Robert I. Liem

Challenges of alloimmunization in patients with haemoglobinopathies

Red blood cell (RBC) transfusions can be life‐sustaining in chronic inherited anaemias, such as thalassaemia, and the indications for blood transfusions in patients with sickle cell disease continue to expand. Complications of transfusions, such as allosensitization, can create significant medical challenges in the management of patients with haemoglobinopathies. This review summarizes key findings from the medical literature related to alloimmunization in haemoglobinopathies and examines potential measures to mitigate these risks. Areas where future studies are needed are also addressed.

Tricuspid regurgitant jet velocity is associated with hemolysis in children and young adults with sickle cell disease evaluated for pulmonary hypertension

Tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/sec. on echocardiography is a surrogate marker for pulmonary hypertension (PHT) in adults with sickle cell disease (SCD). We prospectively examined the relationship between TRJV and laboratory markers of hemolysis in 51 children and young adults with SCD at baseline. We found significant correlations between TRJV and lactate dehydrogenase (LDH), hemoglobin (Hb), reticulocyte count (retic) and aspartate aminotransferase (AST). LDH, retic and AST were significantly higher and Hb was lower in subjects with TRJV ≥ 2.5 m/sec. We conclude that hemolysis significantly contributes to TRJV elevation in children and young adults with SCD.

Alloimmunization in sickle cell anemia in the era of extended red cell typing.

Red blood cell (RBC) transfusion remains an essential part of the management of patients with sickle cell disease (SCD). Alloimmunization is a major complication of transfusions. Extended RBC typing is advocated as a means to reduce alloimmunization in SCD. Our goal was to assess alloimmunization among individuals with SCD at our center since implementing extended RBC typing.

Technology Access and Smartphone App Preferences for Medication Adherence in Adolescents and Young Adults With Sickle Cell Disease

Hydroxyurea is the only Food and Drug Administration approved medication for sickle cell disease (SCD) with short‐ and long‐term benefits for both morbidity and mortality. However, hydroxyurea underutilization and adherence remain challenges for patients with SCD. The objectives of this study were to determine access to technology among adolescents and young adults (AYA) with SCD and to identify their preferred technology‐based strategies for improving medication adherence.

A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children

Magnesium, a vasodilator, anti-inflammatory, and pain reliever, could alter the pathophysiology of sickle cell pain crises. We hypothesized that intravenous magnesium would shorten length of stay, decrease opioid use, and improve health-related quality of life (HRQL) for pediatric patients hospitalized with sickle cell pain crises. The Magnesium for Children in Crisis (MAGiC) study was a randomized, double-blind, placebo-controlled trial of intravenous magnesium vs normal saline placebo conducted at 8 sites within the Pediatric Emergency Care Applied Research Network (PECARN). Children 4 to 21 years old with hemoglobin SS or Sβ(0) thalassemia requiring hospitalization for pain were eligible. Children received 40 mg/kg of magnesium or placebo every 8 hours for up to 6 doses plus standard therapy. The primary outcome was length of stay in hours from the time of first study drug infusion, compared using a Van Elteren test. Secondary outcomes included opioid use and HRQL. Of 208 children enrolled, 204 received the study drug (101 magnesium, 103 placebo). Between-group demographics and prerandomization treatment were similar. The median interquartile range (IQR) length of stay was 56.0 (27.0-109.0) hours for magnesium vs 47.0 (24.0-99.0) hours for placebo (P = .24). Magnesium patients received 1.46 mg/kg morphine equivalents vs 1.28 mg/kg for placebo (P = .12). Changes in HRQL before discharge and 1 week after discharge were similar (P > .05 for all comparisons). The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis. This trial was registered at www.clinicaltrials.gov as #NCT01197417.

Mutation of a barrier insulator in the human ankyrin-1 gene is associated with hereditary spherocytosis

Defects of the ankyrin-1 gene are the most common cause in humans of hereditary spherocytosis, an inherited anemia that affects patients of all ethnic groups. In some kindreds, linked -108/-153 nucleotide substitutions have been found in the upstream region of the ankyrin gene promoter that is active in erythroid cells. In vivo, the ankyrin erythroid promoter and its upstream region direct position-independent, uniform expression, a property of barrier insulators. Using human erythroid cell lines and primary cells and transgenic mice, here we have demonstrated that a region upstream of the erythroid promoter is a barrier insulator in vivo in erythroid cells. The region exhibited both functional and structural characteristics of a barrier, including prevention of gene silencing in an in vivo functional assay, appropriate chromatin configuration, and occupancy by barrier-associated proteins. Fragments with the -108/-153 spherocytosis-associated mutations failed to function as barrier insulators in vivo and demonstrated perturbations in barrier-associated chromatin configuration. In transgenic mice, flanking a mutant -108/-153 ankyrin gene promoter with the well-characterized chicken HS4 barrier insulator restored position-independent, uniform expression at levels comparable to wild-type. These data indicate that an upstream region of the ankyrin-1 erythroid promoter acts as a barrier insulator and identify disruption of the barrier element as a potential pathogenetic mechanism of human disease.

