Hydroxyurea utilization among individuals with sickle cell disease in Tennessee: a pooled analysis of claims data

Importance: Hydroxyurea reduces severe disease among individuals living with sickle cell disease (SCD). These individuals experience high acute care utilization, but the associations between patterns of hydroxyurea utilization and healthcare utilization are not well investigated.

Objective: This study aimed to determine the association between hydroxyurea use and healthcare utilization among individuals with SCD in Tennessee (TN).

Design: We conducted a population-based, retrospective cohort study of individuals with SCD using secondary data analysis of Tennessee Medicaid, Medicare, and BlueCross BlueShield of Tennessee (BCBS-TN).

Participants: A total of 4,901 individuals with SCD were included in the study.

Exposure: Hydroxyurea adherence was estimated using the medication possession ratio (MPR).

Main Outcomes and measures: The incidence rate ratios of hospitalizations, emergency department visits, and mortality were calculated using negative-binomial models.

Results: The prevalence of hydroxyurea prescription dispensation for the state was low (21% for TennCare, 21% for Medicare, and 17% for BCBS-TN). In TennCare and BCBS-TN, those younger than 18 had more hydroxyurea utilization, and individuals with HbSS or HbSβ⁰ thalassemia filled more hydroxyurea than those with other subtypes (30.5% in TennCare and 23.4% in BCBS-TN). The MPR for the entire state was 19.7%. There was a dose–response relationship between hydroxyurea adherence and the incidence of acute healthcare utilization, except in 18–25-year-olds. We also found lower mortality in those with higher hydroxyurea adherence.

Conclusion and relevance: In our pooled statewide analysis, hydroxyurea MPR was low. Higher hydroxyurea use was associated with decreased acute healthcare utilization and lower mortality. Interventions to support patient adherence and provider prescribing are required to improve health outcomes among individuals with SCD.

Highlights

1. The prevalence of hydroxyurea prescription dispensation and medication adherence in individuals with sickle cell disease living in Tennessee was low.

2. There was a dose–response relationship between hydroxyurea adherence (calculated by the medication possession ratio) and acute healthcare utilization, except for 18–25-year-olds.

3. Individuals with sickle cell disease who had higher hydroxyurea adherence had lower mortality rates.

Introduction

In the United States, health-related outcomes for individuals with sickle cell disease (SCD) have improved substantially with increased access to and adherence to evidence-based care in recent years (Neumayr et al., 2019). Along with shortened overall life expectancy, individuals living with SCD have significant impairment in the quality of life (QOL) compared to those without SCD (Stokoe et al., 2022; Freitas et al., 2018). The impact of SCD on QOL is substantial and is associated with numerous and compounding clinical complications leading to increased acute healthcare utilization (Moody, 2022). Individuals with SCD live approximately 2 decades less than those without the disease, with life expectancy in the United States estimated to be 54 years (Lubeck et al., 2019; Lee et al., 2019). Chronic clinical complications of SCD have a profound impact on patients, their caregivers, and society (Asnani et al., 2016; Hood et al., 2021).

Hydroxyurea is associated with decreased SCD-related severe clinical outcomes (e.g., pain crises, stroke, and organ damage) and healthcare resource utilization (Candrilli et al., 2011; Alina et al., 2001; Hankins et al., 2014; Steinberg et al., 2010; Agrawal et al., 2014; Mathias et al., 2020). However, the effectiveness of hydroxyurea is contingent on the initiation of and continued adherence to hydroxyurea (Creary et al., 2015; Ware et al., 2019). Despite overwhelming evidence of safety, efficacy, ease of use, and national guideline recommendations, hydroxyurea remains underutilized, with suboptimal adherence (Candrilli et al., 2011; Badawy et al., 2017a; Dean et al., 2010; Loiselle et al., 2016; Badawy et al., 2017b; Badawy et al., 2017c; Tshilolo et al., 2019; Ware et al., 2016; Wong et al., 2014).

Population-level studies on hydroxyurea utilization are limited, with few studies examining medical claims data from the United States, and those that did included only individuals with continuous Medicaid enrollment (Candrilli et al., 2011; Brousseau et al., 2019; Kang and Barner, 2020; Crego et al., 2020). The extent of the consequences of hydroxyurea underutilization is, thus, understudied at the population level and across different health insurance coverages. To better represent the broad population of people with SCD, we analyzed enrollees of Tennessee Medicaid or TennCare, Medicare, and BlueCross BlueShield of Tennessee (BCBS-TN) with a diagnosis of SCD in a single state. Collectively, these three plans (two governmental plans, TennCare and Medicare; one private plan, BCBS-TN) account for over 80% of Tennesseans with SCD; therefore, our analysis constitutes a statewide, population-based, cross-sectional sample, which is likely representative of the state’s SCD population.

We aimed to investigate the affect of hydroxyurea adherence on acute healthcare utilization and mortality among individuals with SCD in Tennessee. We hypothesized that higher hydroxyurea possession, as a surrogate for medication adherence, was associated with lower acute healthcare utilization and mortality in individuals eligible for hydroxyurea therapy.

Methods

Study cohort

We constructed the cohort retrospectively from TennCare, Medicare, and BCBS-TN claims of individuals with SCD during the study period of 1 January 2010 to 30 September 2015. The timeframe was chosen to restrict the analysis to only the ICD-9 classification since the ICD-10 diagnosis codes began being used in October 2015.

TennCare is the state of Tennessee’s Medicaid program. It provides healthcare coverage to people who meet certain income and resource eligibility criteria. More than 1.4 million Tennesseans have access to TennCare, including low-income individuals, pregnant women, children, caretakers of young children and older adults, and adults with disabilities (TennCare, 2025). The Tennessee Medicare program, a federal medical insurance plan, provides coverage to more than 800,000 Tennesseans who are either older than 65 years of age or have a qualifying disability (Disability TCoA, 2025). TennCare currently provides data to the Tennessee Sickle Cell Data Collection Program (SCDC-TN). BCBS-TN is a private, non-profit insurance company that covers 3.3 million members. They are the state’s largest insurance provider, and over 10,000 employers use BCBS-TN to provide health plans for their employees (Tennessee BBo, 2025). Collectively, these three insurance plans cover 83.4% of Tennesseans.

