Tissue Plasminogen Activator Use in Pediatric Patients: A Single Center Experience.

INTRODUCTION: Thrombosis is rare in children and antithrombolytic treatment is controversial. Most commonly used thrombolytic agent is tissue plasminogen activator (t-PA) in pediatrics. In this study, we report our experience in the use of thrombolytic treatment. METHODS: Eighteen patients who had received systemic t-PA between January 2006 and December 2013 were recorded. The response to t-PA was evaluated as complete, partial, and no. The bleeding complication during t-PA administration was graded as minor or major. RESULTS: There were 18 patients (2 mo to 12 y) who received systemic t-PA. Three patients had venous, 14 patients had arterial, and 1 patient had intracardiac thrombosis. Thrombosis was related to cardiac catheterization (61.1%), central venous catheterization (16.7%), cardiac surgery (11.1%), and arrhythmia (5.5%). In 1 patient thrombosis occurred spontaneously (5.5%). Eighteen patients received 25 courses of systemic t-PA (0.15 to 0.3 mg/kg/h). A total of 55.6% of cases had complete, 27.8% had partial, and 16.6% showed no resolution. CONCLUSION: t-PA infusion at doses of median 0.2 mg/kg/h (0.15 to 0.3) seems effective and safe. There is still no consensus on indications and dosing of antithrombolytic treatment in children but in selected patients it decreases long-term complications due to thrombosis.

Toxicity of Vincristine Combined With Posaconazole in Children With Acute Lymphoblastic Leukemia.

BACKGROUND: Vincristine (VCR) is one of the main drugs of acute lymphoblastic leukemia (ALL) treatment. Azole antifungal medications are used for treatment or prophylaxis of invasive fungal infections in acute leukemia. Coadministration of these drugs increases the risk of VCR toxicity. OBSERVATIONS: We presented a girl with ALL using posaconazole prophylaxis. She developed VCR toxicity that included tubulopathy, high blood pressure, neuropathic pain, difficulty walking, diffuse muscular weakness, constipation, abdominal pain. CONCLUSIONS: There are limited data in children with ALL for posaconazole prophylaxis. We recommend that VCR side effects should be evaluated by careful monitoring of the patients who are on this combination therapy.

Evaluation of engraftment syndrome in children following full-matched related donor hematopoietic stem cell transplantations.

The term "ES" has been widely used for describing a clinical condition consisting of skin rash, fever, and weight gain that occur during neutrophil recovery period following HSCT. In this study, the incidence, clinical features, risk factors, and outcomes of ES were evaluated in 169 children following allogeneic HSCT from full-matched related donor according to the Spitzer criteria. Seventeen patients (10.1%) presented with clinical conditions suggesting ES. In both univariate and multivariate analysis underlying malignant disease and early release of monocytes to the PB, and in univariate analysis using only CsA for GVHD prophylaxis were found to be the significant risk factors for the development of ES. Patients with ES experienced significantly higher incidence of acute and chronic GVHD and propensity toward a higher rate of TRM. OS did not differ between the patient groups. Thirteen of 17 patients received steroid therapy, and all but one patient responded to therapy. Monitoring for early detection of ES and early intervention with steroid therapy is the key for recovery. The most crucial approach for this purpose mainly is to find out and use the most useful and feasible diagnostic criteria for routine medical practice.

The impact of donor age and sex on the nucleated cell count and CD34 count in healthy bone marrow donors.

BM remains an important source of stem cells. The BM characteristics change with age but the estimation of CD34 calculation of one CD34+ cell per 100 nucleated cells is used for all donors including pediatric donors in the operating room before getting the actual CD34 count. In order to see whether this formula is applicable for pediatric donors, we designed a retrospective study to see the affect of the age and sex on the BM NCC, CD34 count, and CD34/NCC ratios. Ninety-eight BM collections from 91 related donors were evaluated retrospectively (median age: nine yr [1.5-54 yr]; M/F: 41/50). A significant negative correlation was found between the donor age and NCC (r = -0.229, p < 0.05), CD34 count (r = -0.563, p < 0.01), and CD34/NCC (r = -0.664, p < 0.01). The negative correlation for CD34 count and CD34/NCC persisted in female and male donor groups. When donors younger than 16 yr of age were compared with the older donor group, the median NCC, median CD34 count, and CD34/NCC were significantly lower in the older group (p < 0.01). Age and sex have to be taken into consideration to avoid unnecessary high-volume collections and increased operating room time in the younger donors.

