Aikaterini Teli

Renal dysfunction in patients with beta-thalassemia major receiving iron chelation therapy either with deferoxamine and deferiprone or with deferasirox.

There are limited studies on renal involvement in β-thalassemia, mainly involving patients on deferoxamine, reporting both glomerular and tubular dysfunction. The aim of the present study was to investigate renal involvement in young thalassemia patients, using both conventional and early markers of renal dysfunction, and to correlate findings to iron chelation therapy. Forty-two patients aged 4–23 years were studied and, for analysis purposes, were divided into two groups based on chelation therapy (group A receiving deferasirox and group B receiving deferoxamine and deferiprone combination therapy). In addition to conventional renal biochemistries, creatinine clearance, estimated glomerular filtration rate, serum cystatin C (Cys C), fractional excretion of sodium, tubular phosphorus reabsorption and urine calcium, protein, β2-microglobulin (β2-MG) and glucose levels were measured. A considerable number of patients demonstrated impaired renal function with elevated Cys C levels (36%), glomerular dysfunction with proteinuria (24%) and tubulopathy with hypercalciuria (35.5%) and elevated excretion of β2-MG (33.5%). Renal involvement seems to be present even in young patients with β-thalassemia, therefore, routine use of early markers of renal dysfunction is recommended. Further studies are needed in order to investigate the role of new chelators in tubular function parameters.

Sequential therapy with activated prothrombin complex concentrate (FEIBA) and recombinant factor VIIa in a patient with severe haemophilia A, inhibitor presence and refractory bleeding

Patients with haemophilia A are at risk for developing inhibitors which render conventional factor replacement therapy ineffective. In such cases, bypassing the inhibitor is required to achieve haemostasis. Both activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa (rVIIa) have demonstrated efficacy in treating bleeds in patients with inhibitor presence [1,2]. However, clinical response may be variable between patients or between bleeding episodes and, in some cases, either therapeutic intervention may fail. Sequential use of multiple bypassing agents has been shown in vitro to provide a mechanism to increase efficacy but has not met with wide clinical use because of concern regarding the possibility of thrombosis [3]. The present case report concerns a 13-year-old boy with severe haemophilia A, haemophilic arthropathy and inhibitor presence not responding to previous therapy with retuximab. The patient was admitted to the paediatric surgery department because of abdominal pain, with a possible diagnosis of acute appendicitis. He underwent surgery, receiving rVIIa (90 lg kg) prior to and following operation, however, diagnosis of appendicitis was not confirmed in the operating room. Laboratory work up on admission was as follows: Hb 12.6 g dL, WBC 14 300 mm [3] (63% neutropohils), PLT 559 000 mm and FVIII antibody titre 6 BU. Postoperatively, the patient presented with severe haematuria and rectum bleeding. Despite continuous treatment with rVIIa (90 lg kg every 2 h), bleeding persisted. On the fifth postoperative day laboratory examination showed: aPTT 63.6¢¢/31¢¢, INR 0.67, fibrinogen 201 mg dL, D-dimers > 1000 mg L. The haemoglobin level dropped to 5.6 g dL, the patient requiring multiple packed red cell transfusions. CT scan revealed multiple blood collections: in the chest (haemothorax), around the liver and spleen, in the small pelvis, in the small and large intestine, in the left kidney and the right perinephral area (Figs 1 and 2). Still on monotherapy with rFVII, the patient was transferred to the paediatric department on the 10th postoperative day where, because of refractory bleeding, a combined bypassing agent therapy was decided. The initial regimen consisted of 90 lg kg of rFVIIa given two hourly and 50 U kg of Factor

Fok-I polymorphism of vitamin D receptor gene and the presence of renal dysfunction in patients with β-thalassemia major.

