Immune regulation in chronically transfused allo-antibody responder and nonresponder patients with sickle cell disease and β-thalassemia major

Abstract The aims of this review are to highlight the mechanisms and consequences of iron distribution that are most relevant to transfused sickle cell disease (SCD) patients and to address the particular challenges in the monitoring and treatment of iron overload. In contrast to many inherited anemias, in SCD, iron overload does not occur without blood transfusion. The rate of iron loading in SCD depends on the blood transfusion regime: with simple hypertransfusion regimes, rates approximate to thalassemia major, but iron loading can be minimal with automated erythrocyte apheresis. The consequences of transfusional iron overload largely reflect the distribution of storage iron. In SCD, a lower proportion of transfused iron distributes extrahepatically and occurs later than in thalassemia major, so complications of iron overload to the heart and endocrine system are less common. We discuss the mechanisms by which these differences may be mediated. Treatment with iron chelation and monitoring of transfusional iron overload in SCD aim principally at controlling liver iron, thereby reducing the risk of cirrhosis and hepatocellular carcinoma. Monitoring of liver iron concentration pretreatment and in response to chelation can be estimated using serum ferritin, but noninvasive measurement of liver iron concentration using validated and widely available MRI techniques reduces the risk of under- or overtreatment. The optimal use of chelation regimes to achieve these goals is described.

Download Full-text

Hydroxyurea can eliminate transfusion requirements in children with severe β-thalassemia

Blood ◽

10.1182/blood-2003-01-0117 ◽

2003 ◽

Vol 102 (4) ◽

pp. 1529-1530 ◽

Cited By ~ 80

Author(s):

Mohamed Bradai ◽

Mohand Tayeb Abad ◽

Serge Pissard ◽

Fatima Lamraoui ◽

Laurent Skopinski ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Chelating Agents ◽

Fetal Hemoglobin ◽

Thalassemia Major ◽

Thalassemia Intermedia ◽

Cell Disease ◽

Marked Elevation ◽

Transfusion Requirements

Abstract Hydroxyurea (HU) enhances fetal hemoglobin (Hb) production. An increase in total Hb level has been repeatedly reported during HU treatment in patients with sickle cell disease and in several patients with β-thalassemia intermedia. Effects in patients with β-thalassemia major are controversial. We now report a marked elevation of total Hb levels with HU that permitted regular transfusions to be stopped in 7 children with transfusion-dependent β-thalassemia. The median follow-up was 19 ± 3 months (range, 13-21 months). We conclude that HU can eliminate transfusional needs in children with β-thalassemia major, which could be particularly useful in countries such as Algeria, where supplies of blood or chelating agents are limited.

Download Full-text

Hidden Brain iron content in Sickle cell disease: Impact on Neurocognitive Functions

10.21203/rs.3.rs-399346/v1 ◽

2021 ◽

Author(s):

Mohsen Saleh ElAlfy ◽

Ahmed Samir Ibrahim ◽

Ghada Samir Ibrahim ◽

Hanaa Midhat Abdel Gader Hussein ◽

Hend Galal Eldeen Mohammed ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Brain Mri ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Brain Iron ◽

Cell Disease ◽

Neurocognitive Dysfunction ◽

Neurocognitive Functions

Abstract Children with sickle cell disease (SCD) are at a high risk for neurocognitive impairment. We aim to quantitatively measure cerebral tissue R2* to investigate the brain iron deposition in children and young adults with SCD in comparison to beta thalassemia major (BTM) and healthy controls and evaluate its impact on neurocognitive functions in patients with SCD. Thirty-two SCD, fifteen BTM and eleven controls were recruited. Multi-echo fast-gradient echo sequence brain MRI was performed and brain R2* values of both caudate and thalamic regions were calculated. SCD patients were examined for the neurocognitive functions. SCD had high iron overload 0.30±0.12 mg/kg/day. 68.9% of SCD had under- threshold IQ, 12.5% had moderate to severe anxiety and 60.8% had depression. There was no differences between SCD, BTM and controls in brain MRI except that left thalamus R2* higher in BTM than both SCD and controls (p=0.032). Mean right caudate R2* was higher in female than male (p=0.044). No significant association between brain R2* and LIC or heart R2* values in SCD. Left caudate R2* directly correlate with age and HbS%, negative correlate with HbA% while right thalamus R2* negatively correlate with transfusion index and among SCD patients. Conclusion: Neurocognitive dysfunction in SCD could not be explained solely by brain iron overload.

Download Full-text

Complications of Central Venous Access Devices in Patients With Sickle Cell Disease and Thalassemia Major

Journal of Pediatric Hematology/Oncology ◽

10.1097/mph.0000000000001972 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Author(s):

Javier Ordóñez ◽

Agustín del Cañizo ◽

Cristina Beléndez ◽

Marina García-Morín ◽

Laura Pérez-Egido ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Central Venous Access ◽

Thalassemia Major ◽

Venous Access ◽

Cell Disease ◽

Central Venous ◽

Venous Access Devices

Download Full-text

Differential Iron Loading of R2* Pancreas in Children with Thalassemia Major and Sickle Cell Disease.

