Essential thrombocythemia (ET) may occur in women of childbearing age. To investigate the risk of pregnancy complications, we studied 103 pregnancies that occurred in 62 women with ET. The 2-tailed Fisher exact test showed that pregnancy outcome was independent from that of a previous pregnancy. The rate of live birth was 64%, and 51% of pregnancies were uneventful. Maternal complications occurred in 9%, while fetal complications occurred in 40% of pregnancies. The Mantel-Haenszel method showed that fetal loss in women with ET was 3.4-fold higher (95% confidence interval [CI]: 3-3.9; P < .001) than in the general population. Half of the women studied carried the JAK2 (617V>F) mutation, and a multivariate logistic regression model identified this mutation as an independent predictor of pregnancy complications (P ‫؍‬ .01). Neither the platelet count nor the leukocyte count was a risk factor. JAK2 ( IntroductionEssential thrombocythemia (ET) is a chronic myeloproliferative disorder with an increased risk of vascular complications. Despite these events, life expectancy of patients with ET is not significantly affected by the disease in any age category. 1 Patients with ET are predominantly women, and some of them are diagnosed at childbearing age. 2 Decision-making on pregnancy is therefore a common issue in the clinical management of young women with ET.There is limited information regarding the outcome of pregnancy in patients with ET, mainly from case reports. Papers reviewing published studies on pregnancies in patients with ET 3-5 report live birth rates of 50% to 70% and spontaneous abortion rates of 25% to 50%. Concerning risk factors, the study of Wright and Tefferi 6 on 43 pregnancies indicates that preconception platelet count and aspirin therapy do not predict the risk of abortion.The JAK2 (617VϾF) mutation has been recently identified in approximately half of patients with ET. 7-10 It has been suggested that the presence of the mutation in patients with ET characterizes a disease with a higher risk of vascular events. 9 To date, the relationship between JAK2 mutational status and the outcome of pregnancy in women with ET is unknown.We studied 103 pregnancies occurring in 62 patients with ET to investigate the risk of complications and to find predictors of pregnancy outcome. Patients, materials, and methods PatientsThis study includes 103 consecutive pregnancies that occurred in 62 patients with ET who were followed between 1980 and 2006 at the Division of Hematology of the Fondazione Policlinico San Matteo, University of Pavia; the Division of Internal Medicine of the University of Padova; and the Division of Hematology of the Niguarda Ca' Granda Hospital of Milan, Italy. The study was approved by the institutional ethics committee of Pavia, and the procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000. Samples for molecular analysis were obtained after patients provided written informed consent.Diagnostic criteria of ET were those in use at the time of the fi...

A nuclear variant of phospholipid-hydroperoxide glutathione peroxidase (PHGPx, GPx-4) was considered to be derived from alternative pre-mRNA splicing in testis and to regulate sperm maturation. The genomic sequence of rat gpx-4 was established and investigated in respect to expression into the cytosolic, mitochondrial, and nuclear forms of PHGPx. In silico analysis suggested the presence of two distinct promoter regions, the upstream one leading to transcripts translating into cPHGPx or mPHGPx and the downstream one yielding nPHGPx. The promoter activity of both regions was verified by luciferase-based reporter constructs in A7r5 and H9c2 cells. The data reveal that the formation of nPHGPx is due to alternative transcription and not to alternative splicing. Transcripts encoding nPHGPx were most abundant in testis although not restricted to this organ. This observation points to a general role of the nuclear PHGPx variant in regulating cell division.

In Italy, a significant proportion of patients with autosomal dominant inheritance of macrothrombocytopenia have been recognized as having heterozygous Bernard-Soulier syndrome carrying the Bolzano-type defect. This condition prompted a systematic review of our outpatients with chronic isolated macrothrombocytopenia. We recognized that the affected members of two unrelated families represented a new variant of heterozygous Bernard-Soulier Syndrome with autosomal dominant inheritance. Sequencing analysis of the GPIbα gene revealed a novel heterozygous mutation, A169C, resulting in an N41H substitution in the protein. This aminoacid belongs to the first leucine-rich repeat of the chain. The molecular modeling suggests that the replacement of the N41 with a histidine (N41H) drastically disturbs the structure of the first portion of GPIbα N-terminal, directly involved in von Willebrand factor binding. As a consequence, platelet aggregation to 1.2 mg/mL of ristocetin is slightly impaired and flow cytometry reveals a reduced binding of monoclonals directed against N-terminal epitopes of the GPIbα.