Recent evidence supports the presence of renal dysfunction even among young patients with β-thalassemia major. However, the possible genetic contribution has never been investigated. The aim of this study was to correlate the presence of Fok-I polymorphism of the vitamin D receptor gene with abnormal levels of early markers of renal impairment in children and young adults with thalassemia. Thirty-four patients (19 male and 15 female) with β-thalassemia major on conventional treatment, with a mean decimal age of 14.62 ± 5.47 years (range: 5–22 years), were included in the study. Markers of renal function were determined in serum and in urine and patients were genotyped for Fok-I gene polymorphism. Genotype frequencies were similar to those previously reported for other populations: 47.06% of the patients were homozygous for the F allele, 41.18% were heterozygous, and 11.76% were homozygous for the f allele. A considerable number of patients demonstrated impaired renal function with increased serum cystatin C levels (29.41%), glomerular dysfunction with proteinuria (68%), as well as significant tubulopathy with hypercalciuria (73.08%), and increased levels of urinary β2-microglobulin (29.41%). When patients were stratified according to Fok-I polymorphism, a significantly higher prevalence of abnormally increased serum levels of cystatin C was observed in patients being homozygous for the f allele (75%) compared with those being heterozygous (Ff) or homozygous for the F allele (14.29% and 31.25%, respectively, P = .02). Further studies are needed to confirm these preliminary results and elucidate the possible mechanisms involved.

Nephrolithiasis in beta thalassemia major patients treated with deferasirox: an advent or an adverse event? A single Greek center experience

Dear Editor, Thalassemia major (TM) is characterized by grossly defective synthesis of hemoglobin A and impaired red blood cells (RBC). Affected individuals need repeated blood transfusions, while shortened RBC life span and iron overload cause functional abnormalities in various organs. Iron chelation therapy is considered mandatory in order to expand their life. While cholelithiasis due to the high level of bilirubin has been extensively studied in thalassemia, reports concerning nephrolithiasis and thalassemia are fewer. Hemolysis, urogenital infections, diet or drugs rich in calcium and vitamin D, parathyroid gland diseases, hypercalciuria, hyperuricosuria, and hyperuricemia are equally accused as causes of nephrolithiasis in thalassemia. One hundred eighty-five patients with TM, following transfusion protocols (pre-transfused hemoglobin 9 mg/dl) were analyzed in our center. Ninety-two patients were under deferasirox (DFX 20 mg/kg/day). Nine of them experienced episodes of nephrolithiasis (Table 1). Two of them were splenectomized [1]. None had any illness predisposing to nephrolithiasis. The presence of the stone was confirmed by an ultrasound. The chemical analysis of the excreted stones confirmed a calcium oxalate calculi. Four changed their chelation therapy to deferiprone alone or in combination. None of them had similar episode in the last year of followup with the recommendations for increase water intake and lower calcium intake. Transfusion is a life-saving measure for TM patients, but it loads the body with iron that causes organ damages like endocrinopathies, cardiomyopathy, and hepatic failure. Survival of patients has improved due to the regular iron chelation. Nowadays, due to extension of life expectancy, beta thalassemic patients have additional pathological problems. Renal function may be affected in TM both by iron overload and by hyperuricemia due to increased breakdown of RBCs. Also, hypercalcemia and hypercalciuria and acid–base disbalance, especially in acid urine PH, are considered responsible for renal stones in TM [2]. Several authors have reported renal tubular dysfunction in TM patients such as proteinuria, hypercalciuria, and hyperphosphaturia [3–7]. Recently, a study showed that renal hyperfiltration was common in TM patients [8]. Regular transfusions improved the abnormally high creatinine clearance of the irregularly transfused patients. Hypercalciuria and albuminuria were also common. Hypercalciuria is more probably associated with systematic transfusions [9]. Recently, the orally administered chelation agent DFX is reported as nephrotoxic. Clinical trials have shown that DFX is effective in adults and children. Its recommended starting dose (20 mg/kg/day) can be modified dependently on the patient. Mild, nonprogressive increase in serum creatinine has been observed in approximately one third of patients. Creatinine levels returned largely to normal [10]. Nephrolithiasis is observed in TM patients receiving DFX or deferiprone as chelation therapy, but the causes are unknown. In our unit, 9 out of 92 patients treated with DFX were admitted with renal colic. In the same period of time, only 1 out of 93 patients treated with other chelators had similar experience. However, more studies are needed to verify the correlation of nephrolithiasis and DFX. Similarly, it is still unknown whether treatment with calcium and V. Efthimia :A. Agapidou :M. Economou : E. Vetsiou :A. Teli : V. Perifanis Thalassaemia Unit, Ippokratio Hospital, Konstantinoupoleos 49, Thessaloniki 54642, Greece