Blood ◽

10.1182/blood.v110.11.3817.3817 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3817-3817

Author(s):

Jhansi L. Papudesi ◽

Shahriar Mokrian ◽

Thomas D. Coates ◽

John C. Wood

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Pulse Sequence ◽

Thalassemia Major ◽

The Body ◽

P Value ◽

Cell Disease ◽

Liver Iron ◽

Patient Demographics ◽

Control Subjects

Abstract MRI is a noninvasive method for detection of transfusional siderosis in the liver and heart of children with thalassemia major (TM) and sickle cell disease (SCD). Previous studies from our laboratory demonstrated that cardiac siderosis and cardiac failure are relatively uncommon in chronically transfused SCD, despite heavy somatic iron burdens. Others have reported correspondingly low rates of endocrinopathies. We used the MRI relaxation rate R2* as a surrogate for pancreatic iron to test the hypothesis that TM patients develop greater pancreatic iron load than SCD patients having comparable liver iron burdens. Methods We studied 70 TM and 31 chronically-transfused SCD patients. Pancreatic R2* was assessed in several mid pancreatic slices using a multi-echo, gradient echo pulse sequence with 8 echo times spaced from 2 to 16 ms. Pixelwise, monoexponential R2* reconstruction was performed with offset correction. Mean R2* was calculated from a region of interest (ROI) drawn around the body and tail of the pancreas. Control values for pancreatic R2* were derived from 14 normal volunteers, ages 19–31. Results Patient demographics are summarized in Table 1. TM patients were an average of 5 years older but less heavily iron loaded (liver iron 5 mg/g lower and ferritin 1800 ng/mL lower). Despite this, transferrin saturations trended higher in the TM patients (76% versus 58%). SCD patients had higher high sensitivity CRP and white blood cell count, consistent with greater inflammation. Figure 1 demonstrates pancreatic R2* distribution in TM, SCD, and control subjects; dotted line indicates the 95th confidence interval for the control subjects. Pancreatic R2* was elevated in 74% of the TM patients (R2* 148.9±200.9), compared with 48% of the SCD patients (R2* 39.6±37, p<0.021). In the TM patients, pancreatic R2* was correlated to cardiac R2*, but not to liver R2*. Discussion Pancreatic R2* is more common and more severe in TM compared to SCD, consistent with previously reported endocrinopathy rates. The younger age (decreased transfusion exposure) of the SCD patients and their lower transferrin saturations (secondary to inflammation) probably contribute to this observation. Prospective trials are necessary to determine the functional correlations and predictive value of pancreatic R2* measurements in these populations. Patient Demographics Parameter Thalassemia (n=70) Sickle Cell Disease (n=31) P Value Age 19.4 ± 10 14.5 ± 5.6 0.013 Gender 40M, 30F 17M, 14F NS Height(cm) 145 ± 29 147 ± 20 NS Weight(kg) 45.4±17 43.8 ± 19 NS Reticulocyte 2.0±1.9 (n=34) 9.6 ± 7.8 <0.001 Iron(mcg/dL) 193±99 (n=64) 146 ± 89 0.003 Ferritin(ng/mL) 4064±5661 5905 ± 6320 0.15 Transferrin (mg/dL) 174±70 169 ± 87 NS HIC(mg/g) 10.9 ± 12.2 (n=68) 16.1 ± 11.9 (n=30) 0.06 Iron % Sat(%) 76 ± 39 (n=38) 58 ± 29 (n=14) 0.11 TIBC(mcg/dL) 255 ± 119 219 ± 104 (n=13) 0.06 AST(U/L) 62.7 ± 63 (n=34) 72 ± 71 NS ALT(U/L) 77.6 ± 94.4 (n=34) 72 ± 99 NS hs-CRP(mg/L) 1.6 ± 1.9 (n=46) 6.2 ± 7 <0.001 WBC 10 ± 7 12.5 ± 7 0.04 Figure Figure

Download Full-text

Phlebotomy and Bolus Subcutaneous Deferoxamine in Algerian Patients with Thalassemia Major or Intermedia or Sickle Cell Disease Treated with Hydroxyurea.

Blood ◽

10.1182/blood.v110.11.3812.3812 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3812-3812

Author(s):

Mohamed Bradai ◽

Dora Bachir ◽

Mariane De Montalembert

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Combined Therapy ◽

Iron Chelation ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Cell Disease ◽

