Search

The region surrounding the Caribbean Sea is predominantly composed of island nations for its Eastern part and the American continental coast on its Western part. A large proportion of the population, particularly in the Caribbean islands, traces its ancestry to Africa as a consequence of the Atlantic slave trade during the XVI&ndash, XVIII centuries. As a result, sickle cell disease has been largely introduced in the region. Some Caribbean countries and/or territories, such as Jamaica and the French territories, initiated newborn screening (NBS) programs for sickle cell disease more than 20 years ago. They have demonstrated the major beneficial impact on mortality and morbidity resulting from early childhood care. However, similar programs have not been implemented in much of the region. This paper presents an update of the existing NBS programs and the prevalence of sickle cell disease in the Caribbean. It demonstrates the impact of the Caribbean Network of Researchers on Sickle Cell Disease and Thalassemia (CAREST) on the extension of these programs. The presented data illustrate the importance of advocacy in convincing policy makers of the feasibility and benefit of NBS for sickle cell disease when coupled to early care.

Objective To establish the birth prevalence of sickle cell disease in Grenada, with a view to assess the requirement for a population-based neonatal screening programme. Methods A two-year pilot neonatal screening programme, involving the Ministry of Health of Grenada, the Sickle Cell Association of Grenada, and the diagnostic laboratory of hemoglobinopathies of the University Hospital of Guadeloupe, was implemented in 2014–2015 under the auspices of the Caribbean Network of Researchers on Sickle Cell Disease and Thalassemia. Results Analysis of 1914 samples processed identified the following abnormal phenotypes: 10 FS, 2 FSC, 183 FAS, 63 FAC. These data indicate βs and βc allele frequencies of 0.054 and 0.018, respectively. Conclusion Neonatal screening conducted in the framework of this Caribbean cooperation can allow rapid detection and earlier management of affected children.

The presence of sickle hemoglobin (HbS) in red blood cells (RBC) of patients with sickle cell anemia (SCA) is at the origin of their rheological abnormalities. Abnormal blood rheology has been shown to modulate the clinical severity and to also be involved in several complications of SCA.[1][1]–[3

International audience; Sickle cell disease (SCD) is a significant problem in the Caribbean, where many individuals have African and Asian forebears. However, reliable prevalence data and specific health care programs for SCD are often missing in this region. Closer collaboration between Caribbean territories initiated in 2006 to set up strategies to promote better equity in the health care system for SCD patients led to the formation of CAREST: the Caribbean Network of Researchers on Sickle Cell Disease and Thalassemia. We present the effectiveness of collaborations established by CAREST to promote SCD newborn screening programs and early childhood care, to facilitate health worker training and approaches for prevention and treatment of SCD complications, and to carry out inter-Caribbean research studies.

The molecular backgrounds of variants encountered in Afro-Caribbean black individuals and associated with the production of clinically significant antibodies against high-incidence antigens (anti-RH18, anti-RH34) and against Rhe epitopes were determined. We showed that RH:−18 phenotypes are produced by 3 distinct RHCEalleles: ceEK carrying 48G>C (exon 1), 712A>G, 787A>G, 800T>A (exon 5); ceBI carrying 48G>C (exon 1), 712A>G (exon 5), 818C>T (exon 6), 1132C>G (exon 8); and the already knownceAR allele carrying 48G>C (exon 1), 712A>G, 733C>G, 787A>G, 800T>A (exon 5), and 916A>G (exon 6). The RH:−34 phenotype is produced by the (C)ces haplotype described previously and composed of a hybrid D-CE(3-8)-D gene with 4 extra mutations next to a ces allele (733C>G; exon 5) with an extra mutation in exon 7 (1006G>T). Partial Rhe with risk of immunization against lacking epitopes can be produced by the new ces allele carrying an extra mutation in exon 3 (340C>T) and by the ceMO allele described previously. A population of sickle cell disease patients was screened to estimate the incidence of these rare alleles, with the conclusion that a procedure is required to detect the associated phenotypes in black donors to ensure transfusion safety for patients. We also described a new variant [ces(748)] and variants carrying different altered alleles in nonimmunized patients and for whom the risk of immunization is discussed.

