Mahendra Umadat (1015117)

DMT 3206: Clinical Chemistry

The Features and Positive Effects of Hydroxyurea Therapy in Sickle Cell Disease

Abstract

Sickle cell anemia reduces the amount of oxygen carried to tissue due to its sickled appearance
upon deoxygenation. Drugs that can induce foetal haemoglobin can help to reduce vaso-
occlusive crises and acute chest syndrome which are common in sickle cell disease.

The main objective of this paper is to discuss the features of hydroxyurea and the positive effects
of hydroxyurea therapy in sickle cell disease. Hydroxyurea is a treatment of choice for sickle cell
disease since it increases the level of foetal haemoglobin in the circulating blood, thus, reducing
the severity of the disease, prolonging lives and reducing the medical costs.

Introduction

- Sickle cell anemia

Sickle cell disease is genetically inherited and can either be homozygous (S/S) or heterozygous
(A/S) due to the defective haemoglobin gene present. Haemoglobin S is formed due to a single
substitution in amino acids in the beta globin chain. In the 6th position, valine replaces glutamic
acid. When oxygen is depleted from red blood cells, the membrane of the cell becomes rigid
forming the sickle cell appearance. The rigid cells cause acute chest syndrome and vaso-
occlusive crises which are typical of sickle cell anemia.

Depending on the inherited gene, the level of foetal haemoglobin concentration and the severity
of the cases vary. In the homozygous state (symptomatic), the presence of 80 to 99 percent
haemoglobin S can be detected using haemoglobin electrophoresis whereas, in the heterozygous
state, 35 to 45 percent haemoglobin S is found and is usually asymptomatic.

Due to this phenomenon, erythrocyte’s oxygen carrying capacity diminishes and premature
death of red blood cells is common, thus, decreasing the amount of circulating red blood cells.
The fact that red blood cells are constantly being haemolyzed, arginase 1 is being released,
which reduces the level of nitric oxide. Nitric oxide is an important vasodilator. Reduced
amounts of this vasodilator lead to endothelial dysfunction.
 Mahendra Umadat (1015117)
DMT 3206: Clinical Chemistry
The Features and Positive Effects of Hydroxyurea Therapy in Sickle Cell Disease
- Hydroxyurea

Sickle cell disease was discovered decades ago, however, a definitive treatment hasn’t
progressed much over time. In the mid 1990’s, the publication of the drug, hydroxyurea, showed
outstanding positive effects in sickle disease by Charache et al, 1995 and Schechter & Rodgers,
1995. The USA approved the drug and was used to manage the severity of sickle cell disease.
Several clinical trials/research on hydroxyurea effects on sickle cell has been carried out.

Hydroxyurea is a medication which induces foetal haemoglobin where the definite mechanism is
not known. The action of hydroxyurea is indirectly rather than directly. The fact that it is a
ribonucleotide reductase inhibitor, hydroxyurea inhibits the division of cells in the S phase of
cycle. Therefore, it is theorized that due to this impairment, foetal haemoglobin may be increased
since the drug inhibits or kills late erythroid cells that are dividing quickly. The increase in foetal
haemoglobin is due to the body compensating for the loss of erythroid cells in the S phase.

Hydroxyurea reduces the painful crises of sickle cell disease by 50% in moderate to severe cases.

Discussion:

Action of Hydroxyurea

Over the years, a new drug, hydroxyurea, has become popular. It is a ribonucleotide reductase
inhibitor. It is a cytotoxic agent in the S phase of cell cycle. Hydroxyurea inhibits DNA repair
along with RNA and protein synthesis. Due to the destruction of late erythroid cells, foetal
haemoglobin is increased to compensate for the loss.

It is noted that 45% to 70% of hydroxyurea is excreted in the urine without any conversion. After
a dose, within 3 to 6 hours, hydroxyurea reaches a peak serum concentration. However, some
individuals may be resistant to this therapeutic drug which relates to overproduction of
ribonucleotide reductase protein (B2), along with resistant mutant enzyme production and other
factors.

