Hydroxyurea Effects on Sickle Cell Disease Progression

HU Effects on Progression of SCD Symptoms

Sickle cell disease (SCD) is a lifelong, debilitating medical condition which is associated with specific chronic and acute patient complications. The clinical course of the disease can be highly variable in different patients and may range from an early death to merely a few adverse co-morbidities across the lifespan (De Almeida et al., 2013). However, organ damage and tissue damage, as well as the consequent organ dysfunction, is the primary cause of morbidity in SCD. It develops as a result of repeated episodes of sickle cell crisis (SCC) or vaso-occlusive episodes, which also lead to frequent hospitalizations and increase the risk for premature mortality (Nottage et al., 2014). However, research evidence suggests that hydroxyurea (HU) may change the prognosis for patients with SCD in a positive way. According to De Almeida et al. (2013), this antineoplastic drug is the best available option for all patients with SCD regardless of their age and other physiologically significant characteristics. The evidence on the effects of HU in terms of the severity and frequency of SCC, patient hospitalization, and organ damage will be discussed in the following paragraphs.

Painful SCC

Darbari et al. (2014) state that “polymerisation of HbS occurs during deoxygenation and causes erythrocyte rigidity and sickling” (p. 341). The given pathophysiological process largely contributes to microcirculatory obstruction and occurrence of painful SCC in patients with SCD. Frei-Jones, Baxter, Rogers, and Buchanan (2008) state that severe pain during SCC is a major cause of acute morbidity among patients of different ages and, moreover, it is the main factor leading to death in adults with SCD. At the same time, HU is the primary drug clinically used to reduce the incidence and prevent the symptoms of SCC including pain in different parts of the body, headaches, severe tiredness, and others.

The questions posed by researchers included the HU-related reduction in SCC in different population groups (Darbari et al., 2014) and examination of clinical biomarkers in on-HU patients (Araujo et al., 2016). The sizes of employed samples varied from 50 to 299 SCD patients. The study by Darbari et al. (2014) showed results in support of HU effectiveness in reduction of SCC, while Araujo et al. (2016) did not observe a significant difference in this regard between on-HU and off-HU patients. It could be caused by the inability of researchers to track the severity of SCD and level of patients’ adherence across all study participants.

Hospitalizations

Severe SCC is among the primary reasons for hospitalizations among patients with SCD (Araujo et al., 2016). The evidence shows that HU treatment can help reduce the number of hospitalizations by over 50% (Keikhaei, Yousefi, & Bahadoram, 2016; Wang et al., 2013), as well as their duration (Adewoyin, Oghuvwu, & Awodu, 2017). Similar results are obtained in the research by Ballas et al. (2010) who state that patients undergoing HU treatment are less frequently admitted to hospitals and are more likely to stay at least two days less in the clinical settings than those who do not take or do not respond to HU. Additionally, the study by Nwenyi, Leafman, Mathieson, and Ezeobah (2014) demonstrates that by decreasing the rate of hospital attendance due to various SCD exacerbations, on-HU patients can significantly improve the quality of their lives.

The results related to this sub-concept were obtained in research papers aimed to evaluate clinical effects and economic benefits of HU, as well as the degree to which the intake of drug can affect the overall functional status of patients. Additionally, the main focus of the study by Ballas et al. (2010) was on the effects of HU on the duration and frequency of hospitalizations, as well utilization of opioids for pain management among patients. While Wang et al. (2013), Nwenyi et al. (2014), and Keikhaei et al. (2016) focused on the assessment of pediatric population (n=48, n=100, and n=193 respectively), Adewoyin et al. (2017) and Ballas et al. (2010) examined adults with SCD (n=60 and n=299). Among all the study designs, the one implemented by Ballas et al. (2010) may be regarded as the most efficient because they used samples gathered at 21 settings and compared the findings between on-HU and placebo groups. As for the future research, Keikhaei et al. (2016) suggested comparing the efficacy of multiple SCD treatment means to increase the credibility of obtained positive results.

