Review Articles

Sickle Cell Disease and Hydroxyurea Treatment


Introduction: Sickle cell disease (SCD) is a genetic disorder impacting the patient’s haemoglobin. This condition is accompanied by many dangerous phenotypes, which are the result of pathological haemoglobin polymerisation within the red blood cell (RBC). The primary aim of this piece is to review the accepted literature on the SCD pathophysiology and its pharmacological treatment option, hydroxyurea.

Summary: Hydroxyurea has multiple posited mechanisms of action but most importantly it is the only SCD treatment that targets the underlying pathology. It was found that hydroxyurea significantly decreases the frequency of hospitalisations, vaso-occlusive events and blood transfusions required. In summary, SCD is a complex hereditary disorder in which for a medical practitioner to effectively manage requires a comprehensive understanding of both normal haemoglobin physiology and its pathophysiology.


Sickle cell disease (SCD) is a common monogenic autosomal recessive disorder of haemoglobin, occurring in approximately 1-2% of Europeans and Americans of African descent and has a prevalence of 4% or higher in West Africa [1]. The primary role of haemoglobin is the transport of oxygen from highly oxygenated areas, such as the lungs, to the comparatively poorly oxygenated tissues. However, in SCD, low oxygen conditions result in the polymerisation of the pathological haemoglobin which downstream leads to the SCD signs and symptoms, including vaso-occlusive events, chronic haemolytic anaemia, organ dysfunction, and increased infections.

To extensively investigate SCD, this review will first address normal RBC physiology, the SCD pathophysiological models, and finally a treatment option for the condition. Regarding SCD treatment, this review will examine the pharmacological use of hydroxyurea, an antineoplastic agent. Finally, this topic is relevant and of considerable importance as it frequently leads to patient hospitalisations, life-threatening characteristics, and significant global prevalence.

Materials and Methods

A comprehensive review of literature was conducted using the computerised search databases, PubMed and Ovid MEDLINE. The obtained articles were then filtered and case reports and articles written in languages other than English were excluded. The review was conducted during September of 2016, with the most recent literature used where appropriate.

Normal physiology

The primary function of the RBC is O2 delivery from the lungs to the body’s tissues, mainly to allow oxidative phosphorylation in the mitochondria [2]. Within the RBC it is the chromo-protein haemoglobin that allows for the loading and unloading of O2. Haemoglobin contains four globin chains, with a corresponding haem molecule for which each has the ability to reversibly bind oxygen [3]. As haemoglobin binds O2 to its haem groups, its affinity for oxygen increases due to the alteration of the haemoglobin molecular structure. However, haemoglobin has more functions, those being; CO2 transport to the lungs from tissues as carbaminohaemoglobin, buffering of H+ via the carbamoyl anhydrase reaction within the RBC, and nitric oxide (NO) metabolism [3,4].

There are two types of adult haemoglobin, those being the major haemoglobin HbA and minor haemoglobin HbA2, comprising of two α-globin and two β-globin chains and two α-globin and two δ-chains, respectively [3]. These differing globin chains make HbA2 a considerably poorer oxygen carrier. Each of the α-chains are made of 141 amino acids, and β-chains of 146 amino acids. Chromosome 16 contains the genes for the α-chain and chromosome 11 has those for the β-chain [3].

The other type of haemoglobin is foetal haemoglobin (HbF) and is clinically and therapeutically significant in SCD, as discussed below. Structurally, HbF comprises of two α-globin and two γ-globin chains. Studies have shown that after 6 months, HbF begins to disappear from infant RBCs, however, the signalling mechanism of this is not known [5,6].


