Phu-Quoc Le

Survival among children and adults with sickle cell disease in Belgium: Benefit from hydroxyurea treatment.

To evaluate the survival of patients with sickle cell disease (SCD) recorded in the Belgian SCD Registry and to assess the impact of disease‐modifying treatments (DMT).

Etanercept improves linear growth and bone mass acquisition in MTX-resistant polyarticular-course juvenile idiopathic arthritis

OBJECTIVES Chronic inflammation in juvenile idiopathic arthritis interferes with linear growth and bone mass acquisition. We prospectively evaluated and compared linear growth and evolution of bone mass acquisition and body composition in MTX-resistant polyarticular-course JIA (polyJIA) patients started on etanercept and in recently diagnosed polyJIA patients started on MTX monotherapy. METHODS Sixteen MTX-resistant polyJIA patients were given add-on etanercept, eight recently diagnosed polyJIA patients were started on MTX. Patients were evaluated at baseline and at 1, 6, 12 and 18 months with respect to disease activity, linear growth, BMD and body composition. RESULTS Baseline patient and disease characteristics were similar in both groups. Clinical disease activity (Pediatric ACR30) was equally well controlled in both groups. Growth velocity increased significantly allowing catch-up growth in the etanercept + MTX group only. BMD (lumbar spine Z-score) improved significantly in both groups. A significant increase of bone mineral content and lean:fat mass ratio was seen in the etanercept + MTX group, but not in the MTX group. CONCLUSION Clinical control of disease activity by etanercept in MTX-refractory polyJIA is associated with rapidly instituted catch-up growth and improvement of bone mineralization and body composition. In recently diagnosed polyJIA patients treated with MTX the relation between clinical response and these parameters was less evident. Preliminary data on serum IL-6 and osteoprotegerin levels indicate that the beneficial effects seen with etanercept therapy may be related to its control of systemic IL-6 production and enhancement of osteoblast activity.

Neonatal haemoglobinopathy screening in Belgium

Background: A neonatal haemoglobinopathy screening programme was implemented in Brussels more than a decade ago and in Liège 5 years ago; the programme was adapted to the local situation. Methods: Neonatal screening for haemoglobinopathies was universal, performed using liquid cord blood and an isoelectric focusing technique. All samples with abnormalities underwent confirmatory testing. Major and minor haemoglobinopathies were reported. Affected children were referred to a specialist centre. A central database in which all screening results were stored was available and accessible to local care workers. A central clinical database to monitor follow-up is under construction. Results: A total of 191 783 newborns were screened. One hundred and twenty-three (1:1559) newborns were diagnosed with sickle cell disease, seven (1:27 398) with β thalassaemia major, five (1:38 357) with haemoglobin H disease, and seven (1:27 398) with haemoglobin C disease. All major haemoglobinopathies were confirmed, and follow-up of the infants was undertaken except for three infants who did not attend the first medical consultation despite all efforts. Conclusions: The universal neonatal screening programme was effective because no case of major haemoglobinopathy was identified after the neonatal period. The affected children received dedicated medical care from birth. The screening programme, and specifically the reporting of minor haemoglobinopathies, has been an excellent health education tool in Belgium for more than 12 years.

Use of hydroxyurea in prevention of stroke in children with sickle cell disease

To the editor: We carefully read the paper by Zimmerman and colleagues[1][1] about the possible effect of hydroxyurea on the transcranial doppler flow velocities in children with sickle cell disease. We reviewed the transcranial dopplers (TCD) performed on the children with sickle cell disease in

Hydroxyurea treatment for sickle cell disease: impact on haematopoietic stem cell transplantation's outcome

