Khaled M. Musallam

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.

Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders

Summary.  Background:  The European Network of Rare Bleeding Disorders (EN‐RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs.

Optimal management of β thalassaemia intermedia

Our understanding of the molecular and pathophysiological mechanisms underlying the disease process in patients with β thalassaemia intermedia (TI) has substantially increased over the past decade. The hallmark of disease process in patients with TI includes ineffective erythropoiesis, chronic haemolytic anaemia, and iron overload. There are a number of options currently available for managing patients with TI including splenectomy, transfusion therapy, iron chelation therapy, modulation of fetal haemoglobin production, and several other agents targeting specific clinical complications. Limited studies assessed the efficacy and safety of these modalities; hence, there are currently no clear guidelines for managing patients with TI. Until solid evidence‐based guidelines are available, individualised treatment should be entertained.

Elevated liver iron concentration is a marker of increased morbidity in patients with β thalassemia intermedia

Background Patients with β thalassemia intermedia can have substantial iron overload, irrespectively of their transfusion status, secondary to increased intestinal iron absorption. This study evaluates whether iron overload in patients with β thalassemia intermedia is associated with morbidity. Design and Methods This was a cross-sectional study of 168 patients with β thalassemia intermedia treated at two centers in Lebanon and Italy. Data on demographics, splenectomy status, transfusion status, and presence of co-morbidities were retrieved. Laboratory values of serum ferritin, fetal and total hemoglobin levels, as well as platelet and nucleated red blood cell counts were also obtained. Iron burden was determined directly by measuring liver iron concentration using magnetic resonance imaging. Patients were subdivided according to transfusion and splenectomy status into groups with phenotypes of different severity. Results The mean age of the patients was 35.2±12.6 years and 42.9% of them were male. The mean liver iron concentration was 8.4±6.7 mg Fe/g dry weight. On multivariate logistic regression analysis, after adjusting for age, gender, splenectomy status, transfusion status, and laboratory indices, an increase in 1 mg Fe/g dry weight liver iron concentration was independently and significantly associated with higher odds of thrombosis, pulmonary hypertension, hypothyroidism, osteoporosis, and hypogonadism. A liver iron concentration of at least 7 and at least 6 mg Fe/g dry weight were the best thresholds for discriminating the presence and absence of vascular and endocrine/bone morbidities, respectively (area under the receiver-operating characteristic curve: 0.72, P<0.001). Elevated liver iron concentration was associated with an increased rate of morbidity in patients with phenotypes of all severity, with a steeper increase in the rate of vascular morbidity being attributed to aging, and an earlier appearance of endocrine and bone disease. Conclusions Elevated liver iron concentration in patients with β thalassemia intermedia is a marker of increased vascular, endocrine, and bone disease.

Non-transfusion-dependent thalassemias

Non-transfusion-dependent thalassemias include a variety of phenotypes that, unlike patients with beta (β)-thalassemia major, do not require regular transfusion therapy for survival. The most commonly investigated forms are β-thalassemia intermedia, hemoglobin E/β-thalassemia, and α-thalassemia intermedia (hemoglobin H disease). However, transfusion-independence in such patients is not without side effects. Ineffective erythropoiesis and peripheral hemolysis, the hallmarks of disease process, lead to a variety of subsequent pathophysiologies including iron overload and hypercoagulability that ultimately lead to a number of serious clinical morbidities. Thus, prompt and accurate diagnosis of non-transfusion-dependent thalassemia is essential to ensure early intervention. Although several management options are currently available, the need to develop more novel therapeutics is justified by recent advances in our understanding of the mechanisms of disease. Such efforts require wide international collaboration, especially since non-transfusion-dependent thalassemias are no longer bound to low- and middle-income countries but have spread to large multiethnic cities in Europe and the Americas due to continued migration.

Bone disease and skeletal complications in patients with β thalassemia major

Increased survival in patients with β thalassemia major (TM) allowed for several complications of the disease and its treatment to manifest, one of which is bone disease. Osteoporosis in this patient population results from a variety of genetic and acquired factors. Early diagnosis and prevention are essential and several measures have been evaluated for management including bisphosphonates. Fracture prevalence in TM patients seems to be clustered in mid adulthood, and is related to vitamin D deficiency and low bone mineral density. Fracture healing in patients with TM does not seem to be different from that in normal individuals. Bone and joint pain are a common manifestation of the underlying pathophysiology or may be related to iron chelator intake. Intervertebral disc changes are seen in patients who are heavily iron overloaded or those who are chelated with deferoxamine. Spinal deformity is common in TM, yet the prognosis is benign with spontaneous resolution frequently observed. Further research is warranted to evaluate the mechanisms, clinical implications, and optimal management of bone disease in this patient population.

Clinical experience with fetal hemoglobin induction therapy in patients with β-thalassemia

Recent molecular studies of fetal hemoglobin (HbF) regulation have reinvigorated the field and shown promise for the development of clinical HbF inducers to be used in patients with β-thalassemia and sickle cell disease. However, while numerous promising inducers of HbF have been studied in the past in β-thalassemia patient populations, with limited success in some cases, no universally effective agents have been found. Here we examine the clinical studies of such inducers in an attempt to systematically review the field. We examine trials of agents, including 5-azacytidine, hydroxyurea, and short-chain fatty acids. This review highlights the heterogeneity of clinical studies done on these agents, including both the patient populations examined and the study end points. By examining the published studies of these agents, we hope to provide a resource that will be valuable for the design of future studies of HbF inducers in β-thalassemia patient populations.

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.

β-Thalassemia Intermedia: A Clinical Perspective

Our understanding of the molecular and pathophysiological mechanisms underlying the disease process in patients with β-thalassemia intermedia has substantially increased over the past decade. Earlier studies observed that patients with β-thalassemia intermedia experience a clinical-complications profile that is different from that in patients with β-thalassemia major. In this article, a variety of clinical morbidities are explored, and their associations with the underlying disease pathophysiology and risk factors are examined. These involve several organs and organ systems including the vasculature, heart, liver, endocrine glands, bone, and the extramedullary hematopoietic system. The effects of some therapeutic interventions on the development of clinical complications are also discussed.

Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura

The quantification of residual plasmatic ADAMTS13 activity in congenital thrombotic thrombocytopenic purpura (TTP) patients is constrained by limitations in sensitivity and reproducibility of commonly used assays at low levels of ADAMTS13 activity, blunting efforts to establish genotype-phenotype correlations. In the present study, the residual plasmatic activity of ADAMTS13 was measured centrally by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (limit of detection = 0.5%) in 29 congenital TTP patients. The results were used to study correlations among ADAMTS13 genotype, residual plasmatic activity, and clinical phenotype severity. An ADAMTS13 activity above 0.5% was measured in 26 (90%) patients and lower levels of activity were associated with earlier age at first TTP episode requiring plasma infusion, more frequent recurrences, and prescription of fresh-frozen plasma prophylaxis. Receiver operating characteristic curve analysis showed that activity levels of less than 2.74% and 1.61% were discriminative of age at first TTP episode requiring plasma infusion < 18 years, annual rate of TTP episodes > 1, and use of prophylaxis. Mutations affecting the highly conserved N-terminal domains of the protein were associated with lower residual ADAMTS13 activity and a more severe phenotype in an allelic-dose dependent manner. The results of the present study show that residual ADAMTS13 activity is associated with the severity of clinical phenotype in congenital TTP and provide insights into genotype-phenotype correlations.