Professional Documents
Culture Documents
Volume 12, Issue 15, 303-323. Review Article ISSN 2277– 7105
Akanksha Patel*
ABSTRACT
Article Received on
09 July 2023,
Sickle cell disease is a common and life-threatening blood disorder that
Revised on 30 July 2023, affects millions of people in the world. Abnormal sickle-shaped RBCs
Accepted on 20 August 2023
disrupt the flow of blood in small blood vessels, and this Vaso-
DOI: 10.20959/wjpr202315-29451
occlusion leads to ischaemia and inflammation, acute painful sickle-
cell crisis, parenchymal injury and chronic organ damage. The main
*Corresponding Author
physiological complicacy is due to the polymerization of sickle
Akanksha Patel
haemoglobin (HbS), sickling process inside the red blood cell (RBC) of
Siddhi Vinayaka Institute of
Technology and these patients during deoxygenating state. The change of RBC from
Sciencebilaspur spherical to sickle shape is due to the polymerization of mutant
Chhattisgarh-495001. haemoglobin (HbS) inside the RBC and membrane distortion during
anoxic condition. The mechanism and the process of sickling are very
complex and multifactor in nature. Currently available treatments are limited like blood
transfusions some therapies and medications, although stem cell transplantation might be a
potentially curative therapy, gene therapy and gene editing. Recent advances like systematic
universal screening for stroke risk, improved management and diagnostic devices. Other
possibilities have to investigated, like traditional medication in the form of medicinal plants
to control the symptoms of the disease. The plants which all have anti-sickling properties are-
Cajanus cajan, Carica papaya, Piper guineense, aloe vera, allium sepa, Moringa oleifera and
Vinga unguiculata seem tobe the more effective species for preventive treatment.
KEYWORDS: Anaemia- sickle cell, sickle cell genetics, complications, screening program,
recent advancetreatment methodology.
INTRODUCTION
Sickle cell anaemia (SCA)/ sickle cell disease (SCD)/ sicklemia / HbS (sickle haemoglobin)
disease / sickle cell disorder / sickling is an inherited disease which characterized by mutation
in the gene sequence of HBB (haemoglobin subunit ). Haemoglobin is a tetrameric/
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Patel. World Journal of Pharmaceutical Research
quaternary protein structure (1, 2, and 1, 2) having heme + globin subunits, heme
contains iron and porphyrin. Oxygen reversibly binds to the ferrous ion atoms in each heme
group.[1] The haematopoiesis includes erythropoiesis, leukopoiesis, and thrombopoiesis, these
all are involved in the production of erythrocytes (red blood cells).[2] Hb expressed by RBCs
for both type immature (reticulocytes) as well as mature (erythrocytes) red blood cells,
multiple type of Hb are normally expressed at different stages of life- HbF for
embryonic/foetal, HbA for adults. A single nucleotide substitution in HBB forms in the sickle
Hb, called HbS allele s (mutant -globin subunit). Hb tetramers that have two mutant HbS
polymer that causes the erythrocytes to form the sickled shape. Sickle erythrocytes can lead
to Vaso- occlusive episodes.[3] The global prevalence of SCA is found in African countries
Saudi Arabia, Yemen, India, Pakistan, Bangladesh, China, US, Europe, Sub- Saharan
Africa.[4,5] Most of the children with sickle cell anaemia maintain a haemoglobin concentration
between 7 and 8.5 g/dl in the steady state.[6] The capacity of erythrocytes undergoes reversible
changes in shape which affect oxygen carrying capacity, when the oxygen pressure is low the
cells change their actual form from normal biconcave disk shape to rigid, crescent, holly
wreath, banana, or sickle shaped and the process is known as sickling.[7] They may result in
progressive end organ damage due torecurrent vasoocclusive crises & iron overload.[8]
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membrane damage.[1] In childhood, the sickle cell patients are smaller than normal people
and the puberty is delayed but considerable growth takes place in late adolescence such that
adults with sickle cell anaemia are at least taller than normal also adults that have suffered
vertebral infraction and collapse may be shorter than normal people.[9] The 2 approaches for
treatment of SCD at genetic level are gene therapy of haemoglobinopathy and replacement
copy of the relevant globin gene (beta or gamma).[10] According to the WHO, approximately
4.5% of the world population carries the sickle cell genes. In which mortality of infants with
SCD is as high as 90% in areas with limited medical facilities and 50% in areas with
improved health infrastructures while 1% of the infants with SCD dies in the United
States.[11] The RFLP (Restriction fragment length polymorphism)-assessed 5 haplotypes of
SCD, name based on their originating locations, the HbF levels can be associated with -
Senegal & Arab-Indian, than Benin/bontu, compared to CAR (Central Africa Republic), and
Cameroon haplotype. The HbF level may vary according to its distribution of erythrocytes.[12]
In India, sickle cell causes high degree of morbidity and mortality rate due to geographical
distributions, social barriers, health care facilities, large population, expand birth rate,
consanguineous marriage. Which dangerously causes the tribal populations. The term „tribe‟
is originated from Latin term „tribus‟, meaning “a group of persons forming a community and
claiming descent from a common ancestor”. The tribal are constitutionally called as
ADIVASI, VANYAJATI, VANVASI, PAHARI, ADIMJATI and ANUSUCHIT JANJATI.
