Low-molecular weight heparins are currently the most commonly used anticoagulants in children and newborns. However, since thrombotic complications rarely occur outside large children’s hospitals, physicians often encounter some practical problems inmanaging these treatments when a pediatric thrombosis specialist is not available. The drug of choice is enoxaparin, due to its favorable FXa/FIIa ratio and the availability of pharmacokinetic and pharmacodynamic data. The treatment of acute thrombosis should be started with two daily injections but when compliance is an issue, a single daily administration schedule could be chosen for secondary prophylaxis ensuring careful measurement of the post 24-hour anti-FXa activity. Furthermore, a subcutaneous device may be a useful tool and a topical dermal anesthetic could be effective in controlling pain without affecting anti-FXa levels. In neonate and toddlers, where mini doses are frequently needed, the dead space of syringes and needles could represent an issue and therefore the use of insulin syringes without dead space is advisable,while a dilution of the drug is useful with other syringes. This article derives froma nonsystematic review of the available literature, with special attention to recent international guidelines and expert recommendations, combined to authors’ clinical practice in large tertiary pediatric hospitals and will provide concise and practical information for the use of low-molecular weight heparin in childhood and infancy in a sort of “answering frequently asked questions.”

Derangement of genetic and immunological factors seems to have a pivotal role in the pathophysiology of immune thrombocytopenic purpura (ITP). We investigated interleukin(IL)-10 genetically determined expression in children with an acute progression of ITP (n=41) compared to young patients with chronic ITP (n=44) and healthy controls (n=60), and attempted to correlate IL-10 production with the course of the disease. We genotyped our study population for three single nucleotide polymorphisms at positions -1082 (A/G), -819 (C/T) and -592 (C/A) in the promoter region of the IL-10 gene. IL-10 levels were measured by enzyme-linked immunoassay. The IL-10 production in our study population was significantly higher in patients carrying the GCC haplotype than those bearing ACC and ATA haplotypes (6.9±1.5 vs 3.6±0.8 vs 3.3±0.3, p=0.03). The serum concentration of IL-10 was significantly higher in patients with an acute course of their disease, who mainly carried the GCC haplotype (92%), compared to chronic subjects, bearing the non-GCC haplotypes, and controls [17pg/mL (1.7-18) vs 3.5pg/mL (0.6-11) vs 3pg/mL (1-7), p<0.01)]. Our findings show that patients carrying the GCC-high producer IL-10 haplotype have an acute development of ITP and that IL-10 levels might represent a useful predictive biomarker of the disease course.

Kabuki syndrome (also called Niikawa-Kuroki syndrome) is a rare genetic disease described for the first time in Japan, characterised by anomalies in multiple organ systems and often associated with autoimmune disorders and impaired immune response. We herein report the clinical history, the therapeutic approach and the outcome of two children with Kabuki syndrome who developed autoimmune haematological disorders (haemolytic anaemia and immune thrombocytopenia). Factors regarding differential diagnosis and interventions in better management of this syndrome and its complications are discussed. This is the first report of Italian children with autoimmune haematological disorders complicating Kabuki syndrome.

Immune thrombocytopenic purpura (ITP) is characterized by reduced platelet count secondary to immune-mediated destruction, this results in an increased bleeding risk. Autoantibodies binding to platelets tag them for premature destruction in the spleen. For this reason, splenectomy is often performed as treatment of chronic forms of disease that are resistant to pharmacological therapy.

Abstract: Fruits and vegetables (typically associated with the Mediterranean diet) are very rich in carotenoids, i.e. fat-soluble pigments really important in human life. Structurally, carotenoids consists of eleven (beta-carotene, zeaxanthin, lycopene) or ten (alpha-carotene, lutein) conjugated double bonds, responsible for their antioxidant capability in agreement with their substituents. Low-Density Lipoprotein (LDL) particles oxidation process is the one of the most important first steps of atherosclerotic disease and, consequentially, the first pathogenetical step of cerebro- and cardiovascular events like myocardial infarction and stroke, which are the first cause of death in industrialized countries. Reactive oxygen species (ROS) also seem to be the target of Carotenoids main action, by scavenging singlet oxygen ( 1 O ) and free radicals. Literature data showed that ROS increase atherosclerotic individual burden. The carotenoids scavenging action could reduce atherosclerosis progression partly due to such a decrease in ROS concentrations. Many studied demonstrated such a 2 reduction by analyzing the relationship between carotenoids and Intima-Media Thickness of common carotid artery wall (CCA-IMT), [a well established marker of atherosclerosis evolution] reduction. Aim of this review is to evaluate actual knowledge about the importance of carotenoids molecules in slowing down the starting and the progression of atherosclerotic plaque, and to consider their implementation in everyone's diet as a tool to obtain a sharp decrease of LDL oxidation and their possible effect on endothelial function.

Central venous catheters (CVCs) are essential in the management of pediatric patients receiving antineoplastic therapy or bone marrow transplants, and have significantly improved their quality of life, but CVC-related infectious complications are a major source of morbidity. It has been estimated that 14–51 % of the CVCs implanted in children with malignancies may be complicated by bacteremia, and that the incidence of infections is 1.4–1.9 episodes per 1,000 CVC days. However, there are few recent data concerning the epidemiology of CVC-related infections, the prevalence of antimicrobial resistance in their etiology, or the main factors associated with an increased risk of infection by type of catheter, patient age, the type of cancer, or the presence of neutropenia. Moreover, although various new strategies have been proposed in an attempt to reduce the risk of CVC-related infections, such as catheters impregnated with antiseptics/antibiotics, lock antibiotic prophylaxis, the use of ointments at the exit site, and antithrombotic prophylaxis, their real efficacy in children has not yet been demonstrated. The management of CVC-related infections remains difficult, mainly because of the number of still open questions (including the choice of optimal antimicrobial therapy because of the increasing isolation of multiresistant bacterial strains, treatment duration, whether catheters should be removed or not, the feasibility of guidewire exchange, and the usefulness of antibiotic lock therapy) and the lack of studies of children with cancer. Only well-designed, prospective clinical trials involving pediatric cancer patients can clarify optimal prevention and treatment strategies for CVC-related infections in this population.