Organ Damage

SCC exacerbates the pro-inflammatory environment supported by sickle red blood cells (RBCs). As a result, acute crises may lead to the development of chronic problems including organ dysfunction. Chronic SCD-related organ damage usually develops early in life. For instance, as Nottage et al. (2014) note, “in the pediatric population, splenic function is lost early, with 90% of children developing impaired splenic function within the first 2 yrs of life” (p. 377). At the same time, they found that a 3-year treatment with HU can significantly increase the splenic filtrative function in children (aged 2-17). Additionally, a randomized control study conducted by Wang et al. (2011) on young children with the disorder (n=193) revealed an insignificant improvement in spleen function. However, Fitzhugh et al. (2015) who assessed 383 adults with homozygous SCD concluded that HU is not associated with a pronounced improvement in organ function over time.

The findings indicate that HU may not be effective in reversing and preventing organ dysfunction in adults, conversely to its significant effectiveness in the alleviation of acute SCD-related problems. To further explore this problem and address possible study limitations (such as low sample randomization), Fitzhugh et al. (2015) recommended evaluating the links between HU dosage and changes in organ damage over time.

Summary

The evidence in the reviewed studies suggests that HU is strongly correlated with the decrease in the severity of SCC crises, the frequency of hospital attendance, and the duration of hospitalization. As for the effects on organ damage, it is likely that HU may have restorative and organ protective effects only if taken regularly during early stages of the disease progression. The evidence verifying the positive effects of HU treatment is of moderate to high quality. Moreover, the review shows that results of multiple empirical studies devoted to this matter often support each other. However, there is a need to investigate the issue of HU effects on patients’ health status more profoundly across all ages during a longitudinal study or a clinical control trial with large samples and a narrow research focus to address such common research design deficiencies as the limited ability to generalize findings.

Pathophysiological Mechanisms of HU

The intake of HU helps individuals with SCD prevent RBC malformations. Although the drug is proved to be effective in reducing patient morbidity and mortality by increasing the level of fetal haemoglobin (HbF), which is considered the main pharmacological effect of HU. Nevertheless, the knowledge about the mechanisms of its beneficial impact on patient condition remains limited. A few other possible beneficial effects of the drug may include enhanced nitric oxide metabolism, reduced erythrocyte density, improved mean cell volume (MCV) and leukocyte count (De Almeida et al., 2013; Silva-Pinto et al., 2013). Some of them will be discussed in the following sub-sections.

HbF

Improved production of HbF due to HU intake was mentioned in all the reviewed studies. According to Silva-Pinto et al. (2013), by blocking the formation of abnormal erythrocytes, enhanced secretion of HbF supports the decrease in HbS polymerization − the major factor defining SCC development. It is also observed that compared to off-HU patients, individuals taking the drug regularly show significant increases in HbF (Araujo et al., 2016; Fitzhugh et al., 2015).

Researchers aimed to reveal the physiological ways through which HU benefits patients with SCD and describe their clinical and laboratory characteristics. Araujo et al. (2016) examined a small and non-randomly selected sample comprised of 50 patients (aged 20-50), which limits generalization of findings. The researchers concluded that HU remains an effective therapeutic measure as it enhances laboratory parameters and reduces SCD-related complications. At the same time, Fitzhugh et al. (2015) revealed that a positive HbF response provoked by HU intake was correlated with reduced patient morbidity. Conclusions by Silva-Pinto et al. (2013), who evaluated a sample comprised of 37 patients, are consistent with the findings obtained by other researchers.

Shome, Al Ajmi, Radhi, Mansoor, and Majed (2016) assessed the hematological parameters of 51 randomly selected adult SCD patients before and after the initiation of HU therapy in a retrospective study. They revealed that after one year, HbF increased only in 77% of patients. Nevertheless, all clinical parameters including the number of SCC crises, hospital admissions, and inpatient days improved in patients whose HbF levels did not elevate. It may be related to changes in other laboratory parameters such as MCV because the study participants showed consistent improvements in them.

