Galila M. Mokhtar

Randomized Trial of Anti-D Immunoglobulin versus Low-Dose Intravenous Immunoglobulin in the Treatment of Childhood Chronic Idiopathic Thrombocytopenic Purpura

Background: Chronic idiopathic (immune) thrombocytopenic purpura (ITP) develops in approximately 20% of children with acute ITP. Six years ago, low-dose intravenous immunoglobulin (IVIG) treatment of childhood ITP was started at the Pediatric Hematology Unit, Ain Shams University, while intravenous anti-D has been introduced in Egypt in 2001. Objectives: To assess the efficacy and safety of intravenous anti-D compared to low-dose IVIG in the treatment of children with chronic ITP. Patients and Methods: This randomized trial comprised 34 patients with chronic ITP (18 boys and 16 girls) with recurrent bleeding episodes . Median age of the patients was 6.5 years, duration of thrombocytopenia was >6 months, and platelet count (PC) was <30 × 109/l (30 K). The patient cohort was divided into two subgroups: group A comprised 18 patients treated with anti-D in a dose of 50 µg/kg i.v. initially, and in 12 of them repeated doses (50 µg/kg) were given every 4 weeks, and group B consisted of 16 children who received IVIG in a dose of 250 mg/kg for 2 consecutive days. Bleeding manifestations, complete blood cell and reticulocyte counts were assessed at baseline and 3, 7, 14 and 28 days after infusion. Results: Clinically, more than 80% of the patients (82.3%) showed good control of bleeding. On day 3, 33.3% of group A versus 37.5% of group B, and on day 7: 66.6% of group A versus 75% of group B patients demonstrated a good response (PC >50 K and/or doubling of baseline PC). On days 14 and 21, no significant changes in PCs were observed between both groups. However, only 11.1% of group A and 12.5% of group B patients could maintain PC >100 K on day 28, while 38.8 versus 37.5% of group A and group B, respectively, still had PC ≧ double the initial count. The peak response to anti-D was noticed 7 and 14 days following infusion and to IVIG on days 3 and 7. Repeated doses of anti-D could maintain PC > 50 K (or > double the baseline PC) in 75% of patients 1 week after infusion, and in 60% of them by day 28, with good control of bleeding. Splenectomy was postponed and/or avoided in 4 (33.3%) patients on anti-D maintenance therapy who experienced recurrent severe bleeding episodes before starting therapy. The safety of anti-D was judged by the degree of intravascular hemolysis. The mean hemoglobin decrease was 0.8 ± 0.4 g/dl; in 61.1% of patients the Hb level dropped but none of them experienced a drop of more than 3 g/dl or required transfusion. Conclusion: Both single intravenous anti-D and low-dose IVIG effectively increased PC in children with chronic ITP at risk of bleeding or those with previous bleeding episodes. Repeated doses of anti-D could maintain PC above the critical values or double baseline counts in nearly two thirds of the patients showing good control of bleeding and may serve as an alternative to splenectomy in these patients.

N-Terminal Natriuretic Peptide and Ventilation-Perfusion Lung Scan in Sickle Cell Disease and Thalassemia Patients with Pulmonary Hypertension

The aim of this study was to determine the prevalence of pulmonary hypertension (PH) in sickle cell disease and thalassemia patients in relation to clinical and laboratory parameters of hemolysis and hemosidersosis, as well as plasma N-terminal pro-brain natriuretic peptide (NT-pro-BNP). The study also aimed to define the role of thromboembolic pulmonary artery (PA) obstruction in its etiology. Forty sickle cell disease and 30 thalassemia patients [15 β-thalassemia major (β-TM) and 15 β-thalassemia intermedia (β-TI)] were screened for PH defined as tricuspid regurgitant velocity (TRV) >2.5 m/sec and evaluated for PA obstruction using ventilation-perfusion lung scan (V/Q), together with measurement of their plasma levels of NT-pro-BNP. Patients were prospectively followed up for a mean of 18 ± 6.1 months. The prevalence of PH was 37.5, 40.0 and 26.7% in sickle cell disease, β-TI and β-TM patients, respectively. Pulmonary hypertension patients were older, had longer disease duration, higher serum ferritin, serum lactate dehydrogenase (LDH) and NT-pro-BNP with lower hemoglobin (Hb) levels compared to patients without PH. N-terminal pro-BNP was positively correlated with duration of illness, TRV, LDH, serum ferritin, and negatively correlated with Hb levels. The strongest predictor for TRV was serum ferritin followed by the NT-pro-BNP level. Forty-six-point-seven percent of sickle cell disease patients with PH had either high or intermediate probability V/Q scan results compared to 10% of thalassemic patients with PH who had high probability V/Q scan results. Pulmonary hypertension is highly prevalent in young sickle cell disease and thalassemia patients, where elevated serum ferritin and NT-pro-BNP are the main indicators.

Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia

Romiplostim, a thrombopoiesis-stimulating peptibody, represents a new therapeutic option in adult refractory chronic immune thrombocytopenia (ITP). This study aimed to assess the short-term efficacy and safety of romiplostim in children with chronic ITP. Eight non-splenectomized patients with chronic ITP refractory to standard lines of medical therapy were recruited from the Pediatric Hematology Unit, Childrens Hospital, Ain Shams University, Cairo, Egypt. One patient was initially excluded because of increased bone marrow reticulin (grade 3). Therapy was initiated in seven patients, aged 3.4–15.2 years (median 5.5 years), and the disease duration ranged from 13 months to 7.3 years (median 2.4 years); none were splenectomized. Romiplostim dose was started as 1 µgm/kg/week and the dose escalated by 1 µgm/kg/week according to platelet count. The duration of therapy varied between 1 and 22 weeks (median 12 weeks). Results revealed that four out of the seven patients achieved variable response. Four patients demonstrated rapid increase in platelet count when pulse steroid therapy was added. Most reported adverse events were mild and transient. This case series study reveals variable response rate in children with chronic ITP to romiplostim therapy; addition of steroids especially in emergency bleeding situations could potentiate romiplostim thrombopoietic effect even in patients initially refractory to steroids. Romiplostim safety and efficacy in pediatric ITP needs further long-term studies.

A trial to assess the efficacy of glutamic acid in prevention of vincristine-induced neurotoxicity in pediatric malignancies: a pilot study.

Vincristine is considered as a backbone of therapy in the induction and consolidation phases of pediatric malignancies. Neurotoxicity is a principal side effect of its use. This study is a randomized single-blinded placebo-controlled clinical trial to evaluate the role of glutamic acid in ameliorating neurotoxicity in pediatric patients with hematologic and solid tumors receiving vincristine during induction course. Fifty-four patients in the glutamic acid group received glutamic acid 1.5 grams daily orally in 3 divided doses during the 4-week induction with vincristine in a dose of 1.5 mg/m2 IV weekly. Placebo group (40 patients) received oral placebo 3 times daily in the same way as the glutamic acid group. The onset of neurotoxicity was significantly earlier in placebo group than in glutamic acid group regarding tendon Achilles reflex, Patellar reflex, parasthesia, and increased frequency of constipation. This was statistically significant mostly in third and fourth visits, no severe cases of strength and mental alteration side effects in both groups. Glutamic acid was well tolerated with no gastrointestinal side effects in patients. This study suggests that the coadministration of oral glutamic acid with repetitive intravenous bolus injections of vincristine resulted in a reduction of its neurotoxicity.

13‐valent pneumococcal conjugate vaccine (PCV13) is immunogenic and safe in children 6‐17 years of age with sickle cell disease previously vaccinated with 23‐valent pneumococcal polysaccharide vaccine (PPSV23): Results of a phase 3 study

A large population of older children with sickle cell disease (SCD) is currently vaccinated with only 23‐valent pneumococcal polysaccharide vaccine (PPSV23). In immunocompetent adults, PPSV23 vaccination reduces immune responses to subsequent vaccination with a pneumococcal vaccine. The 13‐valent pneumococcal conjugate vaccine (PCV13), which addresses this limitation, may offer an advantage to this population at high risk of pneumococcal disease. [This article was corrected after initial online publication with an erratum. The National Clinical Trial (NCT) number was omitted from the article abstract. That number is NCT00918580.]

Clinicopathological and radiological study of Egyptian β-thalassemia intermedia and β-thalassemia major patients: relation to complications and response to therapy.

The clinico epidemiological characteristics, frequency of complications, and response to various therapeutic modalities in 80 Egyptian β-thalassemia intermedia (β-TI) patients were compared with 70 β-thalassemia major (β-TM) patients. β-Thalassemia intermedia patients had a higher incidence of left atrium dilatation, right ventricular dilatation and pulmonary hypertension, whereas, β-TM patients showed a higher incidence of left ventricular (LV) dilatation, restrictive LV filling and impaired LV contractility, with an overall higher incidence of heart disease (p <0.001). Short stature, delayed puberty, osteoporosis, bone fractures, diabetes mellitus and viral hepatitis was frequently observed in β-TM patients compared with β-TI patients (p <0.05). Administration of hydroxyurea (HU) alone was associated with significant improvement in hematological parameters and quality of life for β-TI patients. In conclusion, the risk of complications still burdens the life of Egyptian thalassemia patients and their frequency varies between β-TI and β-TM. We provide evidence that calls for the use of HU in β-TI patients.

A longitudinal prospective study of bleeding diathesis in Egyptian pediatric patients: single-center experience.