To characterize the antigenic targets of anti-platelet antibodies (APA) found in systemic lupus erythematosus (SLE)-associated thrombocytopenia, 48 patients with immune thrombocytopenia and SLE were compared with 20 patients with SLE who had never been thrombocytopenic. Both cases and controls were tested for circulating APA by an indirect platelet suspension immunofluorescence assay (PSIIFT) and by indirect monoclonal antibody specific immobilization of platelet antigens (MAIPA). A direct platelet suspension immunofluorescence assay (PSIFT) was also used for antibodies bound to platelets in vivo in thrombocytopenic patients; 13 of them with high titres of platelets-bound APA were investigated by direct and indirect MAIPA and platelet eluate analysis. Circulating APA were detected by PSIIFT in 88% of cases and 55% of controls (P = 0.0066) and platelet-bound antibodies were detected by PSIFT in 90% of cases. Indirect MAIPA detected specific APA (mainly directed against GpIIbIIIa) in 36% of cases and only 5% of the controls (P = 0.0076). Nine out of the 13 fully investigated thrombocytopenic patients (69%) had a positive direct MAIPA and/or APA detected in platelet eluates. In conclusion, the production of specific anti-platelet autoantibodies, mainly directed against GpIIb/IIIa, and their binding to platelet membrane plays an important role in the pathogenesis of SLE-associated thrombocytopenia.

It is thought that an increase in the adhesion of circulating reticulocytes to the vascular endothelium may initiate the vascular occlusion underlying the painful crises and organ failures typical of sickle cell disease (SCD). At least 2 receptors, usually present on reticulocytes, seem to be involved in this adhesion process: glycoprotein CD36 (glycoprotein IV) and integrin alpha(4)beta(1) (very late activation antigen--4). Recently, a high frequency of the platelet CD36--deficient phenotype was reported in black Africans. The frequency of this deficiency was similar in subjects with and without SCD. The role of CD36 in vaso-occlusion was then investigated by comparing the clinical course in 2 groups of black Africans homozygous for hemoglobin S, with and without CD36 deficiency, but similar in age, sex, geographical origin, number of alpha-globin genes, and beta-globin gene haplotype. Flow cytometry showed that CD36 was absent from the circulating red blood cells and reticulocytes of platelet CD36--deficient individuals but present on those from patients with normal platelet CD36 expression, and that alpha(4)beta(1) integrin levels were similar on the reticulocytes of the 2 groups. Neither clinical severity, as evaluated by the frequency and characteristics of vaso-occlusive events, nor biological data differed significantly in the 2 groups of patients. Finally, although CD36 has been suggested to play a critical role in the pathogenesis of vaso-occlusion, this study, despite including only a small number of patients, supports the idea that the modulation of expression of a single type of adhesion molecule is insufficient to counteract the pathological process leading to vaso-occlusion in SCD patients. (Blood. 2001;98:966-971)

Sickle cell disease (SCD) frequently affects the liver; if acute liver failure (ALF) develops, the only potentially effective therapeutic option is liver transplantation (LT). Only 12 patients for whom LT was performed for SCD-related ALF have been described so far. We report a retrospective series of 6 adult patients with SCD (3 men and 3 women, median age = 40.1 years) who underwent emergency LT. The indication for LT was ALF complicating cirrhosis in 5 patients (hepatitis C/iron overload-induced cirrhosis in 3 and iron overload-induced cirrhosis in 2); one patient had autoimmune hepatitis. The median follow-up was 52.7 months (0.5-123 months). The 1-, 3-, 5-, and 10-year survival rates were 83.3%, 66.7%, 44.4%, and 44.4%, respectively. One patient died of hepatocellular failure precipitated by hyperacute allograft rejection on post-LT day 10. Soon after LT, 2 patients developed seizures; in 1 case, the seizures were a complication of early calcineurin inhibitor-induced leukoencephalopathy. Four long-term survivors benefited from specific management of SCD; specifically, the hemoglobin S fraction was maintained below 30% and the total hemoglobin level was maintained between 8 and 10 g/dL. Two patients had mild vaso-occlusive crises. Three patients experienced a recurrence of hepatitis C virus (HCV) infection; 2 of these patients experienced reversible neurological complications while they were receiving antiviral treatment. Carefully selected patients with SCD may benefit from emergency LT. However, such patients seem to be particularly susceptible to neurological complications after LT. In contrast, severe SCD-related crises do not seem to recur if specific management is provided. Outcomes may be improved if the neurological complications can be minimized; for example, the administration of a calcineurin inhibitor can be delayed, and the management of HCV infection recurrence can be improved.

