Deferiprone for transfusional iron overload in sickle cell disease and other anemias: open-label study of up to 3 years.

Long-term safety and efficacy data on the iron chelator deferiprone in sickle cell disease (SCD) and other anemias are limited. FIRST-EXT was a 2-year extension study of FIRST (Ferriprox in Patients With Iron Overload in Sickle Cell Disease Trial), a 1-year, randomized noninferiority study of deferiprone vs deferoxamine in these populations. Patients who entered FIRST-EXT continued to receive, or were switched to, deferiprone. Altogether, 134 patients were enrolled in FIRST-EXT (mean age: 16.2 years), with mean (SD) exposure to deferiprone of 2.1 (0.8) years over the 2 studies. The primary end point was safety. Secondary end points were change in liver iron concentration (LIC), cardiac T2∗, serum ferritin (SF), and the proportion of responders (≥20% improvement in efficacy measure). The most common adverse events considered at least possibly related to deferiprone were neutropenia (9.0%) and abdominal pain (7.5%). LIC (mg/g dry weight) decreased over time, with mean (SD) changes from baseline at each time point (year 1, -2.64 [4.64]; year 2, -3.91 [6.38]; year 3, -6.64 [7.72], all P < .0001). Mean SF levels (µg/L) decreased significantly after year 2 (-771, P = .0008) and year 3 (-1016, P = .0420). Responder rates for LIC and SF increased each year (LIC: year 1, 46.5%; year 2, 57.1%; year 3, 66.1%; SF: year 1, 35.2%; year 2, 55.2%; year 3, 70.9%). Cardiac T2∗ remained normal in all patients. In conclusion, long-term therapy with deferiprone was not associated with new safety concerns and led to continued and progressive reduction in iron load in individuals with SCD or other anemias. The trial was registered at www.clinicaltrials.gov as #NCT02443545.

Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study.

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was -4.04 (0.48) mg/g dry weight for deferiprone vs -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, -0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.

Expression of CD4+ CD28null T lymphocytes in children and adolescents with type 1 diabetes mellitus: Relation to microvascular complications, aortic elastic properties, and carotid intima media thickness.

BACKGROUND: Cardiovascular risk in type 1 diabetes mellitus (T1DM) is associated with endothelial dysfunction, inflammation, and altered immunity. CD4+ CD28null T-cells are a subset of long-lived cytotoxic CD4+ T-lymphocytes with proatherogenic and plaque-destabilizing properties. We hypothesized that the frequency of CD4+ CD28null T-cells may be altered in T1DM and related to vascular complications. AIM: To assess the percentage of CD4+ CD28null T-lymphocytes in children and adolescents with T1DM and their relation to vascular structure and glycemic control. METHODS: Totally 100 patients with T1DM were divided into 2 groups according to the presence of microvascular complications and compared with 50 healthy controls. CD4+ CD28null T-lymphocytes were analyzed using flow cytometry. Aortic elastic properties and carotid intima media thickness (CIMT) were assessed. RESULTS: Aortic stiffness index and CIMT were significantly higher among patients compared with healthy controls while aortic strain and distensibility were decreased. The percentage of CD4+ CD28null T-cells was significantly higher in patients with and without microvascular complications compared with controls. High frequency of CD4+ CD28null T-cells was found among patients with microalbuminuria or peripheral neuropathy. Patients with CD4+ CD28null T-cells ≥10% had higher HbA1c, urinary albumin creatinine ratio, aortic stiffness, and CIMT. CD4+ CD28null T-cells were positively correlated to HbA1c, aortic stiffness index, and CIMT. CONCLUSIONS: Changes in aortic elastic properties and increased CIMT among young patients with T1DM may enable the recognition of preclinical cardiac impairment. The correlation between CD4+ CD28null T-cells and assessed parameters of vascular structure highlights the role of altered immune response in the occurrence of diabetic vascular complications.

Influence of thiopurine methyltransferase gene polymorphism on Egyptian children with acute lymphoblastic leukaemia.

