|Year : 2018 | Volume
| Issue : 1 | Page : 1-5
Hydroxyurea: Modifier of pathophysiology in sickle cell anemia
Akinsegun Akinbami1, Ebele Uche1, Adedoyin Dosunmu1, Adewumi Adediran2, Sarah John-Olabode2
1 Department of Hematology and Blood Transfusion, Lagos State University College of Medicine, PMB 21266, Ikeja, Nigeria
2 Department of Hematology and Blood Transfusion, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
|Date of Web Publication||11-Jun-2018|
Department of Hematology and Blood Transfusion, Lagos State University College of Medicine, PMB 21266, Ikeja, Lagos
Source of Support: None, Conflict of Interest: None
Sickle cell anemia (SCA) patients have a point mutation in the 6th codon of the hemoglobin gene in which adenine is replaced by thymine resulting in replacement of glutamic acid with valine on the 6th amino acid in the β globin chain of the hemoglobin. Despite identical basic genetic mutation in all SCA patients, significant variation in clinical severity occurs. Clinical severity of SCA varies from mild to very severe types requiring more intensive medical interventions such as use of hydroxyurea (HU) and stem cell transplantation. Use of HU has improved clinical outcome in SCA and is recommended for moderate-to-severe varieties of SCA. This review brings to the fore mode of action, indications, commencement of therapy, monitoring, toxicity, and discontinuation of HU in selected SCA patients.
Keywords: Hydroxyurea, pathogenesis, sickle cell anemia
|How to cite this article:|
Akinbami A, Uche E, Dosunmu A, Adediran A, John-Olabode S. Hydroxyurea: Modifier of pathophysiology in sickle cell anemia. Ann Trop Pathol 2018;9:1-5
|How to cite this URL:|
Akinbami A, Uche E, Dosunmu A, Adediran A, John-Olabode S. Hydroxyurea: Modifier of pathophysiology in sickle cell anemia. Ann Trop Pathol [serial online] 2018 [cited 2019 May 24];9:1-5. Available from: http://www.atpjournal.org/text.asp?2018/9/1/1/234150
| Introduction|| |
Sickle cell anemia (SCA) was first described in 1910 by Dr. James Herrick in a Dental student in Chicago, USA. A point mutation in the 6th codon of the hemoglobin gene in which adenine is replaced by thymine (GAG → GTG) is responsible for the sickle cell gene. The consequence of the mutation is the replacement of glutamic acid with valine on the 6th amino acid in the β globin chain of the hemoglobin molecule. Despite the presence of basic identical genetic mutation (GAG → GTG) in all SCA patients, significant variation in clinical severity occurs. Well established causes of the variations of clinical severity in SCA have been reported, these include hemoglobin haplotypes and fetal hemoglobin (HbF) concentrations, socioeconomic status, coinheritance of α-thalassemia, expression of adhesion molecules on white blood cells (WBCs), steady-state neutrophil counts and function, plasma level of IgG and in particular IgG3, levels of circulating immune complexes, and levels of transferrin and C-reactive protein. Clinical severity varies from mild to very severe requiring more intensive medical interventions such as use of hydroxyurea (HU) and stem cell transplantation.
| Pathogenesis of Vaso-Occlusion in Sickle Cell Anemia and the Role of Hydroxyurea|| |
Chronic hemolysis in SCA is associated with hemoglobinemia. Hemoglobin is an avid scavenger of nitric oxide (NO), resulting in the reduction of intracellular NO which is associated with numerous complications of SCA such as, priapism and acute chest syndrome (ACS) among others. Metabolism of HU generates NO, which compensates for the loss of endogenous NO from chronic hemolysis and hemoglobinemia, thus ameliorating the effects of NO deficiency. Furthermore, the NO available from HU metabolism stimulates soluble guanyl cyclase which in turn increases HbF concentration. Similarly, HU inhibits two iron molecules of the cellular's ribonucleotide reductases enzymes, which favors the production of HbF because the latter red-cell progenitors divide less rapidly unlike hemoglobin S (HbS) whose production is severely depressed because of its rapidly dividing precursors.