MCV

According to Silva-Pinto et al. (2013), MCV “increases during the first four to six weeks of HU treatment” (p. 239). The given timeframe is correlated with HU-linked clinical improvements in patients. Moreover, among all the hematological parameters, the increase in MCV is one of the most clearly associated with the reduction of painful SCC episodes (Silva-Pinto et al., 2013; Al Hawsawi & Turkistani, 2008). The study by Santos and Maia (2011) in which they assessed the hematological indices of 20 on-HU patients (aged 6-40) also revealed that MCV is correlated with a level of HbF before and after the treatment. Thus, “it can be stated that in this study the increased HbF is directly related to the increase of cell volume” (Santos & Maia, 2011, p. 108).

The studies linked to the given sub-concept focused on the investigation of HU effects through evaluation of laboratory and clinical data. Compared to Santos and Maia (2011) who investigated patients of different ages, Al Hawsawi and Turkistani (2008) assessed 14 pediatric patients with severe SCD (aged 5-15). Although the researchers concluded that HU was highly beneficial for patients, the research of children alone may be regarded as the limitation in terms of the proposed PICOT research project, which is focused on adults.

White Blood Cell Count

An abnormal leukocyte count is regarded as a major inflammation marker in patients with SCD and is associated with an increased frequency of SCC, total hospitalizations, and emergency department referrals (Curtis et al., 2015; Akinlosotu, Adegoke, Oseni, & Adeodu, 2017). As Akinlosotu et al. (2017) state higher white blood cell (WBC) counts in patients with SCD compared to healthy individuals may be due to increased stress linked to recurrent SCC and pain. In their cohort study examining 432 adult patients, Curtis et al. (2015) concluded that high white blood cell (WBC) count was present in both younger and older patients prescribed HU or other treatment methods. Nevertheless, evidence provided by Akingbola et al. (2015), Araujo et al. (2016), Fitzhugh et al. (2015) and others demonstrated a moderate/high decrease in the WBC count in on-HU patients.

The difference in findings may be explained by distinctive research questions posed by Curtis et al. (2015): they focused on the evaluation of the role of WBC in the progression of SCD and did not consider the history of patients’ adherence to HU treatment. Additionally, the limitation of the study by Akinlosotu et al. (2017) in which they compared the haematological indices between Nigerian off-HU pediatric patients and healthy children (n= 91 each) is that the research did not investigate how HU may alter the WBC levels because the level of treatment with this drug in Nigeria is low. However, the given study still provided important background information necessary to rationalize and answer the proposed PICOT question.

Summary

The findings indicate that the results of HU may be associated with significant variations in terms of patients’ laboratory parameters after the initiation of the therapy. The drug improves HbF production in the majority of patients. However, some of them may experience a decrease in SCC and related clinical parameters without a significant increase in HbF as well. It means that HU may also better the overall condition of individuals with SCD through other pathways. Based on the reviewed research findings, it is possible to say that, along with HbF, MCV is one of the most important laboratory indices which is correlated with the improvement of patients’ condition.

Factors of HU Efficacy

Evidence in selected studies revealed that the degree of favorable effects of HU might vary in different individuals. The factors defining the drug efficacy may be both external and internal. For instance, it is suggested that the severity of the disease can define if the patient will have fewer SCCs after the initiation of HU treatment or if it will still be relatively high. Nevertheless, such factors as genes, age, and duration of therapy seem to determine the HU efficacy to a larger extent. Thus, the following discussion will be focused on them.

Genetic Factors

Various genetic determinants can affect one’s response to HU treatment. It is observed that a small number of genetic loci are strongly correlated with higher expression of HbF in individuals, which may facilitate the favorable impact of HU (Tafrali et al., 2013; Darbari et al., 2014). The reviewed studies exploring this matter focused on the analysis of genes possibly defining the severity of SCD, as well as prediction of individual response to HU based on different genetic variations. Tafrali et al. (2013) concluded that “MAP3K5 gene expression is associated with elevated HbF levels and HU treatment” (p. 480), while Darbari et al. (2014) noted that HU-linked reduction in SCC is more pronounced in individuals with alpha-globin gene deletion. Additionally, the study by De Almeida et al. (2013) found that the inheritance of Bantu/Benin haplotype is associated with a high level of lipid peroxidation in SCD patients, which increases the risk of organ damage. At the same time, this haplotype is correlated with a better response to HU treatment (De Almeida et al., 2013).

