Magnetic resonance imaging screening of cerebral thromboembolic events in children with acute lymphoblastic leukemia: a pilot study.

BACKGROUND: Thromboembolism is a complication of acute lymphoblastic leukemia therapy in children. The majority of thromboembolic events are cerebral thromboses and deep venous thromboses; many asymptomatic deep venous thromboses are detected in children with acute lymphoblastic leukemia by instrumental screening. The aim of this study was to assess the incidence of asymptomatic cerebral thromboembolic events in children with acute lymphoblastic leukemia (ALL) screened by magnetic resonance imaging and magnetic resonance venography. METHODS: 46 children with acute lymphoblastic leukemia, during the induction phase of the AIEOP ALL 2000 protocol, were stratified into 2 groups. In group "A" cerebral thromboembolic events were suspected following the appearance of suggestive signs and symptoms and confirmed by cerebral magnetic resonance imaging and magnetic resonance venography; in group "B" children underwent a screening by cerebral magnetic resonance imaging and magnetic resonance venography, at set times, in absence of symptoms. RESULTS: We observed one cerebral thromboembolic event in both groups; we found no differences between early detecting asymptomatic cerebral thromboembolic events among monitored and not monitored patients. CONCLUSIONS: Our study does not seem to suggest a screening for asymptomatic cerebral thromboembolic events in children with ALL during the induction phase.

HHT in childhood: screening for special patients.

Hereditary hemorrhagic telangiectasia (HHT) or the Rendu-Osler-Weber disease is a systemic fibrovascular autosomal dominant dysplasia, recognised when three of the following four clinical manifestations are present, according to the proposal of Shovlin.: recurrent nosebleeds, lelangiectasias of the skin, visceral lesions, and positive family history. HHT is often difficult to diagnose on the basis of history and physical examination alone, especially in infants and children. The signs and symptoms of HHT are nonspecific and are extremely variable within families. Given the frequent occurrence of clinically silent lesions in lung and brain arteriovenous malformations which can result in morbidity or death, much consideration should be given to screening patients with HHT for asymptomatic fistulae and to their treating once they are discovered. Presymptomatic interventions in such cases may substantially affect the outcome. It may be possible to state that lesions of HHT arise early in life, but do not reach sufficient size to cause symptoms until the second decade. Furthermore, as clinical manifestations often occur later in life, the development and the implementation of a molecular diagnosis will allow the identification of subjects with no evident signs of the disease but carrying the familial mutation. This is fundamental in order to establish reliable screening protocols for the prevention and cure of the disease and, to determine the presence of family members with no disease-associated mutation, who do not require further clinical screening.

Survival and complications in thalassemia.

The life expectancy of patients with thalassemia major has significantly increased in recent years, as reported by several groups in different countries. However, complications are still frequent and affect the patients' quality of life. In a recent study from the United Kingdom, it was found that 50% of the patients had died before age 35. At that age, 65% of the patients from an Italian long-term study were still alive. Heart disease is responsible for more than half of the deaths. The prevalence of complications in Italian patients born after 1970 includes heart failure in 7%, hypogonadism in 55%, hypothyroidism in 11%, and diabetes in 6%. Similar data were reported in patients from the United States. In the Italian study, lower ferritin levels were associated with a lower probability of experiencing heart failure and with prolonged survival. Osteoporosis and osteopenia are common and affect virtually all patients. Hepatitis C virus antibodies are present in 85% of multitransfused Italian patients, 23% of patients in the United Kingdom, 35% in the United States, 34% in France, and 21% in India. Hepatocellular carcinoma can complicate the course of hepatitis. A survey of Italian centers has identified 23 such cases in patients with a thalassemia syndrome. In conclusion, rates of survival and complication-free survival continue to improve, due to better treatment strategies. New complications are appearing in long-term survivors. Iron overload of the heart remains the main cause of morbidity and mortality.

Management of liver disease in thalassemia: main drug targets for a correct therapy.

Liver disease is the second cause of mortality in thalassemia major. We present a review on the hepatic damage in thalassemic patients aimed at a knowledge of current preventive, diagnostic and therapeutic approaches, useful to guide in clinical judgment and treatment decisions. Transfusion related iron overload and hepatitis are the causes of liver damage in thalassemic patients. We examined means of primary prevention, anti-hepatitis vaccinations, blood donors screening; diagnostic tests for secondary prevention (computed tomography, magnetic resonance imaging, super conducting quantum interference device and biopsy) were also discussed about. A survey of treatment methods and strategies ( chelation therapy, antiviral treatments and liver and bone marrow transplantation) follows.

Plasma protein Z levels in healthy and high-risk newborn infants.