Asthma and obesity are two common disorders often associated in children and characterized by an inflammatory status. Growing evidences support a connection between obesity and asthma since weight reduction can improve asthmatic symptoms. In this study, we have enrolled eighty children: 17 non asthmatics and non obese, 19 obese, 28 asthmatics-obese and, 16 asthmatics non-obese, respectively. In all participants, respiratory functional tests and body mass index (BMI) were calculated. Moreover, systemic inflammation of biomarkers such as T helper (h)1-type, Th2-type and T regulatory-type serum cytokines along with major adipokines was determined. Data will show that the association between asthma and obesity leads to a predominant Th1-type response with an increase in pro-inflammatory cytokines. This inflammatory profile in asthmatics-obese children is sustained by elevated serum levels of leptin and visfatin, while adiponectin concentration is rather diminished. Finally, levels of systemic inflammatory biomarkers positively correlate with the increase in BMI values in all population subgroups.

Objective To evaluate clinical data and associated risk conditions of noncerebral systemic venous thromboembolism (VT), arterial thromboembolism (AT), and intracardiac thromboembolism (ICT) in neonates. Study design Data analysis of first systemic thromboembolism occurring in 75 live neonates (0-28 days), enrolled in the Italian Registry of Pediatric Thrombosis from neonatology centers between January 2007 and July 2013. Results Among 75 events, 41 (55%) were VT, 22 (29%) AT, and 12 (16%) ICT; males represented 65%, and 71% were preterm. In 19 (25%), thromboembolism was diagnosed on the first day of life. In this "early onset" group, prenatal-associated risk conditions (maternal/placental disease) were reported in 70% and inherited thrombophilia in 33%. Postnatal risk factors were present in 73%; infections and central vascular catheters in 56% and 54% VT, respectively, and in 67% ICT vs 27% AT (<.05). Overall mortality rate was 15% and significant thromboembolism-related sequelae were reported in 16% of discharged patients. Conclusions This report from the Registro Italiano Trombosi Infantili, although limited by representing an uncontrolled case series, can be used to develop future clinical trials on appropriate management and prevention of neonatal thrombosis, focusing on obstetrical surveillance and monitoring of critically ill neonates with vascular access. A thrombosis risk prediction rule specific for the neonatal population should be developed through prospective controlled studies. © 2016 Elsevier Inc.

Background. Biological markers useful for defining children with newly diagnosed immune thrombocytopenic purpura (ITP) who are likely to develop the chronic form of the disease are partially lacking. The purpose of this study was to assess the clinical role of both immunological and thrombopoietic markers in children with ITP and correlate their levels with different disease stages. Materials and methods. We enrolled 28 children with ITP at the onset of their disease, who were followed-up for a whole year and divided according to whether their disease resolved within the 12 months (n=13) or became chronic (n=15), 11 subjects with chronic ITP off therapy for at least 1 month at the time of enrolment, and 30 healthy matched controls. Serum levels of T helper type 1 and 2 and T regulatory-associated cytokines, such as interferon γ, tumour necrosis factor α, interleukin (IL) 2, IL6, IL10, and thrombopoietin were measured in all children using quantitative immunoenzymatic assays, while reticulated platelets were evaluated by flow cytometric analysis. Results. Serum IL10 levels were significantly higher in patients with an acute evolution of ITP than in either healthy controls (p<0.001) or patients with chronic progression of ITP (p<0.05). Reticulated platelet count and thrombopoietin levels were significantly higher in ITP patients at the onset of their disease, whether with acute resolution or chronic progression, than in healthy subjects (p<0.01; p<0.001), but did not differ between the groups of patients. Conclusion. IL-10 seems to predict the clinical course of ITP, as it is significantly higher at the onset of disease in patients who obtain disease remission in less than 1 year.

BACKGROUND: The prevalence of chronic pain is about 30% in children and adolescents which suffer from severe emotional distress. The aim of this observational study is to investigate cognitive, emotional and behavioral consequences of benign chronic pain in children and adolescents suffering of reumathologic diseases. MATERIALS AND METHODS: A total of 49 participants, chronic pain participants (CPPs) and controls (CGPs), affected by rheumatic diseases, were enrolled. Assessment included collection of sociodemographic data, pain characteristics, and administration of Visual Analog Scale (VAS), Depression Inventory for Children and Adolescents (CDI), Conners' Parent Rating Scales-Revised (CPRS-R), Child Behavior Checklist (CBCL), and Screen for Child Anxiety-Related Disorders (SCARED). For the statistical analysis, Student's t-test for independent samples and Pearson's correlation were used. The significance value was set at p less than .05. RESULTS: A significant difference of mean scores of CBCL items and of CPRS items between the two groups was found. In CPPs, a significant correlation between VAS and mean scores of several CBCL items and between VAS and mean scores of several CPRS items was found. CONCLUSION: Chronic pain is a real syndrome in which an interdisciplinary treatment should be applied, considering the psychopathological risk, especially in developmental age.

Hemophilias are the most known inherited bleeding disorders. The challenges in the management of hemophilic children are different from those in adults: prophylaxis regimen removed the hallmark of crippling disease with lifelong disabilities; individualized regimens are being implemented in order to overcome venous access problems. Presently, at least in high-income countries, advances in treatment of hemophilia resulted in continuous improvement of the patients' quality of life and life expectancy. Inhibitors remain the most severe complication of hemophilia therapy. The treatment' compliance is the key to achieve a successful management. The patient, his family, the medical and psychological team are the players of a comprehensive care system. The current management of hemophilic children is the example of huge resource investments enabling long-term benefits in particular quality of life as a primary objective of the healthcare process.