Two studies presented in this sub-section employed relatively large samples: 299 SCD patients in research by Darbari et al. (2014), and 92 adults in research by Tafrali et al. (2013). De Almeida et al. (2013) compared small samples of on-HU and off-HU patients, n=13 and n=15 each. The findings obtained by researchers indicate that the further research of genes as pharmacogenomic markers for HU treatment efficacy is required.

Age

HU is considered to benefit patients of different age. Nevertheless, the degree of treatment effectiveness, as well as the progression of SCD derivatives, may be substantially defined by this demographic factor. For instance, Fitzhugh et al. (2015) note that, in adults, HU is not associated with improvements in organ function over time but previous pediatric studies, which examined the effects of maximum drug doses on splenic regeneration, demonstrated positive results. Additionally, Steinberg et al. (2010) state that patients over 40 years old with severe SCD are the least likely to receive favorable outcomes of treatment with any HbF-stimulating drugs.

Although both of the mentioned studies employed research designs ensuring a high level of findings credibility, they investigated the effect of age on SCD development and patients’ response to treatment only indirectly. The study by Renoux et al. (2016), who analyzed the samples of 405 SCD patients and 144 healthy individuals in order to reveal their rheological characteristics, investigated the impact of age and HU treatment on SCD manifestations directly. An important research finding showed that blood viscosity in SCD patients elevates with age. As Renoux et al. (2016) note this factor largely predicts the increase in SCCs. It may be presumed that it can also modify the effectiveness of HU treatment. Overall, the results of all the three studies suggest that the further comparative examination of HU efficacy in different demographic groups is needed.

Treatment Duration

Irregular use may be associated with the increased SCC frequency and severity. The benefits of HU intake compared to non-administration of the drug are outlined by Adewoyin et al. (2017), Akingbola et al. (2015), Araujo et al. (2016) and other studies aimed to answer the questions about clinical effects of the therapy. When examining 214 children with SCD over two years, Penkert et al. (2018) found out that not only does the continual HU therapy help reduce inflammatory markers in patients but also allows sustaining their low levels along with lowering the number of SCC compared to transfusions. Moreover, the longitudinal examination of 299 patients throughout 17.5 years by Steinberg et al. (2010) revealed that the long-term HU treatment was strongly associated with reduced mortality and morbidity rates. Compared to other articles that mentioned the problem of adherence and treatment duration, research by Steinberg et al. (2010) and Penkert et al. (2018) is characterized by greater validity and credibility as the samples employed by these researchers were sufficiently randomized and large. Since the provided evidence indicates that “individuals with the greatest exposure to the drug appeared to have improved survival” (Steinberg et al., 2010, p. 408), the research of dosage-duration links must be conducted in the future. Additionally, the study of the same issue in the adult population is needed.

Summary

Age and genes are non-modifiable factors defining the person’s response to HU treatment, while the duration of therapy is the modifiable one. Healthcare providers should consider them when initiating the intervention with HU in order to increase the chance of obtaining favorable patient outcomes. However, it is possible to say that greater attention should be paid to the factor of treatment duration because it is linked to individual behaviors and thus can be corrected in most of the cases.

Barriers to Patient Compliance

Although the efficacy of HU treatment in the reduction of SCC episodes and other adverse symptoms of SCD is supported by high-quality evidence, a significant number of patients do not receive the drug or fail to comply with the treatment. The main barriers to compliance identified in the literature include individual perceptions, level of knowledge, and poor clinical attendance. According to Oyeku et al. (2013), knowledge of HU among patients and their caregivers is especially valuable and is correlated with the drug use. To ensure better patient compliance, it is also important to address individuals’ concerns about HU safety and long-term effectiveness. The evidence related to the given matter will be summarized in the following sub-sections.

