Successful Treatment With Bortezomib for Refractory and Complicated Acquired Thrombotic Thrombocytopenic Purpura in an Adolescent Girl.

Thrombotic thrombocytopenic purpura (TTP) is a rare, dangerous, life-threatening disease characterized by microangiopathic hemolytic anemia and thrombocytopenia, along with organ dysfunction due to microangiopathy-related ischemia. Plasma exchange and steroids are used for initial treatment, and rituximab is often used in refractive patients. Caplacizumab, cyclophosphamide, and splenectomy are among other treatment options. It has been reported that bortezomib, a proteasome inhibitor, can be used in the management of refractory acquired TTP. Herein, we present a 16-year-old female patient who was monitored for acquired TTP and treated with high-dose steroids, plasma exchange, rituximab, cyclophosphamide, and N-acetylcysteine but developed renal, cardiac, gastrointestinal, and neurologic complications. The girl was then successfully treated with bortezomib, and she has been monitored in remission for 6 months. We consider that bortezomib is a beneficial treatment, especially in patients with refractory TTP.

Inherited coagulation disorders in Turkish children: A retrospective, single-center cohort study.

OBJECTIVE: This study aims to investigate the distribution, clinical characteristics and outcome of inherited coagulation disorders (ICD) in Turkish children. SUBJECTS AND METHODS: Data from all children (age<18 years) with ICD examined in our center were retrospectively reviewed. RESULTS: There were 403 children with ICD (233 males and 170 females) with a median age of four years at diagnosis. The percentages of von Willebrand disease (vWd), hemophilia and rare bleeding disorders (RBD) were 40 %, 34 % and 26 %, type-1, type-2 and type-3 vWd were 63 % 17 % and 20 %, hemophilia A and B were 84 % and 16 %, and severe, moderate and mild hemophilia were 48 %, 30 % and 22 %, respectively. Factor VII and FXI deficiencies were the most prevalent, comprising 56 % and 22 % of all children with RBD, respectively. Parental consanguinity rates were 72 % in type-3 vWd and 61 % in severe RBD. The overall prevalence of gastrointestinal bleedings was 4.5 % (18/403), intracranial bleeding (ICB) was 4.96 % (20/403), mortality from ICB was 30 % (6/20) and the overall mortality rate was 1.49 % (6/403). No life-threatening bleeding was seen during regular prophylaxis. Chronic arthropathy prevalence in severe hemophilia was 8 % with primary prophylaxis and 53 % with demand therap. Inhibitor prevalence was 14 % in hemophilia-A and 5 % in hemophilia-B. CONCLUSIONS: These data show that vWd is the most common ICD, type-3 vWd and RBD are prevalent due to frequent consanguineous marriages and diagnosis of ICD is substantially delayed in Turkish children. Prophylactic replacement therapy prevents occurrence of life-threatening bleedings and reduces the development of hemophilic arthropathy.

Association of CYP3A5 Expression and Vincristine Neurotoxicity in Pediatric Malignancies in Turkish Population.

Vincristine is a widely used chemotherapeutic agent in the treatment of childhood malignancies. Neuropathy is the most common adverse effect. CYP3A4 and CYP3A5 enzymes of cytochrome p450 enzyme system are responsible in vincristine metabolism. Genetic polymorphism may alter the vincristine metabolism and the neurotoxicity rate. In this study, distribution of CYP3A5 alleles among Turkish children with malignancies, relation between CYP3A5 genotype and neurotoxicity rates, as well as severity and duration of neuropathy and total vincristine doses were investigated. Patient group consisted of 115 patients (age, 1 to 17 y) with acute lymphoblastic leukemia and solid tumors, who were treated with vincristine consisting chemotherapy protocols. Control group consisted of 50 children without any neurological symptom or disorders. All patient files were reviewed for presence and severeness of neurotoxicity symptoms. Blood samples were obtained and CYP3A5 genotypes were analyzed. Neurotoxicity occurred in 20.8% of patients. Although it was found to occur more frequently after 4 doses of vincristine, and rates were higher in the low-dose vincristine group suggesting other contributing factors. Although neurotoxicity rate in the CYP3A5*1/*3 genotype was 17.6%, it was 21.6% in the CYP3A5*3/*3 genotype and the difference was not statistically significant (P<0.05). This study suggested that vincristine-related neurotoxicity is dose-independent and genotype is not the only causative factor in the occurrence of neurotoxicity in these patients.

Prognostic Factors and Long-Term Outcome in 52 Turkish Children With Hemophagocytic Lymphohistiocytosis.