Hydroxyurea-derived clinical and biological benefits and safety were retrospectively studied for 123 adult patients from 2 sickle cell disease referral centers during a total follow-up of 654 patient-years and total hydroxyurea exposure of 549 patient-years. Fifty-six adverse events occurred (incidence: 12%/patient-year), with leg ulcers being the most frequent. Adverse events could arise at any time and were usually reversible. No malignancy was observed. Clinical and biological benefits of our cohort were similar to those previously reported. Based on this relatively long retrospective study, the risk/benefit ratio for moderate hydroxyurea doses was satisfactory.

To the editor: Drug-induced immune thrombocytopenia (DITP) may occur after exposure to many medications and is sometimes indistinguishable from idiopathic thrombocytopenic purpura (ITP).[1][1]–[3][2] When suspected, the causative drug must be stopped and the platelet count returns to normal in

Objectives. Priapism is a common and currently unsatisfactorily managed complication of sickle cell disease (SCD). In June 1994, 6 SCD patients received a new therapeutic regimen to prevent the occurrence and recurrence of priapism. Methods. The patients (5 with SS and 1 with SC) were adults and had frequent episodes of stuttering priapism (SP), and two of them had had acute episodes (AP) lasting more than 3 hours. The treatment consists of preventive oral administration of the alpha-adrenergic agent etilefrine, and self-administered intracavernous injection (SICI) of the same agent to reverse episodes lasting more than 1 hour. Results. Since the beginning of treatment, all patients were protected against AP, 4 patients had no recurrence with the oral treatment alone, 2 had to use SICI, 1 occasionally and 1 constantly. There was no modification of sexual activity and no complications. Blood pressure was unaffected. Conclusions. This treatment is simple, cheap, and self-administered. It should be proposed to all patients with SCD in all geographic areas as part of an educational program for active prevention of this severe complication.

Although antibodies implicated in red blood cell (RBC) alloimmunization have been studied for many years, little is known about helper T-cell responses that drive their production.[1][1]-[3][2] The aim of this work was to determine T-cell antigenic determinants involved in T-cell responses against

Abstract 1536 Poster Board I-559 Background Pulmonary hypertension (PHT) is a widely recognized complication of sickle cell disease (SCD). It affects 32% of adults with SCD and is associated with an increased risk for early mortality. Screening of children with SCD by Doppler echocardiography has been recommended, using tricuspid regurgitant jet velocity (TRJV) to estimate pulmonary artery systolic pressure. However, the prevalence and risk factors of elevated TRJV in children with SCD at steady state have not been extensively defined. Methods SCD patients of the CHIC-cohort were prospectively assessed : alpha and beta genotype, G6PD, platelet-CD36 expression were determined; baseline blood parameters between 1 and 3 years of age were recorded and re-assessed every year at steady state with clinical data, TCD screening, abdominal sonography and every two years by Doppler echocardiography, evaluation of lung function and cerebral MRI/MRA. Pulmonary hypertension was defined as a TRJV ≥2.5 m/s. Univariate and multivariate logistic regression analyses were performed to evaluate risk factors for elevated TRJV. Results A total of 662 echocardiograms with available measure of TRJV were performed away from vaso-occlusive crises (VOC) and acute chest syndromes (ACS) in 320 SCD-patients (268 SS, 1 SDPunjab, 7 Sb0; 14 Sb+, 30 SC) between 12/98 and 07/09 and were included in the analyzes: 127/662 were performed in patients on hydroxurea (HU) therapy, 121 on transfusion program (TP) and 63 after stem cell transplantation (SCT). In SS/Sb0 patients, TRJV did not correlate with fractional shortening, ejection fraction, TCD velocities, systemic and diastolic blood pressure, cumulative number of VOC and ACS, LDH and SpO2, but correlated with age (r=0.258,p Conclusion In this pediatric cohort, early assessed by TCD and transfused in case of abnormal occurrence, no association was found between cerebral vasculopathy and elevated TRJV, which could be the result of early initiation of transfusion programs as soon as TCD became abnormal. The data also confirm the link between pulmonary hypertension, low oxygen saturation and hemolysis, previously reported by others. In addition, we show for the first time that CD36 deficiency is a risk factor for elevated TRJV in SCD patients. CD36 deficiency has been shown to be a common occurrence in subjects of African descent. The CD36 scavenger receptor is a multifunctional receptor, which is expressed on the surface of various cell types, and is involved in immunity, metabolism and angiogenesis. Previous studies suggested that CD36 deficiency did not modify the clinical course of SCD patients but echocardiograms had not been analyzed. Recent studies showed that hypoxia increases CD36 expression via its HIF-1 responsive promoter element and activation of the PI3K pathway, suggesting that CD36 deficient SCD patients could have an abnormal response to hypoxia. Additional studies will be needed to understand the relationship between PHT and CD36 deficiency and the role of hypoxia in these patients. Disclosures No relevant conflicts of interest to declare.