The study cohort constituted participants who satisfied the following criteria: i) had a diagnosis of SCD, defined as having one of the ICD-9 (282.60–64, 68, 69) diagnosis codes; ii) had at least one hospitalization or two outpatient visits or emergency department (ED) encounters (or a combination of one ED visit and one outpatient visit) with the aforementioned diagnoses codes; and iii) were enrolled in TennCare, Medicare, or BCBS-TN plans during the study period. We defined the eligibility for hydroxyurea prescription similarly to the published national guidelines, which are detailed in Supplemental Methods (Yawn et al., 2014). Although the national hydroxyurea guidelines were not published until 2014, we based this decision on evidence from phase-III clinical trials (Charache et al., 1995; Wang et al., 2011) that used similar hydroxyurea initiation criteria to reflect the current indications as a benchmark for future comparisons. The study follow-up time for an individual began on the date of hydroxyurea eligibility fulfillment. The participants’ follow-up period ended at death, loss of enrollment in the health plans, or at the end of the study period, whichever occurred first. Individuals included in the analysis were able to re-enter the study cohort after a lapse in coverage. In this case, the new cohort entrance is considered a new “segment,” which is treated as a new independent observation from the prior study segment.

With approval from the Tennessee Department of Health and the Vanderbilt University Medical Center Institutional Review Boards, we obtained research identification files that consisted of individual-level protected health information, including enrollment records, pharmacy files, and inpatient and outpatient records that were customizable for a specific cohort, such as SCD.

Hydroxyurea exposure

Participants were classified according to their estimated amount of exposure to hydroxyurea. We defined current hydroxyurea users as those who had a hydroxyurea prescription dispensed on the day hydroxyurea eligibility was fulfilled. Prescriptions that were not dispensed are not captured in these data sources. The medication possession ratio (MPR) was used as a proxy of hydroxyurea adherence and calculated by dividing the number of days of hydroxyurea prescriptions dispensed by the total number of follow-up days for each patient (Supplemental Methods) (Candrilli et al., 2011; Kang and Barner, 2020; Shah et al., 2019). The hydroxyurea exposure variable was categorized as <40% (reference), 40%–80%, and >80% for TennCare and BCBS-TN and 0%, 0%–20%, and >20% for Medicare to account for small (n < 11) cell sizes. For the negative binomial modeling described in the Statistical Analysis subsection below, <40% was used as the reference, but this did not include those who had no utilization. No utilization was defined as a separate category for modeling purposes.

Outcomes

Study outcomes included acute healthcare utilization (hospitalizations, transfusions, and ED visits) and all-cause mortality. For each outcome, the incidence rate was calculated by enumerating specific utilization (i.e., hospitalizations, transfusions, ED visits, or mortality) occurring in an interval (a time period representing no changes in comorbidities, hydroxyurea eligibility, or hydroxyurea use status) and dividing it by the follow-up time in days during that interval.

Covariates

Demographic covariates that were evaluated as potential confounders included the age group (<18 for TennCare and BCBS-TN, 18–25 years, and >25 years), sex, disease type (HbSS or HbSβ⁰ thalassemia versus HbSC, HbSβ⁺ thalassemia, and others), and the region of the state (East, Middle, and West TN). Clinical covariates included the presence of any comorbidities (asthma, diabetes, pulmonary hypertension, stroke, chronic renal failure, congestive heart failure, seizure, hypertension, cancer, hematologic disease other than sickle cell, neuromuscular disease, chromosomal anomaly, cardiovascular and non-cardiovascular congenital anomalies, gastrointestinal disease, HIV or other serious infections, immune deficiency, cardiorespiratory disease, organ transplantation, and other serious ailments) at baseline and a visit to a hematologist in the year prior to study initiation.

Statistical analyses

Chi-squared and Kruskal–Wallis tests were used to assess whether the prevalence of hydroxyurea use varied by demographic characteristics and whether ordered categories of hydroxyurea adherence varied by demographic characteristics, respectively. A similar analysis was repeated for the subset of individuals with HbSS or HbSβ⁰ thalassemia. For mortality analysis, we reported deaths by categories of hydroxyurea adherence among hydroxyurea-eligible patients who were current users. This could only be reported in TennCare recipients.

Negative binomial models were developed to assess the association between hydroxyurea adherence (exposure) and the number of acute care events, including hospital admissions and ED visits, which were de-duplicated for hospital visits that began in the ED (outcome). In each segment, the amount of time that each person was eligible for hydroxyurea was identified for those under the age of 18 (for TennCare and BCBS-TN), between the ages of 18 and 25, and over the age of 25. Acute care events occurring in the span of hydroxyurea eligible time were counted for each applicable age category within each study segment.

Crude and adjusted negative binomial models were constructed, offset by the amount of hydroxyurea-eligible time that each person contributed to each age category within each study segment. During the model-building process, potential interaction terms were assessed via preliminary modeling, and potential confounders were assessed using the 10% rule (when the difference between the crude and adjusted measures of association was greater than 10%, we concluded that there was confounding). Results were reported by age and by the hydroxyurea adherence levels. Each model’s reference hydroxyurea adherence group was less than 40% hydroxyurea adherence but more than 0. Model-based incidence rate ratios (IRRs) were reported with 95% confidence intervals (CIs). All analyses were performed using the Statistical Analysis System (SAS) software package, version 9.4 (SAS Institute Inc., Cary, NC, United States).

Results

Cohort characteristics

A total of 4,901 individuals with SCD across three health plans (TennCare, Medicare, and BCBS-TN) were included. There were 3,602 qualifying enrollment segments in TennCare, 774 in Medicare, and 525 in BCBS-TN (Table 1; Figure 1). The age at the study entry was lower for individuals in TennCare than for those in Medicare and BCBS-TN (Table 1; Figure 1). There were more female individuals in all three health plans (63% in TennCare, 63% in Medicare, and 54% in BCBS-TN) (Table 1; Figure 1). Most SCD patients had HbSS or HbSβ⁰ thalassemia (68% in TennCare, 66% in Medicare, and 70% in BCBS-TN) (Table 1; Figure 1). The majority of those covered by governmental plans lived in West TN, while those with private coverage lived in East TN (Table 1; Figure 1). For all three plans, more than half of the patients met the eligibility criteria for hydroxyurea prescription (67% TennCare, 61% Medicare, and 54% BCBS-TN) (Table 1; Figure 1). A greater percentage of individuals with SCD covered by TennCare (52%) visited hematologists before the start of the study period, while most of those covered by Medicare and BCBS-TN did not (Table 1; Figure 1).