Patient Perceptions

Patient perceptions are associated with an emotional response to disease and treatment, as well as subjective views of its efficacy. Research evidence provided by Badawy et al. (2017) makes it clear that individuals who have positive perceptions of HU effects are likely to intake the drug regularly. It is also observed that patients with mild forms of SCD and those individuals who experience fewer SCC often avoid administering HU due to perceived risks of complications (Adewoyin et al., 2017; Badawy et al., 2017). The evidence related to this sub-concept is derived from the articles directly investigating the issue of treatment adherence and patient perceptions. They were hospital-based and employed non-randomized samples comprised of adult and pediatric patients. To address their limitations, participants for future research should be selected across multiple settings and cover the issue of whether health-related quality of life defines negative HU and SCD perceptions or vice versa.

Level of Knowledge

Limited knowledge of available treatment options and misconceptions about HU often translate into the fear of possible unfavorable effects. Misinformation and fear of HU-induced cancer are mentioned by Adewoyin et al. (2017) and Badawy et al. (2017) among the major reasons for irregular use of the drug. At the same time, Akingbola et al. (2015) state that the lack of awareness is one of the primary causes of limited HU use in the African population in general. Additionally, when investigating parental factors of HU non-use, Oyeku et al. (2013) noted that some patients are not aware of HU as a highly beneficial treatment option because physicians do not recommend it. Similarly, Lanzkron, Rand, Haywood, and Hassell (2008) conclude that the level of physicians’ agreement and belief in the effectiveness of HU is positively correlated with the rate of drug prescription and patient adherence to treatment. The main limitation of the discussed studies in relation to the selected sub-concept is that some of them do not explore it in-depth, while others focus on parents and pediatric population instead of adults. The identified evidence gaps suggest that the problem of awareness regarding HU benefits should be addressed in future research.

Poor Clinic Attendance

Poor hospital attendance among SCD patients, as well as minority status and low socio-economic status, may be associated with low levels of care satisfaction, motivation, and understanding of treatment significance. For this reason, there is a need to modify the rate of clinical attendance among individuals with the disease through eliminating possible patient and provider-related barriers.

Crosby et al. (2009) who interviewed 32 SCD patients (aged 13-21) state that the lack of disease management skills, the overall health status, and quality of communication with health providers largely define one’s decision about clinical attendance. In the study by Akingbola et al. (2015), 9 out of 31 adults (aged 18-42) failed to come to the hospital to pick up the drug regularly as well. Similarly to studies evaluated in the previous sub-section, in their research Akingbola et al. (2015) utilized a small and non-randomized sample (n=31). However, compared to Crosby et al. (2009), they did not research the metrics for treatment adherence in detail, focusing primarily on hematological and clinical data of HU effects. Lastly, the study by Ward, Lewis, and Tsitsikas (2018) was directly focused on the problem of hospital attendance. The researchers evaluated the sample of 31 patients undergoing HU treatment and receiving regular outpatient monitoring. Ward et al. (2018) concluded that patient monitoring programs aimed to promote regular hospital attendance and evaluation of HU treatment outcomes through the assessment of blood samples every two months could increase patients’ confidence in the efficacy and safety of the drug, leading to better hospital attendance.

Summary

To maximize the favorable effects of HU therapy, hospitals should motivate patients to intake the drug regularly and educate them about all possible risks and benefits associated with HU. The outpatient monitoring program suggested by Ward et al. (2018) is very promising in this regard as, through the regular assessment of patients’ blood indices, it is possible to provide them with clear data in support of the drug efficacy and safety. Such an approach can also help healthcare providers modify the treatment regimen and dosage according to patients’ response to HU.

Risks

HU has a good safety profile supported by the evidence obtained from multiple studies. Nevertheless, the concern about drug toxicity and its possible dangerous effects remains unresolved. As stated by Mendonça, Gueiros, Capellaro, Pinheiro, and Lopes (2011), “despite of usually be well tolerated, sometimes it can induce immunosuppression and mucocutaneous adverse effects associated with discomfort or pain” (p. 869). HU may also have some short-term adverse effects including neutropenia (Hankins et al., 2014). Thus, when administering it, one should take all the necessary precautions to prevent undesired outcomes.

