Hemoglobin

international journal for hemoglobin research

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The Sub-Phenotypes of Sickle Cell Disease in

Kuwait

Adekunle D. Adekile, Sondus Al-Sherida, Rajaa Marouf, Nada Mustafa &

Diana Thomas

To cite this article: Adekunle D. Adekile, Sondus Al-Sherida, Rajaa Marouf, Nada Mustafa & Diana
Thomas (2019) The Sub-Phenotypes of Sickle Cell Disease in Kuwait, Hemoglobin, 43:2, 83-87,
DOI: 10.1080/03630269.2019.1610427

To link to this article: https://doi.org/10.1080/03630269.2019.1610427

Published online: 30 May 2019.

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HEMOGLOBIN
2019, VOL. 43, NO. 2, 83–87
https://doi.org/10.1080/03630269.2019.1610427

ORIGINAL ARTICLE

The Sub-Phenotypes of Sickle Cell Disease in Kuwait

Adekunle D. Adekilea,b, Sondus Al-Sheridab, Rajaa Maroufc, Nada Mustafaa and Diana Thomasa
a
Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait; bPediatric Hematology Unit, Mubarak Al-Kabeer Hospital,
Jabriya, Kuwait; cDepartment of Pathology, Faculty of Medicine, Kuwait University, Jabriya, Kuwait

ABSTRACT ARTICLE HISTORY

Kuwaiti patients with sickle cell disease generally have a mild phenotype, but exhibit considerable het- Received 10 January 2019
erogeneity, in spite of high Hb F levels. We have carried out a cross-sectional study of patients with Revised 1 April 2019
sickle cell disease in the five major hospitals in Kuwait. Details of their hemoglobin (Hb) genotypes, Accepted 1 April 2019
clinical presentations and complications are presented. The study was over a span of 3 years and
KEYWORDS
involved 396 patients, made up of 351 (88.6%) Kuwaitis and 45 (11.4%) expatriates. They were aged High Hb F levels; Kuwait;
<1 to 73 years. Hb SS (bS/bS) was the most common (in 246 patients, i.e. 62.1%) followed by Hb S sickle cell disease
(HBB: c.20A>T)-b-thalassemia (Hb S-b-thal) in 138 (34.8%) and 11 (2.8%) Hb S/Hb D-Punjab (HBB:
c.364G>C). Hb F ranged from 1.0 to 55.0%, with a mean of 21.2 ± 9.8%. The most common presenta-
tion was vaso-occlusive crises (VOCs), with 230 (54.8%) having had at least one prior to the study with
54 (13.2%) and 74 (18.9%) having between 2-3 and >3 VOCs, respectively. Hydroxyurea (HU) was pre-
scribed to 157 (39.6%) patients. The most common complication was gallstones in 131 (33.1%), fol-
lowed by acute splenic sequestration in 26.8% and avascular necrosis of the femoral head in 21.2%
patients, respectively. Stroke, priapism and leg ulcers were rare. Gallstones, splenic sequestration and
osteonecrosis were significantly more common in patients aged >16 years. Patients with Hb S-b-thal
were similar to those with Hb SS in their clinical profiles. The phenotypic expression of sickle cell dis-
ease in Kuwaitis is unique in many respects. The role(s) of Hb F and other genetic modifiers require fur-
ther elucidation.

