The reagents most frequently used for FVII activity assay are obtained by rabbit brain or human placenta. In recent years, human recombinant thromboplastins have received great attention. FVII activity in FVII deficiency is usually low, regardless of the thromboplastin used. There are a few exceptions to this rule. These are represented by FVII Padua (Arg304Gln), FVII Nagoya (Arg304Trp), and FVII (Arg79Gln). In these three instances, clear discrepancies were noted in the FVII activity depending on the thromboplastin used. This indicates that at least two areas of FVII are involved in tissue binding, namely an epidermal growth factor domain of the light chain (Arg79Gln) and the catalytic domain (Arg304), controlled by exons 4 and 8, respectively. Since these three variants are cross reactive material positive, namely they are Type 2 defects, all other variants with normal antigen should be investigated by a panel of at least three tissue thromboplastins (rabbit brain, human tissue or human recombinant, and ox brain derived) in order to obtain a satisfactory classification.
University of Padua Medical School, Department of Medical and Surgical Sciences, Padua, Italy Correspondence to Professor Antonio Girolami, MD, University of Padua Medical School, Department of Medical and Surgical Sciences, Via Ospedale 105, 35128 Padua, Italy Tel: +39 049 8213026; fax: +39 049 657391; e-mail: [email protected]
Chronic Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) include polycythemia vera (PV), essential thrombocythemia (TE) and primary myelofibrosis (PMF). They are clonal diseases of the stem cell, typically affecting patients in middle-advanced age; they are extremely rare in pediatrics: in the literature only some case reports or small cohorts are found.
At the base of these diseases there is an altered signaling, as evidenced by the presence of the JAK2V617F mutation in approximately 70% of adult patients (95% PV, 50-60% in ET and PMF).
In adults, other rare mutations were identified in addition to JAK2V617F. In particular respectively 1% and 5% of cases of ET and PMF are characterized by the presence of W515L, W515K, W515A mutations of thrombopoietin receptor (MPL). Other mutations on MPL and thrombopoietin (TPO) have been found in familiar Ph-MPN.
In adults PV patients other JAK2 gene mutations were identified on exon 12 (3%).
Rare familial forms with increased serum erythropoietin (EPO) levels are due to mutations of the oxygen sensing pathway (HIF2α, PHD2, VHL genes); others with decreased EPO are associated to EPO receptor (EPOR) gene.
Paediatric MPN, when compared to adult MPN, seem to have different biological characteristics, but few data are published on this subject.
In the absence of established criteria for diagnosis, prognosis and therapeutic approach in children with MPN, a European registry of paediatric ET is built, in collaboration with the Italian Institution for Paediatric Haematology (AIEOP).
The collection of clinical and biological data on children with MPN might help in drawing correlations, in identifying differences between children and adults, in order to establish diagnostic and prognostic criteria and therapeutic guidelines, specific for the pediatric age.
ERG gene is involved in the pathogenesis of many cancers including prostate cancer, breast cancer, thyroid cancer and acute leukemia in adults. ERG is also expressed in haemopoiesis, angiogenesis, regulation of inflammation and osteogenesis. Recently ERG highlighted a role in the regulation of hematopoietic stem cells and embryonic and adult megakaryocytic maturation. In particular the overexpression of ERG induces an increase in STAT3 phosphorylation and increased intracellular levels of JAK2 and STAT5.
In hematology ERG gene expression was analyzed only in cases of pediatric and adult acute leukemia.
The purpose of the study is to evaluate the importance of gene ERG in the pathogenesis of pediatric chronic myeloproliferative neoplasms. In children chronic myeloproliferative neoplasms are not characterized by a specific marker of clonality. Therefore it is difficult to distinguish with absolute certainty from secondary forms of thrombocytosis and polyglobulia, which are extremely common in children.
Telomeres are the ends of linear chromosomes and are constituted of repeated DNA sequences associated with specific proteins.
Different studies had shown that, in patients with haematological tumour, leukocytes telomere length is shortened.
Some recent studies have reported a marked telomere length reduction in patient with Ph-negative Chronic Myeloproliferative Neoplasms. This support the possible influence of telomere length in the development of this diseases. Moreover , telomere length might be a putative indicator of the rate of neoplastic proliferation.
The aim of this study is evaluating telomere length in paediatric patients with thrombocytosis and erythrocytosis.