Idiopathic Pulmonary Hemosiderosis With Allergic Asthma Diagnosis in a Pediatric Patient.

Idiopathic pulmonary hemosiderosis (IPH) is a rare disorder with unknown pathogenesis that usually presents in the first decade of life. As a result of diffuse alveolar hemorrhage, respiratory symptoms such as cough attacks, hemoptysis, dyspnea, and recurrent and refractory iron-deficiency anemia (IDA) are observed. We present an 8-year-old girl who was followed up with recurrent IDA and allergic asthma and later diagnosed with IPH. IPH was confirmed by the presence of hemosiderin-laden macrophages in bronchoalveolar lavage obtained by bronchoscopy and exclusion of the secondary causes of pulmonary hemosiderosis. Glucocorticoids and iron supplementation were started. Clinical and laboratory improvement was observed with therapy. Our case illustrates that refractory/recurrent IDA with any pulmonary symptoms may be the only presenting feature of IPH.

A novel protein C inhibitor gene mutation in pediatric stroke patients after bone marrow transplantation.

Protein C inhibitor is a heparin dependent serine protease inhibitor found in human plasma, urine and other body fluids. It was originally identified as an inhibitor of activated protein C. Stroke is an important cause of morbidity and mortality in the pediatric age group. In this study we analyzed the protein C inhibitor gene mutations in Turkish pediatric stroke patients. We found a missense mutation of G to A at nucleotide 6760 in exon 2, resulting in a transition serine to asparagine (p.Ser188Asp) and in a child and his father and also we found same alteration in exon 2 in an another pediatric stroke case following bone marrow transplantation.

Blood group genotyping in multi-transfused patients.

BACKGROUND: In chronically transfused patients, the classical hemagglutination assays may be inaccurate in defining the RBC phenotypes of the patients due to previous transfusions. DESIGN: DNA samples from 39 multi-transfused patients including thalassemia and sickle cell disease were used for red blood cell genotyping. The Rh-Type and KKD-Type (BAGene, BAG Healthcare) were used to determine the polymorphisms associated with antigen expression for RHD, RHCE and Kell, Kidd, Duffy blood group systems, respectively. Results were compared with previously determined phenotyping results for RhD, RhCcEe and Kell by hemagglutination method. RESULTS: Nineteen out of the 37(51%) patients had discrepancies between genotyping and phenotyping results in a total of 25 alleles. In 12 patients, the discrepancies had the potential of alloimmunization. CONCLUSION: Blood group genotyping has vital importance in transfusion management of chronically transfused patients especially if the patients were not phenotyped before starting the initial transfusions.

Primary adrenal insufficiency in a child after busulfan and cyclophosphamide-based conditioning for hematopoietic stem cell transplantation.

High rates of skeletal complications, growth disturbances, thyroid and gonadal dysfunction have been described in children undergoing stem cell transplantation. Although secondary adrenal insufficiency has been diagnosed, no primary adrenal insufficiency has been reported after busulfan and cyclophosphamide (Bu/Cy)-based conditioning regimens for stem cell transplantation in children. A 9-year-old girl with myelodysplastic syndrome was treated with stem cell transplantation of allogeneic origin. She received myeloablative conditioning chemotherapy, Bu and Cy. Her serum cortisol level was normal before stem cell transplantation. Then, 17 months after stem cell transplantation, chronic graft-versus-host disease developed and was treated with methyl prednisolone for 3 months. The control endocrinological investigation revealed low serum cortisol and high serum adrenocorticotropin (ACTH) levels 6 months after completion of methyl prednisolone treatment. The ACTH stimulation test demonstrated primary adrenal insufficiency, and the other etiologies of primary adrenal insufficiency were excluded. The patient received oral prednisolone replacement therapy. She was followed-up for 44 months and required increases in steroid doses during stress periods. Primary adrenal insufficiency which was observed in our patient after Bu/Cy-based conditioning regimen for stem cell transplantation has not been reported in children and adrenal function should be closely monitored in these patients both before stem cell transplantation and after stem cell transplantation.

Invasive Candida infections in children: the clinical characteristics and species distribution and antifungal susceptibility of Candida spp.

