Complications Of Thalassemia Research Articles

Paraplegia due to Extramedullary Hematopoietic Tissue Compression of Thoracic Thecal Sac in a Patient with Thalassemia Treated Successfully with Surgical Decompression: A Case Report

Spinal cord compression due to extramedullary hematopoiesis (EMH) is a rare complication of thalassemia and generally presents as paraparesis with sensory impairment. Complete paraplegia is extremely rare in EMH due to thalassemia although it is known to occur in polycythemia vera and sickle cell anemia. Cases presenting with paraparesis have been treated with either surgery or radiotherapy with equal frequency and efficacy. Almost all reported cases with paraplegia have been treated with surgery with or without radiation therapy. As paraplegia secondary to EMH is rare, there is no consensus on treatment. We hereby report a case of thalassemia with paraplegia treated successfully with surgery. Treatment options for cord compression include primarily blood transfusion, surgery, and radiation therapy. Because of the extreme rarity of this condition, direct comparisons between various treatment modalities are not possible. The bias toward surgery is due to its immediate decompressing effect. EMH in thalassemia has also been treated with transfusion therapy with the rationale that correction of anemia would downregulate erythropoietin and lead to reversal of EMH. However, improvement with blood transfusion alone is usually incomplete and slow. Our patient did not improve after adequate blood transfusion and hence underwent surgical decompression after which he showed rapid and complete neurologic recovery. Therefore, we conclude that surgical decompression of EMH tissue has to be considered early in patients presenting with paraplegia if symptom shows no improvement after adequate blood transfusion.

Early Cardiac Involvement and Risk Factors for the Development of Arrhythmia in Patients With β-Thalassemia Major.

Cardiac iron overload is the most serious complication in thalassemia; even patients treated with intensive chelation suffer at a certain point from cardiomyopathy and arrhythmia. The aim of the study was to identify indicators of cardiac dysfunction in thalassemia as well as risk factors associated with the development of arrhythmia. A total of 45 patients with β-thalassemia major were enrolled in this cross-sectional study. Patients were divided into 2 groups according to the absence (group A) or the presence of arrhythmia (group B). Cardiac parameters in thalassemic groups were evaluated using 24-Holter recording, Stress electrocardiogram, and M-mode echocardiography. Serum ferritin and Cardiac T2* were used to assess the iron status. Group B showed significantly higher values of cardiac T2* and serum ferritin (P<0.05). Group B patients had significantly higher maximum heart rate with significant attacks of bradycardia and ST segment changes. In addition, they achieved a lower percentage of maximum age predicted heart rate and lower values of maximum metabolic equivalents (P<0.05). Significantly higher values of the left atrial diameter, the interventricular septum diameter, and the left-ventricle posterior wall diameter (P<0.05) were identified in group B. The increase in left atrial diameter, interventricular septum diameter, and left-ventricle posterior wall diameter seems to be related to the development of arrhythmia in patients with thalassemia, especially supraventricular arrhythmias.

Correspondence: Acute Lymphoblastic Leukaemia and HbE-alpha Thalassaemia.

Sir, The recent report on “Acute Lymphoblastic Leukaemia and HbE-alpha Thalassaemia” is very interesting [1]. Rajendran et al., presented a case study and mentioned that “though malignancies are one of the complications in thalassaemia, occurrence of leukaemia is a rare event [1]”. The occurrence of both disorders in the same patient is extremely and unusual case report [2]. The interesting concern is the co-existence between two disorders. Some reports mentioned for the common pathogenesis between thalassaemia and leukaemia. For example, Chiewsilp et al., noted that “HLA class I was associated with CML, ANLL and Thal [3]”. Genetically, the rooted cause of the two disorders are totally different, different mutation sites, although both are genetic diseases. Hence, the finding of both diseases in the same patient should be an accidental finding. The remained interesting question is the exact prevalence of co-occurrence of the disease. The incidence of acute lymphoblastic leukaemia in general population might not different from that of thalassaemic patients. Based on the experience from Thailand where thalassaemia is highly endemic, there is still no report on such co-occurrence.