Abstract 4615 INTRODUCTION Long-term blood transfusion is essential for patients with sickle cell disease (SCD) in case of cerebral vasculopathy, organ dysfunction, leg ulcer, failure or intolerance of hydroxyurea treatment. Secondary iron overload is a factor of morbidity and mortality by organ damage. In practice, three chelators are available: deferoxamine (DFO) which is administrated by subcutaneous infusion and therefore source of poor compliance in SCD. Deferasirox (DFX), the new oral chelator is the first line therapy since 2007. Deferiprone (DFP) is an option when DFX or DFO are contraindicated or inadequate. However, DFP has no approval for SCD. The purpose of this study is to describe the characteristics of SCD patients treated by DFP. METHODOLOGY The patients included in this study arise from the group of the patients with long-term blood transfusion by manual exchange in Henri Mondor's SCD center, and in whom iron overload is treated by DFP. The monitoring of iron overload is obtained by regular serum ferritin level, combined liver and heart MRI. Only one iron measure by MRI is available for each patient throughout the study. RESULTS Nine patients (8 SS and 1 Sβ0thal) are included: 5 men and 4 women. The mean age is 44.2 years (22 to 64 years). The median duration of chronic transfusion is 10 years (4 to 27 years). The average dose of DFP is 68 mg / kg / day (50 to 93 mg / kg / day). The median follow-up under DFP is 30 months (7 to 60 months). The median level of serum ferritin before the initiation of DFP is 5830 μg / l (1800 to 9300 μg / l); and the median level of serum ferritin at the end point is 7940 μg / l (4540 to 11300 μg / l). MRI shows an important hepatic iron overload (up to 320 μmol) in all patients and one cardiac iron overload (T2* = 12 ms). Three patients stopped DFP and switch to deferasirox (DFX) as soon as DFX was available. For the other patients, the reason of prescribing DFP instead of DFX was renal failure in 5 patients and DFX related GI symptoms in one patient. No agranulocytosis is observed. The weekly then monthly monitoring of blood count is insured for all patients. No cytolysis by drug's toxicity is observed, except for one patient with liver transplant and who has an active HCV infection. DISCUSSION Serum ferritin level is the easiest marker of iron overload follow-up, but is subject of important variations due to inflammation, hemolysis, and cytolysis. Indeed, MRI is the only one reliable measure. The evidence of cardiac iron overload is proved in one patient, and confirms the importance of this measure on SCD patients. This motivates the edition of guidelines concerning the prevention and monitoring of iron overload among these patients. The dosage of DFP remains reasonable compared to the mean dosage use in other pathologies. This dosage depends of the degree of iron overload and the individual tolerance. Data are not sufficient at these days to evaluate the efficacy of DFP to reduce or to stabilize the level of iron overload. However, we observe globally a good clinical and biological tolerance, even in patients who have organ transplant and therefore have several concomitant treatments. CONCLUSION DFP in patients with SCD is globally well-tolerated, but its efficiency is not proved yet. Approval of DFP for SCD is needed. As life expectancy improves in SCD, more patients will require long-term transfusion and thus iron chelation therapy. Cardiac Iron overload is possible in patients with SCD. So, it would be systematically looked after. Disclosures: No relevant conflicts of interest to declare.

