Shahina Daar

Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study

Despite recent advances in understanding the pathophysiologic mechanisms behind the thalassemia intermedia (TI) phenotype, data on the effects of treatment are deficient. To provide such data, we evaluated 584 TI patients for the associations between patient and disease characteristics, treatment received, and the rate of complications. The most common disease-related complications were osteoporosis, extramedullary hematopoeisis (EMH), hypogonadism, and cholelithiasis, followed by thrombosis, pulmonary hypertension (PHT), abnormal liver function, and leg ulcers. Hypothyroidism, heart failure, and diabetes mellitus were less frequently observed. On multivariate analysis, older age and splenectomy were independently associated with an increased risk of most disease-related complications. Transfusion therapy was protective for thrombosis, EMH, PHT, heart failure, cholelithiasis, and leg ulcers. However, transfusion therapy was associated with an increased risk of endocrinopathy. Iron chelation therapy was in turn protective for endocrinopathy and PHT. Hydroxyurea treatment was associated with an increased risk of hypogonadism yet was protective for EMH, PHT, leg ulcers, hypothyroidism, and osteoporosis. Attention should be paid to the impact of age on complications in TI, and the beneficial role of splenectomy deserves revisiting. This study provides evidence that calls for prospective evaluation of the roles of transfusion, iron chelation, and hydroxyurea therapy in TI patients.

Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with β-thalassaemia: the ESCALATOR study

Objective:  Many patients with transfusional iron overload are at risk for progressive organ dysfunction and early death and poor compliance with older chelation therapies is believed to be a major contributing factor. Phase II/III studies have shown that oral deferasirox 20–30 mg/kg/d reduces iron burden, depending on transfusional iron intake.

Splenectomy and thrombosis: the case of thalassemia intermedia

See also Mannucci PM. Red cells playing as activated platelets in thalassemia intermedia. This issue, pp 2149–51.

Splenectomy and thrombosis: The case of thalassemia intermedia

See also Mannucci PM. Red cells playing as activated platelets in thalassemia intermedia. This issue, pp 2149–51.

Reduction in labile plasma iron during treatment with deferasirox, a once-daily oral iron chelator, in heavily iron-overloaded patients with β-thalassaemia

This subgroup analysis evaluated the effect of once‐daily oral deferasirox on labile plasma iron (LPI) levels in patients from the prospective, 1‐yr, multicentre ESCALATOR study. Mean baseline liver iron concentration and median serum ferritin levels were 28.6 ± 10.3 mg Fe/g dry weight and 6334 ng/mL respectively, indicating high iron burden despite prior chelation therapy. Baseline LPI levels (0.98 ± 0.82 μmol/L) decreased significantly to 0.12 ± 0.16 μmol/L, 2 h after first deferasirox dose (P = 0.0006). Reductions from pre‐ to post‐deferasirox administration were also observed at all other time points. Compared to baseline, there was a significant reduction in preadministration LPI that reached the normal range at week 4 and throughout the remainder of the study (P ≤ 0.02). Pharmacokinetic analysis demonstrated an inverse relationship between preadministration LPI levels and trough deferasirox plasma concentrations. Once‐daily dosing with deferasirox ≥20 mg/kg/d provided sustained reduction in LPI levels in these heavily iron‐overloaded patients, suggesting 24‐h protection from LPI. Deferasirox may therefore reduce unregulated tissue iron loading and prevent further end‐organ damage.

Cytokines in Sickle Cell Disease

Abstract Sickle red cells express adhesion molecules including integrin 4β1, CD36, band 3 protein, sulfated glycolipid, Lutheran protein, phosphatidylserine and integrin-associated protein. The proadhesive sickle cells may bind to endothelial cell P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD36 and integrins leading to its activation. Monocytes also activate endothelium by releasing proinflammatory cytokines like tumor necrosis factor alpha (TNF-) and interleukin 1β (IL-1β). Sickle monocytes also express increased surface CD11b and cytoplasmic cytokines TNF and IL-1β indicating activated state. Polymorphonuclear leukocytes (PMNs) are also activated with reduced L-selectin expression, enhanced CD64 expression and elevated levels of sL-selectin, sCD16 and elastase resulting in increased adhesiveness to the endothelium. Platelets are also activated and secrete thrombospondin (TSP) and cytokine IL-1. They also form platelet- monocytes aggregates causing endothelial cell P-selectin expression. Endothelial cell activation by these multiple mechanisms leads to a loss of vascular integrity, expression of leukocyte adhesion molecules, change in the surface phenotype from antithrombotic to prothrombotic, excessive cytokine production and upregulation of HLA molecules. Furthermore, contraction of these activated endothelial cells leads to exposure of extracellular matrix proteins, such as TSP, laminin, and fibronectin and their participation in adhesive interactions with bridging molecules from the plasma such as von Willebrand factor (vWf) released from endothelial cells, ultimately culminating in vasoocclusion and local tissue ischemia, the pathognomonic basis of vasoocclusive crisis.

Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration.

Magnetic resonance imaging (MRI)‐based techniques for assessing liver iron concentration (LIC) have been limited by single scanner calibration against biopsy. Here, the calibration of spin‐density projection‐assisted (SDPA) R2‐MRI (FerriScan®) in iron‐overloaded β‐thalassemia patients treated with the iron chelator, deferasirox, for 12 months is validated.

International survey of T2* cardiovascular magnetic resonance in β-thalassemia major

Accumulation of myocardial iron is the cause of heart failure and early death in most transfused thalassemia major patients. T2* cardiovascular magnetic resonance provides calibrated, reproducible measurements of myocardial iron. However, there are few data regarding myocardial iron loading and its relation to outcome across the world. A survey is reported of 3,095 patients in 27 worldwide centers using T2* cardiovascular magnetic resonance. Data on baseline T2* and numbers of patients with symptoms of heart failure at first scan (defined as symptoms and signs of heart failure with objective evidence of left ventricular dysfunction) were requested together with more detailed information about patients who subsequently developed heart failure or died. At first scan, 20.6% had severe myocardial iron (T2*≤10ms), 22.8% had moderate myocardial iron (T2* 10–20ms) and 56.6% of patients had no iron loading (T2*>20ms). There was significant geographical variation in myocardial iron loading (24.8–52.6%; P<0.001). At first scan, 85 (2.9%) of 2,915 patients were reported to have heart failure (81.2% had T2* <10ms; 98.8% had T2* <20ms). During follow up, 108 (3.8%) of 2,830 patients developed new heart failure. Of these, T2* at first scan had been less than 10ms in 96.3% and less than 20ms in 100%. There were 35 (1.1%) cardiac deaths. Of these patients, myocardial T2* at first scan had been less than 10ms in 85.7% and less than 20ms in 97.1%. Therefore, in this worldwide cohort of thalassemia major patients, over 43% had moderate/severe myocardial iron loading with significant geographical differences, and myocardial T2* values less than 10ms were strongly associated with heart failure and death.

Risk factors for pulmonary hypertension in patients with β thalassemia intermedia

BACKGROUND Pulmonary hypertension (PHT) is a common yet poorly understood complication of β thalassemia intermedia (TI). METHODS We herein evaluated risk factors for PHT in TI, through comparing 64 TI patients with evidence of PHT by symptomatology and echocardiography (Group I) to age- and sex-matched TI patients without PHT (Group II). Retrieved data included demographics, laboratory parameters, clinical characteristics, and received treatments that may influence PHT development; and reflected the period prior to PHT occurrence in Group I. RESULTS The mean age of Group I patients at development of PHT was 37.3±10.6years; with 44% being males. Among studied parameters, Group I patients were more likely to be splenectomized (4.9-times), transfusion-naive (3.5-times); hydroxyurea-naive (2.6-times), or iron chelation-naive (2.3-times); and have nucleated red blood cell count ≥300×10(6)/l (2.59-times) or a previous history of thromboembolic events (3.69-times). CONCLUSION TI patients who eventually develop PHT may be identified early on by being splenectomized, having high nucleated red blood cell counts and a previous history of thromboembolism. Prospective clinical trials that evaluate the efficacy, safety, and cost effectiveness of transfusion, iron chelation, and hydroxyurea therapy in preventing PHT in TI are invited.

Molecular Characterization of G6PD Deficiency in Oman

Screening of unselected university students in the Sultanate of Oman revealed an overall frequency of glucose-6-phosphate dehydrogenase (G6PD) deficiency of 26% in males. Samples from 23 G6PD-deficient individuals (a random sub-sample of the student population), were characterised biochemically and at the molecular level. Of 20 deficient men, 15 had G6PD Mediterranean, 2 had G6PD Chatham, 1 had G6PD A- and in 2 the mutation is not yet known. Of the 3 G6PD-deficient woman, 2 were homozygous for the G6PD Mediterranean mutation and 1 was a genetic compound, G6PD Mediterranean/G6PD A- (the first report of this genotype). Our findings establish that the G6PD Mediterranean mutation accounts for most cases of G6PD deficiency in Oman. The presence of G6PD A- at a polymorphic frequency can be regarded as evidence of significant gene flow from Africa.