Effects of Iron Chelators on Pulmonary Iron Overload and Oxidative Stress in β-Thalassemic Mice

Aim: To evaluate the effect of iron chelators on iron-related pulmonary pathology and oxidative stress in an animal model of β-thalassemia. Methods: Pulmonary iron overload was induced in heterozygous β-globin knockout mice (^muβ^th-3/+, BKO). Over a period of 2 weeks, 180 mg of iron/mouse was loaded by intraperitoneal injection of iron dextran, and subsequently treated daily via intraperitoneal with either deferoxamine (DF) or deferiprone (L1) at an equimolar concentration of iron binding (0.2 and 0.6 μmol/g body weight, respectively) for 7 days. Results: Iron loading resulted in iron deposition in peribronchial regions, septa and also in alveolar macrophages with a grading score of 3. This iron burden resulted in lung epithelial injuries, fibrosis and corresponded with increased lipid peroxidation and decreased tissue catalase activity. Treatment with DF or L1 resulted in a reduction of iron-laden alveolar macrophages and decreased oxidative stress and tissue damage, showing the iron mobilizing ability of both compounds. Conclusion: Iron chelation therapy, with DF and L1, may protect against pulmonary damage by sequestering catalytic iron and improving oxidative status. It may be beneficial in the prevention of pulmonary complications in thalassemia.

A mouse model to study thrombotic complications of thalassemia

Patients with β-thalassemia major and mainly intermedia have an increased risk for developing venous and arterial thrombosis which may be related to circulating pathological red blood cells (RBC) and continuous platelet activation. In the present study we used a modified thalassemic mice model in conjunction with a "real-time" carotid thrombus formation procedure to investigate thrombotic complications of thalassemia. Heterozygous Th3/+ mice, which lack one copy of their β-major and β-minor globin genes, exhibit anomalies in RBC size and shape, chronic anemia and splenomegaly which recapitulate the phenotype of human β-thalassemia intermedia. Flow cytometry measurements showed higher reactive oxygen species generation, indicating oxidative stress, in platelets and RBC of the thalassemic mice compared with wild type mice concomitant with an increase in reduced glutathione content which may represent a compensatory response to oxidative stress, and exposed phosphatidylserine which indicates platelet activation. To elucidate the effect of thalassemia on the development of arterial thrombosis, we studied photochemical-induced real-time thrombus formation in the carotid artery of these mice. The results indicated a significantly shorter "time to occlusion" in the thalassemic mice compared to wild type mice, which was prolonged following in vivo aspirin treatment. We suggest that this mouse model may contribute to our understanding of platelet activation and the hypercoagulable state in thalassemia and lay foundations to screening of anti-platelet drugs as well as anti-oxidants as possible therapeutics for prevention of thrombosis in thalassemia patients.

Association of Activated Circulating Endothelial Cells with Vascular Complications in Egyptian Beta-Thalassemic Patients

Background: There is evidence of an association between circulating endothelial cells (CECs) and vascular complications in thalassemic patients. Objectives: To quantify CECs and its activated fraction (AECs) in Egyptian s-thalassemic patients and to investigate their association with incidence of vascular complications. Subjects and Methods: Eighty pediatric patients and 30 healthy pediatric volunteers were studied for the proportion of CECs and AECs using cellular expression of endothelial adhesion receptors: CD146 and CD106 by flow cytometry. Results: CECs, AECs were higher in patients’ group than control group (p=0.001). AECs, serum ferritin, total leucocyte count (TLC), platelet (PLT) count were higher in patients with vascular complications and splenectomized patients (p=0.001for all). Percent of AECs was positively correlated to each of serum iron (p=0.001) and serum ferritin (p=0.001). No correlation was found between AECs (percent/absolute count) or MFI of CD106 and serum ferritin neither in group with vascular complications nor in splenectomized group (p>0.05). Also, no correlation was found between red blood cell (RBC) and PLT counts neither in group with vascular complication and who underwent splenectomy, nor in those without vascular complications and did not undergo splenectomy or those who underwent splenectomy but has no vascular complications (p=0.05). Size of the AEC compartment, intensity of CD106 expression were positively correlated to each of TLC, PLT count (p=0.001 for all). Risk of vascular complications was identified if percent of ACEs was ≥58.3% of CECs, absolute count of AECs was ≥0.059 x 103 /µl, MFI of CD106 was ≥7.9, with an effectiveness of 95%, 91.3%, 95% respectively. Conclusion: Measurement of AECs presents an effective quantitative method for assessment of risk of vascular complications in thalassemia.

