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Sickle cell disease results from a single nucleotide mutation determining the insertion of valine for glutamic acid at the sixth position from the amino terminus of the beta chain significantly changes the behavior of the hemoglobin (Hb) molecule. When deoxygenated, molecules of sickle hemoglobin (HbS) polymerize, raising the internal cellular viscosity, reducing membrane pliability, and distorting the red blood cell (RBC). Such cells have difficulty negotiating capillary beds, resulting in the two independent but closely interrelated pathophysiologic features of the disease.

Hemolysis reduces RBC survival from a normal mean of 120 days to an average of 10 to 18 days, resulting in anemia (average Hb value, 6 to 9 grams per dL in homozygous sickle cell [SS] disease), jaundice, increased prevalence of pigment gallstones, and expansion of the bone marrow spaces. The expanded bone marrow can change the configuration of some bones, and its metabolic and nutritional demands may compromise growth and development. Generally, the hemolytic features are well tolerated and, with the exception of a superimposed aplastic crisis, rarely lead to mortality. The tendency to compromise blood flow damages the tissue supplied, the features depending on the site of nonperfusion. This ischemia most commonly affects the bone marrow (dactylitis, painful crisis, avascular necrosis of the femoral head), skin (leg ulceration), spleen (acute and chronic sequestration, impaired function), brain (stroke), and lungs (acute chest syndrome).


Among communities in which sickle cell disease is predominantly of African origin, there are four principal genotypes. SS disease and sickle cell-beta0 -thalassemia.


Steady State

Most patients with SS disease have steady-state hemoglobin levels of 6 to 9 grams per dL. At steady-state levels, symptoms of anemia are unusual, and oxygen carriage appears to be close to normal.

Lowered Hemoglobin Levels

A variety of complications are associated with acute and chronic lowering of hemoglobin below steady-state values. In each case, the physician should seek and treat the cause rather than resorting to the blanket therapy.


Aplastic crisis affected 30% of patients with SS disease in the Jamaican Cohort Study by the age of 15 years. Defined clinically by marked lowering of hemoglobin level and absence of reticulocytes from the peripheral blood, aplastic crises are most common before 15 years of age, occur in epidemics, and cluster in families.


Acute enlargement of the spleen with pooling of a significant proportion of the RBC mass may lead to a life-threatening anemia in young children. In the Jamaican Cohort Study, this complication had affected 25%.


Chronic splenic sequestration or hypersplenism differs from ASS in its gradual development, greater degree of splenomegaly, and markedly expanded bone marrow activity, which allows a new hematologic equilibrium but at a greatly increased hemolytic rate (mean RBC life, 1 to 3 days).


Renal tubular damage is common in SS disease, resulting in an inability to concentrate urine and in other functional tubular abnormalities, but the progressive loss of glomeruli results in chronic renal failure. The most likely mechanism is glomerular hyperfiltration leading to glomerulosclerosis and a progressive fall in glomerular filtration rate with eventual elevation of serum creatinine level.


Patients with SS disease are more prone to several bacterial infections.


Septic patients with high fever must be assumed to have infections with S. pneumoniae, Hib, or Salmonella and should be given suitable antibiotics pending the results of blood culture.


The increased bilirubin production consequent to hemolysis is associated with both clinical jaundice and pigment gallstones. The severity of clinical jaundice varies among patients and also in the same patient, becoming more obvious during fever, dehydration, or painful crises.



A common early manifestation of SS disease, dactylitis affects 50% of Jamaican Cohort Study children by the age of 2 years. Because it may start in children as young as 3 to 4 months.

Painful Crisis

With increasing age, erythropoietic activity ceases in the bone marrow of the small bones of the hands and feet, and greatest activity occurs in the juxta-articular areas of the long bones, the spine, and the flat bones of the sternum, ribs, and pelvis. Avascular necrosis of bone marrow at these sites causes the typical painful crisis.

Avascular Necrosis of the Femoral Head

Avascular necrosis of bone marrow may also occur in the femoral head and, with continued weight bearing, may result in permanent deformity. Treatment depends on early diagnosis and avoidance of weight bearing for approximately 6 months to allow the femoral head to heal without deformity. Traction may be necessary.

Avascular Necrosis of Bone

Avascular necrosis forms part of the spectrum of syndromes resulting from bone marrow necrosis, but rather than the commonly symmetrical distribution of sites seen in the painful crisis, the term "avascular necrosis of


Osteomyelitis, usually caused by Salmonella organisms, although occasionally by Hib, Staphylococcus, or Escherichia coli, is a well-recognized complication. It is believed to be secondary to sterile avascular


The acute chest syndrome covers a spectrum of lung disease characterized by fever, cough, pleuritic pain, clinical signs, and radiologic evidence of new pulmonary infiltrates. It is one of the major manifestations of SS.



Stroke occurred in 8% of patients in the Jamaican Cohort Study by 14 years and at a median age of 8 years. The risk factors for initial stroke are largely unknown, so prevention is not possible.


Retinal vaso-occlusion, affecting predominantly the peripheral retina, results in the development of fragile new vessel systems in the periphery supplied by feeding arterioles. These proliferative sickle retinopathy (PSR) lesions may bleed, causing vitreous hemorrhage with transient blurring of vision, and large lesions.


Chronic leg ulcers around the ankles are particularly common in Jamaica, affecting 75% of adults with SS disease at some time. They are believed to be multifactorial, with components from trauma, skin infarction.


Involuntary painful erection of the penis unassociated with sexual desire affects approximately 30 to 40% of postpubertal Jamaican male patients with SS disease. It is commonly not reported because of embarrassment.



Sexual development is retarded in patients with sickle cell disease, with a mean delay in menarche of 2.5 years. The interval between first unprotected sexual exposure and pregnancy is similar in SS disease and normal control subjects, contrary to the concept of relative infertility in this condition.


Patients requesting contraception should be given the best methods available. The frequent assumption that there are serious risks to contraception in SS disease is unjustified, and the risks of pregnancy.