SCD is defined by the presence of sickle haemoglobin (HbS) in the RBCs, which causes the distinctive sickle RBC shape. SCD is an inherited disease done so in an autosomal recessive fashion. The carriers for the disease are heterozygous for the mutation and are said to have the sickle cell trait [7]. Patients that are disease compound heterozygous or homozygous have SCD and will exhibit some level of symptoms. In the U.S., the common SCD genotypes include: sickle cell anaemia (HbSS), HbS/β° thalassaemia, and HbS/β+ thalassaemia [7]. There are, however, many more compound heterozygous sickle cell genotypes, though most are rare.

HbS occurs due to a single nucleotide β-globin gene mutation, causing the 6th amino acid to be changed from glutamic acid to valine [8]. The mutation results in the binding of β1 and β2 chains of two deoxygenated HbS tetramers. This crystallisation process continues within the RBC, growing until the flexibility and structure is disturbed. Disease severity is dependent upon the degree of HbS polymerisation, which relies on the degree of haemoglobin deoxygenation and the concentration of intracellular HbS. For HbS, this deoxygenation results in the exposure of the mutated valine residue on the molecule surface, this causes hydrophobic interactions with surrounding chains. The consequently formed polymers develop into bundles, causing RBC distortion into its distinguishing sickle appearance. This reduces flexibility which impairs the flow of sickled RBCs through narrow vasculature.

The signs and symptoms of SCD can be understood via the three mechanisms: vascular occlusion, haemolytic anaemia, and increased infection tendency (Figure 1).

Figure 1. Sickle cell disease pathophysiology. The pathophysiological effects of sickled haemoglobin (HbS) polymerisation can be seen, being; vaso-occlusion, ischemia, haemolysis and decreased nitric oxide (NO) bioavailability. HbS polymerisation develops following RBC deoxygenation which consequently gives the RBC the characteristic sickle shape. Vaso-occlusion is the effect of interactions between the rigid sickled RBCs and the endothelial surface, causing downstream necrosis, organ dysfunction, acute pain and oxidative reperfusion stress. Haemolysis results in the release of haemoglobin into the plasma which removes bioavailable NO.

Vaso-occlusion most frequently occurs in the bones – but can occur anywhere – which is the result of sickled cells blocking blood vessels. Venous blockage results due to the physiological requirement for haemoglobin deoxygenation at the tissues which then allows for the formation of the pathological sickled RBC shape. Subsequent systemic disturbances and pain can be felt downstream from the blockage, caused by ischemia, necrosis and organ dysfunction. Fat embolisms can occur secondary to a bone marrow infarct which could exacerbate the vascular occlusion issue, especially in the respiratory and neurological systems [9].

Initially, it was thought that only the less soluble deoxygenated polymerised HbS caused the sickled RBCs to be ridged and dense, resulting in vaso-occlusion [10,11]. However, the process is multifaceted and dynamic incorporating stimulatory interactions of the vascular endothelium to increase numerous adhesion molecules, such as integrin. This produces an inflammatory response, RBC and leukocyte adhesion to vessel walls, as well as, tissue damage predisposing the patient to vaso-occlusion [12-14]. Such vaso-occlusion causes interrupted blood flow, oxidative reperfusion stress, thrombus formation, stroke, and potentially severe ischemia [15-18]. The later mentioned endothelial dysfunction which occurs due to decreased NO levels causing vasoconstriction, also contributes to this dangerous vaso-occlusive state [19].

Haemolytic anaemia is another marked pathology in sickle-cell disease, which too is promoted by HbS polymerisation. It is accepted that such haemolysis results in fatigue, anaemia, and cholelithiasis, and now is also being linked to the advancement of progressive vasculopathy. As patients with SCD age, their vasculopathy risk increases, primarily distinguished by pulmonary and systemic hypertension, as well as vascular intimal and smooth muscle proliferative modifications [20-22]. Clinically, the severity of intravascular haemolysis in SCD patients is determined by measuring the serum levels of lactate dehydrogenase [23].