Management of Liver Complications in Haemoglobinopathies

Liver complications in haemoglobinopathies (thalassaemia and sickle cell disease) are due to several factors, dominated (beside chronic viral infections, not considered here) by chronic iron overload, biliary obstruction and venous thrombosis. Whereas the latter two factors can cause acute hepatic syndromes, all three mechanisms - when becoming chronic- can produce fibrosis and cirrhosis and even, in thalassaemia, hepatocellular carcinoma. These chronic hepatic complications are an indirect consequence of the significant improvement in life expectancy due to the overall amelioration of disease management. The diagnostic approach has benefited from non invasive (biochemical and imaging) approaches which have considerably reduced the indication of liver biopsy. The therapeutic management involves relatively efficient curative medical, endoscopic or surgical methods, but should rest primarily on preventive measures focused on the haematological causative factors but also on hepatic co-morbidities. This chapter will focus on hepatic complications in thalassaemia and sickle cell disease (SCD), without considering the complications related to virus B or C infections which will be described in another chapter.

Platelet hyperactivity in thalassemia patients with elevated tricuspid regurgitant velocity and the association with hemolysis

IntroductionPulmonary arterial hypertension is a life-threatening complication in thalassemia characterized by elevated pulmonary arterial pressure. Increased platelet activation is associated with this complication; however, its role remains unclear. MethodsPlatelet activation in splenectomized β-thalassemia/hemoglobin E (Hb E) patients was measured using flow cytometric determination of P-selectin and activated glycoprotein (aGP) IIb/IIIa expression, and platelet-leukocyte aggregates (platelet-neutrophil, platelet-monocyte and platelet-lymphocyte aggregates). Tricuspid regurgitant velocity (TRV) was measured and used as an indicator of pulmonary arterial pressure. Plasma hemoglobin served as markers of hemolysis. ResultsFifteen of 27 patients had elevated TRV (>2.5m/s). Platelet expression of P-selectin and aGPIIb/IIIa, and platelet-leukocyte aggregates were higher in thalassemia patients with elevated TRV than healthy control. Platelet-neutrophil aggregates increased in thalassemia patients with elevated TRV compared to patients with normal TRV. The increase in P-selectin and aGPIIb/IIIa expression induced by adenosine diphosphate (ADP) was higher in patients with elevated TRV than those with normal TRV. Platelet P-selectin expression and platelet-neutrophil aggregates correlated positively with TRV. Plasma hemoglobin levels in patients with elevated TRV were higher than those of the control subjects, and correlated with TRV. ConclusionThalassemia patients with elevated TRV have a further increase in platelet activation that correlates with hemolysis.

Impact of educational programme regarding chelation therapy on the quality of life for B-thalassemia major children

ObjectivesThalassemia is the most common genetic disorder in Egypt, with an estimated carrier rate of 9–10%. It is a genetic blood disorder which can be fatal if proper chelation is not received. The introduction of chelating agents capable of removing excessive iron from the body has dramatically increased life expectancy and improved the overall quality of life. The aim of this study was to assess the impact of educational programmes regarding chelation therapy on the quality of life of thalassemic children.MethodsThe study was carried out at the Mansoura University Children's Hospital in the period between March 2010 and May 2011. It included 173 B-thalassemia children (84 boys and 89 girls) with age ranging between 8–18 years. The researcher used a predesigned interviewing questionnaire to collect data regarding children's knowledge about thalassemia and its management, especially regarding chelation therapy. The paediatric quality-of-life inventory tool (Peds QL 4.0 generic core) was also used to assess the studied children's quality of life.ResultsThere was a significant statistical difference of the studied children's knowledge regarding chelation therapy and their quality of life.ConclusionThere was a positive effect of the educational programme in improving children's knowledge score and their quality of life. Application of educational programmes for thalassemic children and their nurses regarding chelation therapy and its importance in preventing thalassemia complications is established.

