death and the life expectancy in haemophilic populations, no investigations have been conducted among Italian haemophilia centres. Thus, the aim of this study was to investigate mortality, causes of deaths, life expectancy and co-morbidities in Italian persons with haemophilia (PWH). Data pertaining to a total of 443 PWH who died between 1980 and 2007 were retrospectively collected in the 30 centres who are members of the Italian Association of Haemophilia Centres that chose to participate. The mortality rate ratio standardized to the male Italian population (SMR) was reduced during the periods 1990-1999 and 2000-2007 such that during the latter, death rate overlapped that of the general population (SMR 1990-1999: 1.98 95% CI 1.54-2.51; SMR 2000-2007: 1.08 95% CI 0.83-1.40). Similarly, life expectancy in the whole haemophilic population increased in the same period (71.2 years in 2000-2007 vs. 64.0 in 1990-1999), approaching that of the general male population. While human immunodeficiency virus infection was the main cause of death (45%), 13% of deaths were caused by hepatitis C-associated complications. The results of this retrospective study show that in Italian PWH improvements in the quality of treatment and global medical care provided by specialized haemophilia centres resulted in a significantly increased life expectancy.

Pharmacokinetics and safety of fibrinogen concentrate.

BACKGROUND: Although fibrinogen concentrate has been available for the treatment of congenital fibrinogen deficiency for years, knowledge of its pharmacokinetics comes from only two small studies. OBJECTIVES: To assess the pharmacokinetic (PK) profile, clot integrity and safety of fibrinogen concentrate (human) (FCH) in patients with afibrinogenemia. PATIENTS AND METHODS: A multinational, prospective, open-label, uncontrolled study of patients with afibrinogenemia > or = 6 years of age was conducted in the USA and Italy. Plasma was collected before and after infusion for PK analyses and evaluation by rotational thromboelastometry of maximum clot firmness (MCF) to assess clot integrity. Safety was assessed on the basis of adverse events and laboratory parameters. RESULTS: After a single dose of 70 mg kg(-1) body weight (b.w.) FCH in 14 patients, median incremental in vivo recovery was a 1.7 mg dL(-1) increase per mg kg(-1) b.w., and median levels were 1.3 g L(-1) for fibrinogen activity and antigen 1 h after infusion. Median half-life (t(1/2)) was 77.1 h for fibrinogen activity and 88.0 h for antigen. Plasma recovery in children < 16 years old was similar to that in adults aged 16 to < 65 years, but the t(1/2) and area under the curve were decreased, with an increased steady-state volume and clearance. MCF increased by a mean of 8.9 mm from baseline to 1 h after infusion of FCH (P < 0.0001). All four adverse events reported were mild, and none was serious or related to study drug. CONCLUSIONS: These PK findings confirm a rapid increase in plasma fibrinogen levels after infusion with FCH. Together with the clot integrity and safety data and published data on efficacy, the results support the idea that FCH substitution can restore hemostasis with a good safety profile.

Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response.

Immune tolerance induction (ITI) is effective in approximately 70% of haemophilia patients with inhibitors. Poor prognostic factors are age >6 years, ITI started >1 year from inhibitor development, inhibitor peaks >200 BU, inhibitor titre >10 BU when ITI is started and previously failed ITI. The objective of this study was to identify the effectiveness in ITI of a high purity von Willebrand factor/factor VIII (VWF/FVIII) complex concentrate in inhibitor patients at high risk of failure. Patients with severe or moderate haemophilia A and high responding inhibitors who had at least one poor prognostic factor for ITI failure were prospectively followed-up. Success was defined by undetectable inhibitor, recovery and half life >66% of expected values. ITI dose regimens were chosen by each haemophilia centre. Seventeen haemophiliacs (16 severe, one moderate), aged 4-54 years (median 23) were followed-up for 6-71 months. Poor prognostic factors were delayed-onset ITI (n = 16), age >6 years (n = 16), previously failed ITI (n = 4), inhibitor peak >200 BU (n = 2) and inhibitor >10 BU when ITI was started (n = 4). Complete success was obtained in nine patients (53%) after 4-30 months of treatment (median 24), including two of four patients who had previously failed ITI. Seven patients achieved a partial success, with sustained low inhibitor titres (median 1.5 BU, range 1.1-2.8) but abnormal recovery and/or half-life, while the remaining patient withdrew ITI after 12 months when the inhibitor titer was still 70 BU. These findings suggest that high purity VWF/FVIII complex concentrates are effective in ITI, even in patients at high risk of failure.

Congenital afibrinogenemia: mutations leading to premature termination codons in fibrinogen A alpha-chain gene are not associated with the decay of the mutant mRNAs.