Thiopurine methyltransferase (TPMT) gene polymorphism regulates thiopurine therapeutic efficacy and toxicity. The aim of this study was to determine the influence of TPMT gene polymorphism in Egyptian children with acute lymphoblastic leukaemia (ALL). Sixty-four patients with ALL, T lineage (27%) and pre-B phenotype (73%), who were treated with BFM 90 or CCG 1991 standard risk protocol, and who also experiencedmyleosuppresion toxicity and required interruption and/ormodification of thiopurine chemotherapy were recruited over a year period. Thirty-two patients were on maintenance and another 32 completed their chemotherapy. Seventy healthy age-matched and sex-matched children served as controls. They were subjected to clinical assessment, haematological panel investigations and TPMT gene polymorphism for G238C, G460A and A719G alleles assessment using PCRfollowed byRFLP analysis.Although none of the studied patients had themutantTPMTvariant alleles,myelosuppression toxicity in the form of different degree of neutropenia was detected in all patients. As a result of myelosuppression toxicity, most of the patients needed 6-MP dose modification either once (53.1%), twice (15.6%), or ≥ thrice (25.1%) during their maintenance course and 96.9% of the patients required to stop 6-MP for less than a week (62.5%), up to 2 weeks (28.1%), or > 2 weeks (6.3%). Patients also developed infection who mostly (71%) needed hospitalization. None of the studied G238C, G460A and A719G TPMT variant alleles were detected. Infections and febrile neutropenia were common causes of 6-PM dose modification and interruption.

Endothelial monocyte activating polypeptide II in children and adolescents with type 1 diabetes mellitus: Relation to micro-vascular complications.

OBJECTIVES: Endothelial monocyte-activating polypeptide II (EMAP II) is a multifunctional polypeptide with proinflammatory and antiangiogenic activity. Hyperglycemia and dyslipidemia appears to be significant factors contributing to increased EMAP-II levels. We determined serum EMAP II in children and adolescents with type 1 diabetes as a potential marker for micro-vascular complications and assessed its relation to inflammation and glycemic control. METHODS: Eighty children and adolescents with type 1 diabetes were divided into 2 groups according to the presence of micro-vascular complications and compared with 40 healthy controls. High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c) and EMAP II levels were assessed. RESULTS: Serum EMAP II levels were significantly increased in patients with micro-vascular complications (1539 ± 321.5 pg/mL) and those without complications (843.6 ± 212.6 pg/mL) compared with healthy controls (153.3 ± 28.3 pg/mL; p<0.001). EMAP II was increased in patients with microalbuminuria than normoalbuminuric group (p<0.001). Significant positive correlations were found between EMAP II levels and body mass index, fasting blood glucose, HbA1c, serum creatinine, triglycerides, total cholesterol, urinary albumin creatinine ratio (UACR) and hs-CRP (p<0.05). A cutoff value of EMAP II at 1075 pg/mL could differentiate diabetic patients with and without micro-vascular complications with a sensitivity of 93% and specificity of 82%. CONCLUSIONS: We suggest that EMAP II is elevated in type 1 diabetic patients, particularly those with micro-vascular complications. EMAP II levels are related to inflammation, glycemic control, albuminuria level of patients and the risk of micro-vascular complications.

One-Year Prospective Study of Community Acquired Influenza and Parainfluenza Viral Infections in Hospitalized Egyptian Children with Malignancy: Single Center Experience.

BACKGROUND: Respiratory viruses are widespread in the community and easily transmitted to immunocompromised patients. AIMS: Assess the prevalence of community-acquired respiratory viral infections among children with cancer presenting with clinical picture suggestive of lower respiratory tract infections (LRTIs), and evaluate its risk factors and prognosis. METHODS: Over a year, 90 hospitalized children with malignancy and LRTIs recruited, subjected to clinical assessment, investigated through hematology panel, blood culture, chest x-ray, CT chest and PCR for influenza A and B, parainfluenza (PIV) types 1 and 3 viruses, and respiratory syncytial virus (RSV), and prospectively followed up for the clinical outcome. RESULTS: Viral pathogens were identified in 34 patients (37.7%), with a seasonal peak from April to May. The most frequently detected virus was influenza virus [type A (16 cases; 47%), type B (4 cases; 12%)] followed by parainfluenza virus [PIV1 (9 cases; 26%), PIV3 (3 cases; 15%)], and none had RSV. Bacteria were identified in 26 patients, fungi in four, mixed infections [bacterial/viral and bacterial/fungal] in 13, and 36 cases had unidentified etiology. The majority of patients with influenza and parainfluenza infections had hematological malignancy, presented with fever, and had mild self-limited respiratory illness. Five patients with mixed viral and bacterial infection had severe symptoms necessitating ICU admission. Six patients died from infection-related sequelae; two had mixed PIV and Staphylococcal infections. CONCLUSIONS: Community acquired influenza and parainfluenza infections are common in pediatrics patients with malignancy, either as isolated or mixed viral/bacterial infections. Clinical suspicion is essential as hematological and radiological manifestations are nonspecific. Rapid diagnosis and management are mandatory to improve patients' outcome.

