[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.

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.

The natural history of asymptomatic osteonecrosis of the femoral head in adults with sickle cell disease.

BACKGROUND: Osteonecrosis of the femoral head is a frequent complication in adult patients with sickle cell disease. However, little is known about the natural history of asymptomatic lesions. METHODS: One hundred and twenty-one patients (121 hips) with sickle cell disease and asymptomatic osteonecrosis of the femoral head that was contralateral to a hip with symptomatic osteonecrosis were identified with magnetic resonance imaging between 1985 and 1995. The lesions were graded with use of the Steinberg classification system. The patients were followed with annual plain radiographs. The mean duration of follow-up was fourteen years. RESULTS: At the time of the initial evaluation, fifty-six hips were classified as Steinberg stage 0, forty-two hips were classified as Steinberg stage I, and twenty-three hips were classified as Steinberg stage II. At the time of the most recent follow-up, pain had developed in 110 previously asymptomatic hips (91%) and collapse had occurred in ninety-three hips (77%). Symptoms always preceded collapse. Of the fifty-six hips that were classified as Steinberg stage 0 at the time of the initial evaluation, forty-seven (84%) had symptomatic osteonecrosis and thirty-four (61%) had collapse at the time of the most recent follow-up. Of the forty-two asymptomatic stage-I hips, forty (95%) became symptomatic within three years and thirty-six (86%) had collapse of the femoral head. Of the twenty-three asymptomatic stage-II hips, all became symptomatic within two years and all collapsed; the mean interval between the onset of pain and collapse was eleven months. At the time of the final follow-up, ninety-one hips (75%) had intractable pain and required surgery. CONCLUSIONS: Untreated asymptomatic osteonecrosis of the femoral head in patients with sickle cell disease has a high likelihood of progression to pain and collapse. Because of the high prevalence of complications after total hip arthroplasty in patients with this disease, consideration should be given to early surgical intervention with other procedures in an attempt to retard progression of the disease.

[Total hip arthroplasty for the treatment of septic hip arthritis in adults with sickle-cell disease]. / Traitement des arthrites septiques de hanche chez l'adulte drépanocytaire par prothèse totale de hanche.

PURPOSE OF THE STUDY: Septic hip arthritis is a recognized complication of sickle-cell disease. The incidence is difficult to assess but is significant since certain authors estimate that 11% of children with sickle-cell disease develop orthopedic complications. We report our experience with hip joint infection in adults with sickle-cell disease. MATERIAL AND METHODS: We diagnosed ten cases of hip joint infection in seven adults with sickle-cell disease. The characteristic feature of the septic arthritis was the development of a septic focus in a zone of osteonecrosis of the femoral head. Diagnosis was difficult due to the presence of prior hip disease and also the circumstances of development: other infectious foci, septicemia, distant osteomyelitis. The diagnosis was confirmed by joint puncture and isolation of the causal germ. Despite adapted antibiotics and immobilization with traction-suspension, hip joint destruction could not be prevented and all patients became bedridden. Surgery was therefore undertaken to remove the head and neck and institute local antibiotic treatment. A total hip prosthesis was implanted in all patients. RESULTS: At 2 to 12 years follow-up, all seven patients had nearly normal hip function (all 10 hips). Recurrent infection nevertheless developed in 2 hips, demonstrating the limitations of this technique.

The natural history of symptomatic osteonecrosis in adults with sickle-cell disease.