Congenital FVII deficiency is usually subdivided into two forms: type I and type II. Type I is characterized by a concomitant deficiency of FVII activity and FVII antigen (true deficiency). Type II is characterized by a discrepancy between FVII activity which is always low and FVII antigen which may be normal, near normal, or reduced. Thromboplastins of different origins may show a discrepant behaviour towards type II FVII deficiencies. The abnormal factor VII present in these forms may, in fact show, different levels of activity, according to the thromboplastin used in the assay system. Typical of these variants is the Arg304Gln mutation (know as FVII Padua). In this variant, FVII level is low when rabbit brain thromboplastin is used, whereas the level is perfectly normal when ox-brain thromboplastin is employed. Intermediate levels are obtained if human placenta or human recombinant is used. Since ox-brain thromboplastin is very sensitive to activated FVII, the normal FVII levels obtained in FVII Padua could be due to abnormally high circulating levels of activated FVII. The purpose of the present paper was to investigate the level of activated FVII present in homozygotes and heterozygotes with FVII Padua. For comparison, a group of patients with type I or 'true' deficiency was also investigated. A group of 21 normal patients served as controls. The activated FVII level found in FVII Padua was 8·4 and 41·0 mU/ml for homozygotes and heterozygotes, respectively. The level found in homozygous true deficiency was unassayable, whereas that found in heterozygotes was 36·2 mU/ml. The level found in the control population was 64·9 mU/ml in agreement with other reports. The low levels of activated FVIIa found in homozygotes with FVII Padua indicate that the normal FVII activity found with ox-brain thromboplastin cannot be attributed to higher than normal circulating levels of FVIIa.
Patients with a low platelet count are prone to bleeding. The occurrence of a thrombotic event in congenital thrombocytopenic patients is rare and puzzling. At least nine patients with Glanzmann thrombasthenia have been reported to have had a thrombotic event, eight venous and one arterial (intracardiac, in the left ventricle). On the contrary, three patients with Bernard-Soulier syndrome have been shown to have had arterial thrombosis (myocardial infarction) but no venous thrombosis. Finally, seven patients with the familiar macrothrombocytopenia due to alterations of the MYH9 gene have been reported to have had thrombosis (five myocardial infractions, one ischemic stroke, one deep vein thrombosis and one portal vein thrombosis). The significance of these findings is discussed with particular emphasis on the discrepancy between venous and arterial thrombosis seen in patients with Glanzmann thrombasthenia and Bernard-Soulier syndrome.
FVII Padua is a Type 2 defect owing to an Arg304Gln substitution in exon 8. The defect was originally discovered in an isolated valley in northeastern Italy. Subsequently, it was described in several other countries of the Mediterranean basin and Middle East. Recently, several proven or suspected cases have been described among Afro-Americans in the USA. This study has demonstrated the existence of at least a two-founder effect for this FVII abnormality, Mediterranean countries, and USA Afro-Americans. Patients are usually asymptomatic or only paucisymptomatic. The defect is characterized by low FVII activity when rabbit brain thromboplastins are used in the assay system. On the contrary, FVII levels are normal when ox-brain thromboplastins are used. FVII antigen is always normal.
Venous thrombosis usually involves the veins of the limbs, most frequently the leg veins. All other venous districts may sometimes be affected by the thrombotic process. Sometimes, the thrombotic occlusion of the veins of a given region show typical signs and symptoms. In other cases, the picture may not be clear and a high degree of clinical suspicion is needed for a correct approach to patient diagnosis and management. Thrombosis of retinal and jugular veins, right heart thrombosis including thrombosis of coronary sinus and thrombosis of the azygos system may be included in this group. In addition, thromboses of umbilical, renal, ovarian, spermatic, and iliac veins also require attention. Finally, the dorsal veins of the penis may also be affected by thrombotic events. The main clinical features of these thromboses are reviewed herein with suggestions for a correct diagnostic approach. The importance of sonography and of other imaging techniques is emphasized. A prompt diagnosis is of paramount importance as most of these thromboses in rare or unusual sites may still cause severe systemic complications (pulmonary embolism, sepsis, and heart failure).
Recombinant FVIIa concentrate has been originally used in the treatment of hemophilia patients with inhibitors. Recently, its use has been expanded to a variety of off-label indications. Thrombosis is the most important side effect. This may occur especially in off-label use but also in hemophiliacs with inhibitors. The present study investigated the occurrence of thrombosis in congenital bleeding disorders other than hemophilias as gathered from personal files and from the literature. Fifteen patients (seven FVII deficiency, one fibrinogen defect, four FXI deficiency, one von Willebrand disease, and two Glanzmann's Thrombasthenia) have been evaluated. Thrombosis was arterial in eight instances, venous in six, whereas in one case the type of thrombosis was unspecified. In eight cases, associated risk factors were present. Two patients with FXI deficiency had inhibitors. Dosage was variable. There was at least one fatality but in five cases evolution was not reported. The remaining patients recovered with variable sequels.
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