Frequency of neutropenia among Turkish and Syrian pediatric thalassemia patients under deferiprone monotherapy.

Weekly monitoring of absolute neutrophil count (ANC) under deferiprone therapy in thalassemia patients is recommended to avoid agranulocytosis adverse event. Actually, this recommendation may not be applicable in clinical setting. Our study aimed to establish incidence of neutropenia under deferiprone (DFP) monotherapy when it was monitored bimonthly due to socioeconomic conditions effecting local and refugee thalassemic patients including Syrian origin (SYR; n = 26) and Turkish origin (TR; n = 26) groups. Patients on DFP were followed up for 12 months. Fifteen neutropenic episodes were seen in 5 patients. All 5 patients (4 from SYR group and 1 from TR group) had splenomegaly and hypersplenism, and neutropenia ceased in 4 patients after splenectomy despite continuation of deferiprone. In the TR group, the frequency of patients who have neutropenia (absolute neutrophil count [ANC] <1500/mm(3)) was 3.8% (n = 1) in the 1st month, no patients in TR group had neutropenia until 10th month when again there was 1 patient with mild neutropenia. In SYR group, the frequency of patients who have neutropenia was 3.8% (n = 1), 7.7% (n = 2), and 11.5% (n = 3) in the 1st, 2nd, and 3rd months, respectively, and was found to be 3.8% (n = 1) between 6 and 12 months. Whether or not DFP therapy should be interrupted in case of mild neutropenia and the frequency of monitoring ANC in real-life conditions should be documented with further studies. Other causes of neutropenia in DFP-treated patients should also be kept in mind.

Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A/*3C Polymorphisms in a Patient with Pediatric Leukemia and the Effect of Steroid Therapy.

Myelosuppression is a serious complication during treatment of acute lymphoblastic leukemia and the duration of myelosuppression is affected by underlying bone marrow failure syndromes and drug pharmacogenetics caused by genetic polymorphisms. Mutations in the thiopurine S-methyltransferase (TPMT) gene causing excessive myelosuppression during 6-mercaptopurine (MP) therapy may cause excessive bone marrow toxicity. We report the case of a 15-year-old girl with T-ALL who developed severe pancytopenia during consolidation and maintenance therapy despite reduction of the dose of MP to 5% of the standard dose. Prednisolone therapy produced a remarkable but transient bone marrow recovery. Analysis of common TPMT polymorphisms revealed TPMT *3A/*3C.

ALL-BFM 95 treatment in Turkish children with acute lymphoblastic leukemia--experience of a single center.

Little is known about the likelihood of curing children with high-dose chemotherapy regimens for treatment of childhood acute lymphoblastic leukemia (ALL) in Turkey. The authors here report their 13 years' experience with original ALL-BFM (Berlin-Franfurt-Münster) 95 protocol in a cohort of 140 Turkish children with ALL. Complete remission rate was 97.7% with a relapse rate of 12.9% and death rate 17.9% during a median follow-up of 69 months. The event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) in these patients at 12 years were 75.0%, 87.1%, and 80.6%, respectively. These results show that ALL-BFM 95 protocol is equally applicable in the experienced centers, even in developing countries without substantial treatment-related toxicity. High rate of infection deaths are to be reduced with correct policies.

Thrombolysis with Systemic Recombinant Tissue Plasminogen Activator in Children: A Multicenter Retrospective Study

Objective: This study aimed to evaluate systemic thrombolysis experiences with recombinant tissue plasminogen activator (rtPA). Materials and Methods: Retrospective data were collected from 13 Turkish pediatric hematology centers. The dose and duration of rtPA treatment, concomitant anticoagulant treatment, complete clot resolution (CCR), partial clot resolution (PCR), and bleeding complications were evaluated. Low-dose (LD) rtPA treatment was defined as 0.01-0.06 mg/kg/h and high-dose (HD) rtPA as 0.1-0.5 mg/kg/h. Results: Between 2005 and 2019, 55 thrombotic episodes of 54 pediatric patients with a median age of 5 years (range: 1 day to 17.75 years) were evaluated. These patients had intracardiac thrombosis (n=16), deep vein thrombosis (DVT) (n=15), non-stroke arterial thrombosis (n=14), pulmonary thromboembolism (PE) (n=6), and stroke (n=4). The duration from thrombus detection to rtPA initiation was a median of 12 h (range: 2-504 h) and it was significantly longer in cases of DVT and PE compared to stroke, non-stroke arterial thrombosis, and intracardiac thrombosis (p=0.024). In 63.6% of the episodes, heparin was initiated before rtPA treatment. LD and HD rtPA were administered in 22 and 33 of the episodes, respectively. Concomitant anticoagulation was used in 90% and 36% of the episodes with LD and HD rtPA, respectively (p=0.0001). Median total duration of LD and HD rtPA infusions was 30 h (range: 2-120 h) and 18 h (2-120 h), respectively (p=0.044). Non-fatal major and minor bleeding rates were 12.5% and 16.7% for LD and 3.2% and 25.8% for HD rtPA, respectively. At the end of the rtPA infusions, CCR and PCR were achieved in 32.7% and 49.0% of the episodes, respectively. The most successful site for thrombolysis was intracardiac thrombosis. HD versus LD rtPA administration was not correlated with CCR/PCR or bleeding (p>0.05). Conclusion: Systemic thrombolytic therapy may save lives and organs effectively if it is used at the right indications and the right times in children with high-risk thrombosis by experienced hematologists with close monitoring of recanalization and bleeding.