OBJECTIVES: Hemophagocytic lymphohistiocytosis is a syndrome of pathologic immune activation that shares similar clinical and laboratory phenotypes with severe sepsis. Recent studies led to better recognition of hemophagocytic lymphohistiocytosis by clinicians, but no consensus exists on the criteria for high-risk patients. DESIGN: We retrospectively reviewed the medical records of patients diagnosed with hemophagocytic lymphohistiocytosis to analyze the risk factors associated with poor outcome. SETTING: Pediatric intensive care and hematology units of three tertiary hospitals in Turkey. PARTICIPANTS: Fifty-two children with hemophagocytic lymphohistiocytosis. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: There were a total of 52 children meeting the diagnostic criteria of Histiocytic Society. Of them, 28 (54%) had a primary hemophagocytic lymphohistiocytosis. Mutation studies were performed in 18 of 28 patients (65%). Fourteen of them had PRF1, STX11, STXBP2, and UNC13D mutations, and four had Rab27a and LYST mutations. The remaining 24 patients (46%) were defined as having secondary hemophagocytic lymphohistiocytosis. Twenty-one of them had infection-associated hemophagocytic lymphohistiocytosis, and three had lysinuric protein intolerance. The mortality rate was significantly higher in primary hemophagocytic lymphohistiocytosis (64%) than in secondary hemophagocytic lymphohistiocytosis (16%) (p < 0.05). There were no significant differences for survival rate between hemophagocytic lymphohistiocytosis 94 (44%) and hemophagocytic lymphohistiocytosis 2004 (64%) protocols (p > 0.05). Age below 2 years, hyperferritinemia, thrombocytopenia, high disseminated intravascular coagulation score at diagnosis, and no clinical response at 2 weeks of treatment were independent prognostic factors for poor prognosis. CONCLUSIONS: Our data suggest that disseminated intravascular coagulation score greater than or equal to 5 can be used in the definition of high-risk patients. Early recognition of poor risk factors has important prognostic and therapeutic implications.

Resolution of inflammatory colitis with pegfilgrastim treatment in a case of severe congenital neutropenia due to glucose 6 phosphatase catalytic subunit-3 deficiency.

Glucose 6 phosphatase catalytic subunit-3 (G6PC3) deficiency is a heterogenous disorder characterized by severe congenital neutropenia and a variety of extrahematopoietic manifestations. Inflammatory bowel disease like colitis is an uncommon complication of G6PC3 deficiency, described only in adolescent and adults. Herein, we describe inflammatory colitis in a 10-year-old girl with severe congenital neutropenia due to G6PC3 deficiency while she was on a high-dose filgrastim. Switching from filgrastim to (pegylated filgrastim) Pegfilgrastim led to rapid resolution of colitis, weight gain, and decreased infections. Pegfilgrastim seems to be a better remedy for treatment of G6PC3 deficiency complicated with inflammatory bowel disease.

The frequency of menorrhagia and bleeding disorders in university students.

STUDY OBJECTIVE: Menorrhagia is an important health problem in women of reproductive age. The aims of this study were to assess the prevalence of menorrhagia and hemostatic abnormalities associated with menorrhagia in university students. METHODS: The pictorial blood assessment chart (PBAC) was used to identify students with menorrhagia. Those with a PBAC score > 100 were examined by pelvic ultrasound and laboratory tests including complete blood count, levels of clotting factors, von Willebrand factor antigen, and ristocetin cofactor activity and Platelet Function Analyser-100 (PFA-100). Platelet aggregation was studied in students with prolonged PFA-100 closure time. RESULTS: Menorrhagia was identified in 82 (21.8%) of 376 students. Six of 82 students who had pelvic pathologies were excluded. Eleven (14.5%) of the remaining 76 students were found to have bleeding disorders, including von Willebrand disease in five (6.5%), platelet function disorder in four (5.2%), and clotting factor deficiencies in two (2.6%). CONCLUSIONS: Menorrhagia is a common but mostly unrecognized and untreated problem among university students. Underlying bleeding disorders are not rare and require comprehensive hemostatic evaluation for identification.

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.

Colonic lithobezoar: a rare cause of partial intestinal obstruction.

Bezoar is the accumulation of indigestible foreign substances in the digestive tract and a rare cause of intestinal obstruction in children. The accumulation of stones within the digestive system is called lithobezoar, and the colon is the rarest site for accumulation. A 13-year-old female patient was admitted to our hospital with colicky abdominal pain and constipation. She had been unable to pass her stool for the last six days and had passed stones-containing stools previously. She had a history of pica and iron-deficient anemia. The case is presented to discuss the diagnostic and therapeutic features of partial colonic obstruction secondary to colonic lithobezoar accumulation.

Evaluation of Patients with Neonatal Thrombosis.