BACKGROUND: Adult patients with sickle-cell disease are at risk for the development of osteonecrosis of the hip. However, there is little information in the literature about the rate of progression of osteonecrosis once symptoms begin. The purpose of this study was to evaluate the natural history of the symptomatic hip in adult patients with osteonecrosis and sickle-cell disease. METHODS: Ninety-two symptomatic hips in sixty-four consecutive adult patients with sickle-cell disease were initially evaluated between 1980 and 1987. Sixty symptomatic hips had radiographic evidence of osteonecrosis at the initial evaluation: forty-three were classified as stage II; two, as stage III; and fifteen, as stage IV, according to the system of Steinberg et al. The other thirty-two hips had lesions (stage I) that were evident only on magnetic resonance imaging. All patients were evaluated after a mean duration of follow-up of seventeen years. RESULTS: Of the seventy-five hips without collapse of the femoral head at the initial evaluation, sixty-five demonstrated collapse within five years after the diagnosis. The average time between the diagnosis and collapse was forty-two months for stage-I hips and thirty months for stage-II hips. At the most recent follow-up examination, ninety hips had had collapse of the femoral head and eighty-eight of the ninety-two hips had had surgery because of intractable pain. CONCLUSIONS: Symptomatic osteonecrosis of the hip in sickle-cell disease has a high likelihood of leading to femoral head collapse, necessitating surgical intervention. When osteonecrosis develops, the deterioration is rapid and, in most patients, operative intervention is necessary because of intractable pain. LEVEL OF EVIDENCE: Prognostic study, Level II-1 (retrospective study). See Instructions to Authors for a complete description of levels of evidence.

Resveratrol, a natural dietary phytoalexin, possesses similar properties to hydroxyurea towards erythroid differentiation.

Resveratrol, a natural dietary polyphenol, has been postulated to be implicated in the cardioprotective effect of red wine and the low incidence of breast and prostate cancers among vegetarians and Orientals respectively. This compound inhibits ribonucleotide reductase as does hydroxyurea, the first therapeutic agent used in the treatment of sickle cell disease. Using the human erythroleukaemic K562 cell line as an in vitro model, we show here that 50 micromol/l of resveratrol induced a higher haemoglobin production (sevenfold) in K562 cells than 500 micromol/l of hydroxyurea (3.5-fold). This erythroid differentiation was linked to a dose- and time-dependent inhibition of cell proliferation associated with an equivalent increased expression of p21 mRNA, but with a higher increased level of p21 protein (sixfold) for cells treated with resveratrol than for those treated with hydroxyurea (1.5-fold). We also show that 50 micromol/l of resveratrol and 25 micromol/l of hydroxyurea induced variable but similar enhancements of fetal haemoglobin synthesis in cultured erythroid progenitors for the majority of the sickle cell patients studied. These inductions were linked to, but not correlated with, a variable decrease in erythroid burst-forming unit clone number. Taken together, these results show that resveratrol merits further investigations in sickle cell disease therapy.

Preliminary report of a toxicity study of hydroxyurea in sickle cell disease. French Study Group on Sickle Cell Disease.

AIM: To evaluate the tolerance of hydroxyurea in children affected with sickle cell disease. DESIGN: Questionnaire study of French physicians likely to treat patients with sickle cell disease. Data were collected on 101 children with sickle cell disease, treated for a median of 22 months, 36 of whom were treated for more than three years. 13 children were younger than 5 years of age at inclusion. RESULTS: Hydroxyurea was stopped for medical reasons in 11 patients: 6 failures, 1 pregnancy, 1 cutaneous rash, 1 leg ulcer, 1 lupus. Acute lymphoblastic leukaemia occurred in a girl treated for 1.5 months with hydroxyurea, this short interval arguing against a causative association. One 17 year old boy had paraparesis after 8 years of treatment. CONCLUSIONS: No major short or medium term toxicity was related to hydroxyurea in this cohort of 101 children. However, the number of children treated for more than 3 years is too few to make firm conclusions on the long term tolerance of this drug.

Pulmonary function in sickle cell disease with or without acute chest syndrome.