They commonly do not show any symptoms related to malarial infections.[13] SCD present in
the non-malarial regions is related to the recent migration patterns.[14] Malaria is a most
common infectious disease caused by female anopheles mosquitos mostly in the tropical and
subtropical regions. In HbAS (trait) patients have some resistance for malaria comparison to
HbAA (normal) or HbSS (homozygous state). The exact mechanism is unknown but several
studies are available (conclusion by Kodjo et al) that the ring parasitized RBC in sickle cell
trait patients was predominantly complement mediated and damaged normal RBCs,
phagocytosis of ring parasitized red cells by reduced parasitic growth, density and process. In
another study it shows that malarial infected sickle trait RBC are under low oxygen tension,
this cells are removed from circulation and destroyed in reticuloendothelial system which
reduce the burden of malarial parasite.[15]
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Figure 2: Formation and destruction of RBCs and Circulation throughout the body.
Normally RBCs have sufficient space for oxygen for growing malarial parasites but in SCD
condition it lacks the space for oxygen thus early destruction of sickled RBC occurs by
macrophages. Eventually it takes less duration of formation and destruction.
TYPES OF SCD
1) HbSS: People who have this form of SCD inherit two sickle cell genes (“S”), one from
each parent. This is commonly called sickle cell anaemia and is usually the most severe
form of the disease.
2) HbSC: People who have this form of SCD inherit one sickle cell gene (“S”) from one
parent and from the other parent a gene for an abnormal haemoglobin called “C”.
Haemoglobin is the protein that allows red blood cells to carry oxygen to all parts of the
body.
3) HbS -thalassemia: People who have this type of SCD inherit one sickle cell gene (“S”)
from one parent and one gene for beta thalassemia, another type of anaemia, from other
parent.
Two types of beta thalassemia: “0” and “+”.
“0”- Those with HbS beta 0 thalassemia usually have severe form of SCD. “+”- People with
HbS beta + thalassemia tend to have milder form of SCD.
Rare types of SCD: HbSD, HbSE and HbSO. People who have these forms of SCD inherit
one sickle cell gene (“S”) and one gene from an abnormal type of haemoglobin (“D”, “E”, or
“O”).[2,16]
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HISTORY
In India: sickle cell disease is a genetically transmitted haemoglobinopathy. In 1952, Dunlop
and Mazumder, first case detect the 5 sickle cell trait haemoglobin and 3 presumptive cases
of sickle cell anaemia from tea tree garden labours of upper Assam, which originate from
tribal population of Bihar and Orissa. In the same year (1952), Lehmann and Cutbush detect
SCD in the hills of Nilgiri of South India. In 1958, the first sickle cell case reported from
Central India by Solanki and Shukla. In 1991, Kar‟s statement- the sickle cell gene is not
limited to tribal populations, but it also prevalent in society, more frequent in scheduled
castes & in Hindus.[13] In 2005, hoffbrand used to describe the term sickle cell disease all the
entities associated with sickling of haemoglobin within RBCs.[17]
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replaced with the valine at the sixth position the changes of codon from GAG to GTG. That
produce 2 genotypes; homozygote (SS) and heterozygote (AS), as resulting 2 clinical
syndromes; sickle cell disease and sickle cell trait.[18] The surface of HbS consist of
hydrophilic amino acid chains some with hydrophobic side chains, since adult Hb is present
at a very high concertation within RBCs to remain free from of saturated oxygen aggregation,
the arrangement of amino acid the surface of molecules to avoid attraction between adjacent
molecules.[1] HBS under low oxygen condition, the absence of a polar amino acid at position
six of the β globin chain promotes the noncovalent polymerization of haemoglobin, which
distorts red blood cells into a sickle shape and decreases their elasticity, which allows the cells
to deform to pass through capillaries and repeated episodes of sickling damage the cell
membrane and decreases the cell's elasticity. These cells fail to return in normal shape when
normal oxygen tension is restored and rigid blood cells are unable to deform as they pass
through narrow capillaries, leading to several complications.