BACKGROUND: The eradication of Helicobacter pylori has been associated with remission of immune thrombocytopenia (ITP) in approximately half of eradicated patients. Data on children are limited to small case series. PROCEDURE: Children from 16 centers in Italy, who were less than 18 years of age and diagnosed with chronic ITP (cITP), were screened for H. pylori infection. Positive patients underwent standard triple therapy with amoxicillin, clarithromycin, and omeprazole. The eradication response was defined as follows: complete response, platelet (PLT) count ≥ 150 × 10(9) /L; partial response, PLT count of at least 50 × 10(9) /L; no response, PLT count <50 × 10(9) /L. RESULTS: Of 244 screened patients, 50 (20%) had H. pylori infection, 37 of which received eradication therapy and completed follow-up. Eradication was successful in 33/37 patients (89%). PLT recovery was demonstrated in 13/33 patients after eradication (39%), whereas spontaneous remission was observed in 17/166 (10%) H. pylori-negative patients (P < 0.005). Responders more often required second line eradication (9/13), whereas a second cycle was required in 3/20 non-responders (P < 0.005). CONCLUSIONS: Among the large cohort of patients, those who underwent successful H. pylori eradication showed a significantly higher PLT response. Therefore, it may be appropriate to look for H. pylori and eventually eradicate it in children with cITP.

Background. The aim of this study was to investigate the effect of the combined administration of intravenous immunoglobulins and steroids as a second-line therapy in 34 children with primary immune thrombocytopenia and persistent, symptomatic bleeding. Materials and methods. Combined therapy (intravenous immunoglobulins 0.4 g/kg daily on days 1 and 2, and methylprednisolone 20 mg/kg daily on days 1-3) was administered to 12 patients with newly diagnosed ITP who did not respond to the administration of a single therapy (either intravenous immunoglobulins or steroids) and to 22 children with persistent and chronic disease who required frequent administrations (i.e. more frequently than every 30 days) of either immunoglobulins or steroids (at the same standard dosages) in order to control active bleeding. Results. A response (i.e. platelet count >50×109/L and remission of active bleeding) was observed in 8/12 (67%) patients with newly diagnosed ITP. The clinical presentation of responders and non-responders did not differ apparently. Patients in the chronic/persistent phase of disease had a significantly longer median period of remission from symptoms compared with the previous longest period of remission (p=0.016). The treatment was well tolerated. Discussion. Our data suggest that the combined approach described is a well-tolerated therapeutic option for children with primary immune thrombocytopenia and persistent bleeding symptoms that can be used in both emergency and/or maintenance settings.

Context: Pediatric obesity is associated with endothelial dysfunction and hypoadiponectinemia, but the relationship between these two conditions remains to be fully clarified. Whether enhanced release of endothelin-1 (ET-1) may directly impair adiponectin (Ad) production in obese children is not known. Objective: The aim of the study was to explore whether and how high circulating levels of ET-1 may contribute to impair Ad production, release, and vascular activity. Design and Participants: Sixty children were included into obese (Ob; n = 30), overweight (OW; n = 11), and lean (n = 19) groups. Total and high-molecular-weight Ad, ET-1, vascular cell adhesion molecule-1, and von Willebrand factor levels were measured in serum samples. Adipocytes were stimulated with exogenous ET-1 or with sera from lean, OW, and Ob, and Ad production and release measured in the absence or in the presence of ET A (BQ-123) and ETB (BQ-788) receptor blockers, p42/44 MAPK inhibitor PD-98059, or c-Jun NH2-terminal protein kinase inhibitor SP-600125. Vasodilation to Ad was evaluated in rat isolated arteries in the absence or in the presence of BQ-123/788. Results: Total and high-molecular-weight Ad was significantly decreased and ET-1 levels significantly increased in OW (P < .01) and Ob (P < .001) children. A statistically significant linear regression (P < .01) was found between Ad and ET-1. Exposure of adipocytes to exogenous ET-1 or serum from OW and Ob significantly decreased Ad mRNA and protein levels (P < 0.001). The inhibitory effect of ET-1 on Ad was reverted by BQ-123/788 or PD-98059 but not SP-600125. Admediated vasodilation was further increased in arteries pretreated with BQ-123/788. Conclusions: ET-1-mediated inhibition of Ad synthesis via p42/44 MAPK signaling may provide a possible explanation for hypoadiponectinemia in pediatric obesity and contribute to the development of cardiovascular complications.

AIM: Although the underlined mechanisms are still unknown, metabolic/coagulation alterations related to childhood obesity can induce vascular impairments. The aim of this study was to investigate the relationship between metabolic/coagulation parameters and endothelial function/vascular morphology in overweight/obese children. METHODS: Thirty-five obese/overweight children (22 pre-pubertal, mean age: 9.52±3.35 years) were enrolled. Body mass index (BMI), homeostasis model assessment index (HOMAIR), metabolic and coagulation parameters, [adiponectin, fibrinogen, high molecular weight adiponectin (HMW), endothelin-1, and vonWillebrand factor antigen] ultrasound early markers of atherosclerosis [flow-mediated dilatation (FMD), common carotid intima-media thickness (C-IMT), and anteroposterior diameter of infra-renal abdominal aorta (APAO)] were assessed. RESULTS: APAO was related to anthropometric (age: r=0.520, p=0.001; height: r=0.679, p＜0.001; weight: r=0.548, p=0.001; BMI: r=0.607, p＜0.001; SBP: r=0.377, p=0.026) and metabolic (HOMAIR: r=0.357, p=0.035; HMW: r=－0.355, p=0.036) parameters. Age, height, and systolic blood pressure were positively related to increased C-IMT (r=0.352, p=0.038; r=0.356, p=0.036; r=0.346, p=0.042, respectively). FMD was not related to any clinical and biochemical characteristics of the pediatric population. Age, HOMAIR, fasting glucose levels, and HMW were independent predictors for APAO increase. Each unit decrease in HMW concentrations (1 μg/ml) induced a 0.065 mm increase in APAO. CONCLUSION: High molecular weight adiponectin is related to cardiovascular risk in overweight/obese children.