The accentuated chronic intravascular and extravascular hemolysis resulting from membrane damage causes a reduction in intravascular NO secondary to hemoglobinemia which results in increased vascular tone and pulmonary artery hypertension., Apart from NO depletion secondary to chronic hemolysis and hemoglobinemia, the pathogenesis of painful crises, ACS, functional asplenia and acute stroke in SCA are majorly due to high levels (concentrations) of HbS in red cells of SCA patients. HbSS red cells lose deformability when deoxygenated, the consequences of this are vascular obstruction and ischemia.
High steady-state leukocytes count has been reported to directly impact on clinical severity. HU induces cytoreduction and decreases inflammatory reactions, thus decreasing vascular injury, hemolysis and vaso-occlusion.
Finally, the abnormal surfaces of the damaged red cells predispose to increased adherence to and impair the vascular endothelium, thus provoking vascular proliferative lesions through the activation of WBC and platelets with production of cytokines, growth factors, and coagulation proteins leading to acute vaso-occlusion.
| History of Hydroxyurea|| |
In 1970s, patients with SCA who had increased red blood cell HbF were observed to have less severe presentations., Following a decade of relative inactivity, Platt et al. in 1984 reported HU induced an increase in HbF in red blood cell of SCA.
HU was approved in February 1988 after four years of clinical trials for adult sickle cell disease patients by the United States Food and Drug Authority. The National Heart Lung and Blood Institute also recommended its daily use on some selected SCD patients in 2002.,,
In 2007, the use of HU in SCD was approved by the European Medicines Agency for recurrent vaso-occlusive crises (VOC) and ACS in pediatric and adult patients.
By 2008, the National Institutes of Health Consensus Development held a Conference on the use of HU in the treatment of SCD  following a published comprehensive systematic review by Agency for Healthcare Research and Quality. The use of HU secondary to its approval and recommendation in adult SCA by various agencies and organizations, resulted in observed clinical improvements which have been incontrovertibly reported to significantly reduce the frequencies of VOC and ACS and the rate of blood transfusions in SCA by several studies ,,,,, Several studies have also demonstrated the decreased rate of hospitalization in patients on HU compared to pre-HU era.,,
| Pharmacology of Hydroxyurea|| |
HU belongs to the group of drugs described as anti-metabolites. First synthesized in 1869 in Germany by Dressler and Stein, it has a molecular weight of 76.05 with a structural formula of CH4N2O2. HU is converted to NO in vivo. The NO diffuses into cells inhibiting ribonucleotide reductase's two iron molecules, thus inactivating its tyrosyl free radical. This selectively inhibits DNA synthesis causing cell death in S phase.
HU exists in 100, 200, 300, 400, and 500 mg formulations. Individual reactions to use of HU in SCD are variable for unknown reasons, thus limiting its usefulness in some individuals., It modifies SCD pathogenesis  decreasing the incidence of VOC, priapism, and overall mortality in adults.
The effects of HU's clinical improvement in SCD are mediated majorly through increased HbF concentrations. It is also known to increase erythrocyte volume and hydration, decrease steady-state neutrophils count and activation, decrease adhesion of red cells and granulocytes to vascular endothelium as well as increased NO production with resultant improved cellular oxygen perfusion. Apart from its usefulness in HbSS, it is use in the management of HbSC was recommended by some authors  but neither recommended nor discouraged in another study.
| Metabolism of Hydroxyurea|| |
HU belongs to the class of hydroxamic acids. It has ability to bind metals and also inhibits ribonucleotide reductase. This inhibition reduces the production of HbS and increases production of HbF. It also reduces WBCS and platelet counts, thus reducing their roles in vascular injury and occlusion. When metabolized, it generates NO. NO stimulates soluble guanylate cyclase resulting in the production of HbF. NO generated also compensates for NO loss in intravascular hemolysis. The half-life of HU is 3–4 h; it is well absorbed orally and excreted through the kidneys.
| Indications for Hydroxyurea|| |
HU indications recommended by National Heart Lung, and Blood Institute is presented in [Table 1]. Summary of indications for use of HU recommended by Wong et al., include
- Adults with SCA who have ≥3 moderate-to-severe VOC in 1 year (Grade 1A)
- Adults and children with SCA who have history of ACS or symptomatic anemia (Grade 1B)
- In children with SCA who have ≥3 moderate-to-severe VOC in 1 year (Grade 1 B)
- In patients with SCA with a history of stroke and contraindications to chronic transfusion (Grade 2 B)
- In adults with HbS β+ thalassemia with ≥3 moderate to severe VOC in a one year period or a history of ACS (Grade 2C)
- In patients with HbSC and children with HbS β+ thalassemia, there is insufficient evidence to provide recommendations for HU therapy.