Endocrine complications of thalassemia and its treatment: a local experience

Endocrine complications of thalassemia and its treatment: a local experience

Adipocytokine concentrations in children with different types of beta-thalassemia

Background. Beta-thalassemia is an inherited blood disorder. It results from the impaired production of β-globin chains, leading to a relative excess of alpha-globin chains. Clinical severity separates this disease into three main subtypes: β- thalassemia major, β-thalassemia intermedia and β-thalassemia minor, the former two being clinically more significant. Inflammatory processes may play an important role in some of the complications of thalassemia. Adipose tissue is one of the most important endocrine and secretory organs that release adipocytokines like adiponectin, resistin and visfatin. Aim. The aim of our study was to analyze adipocytokine concentrations (adiponectin, resistin and visfatin) in different types of β-thalassemia patients and determine any possible correlations with disease severity. Methods. We recruited 29 patients who were transfusion-dependent β-thalassemia-major patients, 17 patients with β-thalassemia intermedia, 30 β-thalassemia minor patients. The control group consisted of 30 healthy children. Anthropometric measurements, complete blood count, biochemical parameters, serum concentrations of adiponectin, resistin, visfatin were performed for all subjects. Results. Resistin and visfatin concentrations were significantly higher in β-thalassemia minor patients than in controls. Adiponectin, resistin and visfatin concentrations were significantly higher in both β-thalassemia intermedia and major patients than in controls. The concentrations of adiponectin, resistin and visfatin were significantly higher in both β-thalassemia intermedia and major patients than in β-thalassemia minor patients. There was no significant difference between β-thalassemia intermedia and β-thalassemia major patients for adipocytokines concentrations. Conclusion. We speculate that these adipocytokines may play a role in the development of complications in β-thalassaemia.

Towards an optimization of the management of endocrine complications of thalassemia.

Children with thalassemia are living longer due to better care. Physicians dealing with this group of patients now have to contend with new challenges resulting from iron overload. Endocrine complications represent the most common morbidities encountered. To provide a better quality of life, these complications have to be addressed in a consistent way. For this purpose, we have compiled a set of recommendations to help physicians provide the best care possible to these patients.

Health of adults living with a clinically significant haemoglobinopathy in New South Wales, Australia

To comprehensively review the health needs of patients living with clinically significant haemoglobinopathies (thalassaemia and sickle-cell disease (SCD)) in New South Wales, Australia. A survey-based health needs assessment was undertaken in outpatients cared for at five tertiary institutions in metropolitan and regional centres. Sixty-three of 121 adults (approximately 80-90% of adult patients with transfusion-requiring haemoglobinopathies in New South Wales) completed an in-house and commercial health-related quality assessment survey (SF-36v2). Subjects came from more than eight world regions, with those with SCD being more likely to be born outside of Australia than subjects with thalassaemia (P < 0.001, likelihood ratio 20.64) as well as more likely to have been refugees (26% vs 2%). The population contained socially disadvantaged subjects with 13 subjects (20.6%) having incomes below the Australian poverty line. Complications of thalassaemia were comparable to previous international reports although our subjects had a high rate of secondary amenorrhea (>12 months = 27%) and surgical splenectomy (55.6%). Use of hydroxyurea in SCD was less than expected with only 46.6% of subjects having prior use. Lack of universal access to magnetic resonance imaging-guided chelation (international best practice) was evident, although 65.5% had been able to access magnetic resonance imaging through clinical trial, or self-funding. Patients with SCD and thalassaemia experience considerable morbidity and mortality and require complex, multidisciplinary care. This study revealed both variance from international best practice and between specialist units. The results of this research may provide the impetus for the development of clinical and research networks to enable the uniform delivery of health services benchmarked against international standards.

Hypoxia Biomarkers, Oxidative Stress, and Circulating Microparticles in Pediatric Patients With Thalassemia in Upper Egypt

This study aimed to investigate the oxidative stress, hypoxia biomarkers, and circulating microparticles (MPs) in β thalassemia major. The study included 56 children with thalassemia and 46 healthy controls. Hypoxia biomarkers, oxidative stress biomarkers, and total plasma fragmented DNA (fDNA) were detected by the standard methods. The MPs were assessed by flow cytometry. Hypoxia and oxidative stress biomarkers, fDNA, and MPs were higher and total antioxidant capacity (TAC) was lower in patients with thalassemia than the controls. In splenectomized patients and those who had complications, vascular endothelial growth factor (VEGF), malondialdehyde, fDNA, endothelial, platelet, and activated platelet MP levels were higher while, TAC was lower than the nonsplenectomized patients. In conclusion, the increased tissue hypoxia, oxidative stress in β thalassemia, and its relationship with DNA damage and MPs release could explain many complications of thalassemia and may have therapeutic implications. The VEGF could serve as an important indicator for adequacy of blood transfusion in thalassemia.

Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines

The current management of thalassemia includes regular transfusion programs and chelation therapy. It is important that physicians be aware that endocrine abnormalities frequently develop mainly in those patients with significant iron overload due to poor compliance to treatment, particularly after the age of 10 years. Since the quality of life of thalassemia patients is a fundamental aim, it is vital to monitor carefully their growth and pubertal development in order to detect abnormalities and to initiate appropriate and early treatment. Abnormalities should be identified and treatment initiated in consultation with a pediatric or an adult endocrinologist and managed accordingly. Appropriate management shall put in consideration many factors such as age, severity of iron overload, presence of chronic liver disease, thrombophilia status, and the presence of psychological problems. All these issues must be discussed by the physician in charge of the patient's care, the endocrinologist and the patient himself. Because any progress in research in the field of early diagnosis and management of growth disorders and endocrine complications in thalassemia should be passed on to and applied adequately to all those suffering from the disease, on the 8 May 2009 in Ferrara, the International Network on Endocrine Complications in Thalassemia (I-CET) was founded in order to transmit the latest information on these disorders to the treating physicians. The I-CET position statement outlined in this document applies to patients with transfusion-dependent thalassemia major to help physicians to anticipate, diagnose, and manage these complications properly.

Cardiopulmonary and Laboratory Profiling of Patients with Thalassemia At Risk for Pulmonary Hypertension: Report From the Thalassemia Clinical Research Network.

Abstract 2122 Introduction:Pulmonary hypertension (PH) commonly develops in thalassemia syndromes, but is poorly characterized. Since limited data are available we set out to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassemia at-risk for PH. Methods:We designed a case-control study of thalassemia patients at-risk for PH, defined by a tricuspid-regurgitant-jet velocity (TRV)≥2.5m/s on Doppler-echocardiography (echo) compared to those with low PH-risk, define by a TRV<2.5m/s, similar in age, gender, ethnicity and transfusion dependence. A single cross-sectional measurement for variables reflecting cardiopulmonary status and biological pathophysiology were obtained, including echo, 6-minute-walk-test (6MWT), Borg Dyspnea Score, New York Heart Association (NYHA) functional class, cardiac MRI, pulmonary function testing, laboratory analyses and biomarkers of hemolysis, inflammation, coagulation and adhesion, compared in thalassemia patients at high vs. low PH-risk. Results:Twenty-seven thalassemia patients with a mean TRV=2.5±0.6m/s (range:1.0–4.9m/s) were evaluated, 14 with a TRV≥2.5m/s. Mean age was 35±12 years, 70% were male, 74% were splenectomized, and 67% had thalassemia major (TM). Patients with PH-risk (mean TRV=3.1±0.7m/s) had a significantly higher frequency of splenectomy (OR:11.1 [95% CI: 1.11–112.0], p=0.04), higher NYHA functional class, Borg Dyspnea Score after 6MWT, and significantly larger right atrial size, left atrial volume, and left septal-wall thickness on echo and/or MRI, with elevated biomarkers of coagulation abnormalities, lactate dehydrogenase (LDH) levels, arginase concentration (5.7±7 vs. 78.7±108 ng/ml, p=0.003) and arginase activity, and lower arginine-bioavailability compared to low-risk patients (mean TRV=2.1±0.4m/s). Arginase concentration and activity correlated significantly to several echo/MRI parameters of cardiovascular function including cardiac index (r=0.75, p<0.0001), in addition to white blood cell count, several adhesion biomarkers, global-arginine-bioavailability and biomarkers of hemolytic rate, including LDH, hemoglobin and bilirubin. Arginase activity, but not concentration, correlated strongly to brain natriuretic factor (r =0.45, p=0.03). Diffusion capacity for carbon monoxide (DLCO) was generally low in our cohort (mean % predicted: 68.2±16.3 (range 45–115), however other measurements of pulmonary function were within the normal range, and together with DLCO, did not differ significantly by TRV. No significant difference was found in 6MWT in cases vs. controls, however the 6MWT paradoxically trended higher in patients with a TRV≥2.5m/s and may not be an ideal PH biomarker in thalassemia. The 6MWT was significantly worse in TM patients compared to patients with thalassemia intermedia (460±106 vs. 539±66 m, p=0.05), despite similar TRVs, was a poor predictor of echo/MRI parameters, and paradoxically correlated to increased right atrial size (r =0.42, p=0.03). A strong correlation of 6MWT to DLCO (r =0.51, p=0.008) may indicate a pulmonary contribution to 6MWT in this cohort as an additional confounding factor. Conclusions:Thalassemia patients with a TRV≥2.5m/s have additional echo and MRI parameters suggestive of PH-risk. Dysregulation of the arginine metabolome and the consequences of excess plasma arginase are associated with cardiopulmonary complications in thalassemia and warrants further study. Disclosures:Taher:Novartis: Research Funding, Speakers Bureau.