Abstract There are conflicting data regarding the potential impact of chronic glucocorticoid (GC) therapy on the bone mineral density of patients with congenital adrenal hyperplasia (CAH). Previous studies performed by dual-energy X-ray absorptiometry reported conflicting results. The purpose of this study was to assess the impact of chronic GC replacement treatment in children with classical and non classical CAH due to 21-hydroxylase deficiency (21-OHD) by quantitative ultrasonometry (QUS), an easy, cheap, and radiation-free technique. The study population consisted of nineteen 21-OHD patients (nine males) on lifelong GC treatment. Anthropometric, hormonal, and treatment data were recorded for each patient, and bone quality was assessed by QUS measurements. QUS findings (amplitude-dependent speed of sound and bone transmission time) were normal in 21-OHD patients and did not correlate with duration of treatment, daily, total, and yearly hydrocortisone dose. Furthermore, no significant correlation was found between QUS findings and 17α-hydroxy progesterone, Δ4-androstenedione, and testosterone levels. In conclusion, our results provide reassurance that currently used replacement doses of GC do not have a major impact on bone in patients with CAH. QUS seems to be a reliable tool for screening of bone health in children with 21-OHD

Paediatric obesity, like adulthood obesity, is associated with an increase of fibrinolysis inhibitors. No study, however, has evaluated the impact of these changes on plasma fibrinolytic capacity. We investigated plasma fibrinolysis and the role therein of the fibrinolytic changes associated with obesity in 59 obese children (body mass index > 95th percentile) and 40 matched controls. Fibrinolysis was investigated by measuring 1) the plasma levels of relevant fibrinolytic factors; 2) the in vitro fibrinolytic capacity under different conditions, using a microplate plasma clot lysis assay; 3) the circulating levels of markers of clotting and fibrinolysis activation. Plasminogen activator inhibitor 1 (PAI-1), total thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen levels were higher in obese children as compared to controls (p<0.01). Plasma clots from obese children lysed significantly slower than control clots when exposed to exogenous plasminogen activator, indicating a greater resistance to fibrinolysis. By the use of a selective inhibitor of activated TAFI and by regression analyses we found that fibrinolysis resistance in obese samples was attributable to PAI-1 increase and to enhanced TAFI activation. The ratio between the circulating levels of D-dimer and thrombin-antithrombin complex, a marker of in vivo fibrinolysis, was significantly lower in obese children, suggesting a reduced fibrinolytic efficiency. These data indicate that paediatric obesity is associated with a hypofibrinolytic state which might contribute to the increased thrombotic risk associated with this condition.

In the last 30 years, the use of long-term central venous catheters (CVC) is increased especially for children with hemato-oncological disorders. However, the use of CVC is associated to complications, as mechanical accidents, thrombosis, and infections that can determine a prolongation of hospital stay, an increase of costs, and sometimes life-threatening conditions that require urgent systemic treatment or CVC removal. CVC removal may be troublesome especially in neonates, infants, or any other “highly needed CVC patients”; in these selected cases, the prevention and treatment of CVC-related complications play a pivotal role and specific surveillance programs are crucial. While extensive literature is focused on CVC management in adults, no guidelines are available for children. To this aim, the first recommendations for the management of CVC infectious complication in pediatric age have been written after pediatric and adult literature review and collegial discussion among members of Supportive Therapy working group of Italian Association of Pediatric Hematology and Oncology. Compared to the adult age, the necessity of peripheral vein cultures for the diagnosis of CVC-related infection remains controversial in children because of the poorer venous asset and a conservative, pharmacologically focused management through CVC remains mandatory, with CVC removal to be performed only in selected cases.

Obstructive sleep apnea syndrome (OSAS) in children can induce endothelial dysfunction, a well-known early marker of atherosclerosis. The study aimed to evaluate a link among endothelial function (measured by flow-mediated vasodilation (FMD)), obesity (evaluated by body mass index (BMI)), and sleep disordered breathing (SDB), assessed with apnoea/hypopnoea index (AHI), in a paediatric population. We demonstrated that our little OSAS patients showed an impaired endothelial function as compared to controls. In particular, the higher the AHI, the worst the FMD values and thus the endothelial function. Although the population sample is small, this study demonstrated that OSAS could impair endothelial function and worsen cardiovascular risk profile since childhood.

The hemophilias are the most common X-linked inherited bleeding disorders. The challenges in children are different from that in adults and, If not properly managed, can lead to chronic disease and lifelong disabilities.Currently, inhibitors are the most severe complication and prophylaxis is emerging as the optimal preventive care strategy. Quality of life has become in the western countries the primary objective of the process of providing care, thus all the strategies (psychotherapy, physiotherapy, community life), not just the infusion of the missing factor, should be activated for the patient and family to give them the perception of being healthy.

Background: The ITP-QoL is a disease-specific questionnaire for the assessment of health-related quality of life (HRQoL) in children with immune thrombocytopenia (ITP) and their parents. The aim of this study was to test the psychometric characteristics of the ITP-QoL in the Italian pediatric population in terms of validity and reliability. Procedure: Children aged 8–16 years with acute or chronic ITP and their parents were recruited in Italy. Participants completed the ITP-QoL together with other patient-reported outcomes (PROs). Reliability was calculated using Cronbach's alpha. Convergent validity was determined by means of the Pearson correlation coefficients. Results: A total of 91 ITP patients, mean age of 12.11 ± 2.47 years, and their parents participated; 61.5% of the patients were female. Two patients had acute ITP and 30.2% had a moderate to severe status of ITP. Cutaneous symptoms were more frequent than mucosal symptoms. Due to item and scale analyses 20 items were deleted from the original ITP-QoL. Internal consistency of the ITP-QoL was found to be good with Cronbach's alpha exceeding α = 0.70 for all but one subscale. Concerning convergent validity “moderate” to “high” negative correlations were found between ITP-QoL and KINDL subscales. The ITP-QoL was able to discriminate between clinical subgroups such as number of days lost at school due to ITP and hospitalization. Conclusions: Our study was able to demonstrate that the Italian version of ITP-QoL (for children aged 8–16 years) is a valid and reliable instrument for the assessment of HRQoL in children with ITP.