Keeping an updated registry of bleeding disorders is crucial for planning care and documenting prevalence. We aimed to assess the prevalence of various bleeding disorders including rare inherited coagulation and platelet disorders concerning their clinico-epidemiological, diagnostic data and bleeding manifestations severity. Patients suffering from manifestations of bleeding or coagulation disorders presented to Hematology Clinic during 16 years were included and prospectively followed up. Demographics, clinical characteristics, complete blood count, bleeding, prothrombin and activated partial thromboplastin times, platelet aggregation tests and bone marrow aspiration were recorded. Overall 687 patients with bleeding disorders from total 2949 patients were identified. Inherited coagulation defects were found in 27.2%; hemophilia A (70.6%), hemophilia B (13.9%), factor I deficiency (2.3%), factor V deficiency (1.6%), factor X deficiency (4.2%), factor VII deficiency (2.6%), factor XIII deficiency (1.1%), combined factor deficiency (2.1%) and unclassified coagulation disorders in 1.6% of studied patients. Overall 72.7% had diagnosed with platelet disorders; immune thrombocytopenia was the commonest (74.8%), and inherited conditions represent (25.2%) in the following order: Glanzmans thrombasthenia (11.2%), von Willebrand disease (6.6%), Bernard–Soulier syndrome (1%) and Chediak Higashi in 0.4% and unclassified in 6%. Median age of diagnosis of coagulation and platelet disorders were 33 and 72 months. Presenting symptoms of coagulation disorders were: 25.1% post circumcision bleeding, 22.5% ecchymosis, 20.9% hemoarthrosis and 15% epistaxis. Symptoms of rare coagulation disorders were postcircumcision bleeding (20%), bleeding umbilical stump (20%), epistaxis (12%), hemoarthrosis (8%) and hematomas (4%). Presenting symptoms in rare inherited platelet disorders were purpura, ecchymosis, epistaxis and bleeding gums, respectively. Analysis of the clinico-epidemiological data of patients with bleeding disorders is a useful tool for monitoring and improving their quality of care.

Health-related quality of life of Egyptian children with immune thrombocytopenia and their parents.

Health-related quality of life has been recognized as an important pediatric outcome measurement. Kid’s ITP Tool was used to measure health-related quality of life of 80 Egyptian children with immune thrombocytopenia and their parents in relation to different disease parameters. A positive correlation between scores of child/proxy reports and parent report was found. Patients with newly diagnosed immune thrombocytopenia had significantly lower scores of both child/proxy reports and parent reports than chronic patients. Longer duration of illness was correlated with higher scores of child/proxy reports. Negative correlations were found between severity of bleeding and both scores of child/proxy reports and parent reports. Platelet count was positively correlated with parent report score. Regression analysis revealed that severity of bleeding had the highest significant impact on parent report score. Improving parents’ knowledge about the pathogenesis and course of the disease may improve their quality of life.

THROMBIN ACTIVATABLE FIBRINOLYSIS INHIBITOR (TAFI): Relationship to Hemostatic Alteration in Patients with β-Thalassemia

Profound hemostatic changes have been observed among thalassemic patients. Thrombin activatable fibrinolysis inhibitor (TAFI) is a newly discovered protein that potentially attenuates fibrinolysis. The authors aimed to investigate plasma level of TAFI in β-thalassemia patients in relation to clinical severity and hemostatic alteration. Fifty-one thalassemic patients (mean age 10.79 ± 5.59 years) (21 splenectomized thalassemia major patients, 18 nonsplenectomized thalassemia major patients, 12 nonsplenectomized thalassemia intermedia) were recruited from Pediatric Hematology Clinic, Ain Shams University; in addition, 32 healthy age- and sex-matched controls (10.31 ± 5.58 years) were also included. In addition to clinical assessment, laboratory investigations included complete blood count (CBC), hemoglobin electrophoresis, prothrombin time (PT), activated partial thromboplastin time (PTT), liver function tests, viral hepatitis markers, serum ferritin, and plasma TAFI levels. Nine out of 51 patients (17.5%) suffered from bleeding manifestations mainly in the form of epistaxis; none of the studied patients had thromboembolism. Significant reduction in TAFI levels was shown in thalassemic patients compared to controls (P < .0001), in splenectomized compared to nonsplenectomized thalassemia group (P < .0001), and in thalassemia major compared to thalassemia intermedia group (P < .0001). Negative correlation was present between TAFI levels and both liver enzymes and serum ferritin levels (P < .05). Thalassemic patients suffering from bleeding showed lower mean TAFI levels compared to those not suffering from bleeding (P < .001). Marked reduction in TAFI levels was observed in thalassemic patients with splenectomy, altered liver functions, and poor chelation who therefore might be at a higher risk for altered hemostasis.

Effect of Desferrioxamine B on Hemolysis in Glucose-6-Phosphate Dehydrogenase Deficiency

Twenty-four infants and children suffering from glucose-6-phosphate dehydrogenase (G6PD) deficiency during hemolytic crisis were included in this study. Their ages ranged between 3 and 36 months with a median of 10 months. 22 were males and 2 were females. Fourteen out of them received a single bolus dose of desferrioxamine B 500 mg intravenously followed by packed red cell transfusion, while the remaining 10 cases were only transfused. Sequential estimation of hemoglobin level, reticulocytic count and hemoglobinuria was done before treatment, 3, 24, 48 and 72 h thereafter. The hemoglobin level was higher in the desferrioxamine B group. The degree of increase was statistically significant at 48 and 72 h (p less than 0.01). Hemoglobinuria stopped in 78.5% in the first group and only in 30% of the second group at 72 h. It was concluded that desferrioxamine B is helpful in shortening the course of hemolytic crisis in G6PD-deficient patients. It could be used as an adjuvant to packed red cell transfusion.