Le globule rouge drépanocytaire. Données génétiques et structurelles: The sickle cell. Genetic and structural data.

Sickle cell disease is syndromic, associating a hemolytic anemia, a vaso-obstructive vascular disease, and an infectious risk linked to the precocity of the splenic function loss. The willingly hyperacute and potentially fatal character of the two last elements of the pathophysiologic syndrome, has, quite rightly, focused the therapeutic researches on them. Great success in those two domains have allowed a very important gain in life expectancy. However, chronic progressive organ dysfunction began to appear in older than 25 years-old patients. It concerns mainly renal, hepatic, cardiac functions and pulmonary arterial pressure and may lead to organ failure and premature death. Since some 25 years, the clinical research demonstrated an association between such complications and intravascular hemolytic rate, and it turned to a causative relationship. This present paper try to summarize the actual knowledge on the structural and genetic aspects of sickle cell anemia hemolysis. © 2023 Société nationale française de médecine interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.

Evaluation of a prophylactic transfusion program on obstetric outcomes in pregnant women with sickle cell disease: A single centre retrospective cohort study.

OBJECTIVE: To evaluate the effects of a prophylactic transfusion program (TP) on obstetric and perinatal outcomes in pregnant women with sickle cell disease (SCD). METHODS: This retrospective cohort study included all singleton pregnancies among women with SCD in a French university tertiary care center between 1 January 2004 and 31 December 2017. The TP group included patients selected according to the French guidelines who received regular red blood cell transfusions during pregnancy until delivery. The factors associated with TP indication [year of birth, SCD genotype, history of acute chest syndrome and delayed hemolysis transfusion reaction (DHTR) risk score] were taken into account in a propensity score. A composite obstetric adverse outcome was defined associating birth before 34 gestational weeks and/or pre-eclampsia and/or small for gestational age and/or abruption and/or stillbirth and/or maternal death and/or neonatal death. RESULTS: In total, 246 pregnancies in 173 patients were analyzed. Twenty-two pregnancies with a history of DHTR were excluded. A higher frequency of TP was found before 2013 [119/148 (80.4%) vs 38/76 (50%); p < 0.001]. Rates of preterm birth before 34 gestational weeks (5.6% vs 19.7%; p = 0.001), vaso-occlusive crisis (36.5% vs. 61.8%; p < 0.001), and acute chest syndrome (6.1% vs. 14.5%; p = 0.04) during pregnancy were decreased significantly in the TP group. Among the groups with and without composite obstetric adverse outcomes, the frequency of TP was 52.6% and 74.7%, respectively [odds ratio (OR) 0.30, 95% confidence interval (CI) 0.09-1.02]. The multivariate analysis shows that the TP was associated with a significant reduction in the risk of composite obstetric adverse outcomes (OR 0.28, 95% CI 0.08-0.97; p = 0.04). CONCLUSION: A red blood cell TP may have an independent protective effect on maternal and perinatal adverse outcomes during pregnancy in women with SCD.

[Prevention of genetic diseases : the return of the family practitioner ?] / Prévention des maladies génétiques. Le retour du médecin de famille ?

BACKGROUND: Information to kin is one of the major ethical problems of the new genetics. In France, the revised bioethics law in 2011 created the possibility for patients to authorize professionals, under certain conditions, to directly contact their relatives at risk. Beyond this, other actors, such as GPs, could however play a role in this process. METHODS: Our article is based on an ethnographic-type sociological study by observations and semi-structured interviews with patients (n=59) and genetic professionals (n=16) that took place from 2014 to 2016 in three genetic hospital wards in France and Canada. It focuses particularly on genetic predispositions to breast and ovarian cancers as well as genetic hemochromatosis. RESULTS: Because of its position as a primary care specialist, the general practitioner can play a decisive role in the process of informing relatives about genetic disorders. Upstream of the genetic test, the generalist, thanks to his knowledge of the family context of his patients, can play a referral role towards a specialized consultation. Downstream, it can also ensure a more effective follow-up of the information procedures undertaken by its patients thanks to the medical follow-up that it carries out. CONCLUSION: The data collected during our study highlight the unprecedented place that could be that of the general practitioner in the field of prevention in genetics. At the articulation between primary care and highly specialized care, it is the figure of the "family" doctor who seems to be called here to be renewed by genetics.

