Prophylactic fibrinogen concentrate administration in surgical correction of paediatric craniosynostosis: A double-blind placebo-controlled trial.

BACKGROUND: Surgical craniosynostosis repair in children is associated with massive blood loss and significant transfusion of blood products. Fibrinogen concentrate is claimed to be useful in reducing blood loss and transfusion requirements. OBJECTIVE: We investigated whether prophylactic administration of fibrinogen concentrate will reduce blood loss and transfusion requirements during paediatric craniofacial surgery. DESIGN: Randomised, placebo-controlled, double-blind clinical trial. SETTING: University medical centre. PATIENTS: A total of 114 infants and children up to 25 months of age (median age 10 months). INTERVENTION: Surgical craniosynostosis repair by calvarial remodelling was performed in each patient. Patients were randomised to receive prophylactic fibrinogen concentrate (Haemocomplettan P) at a mean dose of 79 mg kg-1 body weight or placebo. MAIN OUTCOME MEASURES: Primary outcome was the volume of transfused blood products. Secondary outcomes were peri-operative blood loss, duration of surgery, length of stay in the paediatric ICU, length of hospital stay, postoperative complications and adverse effects of fibrinogen concentrate infusion. RESULTS: No significant differences (P < 0.05) were found in the volume of transfused blood products (median 29 ml kg-1 body weight vs. 29 ml kg-1 body weight), intra-operative estimated blood loss (45 vs. 46 ml kg-1), calculated blood loss (57 vs. 53 ml kg-1), or postoperative blood loss (24 vs. 24 ml kg-1) between the intervention and placebo groups. In addition, duration of surgery, length of stay in the paediatric ICU, hospital stay and complications were not significantly different between the two groups. CONCLUSION: During surgical craniosynostosis repair in young children, prophylactic administration of high-dose fibrinogen concentrate did not reduce the amount of transfused blood products or decrease peri-operative blood loss. TRIAL REGISTRATION: National Trial Register (NTR2975) and EudraCT (2011-002287-24).

Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory.

TMPRSS6 variants that affect protein function result in impaired matriptase-2 function and consequently uninhibited hepcidin production, leading to iron refractory iron deficiency anemia (IRIDA). This disease is characterized by microcytic, hypochromic anemia and serum hepcidin values that are inappropriately high for body iron levels. Much is still unknown about its pathophysiology, genotype-phenotype correlation, and optimal clinical management. We describe 14 different TMPRSS6 variants, of which 9 are novel, in 21 phenotypically affected IRIDA patients from 20 families living in the Netherlands; 16 out of 21 patients were female. In 7 out of 21 cases DNA sequencing and multiplex ligation dependent probe amplification demonstrated only heterozygous TMPRSS6 variants. The age at presentation, disease severity, and response to iron supplementation were highly variable, even for patients and relatives with similar TMPRSS6 genotypes. Mono-allelic IRIDA patients had a milder phenotype with respect to hemoglobin and MCV and presented significantly later in life with anemia than bi-allelic patients. Transferrin saturation (TSAT)/hepcidin ratios were lower in IRIDA probands than in healthy relatives. Most patients required parenteral iron. Genotype alone was not predictive for the response to oral iron. We conclude that IRIDA is a genotypically and phenotypically heterogeneous disease. The high proportion of female patients and the discrepancy between phenotypes of probands and relatives with the same genotype, suggest a complex interplay between genetic and acquired factors in the pathogenesis of IRIDA. In the absence of inflammation, the TSAT/hepcidin ratio is a promising diagnostic tool, even after iron supplementation has been given. Am. J. Hematol. 91:E482-E490, 2016. © 2016 Wiley Periodicals, Inc.

Serial cranial US for detection of cerebral sinovenous thrombosis in preterm infants.

