Disparity in the management of iron overload between patients with sickle cell disease and thalassemia who received transfusions

BACKGROUND: Transfusion therapy is frequently used to prevent morbidity in sickle cell disease (SCD), and subsequent iron overload is common. The objective of this study was to evaluate the current standard of care in monitoring iron overload and related complications in patients with SCD compared to thalassemia (Thal). STUDY DESIGN AND METHODS: A cross‐sectional study was conducted at 31 hematology clinics in the United States, Canada, or the United Kingdom. Patients who received transfusions with a mean serum ferritin level of least 2000 ng per mL were eligible. A total of 199 patients with SCD (113 female; 24.9 ± 13.2 years) and 142 with Thal (66 female; 25.8 ± 8.1 years) were recruited, and data were collected between 2001 and 2003 by interview and medical record review. RESULTS: Although both groups were recruited on the basis of significant iron overload, the likelihood of performing a liver biopsy for routine iron monitoring was significantly higher (odds ratio [OR], 3.4; 95% confidence interval [CI], 2.2‐5.3) in Thal than SCD. Thal patients were also more likely to be screened for iron‐related organ injury including an echocardiograph for cardiomyopathy (OR, 2.6; p < 0.001; 95% CI, 1.6‐4.2), alanine aminotransferase for liver function (OR, 8.3; CI, 1.05‐64.4), and thyroid‐stimulating hormone for hypothyroidism (OR, 12.3; CI, 7.0‐21.5). For adult SCD patients, those maintained on simple transfusion with a serum ferritin level of greater than 2500 ng per mL were the least likely to have a liver biopsy (p < 0.03). CONCLUSIONS: These data highlight the unsystematic monitoring of iron and related organ injury in SCD. Until the relationship between iron and related comorbidities is better understood, routine monitoring of iron overload in SCD patients who receive transfusions should be considered a standard part of clinical care.     

Caregiving time in sickle cell disease: psychological effects in maternal caregivers

Background

Providing home care for a child with a chronic illness can be stressful for the family. The purpose of this paper is to examine patterns of caregiving and the associated psychological impact on maternal caregivers of children with sickle cell disease (SCD).

Procedure

Fourteen maternal caregivers of children with SCD were interviewed as part of a larger study of maternal caregivers of children with chronic illness. Forty‐four caregivers of children with HIV and 36 caregivers of healthy children were included as comparison groups. Interviews included questions regarding amount of time spent providing care for the child (technical care, non‐technical care, health care management), hospitalization, emergency room visits, illness stigma, and mental health of the caregiver.

Results

Children with SCD had significantly lower functional status and significantly more hospitalizations in the previous 3 months than children with HIV. Caregivers of children with SCD were more likely to work full‐time and had higher incomes than caregivers of children with HIV. The three caregiving groups did not differ significantly on amount of total care, although caregivers of children with SCD and caregivers of children with HIV both reported significantly more time spent in technical care than caregivers of healthy children. Despite lower functional status of the children in the SCD group, when group comparisons on caregiving time variables were adjusted for child's functional status, the differences between groups increased. This appeared to be due to the fact that caregivers in the HIV group spent more time in all caregiving categories except skin, crisis, and other care. In terms of caregiver mental health, caregivers of children with HIV and SCD had significantly higher depressive mood scores than caregivers of healthy children but the groups did not differ on caregiving burden.

Conclusions

The perceived care burden of caregivers of children with SCD may be related to the unpredictable nature of the crisis care they provide. Additional attention is warranted to developing adequate resources for caregivers of children with SCD to mitigate the stress of unexpected crises. Pediatr Blood Cancer 2007;48:64–71. © 2006 Wiley‐Liss, Inc.     

Bioelectrical impedance analysis of the body composition of children and adolescents with sickle cell disease

OBJECTIVES: To examine the body composition of children and adolescents with sickle cell disease (SCD) using bioelectrical impedance analysis and to determine if the impedance parameters resistance, reactance, and phase angle are able to distinguish between subjects with SCD and age- and gender matched controls. STUDY DESIGN: Total body resistance and reactance were obtained for a total of 53 subjects with SCD (27 male and 26 female) between 10 and 18 years of age and 49 control subjects (23 male and 26 female). The fat-free mass, body cell mass, phase angle, and capacitance were also determined. Group comparisons were made using the 2-sample t test. RESULTS: Male subjects with SCD had significantly lower fat-free mass (37.5 +/- 8.8 vs 43.9 +/- 12.3 kg, P =.04), body cell mass (17.4 +/- 4.3 vs 21.7 +/- 5.8 kg,P =.005), and body fat (3.7 +/- 2.6 vs 6.6 +/- 4.7 kg, P =.008) compared with controls. No significant differences in any body composition components were found for the female subjects. Both male and female subjects had significantly lower phase angle measurements (P <.001 and.006, respectively) than their respective controls, indicating possible alterations in cell membrane properties because of an imbalance in membrane composition or function. CONCLUSIONS: Bioelectrical impedance analysis can be used to determine body composition differences in children with SCD. The phase angle may provide a useful method to monitor the efficacy of therapeutic interventions in patients with SCD.     