Recurrent acute chest syndrome (ACS) has been suggested as a risk factor for chronic lung dysfunction in sickle cell disease. To investigate this hypothesis, lung function tests were performed in 49 sickle cell disease outpatients whose condition was stable, including 23 patients with a history of two to four episodes of ACS (ACS+) and 26 with no history of ACS (ACS-). The two groups were comparable regarding the sex ratio, body mass index, smoking history, physical characteristics, clinical history and usual lung function tests. Respiratory resistance (Rrs), measured using the forced oscillation technique, increased with the number of ACS episodes (r=0.55, p<0.0001) and a significant relationship was observed between Rrs as an independent variable and the expiratory flow rates at 25, 50 and 25-75% of the forced vital capacity as explanatory variables (r= 0.36, p<0.02; r=0.35, p<0.02; and r=0.4, p<0.006, respectively), with higher Rrs being associated with lower expiratory flow rates. The transfer factor (TL,CO) and transfer coefficient (KCO) for CO were significantly higher in the ACS+ group than in the ACS-group (TL,CO=84+/-4 versus 71+/-3%, p<0.004 and KCO=102+/-5 versus 90+/-3%, p<0.05, respectively). The data demonstrate that obstructive lung dysfunction is fairly common in sickle cell disease and suggest that recurrent acute chest syndrome may contribute specific obstructive defects. The increase in respiratory resistance associated with acute chest syndrome was accompanied by an increase in diffusion capacity, suggesting that it may have been related to an increase in lung blood volume.

Oral magnesium supplements reduce erythrocyte dehydration in patients with sickle cell disease.

Intracellular polymerization and sickling depend markedly on the cellular concentration of sickle hemoglobin (Hb S). A possible therapeutic strategy for sickle cell disease is based on reducing the cellular concentration of Hb S through prevention of erythrocyte dehydration. The K-Cl cotransporter is a major determinant of sickle cell dehydration and is inhibited by increasing erythrocyte Mg content. We studied 10 patients with sickle cell disease before treatment and after 2 and 4 wk of treatment with oral Mg supplements (0.6 meq/kg/d Mg pidolate). Hematological parameters, erythrocyte Na, K, and Mg content, erythrocyte density, membrane transport of Na and K, and osmotic gradient ektacytometry were measured. We found significant increases in sickle erythrocyte Mg and K content and reduction in the number of dense sickle erythrocytes. Erythrocyte K-Cl cotransport was reduced significantly. We also observed a significant reduction in the absolute reticulocyte count and in the number of immature reticulocytes. Ektacytometric analysis showed changes indicative of improved hydration of the erythrocytes. There were no laboratory or clinical signs of hypermagnesemia. Mild, transient diarrhea was the only reported side effect. We conclude that oral Mg supplementation reduces the number of dense erythrocytes and improves the erythrocyte membrane transport abnormalities of patients with sickle cell disease.

[Ambulatory treatment and prevention of priapism using alpha-agonists. Apropos of 172 cases]. / Traitement ambulatoire et prévention du priapisme par médications alpha-agonistes. A propos de 172 cas.

From 1985 to 1995, 172 patients (149 on self intracavernous injection of vasoactive drugs, 16 with Sickle cell disease, 6 surgical patients under heparin therapy, and 1 after oral administration of trazodone), having experienced one or several episodes of priapism, lasting from 3 h to 8 days have been treated or submitted to self medication with alpha-agonist agents (eprephrine, phenylephrine or etilefrine) with an eventual drainage of the corporae. All episodes have disappeared and sexual function was preserved. A conservative treatment of priapism has been designed using corporal drainage and intracavernous etilefrine for acute priapism; as well as preventive treatment for those of the patients exposed to Sickle cell disease to avoid surgery and its frequent fribrotic sequelae, leading to impotence in 50% of the cases.

Bronchoalveolar lavage in adult sickle cell patients with acute chest syndrome: value for diagnostic assessment of fat embolism.

Fat embolism of necrotic bone marrow could be a frequent cause of acute chest syndrome (ACS) in sickle cell syndromes (SC), as suggested by postmortem findings. To check this hypothesis in living patients, we evaluated the presence of fatty macrophages recovered by bronchoalveolar lavage (BAL) in ACS. We investigated 20 consecutive cases of ACS by BAL, and identification of alveolar cells containing fat droplets was performed using oil red O (ORO), a specific neutral fat stain. The specificity of the method was determined on control groups, including eight SC patients without acute chest syndrome and 15 non-SC patients. A cut-off of > 5% of alveolar macrophages containing fat droplets was determined from the control groups to assess the diagnosis of fat embolism. In 12 ACS episodes, BAL exhibited > 5% of fatty macrophages, ranging from 10% to 100% (median value 46.5%). In 11 cases, fat embolism was associated with proven (n = 8) or probable (n = 3) bone marrow infraction, which mostly predated ACS. Eight ACS episodes were associated with a low percentage (< or = 5%) of fatty alveolar macrophages and could be related to a cause other than fat embolism in six episodes, such as sepsis, in-situ thrombosis, or rib infarcts generating hypoventilation. This study supports the diagnostic yield of BAL for fat embolism, which can be incriminated in 60% of cases of ACS in this adult population.

