CHAPTER ONE
INTRODUCTION
Sickle cell disease refers to a group of disorders caused by inheritance of a pair of abnormal haemoglobin gene, including the sickle cell gene. It is characterized by chronic haemolytic anaemia, dactylitis and acute episodic clinical events called crises.
The term sickle cell disease covers a group of conditions whose pathology may be attributed to the presence of sickle haemoglobin. The five principal phenotypes of sickle cell disease are Homozygous sickle cell ( SS disease), Sickle cell -haemoglobin C disease (SC disease), Sickle cell-Β
thalassaemia (Sβ
thalassaemia), Sickle cell-β+ thalassaemia (Sβ+ thalassaemia) Sickle cell-β±thalassaemia (Sβ± thalassaemia). Homozygous sickle cell disease (also known as sickle cell anaemia, SCA) results from the inheritance of the sickle cell gene from both parents. It is an autosomal recessive disorder of
haemoglobin , and it is the most common of sickle cell diseases and remains the prototype of sickle cell disease. Sickle cell- haemoglobin C disease results from the inheritance of the HbS gene from one parent and the haemoglobin C gene from the other. Inheritance of the genes for β s and for β thalassaemia results in different forms of sickle cell-β thalassaemia depending on the type of β thalassaemia gene and which is dependent on the amount of adult haemoglobin (HbA) produced. In addition to these five major genotypes, three others are: Sickle cell- haemoglobin D Punjab, Sickle cell -haemoglobin O Arab, Sickle cell-haemoglobin Lepore Boston. Other forms of HbD and HbO do not interact with HbS to produce clinical manifestations and are therefore not sickle cell disease. The sickle cell trait in which the sickle cell gene is inherited from one parent and a normal β A
chain gene from the other results in benign condition which is excluded from the definition of sickle cell
Haemoglobinopathies, mainly thalassaemias and sickle cell anaemia are globally widespread.
About 5% of the world’s population carries genes responsible for haemoglobinopathies.
Each year about 300,000 infants are born with major hemoglobin disorders and this include more than 200,000 cases of sickle cell anaemia in Africa.
Globally, there are more carriers (i.e. healthy people who have inherited only one mutant gene from one parent) of thalassaemia than of sickle cell anaemia but the high frequency of the sickle cell gene in certain areas leads to a high rate of affected newborns in these areas.
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The clinical features are of severe haemolytic anaemia punctuated by crisis. The clinical expression is variable, some patients having an almost normal life, free of crises but others develop severe crises even as infants and may die in early childhood or as young adults. Crises may be vaso- occlusive, haemolytic , aplastic or sequestration.
Common complications include ulcer of lower legs,
autosplenectomy, pulmonary hypertension, proliferative retinopathy, priapism, gall stone formations, papillary necrosis and infections. Laboratory findings include low haemoglobin concentration usually between 6-9g/dl, sickle cells and target cells occur in the blood film. Howell-Jolly may also be present. Haemoglobin electrophoresis show HbSS and no HbA detected. The amount of HbF is variable and usually 5-15% and averages about 6% in Nigerians
. 4,5
Management strategies includes prophylaxis: avoiding those factors known to precipitate crises, such as dehydration, anoxia, infections daily folic acid administration, good nutrition, personal hygiene, vaccination (against pneumococal, hemophilus and meningococcal infections). During crises, treatment is by bed rest, warmth, rehydration with oral or intravenous fluids and antimalarial/antibiotics if infection is present. Analgesia at the appropriate dosage should be given. Blood transfusion is given only if there is very severe anemia with symptoms. It is also indicated as a prophylaxis in patients having frequent crises or who have major organ failure. A daily dose of hydroxyurea at 15-20mg/kg has been found to improve the clinical outcome in these patients particularly in those with hitherto frequent vaso-occlusive crisis.
The definitive treatment for this disease is haematopoietic stem cell transplant and many patients have now been successfully cured.
Sickle cell disease (SCD) is generally considered a hypercoagulable state
These patients are thus prone to vasoocclusion (VOC) and thrombotic episodes.
The sequence of patho-physiological events that lead to the sickle
cell VOC is not well understood. Several authors
have outlined a sequence of steps occurring in the microcirculation
that culminate in painful sickle cell crisis. 8,9,10,11
Polymerization
of HbS, decreased blood red cell deformability, micro-vascular
occlusion, hypoxia of tissue involved with the occluded microvascular
network, and tissue damage triggering painful stimuli
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have been
mentioned, although the precise dynamics of these events
and their interrelationships are poorly understood 12. Tissue ischemia
due to vascular occlusion causing infarctive tissue damage,
which in turn initiates secondary inflammatory responses, has
also been reported. 13,14 Ischaemic events produced by the
occlusion of both large and small blood vessels are stressful
and involve intricate interactions between red blood cells,
the endothelium, and leukocytes.
These interactions are
known to be regulated by cytokines (secreted by T cells) and other adhesion molecules. Consequently, the immune response
is implicated in the initiation and propagation of the sickle
cell crisis. Plasma cytokines and related factors represent a burgeoning area of inquiry related to the pathogenesis in sickle cell disease. Cytokines derived from platelets, white blood cells and endothelial cells have all been implicated in the development of several sequelae of this disease. An investigation of the production of inflammatory cytokines (IL-1, IL-6, TNF-α, IL-11), anti-inflammatory cytokines (IL-4, IL-10, IL-13), and inflammatory mediators in SCA patients may further elucidate the pathogenesis of the disorder and its complications and help in assessing disease severity, prognosis and also provide novel therapeutic approaches in the management of the disorder.
RELEVANCE OF THE STUDY TO THE PRACTICE OF HEMATOLOGY
Vaso-occlusive crisis remains the commonest clinical presentation of sickle cell disease. In this study, if a correlation was found between serum cytokines levels and sickle cell disease using interleukin 2, 4 and 10. also if by this study, an elevated serum levels of some inflammatory cytokines was found in SCD in VOC. This could justify the use of Interleukin targeted therapy to control exaggerated inflammatory responses associated with sickle cell ischemia-reperfusion injury. This could also modify the course of disease of such patients. In addition this study will provide baseline cytokine level in sickle cell disease patients.
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