AIM: To evaluate plasma protein Z (PZ) levels in healthy and high-risk newborn infants. METHODS: A longitudinal observational study was conducted. Inclusion criteria were: healthy term and preterm newborns normal for gestational age and newborns belonging to one of the following groups: newborns small for gestational age (SGA), newborns affected by respiratory distress syndrome (RDS), newborns from mothers with pre-eclampsia. Newborns with sepsis, congenital malformation or haemorrhagic disorders were excluded. Plasma PZ levels, protein C (PC) concentration, PC activity and protein-induced vitamin K absence levels were measured. RESULTS: 53 newborns were enrolled into the study. PZ and PC antigen levels varied significantly among analysed subgroups on day 1 (p < 0.01): lower levels of these inhibitors were found in RDS newborns (group C), newborns from mothers affected by pre-eclampsia (group D) and SGA newborns (group E) than in healthy term and preterm newborns (groups A and B). CONCLUSION: PZ deficiency occurs in newborns affected by severe RDS, in newborns from pre-eclamptic mothers and in SGA newborns, probably owing to activated coagulation in the first two conditions and to reduced PZ synthesis in the last condition.

[Nasopharyngeal colonization of Streptococcus pneumoniae in healthy children: percentage of carriers, serotypes distribution and antibiotic resistance]. / Colonizzazione nasofaringea di Streptococcus pneumoniae in bambini sani: percentuale di portatori, distribuzione dei sierotipi e antibiotico-resistenza.

AIM: The nasopharyngeal carriage of Streptococcus pneumoniae is an important risk factor for pneumococcal diseases. Data regarding prevalence and serotype distribution of this pathogen are lacking in our population. EXPERIMENTAL DESIGN: longitudinal observational cohort study. SETTING: healthy children aged 1-7 years attending day-care centers and schools of a district of a Southern Italy city. MEASURES: the nasopharyngeal colonization rate of Streptococcus pneumoniae as well as its antibiotic susceptibility was determined. RESULTS: Of 317 nasopharyngeal cultures obtained, 18.29% of the cultures were positive for Streptococcus pneumoniae; 60.34% of the isolates were serotypes 19A, 19F, 14, 6B, or 23F; 8.62% of the strains were intermediately resistant to penicillin. Erythromycin-resistance was observed in 65.51% of the micro-organisms isolated and particularly serotypes 19, 14, and 6 were more erythromycin-resistant than organisms of other serotypes. Co-trimoxazole resistance was detected in 17.24% of the strains. All the strains resulted uniformly susceptible to cefotaxime and ceftriaxone. CONCLUSION: The high rate of nasopharyngeal carriage of Streptococcus pneumoniae, along with the resistance to antibiotics widely used in the community, suggests the importance of an epidemiological surveillance as well as the application of new vaccine strategies.

Thrombin generation in children with acute lymphoblastic leukemia: effect of leukemia immunophenotypic subgroups.

Elevated plasma concentrations of endogenous thrombin generation markers and thrombotic events have been reported in children with leukemia. The aim of this study was to evaluate the effects of cancer and its treatment on thrombin generation (TAT levels) in children with acute lymphoblastic leukemia (ALL). The authors evaluated 32 children (23 M, 9 F) aged between 1 and 15 years (mean 6) affected by ALL (immunophenotypic subgroups: 16 common, 7 T, and 9 pre-B type). In all patients TAT levels at onset and after 5-6 doses of L-asparaginase were evaluated. TAT levels were higher in patients both at onset (13.04 +/- 10.90 ng/L) and after the 5-6 doses of L-asp (19.41 +/- 11.05 ng/L) with respect to controls (4 +/- 1 ng/L) (p < .001 and p < .001). TAT levels after 5-6 doses of L-asp were higher than those at onset (p < .001). Factorial ANOVA showed that at onset there was a significant effect of leukemia immunophenotypic subgroups upon TAT levels (p < .05) and no effect of inherited thrombotic risk factors. These results indicate that in children with ALL an important role is played by acquired thrombotic risk factors, among which the indirect cancer procoagulant activity has its importance.

Acute childhood idiopathic thrombocytopenic purpura: AIEOP consensus guidelines for diagnosis and treatment. Associazione Italiana di Ematologia e Oncologia Pediatrica.

