A National Registry of Thalassemia in Turkey: Demographic and Disease Characteristics of Patients, Achievements, and Challenges in Prevention.

OBJECTIVE: The Turkish Society of Pediatric Hematology set up a National Hemoglobinopathy Registry to demonstrate the demographic and disease characteristics of patients and assess the efficacy of a hemoglobinopathy control program (HCP) over 10 years in Turkey. MATERIALS AND METHODS: A total of 2046 patients from 27 thalassemia centers were registered, of which 1988 were eligible for analysis. This cohort mainly comprised patients with ß-thalassemia major (n=1658, 83.4%) and intermedia (n=215, 10.8%). RESULTS: The majority of patients were from the coastal areas of Turkey. The high number of patients in Southeastern Anatolia was due to that area having the highest rates of consanguineous marriage and fertility. The most common 11 mutations represented 90% of all ß-thalassemia alleles and 47% of those were IVS1-110(G->A) mutations. The probability of undergoing splenectomy within the first 10 years of life was 20%, a rate unchanged since the 1980s. Iron chelators were administered as monotherapy regimens in 95% of patients and deferasirox was prescribed in 81.3% of those cases. Deferasirox administration was the highest (93.6%) in patients aged <10 years. Of the thalassemia major patients, 5.8% had match-related hemopoietic stem cell transplantation with a success rate of 77%. Cardiac disease was detected as a major cause of death and did not show a decreasing trend in 5-year cohorts since 1999. CONCLUSION: While the HCP has been implemented since 2003, the affected births have shown a consistent decrease only after 2009, being at lowest 34 cases per year. This program failure resulted from a lack of premarital screening in the majority of cases. Additional problems were unawareness of the risk and misinformation of the at-risk couples. In addition, prenatal diagnosis was either not offered to or was not accepted by the at-risk families. This study indicated that a continuous effort is needed for optimizing the management of thalassemia and the development of strategies is essential for further achievements in the HCP in Turkey.

Evaluation of the Clinical and Laboratory Characteristics of Previously Followed-up Thalassemia Intermedia Patients to Provide Them Better Care in the Future.

The increased awareness about the severity of complications in thalassemia intermedia patients led authorities to develop strategies for better management and follow-up of these patients. In this study, we aimed to define the clinical and laboratory characteristics in previously followed-up ß-thalassemia intermedia patients and wanted to gain an insight about the follow-up of this patient population in a developing country to provide them better care in the future. The mean age at diagnosis was 4 years, and the mean hemoglobin was 7.13 g/dL. The mean age at the beginning of regular transfusion was 4.8 years. An overall 74% of patients were on a regular transfusion program. The mean ferritin values at diagnosis and the last follow-up were 487 and 1225 ng/mL, respectively. The most common mutations detected in patients were IVS-I-110, IVS-I-6, IVS-II-1, and FCS 8/9 in order of frequency. Complications were seen in 48% of patients. The most common complications were osteopenia/osteoporosis (34%), growth retardation (24%), hypogonadism (18%), and cardiomyopathy (13%). In conclusion, the relatively higher complication rate in our patients who were previously treated highlights once again the need for an increased effort for optimal management and follow-up of this specific group of patients.

The investigation of relationship between joint findings and serum angiogenic and inflammatory factor levels in severe hemophilia A patients.

Despite the use of primary prophylactic Factor VIII replacement in severe hemophilia A patients, bleeding into joints cannot be prevented completely and early diagnosis and treatment of the joint bleedings are important for prevention of permanent joint damage. Recent studies have shown that neoangiogenesis plays important role in development of synovitis after recurrent joint bleedings. This study aimed to investigate the relationship between joint findings and levels of serum angiogenic and inflammatory factors in severe hemophilia A patients.The patient groups consisted of 10 severe hemophilia A patients with acute joint bleeding and 25 severe hemophilia A patients without acute joint bleeding. They were all inhibitor negative. The control group consisted of 22 healthy male children. Complete blood cell count analysis, C-reactive protein (CRP), serum ferritin, lactic acid, and ELISA-based detection of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1, thrombomodulin, macrophage migration inhibitory factor (MIF), and endostatin were performed from peripheral blood of patient and the control groups. CRP and MIF levels were detected significantly higher in hemophilia patients with acute joint bleeding than patients without acute joint bleeding. There was a positive correlation between serum thrombomodulin, VEGF, and MIF levels. In this study, we demonstrated that serum CRP and MIF levels increases in acute bleeding period regardless of the presence of previous joint damage in children with severe hemophilia. CRP elevation may be a useful and rapid marker for acute bleeding in these patients.

Frequency of red cell allo- and autoimmunization in patients with transfusion-dependent beta thalassemia and affecting factors.

