Yurdanur Kilinç

β-Thalassemia in Turkey

A review is presented of the various β-thalassemia alleles observed in nearly 191 patients with β-thalassemia major and their 182 heterozygous relatives. Determination was by gene amplification and dot-blot hybridization with synthetic probes, specific for 27 different mutations. Eighteen mutations have been observed; six of these acount for nearly 83% of all thalassemia abnormalities (Table I). A new mutation, i.e. a G ↣ C mutation at the acceptor splice site of IVS-I, was found in one teenager who was homozygous for this disease. the high consanguinity among the families was considered the main reason for the high number of patients with a homozygosity for the IVS-I-110 (G ↣ A) mutation. Combinations of different mutations were present in many patients; some were mildly affected because of the specific mutation present on one chromosome. Combinations of classical β-thalassemia and an abnormal hemoglobin mainly concerned Hb S. Hbs Knossos and Lepore were rare occurrences. A comparison of hematological da...

Renal function in pediatric patients with β-thalassemia major

Abstract In patients with β-thalassemia major, the most important cause of mortality and morbidity is organ failure due to deposits of iron.. In this study, the nature of the kidney injury and possible pathogenetic factors were investigated. Seventy children with β-thalassemia major and 14 age and sex-matched healthy children were involved in the study. Blood and timed urine samples were obtained for hematological and biochemical tests. The mean values of blood urea nitrogen (BUN), serum creatinine, creatinine clearance, serum sodium, urine osmolality, fractional excretion of sodium, potassium, and uric acid were not statistically different between the groups. Serum levels of potassium, phosphorus, and uric acid and the urine volume, high urinary protein to creatinine (UP/Cr), urinary N-acetyl-β-d-glucosaminidase to creatinine (UNAG/Cr), and urinary malondialdehyde to creatinine, (UMDA/Cr) and the tubular phosphate reabsorption (TRP) values were statistically different between two groups (P<0.05). Increased serum levels of potassium, phosphorus, and uric acid in the patient group were attributed to the rapid erythrocyte turnover. The presence of high UP/Cr, UNAG/Cr and UMDA/Cr ratios shows that in these patients with proximal renal tubular damage may be secondary to oxidative lipid peroxidation mediated by the iron overload.

A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA).

Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 β-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.

Sickle cell anaemia among Eti-Turks: haematological, clinical and genetic observations

Summary. Haematological and genetic observations have been made on 71 SS Eti‐Turk patients and their relatives from Çukurova (southern Turkey) and of immigrant families in The Netherlands. Similar data were collected for 2 5 Black patients and their relatives from Surinam, Netherlands Antilles, and Kenya. Haematological and clinical results were the same for both groups; the haemolytic anaemia in the Turkish patients was as severe as in the others. Haplotyping, involving nine restriction sites, identified haplotype 19 (Antonar‐akis et al, 1984) as the major type among the Eti‐Turks; this chromosome has previously primarily been observed among SS patients from West Africa. The suggestion that the βS‐chromosome among Eti‐Turks originates from that area is supported by a relatively high incidence of α‐thalassaemia‐2 (the 3.7 kb deletion), also frequently present in the Black population of West Africa, and by the absence of other major haplotypes, such as types 20 and 3, characteristic for the βS‐chromosome in the population of Central Africa and Kenya, and in Senegal, respectively. The Saudi Arabian type of βS chromosome in association with the haplotype 19 βS chromosome was present in only one Eti‐Turk patient; this 30‐year‐old female was mildly affected and exhibited a high level of fetal haemoglobin.

In vivo prooxidant state in werner syndrome (WS) : Results from three WS patients and two WS heterozygotes

The hypothesis was tested that Werner syndrome (WS) phenotype might be associated with an in vivo prooxidant state. A set of redox-related endpoints were measured in three WS patients, two of their parents, and 99 controls within a study of some cancer-prone and/or ageing-related genetic disorders. The following analytes were measured: (a) leukocyte 8-hydroxy-2′-deoxyguanosine; (b) glutathione from whole blood, and (c) plasma levels of glyoxal, methylglyoxal, 8-isoprostane, and some plasma antioxidants (uric acid, ascorbic acid, α- and γ-tocopherol). Leukocyte 8-hydroxy-2′-deoxyguanosine levels showed a significant increase in the 3 WS patients vs. 85 controls (p<10−7). The disulfide glutathione:glutahione ratio was significantly altered in WS patients (p=0.005). Glyoxal and methylglyoxal levels were significantly increased (p=0.018 and p=0.007, respectively). The plasma levels of uric acid (p=0.002) and ascorbic acid (p=0.003) were also increased significantly in WS patients and in their parents. No significant alterations were found in the plasma levels of α- and γ-tocopherol, nor of 8-isoprostane. This is the first report of in vivo alterations of oxidative stress parameters in WS patients. Further investigations on more extensive study populations are warranted to verify the relevance of an in vivo prooxidant state in WS patients.