Spinal Artery Thrombosis: An Unrecognized Severe Complication in Thalassemia and Sickle Disorders

AbstractAbstract 1155 Introduction.Anterior spinal artery thrombosis (AST) results in sudden, often irreversible sensory and motor loss, with partial or complete paraplegia. This is recognized as a complication of: prothrombotic states; right to left shunting; trauma and spinal surgery. Both venous and arterial thrombosis, including the central nervous system, are well-recognized risks in sickle cell disease (SCD) but AST has not been described. In thalassemia disorders (Thal), cerebral infarction, often silent, is increasingly recognized (Mussalam et al, Thromb Res, Aug 2012). However AST is not a recognized complication. Here we describe four cases of acute onset AST in adults (3 Thal major, 1 SCD), leading to severe neurological irreversible or partially reversible deficits. Patients and Methods.Patients described were attending outpatients for monitoring drawn from two large adults clinics in the UK (UCLH, Whittington, over 1500 hemoglobinopathy patients) and Italy (Ospedale Maggiore Policlinico, Milan, 400 patients). All events occurred within a 3 year period. Results.Presenting symptoms and Magnetic Resonance Imaging (MRI) findings are shown in the Table. All cases presented acutely with a sensory level on examination and with bladder dysfunction. Three presented with motor weakness of both lower limbs (1 case initially in one limb). Case 3 presented with a sensory deficit affecting the sacral region but no motor deficit. Partial reversibility occurred in cases 1 and 3. In Thal cases, no prodromal syndrome and no prior history of thrombosis were seen. MRI showed changes consistent with acute cord ischemia (delayed in case 4 until 5 days). Extra-medullary hematopoiesis was demonstrated by MRI only in case 2, but was not sufficient to cause cord compression. Cerebrospinal fluid analysis was normal in all cases. Concomitant risk factors such as autoimmune markers, active hepatitis, trauma, or demonstrable prothrombotic markers other than those expected in SCD or Thal were not detected. In none of the Thal cases was a thrombotic history elicited but the SCD patient had a history of retinal artery and renal artery thrombosis (1 year previously). Discussion.A case series of this serious complication has not been previously reported. The known prothrombotic tendency in SCD and Thal is the most likely risk factor as other risk factors were absent. Thal cases were transfusion dependent, where thrombosis risk is generally about a quarter of that in non transfusion dependent Thal (Cappellini, Blood Reviews, 265, 2012, S20–23). In the SCD case, the prior history of arterial thrombosis, consistent with an embolic etiology, led us to examine whether a patent foramen ovale (PFO) was present, which was confirmed by bubble jet studies. This was subsequently closed. In patients with a history of embolic thrombosis, the presence of PFO should be sought and closure considered. Two cases were treated with Methylprednisolone soon after presentation. Two cases were commenced on Aspirin 75mg once a day to limit extension and as secondary prevention. The use of thrombolytic agents such as tissue thromboplastin activator have not been described in AST. In conclusion, spinal cord ischemia should be considered when facing a Thal or SCD patient with acute neurological symptoms affecting legs or bladder. This may be more common in hemoglobin disorders than is apparent from the literature.TableCase 1Case 2Case 3Case 4Age at presentation24373227GenderMaleMaleFemaleFemaleDiagnosisSCDThal MajorThal MajorThal MajorPresentation symptomsBilateral leg weakness ParaparesisParaplegia Urine retentionSacral paraesthesia Urine retentionLower limb pain paraesthesia, & weakness Urine retentionMRI findingsFusiform cord swelling (T9, T10) Secondary to ischemiaHigh T2 signal (T6 to conus) Swollen cord from T9Low cord signal(T11 - T12) Intramedullary syrinx (T4/5 - T7/8)1stScan: normal Repeat: High T2 posterior dorsal signal to T9 Conus medullary edemaExtramedullary haematopoiesisNoYes but no cord compressionNoNoHb (g/L)8013211389Plt (× 109/L)451191474438WBC (× 109/L)12.75.112.77.7NRBCs (%)0.39NDND0.5TransfusionNoYesYesYesLast transfusionNone− 2 days− 19 days− 20 daysSplenectomyNoNoYesNoPrior thrombosisYesNoNoNoOther risk factors*NoNoNoNoND = not detected.*Autoimmune markers, active hepatitis C, prothrombotic screen - non contributory. Disclosures:Cappellini:Novartis Pharmaceuticals: Research Funding.