We describe a child with thrombocytopenia-absent radius (TAR) syndrome in whom a refractory Langerhans cell histiocytosis (LCH) developed at 9 years. Recently, it has been demonstrated, in a large cohort of patients with TAR syndrome, that microdeletion on chromosome 1q21.1 is the characteristic genetic alteration. This genetic alteration was found in the affected son and in maternal lineage. Our data confirm the role played by the 1q21.1 microdeletion in the pathogenesis of TAR syndrome proposing a panel of polymorphic markers for a rapid and low-cost screening of 1q21.1 microdeletion. We do not know if the occurrence of two rare diseases as of TAR syndrome and LCH could be considered a chance association; at our knowledge, a genetic link does not seem to be present between the diseases. Descriptions of additional cases of LCH in patients with TAR syndrome are necessary before a cause and effect relationship can be proven.

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.

Background/Objective: The management of chronic childhood idiopathic thrombocytopenic purpura (lTP) is distinct from acute lTP. Similar to the publication on acute ITP guidelines, the AIEOP (Associazione ltaliana di Ematologia e Oncologia Pediatrica) considered it appropriate to develop consensus guidelines for chronic childhood ITP to provide useful and shared information for physicians, healthcare professionals, parents and patients. Design/Methods: A preliminary, evidence-based document issued by a select group of AlEOP pediatric hematologists was discussed, modified and approved during a Consensus Conference according to procedures previously validated by the AIEOP Board. Resurts: The guidelines give prominence to the periodical reevaluation of all the etiological hypotheses of thrombocytopenia in relation to its clinical condition. The majority of chronic ITP children do not require treatment, especially if bleeding is absent or minimal. The treatment decision depends on several factors other than the platelet count, and treatment options are suggested in relation to the therapeutic scenarios. Recommendations are given regarding support for surgery, particular hemorrhagic conditions, daily activities/sports, as well as for vaccines and drugs. Experimental treatments are also discussed.

Alkaptonuria (AKU) is a rare disorder characterized by the deficiency of the enzyme homogentisate 1,2-dioxygenase and consequent homogentisate accumulation, which leads to progressive and severe osteoarthopathy starting from the second decade of life. Thus, in AKU patients bone involvement represents an important clinical issue, which we investigated. Serum levels of RANKL, osteoprotegerin, sclerostin, DKK1, and bone remodeling markers were measured in nine AKU patients (two children and seven adults) and 22 controls, together with lumbar spine bone mineral density (LS-BMD) and femoral-BMD. In the two AKU children the average of LS-BMD and femoral-BMD Z-scores were within the normal range, but reduced with respect to the controls. Otherwise, in the adult AKU patients LS-BMD T-score were inside the normal range, but femoral-BMD T-score reached osteopenic levels. Consistently, in AKU adults higher RANKL and CTX and lower osteoprotegerin levels were observed than controls. Otherwise, spontaneous osteoclastogenesis was already evident in peripheral blood mononuclear cell cultures from AKU children together with a high percentage of circulating osteoclast precursors. Osteoclastogenesis was sustained by the high levels of TNFα, RANK, RANKL, and LIGHT. In conclusion, the altered osteoclastogenesis was observed already in AKU children despite the absence of evident injury. Thus, a preventive approach in young patients, targeting osteoclast activity, may prevent the macroscopic bone disease which appears in adult AKU.

A significant number of long-term complications have been described in childhood leukemia survivors. In particular, these patients may present features of metabolic syndrome (MetS), and therefore increased risk for cardiovascular diseases. The aim of this meta-analysis is to evaluate the prevalence and the risk of MetS in survivors of childhood leukemia. Two authors independently performed a systematic literature search in PubMed and EMBASE to March 2014, reviewed and selected articles, based on pre-determined selection criteria. Twelve articles, comprising 2,337 participants (1,462 cases and 875 controls), were included in the meta-analysis. Only three of them were case–control studies eligible for the meta-analysis. The childhood leukemia survivors showed an increased risk of MetS as compared to healthy controls (OR = 4.36; 95 % CI 1.19–16.22). The risk was significantly increased only in patients treated with chemotherapy and radiotherapy (OR = 7.79; 95 % CI 1.27–47.77), and not in patients treated with only chemotherapy (OR = 2.35; 95 % CI 0.40–13.78). Childhood leukemia survivors, in particular if treated also with radiotherapy, are prone to develop MetS more than healthy controls. Monitoring of MetS components in these patients is necessary to avoid cardiovascular consequences later in life.

Childhood obesity and its related comorbidities are increasingly recognised in children, predisposing them to early cardiovascular disease and metabolic syndrome. The objective of the study was to investigate markers of metabolism, inflammation and haemostasis in a group of Italian obese children and adolescents. Fifty-nine obese and 40 non-obese subjects were recruited. Fasting glucose and insulin, total cholesterol, HDL and LDL cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor alpha (TNF-α), and adiponectin were measured. Hypercoagulability was assessed by measuring the circulating levels of thrombin-antithrombin complex (TAT), D: -dimer, fibrinogen, plasminogen activator inhibitor 1 (PAI-1) and von Willebrand Factor (vWF). A significant degree of insulin resistance was present in obese subjects compared with controls (p < 0.0001). The obese showed higher levels of total cholesterol, LDL cholesterol and triglycerides, and lower levels of HDL cholesterol than controls (p < 0.0001). Circulating levels of hsCRP and TNF-α were significantly higher in obese than in controls while serum adiponectin levels were significantly lower in obese than non-obese subjects (p < 0.001; p = 0.031; p < 0.0001, respectively). vWF, TAT, D-dimer, fibrinogen and PAI-1 levels were significant higher in obese subjects compared with control group (p = 0.02; p < 0.0001; p = 0.0037; p < 0.0001; p = 0.017, respectively). In conclusion, our results suggest that childhood obesity per se is associated with a proinflammatory and prothrombotic state.