Factors predictive of leg-ulcer healing in sickle cell disease: a multicentre, prospective cohort study.

BACKGROUND: Leg ulcers (LUs) are a chronic and severe complication of sickle cell disease (SCD). A prospective study in patients with SCD to identify factors associated with complete healing and recurrence of LUs is lacking. OBJECTIVES: To determine clinical and biological factors associated with SCD-LU complete healing and recurrence. METHODS: This prospective, observational cohort study was conducted at two adult SCD referral-centre sites (2009-2015) and included 98 consecutive patients with at least one LU lasting ≥ 2 weeks. The primary end points compared patients with healed vs. nonhealed LUs at week 24, and patients with vs. without recurrence during follow-up. RESULTS: The median (interquartile range) LU area, duration and follow-up were, respectively, 6·2 cm2 (3-12·8), 9 weeks (4-26) and 65·8 weeks (23·8-122·1). At week 24, LUs were healed in 47% of patients, while 49% of LUs recurred. Univariate analyses identified inclusion LU area < 8 cm2 (82% vs. 35%; P < 0·001), inclusion LU duration < 9 weeks (65% vs. 35%; P = 0·0013) and high median fetal haemoglobin level (P = 0·008) as being significantly associated with complete healing at week 24, and low lactate dehydrogenase level (P = 0·038) as being associated with recurrence. Multivariate analyses retained LU area < 8 cm2 (odds ratio 6·73, 95% confidence interval 2·35-19. 31; P < 0·001) and < 9 weeks' duration (OR 3·19, 95% confidence interval 1·16-8·76; P = 0·024) as being independently associated with healing at week 24. Factors independently associated with recurrence could not be identified. CONCLUSIONS: SCD-LU complete healing is independently associated with the clinical characteristics of LUs rather than the clinical or biological characteristics of SCD.

[Symptomatic extramedullary haematopoiesis in ß-thalassemia: A retrospective single centre study]. / Hématopoïèse extra-médullaire symptomatique au cours des ß-thalassémies: étude rétrospective monocentrique.

INTRODUCTION: Symptomatic extramedullary hematopoiesis (EH) is a rare but potentially severe phenomenon which occurs in ß-thalassemia. There are no treatment guidelines. METHODS: Retrospective single centre study including the cases of symptomatic EH encountered between 1997 and 2014 in a unit specialised in red blood cell genetic disorders. Description of clinical, biological and radiological characteristics of the patients, treatments received, and outcomes. RESULTS: Among 182 ß-thalassemia patients followed during the study period, 7 cases of symptomatic EH were diagnosed. They were 5 men and 2 women, and their mean age was 37 years. Four patients were splenectomised, two patients were regularly transfused, and four patients had already received erythropoietin. EH was localised in intravertebral areas and responsible for dorsal spinal cord compression in 5 patients, in paravertebral dorsal area in 1 patient, and in presacral area in 1 patient. The mean hemoglobin level at diagnosis was 7.9 g/dL. Treatment administered included: red cell transfusion in 6 cases, associated with hydroxyurea in 5 cases and/or radiotherapy in 3 patients. One patient was treated with surgery and HU. After a median follow-up of 41 months, clinical recovery was complete in 2 patients and partial in 5 patients. CONCLUSION: EH must be suspected in ß-thalassemia in patients presenting clinical signs of organ compression, and a typical radiological aspect. The functional prognosis depends on the rapidity of treatment, which includes red blood cell transfusion, hydroxyurea, radiotherapy, and rarely surgery. Long-term outcome is uncertain.

Inhaled nitric oxide for acute chest syndrome in adult sickle cell patients: a randomized controlled study.