In this study, we aimed to determine the frequency of red cell allo- and autoimmunization and analyze the factors responsible for the development of antibodies in patients with transfusion-dependent thalassemia. This crosssectional study was conducted on 139 patients with thalassemia major and intermedia who received leukodepleted RBC transfusions on a regular basis. Patients with a positive antibody screen were further tested for antibody identification by a gel method. Red cell alloantibodies were found in 9 (6.4%) patients, and autoantibodies were found in 17 (12.2%) patients. The most common alloantibodies detected were those against Rh and Kell antigen systems. The alloantibody development rate was higher in thalassemia intermedia patients, in Rh(-) patients, in patients with an initial transfusion age >2 years and in patients with a transfusion interval >3 weeks (p<0.05). The autoantibody development rate was found to be higher in adult and splenectomized patients (p<0.05). Data from this study demonstrate that the RBC antibody development rate is high in our region. RBC antigen phenotyping and crossmatching with Kell and Rh subgroups may reduce alloimmunization in chronically transfused beta-thalassemia patients.

Determination of early cardiac deterioration in beta-thalassaemia major by echocardiography.

OBJECTIVES: Cardiovascular involvement is the leading cause of mortality in patients with beta-thalassaemia major (beta-TM). This cross-sectional study was performed to evaluate the earlier cardiac damage in beta-TM by echocardiography, before left ventricular (LV) systolic dysfunction was observed. METHODS AND RESULTS: The study population consisted of 70 patients with beta-TM and was compared with age- and sex-matched healthy controls (n= 47). The study population was divided into subgroups based on serum ferritin levels and the time interval from first diagnosis. All patients and control subjects underwent transthoracic echocardiography. Mean LV ejection fractions were similar between groups (60 +/- 5% vs 62+/- 6%, P= 0.063). beta-TM patients had increased left atrial (LA) volume index, LV mass index, and right ventricle (RV) diameter index (30.3 +/- 9.9 vs 19.9 +/- 4.8, 97.0 +/-17.8 vs 80.2 +/- 13.6, and 1.50 +/- 0.17 vs 1.31 +/- 0.15; P= 0.0001, respectively). Patients with beta-TM had significantly shortened pulmonary acceleration times (133.7+/- 22.4 vs 154.9 +/- 16.5, P= 0.0001). Mitral early inflow (E) velocity and tissue Doppler (TDI) annular velocity (Em) ratios (E/Em) were also elevated (7.5 +/- 3.0 vs 6.2 +/- 1.6, respectively, P= 0.009). Serum levels of ferritin were correlated with interventricular septum (R= 0.308, P= 0.009) and posterior wall (R= 0.312, P= 0.009) thicknesses. CONCLUSIONS: It is often unsuccessful to reverse iron-induced cardiac deterioration in late-stage disease when cardiac failure is already present. Increased LV mass index, LA volume index, RV diameter index, and decreased pulmonary acceleration time could be earlier parameters featuring premature cardiac remodelling in beta-TM. Increased E/Em ratio may also point out early cardiac deterioration in beta-TM patients.

Central nervous system involvement of epstein barr virus associated lymphoproliferative disorder in a child with acute lymphoblastic leukemia: successful treatment with rituximab and interferon-alpha.

UNLABELLED: Central nervous system (CNS) involvement of Epstein-Barr virus (EBV)-associated lymphoproliferative disease is a rare and serious complication in children with leukemia. Although rituximab therapy seems to be promising in these cases, persistent hypogammaglobulinemia may appear after treatment due to complete depletion of normal B lymphocytes in the peripheral blood. Here we report isolated CNS involvement of EBV-associated lymphoproliferative disorder in a 4-year-old boy with acute leukemia. The patient was treated with rituximab and interferon alpha; however, persistent hypogammaglobulinemia developed as a complication. Given the rarity of the complication in children receiving these agents, our experience with such a case may be helpful to others. CONFLICT OF INTEREST: None declared.

Rare coagulation disorders: a retrospective analysis of 156 patients in Turkey.

OBJECTIVE: To retrospectively evaluate the clinical findings, laboratory data, management, and outcome in a group ofTurkish children diagnosed with rare coagulation deficiencies (RCDs) between January 1999 and June 2009. MATERIAL AND METHODS: The Turkish Society of Pediatric Hematology-Hemophilia-Thrombosis-Hemostasissubcommittee designed a Microsoft Excel-based questionnaire for standardized data collection and sent it to participatinginstitutions. RESULTS: In total, 156 patients from 12 pediatric referral centers were included in the study. The cost common RCDswere as follows: FVII (n = 53 [34%]), FV (n = 24 [15.4%]), and FX (n = 23 [14.7%]) deficiency. The most common initialfinding in the patients was epistaxis, followed by ecchymosis, and gingival bleeding. CONCLUSION: Initial symptoms were mucosal bleeding, and fresh frozen plasma (FFP) and tranexamic acid werethe most commonly used treatments. We think that prophylactic treatment used for hemophilia patients should beconsidered as an initial therapeutic option for patients with rare factor deficiencies and a severe clinical course, and forthose with a factor deficiency that can lead to severe bleeding.