BACKGROUND AND OBJECTIVE: A recent evaluation carried out by the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) about practice management of acute childhood idiopathic thrombocytopenic purpura (ITP) revealed a remarkable difference of behaviors among the different AIEOP centers. A need for common practice guidelines for this frequent illness arose from this observation. Our aim was to make the diagnosis and treatment of childhood ITP uniform. In the future we will evaluate the influence of these guidelines on practice behaviors. DATA SOURCES AND METHODS: Our main reference was the 1996 document produced by the American Society of Hematology (ASH). Their recommendations were updated with information from literature searched for in the MEDLINE database (June 1996-October 1998); search terms included: thrombocytopenia, ITP, diagnosis, therapy, children. The computerized search retrieved 83 articles. DATA EXTRACTION: the scientific validity of the literature was evaluated by a panel of members using published guidelines. The strength of the evidence was assessed using level of evidence criteria. Only data from level I and level II studies were taken in account. Only one study out of the 83 retrieved articles met these selection criteria and it was considered in addition to the 11 out of 581 articles selected in the ASH ITP guidelines. This preliminary work pointed out each issue about ITP not addressed by clinical studies and all participants in a Consensus Conference expressed their opinion about these issues. RESULTS: Diagnosis is essentially based on history, physical examination, a complete blood count and an examination of the peripheral blood smear. Treatment is recommended taking into account the clinical picture and number of platelets. The main difference between these guidelines and those from ASH are: AIEOP guidelines rely on the opinion of the members of the consensus conference, ASH ones on a panel of experts; therapeutic options include only products available in Italy; the indications to treatment rely more on clinical picture than on platelet number. INTERPRETATION AND CONCLUSIONS: These are explicitly developed, evidence-based practice guidelines to assist Italian pediatricians in making decisions about diagnosis and appropriate health care for patients with acute childhood ITP.

Lupus anticoagulant, anticardiolipin antibodies and hepatitis C virus infection in thalassaemia.

Anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) have been detected in patients with hepatitis C virus (HCV) infection and have been associated in autoimmune diseases (i.e. systemic lupus erythematosus) with an increased risk of thromboembolic events. Because of the high prevalence of HCV infection and the thrombotic risk described in thalassaemia we decided to investigate the prevalence of ACA and LA in a cohort of 68 thalassaemia patients. We found a high prevalence (34%) of beta2-glycoprotein I independent ACA in our thalassaemia patients which was related to HCV infection. None of patients developed any complications related to antiphospholipid antibodies (APL); therefore the clinical significance of positivity for APL in patients with HCV infection is at present unclear. In conclusion, the results of our study indicate that ACA in the serum of HCV-infected thalassaemic patients exhibit the characteristics of natural autoantibodies rather than those of the pathogenic autoantibodies that are found in patients with systemic lupus erythematosus.

Resistance to activated protein C in thalassaemic patients: an underlying cause of thrombosis.

We evaluated 81 thalassaemia major and 4 thalassaemia intermedia patients (48 M, 37 F), median age 17 years; 62/85 patients were HCV-positive, 3/85 HIV-positive, 19/85 were splenectomized. Forty normal healthy children were recruited as the control group. The number of thrombotic events was studied retrospectively. Platelet poor plasma was filtered and quick-frozen at -70 degrees C until time of assay. APC resistance was measured in an activated thromboplastin time and results were expressed as normalized ratio. All tests were done with diluted 1 in 5 (v/v) factor V deficient plasma and with undiluted plasma. Molecular genetic investigation of factor V gene was performed with polymerase chain reaction, followed by digestion of amplified products with restriction enzyme Mnl I. Data obtained with molecular investigation revealed the presence of 4 heterozygous subjects for factor V Leiden (4.7%). Functional tests were able to detect all heterozygotes for factor V Leiden both with undiluted and with diluted plasma, and there were no false negative subjects. However, undiluted plasma revealed a greater number of false positive subjects (n=15) than did diluted plasma. Therefore, tests done with undiluted and diluted plasma revealed a 100% sensitivity, while specificity was 81% for undiluted plasma and 97% for diluted plasma. Only one thrombotic event was observed in one of the 85 studied patients, as a case of stroke in a thalassaemia intermedia patient with APC resistance. In the same patient an additional thrombogenic risk factor was represented by a pronounced haematocrit increase at the beginning of her transfusion regimen.

rhG-CSF in severe chronic neutropenia: successful intermittent treatment in three infants.

We report three cases of infants affected by severe chronic neutropenia (SCN). All the patients were treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) to avoid or reduce recurrent fevers and severe infections. In order to obtain better compliance and reduce the costs of long-term therapy while achieving the same effectiveness of therapy, we decided to evaluate intermittent treatment in patients with SCN. With a single dose of 3-10 micrograms/kg/d subcutaneously every 3-7 days, the patient attained an absolute neutrophil count (ANC) of 0.5-1.5 x 10(9)/L, a reduction of infections, and no notable side effects.

von Willebrand factor and factor XIII in children with Henoch-Schonlein purpura.

levels of von Willebrand factor antigen (vWf:Ag) and factor XIII activity (F XIII) were studied in relation to the severity of clinical symptoms (scored from 0 to 3) and to immunological parameters [IgA, C3, C4, and circulating immune complexes (CIC)] in 16 children (7 males, 9 females, aged 3-11 years) with Henoch-Schonlein purpura (HSP) at presentation. vWf:Ag was increased in 7 patients, F XIII activity was decreased in 6. In all children we found high levels of IgA, while C3 and C4 levels were normal; CIC were elevated in 11. vWf:Ag correlated with clinical score and with IgA and CIC, probably as a result of immune-mediated endothelial cell damage. The haemostatic alterations observed in HSP are important for understanding the pathophysiology of the disease.