Introduction patient with "20.0% Hb F will have a mild phenotype and

Sickle cell disease is characterized by the two major clinical
phenotypes of chronic hemolysis and recurrent vaso-occlu-
sive crises (VOCs) [1]. The former is secondary to the
reduced lifespan of the red blood cell (RBC), which instead
of the !120 days in the normal individual, is !15-30 days in
patients with sickle cell disease. Vaso-occlusion occurs
because of the rigidity of RBCs secondary to the polymeriza-
tion of Hb S (HBB: c.20A>T) and other rheological changes
that make it difficult for the cells to traverse the slits in the
endothelial walls of small capillaries. The free heme released
from hemolyzed RBCs activates endothelial and other cells,
instigating a slew of inflammatory cascades, culminating in
extensive oxidative stress, mediated mainly through nitric
oxide depletion [2,3]. Also contributing to this vasculopathy
are activation of pro-coagulant systems and expression of
adhesion molecules, which are ultimately expressed as the
sub-phenotypes of pulmonary hypertension, stroke, and pri-
apism [1,4]. The vaso-occlusion phenotype is more associ-
ated with frequent pain crises, osteonecrosis and acute chest
syndrome (ACS).
The sickle cell disease clinical phenotype is, however, very
heterogeneous, and the identified genetic modifiers include
Hb F level, bS-globin gene haplotype and coexistent
a-thalassemia (a-thal) trait [5]. It has been estimated that a
less end-organ pathology [6]. Patients with the Arab/India
haplotype carry the HBG2 –158 (C>T) XmnI allele, which is
associated with a high Hb F expression, and are therefore
protected against some of the complications of the disease
[7]. Some other trans-acting quantitative trait loci influenc-
ing Hb F expression include the BCL11A on chromosome
2p16 and HBS1L-MYB intergenic polymorphisms (HMIP)
on chromosome 6q23 [8–10]. Coexistent a-thal trait is asso-
ciated with less anemia and protects the patients from leg
ulcers, stroke, gallstones and splenic dysfunction, but may
be associated with end-artery thrombotic phenomena leading
to osteonecrosis and retinopathy [11–13].
Kuwaiti sickle cell disease patients carry the Arab/India
haplotype, with an average Hb F level of !20.0% and preva-
lence of a-thal trait between 30.0 and 40.0% [7,14]. While
the phenotype is generally mild, there is still considerable
heterogeneity and the determining factors remain to be elu-
cidated. The population of Kuwait is about 4.2 million, with
the natives being about half [15]. The prevalence of the
sickle cell gene is !3.0% [16] and it has been estimated that
there are !500 patients being followed in different hospitals
in the country. There has been no country-wide study of
these patients and the pattern of presentation, complications
and management have not been documented. This study

CONTACT Professor Adekunle D. Adekile adekile@hsc.edu.kw Department of Pediatrics, Faculty of Medicine, Kuwait University, PO Box 24923, Safat,
Kuwait 13110
! 2019 Informa UK Limited, trading as Taylor & Francis Group
84 A. D. ADEKILE ET AL

was carried out as part of an ongoing registry of patients
with sickle cell disease in Kuwait. The five major govern-
ment hospitals in the country were involved. The aim was to
document demographic, clinical and laboratory parameters
in both pediatric and adult patients. In addition, we wanted
to identify the overall common hemoglobin (Hb) genotypes
and sub-phenotypes. Some of these are described in
this report.
Methods
electrophoresis [20]. b-Globin gene mutations were deter-
mined by allele-specific oligonucleotide hybridization, direct
sequencing or the arrayed primer extension (APEX) (Asper
Biogene, Tartu, Estonia).
Statistical analyses
Data are presented as means ± SD and analyzed using the
Statistical Package for the Social Sciences, version 23 (IBM
SPSSV Statistics for Windows; IBM Corporation, Armonk,
R