The aims of the study were to examine the distribution of Candida spp. isolated from sterile body sites, the antifungal susceptibility of the isolates to amphotericin B, fluconazole, voriconazole, and caspofungin, and factors affecting mortality with invasive Candida infections in children. Thirty-five children with invasive candidiasis between January 2004 and January 2008 were evaluated retrospectively. The antifungal susceptibility of isolated Candida species was studied by Etest. Of the invasive Candida infections, 65.7% were due to C. albicans. The second most common isolated species was C. parapsilosis (11.4%). The rates of resistance to fluconazole, amphotericin B and voriconazole were 8.5%, 2.8% and 5.7%, respectively. Caspofungin was the most effective antifungal agent. 22.8% of the patients died in the first 30 days. In univariate analyses, increased mortality was associated with stay in the intensive care unit, the presence of central venous catheter (CVC), failure to remove CVC, and mechanical ventilation.

The role of tumor necrosis factor-alpha -308 G/A and transforming growth factor-beta 1 -915 G/C polymorphisms in childhood idiopathic thrombocytopenic purpura.

OBJECTIVE: To increase our understanding of the etiology of idiopathic thrombocytopenic purpura (ITP) some cytokine gene polymorphisms were analyzed for susceptibility to the disease. The aim of this study was to investigate the role of tumor necrosis factor-alpha (TNF-α) -308 G/A and transforming growth factor-beta 1 (TGF-ß1) -915 G/C polymorphisms in the development and clinical progression of childhood ITP. METHODS: In all, 50 pediatric patients with ITP (25 with acute ITP and 25 with chronic ITP) and 48 healthy controls were investigated via LightCycler® PCR analysis for TNF-α -308 G/A and TGF-ß1 -915 G/C polymorphisms. RESULTS: The frequency of TNF-α -308 G/A polymorphism was 20%, 16%, and 22.9% in the acute ITP patients, chronic ITP patients, and controls, respectively (p>0.05). The frequency of TGF-ß1 -915 G/C polymorphism was 16%, 8%, and 8.3% in the acute ITP patients, chronic ITP patients, and controls, respectively (p>0.05). The risk of developing ITP and clinical progression were not associated with TNF-α -308 G/A (OR: 0.738, 95% CI: 0.275-1.981, and OR: 0.762, 95% CI: 0.179-3.249) or TGF-ß1 -915 G/C (OR: 1.5, 95% CI: 0.396-5.685, and OR: 0.457, 95% CI: 0.076-2.755) polymorphisms. CONCLUSION: The frequency of TNF-α -308 G/A and TGF-ß1 -915 G/C polymorphisms did not differ between pediatric ITP patients and healthy controls, and these polymorphisms were not associated with susceptibility to the development and clinical progression of the disease.

Prospective evaluation of acute and chronic renal function in children following matched related donor hematopoietic stem cell transplantation.

Acute and chronic renal impairment are important complications after HSCT. A prospective study was conducted to investigate the glomerular renal function in children who received allogeneic HSCT from matched related donors. Non-radiation conditioning regimens were used in all but one patient. CrCl and serial measurements of serum creatinine were evaluated prior to HSCT, within the first 100 days and one yr after. AKI was defined as at least a 1.5-fold rise in pre-HSCT serum creatinine within the first 100 days and classified as grade 1 to 3 according to the new definition criteria proposed by "AKI Network." Fifty-seven patients were enrolled in the study and 24 patients (42%) had AKI. CsA, amphotericin B, and SOS were found as risk factors for AKI. One yr after HSCT five patients (10%) had CKD and none of them required dialysis. None of the parameters were found as a predictor for CKD. We conclude that AKI is an important complication of HSCT. Careful monitoring of renal function, minimizing the use of nephrotoxic medication, prophylaxis, and effective treatment of SOS might be effective preventive measures to decrease the incidence of AKI.

Mixed chimerism following hematopoietic stem cell transplantation in pediatric thalassemia major patients: a single center experience.

OBJECTIVE: Stable mixed chimerism (MC) may result in cure for thalassemia major patients following hematopoietic stem cell transplantation (HSCT), but rejection can occur. Twenty-eight HSCTs for thalassemia major were reviewed retrospectively to evaluate the clinical course of MC with possible risk factors and predictors of outcome, with a median follow-up of 1669 days (811-3576 days). METHODS: Chimerism was detected by fluorescence in situ hybridization (FISH) or multiplex polymerase chain reaction depending on the sex match between the donor and the recipient. RESULTS: Primary rejection, stable MC and full donor chimerism was detected in 3.6%, 17.8% and 78.6% of patients, respectively. Clinically, 4/5 patients with stable MC had thalassemia trait with donor chimerism as low as 14%. One patient was started on pRBC transfusions at 2.5 years postHSCT. CONCLUSION: Stable MC can result in cure for thalassemia major patients. The clinical picture remains as the best guide for intervention until a more reliable predictor is available.