Summary:Since 1988, 24 children have undergone haematopoietic stem cell transplantation (HSCT) for severe sickle cell disease (SCD) in our unit, 13 being grafted after having been exposed to hydroxyurea (HU) to control SCD-related complications. Different pre-transplant conditioning regimens were given over time: Bu14/Cy200 in six patients (group 1), Bu16/Cy200/antithymocyte globulin (ATG) in five (group 2) and Bu16/Cy200/ATG with HU prior to HSCT in 13 (group 3). The aim of this study is to compare the outcome after HSCT of these groups of patients, which differ according to pre-transplant drug exposure. Overall, 20 of the 24 transplanted children had stable engraftment and have remained free of SCD-related symptoms after HSCT; 19 of them are currently alive and cured of SCD. In group 1 (HU−, ATG−), we observed one unexplainable late death, one absent engraftment, one late rejection and one mixed stable chimerism. In group 2 (HU−, ATG+), we observed the absence of engraftment in two patients and one early rejection. In group 3 (HU+, ATG+), we observed no cases of either absent engraftment, mixed stable chimerism or late rejection. In our experience, pre-transplant treatment with HU seems to be associated with a lower incidence of rejection/absent engraftment in severe SCD patients. These results need to be confirmed with a larger number of patients.

Thrombin generation reveals high procoagulant potential in the plasma of sickle cell disease children.

Changes in several components of the clotting system are well documented in sickle cell disease (SCD) patients. However, whether the global hemostatic potential of these patients is altered is still unclear. Calibrated automated thrombogram® method of thrombin generation (TG) was used to characterize the hemostatic potential of 83 SCD children (75 SS, 6 SC, and 2 Sβ thal) at steady‐state as compared with 50 controls of the same range of age. TG was triggered using 1 pM tissue factor and 4 μM phospholipids with and without thrombomodulin. Thirteen SCD children were also evaluated during vaso‐occlusive crisis. Protein C activity, free protein S and D‐dimers levels were measured in parallel. SCD patients showed higher rates of thrombin formation, higher thrombin peak height (with and without thrombomodulin), and higher endogenous thrombin potential (ETP) than controls in the presence of thrombomodulin. Reduction of ETP (RETP) in the presence of thrombomodulin was lower in SCD group compared with controls and correlated both with protein C and protein S levels. ETP, RETP, peak height, and velocity index of TG correlated with D‐dimers. Compound heterozygous patients showed an intermediate hemostatic phenotype at steady‐state. No significant difference was observed when comparing TG parameters during vaso‐occlusive crisis to those obtained at steady‐state in the same patients. The global hemostatic potential is increased and reflects the hypercoagulable state of SCD patients even at steady‐state. The relevance of this finding with respect to the risk of thrombotic complications of the disease needs further investigation. Am. J. Hematol. 2011.

Antibody deficiency due to a missense mutation in CD19 demonstrates the importance of the conserved tryptophan 41 in immunoglobulin superfamily domain formation

Immunoglobulin superfamily (IgSF) domains are conserved structures present in many proteins in eukaryotes and prokaryotes. These domains are well-capable of facilitating sequence variation, which is most clearly illustrated by the variable regions in immunoglobulins (Igs) and T cell receptors (TRs). We studied an antibody-deficient patient suffering from recurrent respiratory infections and with impaired antibody responses to vaccinations. Patients B cells showed impaired Ca(2+) influx upon stimulation with anti-IgM and lacked detectable CD19 membrane expression. CD19 sequence analysis revealed a homozygous missense mutation resulting in a tryptophan to cystein (W52C) amino acid change. The affected tryptophan is CONSERVED-TRP 41 located on the C-strand of the first extracellular IgSF domain of CD19 and was found to be highly conserved, not only in mammalian CD19 proteins, but in nearly all characterized IgSF domains. Furthermore, the tryptophan is present in all variable domains in Ig and TR and was not mutated in 117 Ig class-switched transcripts of B cells from controls, despite an overall 10% amino acid change frequency. In vitro complementation studies and CD19 western blotting of patients B cells demonstrated that the mutated protein remained immaturely glycosylated. This first missense mutation resulting in a CD19 deficiency demonstrates the crucial role of a highly conserved tryptophan in proper folding or stability of IgSF domains.

Evaluation of the procoagulant activity of endogenous phospholipids in the platelet-free plasma of children with sickle cell disease using functional assays.