MYH9-related disorders: Report on a patient of greek origin presenting with macroscopic hematuria and presenile cataract, caused by an R1165C mutation

Myosin heavy chain-9 (MYH9)-related disorders represent a heterogenous group of hereditary diseases caused by mutations in the gene encoding the heavy chain of nonmuscle myosin IIA. May-Hegglin anomaly and Fechtner, Sebastian, and Epstein syndromes are the four phenotypes of the disease, characterized by congenital macrothrombocytopenia and distinguished by different combinations of clinical signs that may include glomerulonephritis, sensorineural hearing loss, and presenile cataract. The spectrum of mutations responsible for the disease is wide and the existence of genotype-phenotype correlation remains a critical issue. We report the first case of an MYH9-RD in a patient of Greek origin presenting with macroscopic hematuria and presenile cataract caused by a p.R1165C mutation. The same mutation was present in the patient’s father, who exhibited no extrahematological features of the disease. The p.R1165C mutation is one of the MYH9 alterations whose prognostic significance is still poorly defined. Thus, the patients described add to the limited existing data on the MYH9 mutations and their resultant phenotypes.

Laboratory Investigation of Platelet Function in Patients with Thalassaemia

The aim of this study was to investigate platelet function in patients with thalassaemia and to detect any relation to chelation treatment (deferasirox or deferiprone/deferiprone plus desferioxamine). Thirty-three transfusion-dependent patients with thalassaemia were included. The investigation consisted of aggregation testing of platelet-rich plasma by light transmission aggregometry (LTA) with the use of 5 agonists as well as the global test of haemostasis by means of the PFA-100 platelet function analyser. In 66.67% of the patients, there was reduced LTA to at least one agonist and in 18.18% there was reduced LTA to two or more agonists. The PFA-100 test was prolonged in 60.6% of the cases. An abnormal LTA and a prolonged PFA-100 time were recorded in 33.3% of the patients and 27.4% had a normal aggregation and PFA-100 test. No correlation between chelation regimen and either LTA or PFA-100 test was found. The abnormal LTA can be explained either by the release of ADP from the haemolysed red blood cells, which leads to defective platelet aggregation, or by the presence of two platelet populations. An in vitro effect without an in vivo impact could be an alternative explanation. In patients with thalassaemia, the reduced LTA and the prolonged PFA-100 closure time could be an in vitro effect and has a close correlation to the bleeding phenotype of each patient.

Cross-sectional study of pulmonary function and MRI-derived liver and myocardial iron content in young patients with β-thalassemia major

To the Editor: Pulmonary dysfunction stands for one of the most undervalued and less recognized complications in patients with b-thalassemia, although it has initially been described almost three decades ago (1). Conflict reports exist regarding the type of the observed pneumonopathy (2, 3), and the exact pathogenetic mechanism is not clearly elucidated; however, the chronic effect of iron overload may reasonably intervene in it. In this report, we present findings from a study that we have conducted to cross-sectionally investigate the type of pulmonary dysfunction as assessed by means of spirometry and in correlation with the level of iron accumulation within the liver and the myocardium as determined by MRI in a cohort of children and young adults with b-thalassemia major. Thirty-nine thalassemic patients on conventional treatment (19 men and 20 women) with a mean decimal age of 21.69 ± 6.13 years (range: 9–34 years) were recruited for the study. Myocardial and hepatic iron concentrations were quantified using standard MRI methods as previously described (4). Pulmonary function was evaluated using spirometry and measurements of lung volumes, and diffusion capacity was carried out by a complete computerized pulmonary function testing system. All measurements were performed 3–5 days after a scheduled blood transfusion to ensure hemodynamic stability. Pulmonary function results were expressed as percentages of predicted normal values provided by the device’s manufacturer and corrected for age, sex, and height. The threshold of abnormality was determined as below 80% of the predicted value. Finally, data including the history of splenectomy, serum ferritin levels, and the amount of red blood cells transfused for 1 year prior to the study were collected from each patient’s medical file. Fourteen patients (35.9%) had restrictive pulmonary pattern, whereas no patient was identified as having obstructive or mixed airway disease. Diffusional impairment characterized by significantly lower DLCO*% values (carbon monoxide diffusion capacity of the lung) was observed in 59% of the patients and in the 93% of the patients having a restrictive pulmonary pattern. When patients were categorized according to their normal or restrictive spirometric pattern, only age differed significantly (P < 0.001) between the two groups formed (Table 1). Patients with restrictive pulmonary pattern had increased liver iron content as detected by MRI (mean MR relaxation time: 5.59 ± 5.48 msec) compared to patients with normal pulmonary function (10.76 ± 10.33 msec), with a difference that was approaching statistical significance (P = 0.095). Neither myocardial iron nor cardiac ventricular volumes or ejection fractions differ between the two groups. No correlations were observed between myocardial MR values, liver MR values, and parameters obtained from pulmonary function testing. As expected, only liver MR values were inversely correlated to serum ferritin concentrations (r = )0.398, P = 0.012). Interestingly enough, ferritin was inversely correlated to DLCO*% (r = )0.336, P = 0.036), but with no other spirometric parameter.