PURPOSE: Previous clinical trials suggested that inhaled nitric oxide (iNO) could have beneficial effects in sickle cell disease (SCD) patients with acute chest syndrome (ACS). METHODS: To determine whether iNO reduces treatment failure rate in adult patients with ACS, we conducted a prospective, double-blind, randomized, placebo-controlled clinical trial. iNO (80 ppm, N = 50) gas or inhaled nitrogen placebo (N = 50) was delivered for 3 days. The primary end point was the number of patients with treatment failure at day 3, defined as any one of the following: (1) death from any cause, (2) need for endotracheal intubation, (3) decrease of PaO2/FiO2 ≥ 15 mmHg between days 1 and 3, (4) augmented therapy defined as new transfusion or phlebotomy. RESULTS: The two groups did not differ in age, gender, genotype, or baseline characteristics and biological parameters. iNO was well tolerated, although a transient decrease in nitric oxide concentration was mandated in one patient. There was no significant difference in the primary end point between the iNO and placebo groups [23 (46 %) and 29 (58 %); odds ratio (OR), 0.8; 95 % CI, 0.54-1.16; p = 0.23]. A post hoc analysis of the 45 patients with hypoxemia showed that those in the iNO group were less likely to experience treatment failure at day 3 [7 (33.3 %) vs 18 (72 %); OR = 0.19; 95 % CI, 0.06-0.68; p = 0.009]. CONCLUSIONS: iNO did not reduce the rate of treatment failure in adult SCD patients with mild to moderate ACS. Future trials should target more severely ill ACS patients with hypoxemia. CLINICAL TRIAL REGISTRATION: NCT00748423.

Maternal mortality among women with sickle-cell disease in France, 1996-2009.

OBJECTIVE: To describe maternal mortality among women with sickle-cell disease in France. STUDY DESIGN: Data from the national confidential enquiry into maternal deaths and from reference centres for sickle-cell disease were examined to identify women with this disease who died in France during 1996-2009. The maternal mortality ratio among women with sickle-cell disease was estimated and compared with the ratio in the general population. Characteristics of these women and their pregnancies and circumstances of their deaths were examined in detail. RESULTS: Fifteen maternal deaths occurred among an estimated 3300 live births to women with sickle-cell disease, for a maternal mortality ratio of 454 per 100000 live births (95% CI [254; 750]), versus 9.4/100000 in the general population. Ten women were homozygous (SS) for sickle-cell disease, and five were composite heterozygotes. The episode leading to death appeared in the antepartum period for seven women (47%). Two women died of septic shock during pregnancy, one at 6 weeks, the other at 24 weeks. The other 13 women (87%) died postpartum. Thirteen deaths were directly attributable to sickle-cell disease. The other two maternal deaths, both considered direct obstetric causes, were due to amniotic fluid embolism and septic shock after post-amniocentesis chorioamnionitis. The expert committee on maternal mortality judged seven of these 15 deaths (47%) to be avoidable. CONCLUSION: Sickle-cell disease is responsible for a major excess risk of maternal death in France, due mainly to direct complications of the disease.

The use of rituximab to prevent severe delayed haemolytic transfusion reaction in immunized patients with sickle cell disease.

BACKGROUND: Delayed haemolytic transfusion reaction (DHTR) is mainly caused by an immune response to transfused red blood cells (RBCs). Immunized patients have a high risk of producing antibodies in response to further transfusion. Controlling the immune response to RBCs is therefore a major goal in sickle cell disease (SCD). STUDY DESIGN: We report an observational study of eight alloimmunized SCD patients with history of severe DHTR who were treated with rituximab before a new transfusion to prevent further immunization and DHTR. RESULTS: Five patients showed a good clinical outcome following transfusion preceded by preemptive treatment with rituximab. The remaining patients presented mild DHTR. In all patients, the results of post-transfusion screening tests were identical to those of pretransfusion tests; no newly formed antibodies were detected. CONCLUSION: These cases suggest that rituximab prevents at least occurrence of newly formed antibodies in high responders and minimizes the risk of severe DHTR. This study confirms that DHTR is complex in SCD and does not rely only on the classical antigens/antibodies conflict. Considering potentially serious adverse effect of rituximab, this treatment should be considered cautiously, and only when transfusion is absolutely necessary in patients with history of severe DHTR linked to immunization.

Iron depletion induced by bloodletting and followed by rhEPO administration as a therapeutic strategy in progressive multiple sclerosis: a pilot, open-label study with neurophysiological measurements.