Infusion Pumps ◽

Hydroxyurea Treatment ◽

Oral Chelators

Abstract Background: Iron chelation with continuous subcutaneous deferoxamine injections is painful and expensive, in particular due to the cost of infusion pumps. Oral chelators are not widely available in Algeria. This prospective study was designed to evaluate the safety and efficacy of bolus subcutaneous deferoxamine (DFO) and phlebotomy in patients with beta-thalassemia major (TM) or intermedia (TI), or sickle cell disease (SCD), treated with hydroxyurea. Methods: 31 patients were enrolled (22 TM, 5 TI, 4 SCD). Mean hydroxyurea dosage was 17 mg/kg/d [15–24]. Phlebotomy was performed when hemoglobin was >8 g/dL and ferritin >1000 ng/ml; 13 patients met these criteria (5 TM, 4 TI, 4 SCD). One TI patient was not compliant; the 12 remaining patients underwent phlebotomy removing 3 to 7 ml/kg, every 2 to 4 weeks as tolerated. Three mild hypotension episodes were noted. Bolus subcutaneous deferoxamine was given to the 25 patients with adequate health insurance. Mean deferoxamine dosage was 30±6 mg/kg/d, in two daily boluses. Skin nodules developed in 6 patients and a subcutaneous abscess in 1 patient. Blood transfusions were given when hemoglobin was <6g/dL. Results: table 1 phlebotomy only DFO only Phlebotomy+DFO N patients 3 TM, 3 TI 17 TM, 2 TI 2 TM, 4 SCD Median age (yrs) 16.5 [7–50] 15 [6–21] 20.5 [15–24] Median F.U. (mos) 27 [12–38] 20 [12–28] 18 [13–23] Median N erythrocyte concentrates transfused during F.U. 0 [0–1] 6 [0–19] 0 Median baseline ferritin (ng/ml) 2800 4130 3760 Median last ferritin (ng/ml) 884 1510 1665 Conclusions: Combination of phlebotomy and bolus subcutaneous deferoxamine very effectively reduced iron overload in patients with TM, TI and SCD. Phlebotomies could be performed in 12 patients thanks to hydroxyurea treatment which had increased their Hb level above 8 g/dL. Such combined therapy can be proposed in countries which can not afford infusion pumps or oral chelators.

Download Full-text

Cardiac Iron Overload In Sickle-Cell Disease

Blood ◽

10.1182/blood.v122.21.1013.1013 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1013-1013

Author(s):

Antonella Meloni ◽

Mammen Puliyel ◽

Alessia Pepe ◽

Massimo Lombardi ◽

Vasilios Berdoukas ◽

...

Keyword(s):

Myocardial Infarction ◽

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Clinical Characteristics ◽

Transferrin Saturation ◽

Thalassemia Major ◽

Cell Disease ◽

Cardiac Iron ◽

Cardiac Iron Overload

Abstract Introduction Chronically transfused sickle cell disease (SCD) patients have lower risk of endocrine and cardiac iron overload load than comparably transfused thalassemia major patients. The mechanisms for this protection remain controversial but likely reflects lower transferrin saturation and circulating labile iron pools because of chronic inflammation and regeneration of apotransferrin through erythropoiesis. However, cardioprotection is incomplete; we have identified 6 patients out of the 201 patients (3%) followed at our Institution who have prospectively developed cardiac iron. We present the clinical characteristics of these patients to identify potential risk factors for cardiac iron accumulation. Methods Cardiac, hepatic, and pancreatic iron overload were assessed by R2* Magnetic Resonance Imaging (MRI) techniques as extensively described by our laboratory. The medical records of the selected patients were reviewed for demographic data, for transfusion and chelation history and for hematologic and biochemical parameters. Results Table 1 describes clinical characteristics of the six patients at the time they developed detectable cardiac iron (R2* ≥ 50 ms). Patient 6 was included because he showed a R2* of 49 Hz that was increasing rapidly. Five of the six patients were managed on simple transfusions. Five patients had been on chronic transfusion for more than 11 years. The three patients who developed cardiac iron the earliest (3.7 – 14 years of transfusions) had more efficient suppression of endogenous red cell production (HbS levels 2-5%) compared with patients who required longer transfusional exposure (HbS levels 13.3 – 41%). All patients had qualitatively poor chelation compliance (<50%), based upon their prescription refill rate. All patients had serum ferritin levels exceeding 4600 and liver iron concentration (LIC) greater than 22 mg/g. Pancreatic R2* was greater than 100 Hz in every patient studied (5/6). Figure 1 shows the longitudinal relationship between iron overload in the heart and in the other organs for each patient; initial iron levels are shown in black. Cardiac R2* appears increase dramatically once a critical LIC “threshold” is reached, qualitatively similar to the 18 mg/g threshold observed in thalassemia major patients. Cardiac R2* rose proportionally to pancreas R2*, similar to thalassemia major patients, with all of the patients having pancreas R2* > 100 Hz at the time cardiac iron was detected. Conclusions Cardiac iron overload occurs in a small percentage of chronically transfused SCD patients and is only associated with exceptionally poor control of total body iron stores. Duration of chronic transfusion is clearly important but other factors, such as levels of effective erythropoiesis, may also contribute to cardiac risk. The relationship between cardiac iron and pancreas R2* suggests that pancreas R2* can serve as a valuable screening tool for cardiac iron in SCD patients. Disclosures: Berdoukas: ApoPharma inc: Consultancy. Coates:ApoPharma inc, Novartis, Shire: Consultancy. Wood:Novartis: Consultancy, Honoraria; Shire: Consultancy, Research Funding; ApoPharma: Consultancy, Honoraria, Use of deferiprone in myocardial infarction, Use of deferiprone in myocardial infarction Patents & Royalties.

Download Full-text