Hemolytic anemia caused by non-D minor blood incompatibilities in a newborn.

Hyperbilirubinemia is one of the most widely seen cause of neonatal morbidity. Besides ABO and Rh isoimmunization, minor blood incompatibilities have been also been identified as the other causes of severe newborn jaundice. We report a newborn with indirect hyperbilirubinemia caused by minor blood group incompatibilities (P1, M, N, s and Duffy) whose hemolysis was successfully managed with intravenous immunoglobulin therapy. A thirty-two gestational weeks of preterm male baby became severely icteric on postnatal day 11, with a total bilirubin level of 14.66 mg/dl. Antibody screening tests revealed incompatibility on different minor groups (P1, M, N, s and Duffy (Fya ve Fyb)). On postnatal day thirteen, the level of bilirubin increased to 20.66 mg/dl although baby was under intensive phototherapy. After the administration of intravenous immunoglobulin and red blood cell transfusion, hemoglobin and total bilirubin levels became stabilised. Minor blood incompatibilities should be kept in mind during differential diagnosis of hemolytic anemia of the newborn. They share the same treatment algorithm with the other types hemolytic anemia. New studies revealed that intravenous immunoglobulin treatment in hemolytic anemia have some attractive and glamorous results. It should be seriously taken into consideration for treatment of minor blood incompatibilities.

The Impact of Transfusion and Chelation on Oxidative Stress in Immigrant Syrian Children with ß-Thalassemia.

Iron overload in ß-thalassemia major and intermedia patients leads to oxidative stress and causes to formation of lipid hydroperoxides. Thiobarbituric acid reactive substances (TBARS) are a well established method for screening and monitoring of lipid peroxidation. We aimed to investigate serum TBARS and its relationship with biochemical and hematologic parameters of Turkish and immigrant Syrian ß-thalassemia children reflecting the effects of this socioeconomic condition on follow up of these patients. Lipid peroxidation products (TBARS) of Turkish (TR) (n = 62, from the cities of Gaziantep and Sivas, Turkey) and Syrian (SYR) (n = 34, from Gaziantep, Turkey) ß-thalassemia patients aged 2-17 years and 58 healthy subjects aged 2-16 years were studied. Liver and renal function tests, serum ferritin levels, white blood cell, absolute neutrophil and platelet counts, hemoglobin (Hb) levels of the patients were analyzed. Serum TBARS concentrations were found to be elevated in ß-thalassemia patients compared to healthy subjects (mean: 12.47 ± 8.53 vs. 9.78 ± 7.09, p = 0.045). In SYR patients mean pretransfusional Hb level (7.26.2.04 vs. 8.49 ± 1.01, p = 0.002) was lower and ferritin levels (5983.56 ± 5065.56 vs. 3234.60 ± 2237.82, p = 0.001), liver enzymes (ALT: 77.82 ± 76.48 vs. 42.13 ± 51.50, p = 0.005) were higher when compared to TR group. Positive correlation between TBARS and ferritin levels (p = 0.029, r = 0.231) and liver enzymes (for ALT p < 0.001, r = 0.373) was observed. ß-thalassemia patients are under more oxidative stress than healthy subjects. Liver is one of the major organs which are mainly affected by oxidative stress. War and migration might have caused inappropriate transfusion conditions and insufficient chelation therapy in the SYR group.

Type I allergic hypersensitivity reactions due to ethylene oxide sterilised leucocyte filters in patients with thalassaemia: report of four cases.

Ethylene oxide (EO) is a highly reactive gas used in sterilisation of heat sensitive medical devices, such as infusion sets, cannulae, intubation materials, ventriculoperitoneal shunts, dialysis catheters and stents. Allergic reactions due to EO have been reported in haemodialysis patients, patients undergoing extracorporeal photopheresis and donors of plasmapheresis. Clinical manifestations vary considerably and generally do not allow differentiation between IgE-mediated anaphylaxis and anaphylactoid reactions. We report four patients with thalassaemia who experienced anaphylaxis during transfusion due to ethylene oxide sterilised leucocyte filters. The aim of this report is to highlight the fact that frequently transfused patients can have allergic reactions due to EO particles left in leucocyte filters.

Evaluation of Pediatric Bleeding Questionnaire in Turkish Children With Von Willebrand Disease and Platelet Function Disorders.