The bone marrow attempts to compensate by creating new red cells, it does not match the rate
of destruction of healthy RBCs live 90 - 120 days, but sickle cells lives 10-20 days according
to - Emedicine.[6,19,20] The sickle cell polymerization causes the cell membrane to lose its
functional abilities that results in loss of K+, water and gain of Na+. Increased intracellular
free Ca2+ in sickling. Small blood vessels are blocked due to clumping of sickled RBCs. It
causes deoxygenation in tissue capillaries, which damage to its endothelium and surrounding
soft tissue. Nitric oxide also plays a vital part in sickle cell disease.[20] Increased scavenging
of NO by superoxide that occur in the sickle context, it involves an abnormal imbalance
between superoxide and NO generation.[21]
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Figure 5: The change in amino acid sequence causes haemoglobin molecules to crystalize
when decreaseoxygen level, as result RBCs are sickle shaped.
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Haemoglobin S with this mutation refer as HbS, which opposed to the normal adult HbA. It is
normally a benign mutation, causing no apparent effects on the secondary, tertiary, or
quaternary structure of haemoglobin. It allows under the condition of low oxygen
concentration, it is the polymerization of the HbS itself.[23,24,25]
A person who receives the defective gene from both father and mother develops the disease; a
person who receives one defective and one healthy allele remains healthy, but can pass the
disease called as a carrier.
If both parents who are carriers have a child, there is a 1 in 4 chance of their child's for
developing the disease and a 1 in 2 chance for child's being just a carrier, carriers can produce
a few sickled red blood cells which are not enough to cause SCD symptoms, but enough to
give resistance to malaria. This is due to the adaptive advantage of the heterozygotes the
disease is still prevalent, especially among people with recent ancestry in malarial stricken
area such as Africa, the Mediterranean, India and the Middle East.[25] Malaria was historically
endemic to southern Europe, but it was declare eradicated in the mid 20th century with the
exception of rare sporadic cases. In a carrier, the presence of malaria parasite complete the
life cycle in human and causes the defective haemoglobin containing red blood cells to
rupture prematurely making the plasmodium unable to reproduce. Further, the polymerization
of Hb affects the ability of the parasite to digest Hb in first place. Therefore, in areas where
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malaria is a problem, people's chances of survival increases, if they carry sickle cell traits.[19]
State wise distribution of SCD in India: the highest frequency of SCD in India is reported
in Orissa, Assam, Madhya-Pradesh, Uttar-Pradesh, Tamil-Naidu, Chhattisgarh, Gujarat for
around 83% of the total scheduled tribe population in the country and majority of these tribal
groups live in rural areas. In report of many studies as 73% in tribal people, 17% are from
lower caste, 9 % from middle caste and 1% from higher castes.[13] In percentage according to
study - Sickle cell anaemia (12- 15%), sickle cell trait (80-85%) and sickle B thalassemia (2-
3%) diseases are commonly seen in hilly areas.[26]
GUJARAT: Gujarat state have as an expect to 6,47,025 Sickle trait and 48,257 Sickle disease
patients, belonging to Dhodia, Dubla, Kukna, Gamit, Chaudhary, Halpati, Varli, Kokni,
Kathodi, Kolcha, Kotwadia, etc casts. According to the several studies the majority of disease
found in vasava caste- 61%, Bouddha-3 (37.5%), Chaudhary, Gamit, Dhodia, Patel have
36.6%, Muslim-2(25%), Matang-2(25%) and Banjara community-1 (12.5%).
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NORTH EAST: According to Dunlop 1952, SCD was found in certain labour tribes drawn
from Orissa for working in tea gardens in Assam.
ODISHA: according to Balgir study the 29.8% of HbAS and 7.5% case of HbSS. The sickle
cell gene is highly prevalent in general castes (0.3-20.7%), schedules castes (0-8.9%), and
schedules tribals (0-5.5%).
MADHYA PRADESH: 27 out of 45 districts are fall under sickle cell gene belt. The
districts are- Jhabua, Barwani, Dindori, Mandla, Dhar, Shahdol, Umaria, Betul, Seoni, West
Nimar, Chhindwara, Harda, East Nimar, Jabalpur, Ratlam, Dewas, Katni, Damoh,
Hoshangabad, Sagar, Satna, Balaghat, Ujjain, Indore, Mandsaur, Neemuch and Narsimhpur.