Nutritional B12 deficiency in infants of vitamin B12-deficient mothers.

AIM: Nutritional vitamin B12 deficiency in infants may occur because the maternal diet contains inadequate animal products. Clinical presentations of the infants who had nutritional vitamin B12 deficiency were analyzed in this study. SUBJECTS AND METHODS: Patients with nutritional vitamin B12 deficiency were enrolled in the study between 2003 and 2010. The diagnosis was based on a nutritional history of mothers and infants, clinical findings, hematological evaluation, and low level of serum vitamin B12. RESULTS: Thirty children aged 1 - 21 months constituted the study group. Poverty was the main cause of inadequate consumption of animal products of the mothers. All infants had predominantly breastfed. The most common symptoms were developmental delay, paleness, apathy, lethargy, anorexia, and failure to thrive. Hematological findings were megaloblastic anemia (83.3 %), thrombocytopenia (30 %), and severe anemia (13.3 %). All of the mothers had low serum B12 levels; eight of them had megaloblastic anemia. CONCLUSION: The unusual clinical manifestations of vitamin B12 deficiency may also be seen apart from neurological and hematological findings. Nutritional vitamin B12 deficiency due to maternal deficiency might be a serious health problem in infants. Therefore, screening and supplementation of pregnant and lactating women to prevent infantile vitamin B12 deficiency should be considered.

Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption.

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder characterized by systemic and central nervous system folate deficiency. Turkish siblings are reported with the clinical syndrome of HFM, homozygous for deletion of 2 bases (c.204_205 delCC) within the first exon of the proton-coupled folate transporter (PCFT) gene, causing a frameshift. Low blood and cerebrospinal fluid folate levels were detected at ages 3.5 and 1 month. Treatment with parenteral 5-formyltetrahydrofolate resulted in normal development now at ages 3 and 1 year. Extending current knowledge on the phenotypic manifestations of HFM and the PCFT mutation spectrum will provide opportunities to define possible genotype-phenotype correlations and clarify the basis for the phenotypic variability that is characteristic of this disorder.

Assessment of clinical and laboratory presentations of familial hemophagocytic lymphohistiocytosis patients with homozygous W374X mutation.

Homozygous W374X mutation was identified in unrelated 13 patients (6M/7F) from consanguineous families, 62% of which had history of deceased sibling. Haplotype analysis provided evidence for the probable existence of a founder effect. Age at disease onset ranged from 1 day to 5.5 months (median 2 months). Hepatic dysfunction was observed in 69%, ascite 62%, hypertriglyceridemia 77%, each hyperferritinemia and hypofibrinogenemia 85%, CNS involvement 46% of patients while birth weights were in normal range. Those with very high ferritin (>20,000ng/ml) had extremely low fibrinogen levels. Two-thirds of patients receiving HLH protocol died within 20 days of therapy.

Variant clinical courses in children with immune thrombocytopenic purpura: Sixteen year experience of a single medical center.

OBJECTIVE: Immune thrombocytopenic purpura (ITP) is the most common cause of acquired thrombocytopenia in children. The objective of this study was to evaluate the presenting features, variation in the clinical courses, initial response rate to therapy, and long-term outcome in patients with ITP. METHODS: Three hundred and fifty out of 491 newly diagnosed patients with ITP between the initial diagnosis ages of 6 months to 16 years were included in this retrospective, descriptive study. Patients with acute vs chronic ITP, acute vs recurrent ITP and chronic vs recurrent ITP were compared in terms of age at diagnosis, gender, initial platelet count, response rate to initial therapy, long-term outcome, and total duration of follow-up. RESULTS: The clinical courses of the patients were determined as acute, chronic and recurrent in 63.8%, 29.1%, and 7.1%, respectively. Platelet count >20x109/L and initial diagnosis age >10 years were found to increase the probability of chronic outcome by at least two-fold. CONCLUSION: It is concluded that ITP in childhood is a common disease with low morbidity and mortality. In addition to the acute and chronic form, a rare recurrent form, which accounts for about 4-7% of all ITP patients, should be considered.

An extremely uncommon complication of ITP: spontaneous rupture of an ovarian follicle cyst and massive intra-abdominal bleeding.