Despite advances in neonatal intensive care and the improvements in surveillance, prevention and vaccination programs, neonatal meningitis still represents an important cause of morbidity and mortality in infants, with the highest mortality in the newborn population.

BACKGROUND/AIMS: We studied the association of low birth weight with ultrasound-assessed nonalcoholic fatty liver disease (NAFLD) to test the hypothesis that fetal growth retardation followed by a rapid weight catch-up growth might be an additional factor responsible for liver steatosis via insulin resistance (IR) and/or intra-abdominal fat. METHODS: We enrolled 23 children born small for gestational age (SGA) with a rapid catch-up growth within the first 6-12 months, and 24 appropriate for gestational age (AGA) children as controls. All children underwent anthropometric, body composition measurements and evaluation of liver function tests, lipid profile, plasma glucose and insulin levels. Abdominal ultrasonography was performed in order to asses liver steatosis and thickness of subcutaneous and visceral adipose tissue. RESULTS: NAFLD were observed in 8 out of the 23 SGA children (34.8%). IR and visceral fat were significantly increased in children with hepatic steatosis compared to those without. IR index was significantly related to liver steatosis, independently of body mass index standard deviation score and visceral fat. CONCLUSIONS: NAFLD should be recognized as an emerging problem in SGA prepubertal children who presented a rapid weight gain in postnatal life, and IR plays the key role. An appropriate diet during pregnancy and in the first year of life might prevent metabolic syndrome and NAFLD in these subjects.

Sickle cell disease (SCD) is the most frequent hemoglobinopathy worldwide but remains a rare blood disorder in most western countries. Recommendations for standard of care have been produced in the United States, the United Kingdom and France, where this disease is relatively frequent because of earlier immigration from Africa. These recommendations have changed the clinical course of SCD but can be difficult to apply in other contexts. The Italian Association of Pediatric Hematology Oncology (AIEOP) decided to develop a common national response to the rising number of SCD patients in Italy with the following objectives: 1) to create a national working group focused on pediatric SCD, and 2) to develop tailored guidelines for the management of SCD that could be accessed and practiced by those involved in the care of children with SCD in Italy. Methods: Guidelines, adapted to the Italian social context and health system, were developed by 22 pediatric hematologists representing 54 AIEOP centers across Italy. The group met five times for a total of 128 hours in 22 months; documents and opinions were circulated via web. Results: Recommendations regarding the prevention and treatment of the most relevant complications of SCD in childhood adapted to the Italian context and health system were produced. For each topic, a pathway of diagnosis and care is detailed, and a selection of health management issues crucial to Italy or different from other countries is described (i.e., use of alternatives for infection prophylaxis because of the lack of oral penicillin in Italy). Conclusions: Creating a network of physicians involved in the day-to-day care of children with SCD is feasible in a country where it remains rare. Providing hematologists, primary and secondary care physicians, and caregivers across the country with web-based guidelines for the management of SCD tailored to the Italian context is the first step in building a sustainable response to a rare but emerging childhood blood disorder and in implementing the World Health Organization’s suggestion “to design (and) implement ... comprehensive national integrated programs for the prevention and management of SCD

Despite great advances in haemophilia care in the last 20 years, a number of questions on haemophilia therapy remain unanswered. These debated issues primarily involve the choice of the product type (plasma-derived vs. recombinant) for patients with different characteristics: specifically, if they were infected by blood-borne virus infections, and if they bear high or low risk of inhibitor development. In addition, the most appropriate treatment regimen in non-inhibitor and inhibitor patients compel physicians operating at the haemophilia treatment centres (HTCs) to take important therapeutic decisions, which are often based on their personal clinical experience rather than on evidence-based recommendations from published literature data. To know the opinion on the most controversial aspects in haemophilia care of Italian expert physicians, who are responsible for common clinical practice and therapeutic decisions, we have conducted a survey among the Directors of HTCs affiliated to the Italian Association of Haemophilia Centres (AICE). A questionnaire, consisting of 19 questions covering the most important topics related to haemophilia treatment, was sent to the Directors of all 52 Italian HTCs. Forty Directors out of 52 (76.9%) responded, accounting for the large majority of HTCs affiliated to the AICE throughout Italy. The results of this survey provide for the first time a picture of the attitudes towards clotting factor concentrate use and product selection of clinicians working at Italian HTCs.

The most frequent forms of inherited thrombocytopenia (IT) are characterized by platelet size abnormalities and it has been suggested that this parameter is useful for their differentiation from immune thrombocytopenia (ITP). Recently, a monocentric study identified cut-off values for mean platelet volume (MPV) and mean platelet diameter (MPD) with good diagnostic accuracy in this respect. To validate these cut-off values in a different and larger case series of patients, we enrolled 130 subjects with ITP and 113 with IT in six different centres. The platelet count and MPV was each measured by the instrument routinely used in each institution. In some centres, platelet count was also measured by optical microscopy. MPD was evaluated centrally by image analysis of peripheral blood films. The previously identified cut-off value for MPV had 91% specificity in distinguishing ITP from inherited macrothrombocytopenias (mono and biallelic Bernard-Soulier, MYH9-related disease), while its sensitivity was greatly variable depending on the instrument used. With an appropriate instrument, specificity was 83%. The diagnostic accuracy of MPD was lower than that obtained with MPV. We concluded that MPV is a useful parameter for differentiating ITP from IT provided that it is measured by appropriate cell counters.

BACKGROUND: A 17-year-old boy was referred to our center with a history of brain abscess (BA) recurring after 9 years. The patient reported 2 previous treatments for pulmonary arteriovenous malformations, sporadic nosebleeds, and familial history for epistaxis. Clinical investigations revealed arteriovenous malformations in lung, brain, and liver, as well as mucocutaneous telangiectases.A definite diagnosis of hereditary hemorrhagic telangiectasia was made based on clinical criteria and confirmed by genetic analysis. This is the first report of BA recurrence at the end of pediatric age. CONCLUSIONS:: The present case and the literature review of all cases of BA thus far reported highlight the need to raise the suspicion of a pulmonary arteriovenous malformations, both isolated and in the context of a possible hereditary hemorrhagic telangiectasia, for any case of BA of unexplained etiology, in children as well as in adults.

