Effects of Age and Sex on Sickle Cell Disease Avascular Necrosi

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Introduction
Eects of Age and Sex on Sickle Cell Disease Avascular Necrosis
Al-Jafar H*1, AlFadhli S2, Al-Feeli M3, Ali A4 and Alhajri F5
1Department of Haematology, Amiri Hospital, Kuwait
2Medical laboratory Sciences, Faculty of Allied Health Sciences, Kuwait University
3Department of Nuclear medicine, Mubarak Al-Kabeer Hospital, Jabria, Kuwait
4Department of Orthopedic Surgeon, Al-Razi Hospital, Shuwaikh, Kuwait
5Department of Clinical Radiology, Amiri Hospital, Gulf street, Kuwait City, Kuwait
*Corresponding author: Al-Jafar H, Consultant Haematologist, Department of Haematology, Amiri Hospital,
Kuwait, E-mail: cbc9@hotmail.com
Citation: Al-Jafar H, AlFadhli S, Al-Feeli M, Ali A, Alhajri F (2016) Eects of Age and Sex on Sickle Cell
Disease Avascular Necrosis. J Hematol Blood Disord 1(2): 204
Introduction: Sickle cell disease (SCD) is a hemoglobinopathy. Based on genotypes, it is classied into sickle cell thalassemia (SC)
and sickle cell anemia (SCA). Red blood cells in SCD are less pliable; therefore, these cells distort to a sickle shape that leads to tissue
infarctions and progressive bone avascular necrosis (AVN).
Abstract
Keywords: Sickle cell anemia; Sickle cell thalassemia; Bone scintigraphy; Osteonecrosis; Sex
Sickle cell disease (SCD) is a heterogeneous disease, which aects men and women equally [1]. Patients with SCD experience
multiple disease-related complications [2]. Although anemia is a common sign in SCD because of the short lifespan of RBCs, the
primary symptomatic manifestation is a pain crisis with wide variation in intensity, quality, duration, and persistence. Essentially,
SCD crises occur when partially or totally deoxygenated hemoglobin (Hb) molecules distort their normal disk shape and lead to
rigid, sticky, sickle-shaped cells that obstruct small blood vessels and cause vaso-occlusive crises (VOC ), which further leads to
disruption of oxygen supply to body tissues [3]. e recurrent acute VOC leads to chronic pain and organ damage in the end. It
potentially aects all the organ systems, particularly the bones. e complete disruption of vascular supply to the articular surfaces
and ends of long bones, particularly the femoral and humeral head and spine, results in avascular necrosis (AVN) [4]. It is a
devastating complication of SCD and is highly prevalent in adults with SCD [5].
Aim: To study the signicant eects of age and sex on AVN in SCD.
Methods: Data of 68 patients with SCD were collected (25 and 43 patients with SC and SCA, respectively). eir age ranged from 4
to 78 years. Statistical test conducted to analyze the signicant eects of age and sex on AVN in all the 68 patients.
Results: AVN prevalent is 76% and 72% in patients with SC and SCA, respectively. In SC age eect on AVN in SC (p=0.546) and
Sex eect on AVN (p=0.013), while in SCA age eect on AVN (p=0.783) and Sex eect on AVN in SCA (p=0.334). e HPLC results
showed HbF mean values in SC 12%, while in SCA 17%. HPLC results showed HbA2 mean values in SC 4.9% (4.9 in children, 4.9
in adults, 4.8 in females and 4.9 in males), and in SCA 2.1% (1.9 in children, 2.4 in adults, 2.1 in females and 2.3 in males.
Conclusion: In age group, no signicant relation found between age and AVN in both SC and SCA. In sex group no signicant
relationship found between sex and SCA. However, a signicant result detected between AVN and sex in SC; males have more
tendency to develop AVN than females in both SC and SCA. HbF was higher in SCA than in SC due to hydroxyurea treatment
and AVN prevalence was also less in SCA.
Several studies have examined risk factors for AVN development in SCD including recurrent VOC, high Hb levels, low Hb F
levels, vitamin D deciency, and alpha thalassemia trait [6,7]. However, very few studies have examined the relationship of this
complication with sex and age. Signicant sex dierences in morbidity and mortality have been reported in adults with SCD
[8]. Garvin observed that morbidity apparently increased in men; further, sex-related dierences in some acute and chronic
complications of this disorder were suggested [9]. In a cooperative study on SCD, Platt et al. reported median death ages for men
and women as 42 and 48 years, respectively; however, this dierence was greater than that observed in black control subjects [10].
In 2011, Adekile et al. observed that femoral head AVN is the most common complication in Kuwaiti patients with SCD [11], and
he reported that it was more common in men than in women in SCD. We studied the signicant eects of age and sex on AVN
development in patients with SCD in Kuwait.