Related donor hematopoietic stem cell transplantation for Fanconi anemia without radiation: a single center experience in Turkey.

Eight children with FA underwent allogeneic HSCT without using irradiation for the conditioning regimen. Patients received two different conditioning regimens: first two patients received BU 1.5 mg/kg/day for four days and CY 10 mg/kg/day for four days and the other regimen was: Flu 30 mg/m(2)/day for five days, CY 10 mg/kg/day for two days, and ATG-Fresenius 9-10 mg/kg/day for four days. GVHD prophylaxis consisted of CsA + MTX for the first two patients and only CsA for the others. All patients received HLA-identical stem cells from related donors. Primary engraftment was demonstrated in all patients. No patient developed acute GVHD and one patient had chronic GVHD. Only one patient who received BU based regimen died because of VOD. Overall, seven patients (87.5%) are alive with stable full donor chimerism at a median follow-up time of 2.5 yr (range: 1.7-8.9 yr). None of the patients developed secondary malignancy. Based on our data, we conclude that Flu-based, non-irradiation conditioning regimen was safe with low organ toxicity and stable engraftment in FA patients undergoing HSCT from matched related donors.

A breast-fed newborn with megaloblastic anemia-treated with the vitamin B12 supplementation of the mother.

Pregnant women with low B12 levels are unable to provide the necessary amount of this vitamin to their fetuses. The mothers are usually not anemic, and failure to thrive and neurologic deficits are more common in their infants than in megaloblastic anemia. We report the case of a newborn that was born to a vegetarian mother and presented with the symptoms of megaloblastic anemia at birth; we also discuss vitamin B12 metabolism during pregnancy and lactation. An interesting feature of the present case is that it is the only reported case of a newborn that was treated by supplementation of the mother.

Extramedullary hematopoiesis with spinal cord compression in a child with thalassemia intermedia.

Spinal cord compression due to extramedullary hematopoiesis is an extremely rare complication of thalassemia intermedia. No cases with this complication have been reported in the first decade of life, because masses of heterotropic marrow developed in patients as a result of continuous erythropoiesis. We report the 9-year-old patient suffering from thalassemia intermedia and presenting spinal cord compression. We also review the literature about treatment options, because there is no consensus about the optimal treatment of these patients. Our patient was successfully treated with radiation therapy followed by hydroxyurea. With this combination therapy, he had no recurrence during the 4-year follow-up period. Clinical awareness of this phenomenon with the early treatment is essential for optimizing the successful outcome.

Excessive naked megakaryocyte nuclei in myelodysplastic syndrome mimicking idiopathic thrombocytopenic purpura: a complicated pre- and post-transplantation course.

A boy 3 years 7 months old with thrombocytopenia and history of intracranial hemorrhage who underwent bone marrow transplantation is presented. He was refractory to steroids, immunoglobulin G, vincristine, azathioprine, cyclosporine A, interleukin-11, chemotherapy, and splenectomy. Idiopathic thrombocytopenic purpura was excluded by light /electron microscopic and flow cytometric findings; the diagnosis of refractory cytopenia, a subgroup of pediatric myelodysplastic syndrome, was made. Naked megakaryocyte nuclei were 55.38 +/- 28.2% vs. 31.67 +/- 23.22% of all megakaryocytes in the patient and the control group of 9 patients with idiopathic thrombocytopenic purpura, respectively (p = .016). The posttransplatation course was complicated by delayed platelet engraftment, bronchiolitis obliterans associated with pneumocystis carinii pneumonia, which resolved completely.

Acute myeloid leukemia in Turkish children with Fanconi anemia. One center experience in the period between 1964-1995.