Idiopathic thrombocytopenic purpura usually presents with minor bleeding such as petechia and purpura. Rarely, life-threatening events as intracranial and intra-abdominal bleedings can be seen. We would like to present a rare case diagnosed as idiopathic thrombocytopenic purpura, presenting with abdominal pain and paleness. In this 17-year-old female patient, extensive abdominal sensitivity was revealed on physical examination and massive intra-abdominal hemorrhage secondary to distended ovarian follicle rupture was seen on ultrasonography and abdominal computed tomography. The case was treated successfully with intravenous immunoglobin, thrombocyte suspension, and pulse methylprednisolone.

Evaluation of plasma tissue factor and tissue factor pathway inhibitor levels in childhood hemangiomas.

BACKGROUND: The purpose of the study was to evaluate the plasma levels of tissue factor (TF), an angiogenic marker, and tissue factor pathway inhibitor (TFPI), an antiproliferative protein, in the childhood hemangiomas at proliferative and regressive stages. PROCEDURE: The study included 30 patients with hemangiomas and 30 healthy children. Localization, number, stage, type, duration of growth, and complications of the hemangiomas were determined. Venous blood samples from all individuals were collected into citrated tubes and centrifuged. Supernatant plasma was separated, aliquated, and stored at -70 degrees C until samples could be assayed. Plasma levels of TF and TFPI were measured with quantitative ELISA kits. RESULTS: Plasma TF and TFPI levels did not show any significant difference between the study and control groups. When plasma TF and TFPI levels of the children in the control group and in the study group who were in proliferative and regressive stage were compared to each other, no statistically significant difference could be detected. CONCLUSIONS: Plasma TF and TFPI levels of our patients with hemangiomas were not different from healthy children and they did not show any significant difference in proliferative and regressive stages.

Hyperleukocytosis in childhood acute lymphoblastic leukemia: complications and treatment outcome.

Hyperleukocytosis, defined as a peripheral leukocyte count ≥ 100x109/L, is seen in 5-20% of newly diagnosed cases of childhood leukemia and is a poor prognostic factor. In this study, we aimed to examine the presenting clinical and laboratory features, complications, and treatment outcome of 47 children with acute lymphoblastic leukemia (ALL) and hyperleukocytosis who were diagnosed and treated in four medical centers of Izmir between January 1990 and January 2001. The median age was 5.0 years (range: 0.1-16.3 years). Median white blood cell count was 495x109/L (range: 107x109/L- 794x109/L). Forty-two of 47 patients (90%) had hepatosplenomegaly, 5 (11%) had respiratory distress, 3 (6%) had neurologic symptoms, 3 (6%) had diffuse cervical lymphadenopathy, and 3 (6%) had acute renal failure at admission. Ten of 47 patients (21%) had central nervous system involvement, and 17 (36%) had mediastinal mass. Ten patients (21%) had coagulopathy and 15 patients (32%) had metabolic complications (8 patients had hyperuricemia, 4 had hyperphosphatemia, 2 had hyperuricemia, hyperphosphatemia and hypercalcemia, and 1 had hypocalcemia) before the initiation of therapy. Forty of 47 patients (85%) with hyperleukocytosis were effectively managed with intravenous hydration, alkalinization, and allopurinol therapy. Early death during remission induction therapy occurred in 5 patients (11%) with respiratory distress and sepsis. Kaplan-Meier estimates of event free survival and overall survival were 37.0% and 40.5%, respectively.

Poor clinical course in a child with myelodysplastic syndrome and del(13)(q14q22).

Myelodysplastic syndromes (MDS) are rare in children, representing 3% or less of all hematopoietic malignancies. Cytogenetic abnormalities, such as -7/7q-, +8, and +21 have been reported in 55-80% of children with MDS. Cytogenetic studies have an important impact on diagnosis, treatment selection, and monitoring therapeutic protocols when combined with morphologic data. We report on a pediatric case of MDS with the presence of the rare clonal abnormality del(13)(q14q22) which underwent a malignant transformation to leukemia and ran a very poor clinical course.

Cerebral venous thrombosis in a patient with Evans syndrome: a rare association.

In this report we describe a case of extensive cerebral venous thrombosis in a patient with Evans syndrome. A 19-year-old male patient with Evans syndrome was admitted to the hospital with the complaints of headache, convulsive seizure, and vomiting. The cerebral venous thrombosis including left lateral, left sigmoid, straight sinus, and vena jugularis interna was diagnosed by cerebral magnetic resonance angiography. When the thrombosis developed, he was in hematological remission and he was not receiving any medications except lamivudine for chronic hepatitis B infection. As a genetic prothrombotic risk factor, he had heterozygous prothrombin G20210A gene mutation. His clinical and radiologic findings improved after unfractionated heparin and subsequently with coumadin therapy. On follow-up, cerebral venous thrombosis reoccurred in different localizations, but complete recanalization could be obtained with antithrombotic therapy. We present the case since the association of cerebral venous thrombosis and Evans syndrome is very rare.