Cultural preferences and limited public resources influence the spectrum of thalassemia in Egypt.

BACKGROUND: Cultural beliefs of Egyptians with respect to the origin of thalassemia and its prevention, as well as national resources available for care, often differ from those of Western countries. OBJECTIVES: To assess the impact of cultural attitudes and the effect of limited medical and financial resources that could affect the management of Egyptian thalassemic patients. SUBJECTS: A cross sectional study included 205 Egyptians ß-thalassemia major (ß-TM) patients, with a mean age of 149±87.90 months and a male to female ratio of 94:111. METHODS: Demographic data stressing on order of birth, consanguineous marriage, and family history of ß-TM, transfusion, and chelation therapy, were reported. HCV-Ab, HBV-Ag, and complete blood count were recorded with calculation of mean pretransfusional hemoglobin. RESULTS: The age distribution was relatively nonhomogenous, with 39% of patients between 10 and 20 years of age and 16% were younger than 5. There were high family birth rates and 35% of patients were third or more in order of birth and a marked cultural preference for consanguineous marriage, representing 61% of all the parents' marriages, as well as a high rate (59.5%) of a positive family history of ß-TM. Patients transfused on low pretransfusion hemoglobin levels around 8 g/dL, and those receiving blood transfusion before the establishment of National Blood Transfusion Services showed a statistically significant higher rate of positive hepatitis B and C viral infections. Chelation therapy tended to start at late age, mean age was around 4 years. Before 2000, subcutaneous deferoxamine was the most widely used chelation, and since then a considerable number of patients (50%) had started to use oral iron chelators. CONCLUSIONS: The strong cultural preferences for consanguineous marriage and limited preventive programmes and resources have had a negative impact on the management of Egyptians thalassemic patients.

Endothelial nitric oxide synthase gene intron 4 variable number tandem repeat polymorphism in ß-thalassemia major: relation to cardiovascular complications.

Endothelial nitric oxide synthase (eNOS), an enzyme that generates nitric oxide, is a major determinant of endothelial function. Several eNOS gene polymorphisms have been reported as 'susceptibility genes' in various human diseases states, including cardiovascular, pulmonary and renal diseases. We studied the 27-base pair tandem repeat polymorphism in intron 4 of eNOS gene in 60 ß-thalassemia major (ß-TM) patients compared with 60 healthy controls and assessed its role in subclinical atherosclerosis and vascular complications. Patients were evaluated stressing on transfusion history, splenectomy, thrombotic events, echocardiography and carotid intima-media thickness (CIMT). Analysis of eNOS intron 4 gene polymorphism was performed by PCR. No significant difference was found between ß-TM patients and controls with regard to the distribution of eNOS4 alleles or genotypes. The frequency of eNOS4a allele (aa and ab genotypes) was significantly higher in ß-TM patients with pulmonary hypertension or cardiomyopathy. Logistic regression analysis revealed that eNOS4a allele was an independent risk factor for pulmonary hypertension in ß-TM patients [odds ratio (OR) 2.2, 95% confidence interval (95% CI) 1.19-5.6; P < 0.001]. We suggest that eNOS intron 4 gene polymorphism is related to endothelial dysfunction and subclinical atherosclerosis and could be a possible genetic marker for prediction of increased susceptibility to cardiovascular complications.

Regulatory T cells with CD62L or TNFR2 expression in young type 1 diabetic patients: relation to inflammation, glycemic control and micro-vascular complications.