Epidemiological studies have proposed a positive correlation to both low levels of non-polymerised haemoglobin and significant intravascular haemolysis with increased rates of the SCD manifestations, some of which include; cholelithiasis, cutaneous leg ulceration, priapism, and pulmonary hypertension [24,25]. Furthermore two prospective cohort studies have reported a relationship between pulmonary hypertension and haemolytic anaemia severity [24,26].

One pathophysiological basis for pulmonary hypertension in SCD is through the effect of haemolysed cells on NO and arginase. NO regulates vasodilation via the stimulation of cGMP dependent protein kinases, it also decreases platelet aggregation, and inhibits the release of endothelin-1, the powerful vasoconstrictor [27,28]. RBC haemolysis causes haemoglobin and the arginase enzyme to enter plasma circulation. This free haemoglobin is a potent NO scavenger, hence acting to impede the vaso-protective qualities of NO. Additionally, arginase catabolises arginine which is required for NO synthesis, hence perpetuating the decreased NO bioavailability [29]. Downstream arginase metabolites further increases vascular proliferation, inflammatory stress, and overall endothelial dysfunction [30]. These homeostatic changes will produce pulmonary vascular endothelial remodelling and constriction, hence resulting in pulmonary hypertension.

Another danger to SCD patients is their increased susceptibility to many encapsulated bacterial infections and is a major cause of mortality and morbidity [31,32]. The primary factors allowing this predisposition to encapsulated bacteria are: post-infarct hypo- or asplenia, abnormal opsonin phagocytosis due to potential defects in the alternative complement pathway, and deficiencies of particular circulating antibodies [33]. Common SCD infections are from Haemophilus influenza, non-typhi Salmonella, and Streptococcus pneumoniae [31,34,35]. The polysaccharide capsule of these bacteria acts to prevent the binding of complement or inhibits complement communication with macrophage receptors [36].


As previously described, the underlying mechanism in SCD pathology is the polymerising of deoxygenated HbS, all stemming from the single nucleotide mutation of the β-globin gene.

Numerous management and treatment options are described in medical literature such as RBC exchange transfusions, however, hydroxyurea – an antineoplastic agent – is the only approved pharmacological intervention that treats the underlying SCD pathology and will be discussed at length for the remainder of this paper [37]. Hydroxyurea was approved for therapeutic use in 1998 by the US Food and Drug Administration in SCD patients suffering from frequent painful crises [38]. Despite much evidence supporting the clinical efficacy for SCD hydroxyurea treatment, its HbF induction mechanism of action continues to be largely unknown [39].

Hydroxyurea is a short-acting cytotoxic ribonucleotide reductase inhibitor which acts to arrest S-phase cells by impairing their DNA replication [40]. It may therefore enhance HbF production indirectly, by killing rapidly proliferating late erythroid cells [41,42]. The recurrent pharmacological injury to the erythropoietic marrow from repeated drug administration results in enhanced erythropoiesis, this increases primitive erythroid precursor recruitment, consequently raising HbF levels [43]. Most of the beneficial effects of hydroxyurea are attributed to the HbF induction, however, clinical improvement has been observed before a marked increase in circulating HbF, which has led to the postulation of additional mechanisms of action, including decreased intercellular adhesion enhancing blood flow and increased NO bioavailability. Hydroxyurea metabolism is the cause of this increase in NO levels [41].

It has been known for some time that the primary effect of hydroxyurea, increased HbF levels, can ameliorate SCD [8]. This works by its reduction of RBC sickling because HbF replaces the mutated β-globin with a γ-globin chain which is non-pathological, hence decreasing the number of vaso-occlusive events and infarction. Even if an infarct occurs, the decreased circulating neutrophils from hydroxyurea administration may regulate the degree of tissue damage and pain felt [44]. There is also evidence that hydroxyurea generates NO and increased cGMP levels which causes the induction of foetal γ-globin mRNA and HbF protein [45].