Essential thrombocythemia (ET) is rare in children, and little or no information is available about clonality or JAK2 mutations. However, the analyses in this work prove useful for the diagnosis of adult myeloproliferative disorders (MPDs). We evaluated the clonality status and V617FJAK2 mutation in 20 children affected by ET and compared them with 47 consecutive adult ET cases. Clonality was evaluated on the DNA of granulocytes and on the RNA of platelets. V617FJAK2 was analyzed by sequencing tests, allelespecific polymerase chain reaction (PCR), and digestion by BsaXI. A monoclonal pattern was found in 4 (28.5%) of 14 children and in 45% of informative adults. Heterozygous V617FJAK2 was found less frequently in children than in adults (P < .009). Only 2 girls showed both the V617FJAK2 mutation and a monoclonal pattern; one of them was the only child presenting a major thrombotic complication. In contrast to adults, most children with ET do not show either a clonal disorder or the V617FJAK2 mutation. IntroductionThe diagnosis of essential thrombocythemia (ET) is usually made by exclusion criteria because no biologic markers are known to differentiate it either from primitive myeloproliferative disorders (MPDs) 1 or from reactive thrombocytosis. 2 The primitively proliferative nature of ET was first documented by Fialkow et al 3 who analyzed female patients for X-chromosome inactivation patterns (XCIPs) of G6PDH. It was found therein that 3 cases showed clonal expansion. However, further studies 4,5 demonstrated that only 20% to 35% of adult ET is monoclonal. Therefore, it is possible that monoclonal and polyclonal patterns define different disorders with a similar phenotype. It is relevant that recently a somatic mutation of Janus kinase 2 (JAK2) was found in about 35% to 50% of adult ET patients. 6,7 ET in pediatric age is a rare disorder that might also embed a spectrum of different diseases. 8 Unaware of previous comparative reports, we evaluated the clonal patterns and JAK2 gene mutations in pediatric ET patients. Study designWe studied 15 girls and 5 boys affected by ET in agreement with the Polycythemia Vera Study Group criteria 9 : ET diagnosed in pediatric age; platelet count continuously more than 800 ϫ 10 9 /L (range, 850-4500 ϫ 10 9 /L); and no known causes of reactive/secondary thrombocytosis. None of the children had any family history of either MPD or thrombocytosis. None had a prothrombotic condition. Moreover, in these patients, serum erythropoietin (EPO) and thrombopoietin (TPO) contents, platelet function, standard cytogenetic analysis, bcr/abl rearrangement, and sequences of TPO and c-MPL genes 10 were evaluated; no abnormality was found. The clinical findings and therapeutic options adopted are summarized in Table 1. Approval for these studies was obtained from the Padua University Department of Medical and Surgical Sciences institutional review board, and informed consent was provided according to the Declaration of Helsinki.For comparison as adult controls, 36 consecutive women and 11 men...

All patients with von Willebrand's disease (vWD) who showed an arterial or venous thrombosis and were reported in the literature have been evaluated. 11 patients had arterial thrombosis while 19 had venous thrombosis for a total of 30 cases. 9 out the 11 cases with arterial thrombosis had myocardial infarction. Two had cerebral thrombosis. Associated risk factors for arterial thrombosis were available only for three patients who showed, respectively, smoking and dyslipidemia (2 cases) and smoking and intravenous desmopressin infusion (1 case). The majority of patients with venous thrombosis showed DVT with or without PE. Four patients presented with apparently isolated PE. In two instances thrombosis occurred in unusual sites (central retinal vein and portal vein, respectively). Several associated risk factors were present, mainly: infusion of FVIII or FVIII + vWF concentrates in 7 cases; surgery in 8 cases, pregnancy in 1, desmopressin infusion in 1, variable coagulation defects or polymorphisms in 5. More than one of these associated conditions were present in a few patients. The majority of vWD patients who showed thrombotic phenomena were type I patient, but in 6 cases were also type 3. The type of defect was not reported in 6 patients. As a conclusion of this review it seems safe to assume that both arterial and venous thrombosis appear rare in vWD. This is confirmed by the fact that arterial or venous thrombosis appears slightly more frequent in hemophilia A and B.