OBJECTIVE: Fanconi's anemia(FA) is an autosomal recessive disorder characterized by a progressive pancytopenia,variable congenital abnormalities and an increased risk for the development of acute myeloid leukemia (AML). The objective of this study is to evaluate AML in the patients with FA diagnosed and followed-up in the Department of Pediatric Hematology at Ankara University School of Medicine in the period between 1964-1995. METHODS: A total of 39 patients within the age range 2-14 years( mean 8.2±3.16),28 male and 11 female were diagnosed as FA on the basis of congenital abnormalities,pancytopenia, bone marrow hypoplasia and diepoxybutane induced chromosomal abnormalities that observed in all patients The hereditary and familial basis of FA was apparent in this series.Common abnormalities were growth retardation,cefe'- au- laitspots,hyperpigmentation,microcephaly, finger and thumb deformities,mental retardation and hypogenitalismus RESULTS: Four AML (10.2%) were observed in our series.Cytogenetic analysis of these cases revealed 46/ XX,dup(3)(q22;q26) t(7;17) (p11;p11) in one where it was unsuccessful in three.Two cases could not achieve remission and died.The other two achieved complete remission and remained in remission for2 and 6 months. CONCLUSION: Acute myelomonocytic type in three cases and acute monocytic type in one patient were diagnosed in our series. The patients with FA should be followed with regard to AML and solid tumors. AML and solid tomors should be taken into the consideration as the first manifestation of FA.

Evaluation of glucose homeostasis in transfusion-dependent thalassemic patients.

Diabetes is an important problem encountered in thalassemic patients. The severity and type of glucose disturbances vary greatly in different studies. Also the pathogenesis seems to be complex; either insulin deficiency or insulin resistance may mediate the glucose disturbances. In a group of thalassemic patients glucose homeostasis was evaluated. Diabetes prevalence was 1.8%. Forty patients were investigated both with an oral glucose tolerance test and first-phase insulin response. Three patients had impaired fasting glucose, 1 patient had impaired glucose tolerance, and 2 patients had hyperinsulinism. Nineteen of 40 patients who were tested had low first-phase insulin response (47.5%) with below 10th centile. Age, BMI, height SDS, age at diagnosis, age at first blood transfusion, number of blood transfusions in a year, percentage of elevated liver enzyme, and hemoglobin and ferritin levels were not different between patients with low first-phase insulin response to patients with normal first-phase insulin response. Four patients are HCV infected, and only 1 of them had low first-phase insulin response. The study group showed a high rate of impairement in insulin secretion by first-phase insulin response to glucose overload, despite the low rate of insulin resistance. Defect of insulin secretion in thalassemic patients may develop earlier than insulin resistance, and then be accompanied by insulin resistance. Increasing insulin resistance with age and the occurrence of additional factors could lead to detoriation of glucose metabolism.

Elevated plasma asymmetric dimethylarginine levels in children with beta-thalassemia major may be an early marker for endothelial dysfunction.

OBJECTIVES: Beta-thalassemia major is associated with the increased risk of cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) has been implicated in the pathogenesis of endothelial dysfunction and atherosclerosis. In this study, we aimed to investigate circulating ADMA concentrations in children with beta-thalassemia major. METHODS: Thirty-one beta-thalassemia major children aged between 4 and 16 year old and age, gender-matched 36 healthy controls were enrolled in the study. Plasma ADMA was measured along with the soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), P-selectin, and Pentraxin-3. RESULTS: Age, gender and body mass index were similar in two groups. Plasma ADMA, sVCAM-1, and sICAM-1 measurements were significantly higher in beta-thalassemia major patients than the control group (p < 0.004 for ICAM-1, p < 0.001 for other parameters). There were positive significant correlations between ADMA, sVCAM-1 and sICAM-1 (r = 0.437, p < 0.001; r = 0.544, p < 0.001; r = 0.405, p < 0.001, respectively) in the whole group. DISCUSSION: The findings of the current study show us that increased plasma ADMA levels in children with beta-thalassemia major may be an early marker for endothelial dysfunction and may play a role in the development of premature atherosclerosis in beta-thalassemia major patients.

Does D-dimer predict cerebral sinovenous thrombosis in the newborn?

Sinovenous thrombosis describes thrombosis in one or more of the cerebral venous sinuses. The incidence of SVT in childhood appears to be highest during the neonatal period. Although plasma level of D-dimer has been shown to be sensitive for the diagnosis of deep vein thrombosis and pulmonary embolism in adult patients, there are few data about the relationship between sinovenous thrombosis and D-dimer levels in childhood, especially in the newborn period. The authors' aim in presenting this case report is to discuss the usefulness of plasma D-dimer measurements as a predictor of cerebral sinovenous thrombosis in the newborn.