|Table 1: Hydroxyurea indications recommended by National Heart Lung, and Blood Institute|
Click here to view
Footnotes of the grading as follows:
- Grade 1A – Very strongly recommended, Grade 1B – Strongly recommended
- Grade 2B – Recommended, Grade 2C – Weakly recommended.
| Starting Hydroxyurea|| |
Mandatory baseline investigations are weight, height, oxygen saturation, full blood count (FBC), and HbF quantification, liver function test, urea, and creatinine. Viral screen includes HbsAg, HCV, HIV, and Parvo virus B19 serology. Lactate dehydrogenase levels and pregnancy tests for women in reproductive age group are important. Starting dose is 15 mg/kg/day. However, if creatinine clearance is <60 ml/min, starting dose is reduced to 7.5 mg/kg/day.
| Monitoring Hydroxyurea Use|| |
[Table 2] gives an overview of monitoring hydroxyurea use.
| Stopping Hydroxyurea|| |
Stop HU temporarily if neutrophils is <2000/mm 3, platelets <80000/mm 3, hemoglobin <4.5g/dl and reticulocytes <80,000/mm 3. Recommence if blood counts recover. Hematologic recovery takes place within 2 weeks.
| Increasing Dose of Hydroxyurea|| |
Increase HU 12 weekly by 5mg if FBC is within acceptable range. The maximum tolerated dose is 35mg/kg/day.
Poor response to Hydroxyurea
- Poor adherence due to fears of side effects and cost of monitoring
- Decreased marrow reserve-precluding adequate dosing
- Genetic factors.
- Increased HbF
- Increased Hemoglobin by 15%–20%
- Improved well being
- Less pain/VOC.
Contraception and pregnancy
Teratogenic effects of HU have been reported from animal studies. Its deleterious effects on spermatogenesis were also reported by Saalu et al. Berthaut et al. reported a reduction in sperm count which failed to increase after discontinuation of HU. Although the use of HU in pregnant women were described in three studies reporting pregnancy outcomes,,, no birth defects were reported in any, however, reproductive counseling is key in adolescents and adults on HU who are of reproductive age group.
HU could present with the following toxicity, hematological, renal/hepatic, and gastrointestinal and dermatological [Table 3].
| Risk of Malignancies|| |
In a prospective study, assessing the risk of secondary malignancies, involving 1638 polycythemia vera patients on long-term HU, no risk of leukemia attributable to HU over the use of 32 P, busulfan or pipobroman was reported. The study concluded that a small risk cannot be ruled out completely. On the contrary, five malignancies were reported in 951 patients on HU (0.5%) and 1 malignancy in 1736 patients not on HU (0.06%).,, Various hematologic malignancies presenting 4-15 years after starting HU in patients with SCA were reported in three studies.,,
| Conclusion|| |
The use of HU has incontrovertibly improved clinical outcome of SCA patients. However, despite its numerous advantages, its use is not risk-free. It is associated with minimal side effects if used in accordance with all recommendations.
The authors would like to thank Miss. Oluwatosin Soetan for editorial assistance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Herrick JB. Peculiar elongated and sickled red blood corpuscle in a case of severe anaemia. Arch Int Med 1910;6:517-21.
Serjeant GR. Sickle-cell disease. Lancet 1997;350:725-30.
Powars DR, Meiselman HJ, Fisher TC, Hiti A, Johnson C. Beta-S gene cluster haplotypes modulate hematologic and hemorheologic expression in sickle cell anemia. Use in predicting clinical severity. Am J Pediatr Hematol Oncol 1994;16:55-61.
Okpala I. The management of crisis in sickle cell disease. Eur J Haematol 1998;60:1-6.
Embury SH, Dozy AM, Miller J, Davis JR Jr., Kleman KM, Preisler H, et al.
Concurrent sickle-cell anemia and alpha-thalassemia: Effect on severity of anemia. N Engl J Med 1982;306:270-4.