The pathophysiology of asthma is complex and involves a number of factors including atopy and bronchial hyperreactivity. A strong body of evidence suggests that structural and functional respiratory epithelial alterations play a crucial role in both development and persistence of this condition. From the onset of symptoms the airways epithelium of asthmatic patients seems to be altered and unable to repair. The interactions between the epithelium and the underlying mesenchyma, which are jointly referred to as the epithelial-mesenchymal trophic unit (EMTU), are thought to result in a self-sustaining damage of the airways and, ultimately, in a chronic inflammatory scenario. A better understanding of the relationship occurring across EMTU, environmental noxae, and factors of susceptibility to epithelial damage is likely to pave the way to future new preventive and therapeutic strategies for this condition.

BACKGROUND: Increased carotid intima-media thickness (cIMT) is considered a marker of early-onset atherosclerosis and it seems to predict cardiovascular events both in obese and diabetic subjects. We aimed to evaluate early signs of atherosclerosis and investigate for predisposing factors in children and adolescents affected by type 1 diabetes (T1DM) or obesity, comparing them with healthy controls. METHODs: Out of 71 enrolled subjects (mean age 12.8 ± 2.3 years), 26 had T1DM and 24 were obese, while 21 age- and sex-matched subjects acted as controls. cIMT was measured using standardized methods. Serum glucose, insulin, cholesterol, triglycerides and C-reactive protein levels were evaluated. An oral glucose tolerance test (OGTT) was performed in obese subjects. RESULTS: Diabetic and obese individuals showed higher cIMT mean values than healthy controls (p < 0.005). cIMT of the three examined segments correlated positively with fasting glucose levels and negatively with units of insulin/kg/day administered in T1DM individuals. A positive correlation between insulin levels (basal and after oral glucose load) and cIMT of common, internal and external carotid artery was found in obese subjects (p < 0.03). High density cholesterol levels represented a protective factor for cIMT in this latter group of the study population. CONCLUSIONS: Our findings show that cIMT correlates with high insulin levels (a sign of insulin resistance) in obese patients and with high fasting glucose levels (a sign of relative insulin deficiency) in T1DM subjects, confirming the need of reducing hyperinsulinism and monitoring blood glucose levels in these subjects to prevent atherosclerosis.

Introduction: Venous thromboembolic events (VTEs) are frequent complications of childhood acute lymphoblastic leukemia (ALL) treatment. The aim of the study was to evaluate the rate of symptomatic VTEs in children with ALL and the predictive value of clinical and biological factors and routine monitoring of coagulation parameters in identifying children at a higher risk of this complication. Materials and Methods: Between September 2000 and July 2006, 2042 children (≥1 and younger than 18 y) with newly diagnosed ALL were enrolled in Italy in the AIEOP (Italian Association of Pediatric Hematology and Oncology)-BFM (Berlin-Frankfurt-Muenster) ALL 2000 trial. Patients with symptomatic VTEs (deep venous thromboses or cerebral venous thromboses) were identified after a careful review of clinical records. The impact of coagulation derangement at the onset of VTEs was evaluated by a nested case-control study. Results: Forty-eight (2.4%) children presented with a VTE. The rate of VTEs was higher in male patients (P=0.001); patients randomized to receive dexamethasone tended to have a higher rate of VTE compared with those who received prednisone (P=0.10). The coagulation derangement at the onset of VTE was not associated with VTE occurrence. The prevalence of a factor V Leiden G1691A mutation and the prothrombin G20210A variant was higher in children with VTE than that expected in the general population.

Dietary omega-3 polyunsaturated fatty acids (ω-3 PUFAs) benefits are not clearly defined in childhood although already well-defined in adults. Recent studies demonstrated their positive effects on bronchial asthma, neuropsychiatric disorders and cognitive brain function in childhood. Furthermore, it has been demonstrated a relationship between the increased incidence of childhood obesity and the role of ω-3 PUFAs in reducing the metabolic and vascular alterations induced by the fat accumulation since young age. Such relationship could be more important in prevention future cardiovascular events. In facts, ω-3 PUFAs could improve endothelial function and structure since childhood. By considering endothelial dysfunction as a well-known early marker of atherosclerosis, its amelioration since first years of individuals life will certainly reduce the cardiovascular risk profile in adulthood. Nevertheless, their use is limited by several factors: the lacking of studies in children and the awful taste of the products enriched with ω-3 PUFAs, although several patents had been managed in order to overcome such defects and develop the use of these molecules. This paper is a literature studies and patents analysis aiming at exploring key issues regarding ω-3 PUFAs administration in childhood in order to take into account the opportunity of their routinely use in everyday life since early moments of life. Nevertheless, it is well-established that further studies are needed to endorse the promising results outlined by literature analysis.

Haemophilia A (HA) patients with high responding inhibitors require therapies with bypassing agents to control bleedings or Immune Tolerance Induction (ITI) to attempt inhibitor eradication and restore FVIII therapy. The aim of this study was to assess the therapeutic management and product consumption of HA inhibitor patients and the relative costs in Italy. A retrospective survey was performed utilizing data from the National Registry of Congenital Coagulopathies and from a specific questionnaire on product consumption of HA inhibitor patients over the year 2011. Among HA patients, 10% had currently detectable inhibitors; 24% of patients were undergoing ITI (mostly children) and 76% utilized bypassing agents. Patients on ITI consumed 45 000 000 IU of FVIII (median consumption/patient of 1 200 000 IU year−1). Patients receiving bypassing agents utilized 21 000 000 IU of aPCC (median consumption/patient of 360 000 IU year−1), and 38 000 mg of rFVIIa (median consumption/patient of 440 mg year−1). The annual cost/patient on ITI and on bypassing agents therapy was analysed. Recombinant products represen-ted the product of choice for children therapies in >90% of the cases. FVIII prophylaxis of severe HA patients without inhibitor costs about half than therapy with bypassing agents and is three times less expensive than prophylaxis with such agents. Therefore, the possibility to restore FVIII prophylaxis, having eradicated the inhibitor through ITI, can justify the high costs of ITI treatment needed in the short term. Consistent with this notion, over the last years a 50% increase in the number of patients undergoing ITI in Italy was registered.