Dosage

HU dosing may play an essential role in patient outcomes regarding the severity of SCD symptoms and the overall individual condition. According to Fitzhugh et al. (2015), the intake of a dose between 15 and 35 mg/kg/day increases patients’ prognosis for survival, while lower doses and non-administration of HU is associated with increased outcome hazards. At the same time, Adewoyin et al. (2017) raised the concern about the organ toxicity of high-dose treatment and its ability to undermine the overall effectiveness of SCD management. Additionally, Akingbola et al. (2015) assessed 31 patients with severe SCD and concluded that lower HU doses might be effective and less hazardous for patients at high risk of infection. Overall, among all the reviewed studies, only Fitzhugh et al. (2015) evaluated the variable of dosing in detail, while other researchers merely assessed the clinical effects of HU. Further comparison of drug dosages is required.

As for the effects of HU overdosing, the available evidence remains insufficient. A single case study by Miller et al. (2012) reported that an accidental intake of a 35-day supply of the drug in a two-year-old child might not lead to significant adverse side effects including hepatic and renal dysfunction. The reason for that could be the rapid renal clearance in infants. However, the data provided in the study is not conclusive because only one young patient was evaluated.

Short-Term Adverse Effects

Regular intake of HU is considered to be relatively safe for patients of all ages, yet some researchers observed various drug-linked adverse symptoms in participants. Some studies measured the level of safety of the administered HU dose and did not reveal any remarkable unfavorable outcomes (Keikhaei et al., 2016; Al Hawsawi & Turkistani, 2008). In a 15-year study of 8 subjects who started to take HU in infancy, Hankins et al. (2014) revealed that toxic effects of HU were rare and reduced to mild forms of neutropenia, thrombocytopenia, and reticulocytopenia with worsened anemia. In turn, they led to a short-term discontinuation of the therapy. Adewoyin et al. (2017) also showed that 4 patients in 60 stop taking HU because of experienced adverse effects including fertility-related issues. Since HU is still regarded as the most efficient and safe drug for SCD, further studies investigating short-term and long-term adverse effects of HU in different patient groups is required to optimize indications for dosage and safety measures.

Long-Term Adverse Effects

Malignancy and irreversible toxic effects are regarded as possible long-term outcomes of HU treatment. The selected studies devoted to the investigation of patient adherence problems and clinical effects of HU addressed the issue only partially. For instance, Adewoyin et al. (2017) and Badawy et al. (2017) stated that the fear of possible long-term drug-linked health problems contributes to HU non-use. At the same time, the reviewed studies including the longitudinal research by Steinberg et al. (2010) did not provide evidence supporting the risk of organ toxicity. Nevertheless, Mendonça et al. (2011) reported two cases of cutaneous abnormalities including skin desquamation and painful oral lesions in adult individuals taking HU for a long time. They indicated that these problems were eliminated within 15 days after the drug withdrawal. It means that the long-term use of HU can be their potential cause. Nevertheless, the evidence is not conclusive, and the lack of clear, high-quality findings indicates the need for more detailed research of the given problem.

Summary

Overall, it is possible to conclude that HU-linked benefits substantially outweigh its potential risks as the drug helps control the manifestations of SCD to a large extent. Nevertheless, some side effects can still occur both in the short run and the long run. To prevent and manage them effectively, healthcare practitioners need to optimize the HU dosage according to individual patient needs and characteristics. The reported cases of severe and highly disturbing adverse outcomes of the therapy are extremely rare but, if they occur, one may consider the withdrawal and change of the drug to ensure patient safety.

References

Adewoyin, A. S., Oghuvwu, O. S., & Awodu, O. A. (2017). Hydroxyurea therapy in adult Nigerian sickle cell disease: A monocentric survey on pattern of use, clinical effects and patient’s compliance. African Health Sciences, 17(1), 255-261.

Akingbola, T. S., Saraf, S. L., Shah, B. N., Ezekekwu, C. A., Sonubi, O., Hsu, L. L.,… Tayo, B. O. (2016). Hydroxyurea for treatment of sickle cell disease in adults in Africa. Blood, 128(22), 1305.