Compound Heterozygosity for Hb Adana (HBA2: c.179G>A) and the –α3.7/αα Thalassemia Deletion in Greece: Clinical Phenotype and Genetic Counseling

Abstract Hb Adana (HBA2: c.179G>A) is found worldwide but is extremely rare and carriers are asymptomatic, with red cell indices similar to α+-thalassemia (α+-thal) carriers. First line screening tests are unable to detect the unstable hemoglobin (Hb). Coinheritance with the α-thal (–α3.7) deletion is herein presented and the challenges involving genetic counseling of couples carrying the mutations are discussed.

Neurological Involvement in a Thalassemic Child Receiving Deferiprone.

To the Editor: We read with great interest the report by Parakh et al1 regarding a young thalassemic patient presenting with neurological complications attributed to treatment with deferiprone (DFP). The safety profile of the drug has been well studied during the past decade and the vast experience gained by its use in the treatment of iron overload in thalassemic patients has shown that related adverse effects are gastrointestinal symptoms, arthropathy, transaminitis, and agranulocytosis.2,3 Neurological complications, such as those described in the paper by Parakh, are extremely rare and have been associated with high doses of the drug. In contrast, DFP has been used effectively for the treatment of patients with neurological diseases such as Friedreich’s ataxia and neurodegeneration with brain iron accumulation, albeit with doses lower than those used in thalassemic patients.4,5 In this context, we would like to report the case of a 9-year-old girl with transfusion-dependent thalassemia presenting with neurological complications associated with the use of DFP, given, however, in a relatively low dose. The patient was on transfusions since the age of 17 months, maintaining a pretransfusion hemoglobin of 9 to 10.5 g/ dL. She was started on chelation therapy with desferrioxamine (DFO) at the age of 2 years and changed to combination therapy (DFO and DFP) at the age of 7 years due to high ferritin levels (B2000ng/mL). DFP was given at 75mg/kg/d every day and DFO at 40mg/kg 5 times a week. As a result of an effective ferritin decrease, combined treatment was stopped after a few months and monotherapy with DFP, at the same dose, was continued. A few months later, the patient started complaining of nonspecific myalgia and arthralgia. In addition, the mother reported behavioral changes in the child, such as separation anxiety and school denial. Clinical evaluation and basic laboratory testing did not reveal any pathology. However, symptoms intensified during the next weeks, followed by episodes of hypotonia with head drop, instability, and inability to walk, as well as episodes of hypertonia with an inability of limp movement and dropping to the ground. Episodes lasted for minutes, presenting several times a day, without loss of conscience. Between episodes, the patient remained dysthymic, with reported loss of appetite. An awake electroencephalogram revealed a brain activity of 6 to 7c/s, with sporadic wake peak complexes in both central records, whereas the brain magnetic resonance imaging was normal. In the absence of other obvious etiology, DFP cessation was decided, after which the patient recovered within days. Chelation with DFO was restarted; the repeat electroencephalogram was normal, and the patient remained free of symptoms for the following 7 months. Because of a ferritin increase, readministration of DFP in the previous low dose was tried. Episodes of hypertonia and walking disability reappeared within a few weeks, and so permanent discontinuation of the drug was decided, with immediate and sustained improvement. Although DFP has been shown to be effective and safe in iron-load reduction in thalassemic patients, increased awareness of rare complications is required, even when the drug is used in lower doses.