Hydroxyurea has been shown to downregulate the expression of specific adhesion molecules on vascular endothelium [46]. This phenomenon is evidently independent of any of the SCD β-globin gene effects. Considering the importance that exposure to hypoxic capillary bed venules has on sickling, and consequently vaso-occlusive events, any reduction in endothelial-sickled RBC adhesion would have salutary effects.

Pregnancy is contraindicated with the use of hydroxyurea because it is known to have mutagenic, carcinogenic, and teratogenic effects in animals [47]. However, this relationship was not observed in 94 pregnancy outcomes of the human SCD patients that participated in hydroxyurea drug trials that despite precautions became pregnant mid-trial [47]. This suggests the foetal exposure to therapeutic hydroxyurea may not be teratogenic. Conversely, another study indicated abnormal sperm parameters in males taking hydroxyurea that possibly could have teratogenic effects or cause infertility [48]. It is important to note, however, that most individuals in this study had abnormal sperm prior to commencing hydroxyurea treatment, thus it was difficult to establish the precise contribution of hydroxyurea. Therefore, considerably more research and follow up time should be allocated to pregnant SCD subjects exposed to hydroxyurea to determine definitive results.

At present, there have only been 5 randomised control trials conducted regarding the efficacy of hydroxyurea treatment in patients with sickle cell anaemia. Of these, all except the Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial indicated benefit for hydroxyurea treatment over the standard of care [49-53]. Study sizes range between 44 and 299 participants. The results from these studies described reduced vaso-occlusive crises, pulmonary pathologies, and blood transfusion frequencies in those receiving hydroxyurea treatment (Table 1) [49,50,52,53].

Table 1. SCD hydroxyurea randomised control trials.
Abbreviations: HU = hydroxyurea, y = year, SCA = sickle cell anaemia, VOC = vaso-occlusive crisis, ACS = acute chest syndrome, Hx = history, mo = months, MTD = maximum tolerated dose.

The Belgian paediatric randomised control trial showed that hydroxyurea treatment resulted in statistically significant increases in levels of HbF and decreased both hospitalisations and vaso-occlusive events when compared to the placebo [49]. Wang and associates found that although changes in renal and splenic function were insignificant, there were statistically relevant decreases in vaso-occlusive events, hospitalisations, and the number of blood transfusions required [52]. A small Indian based study also reported that children treated with hydroxyurea experienced decreased numbers of vaso-occlusive events, hospitalisations, and blood transfusions required, despite the low doses of drug administered [50]. The findings from the Multicentre Study of Hydroxyurea, conducted by Charache et al [53], too demonstrated decreased incidents of vaso-occlusion, hospitalisations, and required transfusions compared to the placebo. However, in Charache et al [53], results were compromised by the substantial loss to follow up, with only 134 of the initial 299 participants completing the full 2-year trial.

At present no phase 3 randomised control trials are enrolling individuals with different genotypes to HbSS and HbS/β° thalassaemia [38]. However, two cohort studies from Italy and Greece have shown that hydroxyurea efficacy observed in HbSS individuals also extends to those with HbS/β+ thalassaemia [54,55]. However, this hydroxyurea recommendation is weak due to the limited sample population when likened to the size of HbSS data.


To conclude, this literature review has discussed the normal physiology of haemoglobin, pathogenesis of sickle cell disease as well as its course of treatment. It was found this haemoglobinopathy is responsible for vaso-occlusive crises, pulmonary pathologies, and increased susceptibility to infection. Nonetheless, hydroxyurea was reviewed as a potential treatment option. Hydroxyurea has multiple posited mechanisms of action but more importantly is the only SCD treatment that targets the underlying pathology. There is opportunity for future research into both the exact hydroxyurea mechanism of action in SCD patients and hydroxyurea efficacy and dangers when used to treat SCD patients expressing one of the rare genotypes. Thus, to summarise, SCD is a complex hereditary disorder in which for a medical practitioner to effectively manage requires a comprehensive understanding of both normal haemoglobin physiology and its pathophysiology.

Conflict of interest
None declared.


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