Association of congenital afibrinogenemia and K-dependent protein C deficiency--a case report.

The authors describe a rare case of congenital afibrinogenemia with concomitant K-dependent protein C deficit that was brought to our observation for ischemic lesions of the foot in association with fibrinogen concentrate infusions. These lesions can be attributed to the association of various factors: fibrinogen infusion without heparin coverage, microtrauma, and protein C (PC) deficit. In fact, thromboembolic complications during afibrinogenemia were previously reported usually in association with substitutive therapy, and it is also known that PC deficit predisposes to thrombotic complications. The the authors' knowledge, the case described by them is the first in which PC deficit is associated with afibrinogenemia. This association cannot be explained by a common genetic mechanism because the genes for fibrinogen and for protein C are located on different chromosomes (chromosomes 4 and 2 respectively).

[Nuclear magnetic resonance and iron overload in thalassemia]. / Risonanza magnetica nucleare e sovraccarico marziale nella talassemia.

We assessed the iron load content in 36 beta-thalassemia patients by NMR correlating the results with serum ferritin levels. 22 of them were affected by beta-thalassemia major on hyper-transfusional regimen (Group A), 4 by beta-thalassemia intermedia (Group B) and 10 by beta-thalassemia major, who had been previously bone marrow transplanted (Group C). In A and C Groups the liver showed the lowest signal intensity on spin echo images (p less than 0.01; p less than 0.06, respectively). A significant correlation between the summation of signals obtained from all the examined organs and serum ferritin levels was observed by evaluating both all the patients globally (r = 0.78; p less than 0.001) and the A and C Group patients. This correlation was confirmed only in the liver both in all the patients (r = 0.77; p less than 0.001) and in A and C Group patients, when the signals obtained from each organ were evaluated.

Thromboembolic risk in children with nephrotic syndrome.

The in vivo activation of the hemostatic system was evaluated in 14 children (4-13 years old) with nephrotic syndrome at different stages of the disease. The blood platelet count, beta-thromboglobulin (beta-TG), platelet factor 4 (PF4), fibrinogen, the coagulation inhibitors antithrombin III and protein C (ATIII:Ag and PC:Ag), and D-dimers were determined. Platelet number was significantly higher at the onset of the disease than in the next stages (p less than 0.05). beta-TG, PF4 and fibrinogen were significantly increased as compared with controls at the onset (p less than 0.001) and decreased progressively during the course of the disease without reaching the control values. Blood coagulation inhibitors behaved differently; PC was higher in patients than in controls at all stages (p less than 0.05) whereas ATIII values were significantly decreased at the onset (p less than 0.05), but increased during the course the disease (p less than 0.01). No changes were observed in the D-dimer plasma levels. These data suggest that the thrombotic risk in nephrotic syndrome is particularly evident at the onset of the disease, and appears to be due mainly to changes in platelet number and function, and to increased fibrinogen levels rather than to alterations of plasma anticoagulant factors.

[Evaluation of the effectiveness of gastro-protected proteoferrin in the therapy of sideropenic anemia in childhood]. / Valutazione dell'efficacia della proteoferrina gastroprotetta nella terapia dell'anemia sideropenica in età pediatrica.

The clinical efficacy and tolerability of gastroprotected ferritin were assessed in children affected by iron deficiency and/or sideropenic anemia. Forty-seven children with iron-deficiency and/or sideropenic anemia were included in the study and were treated with gastroprotected ferritin at a dose of 4-5 mg/kg/day per os for 4 months. Only 33 children correctly completed the entire treatment cycle, achieving a marked improvement of blood parameters (increased Hb, accompanied by higher levels of sideremia and in particular ferritin, with a contemporary decrease in erythrocytic protoporphyrin and transferrinemia) and clinical symptoms, especially pallor, anorexia, debility, somnolence, hyperactivity, disturbed sleep and excessive sweating. Of the remaining 14 children, 9 failed to present for the planned control after the 4 months of therapy, 3 abandoned therapy due to difficulties of assumption and 2 because of intolerance phenomena, such as nausea and diarrhoea. In conclusion, gastroprotected proteoferrin is efficacious and well tolerated in the treatment of iron deficiency in children.