Hyperhaemolytic transfusion reaction in two ß-thalassaemia major patients: The role of eculizumab.

WHAT IS KNOWN AND OBJECTIVE: Hyperhaemolytic transfusion reactions are rare life-threatening events predominantly affecting patients with haemoglobinopathies. We report two cases in ß-thalassaemia major patients on chronic transfusion therapy and highlight the role of eculizumab in its management. CASE SUMMARY: Patient 1 presented with intravascular haemolysis on day 7 (D7) post-transfusion and responded to treatment with corticosteroids and intravenous immunoglobulin. However, patient 2 presented with severe symptomatic anaemia (D4 post-transfusion) unresponsive to the aforementioned measures. Eculizumab administration led to resolution of the hyperhaemolysis. WHAT IS NEW AND CONCLUSION: We report the successful management of hyperhaemolysis with eculizumab in a ß-thalassemia major patient.

Prediction of long-term survival in patients with transfusion-dependent hemoglobinopathies: Insights from cardiac imaging and ferritin.

AIMS: The current study evaluated the association of echocardiography, cardiac magnetic resonance (CMR), and ferritin data with 10-year survival in thalassemia patients. METHODS: Demographics, ferritin, echocardiography, and CMR parameters of stable consecutive thalassemia patients were prospectively collected. RESULTS: In total, 75 patients (mean age 37 ± 11 years, 45% male) with thalassemia were included and dichotomized based on their survival status after a median follow-up period of 10.3 [9.6-10.9] years. Older age (HR: 1.071, p = 0.001), ferritin ≥2000 ng/ml (HR: 4.682, p = 0.007) and ≥1700 ng/ml (HR: 7.817, p = 0.002), elevated LV end-diastolic pressure (HR: 1.019, p = 0.044), TR Vmax >2.8 m/s (HR: 6.845, p = 0.005), and CMR T2∗ ≤20 msec (HR: 3.602, p = 0.043) and ≤34 msec (HR: 5.854, p = 0.026) were associated with increased all-cause mortality (primary endpoint). A baseline model including age was created and became more predictive of worse survival by adding TR Vmax >2.8 m/s instead of elevated LV end-diastolic pressure (C index 0.767 vs. 0.760, respectively), ferritin ≥1700 ng/ml instead of ≥2000 ng/ml (C index 0.890 vs. 0.807, respectively), or CMR T2∗≤34 msec instead of ≤20 msec (C index 0.845 vs. 0.839, respectively). Parameters associated with the combined endpoint of cardiac mortality/cardiac hospitalization (secondary endpoint) after adjusting for age were ferritin ≥1700 ng/ml (HR 3.770, p = 0.014), ratio E/A wave >2 (HR 3.565, p = 0.04), TR Vmax >2.8 m/s (HR 4.541, p = 0.049), CMR T2∗ ≤20 ms (HR 9.462, p = 0.001), and CMR T2∗ ≤34 ms (HR 11.735, p = 0.002). The model including age and T2∗ ≤34 ms instead of T2∗ ≤20 ms was more predictive of the secondary endpoint (C-index 0.844 vs 0.838, respectively). CONCLUSIONS: In thalassemia patients, TR Vmax >2.8 m/s, ferritin ≥2000 ng/ml, and CMR T2∗ ≤20 ms were associated with worse long-term survival. In the current era of advanced chelation therapy, aiming for ferritin ≤1700 ng/ml and CMR T2∗ ≥34 ms may improve their prognosis.

Left Atrial Strain Identifies Increased Atrial Ectopy in Patients with Beta-Thalassemia Major.