Vascular lesions of the liver in sickle cell disease. A clinicopathological study in 26 living patients.

BACKGROUND: Hepatic lesions in sickle cell disease have been studied essentially in autopsy series. Previous reports on living patients are rare and concern a limited number of cases. The aim of the present study is to report the clinical, biochemical, and hepatic histological findings in 26 living patients with sickle cell disease and hepatobiliary disease. PATIENTS AND METHODS: Twenty-six of 510 patients with sickle cell disease, in whom liver tissue was available for histological analysis, were selected. In 21 patients, biopsy was obtained during laparotomy for cholecystectomy; 5 patients underwent needle biopsy for hepatomegaly and/or liver test abnormalities. RESULTS: Twenty of the 21 cholecystectomized patients, as well as the 5 other patients, had liver vascular lesions consisting of sinusoidal dilatation (23 cases), perisinusoidal fibrosis (19 cases), and acute ischemic necrosis (5 cases). It is of interest that the 21 cholecystectomized patients had clinical signs of complicated cholelithiasis, and that 20 of them had gallbladder stones, with common bile duct lithiasis in only 1 case. In the 25 patients without common bile duct obstruction, symptoms might have been due to vascular lesions, but it must also be noted that in the cholecystectomized patients they did not persist or recur following surgery. In one cirrhotic patient, marked sinusoidal lesions might have favored severe hepatocellular failure that led to liver transplantation. In another patient, fatal hepatocellular insufficiency was possibly due to ischemia. The nonvascular lesions that were observed, ie, chronic persistent or mildly active hepatitis (11 cases) and cirrhosis (2 cases), were always associated with vascular lesions. CONCLUSION: These results suggest that in sickle cell disease: (1) hepatic lesions are mainly vascular; (2) these lesions can be responsible for acute and/or chronic ischemia that may be severe; (3) symptoms suggestive of acute cholecystitis and/or biliary tract obstruction might be, at least in part, explained by vascular lesions; and (4) biliary tract surgery indications should be considered more carefully.

[Extensive bone marrow necrosis and major sickle cell syndromes]. / Nécrose médullaire étendue et syndromes drépanocytaires majeurs.

Three cases of extensive bone marrow necrosis in patients with sickle cell disease are reported. All three patients presented severe bone pains with severe anaemia (haemoglobin value less than 5 g/dl) and high increased of LDH serum values (upper than 20 fold normal value). Bone marrow aspirate and biopsy showed typical signs of necrosis. The extent of necrosis was evaluated by reticuloendothelial scan obtained with 111In chloride. Treatment required transfusions of phenotyped red blood cell concentrates. Favourable outcome was observed in all patients.

Avascular necrosis of the femoral head in sickle-cell disease. Treatment of collapse by the injection of acrylic cement.

In ten patients with sickle-cell disease, we used a new technique of cement injection for the treatment of 16 painful hips with a radiographic crescent line or flattening of the articular surface due to avascular necrosis. The necrotic bone and overlying cartilage are elevated by the injection to restore the sphericity of the femoral head. Five days after the operation, full weight-bearing was allowed with the help of crutches for three weeks. The time in hospital averaged eight days; the average blood loss was 100 ml. There was early pain relief and postoperative radiographs showed improvement in the shape of the femoral head. At a mean follow-up of 5 years (3 to 7), 14 of the 16 hips were still improved although some gave slight pain. Only two hips had required revision to total hip arthroplasty, at one year and two years respectively. The increasing longevity of patients with sickle-cell disease means that avascular necrosis will be an increasing problem. Total hip replacement has a poor prognosis because of the risks of infection, high blood loss, and early loosening. Cement injection does not have these problems and allows for earlier, more conservative surgery.