OBJECTIVES: To evaluate the concept that iron depletion (ID) induced by bloodletting and followed by recombinant human erythropoietin (rhEPO) administration could be a therapeutic strategy in progressive multiple sclerosis (PMS) and that it could be assessed by neurophysiological measurements. PATIENTS AND METHODS: In four patients with PMS, bloodletting was performed until ID was induced, and then rhEPO was administered (300 UI/kg/week). The changes induced by the treatment were assessed by clinical scores, biological tests, and neurophysiological study of cortical excitability using transcranial magnetic stimulation techniques. RESULTS: The treatment was well tolerated except for muscle cramps and one popliteal vein thrombosis in a patient confined to chair. ID was obtained within 28 weeks and was associated with endogenous production of EPO. No bloodletting was further required during a six-month period after introduction of rhEPO. At the end of the follow-up (up to one year), fatigue and walking capacities tended to improve in two patients. Neurophysiological changes were characterized by an increased cortical excitability, including a decrease of motor thresholds and an enhancement of intracortical facilitation and cerebellothalamocortical inhibition. CONCLUSIONS: The combined ID-rhEPO therapy could authorize a prolonged administration of rhEPO in PMS patients, able to modify cortical excitability of the glutamatergic and gabaergic circuits. These preliminary data are encouraging to design a larger, controlled therapeutical trial to assess the value of such a strategy to improve functional symptoms in PMS patients, and maybe to prevent axonal degeneration. Neurophysiological measurements based on cortical excitability studies could provide sensitive parameters to evaluate treatment-induced changes in this context.

[Sickle-cell retinopathy: Retrospective study of 730 patients followed in a referral center]. / Rétinopathie drépanocytaire : analyse rétrospective portant sur 730 patients suivis dans un centre de référence.

INTRODUCTION: Sickle-cell disease is the most common genetic disease in the world, frequently complicated by potentially blinding retinal complications. The prevalence of sickle-cell retinopathy in patients followed in a referral center is presented in this study. PATIENTS AND METHODS: The prevalence of proliferative sickle-cell retinopathy by Goldberg classification was determined via a retrospective study of primarily adult SS and SC sickle-cell disease patients and AS sickle trait patients followed in a single referral center for a mean period of 13 years. All patients underwent slit lamp examination and complete fundus examination. RESULTS: Seven hundred and thirty patients (mean age 32.5±10 years), consisting of 492 SS patients (67.4%), 229 SC patients (31.4%) and nine AS patients (1.2%), were included in the study. 54.6% of SC patients and 18.1% of SS patients had grade 3 to 5 proliferative sickle-cell retinopathy. The prevalence of severe forms of sickle-cell retinopathy was higher among SS men than among SS women (21.7% versus 15.5% ; P<0.05). CONCLUSION: The high prevalence of sickle-cell retinopathy and the potentially severe complications associated with this disease justify screening and therapeutic management by a multidisciplinary team in the setting of a referral center.

[Pulmonary complications in adult sickle cell disease]. / Complications pulmonaires des syndromes drépanocytaires majeurs chez l'adulte.

Sickle cell disease is an autosomal genetic condition which represents the most frequent genetic disease in Île-de-France and Caribbean islands. The main clinical manifestations can be divided into infectious disease, hemolytic anemia and vaso-occlusive events. Pulmonary complications represent 20 to 30% of mortality due to sickle cell and can be divided into acute and chronic events. Acute chest syndrome (ACS) is an acute lung injury often preceded by a vaso-occlusive crisis and triggered by different factors including: hypoventilation, pulmonary infectious disease and vascular occlusions. These occlusions can be secondary to fat embolism, thrombosis or sickling. Treatment is mainly supportive combining oxygen supplementation adequate hydration analgesia and sedation. Exchange transfusion may be indicated in severe forms of ACS, characterized by a right ventricular dysfunction and acute respiratory failure. Pulmonary hypertension is the most serious chronic complication. Its frequency is estimated at 6% in adult patients and is more often described in patients with venous ulcers and higher levels of chronic hemolysis. Prognosis is poor with 12.5% of patients dying in the first two years following diagnosis irrespective of the actual pulmonary artery pressure level. There are currently limited data on the effects of any treatment modality. Other respiratory complications such as sleep disorders and nocturnal hypoxemia, infiltrative lung disease and exertional dyspnea are described and should be considered.