BACKGROUND The mechanisms of hypercoagulability in sickle cell disease (SCD) are poorly understood. OBJECTIVE We aimed to explore the procoagulant activity of endogenous phospholipids (ePL) in the platelet-free plasma of SCD children. METHODS A factor Xa clotting time (XACT), thrombin generation (TG) and a capture-based assay for the detection of procoagulant microparticles (PMP) were used. Forty three SCD children (35 SS, 6 SC and 2 Sβ+) were evaluated at steady-state and compared to 20 controls. Fourteen patients were also evaluated during vaso-occlusive crisis. TG was performed using 10 pM tissue factor without addition of exogenous phospholipids. A control condition was also performed using 10 pM tissue factor and 4 μM phospholipids. Percentages of the test/control conditions were calculated for the peak height (% peak), endogenous thrombin potential (% ETP) and velocity index (% VI). RESULTS XACT times were shorter, PMP levels, peak height and velocity index of thrombin generation were higher in SCD patients than controls. Lag time and ETP were not different between the two groups. % peak, % ETP and % VI were higher in patients than controls. Significant correlations were found between PMP levels and XACT, also between PMP levels and peak height, velocity index, ETP and their respective percentages to the control condition, but not with lag time. Double heterozygous patients showed intermediate values for XACT and TG parameters. No significant difference was observed when comparing patients at steady-state versus vaso-occlusive crisis. CONCLUSION High procoagulant activity of ePL was observed in the platelet-free plasma of SCD children, probably borne by procoagulant microparticles. This may contribute to a high hemostatic potential and predisposition to thrombotic complications in these patients.

Transfusion support of autoimmune hemolytic anemia: how could the blood group genotyping help?

Conventional pretransfusion testing based on hemagglutination assays can be challenging for patients with autoimmune hemolytic anemia (AIHA) because of the presence of auto-antibodies. It has been suggested that deoxyribonucleic acid-based methods could be more efficient in the selection of antigen-matched red blood cell units in those settings. Because of the high risk of alloimmunization of these patients and the labor-intensive nature of adsorption techniques, we decided to evaluate the feasibility of selecting antigen-matched units on the basis of RBC genotyping. We included in our routine RBC genotyping program samples from 7 patients with AIHA presenting a strongly positive direct antiglobulin test. This made the routine compatibility tests difficult. Most patients had previously received transfusions because of warm AIHA. Matched donor units were selected according to the genotype. For all but 1 patient, blood group genotyping could be done on time to allow antigen-matched transfusion. Four patients received antigen-matched red blood cell units based on RBC genotyping and for 1 patient the fact that no matched units were available led us to postpone the transfusion. After each transfusion, the recovery was recorded and considered satisfactory for all transfused patients.

Reduction of the Six-Minute Walk Distance in Children with Sickle Cell Disease Is Correlated with Silent Infarct: Results from a Cross-Sectional Evaluation in a Single Center in Belgium

Background The 6-minute walk test (6MWT) is used in adults and children affected by a wide range of chronic diseases to evaluate their sub-maximal exercise capacity. It reflects the global response of various physiological systems in a situation simulating a daily life activity. Methods We analyzed factors affecting the 6MWT in 46 Sickle Cell Disease children. Forty-two were treated with hydroxyurea (HU). Patients with normal test (>80% of the age-standardized predicted value) were compared to patients with abnormal test (≤80%). Baseline hematological values, clinical events, cerebrovascular disease, cardio-pulmonary parameters and disease-modifying treatment were compared according to the performance of the test. Results Among the 46 patients, 14 had an abnormal 6MWT. In univariate analysis, both groups were similar for biological and clinical data. Six of the 14 patients with an abnormal 6MWT had silent infarct (SI) compared to 6/32 with a normal test (P = 0.09). When excluding chronically transfused patients, 4 of the 11 patients with an abnormal 6MWT had SI compared to 1/26 (P = 0.02). Baseline pulse oximetry was normal in both groups but slightly lower in patients with abnormal 6MWT (P = 0.02). No patient presented exercise-induced desaturation. In multivariate analysis, the only factor associated with abnormal 6MWT was the presence of SI (P = 0.045). Conclusions In our cohort of 46 patients characterized by high exposure rate to HU and by the absence of severe cardiopulmonary disease, the sole factor independently associated with 6MWT was the presence of SI. The lower exercise capacity of children with SI may reflect some subclinical neurological impairment as they do not differ by hemoglobin level or cardiopulmonary parameters.