A case of Bernard-Soulier Syndrome due to a homozygous four bases deletion (TGAG) of GPIbalpha gene: lack of GPIbalpha but absence of bleeding.

More than 20 DNA mutations with different inheritance pattern have been described in patients with Bernard-Soulier Syndrome (BSS), leading to abnormal or absent synthesis and/or expression of GPIbalpha. Clinical phenotype shows considerable variation between individuals, such as bleeding, platelet count and the percentage of large platelets. We describe in a BSS patient the first case of homozygous four bases deletion (TGAG) in the gpIbalpha gene coding sequence, leading to a premature stop codon. In the propositus, blood smears revealed giant platelets (30 x 10(9) platelets/L), and platelet agglutination to ristocetin was absent. Propositus' parents are consanguineous. His father and paternal grandmother showed a mild thrombocytopenia (108 x 10(9)/L and 120 x 10(9)/L platelets respectively) while mothers and sister's referred normal platelet counts. The surface expression of GPIbalpha was practically undetectable by flow-cytometry and western blot in the patient and was reduced in the father. Proband's DNA analysis revealed a homozygous four-base-pair deletion (TGAG), starting from the last base of the codon for Ser39, leading to a coding frame shift with a new termination codon after 11 novel amino acids. The same mutation was seen in heterozygosis in both parents. This is the first report of GPIbalpha TGAG deletion in homozygous state even if the defect has already been described in a case of compound heterozygosis. Surprisingly, the propositus does not report any spontaneous bleeding tendency

Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden

The most common causes of morbidity and mortality in myeloproliferative neoplasms (MPN) are thrombotic and hemorrhagic complications. The JAK2V617F mutation, commonly found in MPN, correlates with several clinical and laboratory characteristics even if the relevance of JAK2V617F allele burden in the natural history of these diseases is unclear. In this study we searched, a relation between thrombotic and hemorrhagic complications and JAK2V617F allele burden level in MPN patients. We evaluated 253 consecutive MPN [121 essential thrombocythemia (ET), 124 polycythemia vera (PV), and 8 primary myelofibrosis (PMF)] patients in whom the JAK2V617F allele burden was available, all studied and followed (median 8.8 years) in our department. Patients were stratified accordingly to their JAK2V617F allele burden, into four quartiles (1st 75%). Significantly higher incidence of thromboses (p = 0.001) and hemorrhages (p < 0.001) during follow-up has been observed in higher quartiles when compared to lower ones. Thrombosis- and hemorrhage-free survivals were poorer in patients belonging to the highest quartile. Our data suggest that MPN patients with JAK2V617F allele burden higher than 75% have to be considered as high risk patients, being prone to develop thrombo-hemorrhagic complications during the disease course

JAK2V617F mutation is common in old patients with polycythemia vera and essential thrombocythemia.

Background: JAK2V617F mutation occurs in 90% of polycythemia vera (PV) and in 50% of essential thrombocythemia (ET) patients. Materials and methods: 253 consecutive patients affected by myeloproliferative disorders (MPD, 121 PV, 132 ET) were evaluated and stratified in 4 age groups: 18-39, 40-59, 60-75 and over 75 years (>75). The JAK2V617F mutation was searched and its allele burden was evaluated. Results: The percentage of mutated patients increased progressively with age mainly in patients >75 (p=0.0015 vs 18-39, p=0.0021 vs 40-59 and p=0.012 vs 60-75). We also found a progressive increase in allele burden with age (R(2)=0.042). Thrombotic events were more common in patients carrying the mutation in comparison with wild type (WT) (p=0.006, coefficient risk 1.94). No differences in the percentage of patients carrying the JAK2V617F mutation were found, in spite of different follow-up durations (15 yrs). The JAK2V617F allele burden was similar in patients with (57 +/- 31%) and without (45 +/- 26%) long-term hydroxyurea treatment. Conclusions: JAK2V617F mutation is more common in old than in young patients with MPD. Older patients have an higher allele burden

Hemostatic proteins gene polymorphisms in patients with unusal vein thrombosis and Ph-myeloproliferative disorders

The polymorphisms of FBG, F12 and GPIIIa do not determine an increased thrombotic risk in myeloproliferative disoredrs even if associated wuth JAK2 mutation and the development of spontaneous colony formatio

Effect of busulfan on JAK2V617F allele burden.

not all patients who had undergone BU therapy have a significant decrease in JAK2V617F allele burde

Synthesis and cytotoxicity properties of amiodarone analogues.

IF 3.269, Quartile 1, 6\ub0 nome, punti

Reduced in vivo biological activity of in vitro glycosylated insulin.

We evaluated the in vivo biological activity of in vitro extensively glycosylated insulin (GI) with the euglycemic-hyperinsulinemic glucose-clamp technique in postabsorptive nondiabetic subjects. Insulin-mediated glucose disposal was approximately 30% lower (P less than .03) with GI (9.2 +/- 1.2 mg.kg-1.min-1, mean +/- SE) than with the nonglycosylated hormone (12.6 +/- 0.7 mg.kg-1.min-1) at comparable plasma insulin concentrations (approximately 90 microU/ml). Binding of GI to a specific receptor on circulating cells (erythrocytes and monocytes) was normal. We conclude that in vitro extensive glycosylation of insulin reduces its biological activity in vivo, as reflected by insulin-mediated glucose disposal, probably at a postreceptor level