Pregnancy in sickle cell disease: maternal and fetal outcomes in a population receiving prophylactic partial exchange transfusions.

OBJECTIVE: To describe pregnancy outcomes for pregnant women with sickle cell disease (SCD) receiving prophylactic transfusions. STUDY DESIGN: This retrospective case-control study compared pregnancy outcomes among women with SCD receiving prophylactic transfusions and women without any hemoglobinopathy, matched for ethnicity, parity, age and hospital. RESULTS: The study included two groups of pregnancies: 128 in women with SCD (95 with SS phenotype and 33 with SC) and 128 in women with AA phenotype. No woman died. Two perinatal deaths (2.1%) and five alloimmunizations (5.3%) occurred, all in the SS group. Compared with the control group, HbSS disease was more often associated with pre-eclampsia (9.4% versus 2.3%, p=.03), preterm delivery (15.8% versus 6.2%, p=.01), birth weight <10th percentile (13.7% versus 3.9%, p=.008) and caesarean delivery (73.6% versus 26.4%, p<.01). CONCLUSION: Despite prophylactic blood transfusions, SCD remains a severe complicating factor in pregnancy. The policy of systematic transfusions should be analyzed in a sufficiently large randomized trial.

[Study of 206 transfused sickle cell disease patients: immunization, transfusion safety and red blood cell supply]. / Etude d'une cohorte de 206 patients drépanocytaires adultes transfusés: immunisation, risque transfusionnel et ressources en concentrés globulaires.

BACKGROUND: Prevention of hemolytic transfusion reactions depends upon our capacity to prevent allo-immunization and conflicts between antigens of transfused red blood cells and antibodies produced by the recipient. In this study, we show that to secure transfusion of sickle cell disease patients, it is necessary to take into account their immunohematologic characteristics in the organization of transfusion. METHODS AND RESULTS: Immunohematological data of 206 chronically transfused patients have been collected as well as phenotypes of transfused units. In order to prevent allo-immunization against C and E antigens for patients typed D+C-E-c+e+ (56%), 26% of the transfused units were D-C-E-c+e+. We found that 47% of the patients had a history of allo-immunization, whereas only 15% produced an antibody the day of inclusion in the study. The non-detectable antibodies were frequently known as dangerous for transfusion. Finally, this study shows the frequency of anti-D in D+ patients and anti-C in C+ patients, pointing out the question of partial antigens. CONCLUSION: To insure optimal transfusion safety for sickle cell disease patients, three points have to be improved: blood donation within the Afro-Caribbean community living in France, access to history of immuno-hematological data, detection of variant antigens, especially within the RH blood system.

Role of Lu/BCAM in abnormal adhesion of sickle red blood cells to vascular endothelium.

Lutheran (Lu) blood group and Basal Cell Adhesion Molecule (BCAM) antigens are both carried by two glycoprotein (gp) isoforms of the immunoglobulin superfamily representing receptors for laminin alpha5 chain. They are expressed in red blood cells, in endothelial cells of vascular capillaries and in epithelial cells of several tissues. Lu/BCAM gps are overexpressed in sickle red blood cells (SS RBCs). Stimulation of SS RBCs by epinephrine activates the PKA depending signaling pathway and induces reinforced Lu/BCAM-mediated adhesion to laminin10/11. We have analyzed the phosphorylation state of Lu/BCAM long isoform cytoplasmic tail and showed that it is phosphorylated by CKII, GSK3b and PKA. Phosphorylation of this isoform in transfected K562 cells is stimulated by effectors of the PKA pathway and induces cell adhesion to laminin10/11. Lu/BCAM gps are highly expressed in endothelial cells and exhibit potential integrin binding motifs. We showed that they interact with integrin alpha4beta1, the unique integrin expressed on the surface of young reticulocytes. Adhesion assays under flow conditions showed that SS RBCs adhere to primary human endothelial cells (HUVEC) after selective activation of intergin alpha4beta1 and that this adhesion is mediated by endothelial Lu/BCAM gps. Our studies show that Lu/BCAM gps expressed either on erythroid or on endothelial cells are involved in SS RBC-endothelium interactions and could play a role in the abnormal adhesion of SS RBCs to vascular endothelium contributing to the vaso-occlusive crises reported for sickle cell disease patients.