Akinlosotu, M. A., Adegoke, S. A., Oseni, S. B., & Adeodu, O. O. (2017). Relationship between foetal haemoglobin and haematological indices in children with sickle cell anaemia from South Western Nigeria. Nigerian Postgraduate Medical Journal, 24(4), 195-200.

Al Hawsawi, Z. M., & Turkistani, A. W. (2008). Effect of hydroxyurea in children with sickle cell disease in Saudi Arabia. Journal of Taibah University Medical Sciences, 3(2), 129-134.

Araujo, A. M., Bezerra, M. L., Borjes Jr., S. P., Dias, J. S., Lopes, A. F., Neto, V. M., … Sant’Ana, P. G. (2016). Clinical and laboratory profile of patients with sickle cell anemia. Brazilian Journal of Hematology and Hemotherapy, 39(1), 40-45.

Badawy, S. M., Thompson, A. A., Jin-Shei, L., Penedo, F. J., Rychlik, K., Liem, R. I., & Lai, J. (2017). 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 & Quality of Life Outcomes, 15(136), 1-10.

Ballas, S. K., Bauserman, R. L., McCarthy, W. F., Castro, O. L., Smith, W. R., Waclawiw, M. A., & Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. (2010). Hydroxyurea and acute painful crises in sickle cell anemia: Effects on hospital length of stay and opioid utilization during hospitalization, outpatient acute care contacts, and at home. Journal of Pain and Symptom Management, 40(6), 870-882.

Crosby, L. E., Modi, A. C., Lemanek, K. L., Guilfoyle, S. M., Kalinyak, K. A., & Mitchell, M. J. (2009). Perceived barriers to clinic appointments for adolescents with sickle cell disease. Journal of Pediatric Hematology/Oncology, 31(8), 571-576.

Curtis, S. A., Danda, N., Etzion, Z., Cohen, H. W., & Billett, H. H. (2015). Elevated steady state WBC and platelet counts are associated with frequent emergency room use in adults with sickle cell anemia. PLoS ONE, 10(8), e0133116.

Darbari, D. S., Nouraie, M., Taylor, J. G., Brugnara, C., Castro, O., & Ballas, S. K. (2014). Alpha-thalassaemia and response to hydroxyurea in sickle cell anaemia. European Journal of Haematology, 92(4), 341-345.

De Almeida, E., Lobo, C., Bonini-Domingos, C., Belini Junior, E., Silva, D., Torres, L.,… Ricci Júnior, O. (2013). Genetic and biochemical markers of hydroxyurea therapeutic response in sickle cell anemia. BMC Medical Genetics, 14(1), 1-9.

Fitzhugh, C. D., Hsieh, M. M., Allen, D., Coles, W. A., Seamon, C., Ring, M., … Taylor, J. G. (2015). Hydroxyurea-increased fetal hemoglobin is associated with less organ damage and longer survival in adults with sickle cell anemia. PLoS ONE, 10(11), e0141706.

Frei-Jones, M. J., Baxter, A. L., Rogers, Z. R., & Buchanan, G. R. (2008). Vaso-occlusive episodes in older children with sickle cell disease: Emergency department management and pain assessment. The Journal of Pediatrics, 152(2), 281-285.

Hankins, J., Aygun, B., Nottage, K., Thornburg, C., Smeltzer, M., Ware, R., & Wang, W. (2014). From infancy to adolescence: Fifteen years of continuous treatment with hydroxyurea in sickle cell anemia. Medicine, 93(28), 225.

Keikhaei, B., Yousefi, H., & Bahadoram, M. (2016). Hydroxyurea: Clinical and hematological effects in patients with sickle cell anemia. Global Journal of Health Science, 8(3), 252-256.

Lanzkron, S., Rand, C., Haywood, C., & Hassell, K. L. (2008). Provider barriers to hydroxyurea use in adults with sickle cell disease: A survey of the sickle cell disease adult provider network. Journal of the National Medical Association, 100(8), 968-974.