Congenital afibrinogenemia is a rare coagulation disorder with autosomal recessive inheritance, characterized by the complete absence or extremely reduced levels of fibrinogen in patients' plasma and platelets. Eight afibrinogenemic probands, with very low plasma levels of immunoreactive fibrinogen were studied. Sequencing of the fibrinogen gene cluster of each proband disclosed 4 novel point mutations (1914C>G, 1193G>T, 1215delT, and 3075C>T) and 1 already reported (3192C>T). All mutations, localized within the first 4 exons of the A alpha-chain gene, were null mutations predicted to produce severely truncated A alpha-chains because of the presence of premature termination codons. Since premature termination codons are frequently known to affect the metabolism of the corresponding messenger RNAs (mRNAs), the degree of stability of each mutant mRNA was investigated. Cotransfection experiments with plasmids expressing the wild type and each of the mutant A alpha-chains, followed by RNA extraction and semiquantitative reverse-transcriptase-polymerase chain reaction analysis, demonstrated that all the identified null mutations escaped nonsense-mediated mRNA decay. Moreover, ex vivo analysis at the protein level demonstrated that the presence of each mutation was sufficient to abolish fibrinogen secretion.

Survival after AIDS among Italian haemophiliacs with HIV infection. The Italian Group on Congenital Coagulopathies.

OBJECTIVES: To estimate survival trends for persons with haemophilia and HIV/AIDS. DESIGN AND METHODS: Survival analysis conducted among the cohort of HIV-positive haemophiliacs with AIDS at the Italian Haemophilia Registry. Kaplan-Meier method was used to estimate survival times, stratifying for demographic and clinical covariates. Cox proportional hazards model was applied in order to identify factors independently associated with survival. RESULTS: Median survival from the first AIDS diagnosis to death was estimated to be 17.0 months for 176 individuals with AIDS. Median survival after AIDS diagnosis increased from 12.0 months in December 1983-December 1988 to 17.0 months in January 1989-May 1990 and to 25.0 months in June 1990-December 1991. Median survival times were significantly (P < 0.001) lower for individuals diagnosed with non-infective AIDS indicator diseases (lymphoma, AIDS-associated neurological disease, Kaposi's sarcoma, wasting syndrome: 4.0 months), in comparison with haemophiliacs diagnosed with Pneumocystis carinii pneumonia (PCP; 18.0 months) or other infections (35.0 months). Antiretroviral treatment after AIDS diagnosis was associated with a longer survival than that estimated for individuals with no treatment after AIDS; the same was true for PCP prophylaxis. Younger age at HIV seroconversion and at AIDS diagnosis were associated with a longer survival. Multivariate analysis showed that factors independently associated with survival were type of AIDS indicator disease and antiretroviral administration after AIDS diagnosis. CONCLUSIONS: This study indicates an increasing survival from AIDS diagnosis to death over time, also as a result of the introduction of antiretroviral therapy. Survival trends are similar to those reported among homosexual men and intravenous drug users with AIDS, suggesting a similar access to the health-care system for individuals with AIDS. Survival studies may improve our understanding of the natural history of HIV infection and may indicate the impact of preventive measures.

Isolation, characterization and pharmacological activity of Magydaris pastinacea (Lam) Paol. glucosides.

The glycoside fraction of fresh rhizomes from Magydaris pastinacea (Lam.) Paol. was separated from the alcoholic extract using the method of Kobayashi et al. The fraction was found to have six main constituents, the most abundant of which had previously been isolated and identified as 7-O-beta-D-glucopyranosyl-8-(2',3'-dihydroxy-3-methyl-butylcoumarin++ +). The present paper describes the separation and characterization of the other constituents, all with coumarin or furancoumarin structures. Pharmacological experiments to test these compounds as platelet antiaggregants are also reported.

Orthotopic liver transplantation in a patient with severe hemophilia A: a life-saving treatment for the first Italian case.

Clinical cure of hemophilia A by orthotopic liver transplantation has been reported in 11 cases. We describe the first successful Italian case. A 27-year-old man had cirrhosis caused by previous infections with the hepatitis B, C and D viruses following life-long treatment with factor VIII concentrates made from large plasma pools. He was, however, seronegative for the human immunodeficiency virus. In the year before transplantation, life-threatening gastrointestinal bleeding due to severe esophageal varices required a large transfusion regimen (on average, 13 bags of red cell concentrates and 35,000 U of factor VIII/week). To perform orthotopic liver transplantation 8,000 U of factor VIII were given during surgery together with 10 bags of red cells and 11 of fresh-frozen plasma. Intraoperative bleeding was not different from that of non-hemophilic patients undergoing orthotopic liver transplantation. No additional factor VIII was used after transplantation and factor VIII levels in plasma were always above 50 U/dl, reaching the highest value of 184 U/dl on day 4 post transplantation. He was discharged from hospital 10 weeks after transplantation with factor VIII levels of 68 U/dl. All virological markers are currently negative, except anti-hepatitis C virus antibodies. In this patient orthotopic liver transplantation was a life-saving treatment for end-stage cirrhosis and a cure for hemophilia A.