BACKGROUND: Alteration of regulatory T cells (Tregs) may contribute to ineffective suppression of proinflammatory cytokines in type 1 diabetes. AIM: We determined the percentage of Tregs expressing CD62L or tumor necrosis factor receptor type 2 (TNFR2) in 70 young type 1 diabetic patients compared with 30 controls and assessed their relation to inflammation, glycemic control and micro-vascular complications. METHODS: High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) were assessed with flow cytometric analysis of Tregs, Tregs expressing CD62L or TNFR2. RESULTS: The percentage of CD4(+)CD25(high) T cells and CD4(+)CD25(high)CD62L(high) cells were significantly decreased while CD4(+)CD25(high)TNFR2(+) T cells were elevated in patients with micro-vascular complications than those without and controls (p<0.001). ROC curve revealed that the cutoff values of Tregs, Tregs expressing CD62L and Tregs expressing TNFR2 (7.46%, 24.2% and 91.9%, respectively) could detect micro-vascular complications. Significant negative correlations were observed between Tregs expressing CD62L and disease duration, FBG, HbA1c, urinary albumin excretion and hs-CRP, whereas, positive correlations were found between Tregs expressing TNFR2 and these variables (p<0.05). TNF-α was significantly increased while IL-10 was decreased among patients with micro-vascular complications than those without (p<0.05). CONCLUSIONS: Alteration in the frequency of Tregs and Tregs expressing CD62L or TNFR2 in type 1 diabetes is associated with increased inflammation, poor glycemic control and risk of micro-vascular complications.

Early Predictors of Renal Dysfunction in Egyptian Patients with ß-Thalassemia Major and Intermedia.

BACKGROUND: Better survival of thalassemia patients allowed previously unrecognized renal complications to emerge. OBJECTIVES: Assess prevalence and early predictors of renal dysfunction in young ß-thalassemia major (ß-TM) and intermedia (ß-TI) patients. SUBJECTS: 66 ß-TM (group I), 26 ß-TI (group II) Egyptian patients and 40 healthy controls. METHODS: Clinical assessment and laboratory data including kidney and liver function tests, such as serum ferritin, serum bicarbonate, plasma osmolality and urinary total proteins, microalbuminuria (MAU), N-acetyl-ß-D-glucosaminidase (NAG), retinol binding protein (RBP), α-1 microglobulin, bicarbonate, osmolality, creatinine clearance (CrCl), % fractional excretion of bicarbonate (% FE-HCO3). RESULTS: The prevalent renal abnormality was proteinuria (71%), followed by increased urinary level of RBP (69.4%), NAG (58.1%), α-1 microglobulin (54.8%) and microalbuminuria (29%) and also decreased urinary osmolality (58.1%). CrCl was a better assessment of renal function and significantly lowered in thalassemia patients. Tubular dysfunctions were more significant in splenectomized ß-TM patients who showed more elevation of NAG and α-1 microglobulin and lower urinary osmolality. NAG, RBP and α-1 microglobulin were negatively correlated with CrCl and positively correlated with serum ferritin and urinary total protein. Z-score analysis for identifying patients with renal dysfunction proved superiority of urine total protein and RBP. Comparative statistics of different frequencies revealed significant difference between the urinary total protein and both MAU and % FE-HCO3. CONCLUSION: Asymptomatic renal dysfunctions are prevalent in young ß-TM and ß-TI patients that necessitate regular screening. Urinary total protein and RBP may be cost-effective for early detection.

Circulating soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as diagnostic and prognostic marker in neonatal sepsis.