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Journal of Hematology and Blood Disorders
ISSN: 2455-7641

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is is a retrospective study in which the data were collected from our institute’s electronic database in the years 2008–2015 for
68 patients with SCD. Both male and female patients with age from 4 to 78 years were included; of these, 41 underwent bone
scintigraphy (BSc), and 27 underwent magnetic resonance imaging (MRI) for dierent reasons. Our exclusion criteria were bone
diseases due to factors other than SCD such as tumors and endocrinology disorders, steroid therapy, irradiation treatment, or
alcohol consumption. e patients were divided into two groups based on the SCD genotype as follows: the Hb S-thalassemia
(SC) and HbSS (SCA) groups. In both groups, AVN was tested for signicant relationships with age (child and adult) and sex
(female and male). e patients’ medical charts were reviewed for complete blood count, high performance liquid chromatography
(HPLC), and AVN. Bone scintigraphs were retrieved electronically for all patients in this study and were examined for AVN. Innia
Hawkeye 4.0 SPECT-CT camera (GE Healthcare) was used. For bone scans, technetium-99m hydroxymethylene diphosphonate
(HDP) was administered intravenously. For MRI, Echelon apparatus was used. Statistical analysis was performed by using SPSS;
the crosstab statistical analysis test was conducted to nd the signicant values of age and sex in both SCA and SC groups.
Bone AVN is a frequent outcome in patients with SCD. e objective of the current study was to check if age and sex were associated
risk factors for AVN development in patients with SCD including both the genotypes SCA and SC; the patients underwent BSc
and MRI for dierent reasons. We collected the data of 68 subjects that represented both the SCD genotypes SC and SCA. In all
the patients, AVN was a common complication observed in both the types of SCD.
Results
In SC 93.3% male patients compared to 50% female patients developed AVN. Similarly, among patients with SCA, 78.3% male
patients compared to 65% female patients developed AVN. Number of AVN observed in 25 patients with SC 19 (76%). Number
of AVN observed in 43 patients with SCA 31 (72 %).However in SC the age eect on AVN in SC (p=0.546) and the Sex
eect on AVN (p=0.013). In SCA the age eect on AVN in SCA (p=0.783) and the Sex eect on AVN in SCA (p=0.334) (Table 1).
Materials and Methods
Eect of gender on
AVN in SCA
Eect of age on AVN
in SCA
Eect of gender on AVN
in SC
Eect of age on AVN
in SC
SCA (N = 43)SC (N = 25)
MaleFemaleAdultChildMaleFemaleAdultChild
18 (78.3%)13 (65.0%)22 (73.3%)9 (69.2%)14 (93.3%)5 (50.0%)10 (71.4%)9 (81.8%)AVN
5 (21.7%)7 (35.0%)8 (26.7%)4 (30.8%)1 (6.7%)5 (50.0%)4 (28.6%)2 (18.2%)No AVN
2320301315101411Tot a l
0.3340.7830.0130.546P Valu e
Table 1: Eects of age and sex as possible associated risk factors for AVN development in patients
e HPLC results (Table 2) showed the HbF mean values in SC 12% (13.6 in children , 10.6 in adults , 12.1 in females and 11.9
in males), while it is in SCA 17% (20.5 in children, 15.2 in adults, 18.2 in females and 15.8 in males). Further the HPLC results
showed the HbA2 mean values in SC 4.9% (4.9 in children, 4.9 in adults, 4.8 in females and 4.9 in males), while it is in SCA 2.1%
(1.9 in children, 2.4 in adults, 2.1 in females and 2.3 in males.
MaleFemaleAdultChildMaleFemaleAdultChild
SC-Anemia Group
(n=9) (n=22) (n=13) (n=18)
SC-alassemia Group
(n=9) (n=10) (n=5) (n=14)
AVN
0.45 ± 0.000.45 ± 0.0022.3 ± 5.6918.8 ± 13.717.7 ± 0.0020.9 ± 12.6
Hb A
mean ± SD
15.8 ± 8.2318.2 ± 4.6915.2 ± 6.9920.5 ± 5.5611.9 ± 7.7612.15 ± 4.3810.6 ± 5.4013.6 ± 8.20
Hb F
mean ± SD
79.7 ± 11.679.7 ± 4.4480.6 ± 10.477.7 ± 5.3780.0 ± 10.171.8 ± 11.882.9 ± 6.4472.3 ± 12.5
Hb S
mean ± SD
2.3 ± 0.502.1 ± 0.852.4 ± 0.661.9 ± 0.584.9 ± 0.564.8 ± 0.404.9 ± 0.374.9 ± 0.65
Hb A2
mean ± SD
Normal HPLC reference value: HbA (96 - 98), HbA2 (1.5 - 3.5), HbF <1, HbS = 0
Table 2: e HPLC result for each group of sickle cell disease patients having avascular necrosis
Discussion
SCD is a group of disorders that aects both men and women. ose face a chronic disease, with onset in childhood leading to
devastating consequences [1]. In spite of the impressive improvements in the survival of patients with SCD, scientic advances in
chronic bone diseases are still lagging [12,13]. AVN, which refers to bone destruction due to subchondral oxygen deciency, remains

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Volume 1 | Issue 2
the leading cause of crippling disability and the most common manifestation in patients with SCD [14,15]. Approximately 50% of
the individuals with SCD are likely to develop some form of bone fragility syndrome by the age of 35 years [3]. In Jamaica, Lee et
al. reported that the likelihood of developing AVN was 82% between the age of 10 and 29 years [16]. Little attempt has been made
to survey age and sex-based dierences in AVN in individuals with SCD.