Treatment – Doses/Principle

Hydroxyurea should only be used by patients who would comply with the treatment regimen and
who have severe complications. Patients response to this treatment varies and over time the right
 Mahendra Umadat (1015117)
DMT 3206: Clinical Chemistry
The Features and Positive Effects of Hydroxyurea Therapy in Sickle Cell Disease
dose will be given. Usually a dose of 10 to 15 mg/kg/day is given. After 6 to 8 weeks the dose
may be increased if the blood count is stable. Twice weekly, blood counts are checked until a
stable dose is achieved after which they are checked at 4 to 8 week intervals. Martin H. Steinberg
(2002) emphasized that due to patients’ failure to take medication at required time accounts for
the largest number of poor responders to hydroxyurea. To know if hydroxyurea treatment is
effective in patients, then a trial lasting about 6 to 12 months should be carried out. However,
sometimes patients’ response to hydroxyurea are seen much later.

Clinical Trials/Studies – Effects

Mehmet Rami Helaci et al. (2015), conducted a study with hydroxyurea to determine whether it
is a beneficial drug to use in sickle disease. The study comprised of 337 (Females = 169; Males =
168) patients. In 80.1% of patients, the drug was well tolerated. It was noted that during the
follow up period there were not any major side effects.

In sickle cell disease, a variety of clinical features are seen. The mean body mass index is
retarded along with low levels of LDL (low density lipoprotein), cholesterol, alanine
aminotransferase and blood pressure. Painful crises can be due to the inflammatory process
occurring in the vascular or capillary endothelium.

Mehmet R. H. et al. stated that due to the suppression of cells (hyperproliferation) by

hydroxyurea, the painful crises are reduced. These authors emphasized the use of hydroxyurea
since it is effective and should be given in high doses for patients with moderate to severe sickle
cell disease until more effective treatment regiments for SCD are invented.

In this study, during the 7 years follow up period, the participants were given final doses of 500
mg twice daily, however, 25 patients needed a final dose of 35 mg/kg/day. With treatment, the
mean number of painful crises were depleted, significantly.

Hydroxyurea is said to prolong survival due to its positive effect of reducing pain crises and
complications. It was advised to treatment with hydroxyurea in the early stage of life to reduce
the amount of damage. The following table summarises the positive effects of hydroxyurea.
 Mahendra Umadat (1015117)
DMT 3206: Clinical Chemistry
The Features and Positive Effects of Hydroxyurea Therapy in Sickle Cell Disease

Variables Before HU Standard After HU Standard

(mean) error of mean (mean) error of mean
Mean # of painful crises per year 10.3 ± 10.6 1.7 ± 1.1
Mean severity of painful crises 7.8 ± 2.2 2.2 ± 1.7
Weight (kg) 59.1 ± 11.4 65.2 ± 13.0
Total bilirubin (mg/dL) 5.3 ± 5.6 3.1 ± 2.2
Direct bilirubin (mg/dL) 2 ± 3.4 0.9 ± 0.9
Lactate dehydrogenase (IU/L) 647.5 265.8 509.9 315.4
Table 1: Showing the positive effects of Hydroxyurea Treatment.
In the above table, it can be noted that in this study hydroxyurea has increased the mean weight
of the study sample. The normal ranges for total bilirubin and direct bilirubin are 0.3 to 1.9
mg/dL and 0 to 0.3 mg/dL, respectively. In the sickle cell patients, there were an increase in total
and direct bilirubin. However, after the hydroxyurea therapy both concentrations were reduced.
This is very important since it means that less red blood cells are haemolyzed to increase the
bilirubin concentration.
Also, the mean lactate dehydrogenase level (normal range: 140 to 280 U/L) in the sickle cell
patients was high. Moreover, after hydroxyurea therapy there was a reduced in the mean lactate
dehydrogenase level. This enzyme is found predominantly in body tissues and cells such as
blood cells and the heart. An increase in this enzyme relates to tissue/cell damage as seen in
sickle cell disease. Hydroxyurea helps to decrease the abnormal concentration of the enzyme in
our circulation which means that less tissue/cell damage is occurring.
Y. A. Wali and H. Moheed (2011), carried out a study on the effectiveness of hydroxyurea in
children with sickle cell disease particularly relating to physical fitness indices. The study
comprised of two groups where group A: contained 41 children with sickle disease and were on
hydroxyurea for a minimum of two years and group B: contained 50 healthy children as controls.
However, the children were all males, ages 10.4 to 14.6.
It was concluded that hydroxyurea increased the tolerance of aerobic exercise and other
parameters for physical fitness but still lowered than the control group. In this study, only two
children developed side effects: (i) reduction in absolute neutrophilic count and (ii)
gastrointestinal symptoms; the drug was well tolerated with the other children.
Over the two year follow up period, the patients had much improvement where they had less
yearly voso-occlusive crises, hospitalizations, and no acute chest syndrome. Before the use of
hydroxyurea, the heart rates of these patients were high compared with the heart rates after the
use of hydroxyurea but still it wasn’t as low as the control but the change between the two
groups was not statistically significant.
 Mahendra Umadat (1015117)
DMT 3206: Clinical Chemistry
The Features and Positive Effects of Hydroxyurea Therapy in Sickle Cell Disease