OBJECTIVE: Triggering receptor expressed on myeloid cells-1 (TREM-1) is an important receptor involved in the innate inflammatory response and sepsis. We assessed soluble TREM-1 (sTREM-1) in 112 septic neonates (63 culture-positive and 49 culture-negative) and 40 healthy controls as a potential early diagnostic and prognostic marker for neonatal sepsis (NS). METHODS: Studied neonates were evaluated for early- or late-onset sepsis using clinical and laboratory indicators upon admission. sTREM-1 was measured on initial sepsis evaluation and at 48h after antibiotic therapy. For ethical reasons, cord blood samples were collected from control neonates and only samples from neonates that proved to be healthy by clinical examination and laboratory analysis were further analyzed for sTREM-1. RESULTS: Baseline sTREM-1 levels were significantly elevated in culture-proven (1461.1±523pg/mL) and culture-negative sepsis (1194±485pg/mL) compared to controls (162.2±61pg/mL) with no significant difference between both septic groups. Culture-positive or negative septic preterm neonates had significantly higher sTREM-1 compared to full term neonates. sTREM-1 was significantly higher in neonates with early sepsis than late sepsis and was associated with high mortality. sTREM-1 was significantly decreased 48h after antibiotic therapy compared to baseline or levels in neonates with persistently positive cultures. sTREM-1 was positively correlated to white blood cells (WBCs), absolute neutrophil count, immature/total neutrophil (I/T) ratio, C-reactive protein (hs-CRP) and sepsis score while negatively correlated to gestational age and weight. hs-CRP and sepsis score were independently related to sTREM-1 in multiregression analysis. sTREM-1 cutoff value of 310pg/mL could be diagnostic for NS with 100% sensitivity and specificity (AUC, 1.0 and 95% confidence interval [CI], 0.696-1.015) while the cutoff value 1100pg/mL was predictive of survival with 100% sensitivity and 97% specificity (AUC, 0.978 and 95% CI, 0.853-1.13). However, hs-CRP cutoff 13.5mg/L could be diagnostic for NS with a sensitivity of 76% and specificity of 72% (AUC, 0.762 and 95% CI, 0.612-0.925) and levels were not related to survival as no significant difference was found between dead and alive septic neonates. CONCLUSIONS: Elevated sTREM-1 could be considered an early marker for NS that reflects sepsis severity and poor prognosis.

Therapeutic superiority and safety of combined hydroxyurea with recombinant human erythropoietin over hydroxyurea in young ß-thalassemia intermedia patients.

OBJECTIVE: To assess the efficacy and safety of combined hydroxyurea (HU) and recombinant human erythropoietin (rHuEPO) in ß-thalassemia intermedia (TI) patients compared with single HU therapy. METHODS: An interventional prospective randomized study registered in the ClinicalTrials.gov (NCT01624038) was performed on 80 TI patients (≤ 18 yr) divided into group A (40 patients received combined HU and rHuEPO) and group B (40 patients received single HU therapy). Baseline serum EPO levels were measured, and both groups were followed up for a mean period of 1 yr with regular assessment of transfusion requirements, blood pressure, ferritin, liver and renal functions, hemoglobin, and HbF. Quality of life (QoL) was assessed at the start and end of the study. RESULTS: Transfusion frequency and index were significantly decreased, while QoL was increased in group A compared with group B where 85% of patients showed improvement on combined therapy compared with 50% of patients on HU. Hemoglobin and HbF were significantly increased in both TI groups; however, this was more evident in group A than in group B. Also, 37.5% of patients in group A became transfusion-independent compared with 15% in group B. EPO levels were negatively related to increments of hemoglobin and HbF. Splenectomized patients and those with initial HbF% >40% had the best response to combined therapy. No serious adverse events necessitating discontinuation of therapy in both groups. CONCLUSIONS: HU was effective in management of TI; however, combination with rHuEPO gave a superior therapeutic effect resulting in the best clinical and hematological responses without adverse events.

Effect of antioxidant therapy on hepatic fibrosis and liver iron concentrations in ß-thalassemia major patients.

To assess the effects of combined vitamin therapy on oxidant-antioxidant hepatic status and hemoglobin (Hb) derivatives on ß-thalassemia major (ß-TM), a prospective study of 60 ß-TM patients aged 4 to 17 years, was conducted. Thirty-nine patients with initial low serum vitamins E, C and A, were treated with oral combined vitamins for 1 year compared to 21 patients with normal vitamin levels. Serum transaminases, serum ferritin, hepatic fibroscan elastography (TE) and magnetic resonance imaging R2* (MRI R2*) for liver iron concentration (LIC), were assessed before and after 6 and 12 months of therapy. Antioxidant capacity was assessed by levels of reduced glutathione (GSH), malondialdehyde (MDA), catalase, superoxide dismutase and GSH enzymes. The studied vitamins, reduced GSH and Hb levels were significantly elevated and paralleled by progressive decline in MDA and ferritin during therapy (p <0.001). Serum transaminase and superoxide dismutase were significantly decreased, while GSH reductase was significantly elevated during therapy (p <0.001). Improvement of hepatic fibrosis as 23.0% had TE (>12 kPa) at baseline compared to 20.5% after therapy (p >0.05), although LIC values were significantly decreased (p <0.001). Combined vitamin therapy improves the antioxidant/oxidant balance, LIC and hepatic fibrosis in young ß-TM patients.