The patients were being followed in the pediatric and adult NY, USA). The v2 (with Yates correction) was used to test
hematology clinics of Mubarak, Amiri, Al-Sabah, Farwaniya, the significance of differences between discrete data (with
Jahra and Adan hospitals in Kuwait. They were consecutive Fischer’s correction as indicated). The Student’s t-test or
patients seen in the study period between August 2014 and analysis of variance (ANOVA), was used to test for statistical
November 2017. The study was approved by the Joint significance between different means of continuous data in
Human Research Ethics Committee of the Faculty of the various subgroups, as appropriate and a p values of
Medicine, Kuwait University and Kuwait Ministry of Health. <0.05 was considered to be significant.
Informed consent was obtained from the patients and/or
their parents as appropriate.
A pre-tested, validated questionnaire was used to collect Results
personal and historical data, while the patient’s hospital The total number of patients was 396, with 351 (88.6%)
records were reviewed to document the initial Hb high per- Kuwaitis and 45 (11.4%) expatriates, while 206 (52.0%) were
formance liquid chromatography (HPLC), other relevant
males and 190 (48.0%) were females. The patients were aged
laboratory and clinical data. The latter included frequency of
from <1 to 73 years with a mean of 19.2 ± 15.6 years. The
VOCs, blood transfusions and hospital admissions, with
highest peak was in the 21-40 year range, with a smaller
diagnoses. Complications such as stroke, gallstones, avascu-
peak in the <5 year range. (Table 1). There was a steady
lar necrosis of the femoral head (AVNFH), priapism, leg
decline from the <5 year group to the 16-20 year group
ulcers, etc., were documented, in addition to past surgical
(Figure 1).
history (splenectomy, cholecystectomy, osteotomy, joint
Hb SS was the most common with 246 (62.1%) patients,
replacement, etc.). Details of special imaging studies, e.g.
followed by 138 (34.8%) Hb S-b-thal patients, 11 (2.8%) Hb
magnetic resonance imaging (MRI) of the brain or hips,
S/Hb D-Punjab (HBB: c.364G>C) patients and one Hb S/
transcranial Doppler (TCD) ultrasound of the abdomen,
echocardiogram, etc. and their results were noted. Details of Hb O-Arab (HBB: c.364G>A) patient. Hb F ranged from
physical examination, anthropometric measurements, 1.0 to 55.0%, with a mean of 21.2 ± 9.8% (Table 2). There
respiratory and cardiovascular findings, spleen or liver
Table 1. Age distribution of the patients.
enlargement, leg ulcers, etc. were obtained. Details of man-
Age n %
agement, e.g. folic acid, penicillin prophylaxis, hydroxyurea
#5 85 21.5
(HU), etc. were documented. 6 to 10 72 18.2
As much as possible, 5 mL of blood was obtained by veni- 11 to 15 51 12.9
puncture in EDTA tubes, on each patient. Complete blood 16 to 20 37 9.3
21 to 40 89 22.5
count (CBC) was done using ABX Pentra 120 cell counter >40 60 15.2
(ABX France, Montpellier, France). The Hb genotype was Total 396 100.0
confirmed and Hb F concentration determined using HPLC
(Shimadzu LC-20AT; Shimadzu Corporation, Kyoto, Japan).
25.0
DNA was isolated from peripheral leucocytes using phenol
extraction. The a-globin genotype was determined by poly-
20.0
merase chain reaction (PCR) methods for the –a3.7 (right-
ward) a2-globin gene deletion [17], while an allele-specific
15.0
hybridization method was used to determine the a-globin
%
gene polyadenylation (polyA) signal (AATAAA>AATAAG)
10.0
mutation [7,18]. These two are the most common a-thal
Age
determinants in our population of patients. Lately, we have 5.0
used the Vienna Lab StripAssayV (Vienna Lab Diagnostics
R

GmbH, Vienna, Austria) of reverse dot-blot hybridization to 0.0

identify these alleles [19]. The Gc-globin gene promoter ≤5 6 to 10 11 to 15 16 to 20 21-40 >40
XmnI phenotype was determined by PCR amplification of Years

the region of interest and enzyme digestion followed by gel Figure 1. Age distribution of the patients in the study.
 HEMOGLOBIN 85

Table 2. Hb F Distribution. Table 3. Distribution of complications by age groups.

