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.

[Genetic mutations, acquired coagulation system disorders and obstetric pathology. Personal experience]. / Mutazioni genetiche, disordini acquisiti nel sistema coagulativo e patologia ostetrica.

BACKGROUND: To evaluate the incidence of thrombophilic disorders such as Factor II mutation, Leiden factor V and MTHFR genotype, and anti-phospholipid anti-bodies syndrome in women with or without pregnancy related problems. METHODS: Sixty-three patients (group A) with pregnancy complications were included in the study and tested for Factor V mutation, Factor II mutation, 5-10 MTHFR reductase mutation and anti-phospholipid antibodies syndrome. The incidence of disorders was compared with thirty-six pregnancies without complications (control study, group B). RESULTS: Hemostasis thrombophilic like disorders, were significantly high (p=0.001 vs group B). Nobody in both groups was homozygous for Leiden mutation or prothrombin mutation (Factor II). The prevalence of Factor V mutation in heterozygosis was significantly (p=0.01) higher in group A in comparison with group B. The MTHFR mutation in homozygosis was found in 21.4% of group A while in the control group it was 11%. Factor II mutation in heterozygosis and anti-phospholipid antibodies were found only in group A. CONCLUSIONS: It is important to evaluate the hemocoagulation patterns in women with a history of complicated pregnancies.

A missense mutation (Y1702C) in the coagulation factor V gene is a frequent cause of factor V deficiency in the Italian population.

BACKGROUND AND OBJECTIVES: Factor V (FV) deficiency is a rare bleeding disorder whose molecular bases are poorly characterized. We have recently described a FV missense mutation (Y1702C) predicting reduced FV levels in a thrombophilic patient and in a healthy individual. The aim of the present work was to assess the prevalence of the FV Y1702C mutation among subjects with FV deficiency. DESIGN AND METHODS: Carriership of the FV Y1702C mutation was tested in 8 patients with severe FV deficiency (FV:C <8%), in 16 individuals with asymptomatic partial FV deficiency (mean FV:C 38.0%, SD 11.6%) and in 9 patients with pseudo-homozygous APC-resistance (mean FV:C 46.2%, SD 3.6%). An AccI-restriction protocol was employed for rapid mutation screening. RESULTS: The FV Y1702C mutation was detected in two unrelated patients with unmeasurable FV levels (one being homozygous and the other doubly heterozygous for a still unknown mutation) and in one subject with partial FV deficiency (FV:C 30%). A striking difference in bleeding phenotype was observed between the homozygous patient and her asymptomatic brother with the same FV genotype. A multi-point FV haplotype analysis was performed in all unrelated carriers of the FV Y1702C mutation. Three haplotypes were found to underlie the mutation in different individuals, suggesting that it might have arisen independently more than once. INTERPRETATION AND CONCLUSIONS: FV Y1702C is a common cause of FV deficiency in the Italian population and might be a recurrent mutation.

Arterial and venous thrombosis in two Italian families with the factor V Arg506-->Gln mutation.

APC resistance, due to a point mutation in factor V at amino acid position Arg506, has been identified as a major cause of inherited thrombophilia. Here we report the presence of the factor V Arg506-->Gln mutation in 2 Italian families. In 1 family 3 subjects heterozygous and 2 subjects homozygous for the factor V Arg506-->Gln mutation were identified. The only subject who developed a thrombotic event was a 20-yr-old girl who was found to be homozygous for the factor V Arg506-->Gln mutation. In the second family 10 subjects were identified to be heterozygous for the factor V Arg506-->Gln mutation; among them 2 developed a thrombotic event. In the same family 2 individuals were found to be homozygous for the mutation: the first had a myocardial infarction at age 25 yr and the second suffered from multiple episodes of deep venous thrombosis and had a stroke at age 24 yr. These data show that the risk of developing deep venous thrombosis for the carriers of the factor V Arg506-->Gln mutation is high in the families investigated. Furthermore our data imply that the factor V Arg506-->Gln mutation in its homozygous form may relate to myocardial infarction and stroke.

Accelerated schedule of hepatitis B vaccination in patients with hemophilia.

Early development of immunity after hepatitis B vaccination is particularly important for patients such as hemophiliacs, at high risk for acquiring hepatitis B from potentially infectious plasma-derived concentrates. The purpose of this study was to evaluate whether or not protective antibody titers could be achieved quickly and maintained in hemophiliacs by an accelerated vaccination schedule. A yeast-recombinant hepatitis B vaccine (Engerix B, SKF Ritt) was given subcutaneously in the deltoid region and repeated 2 and 6 weeks later to 85 hemophiliacs negative for hepatitis B virus (HBV) markers. After the first 22 patients had been enrolled, a modification of the schedule involving a fourth booster dose 24 weeks after the first dose of vaccine was applied to the next 63 consecutive vaccines. Fifty-three percent of vaccinees had antibody titers to hepatitis B surface antigen (anti-HBs > or = 10 mlU/ml) by week 6, even though the mean titers of anti-HBs were somewhat lower than those achieved historically in normal individuals. The protection rate had increased to 87% by week 10, one month after the third dose of vaccine, and to 93% by week 24. One year after starting vaccination, the rate for the vaccinees who did not receive the fourth booster dose was 71%, and 96% for those who did receive the fourth dose, with only 2 patients not responding despite the booster dose. It is concluded that even though the accelerated schedule of immunization produced rapidly high rates of protective antibody titers, a booster dose is required to obtain higher titers and provide more persistent immunity.

Cefixime does not affect polymorphonuclear cell and monocyte functions from chronic lymphoid leukemia patients and from healthy donors.

It is well documented that to evaluate the efficacy of an antibiotic treatment it is important to know the relationships between the drug and the cells belonging to the immune system, by studying the possible effects on some cellular functions, particularly in immunosuppressed and immunodeficient patients. We describe the influence of cefixime, a new orally administered cephalosporin, on some polymorphonuclear cell (PMN) and monocyte functions from healthy donors and from patients affected by chronic lymphoid leukemia (CLL).

Diagnosis of hemophilia A in a female subject by using restriction fragment length polymorphisms linked to the factor VIII gene.

A 6-year-old girl, daughter of a male patient with moderate hemophilia A (factor VIII 3%), was referred to our Center because she also had very low levels of factor VIII (4%). The proband's brother has mild hemophilia A (7%); the mother (29%) is a possible carrier, no other case of hemophilia A being reported in her family. Hence, the factor VIII deficiency found in the girl is consistent either with a carrier state with extreme lyonization in favour of the hemophilic gene or with homozygosity for the hemophilia gene. To distinguish these possibilities, we studied the segregation of three restriction fragment length polymorphisms (RFLPs) linked to the factor VIII gene in the 4 members of the family. Employing one intragenic (FVIII-BclI) and two extragenic (St14-TaqI and Dx13-BglII) RFLPs, we showed that the proband has inherited from both parents the defective gene, being therefore homozygous for the hemophilia gene.

Recurrent life-threatening epistaxis in a child with Bernard-Soulier syndrome controlled by bilateral ligation of external carotids and ethmoidal arteries.

Bilateral ligation of external carotids and ethmoidal arteries proved successful in controlling severe recurring epistaxis in a 13-year-old patient with Bernard-Soulier syndrome. In this child, epistaxis was the major bleeding symptom. Despite massive substitutive therapy, the patient suffered several life-threatening episodes of hypovolaemic shock. Although epistaxis is not reported as a cause of death in patients with haemostasis defect, our case might suggest that in selected cases with inherited platelet defect and intractable epistaxis so severe as to make normal or near-normal life impossible, surgical treatment could be considered.