The aim of the study is to characterize acquired and genetic risk factors and to give an account of the hereditary thrombophilia panel in neonatal thrombosis. All newborns diagnosed with neonatal thrombosis in a level III NICU were included in this retrospective cohort study. A total of 1850 patients were admitted to the NICU during the 5-y period; and 11 patients were diagnosed with thrombosis (0.58%). The most common risk factors were central venous catheter placement, hypoxia and prematurity and related complications, and sepsis. Four patients were investigated regarding the inherited risk factors for thrombosis. In these 4 patients, homozygous A1298C alleles of MTHFR and heterozygous FXIIIV34L mutations; homozygous PAI-SERPINE1 and heterozygous MTHFRA1298C mutations; compound heterozygous mutations of MTHFRC677T and MTHFRA1298C; and compound heterozygous mutations of MTHFRC677T, MTHFRA1298C, and PAISERPINE1 were detected respectively. In conclusion, neonatal thrombosis is multifactorial; newborns with acquired risk factors may also have hereditary risk factors. TRIAL INFORMATION: ClinicalTrials.govIdentifier: NCT05367466.

Life-threatening massive upper gastrointestinal bleeding in a term and healthy baby.

Upper gastrointestinal (UGI) bleeding due to gastric ulcer and gastritis can be seen in severely ill or premature infants but is rarely reported in healthy term newborns. UGI endoscopy is crucial for the etiological evaluation and appropriate treatment of UGI hemorrhages. This report discusses the differential diagnosis and treatment approach in a previously healthy infant who was admitted to the neonatal intensive care unit due to life-threatening severe UGI bleeding causing hemodynamic instability.

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.

A novel single point mutation of the LYST gene in two siblings with different phenotypic features of Chediak Higashi syndrome.

Chediak Higashi syndrome (CHS) is an autosomal-recessive disorder characterized by oculocutaneous albinism, recurrent infections and a progressive primary neurological disease. Here, we describe two siblings with CHS due to a novel homozygous R1836X mutation in the LYST gene associated with loss of NK cell degranulation and cytotoxicity. While one sibling was born with fair skin and hair and died of hemophagocytic lymphohistiocytosis (HLH) at 5 months of age, the other sibling had dark black hair and skin and developed HLH at the age of 4 years.

Serum prohepcidin levels in children with solid tumors, inflammatory bowel disease and iron deficiency anemia.

BACKGROUND: Prohepcidin is one of the regulators of iron metabolism. Few studies examined its relation with solid tumors (ST), inflammatory bowel disease (IBD) and iron deficiency anemia (IDA) in children. METHODS: We measured serum prohepcidin (SP), soluble transferrin receptor (sTfR), serum ferritin (SF), serum iron (SI), transferrin saturation (TS), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels in ST (n = 16), IBD (n = 15), IDA (n = 14) and controls (n = 18). RESULTS: The mean SP was significantly higher in ST and IBD than in IDA and controls. SP was significantly correlated with SF in ST, IBD and ESR for IBD and CRP for ST and hemoglobin for ST. CONCLUSION: Elevated SP may be a clinically important predictor of inflammation and leads to anemia by impairing iron utilization in IBD and ST. SP decreases in IDA and is correlated with TS but not with SF or sTfR.

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.

Parathyroid adenoma and chondrosarcoma after treatment of pediatric Hodgkin disease.

Treatment of Hodgkin disease (HD) with chemoradiotherapy in children is associated with increased risk for developing secondary neoplasms. Parathyroid adenoma (PTA) and chondrosarcoma (CS) are quite rare types of secondary neoplasms after HD. We describe a 5-year-old boy with stage IV HD, successfully treated with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone)/ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy followed by 35 Gy mantle radiotherapy who developed primary hyperparathyroidism because of benign PTA at the age of 20 years, and died of CS in thoracic vertebrae at the age of 22 years. Consecutive occurrence of PTA and CS after treatment of pediatric HD, to the best of our knowledge, has not been reported earlier.

Could lower bone turnover be a cause of chest pain during childhood?

Chest pain, a frequent complaint during childhood, rarely originates from a cardiac pathology. Although it usually is idiopathic, it also could be associated with psychogenic, musculoskeletal, respiratory, and digestive disorders. This study aimed to investigate a possible relation between bone mineral density and chest pain in children. Bone mineral density and bone metabolism parameters were measured for 50 children with chest pain, and the findings were compared with those for 40 age- and sex-matched healthy children. Most of the cases (64%) were in the idiopathic group, and musculoskeletal chest pain was the second most frequent complaint (12%). Although bone mineral densities and osteocalcin levels did not differ significantly between the whole chest pain group and the control group, both were found to be lower in the musculoskeletal chest pain group than in other groups and the control group (p < 0.05). Musculoskeletal chest pain may be related to reduced bone mineral metabolism, and monitoring of risk factors is of particular importance.