Table 1

Table 1. Characteristics of the study segments by the payer type.

Figure 1

Figure 1. Characteristics of the study segments by payer type.

Prevalence of hydroxyurea utilization

The prevalence estimates of hydroxyurea prescription dispensation for the full study cohorts were low: 21% for TennCare, 21% for Medicare, and 17% for BCBS-TN (Table 2). Variability was present in hydroxyurea utilization across age groups, disease subtypes, regions of residence, prior visits to a hematologist, and health plans. In each study cohort, male individuals were more likely than female individuals to have a hydroxyurea prescription dispensed in TennCare (28.6% vs. 16.8%, p-value <0.0001), Medicare (25.1% vs. 18.3%, p-value 0.0241), and BCBS-TN (17.4% vs. 16.6%, p-value 0.8200) (Table 2). Those aged younger than 18 had more hydroxyurea utilization in TennCare (29% < 18 years vs. 22% 18–25 years vs. 11% > 25 years; p-value < 18 years vs. 16% 18–25 years vs. 7% > 25 years; p-value <0.0001) (Table 2). Individuals with HbSS or HbSβ⁰ thalassemia had significantly more hydroxyurea prescriptions dispensed than those without these subtypes (30.5% vs. 1.7%, p-value <0.0001 in TennCare, and 23.4% vs. 1.9%, p-value <0.0001 in BCBS-TN) (Table 2). Hydroxyurea prescription filling was the highest among those covered under governmental plans in Middle TN (23% in TennCare) and West TN (22% in Medicare) (Table 2).

Table 2

Table 2. Prevalence of dispensed hydroxyurea (current hydroxyurea use) among different covariates.

Multivariable models were constructed for each individual health plan. For the multivariable models of hydroxyurea use, female individuals were less likely than male individuals to have a hydroxyurea prescription dispensed under governmental plans (TennCare and Medicare) (OR: 0.872, 95% CI: (0.75, 1.01) for TennCare and OR: 0.776, 95% CI: (0.51, 1.18) for Medicare) (Supplementary Table S1). Those with HbSS or HbSβ⁰ thalassemia subtypes had higher odds of hydroxyurea use (OR: 1.752, 95% CI: (1.51, 2.03); OR: 2.03, 95% CI: (1.36, 3.03); OR: 1.852, 95% CI: (1.24, 2.76) in TennCare, Medicare, and BCBS-TN, respectively) (Supplementary Table S1). In TennCare, the odds of being dispensed hydroxyurea were lower among those living in East TN (OR: 0.65, 95% CI: 0.53, 0.79) than among those in West TN (Supplementary Table S1). Hydroxyurea eligibility was associated with having a hydroxyurea prescription dispensed. Among TennCare enrollees, those who were not eligible for hydroxyurea had an odds ratio of 0.34 with 95% CI (0.29, 0.40); Medicare enrollees had an odds ratio of 0.04 with 95% CI (0.02, 0.09), and BCBS-TN enrollees had an odds ratio of 0.40 with 95% CI (0.27, 0.59) of prescribed hydroxyurea (Supplementary Table S1). For all three plans, those with comorbidities had higher odds of ever using hydroxyurea (Supplementary Table S1).

Hydroxyurea adherence among patients who used hydroxyurea

The hydroxyurea adherence or MPR for the entire state of TN among those who ever had a prescription dispensed was 19.7%. Variability in MPR was present across age groups, disease subtypes, regions, prior visits to a hematologist, and health plans. For those with low adherence (<40%) in TennCare, more individuals had disease subtypes other than HbSS or HbSβ⁰ thalassemia (99% vs. 85%) (Supplementary Table S2). Those with low adherence (<40%) had a higher prevalence of no prior hematologist visits (98% vs. 82%) (Supplementary Table S2). A greater percentage of those with low adherence had other comorbidities (91% vs. 88%) (Supplementary Table S2). We obtained similar results for those with BCBS-TN and Medicare coverage (Supplementary Tables S3, S4).

Association between hydroxyurea adherence and acute healthcare utilization

Our analysis demonstrated an association between hydroxyurea adherence and the incidence of acute care utilization for TennCare and BCBS-TN enrollees. In fully adjusted models, those with >80% MPR had lower incidence of acute care utilization than those with <40% MPR in individuals <18 years [IRR: 0.82 (95% CI: 0.63, 1.07)], 18–25 years [IRR: 0.55 (95% CI: 0.37, 0.81)], and those >25 years [IRR: 0.2 (95% CI: 0.1, 0.41)]; those with 40%–80% MPR had lower incidence of acute care utilization than those with <40% MPR in individuals <18 years [IRR: 0.94 (95% CI: 0.72, 1.23)], 18–25 years [IRR: 0.51 (95% CI: 0.33, 0.78)], and those >25 years [IRR: 0.53 (95% CI: 0.35, 0.79)] (Figure 2). IRRs were statistically significant at the 0.05 level, except in the <18-year-old group. The IRR of the crude models, comorbidity and sex-adjusted models, and fully adjusted models demonstrate a dose response relationship, such that higher MPR values were associated with lower acute care utilization (ED and hospital admissions), except in 18–25-year-olds (Figure 2).

Figure 2

25" show more variation, particularly in higher income brackets." id="F2" loading="lazy">

Figure 2. Incidence rate ratios between hydroxyurea adherence and the incidence of acute care utilization.