F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study

Studies on baboons and preliminary observations in three patients with sickle cell anemia (SS) suggested that high doses of pulse administered recombinant human erythropoietin (rHuEPO) stimulate F-reticulocyte production. We now report on the administration of rHuEPO in a double- blind format to ascertain frequency of response and potential precipitation of side effects. Ten patients were enrolled, but one was discontinued due to the indication of a blood transfusion. Of the other nine, five received rHuEPO in escalating doses (from 400 to 1,500 U per kg twice daily [BID] per week), alternating with a placebo, in blinded fashion. The second group, consisting of four patients, followed an identical protocol (except starting dose was 1,000 U/Kg, BID per week) and were iron supplemented during treatment. The criterion of response was a transient doubling (as a minimum) of the steady-state F- reticulocyte level. We found that none of the five patients in the first group responded to rHuEPO, and two of them became iron deficient, as judged by a significant decrease in ferritin. Of the second group, four patients responded with F-reticulocyte increases. In three patients, open label administration of rHuEPO confirmed the effect. We observed seven painful episodes during this study, two during the EPO administration and five during the placebo arm. Three patients were phlebotomized because the hemoglobin level increased 1.5 g/dL more than steady-state levels. Of the six patients followed-up by percent dense cell determinations, one exhibited increased levels during periods of the treatment, whereas the other five showed no change. No anti-rHuEPO antibodies were detected. We conclude that rHuEPO can stimulate F- reticulocyte response in some patients with sickle cell anemia, without apparent negative clinical side effects. The state of iron stores may be critical. Whether higher doses of rHuEPO and/or a different regimen might induce sustained F cells and fetal hemoglobin increases remains to be determined.     

The diagnosis of iron deficiency anemia in sickle cell disease

We determined the prevalence and optimal methods for laboratory diagnosis of iron deficiency anemia in patients with sickle cell disease. Laboratory investigations of 38 nontransfused and 32 transfused patients included transferrin saturation, serum ferritin, mean corpuscular volume (MCV), and free erythrocyte protoporphyrin (FEP). Response to iron supplementation confirmed the diagnosis of iron deficiency anemia in 16% of the nontransfused patients. None of the transfused patients were iron deficient. All iron-deficient patients (mean age 2.4 yr) had a low MCV, serum ferritin less than 25 ng/ml, transferrin saturation less than 15%, and FEP less than 90 micrograms/dl RBC. Following therapy, all parameters improved and the hemoglobin concentration increased greater than 2 g/dl. A serum ferritin below 25 ng/ml was the most reliable screening test for iron deficiency. There were 13% false positive results with transferrin saturation, 3% with MCV, and 62% with FEP. FEP values correlated strongly with reticulocyte counts. The high FEP was in part due to protoporphyrin IX and not completely due to zinc protoporphyrin, which is elevated in iron deficiency. We conclude that iron deficiency anemia is a potential problem in young nontransfused sickle cell patients. Serum ferritin below 25 ng/ml and low MCV are the most useful screening tests.     

Echicetin: a snake venom protein that inhibits binding of von Willebrand factor and alboaggregins to platelet glycoprotein Ib

Echicetin, a new protein isolated from Echis carinatus venom by reverse phase and ion exchange chromatography specifically inhibited agglutination of fixed platelets induced by several platelet glycoprotein Ib (GPIb) agonists, such as bovine von Willebrand factor (vWF), alboaggregins, and human vWF in the presence of botrocetin. Unlike alboaggregins, echicetin bound to GPIb but did not induce agglutination of washed or fixed platelets. In contrast to disintegrins, it did not block adenosine 5'-diphosphate (ADP)-induced platelet aggregation in the presence of fibrinogen. The apparent molecular weight of echicetin measured on sodium dodecyl sulfate (SDS) gel electrophoresis was 26 Kd under nonreducing conditions. On reduction, echicetin showed 16 and 14-Kd subunits suggesting that the molecule is a dimer. Reduced echicetin retained its binding activity and its inhibitory effect on the agglutination of fixed platelets induced by bovine vWF. 125I-echicetin bound to fixed platelets with high affinity (kd = 30 +/- 1.8 nmol/L) at 45,000 +/- 2,400 binding sites per platelet. The binding was selectively inhibited by a monoclonal antibody to the 45-Kd N-terminal domain of platelet GPIb, but not by monoclonal antibodies to other regions on GPIb. Binding of 125I-bovine vWF to fixed platelets was strongly inhibited by echicetin. In contrast, bovine vWF showed a much weaker inhibitory activity on binding of 125I-echicetin to platelets. The half life of echicetin in blood was approximately 170 minutes with no detectable degradation. Echicetin significantly prolonged the bleeding time of mice, suggesting that it may inhibit vWF binding to GPIb in vivo as well as in vitro.     

Effect of surfaces on fluid-phase prekallikrein activation

The activation of prekallikrein by factor XII fragments (XIIf), during incubation in plastic tubes was previously noted to be increased by high molecular weight (HMW) kininogen as well as other plasma proteins. In this report, we investigated the mechanism responsible for this increase. Although we confirmed that HMW kininogen, bovine serum albumin, fibrinogen, cold insoluble globulin, and mixed phospholipids apparently increased prekallikrein activation, we found that the product of prekallikrein activation (kallikrein) lost substantial activity in less than 0.5 min after exposure to a variety of fresh surfaces. This loss was partially prevented by the presence of various proteins and phospholipids. Similar protection against inactivation of XIIf, the enzyme in this reaction, was also found. In contrast, no loss of the substrate, prekallikrein, was observed during incubation. The loss of kallikrein activity was found to be proportional to the surface area of the incubation vessel as well as the concentration of kallikrein. Further loss of kallikrein activity could also be prevented by pretreating the vessel with kallikrein. We therefore conclude that various substances apparently affect prekallikrein activation in a purified system by preventing the enzyme and product in the reaction mixture from losing activity due to adsorption to a surface.