Flow cytometric assessment of circulating platelet and erythrocytes microparticles in young thalassemia major patients: relation to pulmonary hypertension and aortic wall stiffness.

Heart disease is the leading cause of mortality and morbidity in ß-thalassemia major (ß-TM). Aggregability of abnormal red cells and membrane-derived microparticles (MPs) stemming from activated platelets and erythrocytes are responsible for thrombotic risk. We measured platelet and erythrocyte MPs (PMPs and ErMPs) in 60 young ß-TM patients compared with 40 age- and sex-matched healthy controls and assessed their relation to clinicopathological characteristics and aortic elastic properties. Patients were studied stressing on transfusion history, splenectomy, thrombotic events, chelation therapy, hematological and coagulation profiles, flow cytometric measurement of PMPs (CD41b(+) ) and ErMPs (glycophorin A(+) ) as well as echocardiographic assessment of aortic elastic properties. Aortic stiffness index and pulmonary artery pressure were significantly higher, whereas aortic strain and distensibility were lower in TM patients than controls (P < 0.001). Both PMPs and ErMPs were significantly elevated in TM patients compared with controls, particularly patients with risk of pulmonary hypertension, history of thrombosis, splenectomy or serum ferritin >2500 µg/L (P < 0.001). Compliant patients on chelation therapy had lower MPs levels than non-compliant patients (P < 0.001). PMPs and ErMPs were positively correlated to markers of hemolysis, serum ferritin, D-dimer, vWF Ag, and aortic stiffness, whereas negatively correlated to hemoglobin level and aortic distensibility (P < 0.05). We suggest that increased MPs may be implicated in vascular dysfunction, pulmonary hypertension risk, and aortic wall stiffness observed in thalassemia patients. Their quantification could provide utility for early detection of cardiovascular abnormalities and monitoring the biological efficacy of chelation therapy.

Retinal changes in children and adolescents with sickle cell disease attending a paediatric hospital in Cairo, Egypt: risk factors and relation to ophthalmic and cerebral blood flow.

BACKGROUND: Sickle cell disease (SCD) is characterised by occlusion of small blood vessels. This study aimed to assess retinal changes in patients with SCD and its correlation with time-averaged mean flow velocity (TAMV) in middle cerebral arteries (MCA) and ophthalmic arteries (OA). METHODS: Sixty SCD patients (aged 3-18 years) attending a paediatric hospital in Cairo, Egypt, during March 2010 to November 2011, were compared with 30 healthy controls. All underwent clinical and fundus examination by indirect ophthalmoscopy, and assessment of TAMV in MCAs and OAs by transcranial Doppler, repeated 1 year later for those with conditional velocities. RESULTS: HbS/ß was diagnosed in 32 patients and HbSS in 28; 50 patients had normal fundus and 10 had bilateral non-proliferative retinopathy. Risk factors for retinopathy included HbSS, age, previous stroke, non-compliant hydroxyurea (HU) therapy, frequency of sickling crises and HbS level. TAMVs were increased in MCAs, but not in OAs, in sicklers. TAMVs in MCAs and OAs increased with non-compliant HU therapy, previous stroke, age, frequency of sickling crises and level of HbS. No significant interhemispheric difference was found. CONCLUSION: Sickle retinopathy was correlated with TAMV in MCAs but not in OAs. A significant difference was found between initial and follow-up TAMVs in the MCAs, after 1 year of regular HU and transfusion therapy, in those with conditional velocities.

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: Glanzman's 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.

D-dimer levels in type 1 and type 2 diabetic children and adolescents; Relation to microvascular complications and dyslipidemia "own data and review".