Hydroxyurea adherence and healthcare utilization variability by sickle genotypes

The previous analyses were repeated for the 2,597 members of the cohort with HbSS or HbSβ⁰ thalassemia subtypes. Multivariable models were constructed for each individual health plan. For the multivariable models of hydroxyurea adherence, female individuals were less likely to have been prescribed hydroxyurea under TennCare (OR: 0.88, 95% CI: 0.73, 1.05) but were more likely under Medicare (OR: 1.12, 95% CI: 0.65, 1.93) and BCBS-TN (OR: 1.50, 95% CI: 0.93, 2.40) (Supplementary Table S5). The odds of being dispensed hydroxyurea were lower among those living in East TN (OR: 0.74, 95% CI: (0.57, 0.96); and OR: 0.97, 95% CI: (0.57, 1.64) for TennCare and BCBS-TN, respectively) and Middle TN (OR: 0.96, 95% CI: (0.78, 1.19); and OR: 0.76, 95% CI: (0.38, 1.53) for TennCare and BCBS-TN, respectively) (Supplementary Table S5). Hydroxyurea eligibility was associated with adherence. Among TennCare enrollees, those who were not eligible had an odds ratio of 0.29 with 95% CI (0.24, 0.35), Medicare enrollees had an odds ratio of 0.06 with 95% CI (0.03, 0.14), and BCBS-TN enrollees had an odds ratio of 0.58 with 95% CI (0.36, 0.94) (Supplementary Table S5). For all three plans, those with comorbidities had higher odds of hydroxyurea adherence (Supplementary Table S5).

Hydroxyurea adherence and mortality

For hydroxyurea-eligible patients with TennCare coverage, there were 122 (5.9%) deaths in those who had <40% hydroxyurea adherence (Supplementary Table S6). Those with 40%–80% and >80% adherence had lower mortality (4% and 1.6%, respectively) (Supplementary Table S6). Death data were unavailable for those with BCBS-TN coverage (Supplementary Table S7). We were unable to report adverse events, including deaths, for Medicare recipients who were hydroxyurea-eligible because of small cell sizes. Even though the numbers are low, we found that adherence to hydroxyurea treatment was associated with lower mortality.

Discussion

People with SCD face substantial disease complications, shorter life expectancy, and increased healthcare utilization (Yang et al., 2022). Despite the existing evidence of the safety and efficacy of hydroxyurea, it remains vastly underutilized. Our study described hydroxyurea use and adherence patterns and their association with acute healthcare utilization and mortality in the most comprehensive claims data analysis for the state of TN. We found that hydroxyurea dispensation and adherence in the state were low. Those younger than 18 had higher hydroxyurea utilization, and male individuals filled more hydroxyurea prescriptions. Those who had HbSS or HbSβ⁰ thalassemia also filled more hydroxyurea prescriptions than other subtypes. The likelihood of filling a hydroxyurea prescription and adhering to the medication was higher among individuals who visited a hematologist and in those who were eligible to receive hydroxyurea. Hydroxyurea adherence was inversely associated with acute healthcare utilization and deaths. Higher adherence to hydroxyurea was associated with fewer ED visits and hospitalizations and lower mortality.

Overall, <50% of those with SCD in our state had hydroxyurea adherence, which is similar to the reports of previously published studies using claims datasets (Candrilli et al., 2011; Shah et al., 2020). Clinical complications secondary to underutilization and low adherence to hydroxyurea adversely affect QOL in those with SCD (Nwenyi et al., 2014). Previous studies have demonstrated that prescription possession and adherence to hydroxyurea were associated with decreased frequency of pain crises, reduced healthcare utilization, and, thus, improved QOL (Ballas et al., 2006). Some barriers to adherence include the fear of potential side effects, misunderstanding the need for the medication, lack of access to specialized care, and reduced patient involvement in informed decision-making about disease processes and treatment options (Badawy et al., 2017a; Loiselle et al., 2016; Badawy et al., 2017b; Badawy et al., 2017c; Sobota et al., 2011; Badawy et al., 2018a; Badawy et al., 2018b; Badawy et al., 2016; Badawy et al., 2018c; Alberts et al., 2020). Newer techniques, such as telehealth or mobile health apps, need to be further evaluated for their potential to enhance medication adherence (Hankins et al., 2023; Jacob et al., 2021).

We found that those who visited a hematologist had a higher likelihood of being prescribed hydroxyurea and having higher medication adherence. In the era of our study, treatment with hydroxyurea was well-supported by high-quality clinical trials, but no consensus guidelines were available until 2014. Follow-up studies should evaluate whether the publication of consensus guidelines led to increased hydroxyurea prescriptions in individuals who had not previously visited a hematologist. It is well-documented that the lack of detailed knowledge (Sobota et al., 2011; Travis et al., 2020; Lunyera et al., 2017; Kanter et al., 2020) many providers have about the treatment of hemoglobinopathies such as SCD and negative perceptions toward patients with SCD are critical barriers to hydroxyurea use (Pizzo et al., 2023; Smeltzer et al., 2021). Non-adherence is further exacerbated by patients’ ongoing mistrust of healthcare systems, pharmaceutical companies, and physicians’ prescribing practices (Matthie et al., 2016; Mathur et al., 2016; Renedo et al., 2019). These barriers must be addressed to reduce suboptimal hydroxyurea use (Varty and Popejoy, 2020; Smaldone et al., 2018).

In this cohort, we found that those with the SCD subtypes HbSS or HbSβ⁰ thalassemia had more hydroxyurea prescriptions and adherence. This may be explained by the clinical trial eligibility inclusion criteria and recommendations for SCD that have specific criteria for initiating hydroxyurea for certain SCD subtypes and less clear recommendations for other genotypes (National Heart, 2014). We also did not observe a dose–response relationship between hydroxyurea adherence and the incidence of acute care utilization in young adults (18–25-year-olds). Young adulthood is the peak period of acute utilization in those with SCD. Young adults experience changes in care during the pediatric-to-adult transition, a higher potential for disrupted follow-up, and other life transitions, such as relocation, that might impact this association or our ability to evaluate it in this type of analysis. It is also possible that hydroxyurea alone is not sufficient to reduce acute utilization in this age group, and combination therapy with newer agents and structured adult care transition services is needed.