Retinal photocoagulation for proliferative sickle cell retinopathy: a prospective clinical trial with new sea fan classification.

PURPOSE: To compare the clinical outcome of stage III proliferative sickle cell retinopathy (PSR) treated by peripheral retinal scatter photocoagulation to natural course disease. METHODS: Long-term follow-up of 101 patients enrolled in a prospective trial of photocoagulation for PSR has been completed. Among 202 eyes of 101 patients enrolled at the University Eye Clinic of Créteil, 73 eyes showed a stage III PSR, which the authors further divided into five new grades (A, B, C, D, E) considering size, hemorrhage, fibrosis, and visible vessels. Grading was based on a three-mirror fundus examination, 360 degrees color photographs, and fluorescein angiography. Mean follow- up was 4 years. RESULTS: Thirty-eight treated eyes and 35 untreated eyes were included in this study. The evolution was not statistically significant between treated and untreated groups concerning flat sea fan <1 MPS disc area (grade A) or elevated sea fan with partial fibrosis (grade C). Progression and regression were compared between the two groups for grade B, resulting statistically significant (p<0.05). Nine complications (13%) were observed, which only occurred in untreated patients with elevated sea fan and hemorrhage (grade B) or complete fibrosed sea fan with well defined vessels (grade E) (p<0.05). CONCLUSIONS: These data suggest that patients with grade A or C new sea fan classification should not be initially treated but observed.

Characteristics and outcome of connective tissue diseases in patients with sickle-cell disease: report of 30 cases.

OBJECTIVES: To analyze the main characteristics of adults with sickle cell disease (SCD) and concurrent connective tissue disease (CTD). METHODS: A retrospective investigational study was performed. CTD was diagnosed according to standard international criteria. Severity of SCD was assessed by a clinical severity score. RESULTS: Thirty patients, 23 women (76%) and 7 men, with hemoglobin S/S (n = 25) or S/C (n = 5) SCD were included. The subtypes of CTD were rheumatoid arthritis (RA) (n = 15), definite systemic lupus erythematosus or "incomplete lupus" requiring treatment (n = 13), primary Sjögren's syndrome with central nervous system involvement (n = 1), and systemic sclerosis (n = 1). Twenty-five of the 30 patients (83%) received steroid treatment, and 15 (50%) received at least 1 immunosuppressive agent (methotrexate in 14 cases) to control CTD. Four RA patients were given antitumor necrosis factor (TNF)alpha and 1 was treated with rituximab without SCD exacerbation. After a median follow-up of 4.5 years [range: 6 months to 30 years] from CTD diagnosis, 11 of the 25 (44%) patients receiving steroids had at least 1 episode of severe infection (mostly due to Staphylococcus aureus or Escherichia coli). SCD exacerbated in 13 of the 30 (43%) patients after CTD onset; 12 of these patients were receiving prednisone and/or methotrexate. Six patients (20%) had died from sepsis (n = 2), stroke (n = 2), or acute chest syndrome (n = 2). CONCLUSIONS: CTD-related clinical manifestations and outcome were not particularly severe in patients with SCD. However, those with active CTD and undergoing steroid +/- methotrexate treatment had more serious SCD-related manifestations, a higher rate of severe infections, and an overall patient mortality rate of 20%. Thus, the management of patients with CTD and underlying SCD should consider the risk/benefit ratio of each treatment and steroid-sparing strategies should be implemented.

Rituximab for prevention of delayed hemolytic transfusion reaction in sickle cell disease.

Delayed hemolytic transfusion reaction (DHTR), a life-threatening transfusion complication in sickle cell disease (SCD), is characterized by a marked hemoglobin drop with destruction of both transfused and autologous red blood cells (RBCs) and exacerbation of SCD symptoms. One mechanism of RBCs destruction is auto-antibody production secondary to transfusion. As rituximab specifically targets circulating B cells, we thought that it could be beneficial in preventing this immune-mediated transfusion complication. We report the case of a SCD patient who previously experienced DHTR with auto-antibodies and who needed a new transfusion. DHTR recurrence was successfully prevented by rituximab administration prior transfusion, supporting the safe use of rituximab to prevent DHTR in SCD patients as a second line approach when other measures failed.