No abstract

Combined deficiency of factors V and VIII is an autosomal recessive bleeding disorder resulting from alterations in an unknown gene on chromosome 18q, distinct from the factor V and factor VIII genes. ERGIC-53, a component of the ER-Golgi intermediate compartment, was mapped to a YAC and BAC contig containing the critical region for the combined factors V and VIII deficiency gene. DNA sequence analysis identified two different mutations, accounting for all affected individuals in nine families studied. Immunofluorescence and Western analysis of immortalized lymphocytes from patients homozygous for either of the two mutations demonstrate complete lack of expression of the mutated gene in these cells. These findings suggest that ERGIC-53 may function as a molecular chaperone for the transport from ER to Golgi of a specific subset of secreted proteins, including coagulation factors V and VIII.

The form of von Willebrand's disease characterized by a qualitative abnormality of Factor VIII/von Willebrand factor (FVIII/vWF) in plasma has been designated as Type II. We have now identified 20 persons from five families whose qualitatively abnormal FVIII/vWF shows heightened responsiveness to ristocetin. We have classified this form of the disease as Type IIB and reclassified as Type IIA the form previously described as Type II, in which the interaction of the abnormal FVIII/vWF with platelets is decreased or absent in the presence of ristocetin. The enhanced reactivity of FVIII/vWF in Type IIB was evident in studies of ristocetin-induced platelet agglutination and of binding of FVIII/vWF to platelets in the presence of ristocetin. In both Type IIA and IIB, crossed immunoelectrophoresis of plasma FVIII/vWF demonstrated similar absence of the larger, less anodic forms. These findings suggest that ristocetin-mediated interactions between platelets and FVIII/vWF do not accurately reflect the "bleeding-time" (von Willebrand factor) defect in this newly described subtype of von Willebrand's disease.

No abstract

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.