Background: The mechanisms triggering the production of platelet autoantibodies in autoimmune thrombocytopenic purpura (AITP) are poorly understood. Recently, marked improvements in platelet counts have been reported in patients with AITP and concurrent Helicobacter pylori infection after eradication of H pylori by a standard antibiotic regimen. We looked for an association between H pylori infection and AITP in adults. Methods: Fifty-one adults of white French origin, negative for human immunodeficiency virus (mean±SD age, 40±19.8 years), with AITP and a platelet count of less than 5010 3 /µL at onset were included. Thirty-five consecutive nonthrombocytopenic patients (mean±SD age, 43±22 years) of the same origin and with unknown H pylori status served as control subjects. Antibodies against H pylori were detected by means of an agglutination method in both patients and control subjects. Sex ratio, mean age, hemorrhagic manifestations, response to corticosteroid therapy, and final outcome were compared in H pylori–negative and H pylori–positive patients with AITP. To test for a possible molecular mimicry mechanism, we also used an immunoblot assay to look for specific H pylori antibodies in platelet eluates from 3 H pylori– positive patients with AITP. Results: Seroprevalence of H pylori in patients with AITP (15 [29%]) was not significatively different from that in control subjects (10 [29%]). The H pylori–positive and H pylori–negative patients with AITP did not differ in main characteristics at AITP onset, response rate to corticosteroids, and final outcome. None of the 3 patients investigated had H pylori antibodies in platelet eluates. Conclusion: Although the role of H pylori in a subgroup of patients with AITP cannot be excluded, we found no evidence of an association between H pylori infection and AITP. Arch Intern Med. 2002;162:1033-1036

The characteristics of severe neutropenia with delayed onset following administration of rituximab were evaluated in 293 consecutively patients treated for B-cell malignancies between Oct. 1996 and Feb. 2004. Eighteen episodes of severe neutropenia were identified between 2 to 36 weeks after rituximab, delivered alone in 4 cases or combined to chemotherapy in 14 other cases. At the time of occurrence of neutropenia, 10 patients had completed treatment and were in complete remission and 8 were still on therapy. All patients had a normal neutrophil count before rituximab treatment. In 4 cases, neutropenia was complicated by fever requiring hospitalisation. Among the18 patients [diffuse large B-cell lymphoma: 12, follicular lymphoma: 3, mantle cell lymphoma: 1, post transplant lymphoproliferative disorder: 1, chronic lymphocytic leukemia (CLL): 1], 8 had previouly been treated with high-dose therapy followed by autologous stem-cell transplantation. None of the known causes of neutropenia were found. Neutropenia was associated with selective marrow depletion of neutrophil precursors in all episodes. The peripheral blood lymphocyte subset repartition was documented in 16 cases; a severe B lymphopenia was observed in all except one - patient with CLL - and CD4+ lymphopenia was seen in 13. T-cell clonality was studied in 8 cases and was positive in 5. Parvovirus B19 DNA was not detected in the 11 tested cases. Tests for antineutrophil antibodies were positive in 5 cases; no hemolytic anemia, autoimmune thrombocytopenia or large granular natural killer lymphocytosis were observed. Filgrastim was given to 4 patients only. The median time of neutrophil recovery for the entire group was 14 days (range: 2–180). The mechanism of this rare event already reported (Saikia et al. Ann. Oncol 2002, Voog et al. NEJM 2003, Chaiwatanatorn et al. BJH 2003, Lemieux et al. BMT 2004) remains to be established. Since it seems to be more frequent in patients who have received extensive prior chemotherapy (8/18), it is tempting to speculate that cumulative immunosuppression might favor the development of such an event.