Hb F (%) n % Age Age
#10.0 46 11.6 #16 Years >16 Years All
11.0-20.0 133 33.6 Complication n % n % n %
21.0-30.0 103 26.0
31.0-40.0 57 14.4 Gallstonesa 35 15.8 96 55.5 131 33.1
>40.0 7 1.8 Splenic sequestrationa 44 19.9 62 35.8 106 26.9
Total 396 100.0 Avascular necrosisa 15 6.8 69 39.9 84 21.3
Acute chest syndrome 28 12.7 27 15.6 55 14.0
Osteopeniab 14 6.3 22 12.7 36 9.1
Priapism 0 0.0 12 6.9 12 3.0
was no significant difference in the mean Hb F levels in Stroke 3 1.4 4 2.3 7 1.8
patients with different genotypes. Total 221 100.0 173 100.0 394 100.0
Most (230, i.e. 54.8%) patients had only one VOC, while a
p Value of <0.001.
b
13 (3.3%) had 0 VOC per year. These two groups were clas- p Value of <0.05.
sified as mild pain phenotype, while 54 (13.2%) and 74
(18.9%) had moderate (2–3 VOCs) or severe phenotype (>3
VOCs per year), respectively. Table 4. Complications in patients with Hb SS and Hb S-b0-thalassemia.
Hydroxyurea was prescribed for patients who had more Hb SS Hb S All
than three VOCs necessitating hospitalization in a year. It Complication a
n % n % n %
was also used in patients with significant anemia (#7.0 g/dL) Gallstones 83 35.3 47 30.3 131 32.3
or after the second episode of ACS; 157 (39.6%) had received Splenic sequestration 57 21.5 42 27.1 99 24.6
Avascular necrosis 59 22.3 24 15.5 83 20.6
the drug for varying lengths of time. A non escalating dose of Acute chest syndrome 32 12.1 22 14.7 54 13.4
15–20 mgs/kg was used. It was adjusted upwards only in Osteopenia 21 7.9 14 9.0 35 8.7
patients with break-through pain episodes. Of the 60 patients Priapism 9 3.4 3 1.9 12 3.0
Stroke 4 1.5 3 1.9 7 1.8
who were still receiving the drug at the time of analysis and Total 265 100.0 155 100.0 403 100.0
on whom data were available, 36 (60.0%) had Hb S-b-thal, 21 a
There was no statistically significant difference in the distribution of the com-
(35%) had Hb SS and two (5.0%) had Hb S/Hb D-Punjab. plications in both groups.
The ages of the patients on HU ranged from 1 to 73 years,
but 53 (88.3%) were below the age of 16 years. with IVS-I-5 (G>C) were classified as Hb S-b0-thal because
The different sub-phenotypes (or complications) recorded they had no detectable Hb A on multiple HPLC runs. The
in the whole group and their distributions are shown in clinical phenotype in the Hb S-b0-thal patients was not gen-
Table 3. The most common in the whole group was gall- erally distinguishable from those with Hb S-bþ-thal. The
stones in 131 (33.1%), followed by acute splenic sequestra- results of the Hb S-b-thal phenotype have been published
tion (ASS) in 26.9% and AVNFH in 21.3%. Acute chest separately [21], while those for a-globin genotypes and
syndrome was recorded in 14.0%. There were no cases of leg XmnI alleles are being reported separately.
ulcers, while the frequency of stroke and priapism was
<5.0% each. When classified according to age, those
Discussion
>16 years were significantly more likely to have gallstones
(v2 ¼ 68.8, p ¼ 0.000), splenic sequestration (v2 ¼ 12.5, Although the gene pool in indigenous Kuwaitis is derived
p ¼ 0.000), AVN (v2 ¼ 63.4, p ¼ 0.000) and osteopenia (v2 mostly from Saudi, Iraqi and Iranian ancestries, there is con-
¼ 4.76, p ¼ 0.029). The prevalence of ACS was not statistic- siderable homogeneity between patients with sickle cell dis-
ally different in the two age groups (v2 ¼ 0.697, p ¼ 0.404). ease in terms of their bS gene haplotype. Consistently,
There was no significant (p>0.05) difference in the distri- !80.0% are either homozygous or heterozygous for the
bution of the complications between patients with Hb SS HBG2 –158 (C>T) XmnI polymorphism (rs7482144)
and Hb S-b-thal genotypes (Table 4). Among the 32 Hb S- [22,23]. Consequently, most of our patients have a high Hb
b-thal patients, in whom full molecular characterization was F level, which significantly modifies the sickle cell disease
carried out, seven (23.3%) had bþ or bþþ mutations: IVS-I- phenotype [7,24]. It is, however, interesting that the disease
110 (G>A) (HBB: c.93-21G>A) in five (71.4%) and IVS-I-6 still shows so much heterogeneity in the sub-phenotypes
(T>C) (HBB: c.92 þ 6T>C) and IVS-I-128 (T>G) (HBB: that are encountered. This has been more keenly exhibited
c.93-3T>G) in one each (Table 2). Twenty-five patients car- in this nation-wide study.
ried nine different b0 mutations (Table 1), the most com- In the absence of newborn screening, most patients are
mon of which was codon 39 (C>T) (HBB: c.118C>T) in not diagnosed until they are symptomatic or they may be
eight (32.0%), followed by IVS-I-1 (G>A) (HBB: identified through early screening if there is a positive family
c.92 þ 1G>A) in six (24.0%), IVS-II-1 (G>A) (HBB: history. Most of our patients are asymptomatic in the first
c.315 þ 1G>A) in three (12.0%), IVS-I-5 (G>C) (HBB: 2 years of life as their Hb F level at this time is generally
c.92 þ 6G>C) and codons 8/9 (þG) (HBB: c.27_28insG) in above 30.0% [24]. The peak age of patients in this study is
two (8.0%) each and one (4.0%) each of codon 8 (–AA) 2–5 years, with a decline in the adolescent, transition years.
(HBB: c.25_26delAA), codons 36/37 (–T) (HBB: c.112delT), The second peak is in the second to fourth decades of life,