Our study had several limitations. First, we analyzed individuals covered by TennCare, Medicare, and BCBS-TN. Although this cohort includes a large number of individuals with SCD in TN, we could not analyze those who were uninsured or covered by commercial insurance other than BCBS-TN. The true proportion of individuals with SCD who use hydroxyurea could be greater than our estimate if those with commercial insurance other than BCBS-TN had higher utilization. Conversely, those who are uninsured may utilize hydroxyurea less than we have estimated. Future studies within the statewide surveillance program for SCD in TN, the SCDC-TN (Tennessee Sickle Cell Data Collection Program) surveillance program (funded by the Centers for Disease Control and Prevention), will provide even more comprehensive data in the future (Prevention TCfDCa, 2023). Second, we classified genotypes based on previous definitions, which may under- or overestimate disease burden. Additionally, we did not account for two important genetic modifiers of SCD, the hemoglobin F levels (Bao et al., 2019) and co-inherited alpha thalassemia (Hatzlhofer et al., 2021)—none of which were available in our claims datasets. Third, we used hydroxyurea prescription possession as a surrogate for hydroxyurea adherence, which may introduce misclassification bias due to variations in dosing or daily adherence. Additionally, the cut-off for MPR that we applied to the Medicare population, which was necessary due to sparse data, limits the comparability of this population. Fourth, national hydroxyurea guidelines were not published until 2014; therefore, providers’ decision to prescribe hydroxyurea would have been based on evidence from phase-III clinical trials during the majority of this study. These data may not reflect the more recent eligibility and utilization trends. Our study analysis from 1 January 2010 to 30 September 2015 serves as a benchmark for a planned updated analysis. Finally, the population we analyzed was restricted to only one state, which may not necessarily quantify the countrywide disease burden and hydroxyurea utilization patterns for SCD (Ballas et al., 2018).

Conclusion

Individuals with SCD in the state of TN have very low hydroxyurea utilization and adherence rates. The suboptimal use of this safe and effective medication increases healthcare utilization. The factors associated with increased hydroxyurea adherence included being younger than 18, visiting a hematologist, having HbSS or HbSβ⁰ thalassemia, and being eligible to receive hydroxyurea. We also found that better adherence to hydroxyurea was associated with lower mortality. To further alleviate the sufferings of those with SCD, factors associated with hydroxyurea utilization and adherence need to be evaluated and addressed.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material; further inquiries can be directed to the corresponding authors.

Ethics statement

The studies involving humans were approved by the Vanderbilt University Institutional Review Board, IRB #170018. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

Author contributions

AM: Supervision, Conceptualization, Methodology, Writing – review and editing, Writing – original draft, Formal analysis, Visualization. MS: Project administration, Conceptualization, Writing – review and editing. JD: Formal analysis, Writing – review and editing. SB: Writing – review and editing. JM: Writing – review and editing. AP: Writing – review and editing. MR: Writing – review and editing. AW: Writing – review and editing. WS: Writing – review and editing. JG: Writing – review and editing. CN: Writing – review and editing. JP: Writing – review and editing. LK: Funding acquisition, Writing – review and editing. JH: Conceptualization, Supervision, Funding acquisition, Writing – review and editing. WC: Project administration, Methodology, Supervision, Data curation, Conceptualization, Writing – review and editing, Writing – original draft.

Funding

The authors declare that financial support was received for the research and/or publication of this article. LMK received SCDIC funding from NHLBI (U01HL133996). This research was support by the Centers for Disease Control and Prevention (CDC) by 1 NU58DD000035-01-00 and from the National Heart, Lung, and Blood Institute (NHLBI) by U01HL133996. The funders had no involvement in the study.

Conflict of interest

JHE received research support from Global Blood Therapeutics, Pfizer, and Eli Lilly and Co. and serves as a consultant for Daiichi Sankyo, Emmaus Life Sciences, Esperion Therapeutics, Inc., and Global Blood Therapeutics.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The authors declare that no Generative AI was used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2025.1693126/full#supplementary-material

Abbreviations

SCD, sickle cell disease; ED, emergency department; TN, Tennessee; TennCare, TN Medicaid; MPR, medication possession ratio; IRR, incidence rate ratio.

References

Agrawal, R. K., Patel, R. K., Shah, V., Nainiwal, L., and Trivedi, B. (2014). Hydroxyurea in sickle cell disease: drug review. Indian J. Hematol. Blood Transfus. 30 (2), 91–96. doi:10.1007/s12288-013-0261-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Alberts, N. M., Badawy, S. M., Hodges, J., Estepp, J. H., Nwosu, C., Khan, H., et al. (2020). Development of the InCharge health Mobile app to improve adherence to hydroxyurea in patients with sickle cell disease: user-centered design approach. JMIR Mhealth Uhealth 8 (5), e14884. doi:10.2196/14884

PubMed Abstract | CrossRef Full Text | Google Scholar

Alina, F. P. T., Vermylen, C., Sturbois, G., Corazza, F., Fondu, P., Devalck, C., et al. (2001). Five years of experience with hydroxyurea in children and young adults with sickle cell disease. Blood 97 (11), 3628–3632. doi:10.1182/blood.v97.11.3628

CrossRef Full Text | Google Scholar

Asnani, M. R., Quimby, K. R., Bennett, N. R., and Francis, D. K. (2016). Interventions for patients and caregivers to improve knowledge of sickle cell disease and recognition of its related complications. Cochrane Database Syst. Rev. 10, CD011175. doi:10.1002/14651858.CD011175.pub2

PubMed Abstract | CrossRef Full Text | Google Scholar

Badawy, S. M., Thompson, A. A., and Liem, R. I. (2016). Technology access and smartphone app preferences for medication adherence in adolescents and young adults with sickle cell disease. Pediatr. Blood Cancer 63 (5), 848–852. doi:10.1002/pbc.25905

PubMed Abstract | CrossRef Full Text | Google Scholar

Badawy, S. M., Thompson, A. A., Penedo, F. J., Lai, J. S., Rychlik, K., and Liem, R. I. (2017a). Barriers to hydroxyurea adherence and health-related quality of life in adolescents and young adults with sickle cell disease. Eur. J. Haematol. 98 (6), 608–614. doi:10.1111/ejh.12878