RAJASTHAN: In the study conducted of Mandot 2009, in Garasia tribes of Rajasthan, out
of 1676 patients, 155 were found to be sickling positive (9.2%) in the diagnosis of
haemoglobin electrophoresis test, in which 0.83% are homozygous state (Hb SS) and 8.4%
(144) are heterozygous state (carrier, Hb AS).
SOUTH INDIA: in south India the cases of SCD are less than central, east and north India.
The high frequency of SCD has reported in Kerala among tribal communities of Wyanad and
non-tribal Wyanad Chetti. According to Feroze study, in different communities of Attappady
region are Irula, Kurumba, Muduga.
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COMPLICATIONS
There are 2 major types of complications- acute and chronic.
Figure 9: Acute and chronic type of complications in human body because of SCD.
Acute complications: these complications are minor which can easily diagnose and treat
accordingly.[9,27]
Chronic complications: that complications are not easily curable that takes time, such as-
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new born screening, health screening for mother and child. To prevent this situation contact
with haematologist.[28]
SCD inflammation disease: the cells are sticky, stiff, oxidized irritant that cause
inflammation and that disturbs in flow. They exposed to inflammatory cytokines, growth
factors.[29]
Bone marrow necrosis: it is infrequently and rarely reported in association with SCD.
Patients with a mild SCD phenotype are at high risk of bone marrow necrosis.[30]
Restrictive lung disease: in this case DLCO, TLC, and Lung fibrosis are decreases.
Hence, circulating and activated fibrocytes are increases.[31]
LABORATORY DIAGNOSIS
1. Obligatory tests
a) RBC morphology – from blood smear.
b) Routine blood tests – CBC.
c) Sickling/solubility tests
d) Haemoglobin electrophoresis at alkaline/acidic pH
e) Measurement of haemoglobins A2 and F
f) Serum iron, TIBC, serum ferritin
2. Special tests
a) Family studies
b) Measurement of alpha: globin chain ratios
c) Structural studies (Hb fingerprinting)
d) Gene studies (restriction endonuclease, PCR, Allele hybridization).[13]
Also diagnosed by direct analysis of foetal DNA.[36]
Small dried blood spot (DBS) for analysis, collected from cord blood or the infant‟s
heel/toe.
Haemoglobin electrophoresis using isoelectric focusing (IEF), High-performance liquid
chromatography(HPLC), capillary electrophoresis (CE) techniques, and even DNA-based
laboratory diagnosis.[37]
Sample preparation for SCD diagnosis: Peripheral blood samples were collected with
potassium-ethylene diamine tetra-acetic acid (K2-EDTA) (1.2mg/mL) for complete blood
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count (CBC) and haemoglobin analysis. For chemical analysis and enzyme-linked
immunosorbent assay (ELISA), clotted samples were obtained and serum was separated by
centrifugation for 15min at 1000× g then stored at −20 °C until subsequent use in ELISA.[38]
New born screening: NBS for SCD consist of identifying a neonate‟s sickle cell Hb status at
the time of birth or after birth. The NBS program for SCD was implemented in New York,
1975. The state wise programs were implemented in 1980s, Colorado, Texas, Georgia. The
purpose of the program showed the effectiveness of these approaches and provided variable
knowledge on different strategies for NBS. New born screening program activities are
mechanisms by which public health has helped to reduce morbidity and mortality and
improve the well-being of people with SCD.[39] Two types of new born screening
programmes have been used. Selective screening of infants of high-risk parents (targeted
screening) and universal screening. Universal screening is generally more cost-effective,
identifies more new born babies with disease and prevents more deaths. In areas without new
born screening programmes, the initial diagnosis occurs at approximately 21 months of age.