Improvement of microcirculation abnormalities in sickle cell patients upon buflomedil treatment.

The efficacy of the vasoactive compound buflomedil on previously described microcirculation abnormalities observed in sickle cell disease (SCD) was investigated using bulbar conjunctival angioscopy (BCA) and laser doppler flux metering. Eleven sickle cell disease patients at steady state were studied in a double-blind randomized parallel-versus-placebo study (5 patients were given placebo and 6 patients received 600 mg buflomedil per day for 21 days after a washout period of 15 days). The blood flux score measured by BCA improved, indicating reduced entrapment of sickle red blood cells. There was a striking improvement of reactive alterations of vasomotion in the buflomedil group, particularly in postocclusive reactive hyperemia; the half return time was also significantly reduced. These results encourage further studies with buflomedil to investigate long-term effects of this compound in SCD, potential prevention of acute vaso-occlusive events, and degenerative complications.

[Hip dysplasia, a complication of sickle cell anemia]. / La "dysplasie" de hanche, une complication de la drépanocytose.

Eighty-four hips of sickle cell anemia patients were followed up during adulthood after the occurrence during childhood of avascular necrosis of the femoral head. Roentgenograms showed residual dysplasia at completion of growth in a substantial number of cases: coxa magna was found in 11 hips, coxa plana or loss of capital sphericity in 53 hips, and true osteochondritis in 3 hips. Only 20 hips exhibited normal morphological features at completion of growth. Anomalies were found not only in the proximal femur but also in the acetabulum which was altered in 14 hips (inadequate lateral coverage in 8 hips and protrusion in 6). Roentgenological changes suggested that the acetabular alterations were due to triradiate cartilage lesions directly produced by the blood disorder rather than to the effects of the femoral alterations. The anomalies seen also suggested that the adverse effects of sickle cell anemia on growth involve not only epiphyseal ossification centers but also growth plates.

Comparative evaluation of laser Doppler flux metering, bulbar conjunctival angioscopy, and nail fold capillaroscopy in sickle cell disease.

Eleven adult patients with stable sickle cell disease (SCD) were investigated twice at a 15-day interval by nail fold capillaroscopy (NFC), bulbar conjunctival angioscopy (BCA), and laser Doppler flux metering (LDF). NFC and BCA are essentially descriptive. NFC revealed, in some patients, network patterns similar to those observed in vasculitis. BCA provides a reproducible method for the visual assessment of the microcirculation. When using a rating scale with five criteria it identified abnormalities related to both altered red blood cells and vascular morphology but failed to discriminate between patients. LDF, in contrast, is quantifiable and showed reproducible characteristic reactive alterations of vasomotion in response to ischemia after 3 min of occlusion. The SCD patients had a delayed response, best measured by the recovery half time, which was four to five times longer than that of normal subjects. In addition, the cold provocative test was always abnormal, as evidenced by a significant drop in the contralateral flux, and was often poorly tolerated. The observed trends suggest that BCA and LDF should be performed in a large cohort of patients, both in the steady state and during vasoocclusive crises. These methods seem to be useful complementary noninvasive procedures to cellular and clinical evaluation monitoring for therapeutic trials.

Frozen blood and transfusion-transmitted hepatitis C virus.

The purpose of the present study was to evaluate the impact of frozen red cell transfusion on the transmission of hepatitis C virus (HCV) before the introduction of blood donor screening. Anti-HCV antibodies were detected in 59 patients with sickle-cell disease who required chronic transfusions and had exclusively received frozen red blood cells (RBC). The files were reviewed for clinical signs of chronic hepatitis C. Anti-HCV antibodies were detected in 2 adult patients; both also had clinical evidence of HCV infection. No other patient showed signs of acute or chronic HCV hepatitis. In a control group of 28 patients who had received nonfrozen RBC transfusions, the prevalence of anti-HCV antibodies was 25%. So, our study seems to indicate that the use of frozen RBC had reduced the risk of HCV contamination.