High Circulating Sclerostin is Present in Patients with Thalassemia-associated Osteoporosis and Correlates with Bone Mineral Density

Osteoporosis is a severe complication of thalassemia. Sclerostin is a Wnt signaling inhibitor, which is produced by osteocytes and inhibits osteoblast function. Sclerostin is implicated in the pathogenesis of osteoporosis of different etiology. The aim of the study was to evaluate circulating sclerostin in 66 patients (median age 42 years) with thalassemia and osteoporosis who participated in a phase 2, randomized study (zoledronic acid vs. placebo) and the results were compared with those of 30 healthy controls (median age 44 years) without osteopenia/osteoporosis and 62 women with postmenopausal osteoporosis (median age 63 years). At baseline, thalassemic patients with osteoporosis had elevated circulating levels of sclerostin (median: 605 pg/ml, range: 22-1,227 pg/ml) compared to healthy controls without osteopenia/osteoporosis (250 pg/ml, 0-720 pg/ml, p<0.001) and reduced levels of sclerostin compared with postmenopausal women with osteoporosis (840 pg/ml, 181-1,704 pg/ml, p<0.001). Thalassemia patients had also increased serum dickkopf-1 (Dkk-1) and high bone turnover. Circulating sclerostin levels correlated with bone mineral density in lumbar spine (r=0.619, p<0.001), distal radius (r=0.401, p=0.001) and femoral neck (r=0.301, p=0.021). Zoledronic acid did not alter sclerostin levels after 12 months of therapy, although it reduced circulating Dkk-1. We conclude that circulating sclerostin is elevated in thalassemia patients with osteoporosis and correlated with their BMD, but it was not reduced post zoledronic acid administration. These findings suggest that high sclerostin may serve as a marker of increased osteocyte activity in thalassemia patients. Drugs targeting sclerostin may also be used in this difficult to treat disorder associated with bone loss.

Pain and Bone Disease: A Patient’s View

Pain in thalassemia proves to be an emergent issue even if it is not possible to correlate it definitely to bone disease, but we strongly believe that a multidisciplinary approach, may be as decisive in this case as it was in the struggle against thalassemia. In fact, we strongly believe that the involvement of various specialists such as endocrinologists, orthopedist, anesthesiologist, in a close team coordinated by a specialist in thalassemia is absolutely necessary for achieving our aims. First of all, we need to implement clinical trials to identify the mechanisms of disease, to find the optimal management of the problem in order to provide new therapeutic methods for preventing the thalassemia-induced osteoporosis and to reduce the presence of very disabling pain for patients. Patients’ expectations for the future are to continuously improve the quality of life. To do that it is needed to identify pathways to prevent all the complications of thalassemia that cause widespread pain, above all osteoporosis. Although we have seen that osteoporosis is not the sole cause of pain for thalassemia patients, it is true that this seems to have a great incidence in thalassemia patients and it gives a significant contribute to an increased pain.

Overview of Current and Emerging Issues in Endocrinological Complications of Thalassaemia

Clinical advances in the treatment of thalassaemia major (TM) patients have helped to increase substantially the life expectancy of patients. The TM patients today represent the first generation of adult thalassemics. As patients enter puberty, they begin to experience a variety of endocrine abnormalities, presumably the results of chronic anaemia and tissue iron deposition from the chronic transfusion therapy. In patients with TM, the anterior pituitary gland is particularly sensitive to free radical stresses. Recent reports have documented a frequency of severe growth hormone deficiency in 13–32% of adult patients with TM. The prevalence of impaired adrenal function in TM patients has been reported from 0 to 33%, depends on the age of the population studied, although clinical adrenal insufficiency (AI) is rare. Thyroid dysfunction has been observed in 13–60% of patients, but its severity is variable in different series. Acquired central hypothyroidism (CH) is a rare complication.