Natural coagulation inhibitors (protein C, protein S, antithrombin) in patients with sickle cell anemia in a steady state.

Abstract Background : Patients with sickle cell anemia (SCA) run the risk of having decreased levels of natural coagulation inhibitors. This may be due to either hemostatic abnormalities or hepatic dysfunction. This study is designed to evaluate coagulation profiles of patients with SCA in a steady state and to determine whether hypercoagulable state is present or not.

Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload

Deferasirox (DFX) monotherapy is effective for reducing myocardial and liver iron concentrations (LIC), although some patients may require intensive chelation for a limited duration. HYPERION, an open-label single-arm prospective phase 2 study, evaluated combination DFX-deferoxamine (DFO) in patients with severe transfusional myocardial siderosis (myocardial [m] T2* 5-<10 ms; left ventricular ejection fraction [LVEF] ≥56%) followed by optional switch to DFX monotherapy when achieving mT2* >10 ms. Mean dose was 30.5 mg/kg per day DFX and 36.3 mg/kg per day DFO on a 5-day regimen. Geometric mean mT2* ratios (Gmeanmonth12/24/Gmeanbaseline) were 1.09 and 1.30, respectively, increasing from 7.2 ms at baseline (n = 60) to 7.7 ms at 12 (n = 52) and 9.5 ms at 24 months (n = 36). Patients (17 of 60; 28.3%) achieved mT2* ≥10 ms and ≥10% increase from baseline at month 24; 15 switched to monotherapy during the study based on favorable mT2*. LIC decreased substantially from a baseline of 33.4 to 12.8 mg Fe/g dry weight at month 24 (-52%). LVEF remained stable with no new arrhythmias/cardiac failure. Five patients discontinued with mT2* <5 ms and 1 died (suspected central nervous system infection). Safety was consistent with established monotherapies. Results show clinically meaningful improvements in mT2* in about one-third of patients remaining on treatment at month 24, alongside rapid decreases in LIC in this heavily iron-overloaded, difficult-to-treat population. Combination therapy may be useful when rapid LIC reduction is required, regardless of myocardial iron overload. This trial was registered at www.clinicaltrials.gov as #NCT01254227.

Sustained improvements in myocardial T2*over 2 years in severely iron-overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine

Long‐term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion‐dependent beta thalassemia patients. In a 1‐year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving deferasirox for 24 months (n = 74; geometric mean [Gmean] ratio of month 24/baseline 1.38 [95% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; Gmean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* < 10 vs. ≥ 10 ms) or liver (LIC <15 vs. ≥15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 12.1 mg Fe/g dw in DFO patients. The long‐term safety profile of deferasirox or DFO was consistent with previous reports; serious drug‐related AEs were reported in 6.8% of deferasirox and 6.9% of DFO patients. Continued treatment of severely iron‐overloaded beta thalassemia patients with deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron (Clinicaltrials.gov identifier: NCT00600938). Am. J. Hematol. 90:91–96, 2015.

Prevalence and distribution of iron overload in patients with transfusion-dependent anemias differs across geographic regions: results from the CORDELIA study

The randomized comparison of deferasirox to deferoxamine for myocardial iron removal in patients with transfusion‐dependent anemias (CORDELIA) gave the opportunity to assess relative prevalence and body distribution of iron overload in screened patients.

Safety and efficacy of turoctocog alfa (NovoEight®) during surgery in patients with haemophilia A: results from the multinational guardian™ clinical trials

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prevention and treatment of bleeding episodes in patients with haemophilia A. The present investigations from the multinational, open‐label guardian™ clinical trials assessed the haemostatic response of turoctocog alfa (NovoEight®), a rFVIII product, in patients with severe haemophilia A (FVIII ≤ 1%) undergoing surgery. All patients had a minimum of 50 exposure days to any FVIII product prior to surgery and no history of inhibitors. A total of 41 procedures (13 orthopaedic, 19 dental and 9 general) were performed in 33 patients aged 4–59 years. Of the 41 procedures, 15 were major surgeries in 13 patients and 26 were minor surgeries in 21 patients. The success rate for haemostatic response was 100% (success was defined as ‘excellent’ or ‘good’ haemostatic outcome). Turoctocog alfa consumption on the day of surgery ranged from 27 to 153 IU kg−1. The mean daily dose declined over time, while retaining adequate FVIII coverage as measured by trough levels. Overall, no safety issues were identified. No thrombotic events were observed and none of the patients developed FVIII inhibitors. In conclusion, the present results show that turoctocog alfa was effective in controlling blood loss by obtaining a sufficient haemostatic response in patients with severe haemophilia A undergoing surgery.