IVS-I, 25 bp deletion (HBB: c.93-22_95del) and codons 41/ which is when the patients start to develop sickle cell dis-
42 (–TTCT) (HBB: c.126_139delTTCT). The two patients ease-related chronic illnesses and are more likely to show up
86 A. D. ADEKILE ET AL
in the hospital. The adolescent transition period is recog-
nized as the time patients may be rebellious and unwilling
to come for regular clinic visits, especially when they do not
feel ill. Unfortunately, this period is associated with
increased morbidity and mortality [25–27]. We also have to
pay attention to this phenomenon locally and address it
accordingly.
Most patients (88.4%) had Hb F levels of >10.0%, with
42.2% having levels of >20.0%. These are very high levels,
indeed, although the patients on HU were not excluded.
While the persistent expression of Hb F in our patients is
attributed to the HBG2 –158 (C>T) XmnI allele, we have
also investigated the role of BCL11 and HMIP polymor-
phisms. We could not demonstrate a significant role for the
recognized single nucleotide polymorphisms (SNPs) at these
loci and we hypothesized that there are novel loci of import-
ance in our population [22]. More studies, using next gener-
ation sequencing are currently underway.
The profile of complications in this study is different
from what has been reported for African and American
patients [28,29]. Interestingly, gallstones were the most com-
mon, which is unexpected as hemolysis is not a major prob-
lem in our patients. This raises the possibility of a role for
the uridine diphosphate glucuronosyltransferase (UGT)
Gilbert’s phenotype, which predisposes to hyperbilirubine-
mia and gallstones in patients with chronic hemolytic ane-
mias. Our patients have not been screened for this allele.
Since our patients tend to have viable spleens well into
adulthood [13,30], it is not surprising that splenic sequestra-
tion was the second most common complication seen in this
study. Indeed, it was significantly more common in patients
older than 16 years. Many of our patients (mostly with Hb
S-b0-thal), required splenectomy because of recurrence
of ASS.
The most devastating complication that we see in our
patients is AVNFH, which was seen in 21.3%. This is similar
to a figure of 26.0% that we previously reported in pediatric
patients [31], but lower than the 50.0% in adult patients
[32]. This prevalence is probably related to the high packed
cell volume and relative blood viscosity associated with the
vaso-occlusion phenotype, although this has not been specif-
ically investigated in our patients. Also related to this pheno-
type are pain episodes, which were the most common cause
of hospital admission. While most patients had 0–1 admis-
sion, 18.9% had >3 episodes of pain needing hospitalization
per year. Similarly, ACS was seen in 14.0% of patients. The
complications associated with the hemolysis phenotype such
as stroke, priapism and leg ulcers were not common in this
study. We have not been able to demonstrate a direct associ-
ation of AVN with Hb F level or coexistent a-thal
trait [7,24].
The Hb S-b-thal phenotype is seen in <10.0% of patients
in America [33] and it is even more rare in African sickle
cell disease patients [29]. However, because b-thal alleles are
more common in the Mediterranean Basin and Asia (includ-
ing the Arab Peninsula) [16], the Hb S-b-thal compound
heterozygosity is common and was found in 38.4% of
patients in the present study. The diagnosis is based on
family studies, hematological findings, elevated Hb A2 and
identification of the b-thal mutation by molecular techni-
ques. The Hb S-b-thal phenotype is heterogeneous and is
more severe in those with Hb S-b0-thal and milder in Hb S-
bþ-thal, but to a large extent, the severity depends on the
nature of the b-thal mutation. Most of the Hb S-bþ-thal
patients followed in our clinics carry the relatively severe
IVS-I-110 (G>A) and IVS-I-5 (G>C) mutations with phe-
notypes indistinguishable from Hb S-b0-thal patients [21].
Kuwait provides an instructive model of the phenotypic
spectrum in sickle cell disease patients with elevated Hb F.
It illustrates the fact that even in such patients, there is con-
siderable heterogeneity, showing that there are limitations to
the influence of Hb F in predicting clinical course. There are
no significant differences in the phenotype of Hb SS com-
pared to Hb S-b-thal patients, but complications are more
likely to be seen in older patients. There is a need for more
genomic studies to uncover additional novel modifiers of the
disease in Kuwaiti patients.
Acknowledgements
The authors thank all the doctors in the different hospitals who allowed
their patients to be included in the study. Mr. Waqar Azeem developed
and maintains the database that was used in the registry. Drs. Asmaa
Azab, Hammad Ibrahim and Hisham Hegab helped in collecting data.
Disclosure statement
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
Funding
The project was supported by Kuwait Foundation for the Advancement
of Science Grant No: 2013–1302-07.
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