Health-related quality of life in children with sickle cell anemia: impact of blood transfusion therapy

The completion of the Multicenter Silent Infarct Transfusion Trial demonstrated that children with pre‐existing silent cerebral infarct and sickle cell anemia (SCA) who received regular blood transfusion therapy had a 58% relative risk reduction of infarct recurrence when compared to observation. However, the total benefit of blood transfusion therapy, as assessed by the parents, was not measured against the burden of monthly blood transfusion therapy. In this planned ancillary study, we tested the hypothesis that a patient centered outcome, health‐related quality of life (HRQL), would be greater in participants randomly assigned to the blood transfusion therapy group than the observation group. A total of 89% (175 of 196) of the randomly allocated participants had evaluable entry and exit HRQL evaluations. The increase in Change in Health, measured as the childs health being better, was significantly greater for the transfusion group than the observation group (difference estimate = −0.54, P ≤ 0.001). This study provides the first evidence that children with SCA who received regular blood transfusion therapy felt better and had better overall HRQL than those who did not receive transfusion therapy. Am. J. Hematol. 90:139–143, 2015.

Tricuspid regurgitant jet velocity elevation and its relationship to lung function in pediatric sickle cell disease.

Concerns about the morbidity and mortality associated with tricuspid regurgitant jet velocity (TRJV) elevation, which may indicate pulmonary hypertension (PHT), in adults with sickle cell disease (SCD) have prompted growing interest in screening the pediatric sickle cell population. The goals of our study were to estimate the prevalence of TRJV elevation and determine its relationship to pulmonary function in children and young adults with SCD at baseline. Seventy‐eight subjects (10–24 years old) with SCD underwent prospective screening by Doppler echocardiogram (ECHO), complete lung function evaluation, and laboratory testing as part of standard care at steady state. Tricuspid regurgitation was quantifiable in 68/78 (87%) subjects and peak TRJV was ≥2.5 m/sec in 26/78 (33.3%) evaluated. The frequency of obstruction, restriction, or abnormal gas exchange found on lung function evaluation was not significantly different in subjects with and without TRJV elevation. However, significant inverse correlations were observed between TRJV and both % predicted forced vital capacity (FVC) (r = −0.29, P = 0.022) and oxygen saturation (r = −0.26, P = 0.036). When compared to subjects without TRJV elevation, subjects with TRJV elevation had significantly lower % predicted forced expiratory volume in 1 sec (FEV1) (78.9 ± 14.4 vs. 86.6 ± 13.0%, P = 0.023), FVC (82.8 ± 14.1 vs. 90.7 ± 12.9%, P = 0.017), and oxygen saturation (95.8 ± 3.2 vs. 97.5 ± 2.4%, P = 0.016). We found that the combination of low hemoglobin and low % predicted FVC best predicted TRJV elevation (χ2 = 17.05, P = 0.001) in our cohort, correctly identifying 70% of cases and resulting in positive and negative predictive values of 60 and 74%, respectively. We conclude that in this young population with SCD, TRJV elevation that is not significantly associated with abnormal lung function is common at baseline. Pediatr Pulmonol. 2009; 44:281–289.

Functional capacity in children and young adults with sickle cell disease undergoing evaluation for cardiopulmonary disease

Although cardiopulmonary disease is associated with decreased functional capacity among adults with sickle cell disease (SCD), its impact on functional capacity in children with SCD is unknown. We evaluated 6‐min walk (6MW) distance in 77 children and young adults with SCD undergoing screening for cardiopulmonary disease. Of 30 subjects who also underwent cardiopulmonary exercise testing, we found evidence for decreased exercise capacity in a significant proportion. Exercise capacity was related to baseline degree of anemia and was significantly lower in subjects with a history of recurrent acute chest syndrome. We found that 6MW distance adjusted for weight and body surface area was shorter in subjects with restrictive lung disease but that only 6MW adjusted for weight remained significantly shorter when we controlled for baseline hemoglobin. Exercise capacity was not significantly different in subjects with and without cardiopulmonary disease. We conclude that restrictive lung disease is associated with shorter 6MW distances in children and young adults with SCD, but that variables associated with decreased exercise capacity, other than anemia, remain unclear. Our study underscores the importance of further delineating the direct pathophysiologic processes that contribute to decreased exercise capacity observed among individuals with SCD and cardiopulmonary disease. Am. J. Hematol., 2009.

Association of sickle cell trait with hemoglobin A1c in African Americans

Importance Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it. Objective To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans. Design, Setting, and Participants Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures. Exposures Presence of SCT. Main Outcomes and Measures Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure. Results The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, −0.29%; 95% CI, −0.35% to −0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of −0.30% (95% CI, −0.39% to −0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons). Conclusions and Relevance Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.