PubMed Abstract | CrossRef Full Text | Google Scholar

Badawy, S. M., Thompson, A. A., Lai, J. S., Penedo, F. J., Rychlik, K., and Liem, R. I. (2017b). Adherence to hydroxyurea, health-related quality of life domains, and patients' perceptions of sickle cell disease and hydroxyurea: a cross-sectional study in adolescents and young adults. Health Qual. Life Outcomes 15 (1), 136. doi:10.1186/s12955-017-0713-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Badawy, S. M., Thompson, A. A., Lai, J. S., Penedo, F. J., Rychlik, K., and Liem, R. I. (2017c). Health-related quality of life and adherence to hydroxyurea in adolescents and young adults with sickle cell disease. Pediatr. Blood Cancer 64 (6), e26369. doi:10.1002/pbc.26369

PubMed Abstract | CrossRef Full Text | Google Scholar

Badawy, S. M., Barrera, L., Cai, S., and Thompson, A. A. (2018a). Association between participants' characteristics, patient-reported outcomes, and clinical outcomes in youth with sickle cell disease. Biomed. Res. Int. 2018, 8296139. doi:10.1155/2018/8296139

PubMed Abstract | CrossRef Full Text | Google Scholar

Badawy, S. M., Thompson, A. A., Holl, J. L., Penedo, F. J., and Liem, R. I. (2018b). Healthcare utilization and hydroxyurea adherence in youth with sickle cell disease. Pediatr. Hematol. Oncol. 35 (5-6), 297–308. doi:10.1080/08880018.2018.1505988

PubMed Abstract | CrossRef Full Text | Google Scholar

Badawy, S. M., Thompson, A. A., and Liem, R. I. (2018c). Beliefs about hydroxyurea in youth with sickle cell disease. Hematol. Oncol. Stem Cell Ther. 11 (3), 142–148. doi:10.1016/j.hemonc.2018.01.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Ballas, S. K., Barton, F. B., Waclawiw, M. A., Swerdlow, P., Eckman, J. R., Pegelow, C. H., et al. (2006). Hydroxyurea and sickle cell anemia: effect on quality of life. Health Qual. Life Outcomes 4, 59. doi:10.1186/1477-7525-4-59

PubMed Abstract | CrossRef Full Text | Google Scholar

Ballas, S. K., Kanter, J., Agodoa, I., Howard, R., Wade, S., Noxon, V., et al. (2018). Opioid utilization patterns in United States individuals with sickle cell disease. Am. J. Hematol. 93 (10), E345–E347. doi:10.1002/ajh.25233

PubMed Abstract | CrossRef Full Text | Google Scholar

Bao, E. L., Lareau, C. A., Brugnara, C., Fulcher, I. R., Barau, C., Moutereau, S., et al. (2019). Heritability of fetal hemoglobin, white cell count, and other clinical traits from a sickle cell disease family cohort. Am. J. Hematol. 94 (5), 522–527. doi:10.1002/ajh.25421

PubMed Abstract | CrossRef Full Text | Google Scholar

Brousseau, D. C., Richardson, T., Hall, M., Ellison, A. M., Shah, S. S., Raphael, J. L., et al. (2019). Hydroxyurea use for sickle cell disease among medicaid-enrolled children. Pediatrics 144 (1), e20183285. doi:10.1542/peds.2018-3285

PubMed Abstract | CrossRef Full Text | Google Scholar

Candrilli, S. D., O'Brien, S. H., Ware, R. E., Nahata, M. C., Seiber, E. E., and Balkrishnan, R. (2011). Hydroxyurea adherence and associated outcomes among medicaid enrollees with sickle cell disease. Am. J. Hematol. 86 (3), 273–277. doi:10.1002/ajh.21968

PubMed Abstract | CrossRef Full Text | Google Scholar

Charache, S., Terrin, M. L., Moore, R. D., Dover, G. J., Barton, F. B., Eckert, S. V., et al. (1995). Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N. Engl. J. Med. 332 (20), 1317–1322. doi:10.1056/NEJM199505183322001

PubMed Abstract | CrossRef Full Text | Google Scholar

Creary, S., Zickmund, S., Ross, D., Krishnamurti, L., and Bogen, D. L. (2015). Hydroxyurea therapy for children with sickle cell disease: describing how caregivers make this decision. BMC Res. Notes 8, 372. doi:10.1186/s13104-015-1344-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Crego, N., Douglas, C., Bonnabeau, E., Earls, M., Eason, K., Merwin, E., et al. (2020). Sickle-cell disease co-management, health care utilization, and hydroxyurea use. J. Am. Board Fam. Med. 33 (1), 91–105. doi:10.3122/jabfm.2020.01.190143

PubMed Abstract | CrossRef Full Text | Google Scholar

Dean, A. J., Walters, J., and Hall, A. (2010). A systematic review of interventions to enhance medication adherence in children and adolescents with chronic illness. Arch. Dis. Child. 95 (9), 717–723. doi:10.1136/adc.2009.175125

PubMed Abstract | CrossRef Full Text | Google Scholar

Disability TCoA (2025). About us. Available online at: https://www.tn.gov/aging/about-us.html.

Google Scholar

Freitas, S. L. F., Ivo, M. L., Figueiredo, M. S., Gerk, M. A. S., Nunes, C. B., and Monteiro, F. F. (2018). Quality of life in adults with sickle cell disease: an integrative review of the literature. Rev. Bras. Enferm. 71 (1), 195–205. doi:10.1590/0034-7167-2016-0409

PubMed Abstract | CrossRef Full Text | Google Scholar

Hankins, J. S., Aygun, B., Nottage, K., Thornburg, C., Smeltzer, M. P., Ware, R. E., et al. (2014). From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia. Med. Baltim. 93 (28), e215. doi:10.1097/MD.0000000000000215

PubMed Abstract | CrossRef Full Text | Google Scholar

Hankins, J. S., Brambilla, D., Potter, M. B., Kutlar, A., Gibson, R., King, A. A., et al. (2023). A multilevel mHealth intervention boosts adherence to hydroxyurea in individuals with sickle cell disease. Blood Adv. 7 (23), 7190–7201. doi:10.1182/bloodadvances.2023010670