Mendonça, R., Gueiros, L. A., Capellaro, K., Pinheiro, V. P., & Lopes, M. A. (2011). Oral lesions associated with hydroxyurea treatment. Indian Journal of Dental Research, 22(6), 869-870.

Miller, S. T., Rey, K., He, J., Flanagan, J., Fish, B. J., Rogers, Z. R., … Ware, R. E. (2012). Massive accidental overdose of hydroxyurea in a young child with sickle cell anemia. Pediatric Blood & Cancer, 59(1), 170-172.

Nottage, K. A., Ware, R. E., Winter, B., Smeltzer, M., Wang, W. C., Hankins, J. S.,… Aygun, B. (2014). Predictors of splenic function preservation in children with sickle cell anemia treated with hydroxyurea. European Journal of Haematology, 93(5), 377-383.

Nwenyi, E., Leafman, J., Mathieson, K., & Ezeobah, N. (2014). Differences in quality of life between pediatric sickle cell patients who used hydroxyurea and those who did not. International Journal of Health Care Quality Assurance, 27(6), 468-481.

Oyeku, S. O., Driscoll, M. C., Cohen, H. W., Trachtman, R., Pashankar, F., Mullen, C., … Green, N. S. (2013). Parental and other factors associated with hydroxyurea use for pediatric sickle cell disease. Pediatric Blood & Cancer, 60(4), 653-658.

Penkert, R. R., Hurwitz, J. L., Rosch, J., Thomas, P., Dowdy, J., Hankins, J. S.,… Tang, L. (2018). Inflammatory molecule reduction with hydroxyurea therapy in children with sickle cell anemia. Haematologica, 103(2), 54.

Renoux, C., Romana, M., Joly, P., Ferdinand, S., Faes, C., Lemonne, N.,… Martin, C. (2016). Effect of age on blood rheology in sickle cell anaemia and sickle cell haemoglobin c disease: A cross-sectional study. Plos ONE, 11(6), 1-11.

Santos, F. K. de S., & Maia, C. N. (2011). Patients with sickle cell disease taking hydroxyurea in the Hemocentro Regional de Montes Claros. Revista Brasileira de Hematologia E Hemoterapia, 33(2), 105-109.

Shome, D. K., Al Ajmi, A., Radhi, A. A., Mansoor, E. J., & Majed, K. S. (2016). The effect of hydroxyurea therapy in Bahraini sickle cell disease patients. Indian Journal of Hematology & Blood Transfusion, 32(1), 104-109.

Silva-Pinto, A. C., Angulo, I. L., Brunetta, D. M., Neves, F. I. R., Bassi, S. C., Santis, G. C. D., & Covas, D. T. (2013). Clinical and hematological effects of hydroxyurea therapy in sickle cell patients: A single-center experience in Brazil. Sao Paulo Medical Journal, 131(4), 238-243.

Steinberg, M., McCarthy, W., Castro, O., Ballas, S., Armstrong, F., Smith, W., … Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and MSH Patients’ Follow-up. (2010). The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. American Journal of Hematology, 85(6), 403-408.

Tafrali, C., Paizi, A., Borg, J., Radmilovic, M., Bartsakoulia, M., Giannopoulou, E., Giannakopoulou, O.,… Patrinos, G. P. (2013). Genomic variation in the MAP3K5 gene is associated with β-thalassemia disease severity and hydroxyurea treatment efficacy. Pharmacogenomics, 14(5), 469-483.

Wang, W. C., Oyeku, S. O., Luo, Z., Boulet, S. L., Miller, S. T., Casella, J. F., … Grosse, S. D. (2013). Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia. Pediatrics, 132(4), 677-683.

Wang, W. C., Ware, R. E., Miller, S. T., Iyer, R. V., Casella, J. F., Minniti, C. P., … Thompson, B. W. (2011). A multicenter randomised controlled trial of hydroxyurea (hydroxycarbamide) in very young children with sickle cell anaemia. Lancet, 377(9778), 1663-1672.

Ward, J., Lewis, N., & Tsitsikas, D. A. (2018). Improving routine outpatient monitoring for patients with sickle-cell disease on hydroxyurea. BMJ Open Quality, 7(1), 000218.