PURPOSE: To report the incidence of cerebral sinovenous thrombosis (CSVT) in a prospective cohort of preterm infants with a gestational age of less than 29 weeks. MATERIALS AND METHODS: The local medical ethics review board approved this study, and written parental consent was obtained. Preterm infants with a gestational age of less than 29 weeks who were admitted to the neonatal intensive care unit were prospectively studied with cranial ultrasonography (US). The scanning protocol included visualization with color Doppler imaging of the superior sagittal sinus and transverse sinuses through the anterior (8.5-MHz probe) and mastoid (13-MHz probe) fontanelles. When feasible, magnetic resonance imaging was performed to confirm cranial US-diagnosed CSVT. The differences between preterm infants with and those without CSVT were analyzed by using Mann-Whitney tests for continuous variables and Fisher exact tests for categorical data. RESULTS: Cranial US was used to document CSVT in 11 of 249 preterm infants with a gestational age of less than 29 weeks. Transverse sinuses were most frequently affected (in all 11 patients with CSVT). All infants with CSVT were asymptomatic. Postnatal age at diagnosis ranged from 5 to 34 days. The mean gestational age was significantly lower in infants with CSVT (25.9 weeks vs 26.8 weeks, P = .038). Of the risk factors studied, only duration of mechanical ventilation was associated with CSVT; it was significantly longer in the CSVT group. CONCLUSION: Systematic serial cranial US of infants with a gestational age of less than 29 weeks showed a remarkably high incidence of CSVT of 4.4%. Cranial US including color Doppler imaging with scans obtained through the mastoid fontanelle can depict CSVT at an early stage. Treatment of this possibly important condition needs attention.

Paediatric arterial ischaemic stroke: functional outcome and risk factors.

AIM: To study functional outcome in children aged 1 month to 18 years after paediatric arterial ischaemic stroke (PAIS) and to identify risk factors influencing their quality of life. METHOD: In a consecutive series of 76 children (35 males 41 females, median age at diagnosis 2y 6mo, range 1mo-17y 2mo; median length of follow-up 2y 4mo, range [7mo-10y 6mo]) with PAIS diagnosed at the Erasmus Medical Centre Sophia Children's Hospital between 1997 and 2006, we collected clinical, biochemical, and radiological data prospectively. In 66 children surviving at least 1 year after PAIS, functional outcome could be evaluated with the World Health Organization's International Classification of Impairments, Disabilities and Handicaps. RESULTS: Significant risk factors at presentation for a poor neurological outcome were young age, infarction in the right middle cerebral artery territory, and fever at presentation. Fifty-four % of children had severe neurological impairments at 12 months after PAIS, and at last follow-up more than half needed remedial teaching, special education, or institutionalization. Health-related quality of life (HRQOL) questionnaires showed a significantly lower HRQOL in all age groups. Children with a longer follow-up had a lower HRQOL in the cognitive functioning domain. INTERPRETATION: Our study shows significant morbidity and mortality and a reduced HRQOL after PAIS depending on age, fever at presentation, and infarction in the right middle cerebral artery territory.

L-Asparaginase and the effect of age on coagulation and fibrinolysis in childhood acute lymphoblastic leukemia.

Alterations in haemostasis are frequently observed in children with acute lymphoblastic leukemia (ALL). It was the objective of this study to analyse age-related disturbances in coagulation and fibrinolysis parameters during the induction phase of the antileukemic treatment. Sixty-four children were classified by age into three groups (1-5, 6-10, 11-16 years), and studied during induction treatment of ALL including four weeks of dexamethasone, followed by two weeks tapering of dexamethasone during which 6,000 IU/m(2) native L-Asparaginase (total 4 doses) was administered intravenously twice weekly. Blood samples were collected immediately before each L-Asparaginase infusion to analyze procoagulant (fibrinogen, factor [F] II, FV, FVII, F IX, F X) and anticoagulant factors (antithrombin [AT], protein C, protein S), parameters of thrombin generation (F1+2, TAT) and fibrinolysis (alpha2-antiplasmin, plasminogen, PAP, D-dimer). Children were in a hypercoagulable state after four weeks of dexamethasone due to upregulation of coagulation parameters. Upregulation was highest in the two youngest age groups. During L-Asparaginase treatment the 11- to 16-year-olds showed lower values in procoagulant and, even more, in anticoagulant factor levels compared to the younger children. Activation markers of thrombin generation and fibrinolysis did not change over time during the study period. Decreased synthesis of alpha2-antiplasmin and plasminogen during L-Asparaginase treatment resulted in less potential of clot lysis by plasmin in children older than 11 years of age. In conclusion, a more severe decline of anticoagulant and fibrinolytic parameters in children between 11 and 16 years of age underline that these children are at higher risk of thrombosis during ALL induction treatment.