The diagnosis of mild bleeding disorders is not easy as most of the "healthy" individuals also report bleeding symptoms. In order to get a precise bleeding history, Pediatric Bleeding Questionnaire (PBQ) has been developed. In our study, Turkish children diagnosed with Von Willebrand disease (VWD), platelet function defect (PFD), and healthy children without any symptoms (control group 1) and healthy children with symptoms but found hemostatically normal (control group 2) were analyzed with PBQ. The cut off level for "positive bleeding score" was found to be ≥2 (area under the curve [AUC]: 0.785, 95% confidence interval [CI]: 0.718-0.852). The sensitivity, specificity, positive predictive value, and negative predictive value of PBQ to define VWD versus control group 1 was 100%, 97.4%, 96.4%, and 100%; VWD versus control group 2 was 100%, 53.1%, 64.3%, and 100%; PFD versus control group 1 was 93.3%, 53.1%, 73.7%, and 85%; and PFD versus control group 2 was 93.3%, 53.1%, 73.7%, and 85%, respectively.

Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome. A prompt molecular diagnosis is crucial for appropriate clinical management. Here, we validated and prospectively evaluated a targeted high-throughput sequencing approach for HLH diagnostics. METHODS: A high-throughput sequencing strategy of 12 genes linked to HLH was validated in 13 patients with previously identified HLH-associated mutations and prospectively evaluated in 58 HLH patients. Moreover, 2504 healthy individuals from the 1000 Genomes project were analyzed in silico for variants in the same genes. RESULTS: Analyses revealed a mutation detection sensitivity of 97.3%, an average coverage per gene of 98.0%, and adequate coverage over 98.6% of sites previously reported as mutated in these genes. In the prospective cohort, we achieved a diagnosis in 22 out of 58 patients (38%). Genetically undiagnosed HLH patients had a later age at onset and manifested higher frequencies of known secondary HLH triggers. Rare, putatively pathogenic monoallelic variants were identified in nine patients. However, such monoallelic variants were not enriched compared with healthy individuals. CONCLUSIONS: We have established a comprehensive high-throughput platform for genetic screening of patients with HLH. Almost all cases with reduced natural killer cell function received a diagnosis, but the majority of the prospective cases remain genetically unexplained, highlighting genetic heterogeneity and environmental impact within HLH. Moreover, in silico analyses of the genetic variation affecting HLH-related genes in the general population suggest caution with respect to interpreting causality between monoallelic mutations and HLH. A complete understanding of the genetic susceptibility to HLH thus requires further in-depth investigations, including genome sequencing and detailed immunological characterization.

A complication to be aware of: hyperkalaemia following propranolol therapy for an infant with intestinal haemangiomatozis.

Infantile haemangiomas, benign vascular tumours seen in 4-10% of infants are characterised by their spontaneous remission following a 3-9 month period of dynamic growth. Propranolol has been reported to be used as a successful treatment of severe symptomatic infantile haemangiomas. Hyperkalaemia has not been recognised as a serious effect of propranolol since recently. Here, we would like to portray a 2-year-old male patient with intestinal haemangiomatosis who presented with severe hyperkalaemia and was successfully managed with hydration, loop diuretics, potassium binding granules, inhaler ß-2 agonists and insulin. To date, this is the first case of intestinal haemangiomatosis complicated with severe hyperkalaemia. Our case suggested the idea of close monitorisation of potassium levels as well as haemodynamic status at the initialisation of the propranolol treatment.

Severe vitamin B12 deficiency with pancytopenia, hepatosplenomegaly and leukoerythroblastosis in two Syrian refugee infants: a challenge to differentiate from acute leukaemia.

Megaloblastic anaemia due to vitamin B12 deficiency is rare in childhood. However, as most cases are due to maternal insufficiency, it is mainly seen in breastfed infants especially when the mother's socioeconomic status is low and the nutrition is not adequate. We present case of two Syrian refugee infants with severe vitamin B12 deficiency with pancytopenia, hepatosplenomegaly and leukoerythroblastosis.

A case report of amitriptyline poisoning successfully treated with the application of plasma exchange.

Amitriptyline is a very frequently prescribed antidepressant agent and is very often involved in attempted suicides. Amitriptyline intoxication necessitates primary therapeutic approaches that include gastric irrigation and recurrent administration of activated charcoal. In the case of pronounced anticholinergic findings, physostigmine is of proven benefit and hypertonic sodium bicarbonate can be used to shorten the QRS duration and AV interval. In cases of a comatosed state, hemoperfusion and plasma exchange can be used. In this case report we present a case of severe amitriptyline poisoning that we successfully managed with plasma exchange. We confirmed a 59.5% reduction in the amitriptyline plasma level in our patient after a single plasma exchange session. She was discharged by the third day of admission without any complications. According to current literature, our patient is the fifth patient treated with plasma exchange to be the subject of a publication.