PubMed Abstract | CrossRef Full Text | Google Scholar

Hatzlhofer, B. L. D., Pereira-Martins, D. A., de Farias Domingos, I., Arcanjo, G. d. S., Weinhäuser, I., Falcão, D. A., et al. (2021). Alpha thalassemia, but not β(S)-globin haplotypes, influence sickle cell anemia clinical outcome in a large, single-center Brazilian cohort. Ann. Hematol. 100, 921–931. doi:10.1007/s00277-021-04450-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Hood, A. M., Strong, H., Nwankwo, C., Johnson, Y., Peugh, J., Mara, C. A., et al. (2021). Engaging caregivers and providers of children with sickle cell anemia in shared decision making for hydroxyurea: protocol for a multicenter randomized controlled trial. JMIR Res. Protoc. 10 (5), e27650. doi:10.2196/27650

PubMed Abstract | CrossRef Full Text | Google Scholar

Jacob, S. A., Carroll, A. E., and Bennett, W. E., Jr (2021). A feasibility study of telemedicine for paediatric sickle cell patients living in a rural medically underserved area. J. Telemed. Telecare 27 (7), 431–435. doi:10.1177/1357633x19883558

PubMed Abstract | CrossRef Full Text | Google Scholar

Kang, H. A., and Barner, J. C. (2020). The association between hydroxyurea adherence and opioid utilization among Texas medicaid enrollees with sickle cell disease. J. Manag. Care Spec. Pharm. 26 (11), 1412–1422. doi:10.18553/jmcp.2020.26.11.1412

PubMed Abstract | CrossRef Full Text | Google Scholar

Kanter, J., Smith, W. R., Desai, P. C., Treadwell, M., Andemariam, B., Little, J., et al. (2020). Building access to care in adult sickle cell disease: defining models of care, essential components, and economic aspects. Blood Adv. 4 (16), 3804–3813. doi:10.1182/bloodadvances.2020001743

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, L., Smith-Whitley, K., Banks, S., and Puckrein, G. (2019). Reducing health care disparities in sickle cell disease: a review. Public Health Rep. 134 (6), 599–607. doi:10.1177/0033354919881438

PubMed Abstract | CrossRef Full Text | Google Scholar

Loiselle, K., Lee, J. L., Szulczewski, L., Drake, S., Crosby, L. E., and Pai, A. L. (2016). Systematic and meta-analytic review: medication adherence among pediatric patients with sickle cell disease. J. Pediatr. Psychol. 41 (4), 406–418. doi:10.1093/jpepsy/jsv084

PubMed Abstract | CrossRef Full Text | Google Scholar

Lubeck, D., Agodoa, I., Bhakta, N., Danese, M., Pappu, K., Howard, R., et al. (2019). Estimated life expectancy and income of patients with sickle cell disease compared with those without sickle cell disease. JAMA Netw. Open 2 (11), e1915374. doi:10.1001/jamanetworkopen.2019.15374

PubMed Abstract | CrossRef Full Text | Google Scholar

Lunyera, J., Jonassaint, C., Jonassaint, J., and Shah, N. (2017). Attitudes of primary care physicians toward sickle cell disease care, guidelines, and comanaging hydroxyurea with a specialist. J. Prim. Care Community Health 8 (1), 37–40. doi:10.1177/2150131916662969

PubMed Abstract | CrossRef Full Text | Google Scholar

Mathias, J. G., Nolan, V. G., Meadows-Taylor, M., Robinson, L. A., Howell, K. E., Gurney, J. G., et al. (2020). A meta-analysis of toxicities related to hydroxycarbamide dosing strategies. eJHaem 1 (1), 235–238. doi:10.1002/jha2.7

PubMed Abstract | CrossRef Full Text | Google Scholar

Mathur, V. A., Kiley, K. B., Haywood, C., Jr., Bediako, S. M., Lanzkron, S., Carroll, C. P., et al. (2016). Multiple levels of suffering: discrimination in health-care settings is associated with enhanced laboratory pain sensitivity in sickle cell disease. Clin. J. Pain 32 (12), 1076–1085. doi:10.1097/ajp.0000000000000361

PubMed Abstract | CrossRef Full Text | Google Scholar

Matthie, N., Hamilton, J., Wells, D., and Jenerette, C. (2016). Perceptions of young adults with sickle cell disease concerning their disease experience. J. Adv. Nurs. 72 (6), 1441–1451. doi:10.1111/jan.12760

PubMed Abstract | CrossRef Full Text | Google Scholar

Moody, K. L. (2022). Healthcare utilization and the quality of life of children and adolescents with sickle cell disease. Pediatr. Blood Cancer 69, e29685. doi:10.1002/pbc.29685

PubMed Abstract | CrossRef Full Text | Google Scholar

National Heart, L. (2014). Blood institute evidence-based management of sickle cell disease: expert panel report. Available online at: https://www.nhlbi.nih.gov/health-topics/evidence-based-management-sickle-cell-disease.

Google Scholar

Neumayr, L. D., Hoppe, C. C., and Brown, C. (2019). Sickle cell disease: current treatment and emerging therapies. Am. J. Manag. Care 25 (18 Suppl. l), S335–S343.

PubMed Abstract | Google Scholar

Nwenyi, E., Leafman, J., Mathieson, K., and Ezeobah, N. (2014). Differences in quality of life between pediatric sickle cell patients who used hydroxyurea and those who did not. Int. J. Health Care Qual. Assur 27 (6), 468–481. doi:10.1108/IJHCQA-01-2013-0008

PubMed Abstract | CrossRef Full Text | Google Scholar

Pizzo, A., Porter, J. S., Carroll, Y., Burcheri, A., Smeltzer, M. P., Beestrum, M., et al. (2023). Provider prescription of hydroxyurea in youth and adults with sickle cell disease: a review of prescription barriers and facilitators. Br. J. Haematol. 203 (5), 712–721. doi:10.1111/bjh.19099

PubMed Abstract | CrossRef Full Text | Google Scholar

Prevention TCfDCa (2023). Sickle cell data collection (SCDC) program. Available online at: https://www.cdc.gov/sickle-cell-research/php/about/index.html (December 10, 2025).