Impaired dexamethasone-related increase of anticoagulants is associated with the development of osteonecrosis in childhood acute lymphoblastic leukemia.

Coagulation alterations may be involved in osteonecrosis in childhood acute lymphoblastic leukemia. Retrospectively, we evaluated the available coagulation parameters at diagnosis and during induction treatment of 161 acute lymphoblastic leukemia patients: 24 with symptomatic osteonecrosis (median age: 13.8 years, range 4.0-17.2) and 137 without osteonecrosis (median age: 4.9 years, range 1.0-16.7). Coagulation parameters of both groups were similar at diagnosis. After four weeks of treatment including dexamethasone, levels of antithrombin and protein S were significantly less in osteonecrosis-positive than in osteonecrosis-negative patients. Subsequently, after four doses of asparaginase and tapering dexamethasone, these coagulation parameters equally decreased in both groups. Consequently, nadirs of antithrombin and protein S were significantly lower in osteonecrosis-positive than in osteonecrosis-negative patients, even reaching levels below lower normal limits in the osteonecrosis-positive group. A reduced dexamethasone related increase of antithrombin and protein S, and subsequent decline below normal levels after introduction of asparaginase, may result in a hypercoagulable state, contributing to development of symptomatic osteonecrosis.

Effects of age and genetic variations in VKORC1, CYP2C9 and CYP3A4 on the phenprocoumon dose in pediatric patients.

AIM: To study the effects of clinical and genetic factors on the phenprocoumon dose requirement in pediatric patients and to develop a dosing algorithm. METHODS: Pediatric patients who used phenprocoumon were invited to participate in a retrospective follow-up study. Clinical information and genotypes of genetic variations in CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected and tested with linear regression for association with phenprocoumon dose requirement. RESULTS: Of the 41 patients included in the analysis, age, VKORC1, CYP2C9*2/*3 and CYP3A4*1B were statistically significantly associated with dose requirement, and together explained 80.4% of the variability in phenprocoumon dose requirement. CONCLUSION: Our study reveals that age and genetic variations explain a significant part of the variability in phenprocoumon dose requirement in pediatric patients.

Changes in hypercoagulability by asparaginase: a randomized study between two asparaginases.

Alterations in hemostasis have frequently been observed in children with acute lymphoblastic leukemia. Thrombotic events are well documented in patients receiving L-asparaginase as a single agent or in combination with other chemotherapeutic drugs. The present prospective, randomized study evaluated the effect of two different L-asparaginase preparations, native Escherichia coli L-asparaginase (Crasnitin; Bayer AG, Leverkusen, Germany; n = 10) and L-asparaginase derived from Erwinia chrysanthemi (Erwinase; Porton Pruducts, London, UK; n = 10) on the changes in parameters concerning hypercoagulability. Patients were randomized to receive a total of eight doses of 10,000 IU/m2 L-asparaginase intravenously with intervals of 3 days during induction therapy. Before starting L-asparaginase treatment all patients had already demonstrated an increased thrombin generation shown by the elevated levels of prothrombin fragment 1+2 and thrombin antithrombin III, presumably due to therapy with prednisone, daunorubicin and vincristine. A significant decrease in alpha2-antiplasmin and plasminogen levels was measured in the E. coli L-asparaginase but not in Erwinase-treated patients. Increased thrombin generation combined with a decrease in alpha2-antiplasmin and plasminogen levels may lead to a state of increased risk for thrombosis due to a delay in fibrin elimination in E. coli L-asparaginase-treated patients only.

Somatic thrombopoietin (THPO) gene mutations in childhood myeloid leukemias.

We report, for the first time, a non-syndromic infant with a reversible myeloproliferative disease that harbors a germline hereditary thrombopoietin (THPO) gene mutation, a condition that is known to induce familial thrombocytosis at increasing age. In order to investigate whether somatic THPO gene mutations play a role in sporadic pediatric myeloproliferative diseases, we performed a mutation screening of a large representative cohort of pediatric acute myeloid leukemia, myeloid leukemia of Down syndrome, and juvenile myelomonocytic leukemia samples and show that gain-of-function THPO mutations are extremely rare in sporadic pediatric myeloproliferative diseases.