Thrombocytopenia-absent-radius (TAR) syndrome is a rare condition characterized by thrombocytopenia and bilateral absence of the radii with presence of both thumbs. The phenotype has a variable expression. A 200 kb minimal deletion at 1q21.1 is present in all patients. However, the microdeletion, ranging up to 1100 kb in length, is not sufficient to cause the disease. Indeed it is present in 75-80% of unaffected parents. It is assumed that the phenotype develops only in the presence of one or more additional, as-yet-unknown, deletion modifiers (mTARs). We report here on a child affected by TAR syndrome associated with Langerhans cell histiocytosis. Unexpectedly, he showed a 2.029 kb deletion at 1q21.1, almost twice that of the unaffected mother (957 kb). Interestingly, the mother-to-son increased size of the deleted region was already observed in two cases of constitutional diseases, although both resulting as chromosomal terminal deletions. Noteworthy, qPCR experiments, never before performed for patients with TAR syndrome, disclosed that the proband had a statistically significant downregulation of the majority of the genes mapping inside the part of the deletion shared with the mother. The mother, on the contrary, did not show the same downregulation. In summary, the present report adds new insights on the pathogenesis of TAR syndrome, that may represent fruitful directions for future research.

Haemophilia is an X-linked bleeding disorder and is characterised by repeated bleeding, especially in joints. The current management of haemophilia is based on the replacement therapy with intravenous clotting factor and includes plasma-derived and recombinant factor concentrates. The early treatment in pediatrics age has been recognised as an important determinant of better physical development, and several studies have demonstrated that primary prophylaxis has a positive and significant impact on the quality of life and the prevention of arthropathy in haemophiliac children. Also, home treatment has shown to improve both life expectancy and quality of life of patients with haemophilia.

The most important reasons cited by the opponents of vaccines are concerns about vaccine safety. Unlike issues such as autism for which no indisputable documentation of direct relationship with vaccine use is available, immune thrombocytopenic purpura (ITP) is an adverse event that can really follow vaccine administration, and may limit vaccine use because little is known about which vaccines it may follow, its real incidence and severity, the risk of chronic disease, or the possibility of recurrences after new doses of the same vaccine. The main aim of this review is to clarify the real importance of thrombocytopenia as an adverse event and discuss how it may interfere with recommended vaccination schedules. The available data clearly indicate that ITP is very rare and the only vaccine for which there is a demonstrated cause-effect relationship is the measles, mumps and rubella (MMR) vaccine that can occur in 1 to 3 children every 100,000 vaccine doses. However, also in this case, the incidence of ITP is significantly lower than that observed during the natural diseases that the vaccine prevents. Consequently, ITP cannot be considered a problem limiting vaccine use except in the case of children suffering from chronic ITP who have to receive MMR vaccine. In these subjects, the risk-benefit ratio of the vaccine should be weighed against the risk of measles in the community.

Background: Small-for-gestational-age (SGA) children have increased cardiovascular risk, but the mediating factors are poorly understood. We hypothesized that birth size could affect the cardiovascular system since childhood in the absence of other risk factors. We investigated endothelial and myocardial function in SGA children with regular catch-up growth. Methods and Results: Biochemical markers, blood pressure, flow-mediated vasodilation (FMD), common carotid intima-media thickness (cIMT), anteroposterior diameter of the infrarenal abdominal aorta (APAO) and echocardiographic parameters of left and right ventricular (LV and RV) function were studied in 27 SGA and 25 appropriate-forgestational-age (AGA) subjects. SGA subjects had a higher homeostasis model assessment index than controls (2.61±1.27 vs. 1.56±0.40, P=0.01), higher cIMT (0.51±0.04mm vs. 0.45±0.07mm, P=0.007) and APAO (1.31±1.35cm vs. 1.30±0.16cm, P=0.005), and lower FMD (10.11±4.17% vs. 12.34±4.28, P=0.04) than controls. On echocardiography SGA had higher Tei index both at LV and RV than controls (P=0.001). Reduced RV systolic function was also observed in SGA subjects. Conclusions: SGA subjects had vascular morphological and function abnormalities compared with AGA, which increase their cardiovascular risk profile. Furthermore, a subtle cardiac alteration in both RV and LV functions was seen in SGA patients compared with AGA.

More and more cases of venous thrombosis are diagnosed in children thanks to newer imaging modalities. Central venous catheters have become commonplace in the care of critically ill children and have contributed to the increased rate of thrombotic events. Lastly, children who develop life-threatening or chronic medical conditions are surviving longer because of advanced medical therapies; these intensive therapies can be complicated by events such as thrombosis. Over the last 10 years, specific guidelines for treating thrombosis in children have become available. Nevertheless, in many situations anticoagulant treatment is specially tailored to each individual patient's needs. Some new antithrombotic drugs which have undergone clinical testing in adults might be beneficial to paediatric patients with thromboembolic disorders; unfortunately, clinical data and reports on the use of these drugs in children, when available, are extremely limited. The aim of this review is to provide physicians with enough background information to be able to manage thrombosis in children. First, by helping them detect a thrombotic event in a child. Upon confirmation of the diagnosis, the physician will request the appropriate tests and will choose the best treatment on the basis of the guidelines and recommendations. Moreover, the paediatrician will have the information he or she needs to identify which children are at highest risk of acute thrombotic events and relevant long-term sequelae and, therefore, to decide on the appropriate prophylactic or pharmacologic strategy. Lastly, we would like to provide the paediatrician with information on future drugs with regard to the treatment and prophylaxis of thrombosis.