Google Scholar

Renedo, A., Miles, S., Chakravorty, S., Leigh, A., Telfer, P., Warner, J. O., et al. (2019). Not being heard: barriers to high quality unplanned hospital care during young people's transition to adult services - evidence from 'this sickle cell life' research. BMC Health Serv. Res. 19 (1), 876. doi:10.1186/s12913-019-4726-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Shah, N., Bhor, M., Xie, L., Halloway, R., Arcona, S., Paulose, J., et al. (2019). Treatment patterns and economic burden of sickle-cell disease patients prescribed hydroxyurea: a retrospective claims-based study. Health Qual. Life Outcomes 17 (1), 155. doi:10.1186/s12955-019-1225-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Shah, N. R., Bhor, M., Latremouille-Viau, D., Kumar Sharma, V., Puckrein, G. A., Gagnon-Sanschagrin, P., et al. (2020). Vaso-occlusive crises and costs of sickle cell disease in patients with commercial, medicaid, and medicare insurance - the perspective of private and public payers. J. Med. Econ. 23 (11), 1345–1355. doi:10.1080/13696998.2020.1813144

PubMed Abstract | CrossRef Full Text | Google Scholar

Smaldone, A., Findley, S., Manwani, D., Jia, H., and Green, N. S. (2018). HABIT, a randomized feasibility trial to increase hydroxyurea adherence, suggests improved health-related quality of life in youths with sickle cell disease. J. Pediatr. 197, 177–185. doi:10.1016/j.jpeds.2018.01.054

PubMed Abstract | CrossRef Full Text | Google Scholar

Smeltzer, M. P., Howell, K. E., Treadwell, M., Preiss, L., King, A. A., Glassberg, J. A., et al. (2021). Identifying barriers to evidence-based care for sickle cell disease: results from the sickle cell disease implementation consortium cross-sectional survey of healthcare providers in the USA. BMJ Open 11 (11), e050880. doi:10.1136/bmjopen-2021-050880

PubMed Abstract | CrossRef Full Text | Google Scholar

Sobota, A., Neufeld, E. J., Sprinz, P., and Heeney, M. M. (2011). Transition from pediatric to adult care for sickle cell disease: results of a survey of pediatric providers. Am. J. Hematol. 86 (6), 512–515. doi:10.1002/ajh.22016

PubMed Abstract | CrossRef Full Text | Google Scholar

Steinberg, M. H., McCarthy, W. F., Castro, O., Ballas, S. K., Armstrong, F. D., Smith, W., et al. (2010). The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am. J. Hematol. 85 (6), 403–408. doi:10.1002/ajh.21699

PubMed Abstract | CrossRef Full Text | Google Scholar

Stokoe, M., Zwicker, H. M., Forbes, C., Abu-Saris, N. E. L. H., Fay-McClymont, T. B., Désiré, N., et al. (2022). Health related quality of life in children with sickle cell disease: a systematic review and meta-analysis. Blood Rev. 56, 100982. doi:10.1016/j.blre.2022.100982

PubMed Abstract | CrossRef Full Text | Google Scholar

TennCare (2025). TN.gov TSG-. This is TennCare. Available online at: https://www.tn.gov/tenncare/this-is-tenncare.

Google Scholar

Tennessee BBo (2025). About us. Available online at: https://www.bcbst.com/about/our-company/.

Google Scholar

Travis, K., Wood, A., Yeh, P., Allahabadi, S., Chien, L. C., Curtis, S., et al. (2020). Pediatric to adult transition in sickle cell Disease: survey results from young adult patients. Acta Haematol. 143 (2), 163–175. doi:10.1159/000500258

PubMed Abstract | CrossRef Full Text | Google Scholar

Tshilolo, L., Tomlinson, G., Williams, T. N., Santos, B., Olupot-Olupot, P., Lane, A., et al. (2019). Hydroxyurea for children with sickle cell anemia in Sub-Saharan Africa. N. Engl. J. Med. 380 (2), 121–131. doi:10.1056/NEJMoa1813598

PubMed Abstract | CrossRef Full Text | Google Scholar

Varty, M., and Popejoy, L. L. (2020). Young adults with sickle cell disease: challenges with transition to adult health care. Clin. J. Oncol. Nurs. 24 (4), 451–454. doi:10.1188/20.CJON.451-454

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, W. C., Ware, R. E., Miller, S. T., Iyer, R. V., Casella, J. F., Minniti, C. P., et al. (2011). Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 377 (9778), 1663–1672. doi:10.1016/S0140-6736(11)60355-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Ware, R. E., Davis, B. R., Schultz, W. H., Brown, R. C., Aygun, B., Sarnaik, S., et al. (2016). Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD with transfusions changing to hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet 387 (10019), 661–670. doi:10.1016/S0140-6736(15)01041-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Ware, R. E., McGann, P. T., and Quinn, C. T. (2019). Hydroxyurea for children with sickle cell anemia: prescribe it early and often. Pediatr. Blood Cancer 66 (8), e27778. doi:10.1002/pbc.27778

PubMed Abstract | CrossRef Full Text | Google Scholar

Wong, T. E., Brandow, A. M., Lim, W., and Lottenberg, R. (2014). Update on the use of hydroxyurea therapy in sickle cell disease. Blood 124 (26), 3850–3857. doi:10.1182/blood-2014-08-435768

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, M., Elmuti, L., and Badawy, S. M. (2022). Health-related quality of life and adherence to hydroxyurea and other disease-modifying therapies among individuals with sickle cell disease: a systematic review. Biomed. Res. Int. 2022, 2122056. doi:10.1155/2022/2122056

PubMed Abstract | CrossRef Full Text | Google Scholar

Yawn, B. P., Buchanan, G. R., Afenyi-Annan, A. N., Ballas, S. K., Hassell, K. L., James, A. H., et al. (2014). Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 312 (10), 1033–1048. doi:10.1001/jama.2014.10517

PubMed Abstract | CrossRef Full Text | Google Scholar