[Acute illness following chicken pox: spleen infarction as a complication of varicella zoster infection]. / Acuut ziek na waterpokken: miltinfarcten als complicatie van varicella-zosterinfectie.

BACKGROUND: Varicella zoster virus (VZV) infection can cause temporary acquired protein S or C deficiency via cross reacting antibodies and consequently inducing a hypercoagulable state. CASE DESCRIPTION: A 6-year-old girl with a history of congenital cardiac disease was seen at an Emergency Department with acute chest pain, dyspnoea and fever, seven days after developing chicken pox. Diagnostic tests revealed massive infarction of the spleen, and a protein S and C deficiency. In addition, blood cultures revealed a Lancefield group A ß-haemolytic streptococcus (GABHS). The patient recovered fully after treatment with low molecular weight heparin and antibiotics. CONCLUSION: In this patient, septic emboli caused splenic infarction. Thromboembolic complications should be suspected in children with VZV who present with acute symptoms, in particular if bacterial superinfection is found.

Up-regulation of asparagine synthetase expression is not linked to the clinical response L-asparaginase in pediatric acute lymphoblastic leukemia.

L-asparaginase (L-Asp) is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is generally thought to result from a rapid depletion of asparagine in serum and cells. Asparagine synthetase (AS) opposes the action of L-Asp by resynthesis of asparagine. In vitro, resistance to L-Asp has been associated with up-regulation of AS mRNA expression. We monitored AS mRNA levels in leukemic cells before and during 5 days after intravenous administration of 1000 IU/m(2) pegylated L-asparaginase (PEG-Asp) in a therapeutic window in children with ALL at initial diagnosis. Within 24 hours, AS mRNA levels increased by 3.5-fold and remained stable in the following 4 days. Baseline and L-Asp-induced expression levels of AS did not differ between clinically good, intermediate, and poor responders to PEG-Asp. No significant difference of AS mRNA up-regulation was found between precursor B- and T-ALL or between hyperdiploids, TEL/AML1 rearranged ALL or absence of genetic abnormalities. In 3 of 12 patients with T-ALL even a slight down-regulation of AS mRNA expression upon L-Asp exposure was found. In conclusion, although L-Asp exposure induces the expression of AS mRNA, the up-regulated gene expression does not correlate with an early clinical poor response to this drug in children with ALL.

Supratentorial arterial ischemic stroke following cerebellar tumor resection in two children.

We describe two children who developed ischemic strokes in the territory of the middle cerebral artery, one 7 days and one 11 days after resection of a cerebellar tumor. In the first child, another infarction occurred in the territory of the contralateral middle cerebral artery 5 days after the first stroke. No specific cause or underlying risk factor other than the surgical procedure was found. The subacute clinical course at stroke onset resembled that of the 'posterior fossa syndrome', suggesting a common underlying mechanism.

Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia.

Resistance to L-asparaginase in leukemic cells may be caused by an elevated cellular expression of asparagine synthetase (AS). Previously, we reported that high AS expression did not correlate to L-asparaginase resistance in TEL-AML1-positive B-lineage acute lymphoblastic leukemia (ALL). In the present study we confirmed this finding in TEL-AML1-positive patients (n = 28) using microarrays. In contrast, 35 L-asparaginase-resistant TEL-AML1-negative B-lineage ALL patients had a significant 3.5-fold higher AS expression than 43 sensitive patients (P < .001). Using real-time quantitative polymerase chain reaction (RTQ-PCR), this finding was confirmed in an independent group of 39 TEL-AML1-negative B-lineage ALL patients (P = .03). High expression of AS was associated with poor prognosis (4-year probability of disease-free survival [pDFS] 58% +/- 11%) compared with low expression (4-year pDFS 83% +/- 7%; P = .009). We conclude that resistance to l-asparaginase and relapse risk are associated with high expression of AS in TEL-AML1-negative but not TEL-AML1-positive B-lineage ALL.