BACKGROUND: Changes in the coagulation cascade have been implicated in the pathogenesis of the vascular diabetic complications. OBJECTIVE: to assess D-dimer level (as a marker of coagulation cascade/fibrinolysis activation) in type 1 and type 2 diabetics and its correlation with microvascular complications and serum total cholesterol (TC) level. METHODS: Ninety patients were included divided into two groups. Group 1; comprised 50 type 1 diabetics with a mean age of 13.56 years. Their disease duration ranged between 0.4-16 years. Group 2; comprised 40 type 2 diabetics with a mean age of 13.5 years. Their disease duration ranged between 0.4-8 years. Patients were compared to 60 healthy age and sex matched subjects served as controls. Laboratory investigations included; fasting blood glucose, glycosylated hemoglobin, quantitative urinary albumin creatinine ratio (ACR), serum TC and measurement of plasma D-dimer levels. RESULTS: Type 2 diabetics had significantly higher weight and body mass index (BMI) Standard deviation score (SDS) (p<0.0001) compared to type 1 diabetics. Type 2 diabetics had higher TC (p<0.04) and D-dimer levels (p<0.05) compared to type 1 diabetics. D-dimer level was highly significantly elevated among type 1 diabetics with retinopathy, neuropathy and nephropathy compared to non-complicated patients (p<0.01). D-dimer was significantly correlated with ACR (p<0.001) in both studied groups. In type 2 diabetics, TC level was positively correlated with BMI SDS (p<0.05), D-dimer level was significantly correlated with disease duration (p<0.05), blood pressure (p<0.01), and TC (p<0.05). In type 1 diabetics, D-dimer levels were positively correlated with blood pressure (p<0.01). In both types, D-dimer is positively correlated with ACR (p<0.001). CONCLUSION: There was a tendency to hypercoagulability in both types of diabetes. This phenomenon may play a role in the development of diabetic microvascular complications.

Clinicopathological and radiological study of Egyptian ß-thalassemia intermedia and ß-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 ß-thalassemia intermedia (ß-TI) patients were compared with 70 ß-thalassemia major (ß-TM) patients. ß-Thalassemia intermedia patients had a higher incidence of left atrium dilatation, right ventricular dilatation and pulmonary hypertension, whereas, ß-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 ß-TM patients compared with ß-TI patients (p <0.05). Administration of hydroxyurea (HU) alone was associated with significant improvement in hematological parameters and quality of life for ß-TI patients. In conclusion, the risk of complications still burdens the life of Egyptian thalassemia patients and their frequency varies between ß-TI and ß-TM. We provide evidence that calls for the use of HU in ß-TI patients.

D-dimer assay in Egyptian patients with Gaucher disease: correlation with bone and lung involvement.

Gaucher disease is the most frequent lysosomal storage disorder. Bone and lung involvement are two major causes of morbidity in this disease. D-dimer is a reliable indicator of active microvascular thrombosis, even in patients without overt hypercoagulation. This study aimed to assess D-dimer levels in Gaucher disease, correlating this marker to clinical characteristics and radiological parameters to investigate its role as a potential predictor for the occurrence and severity of skeletal and pulmonary manifestations. The study population consisted of 56 Egyptian patients with Gaucher disease, 36 had type 1 Gaucher disease (64.3%) and 20 had type 3 Gaucher disease (35.7%). Thirty healthy individuals were enrolled as a control group. D-dimer levels were significantly higher in all patients with Gaucher disease compared with controls (P < 0.001). Patients with type 3 showed significantly higher D-dimer concentrations compared with type 1 (P < 0.001). Pulmonary involvement was present in a significant proportion among type 3 Gaucher patients (P < 0.05), whereas bone changes were present in a higher percentage in type 1 compared with type 3 Gaucher patients. D-dimers were significantly higher in patients with abnormal MRI findings of the long bones and in those with ground glass appearance on high-resolution computerized tomography of the chest compared with patients with normal radiology (P < 0.001). Splenectomized patients displayed significantly higher D-dimer levels compared with nonsplenectomized patients (P < 0.001). Our results suggest that D-dimer is significantly elevated in Gaucher disease, particularly type 3, and may be considered as a potential marker of risk prediction of bone and lung involvement that could be used to monitor treatment response.

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 beta-thalassemia major (beta-TM) and 15 beta-thalassemia intermedia (beta-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, beta-TI and beta-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.