For many SCD patients, the initial observation is a fatal infection or acute splenic sequestration
crisis. Early diagnosis done by penicillin prophylaxis and family education can reduces the
mortality in the first 5 years of life.[3]
The National Sickle Cell Anaemia Control Act (Public Law 92–294) was sign into law in
1972. The act provided for SCD screening and counselling, education programs for health
professionals and the public, research and training in the diagnosis and treatment of SCD. A
national broad-based programme of basic and clinical research was established at the NIH and
ten centres were established in hospitals and universities located in geographical areas with
large at-risk populations. The centres gradually shifted towards basic and clinical research,
and the NIH comprehensive sickle cell centre program was disassembled in 2008.[3]
Screening program in India: The population of India consists of >2,000 different ethnic
groups, most of which have practised endogamy over centuries. Screening typically consists
of Hb solubility test at the point of care with further testing of initial positive samples by
HPLC analysis at a reference centre. Screening programmes also include education, testing
and genetic counselling. Pilot projects of new-born screening programmes for SCD have
been implemented in the states of Gujarat, Maharashtra and Chhattisgarh, which resulted in
detailed data on the prevalence of HbAS in various populations.[3]
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TREATMENTS
The SCD can prevent with various approaches like gene therapy, through herbal pants, by
allopathic medicines and other therapies but there is no specific substance. The knowledge
can Simply refers to the health approaches, practices, and beliefs in plant, animal, mineral-
based drugs, spiritual therapies, manual techniques and exercises. Rural communities
engaging in practices like traditional medicines, herbalism, psychiatry, acupuncture,
gynaecology, osteopathy, paediatrics to treat SCD.[40] The anti-sickling properties of certain
amino acids such as phenylalanine, alanine, lysine, arginine etc. The modulation of the
activities of the three membrane-based ATPase's (Na+, K+, Ca2+ATPase's) are significantly
lowered in HbSS erythrocytes, while Mg2+ ATPase's was significantly higher than for
HbAA erythrocytes.[25]
Herbal plants used in therapy: There are total 93 species found, from 49 different families.
The best-represented families, containing 5 species; the Leguminosae (12), Apocynaceae (6),
Rubiaceae (5), Euphorbiaceae (5) and Annonaceae (5). Active principles were identified for
27 species (50%). In 21 of these cases, anthocyanins seemed to be responsible for the anti-
sickling effect. They are commonly distributed among flowers, fruits, and vegetables.[56]
Other list of drugs according to 2018 survey: according to these survey different chemical
entities are discovered for SCD.[3]
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DISCUSSION
Sickle cell anaemia is a genetic disorder and characterized by the mutation on the sequence of
haemoglobin chain at beta-position of globin molecule GAG-GTG (glutamic acid to valine),
single nucleotide of HbB is substituted with HbS allele. Many countries are affected with
SCD such as African countries, Saudi Arabia, Yemen, India, Pakistan, Bangladesh, china,
US, Europe etc. In India many states and several casts affected with SCD cases mostly in
Odisha, Maharashtra, MP, CG, Bihar, Assam, Gujarat. The first case of SCD is found in
Chicago at 1904-1906. The sickle shaped RBCs are loss their elasticity and rigidity, hence
they cannot flow easily in blood vessels and then causes vasoocculusion pressure, joint pain,
stroke, chest pain, and other sign and symptoms like Fatigue, Shortness of breath, Dizziness,
Headache, Coldness in the hands and feet, Pale skin, sometimes it may leads to organ
damage. To avoid this complications many preventive therapies are available like gene
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therapy, bone marrow transplantation, blood transfusion, drug therapy like Hydroxyurea,
pneumococcal injection, folic acid, vitamin B12 etc. food materials are also helpful such as
carrot, beat-root, spinach, citrus fruits etc. Some plants are containing anti-sickling property as
Cajanus cajan, Carica papaya, Piper guineense, , aloe vera, alliumsepa, Moringa oleifera and
Vinga unguiculata etc. Many other drugs are in process of clinical trials to treat the sickle cell
anaemia.
CONCLUSION
SCD is a major public health disease worldwide. The origin of this disease is in Nigeria. In
India, it is widely spread especially in rural areas with many specifics casts. It have many
minor and major complications such as vasoocculusion, severe joint pain, and hypoxia. The
objective of this project is mainly for the awareness, to prevent, to control and treatment
for this genetic disorder. It mainly occurs due to lack of knowledge, inter-cast marriage,
deficiency of nutrients, unhygienic food. For the treatment of SCD, many researches are in
progress the most effective drug at this time is Hydroxyurea with other supplementary drugs.
To reduce this complications maintain diet, nutrients, before marriage have to medical test and
follow the physicians/doctors‟ advice, improvetreatment policies.
This kind of new approaches are every day developed in the pharmaceutical companies for
better preventive treatment, discover new different molecules to reduce the crises. Although
may add in new treatment therapy like novel drug delivery system including neosomes,
liposomes, drug directly insert into bone marrow, may formulate different type of gel or lotion
which penetrate into inflamed area or stem cell to produce blood freely.
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