Okpala I, Daniel Y, Haynes R, Odoemene D, Goldman J. Relationship between the clinical manifestations of sickle cell disease and the expression of adhesion molecules on white blood cells. Eur J Haematol 2002;69:135-44.
Anyaegbu CC, Okpala IE, Akren'Ova YA, Salimonu LS. Peripheral blood neutrophil count and candidacidal activity correlate with the clinical severity of sickle cell anaemia (SCA) Eur J Haematol 1998;60:267-8.
Hedo CC, Okpala IE, Aken'Ova AY, Salimonu LS. Correlates of severity in sickle cell anaemia. Blood 1996;88 Suppl 17b.
Anyaegbu CC, Okpala IE, Aken'ova AY, Salimonu LS. Complement haemolytic activity, circulating immune complexes and the morbidity of sickle cell anaemia. APMIS 1999;107:699-702.
Hedo CC, Aken'ova YA, Okpala IE, Durojaiye AO, Salimonu LS. Acute phase reactants and severity of homozygous sickle cell disease. J Intern Med 1993;233:467-70.
Steinberg MH, Hebbel RP. Clinical diversity of sickle cell anemia: Genetic and cellular modulation of disease severity. Am J Hematol 1983;14:405-16.
Cokic VP, Smith RD, Beleslin-Cokic BB, Njoroge JM, Miller JL, Gladwin MT, et al.
Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J Clin Invest 2003;111:231-9.
Yarbro JW. Mechanism of action of hydroxyurea. Semin Oncol 1992;19:1-0.
Schechter AN, Gladwin MT. Hemoglobin and the paracrine and endocrine functions of nitric oxide. N Engl J Med 2003;348:1483-5.
Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al.
Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004;350:886-95.
Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, et al.
Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991;325:11-6.
Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 1984;63:921-6.
Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG, et al.
Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest 1984;74:652-6.
Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood 2010;115:5300-11.
Mulaku M, Opiyo N, Karumbi J, Kitonyi G, Thoithi G, English M, et al.
Evidence review of hydroxyurea for the prevention of sickle cell complications in low-income countries. Arch Dis Child 2013;98:908-14.
Segal JB, Strouse JJ, Beach MC, Haywood C, Witkop C. Hydroxyurea for the treatment of sickle cell disease. Evidence Report Technology Assessment Number 165. AHRQ Publication No. 08. E007; 2008.
Brawley OW, Cornelius LJ, Edwards LR, Gamble VN, Green BL, Inturrisi C, et al.
National institutes of health consensus development conference statement: Hydroxyurea treatment for sickle cell disease. Ann Intern Med 2008;148:932-8.
Segal JB, Strouse JJ, Beach MC, Haywood C, Witkop C, Park H, et al.
Hydroxyurea for the treatment of sickle cell disease. Evid Rep Technol Assess (Full Rep) 2008;165:1-95.
Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, et al.
Hydroxycarbamide in very young children with sickle-cell anaemia: A multicentre, randomised, controlled trial (BABY HUG). Lancet 2011;377:1663-72.
Gilmore A, Cho G, Howard J, Layton M, Afif M, Hughes RG, et al.
Feasibility and benefit of hydroxycarbamide as a long-term treatment for sickle cell disease patients: Results from the North West London sickle cell disease registry. Am J Hematol 2011;86:958-61.
Rigano P, Pecoraro A, Calvaruso G, Steinberg MH, Iannello S, Maggio A, et al.
Cerebrovascular events in sickle cell-beta thalassemia treated with hydroxyurea: A single center prospective survey in adult Italians. Am J Hematol 2013;88:E261-4.
Sharef SW, Al-Hajri M, Beshlawi I, Al-Shahrabally A, Elshinawy M, Zachariah M, et al.
Optimizing hydroxyurea use in children with sickle cell disease: Low dose regimen is effective. Eur J Haematol 2013;90:519-24.
Voskaridou E, Christoulas D, Bilalis A, Plata E, Varvagiannis K, Stamatopoulos G, et al.
The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: Results of a 17-year, single-center trial (LaSHS). Blood 2010;115:2354-63.
Italia K, Jain D, Gattani S, Jijina F, Nadkarni A, Sawant P, et al.
Hydroxyurea in sickle cell disease – A study of clinico-pharmacological efficacy in the Indian haplotype. Blood Cells Mol Dis 2009;42:25-31.