Taken from: Wali Y and Moheeb H. (2011)

Furthermore, the release of arginase 1 in sickle cell disease decreases the nitric oxide levels in
the circulating blood. Arginase 1 is an enzyme which is found predominantly in the liver and
kidneys, however, it can be found in red blood cells also. Due to lysis of red blood cells, arginase
1 level is increased in sickle cell patients. Because nitric oxide is a vasodilator and is being
reduced, high levels of arginase 1 are responsible for endothelial dysfunction leading to increase
vaso-occlusive crises.
J. A. Moreira et al (2017) carried out a study on the levels of nitric oxide in sickle cell disease
with 50 SCD patients and 20 healthy controls. In the normal control group, the mean arginase 1
levels were low (8.610 ng/mL ± 1.609) whereas the mean arginase 1 levels in sickle cell patients
were 71.87 ng/mL ± 31.39.
With hydroxyurea treatment, the successfulness of this drug depended on the dosage. Patients
using a dose < 20 mg/kg/day showed a mean arginase 1 level of 79.43 ± 37.43 while patients
using a dose ≥ 20 mg/kg/day had a mean arginase 1 level of 59.63 ± 13.78. The following graphs
represent the above data.
 Mahendra Umadat (1015117)
DMT 3206: Clinical Chemistry
The Features and Positive Effects of Hydroxyurea Therapy in Sickle Cell Disease

Figures 2 & 3: Arginase 1 level content

D. L. Jain et al. (2012) conducted a study in Indian with children with sickle cell disease with
age ranging from 8 to 18 years. The study consisted of 60 patients (32 females and 28 males) and
were divided into two equal groups: HU group and a placebo group. Hydroxyurea group was
treated with a fixed dose of 10mg/kg/day for 18 months as a single dose.
The Indian children who were treated with hydroxyurea showed great improvement after 18
months compared with the placebo group. There was a decrease in vaso-occlusive crises,
 Mahendra Umadat (1015117)
DMT 3206: Clinical Chemistry
The Features and Positive Effects of Hydroxyurea Therapy in Sickle Cell Disease
hospitalization, and blood transfusion with hydroxyurea treatment by 95.0%, 93.1% and 94.6%,
respectively. The following table summarizes the effects of hydroxyurea.
Parameters Hydroxyurea Placebo
Before After Before After
Hb (g/dL) 8.10 ± 0.68 9.29 ± 0.55 8.21 ± 0.68 7.90 ± 0.58
Hb F (%) 19.80 ± 6.90 24.00 ± 5.90 19.21 ± 6.37 18.92 ± 5.77
Reticulocytes 1.83 ± 0.96 1.15 ± 0.10 1.73 ± 0.49 1.81 ± 0.67
Leucocytes 7.36 ± 6.03 6.54 ± 5.54 7.26 ± 4.91 7.38 ± 2.85
(103/mm3)
Total Bilirubin 2.32 ± 1.42 1.10 ± 0.42 2.27 ± 1.28 2.71 ± 0.93
(mg/dL)
RBC (106/mm3) 2.89 ± 0.57 1.98 ± 0.22 1.84 ± 0.47 3.11 ± 0.20

Table 2: comparing hydroxyurea therapy and placebo in children with SCD.