Patients with beta-thalassemia major (ß-ΤΜ) may develop cardiac arrhythmias through a multifactorial mechanism. The current study evaluated the association of cardiac structure and function on echocardiography with atrial ectopic burden on 24-hour tape recording in ß-ΤΜ patients. This prospective study included consecutive ß-ΤΜ patients. Demographic, laboratory, echocardiographic, cardiac magnetic resonance (CMR) T2* and 24-hour tape recording data were prospectively collected. The patients were classified according to the median value of premature atrial contractions (PACs) on 24-hour tape. In total, 50 ß-TM patients (37.6 ± 9.1 years old, 50% male) were divided in 2 groups; PACs ≤ 24/day and > 24/day. Patients with PACs > 24/day were treated with blood transfusion for a longer period of time (39.0 ± 8.6 vs. 32.0 ± 8.9 years, p < 0.007), compared to their counterparts. Older age (OR: 1.121, 95% CI: 1.032-1.217, p = 0.007), longer duration of blood transfusion (OR:1.101, 95% CI:1.019-1.188, p = 0.014), larger LV end-diastolic diameter (OR: 4.522, 95% CI:1.009-20.280, p = 0.049), higher values of LA peak systolic strain (OR: 0.869, 95% CI: 0.783-0.964, p = 0.008), higher MV E/E' average (OR: 1.407, 95% CI: 1.028-1.926, p = 0.033) and higher right ventricular systolic pressure (OR: 1.147, 95% CI: 1.039-1.266, p = 0.006) were univariably associated with PACs > 24/day. LA peak systolic strain remained significantly associated with PACs > 24/day after adjusting for the duration of blood transfusions or for CMR T2*. The multivariable model including blood transfusion duration and LA peak systolic strain was the most closely associated with PACs > 24/day. Receiver operating characteristic curve analysis identified a left atrial peak systolic strain of 31.5%, as the best cut-off value (83% sensitivity, 68% specificity) for prediction of PACs > 24/day. In ß-TM patients, LA peak systolic strain was associated with the atrial arrhythmia burden independently to the duration of blood transfusions and CMR T2*.

Insulin Secretion and Resistance in Normoglycemic Patients with Sickle Cell Disease.

Diabetes mellitus has been described in chronic hemolytic anemias, but data are scarce regarding glucose metabolism in normoglycemic patients. To address this issue, we evaluated insulin sensitivity and secretion in patients with sickle cell disease (SCD) and normal oral glucose tolerance test (OGTT). Forty-five adult patients with homozygous sickle cell disease and Hb S/ß-thalassemia (ß-thal) (mean age 42.5 ± 9.5 years) and 45 healthy individuals matched for age and body mass index (BMI) were included in the study. All participants underwent an oral glucose tolerance test (OGTT) after an overnight fast. All patients had normal OGTT. Fasting glucose values did not differ significantly between groups, however, fasting insulin levels were significantly lower in the patient group compared to the control group (5.1 ± 2.7 µUI/mL vs. 11.3 ± 6.6 µUI/mL, p <0.005, respectively). Pancreatic ß-cell insulin secretion index in the fasting state was significantly lower in patients with sickle cell disease compared with controls as assessed by calculations of the homeostatic model assessment for ß-cell function (HOMA ß%) (77.0 vs. 106.0%, respectively, p <0.001), while HOMA insulin resistance (HOMA IR), was lower in the sickle cell disease patients, albeit not statistically significant (0.8 vs. 1.1, respectively, p = 0.054). The HOMA ß% was significantly correlated with ferritin levels (r = -526, p <0.001) (negative correlation) and with 25-hydroxy (OH)-vitamin D levels (r = 0.479, p <0.001) (positive correlation), even when adjusted for serum ferritin levels. Normoglycemic patients with sickle cell disease demonstrated impaired ß-cell function with reduced insulin secretion even before OGTT was impaired.

Arterial Stiffness and Peripheral and Central Blood Pressure in Patients With Sickle Cell Disease.

Blood pressure (BP) in patients with sickle cell disease (SCD) has been reported to be lower than in persons in the general population. Data on arterial stiffness, which is an important risk factor for the progression of BP, are inconclusive for this patient population. Forty-five adult patients with SCD and 40 controls matched for sex, age, and body mass index were studied. Brachial systolic BP (SBP) and diastolic BP (DBP) were significantly lower in the patient group (SBP 115.1±13.8 mm Hg vs 121.9±11.3 mm Hg and DBP 68.5±8.0 mm Hg vs 80.6±9.1 mm Hg, P<.05, respectively). Augmentation index (AIx), however, was significantly higher in SCD patients compared with healthy controls (24.9±9.6 for patients vs 12.4±10.8 for controls, P<.001), while carotid femoral pulse wave velocity was comparable between the two groups. The study shows that mechanisms other than arterial elasticity are involved in the low BP phenotype of patients with SCD.

Dynamics of telomere's length and telomerase activity in Philadelphia chromosome negative myeloproliferative neoplasms.