Outcomes of Eltrombopag Treatment and Development of Iron Deficiency in Children with Immune Thrombocytopenia in Turkey

Objective: Immune thrombocytopenia (ITP) is a rare autoimmune disease and hematologic disorder characterized by reduced platelet counts that can result in significant symptoms, such as bleeding, bruising, epistaxis, or petechiae. The thrombopoietin receptor agonist eltrombopag (EPAG) is a second-line agent used to treat chronic ITP purpura in adults and children. Materials and Methods: The present retrospective study evaluated the efficacy, safety, and side effects of EPAG treatment in pediatric patients with acute refractory and chronic immune thrombocytopenia, particularly focusing on iron-deficiency anemia. Results: The diagnosis was chronic ITP in 89 patients and acute refractory ITP in 16 patients. The mean age of patients was 9.5±4.5 years (minimum-maximum: 1.2-18 years) at the beginning of EPAG treatment. The overall response rate was 74.3% (n=78). The mean time for platelet count of ≥50x109/L was 11.6±8 weeks (range: 1-34 weeks). The treatment was stopped for 27 patients (25.7%) at an average of 6.8±9 months (range: 1-38 months). The reason for discontinuation was lack of response in 18 patients, nonadherence in 4 patients, and hepatotoxicity in 2 patients. Response to treatment continued for an average of 4 months after cessation of EPAG in 3 patients. Conclusion: Results of the current study imply that EPAG is an effective therapeutic option in pediatric patients with acute refractory and chronic ITP. However, patients must be closely monitored for response and side effects during treatment, and especially for iron deficiency.

Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis.

BACKGROUND: Children with acute leukemia have increased risk for invasive fungal infections (IFI) but the role of long term antifungal prophylaxis (AFP) in morbidity and mortality of IFI is not well-known. PROCEDURE: Medical records of 154 children with acute leukemia who received AFP with fluconazole during intensive chemotherapy were retrospectively reviewed to determine risk factors, clinical characteristics and outcome of IFI. RESULTS: The overall incidence of IFI was 13.6%. Frequencies of proven, probable and possible infections were 7.2%, 2.6%, and 3.8%, respectively. The causative agent was Candida in 12 (57.2%) and Aspergillus in 9 (42.8%) children. There were 10 children with candidemia (47.6%), 7 with pulmonary aspergillosis (33.4%), 2 with hepatosplenic candidiasis (10.0%), one with sinopulmonary aspergillosis (4.5%) and one with sinus aspergillosis (4.5%). IFI was twice as common in acute myeloid leukemia (AML) (20.7%) than in acute lymphoblastic leukemia (ALL) (10.2%). Duration of profound neutropenia (P = 0.01) and steroid medications (P = 0.001) were significantly associated with IFI in univariate but not in multivariate analysis. Liposomal amphotericin B (L-AMB) was successful in 15 of 21 children as a single agent. Voriconazole produced complete response in four children with invasive aspergillosis and two with hepatosplenic candidiasis, who were unresponsive to L-AMB. The rate of IFI attributable death was 5%. CONCLUSIONS: Our results indicate that AFP with fluconazole and early empirical antifungal therapy may be effective in reducing the incidence and mortality of IFI in children with acute leukemia.

Fatal Epstein-Barr virus infection in a case of familial hemophagocytic lymphohistiocytosis with syntaxin-11 mutation.

Familial hemophagocytic lymphohistiocytosis (FHL) is a fatal disease of early infancy caused by defective natural killer cell activity and is characterized by fever, organomegaly, pancytopenia, and coagulopathy. Disease-causing mutations have been found in perforin, Munc 13-4 and syntaxin-11 genes. We herein describe a case of late-onset FHL with syntaxin-11 mutation in a six-year-old boy in whom only partial response was obtained by immunochemotherapy (HLH-94 protocol) and who died with persistent Epstein-Barr virus (EBV) infection. The role of EBV infection in the prognosis of FHL is discussed.

Bilateral knee and right ankle osteonecrosis in an adolescent girl with acute lymphoblastic leukemia.

Although rare, avascular necrosis of bone is a serious and incapacitating complication seen in children with acute lymphoblastic leukemia receiving high dose steroids. Here we present a 16 year-old girl who developed bilateral knee and right ankle avascular osteonecrosis one year after intensive chemotherapy for medium risk acute lymphoblastic leukemia. Indirect curettage of necrotic tissue and bone grafting were performed for both knees whereas conservative measures had been sufficient for the ankle. Early recognition of this condition is important in prevention of disabling sequela in skeletal system.