Very few studies have shown the high incidence of AVN in male patients, and to our knowledge, none have stressed on sex as a
factor associated with AVN and management of patients with SCD. e results of our study indicated a signicant relationship
between AVN and sex (p = 0.013) in SC, such that, male patients had more tendency to develop AVN than the female patients
did. In patients with SC, 93.3% male patients compared to 50% female patients developed AVN. Similarly, in patients with SCA,
78.3% male patients compared to 65% female patients developed AVN. e female patients with SC had a lower tendency to
develop AVN (50%) than the female patients with SCA did (65%).
We studied the signicant eects of age and sex on AVN in patients with SCD. Pertaining to age, we have observed no signicant
dierences between children and adults in both the sexes aected with SCD. Our nding is not in agreement with the recent
studies on SCD that have suggested a lower prevalence (26%) of AVN among children with Hb SS (mean age, 9.8 years) compared
to adults (48.6%) with a mean age of 26.7 years. In a study by Ware et al. 41% of adults with Hb SS over the age of 15 years had
bone AVN [17]. However, Koduri et al. reported that silent AVN occurred in 41% children aged 4-28 years with the spine and
shoulder being involved in 27% and 28% cases, respectively [18]. is indicates that there is an underestimation of AVN prevalence
in children because of asymptomatic AVN or insensitive AVN investigation by using radiography [19]. Earlier studies on AVN
prevalence in patients with SCD were grossly underestimated, particularly, since 47% and 79% patients with hip and shoulder
disease, respectively had no symptoms at the diagnosis time [20] for that reason bone scintigraphy is recommended to detect the
silent and the multifocal AVN [21]. We screened for AVN in our study by both the following methods: bone nuclear scintigraphy
by utilizing the radionuclide technetium-99m, which is the most sensitive technique, and MRI, which is considered as the gold
standard technique that is the most sensitive and specic one for the diagnosis of this condition. erefore, our estimation of AVN
prevalence in both the adults and children was accurate. Pertaining to sex-based dierences in AVN, prevalence in male versus
female patients, we observed that the phenotypic heterogeneity of SCA, especially, in terms of AVN development was not linked to
sex. e high Hb F level considered a protective factor in SCD [22] .
To date, there is no well-established consensus among providers on the management of SCD complications partly because of lack
of evidence and because of dierences in the experience of the providers [23]. We strongly emphasize on the idea of screening all
patients with SCD for AVN to monitor these complications; we hope to establish it as a routine protocol for all patients with SCD,
in order to reduce the complications and disability associated with this disease. Additionally, the attention of physicians treating
patients with SCD must be drawn to the possibility of AVN in order to prevent or avoid this serious complication, especially in
male patients who are presented with frequent pain crises. By knowing the risk factors, patients with symptomatic SCD who are at
risk for AVN can be identied and additional evaluations can be performed [24].
e HPLC results showed the mean HbF value in sex groups is higher than normal in both SC 12% (male 11.9 ± 7.76, female
12.1 ± 4.38) and SCA 17% (male 15.8 ± 8.23, female 18.2 ± 4.69). It is known that Hb F is high in SC as part of this genetic
disorder. However, the high Hb F in SCA is most likely due to hydroxyurea treatment such patients commenced on. e higher
HbF in SCA correlated with lower AVN 72% than in SC where the AVN was 76%. Although the HbF was almost similar between
both sexes in SC and SCA group, but the male was more aected due to, sex factors which going with our hypothesis in this
study (Table 2). e HbA2 mean value as expected is within normal in SCA 2.1%, while it was higher than normal in SC 4.9%.
is need more research work to detect if it has any inunce on the higher incidence of AVN in SC.
No signicant relationship was found between AVN and age in both SC and SCA, also no signicance was found between
SCA and sex. However, in SC a signicant relationship was detected between AVN and sex, where males had more tendency to
develop AVN. Female patients with SC had less tendency to develop AVN than the female patients with SCA. e higher HbF in
SCA than in SC might be due to hydroxyurea treatment which could decreased the AVN incidence in SCA. e AVN prevalence
in this study was more than in other studies that could be because of bone scintigraphy technique used which is the most sensitive
technique which could detect the silent and the multifocal AVN in SCD.
Conclusion
We are grateful to the sta of the nuclear medicine department in Amiri Hospital and Mubarak Al-Kabeer Hospital for their eorts
in performing scintigraphy.
Acknowledgment
No conicts of interest
Disclosure

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