Smith et al. (2011) mentioned that the Food and Drug Administration has approved hydroxyurea
as the only remittive agent for the homozygous form of sickle cell disease. It was re-emphasized
that over time with the use of hydroxyurea, painful crises are reduced. It should be noted that
increase in small amounts of foetal haemoglobin is significant.
Conclusion:
Hydroxyurea is a beneficial drug in the management of sickle cell disease by increasing foetal
haemoglobin, thus leading to a decrease in vaso-occlusive crises and acute chest syndrome.
However, in some cases adverse effects may occur but the advantages of using this drug
outweighs the negative effects.
References:
1. Martin H. Steinberg, “Hydroxyurea Treatment for Sickle Cell
Disease,” TheScientificWorldJOURNAL, vol. 2, pp. 1706-1728, 2002.
doi:10.1100/tsw.2002.295
2. Zeina A. Salman and Meaad K. Hassan, “Hospitalization Events among Children and
Adolescents with Sickle Cell Disease in Basra, Iraq,” Anemia, vol. 2015, Article ID
195469, 8 pages, 2015. doi:10.1155/2015/195469
3. Moreira J, Machado R, Martins A, et al. Influence of βS-Globin Haplotypes and
Hydroxyurea on Arginase I Levels in Sickle Cell Disease. Disease Markers [serial
online]. May 4, 2016;:1-5. Available from: Academic Search Complete, Ipswich, MA.
Accessed February 12, 2017.
 Mahendra Umadat (1015117)
DMT 3206: Clinical Chemistry
The Features and Positive Effects of Hydroxyurea Therapy in Sickle Cell Disease
4. Creary S, Zickmund S, Ross D, Krishnamurti L, Bogen D. Hydroxyurea therapy for
children with sickle cell disease: describing how caregivers make this decision. BMC
Research Notes [serial online]. August 25, 2015;8:372. Available from: MEDLINE,
Ipswich, MA. Accessed February 12, 2017.
5. Green N, Ender K, Barral S, et al. Candidate Sequence Variants and Fetal Hemoglobin in
Children with Sickle Cell Disease Treated with Hydroxyurea. Plos ONE [serial online].
February 2013;8(2):1-6. Available from: Academic Search Complete, Ipswich, MA.
Accessed February 12, 2017
6. Helvaci M, Hakimoglu S, Aydin S, et al. Preoperative management of sickle cell patients
with hydroxyurea. Middle East Journal Of Family Medicine [serial online]. October
2015;13(7):4-9. Available from: Academic Search Complete, Ipswich, MA. Accessed
February 15, 2017.
7. Smith W, Ballas S, Waclawiw M, et al. The association between hydroxyurea treatment
and pain intensity, analgesic use, and utilization in ambulatory sickle cell anemia
patients. Pain Medicine (Malden, Mass.) [serial online]. May 2011;12(5):697-705.
Available from: MEDLINE, Ipswich, MA. Accessed February 15, 2017.
8. Ballas S, Barton F, Bonds D, et al. Hydroxyurea and sickle cell anemia: effect on quality
of life. Health And Quality Of Life Outcomes [serial online]. August 31, 2006;4:59.
Available from: MEDLINE, Ipswich, MA. Accessed February 15, 2017.
9. Jain D, Sarathi V, Desai S, Bhatnagar M, Lodha A. Low fixed-dose hydroxyurea in
severely affected Indian children with sickle cell disease. Hemoglobin [serial online].
2012;36(4):323-332. Available from: MEDLINE, Ipswich, MA. Accessed February 15,
2017.
10. Wali Y, Moheeb H. Effect of hydroxyurea on physical fitness indices in children with
sickle cell anemia. Pediatric Hematology And Oncology [serial online]. February
2011;28(1):43-50. Available from: MEDLINE, Ipswich, MA. Accessed February 15,
2017.
11. Halsey C, Roberts I. The role of hydroxyurea in sickle cell disease. British Journal Of
Haematology [serial online]. January 15, 2003;120(2):177-186. Available from:
Academic Search Complete, Ipswich, MA. Accessed March 31, 2017.