Lobo CL, Pinto JF, Nascimento EM, Moura PG, Cardoso GP, Hankins JS, et al.
The effect of hydroxcarbamide therapy on survival of children with sickle cell disease. Br J Haematol 2013;161:852-60.
Singh H, Dulhani N, Kumar BN, Singh P, Tiwari P. Effective control of sickle cell disease with hydroxyurea therapy. Indian J Pharmacol 2010;42:32-5.
] [Full text]
Dressler WF, Stein R. Ueberden Hydroxyl harnstoff. Justus Liebigs Ann Chem 1869;150:1317-22.
Bakanay SM, Dainer E, Clair B, Adekile A, Daitch L, Wells L, et al.
Mortality in sickle cell patients on hydroxyurea therapy. Blood 2005;105:545-7.
Charache S, Dover GJ, Moore RD, Eckert S, Ballas SK, Koshy M, et al.
Hydroxyurea: Effects on hemoglobin F
production in patients with sickle cell anemia. Blood 1992;79:2555-65.
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al.
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 1995;332:1317-22.
Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, et al.
Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: Risks and benefits up to 9 years of treatment. JAMA 2003;289:1645-51.
Saad ST, Lajolo C, Gilli S, Marques Júnior JF, Lima CS, Costa FF, et al.
Follow-up of sickle cell disease patients with priapism treated by hydroxyurea. Am J Hematol 2004;77:45-9.
Moore RD, Charache S, Terrin ML, Barton FB, Ballas SK. Cost-effectiveness of hydroxyurea in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. Am J Hematol 2000;64:26-31.
Miller MK, Zimmerman SA, Schultz WH, Ware RE. Hydroxyurea therapy for pediatric patients with hemoglobin SC disease. J Pediatr Hematol Oncol 2001;23:306-8.
Wang W, Brugnara C, Snyder C, Wynn L, Rogers Z, Kalinyak K, et al.
The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: Results of the multi-centre CHAMPS trial. Br J Haematol 2011;152:771-6.
Wong TE, Brandow AM, Lim W, Lottenberg R. Update on the use of hydroxyurea therapy in sickle cell disease. Blood 2014;124:3850-7.
Yan JH, Ataga K, Kaul S, Olson JS, Grasela DM, Gothelf S, et al.
The influence of renal function on hydroxyurea pharmacokinetics in adults with sickle cell disease. J Clin Pharmacol 2005;45:434-45.
Shelby MD. NTP-CERHR Expert Panel Report on the Reproductive and Developmental Toxicity of Hydroxyurea. Research Triangle Park, NC: National Toxicology Program; 2007.
Saalu LC, Osinubi AA, Akinbami AA, Yama OE, Oyewopo AO, Enaibe BU. Moringa oleifera
Lamarck (drumstick) leaf extract modulates the evidences of Hydroxyurea-induced testicular derangement. Int J Appl Res Nat Prod 2011;4:35-45.
Berthaut I, Guignedoux G, Kirsch-Noir F, de Larouziere V, Ravel C, Bachir D, et al.
Influence of sickle cell disease and treatment with hydroxyurea on sperm parameters and fertility of human males. Haematologica 2008;93:988-93.
Finazzi G, Caruso V, Marchioli R, Capnist G, Chisesi T, Finelli C, et al.
Acute leukemia in polycythemia vera: An analysis of 1638 patients enrolled in a prospective observational study. Blood 2005;105:2664-70.
Baz W, Najfeld V, Yotsuya M, Talwar J, Terjanian T, Forte F, et al.
Development of myelodysplastic syndrome and acute myeloid leukemia 15 years after hydroxyurea use in a patient with sickle cell anemia. Clin Med Insights Oncol 2012;6:149-52.
Couronné L, Schneider P, de Montalembert M, Dumesnil C, Lahary A, Vannier JP, et al.
Hodgkin lymphoma in a sickle cell anaemia child treated with hydroxyurea. Ann Hematol 2009;88:597-8.
Taylor JG, Darbari DS, Maric I, McIver Z, Arthur DC. Therapy-related acute myelogenous leukemia in a hydroxyurea-treated patient with sickle cell anemia. Ann Intern Med 2011;155:722-4.
[Table 1], [Table 2], [Table 3]