Telomere exhaustion and increased telomerase activity are associated with the acquisition of aggressive molecular events in a variety of haematological malignancies. In Philadelphia chromosome negative myeloproliferative neoplasms (Ph(neg)MPN's), telomere dynamics during clonal evolution of these diseases have not yet been fully elucidated. Herein we demonstrated that telomere shortening is a global phenomenon in Ph(neg)MPN's, irrespective of disease phenotype, treatment administration and JAK2V617F mutational status but the presence of additional cytogenetic abnormalities further affects them. Consistent with the above finding, TA was upregulated in CD34+ haemopoietic progenitors from almost all Ph(neg)MPN subgroups compared to healthy donors. Moreover, TL below the cut-off value of 27% could predict disease progression in Ph(neg)MPN patients (PFS at 5 years 39% vs 81%). Thus, TL emerges as a new prognostic marker in Ph(neg)MPN, reflecting probably the genetic instability of highly proliferating MPN clones.

Pregnancy in beta-thalassemia trait carriers: an uneventful journey.

Normochromic normocytic anemia during pregnancy reflects the significant increase in plasma volume, which disproportionately exceeds the increase in the red cell volume. In beta-thalassemia (beta-thal) trait carriers who become pregnant the plasma volume expansion may cause more pronounced anemia because the anemia of pregnancy is added to the pre-existed hypochromic microcytic anemia. In beta-thal women, pregnancy outcome and obstetric complications do not differ from the general population. Anemia in beta-thal carriers is generally not severe enough to warrant anxiety. No specific therapy is indicated and pregnant women generally require only supportive care with an anticipated favorable pregnancy outcome.

In vitro effects of the farnesyltransferase inhibitor tipifarnib on myelodysplastic syndrome progenitors.

BACKGROUND: Farnesyltransferase inhibitors (FTIs) target proteins needing prenylation for functioning. Tipifarnib (Zarnestra), a potent and specific inhibitor of farnesyltransferase, showed considerable activity in phase I and II studies in myelodysplastic syndrome (MDS), but the optimal regimen achieving high response rates with minor myelosuppression remains to be determined. Additionally, a direct effect on purified human MDS progenitors has not yet been shown. METHODS: MDS and normal CD34+ cells isolated by using immunomagnetic beads were plated for short-term cultures in semisolid media or liquid cultures for flow-cytometric assessment of apoptosis in the presence of either DMSO or various FTI concentrations. RESULTS: Tipifarnib exerted selective in vitro toxicity against clonal MDS hematopoiesis at concentrations less than 10 nM the effect being more prominent in white cell progenitors. This action was not due to apoptosis induction as both normal and MDS progenitors displayed equivalent DiOC3 and annexin V expression up to 72 h after exposure to tipifarnib. CONCLUSION: The leukemic clone is more susceptible in tipifarnib than normal progenitors. Since myelosuppression represents the main obstacle in the clinical use of tipifarnib in MDS, further reduction of the currently employed dose will potentially result in a more tolerable regimen without compromising its antileukemic action.

Warm autoimmune hemolytic anemia following recurrent mycoplasma pneumonia infections in a child with Down syndrome.

Mycoplasma pneumonia (MP) is mainly associated with cold agglutinin syndrome, whereas both cold IgM and warm IgG autoantibodies have been identified in only two cases in the literature. The authors present an 8-year-old boy with Down syndrome, who suffered from recurrent episodes of MP infection, followed by episodes of hemolytic anemia with normal titer of cold agglutinins. The first 6 episodes were sequenced by nonimmune hemolytic anemia, whereas the latter 7 episodes were followed by episodes of warm autoimmune hemolytic anemia. This is believed to be the first described case of hemolytic anemia with warm IgG autoantibodies, following MP infection.

Amifostine stimulates the formation of hematopoietic bone marrow progenitors from B-cell chronic lymphocytic leukemia.

Amifostine is a phosphorylated aminothiol that not only protects hematopoietic progenitor cells from chemotherapy and radiotherapy, but also stimulates normal hematopoiesis. The effect of amifostine on the in vitro growth of hematopoietic progenitors derived from B-cell chronic lymphocytic leukemia(B-CLL) was investigated. The colony-forming units (CFU)-granulocyte macrophage (CFU-GM), the burst-forming units-erythroid (BFU-E) and the CFU-granulocyte erythroid macrophage megakaryocytes (CFU-GEMM) increased 38, 20 and 100%, respectively, after the incubation with amifostine. There was no statistical difference in the in vitro progenitor growth of patients grouped according to their disease stage, bone marrow lymphocytic infiltration or therapy. Our data indicate that apart from cytoprotection the parallel use of amifostine and chemotherapy in patients with B-CLL could enhance bone marrow recovery.