Clinical features

Sickle cell anemia refers to the homozygous state for the PS gene, in which the majority of the hemoglobin in the red cells is sickle hemoglobin (Hb S). This induces sickling (marked changes in red cell shape produced by intercellular Hb S polymers) when the oxygen tension is reduced, increases in red cell viscosity, decreased pliability and, by consequence, lowering of the sickle cell rheological competence, and hemolysis.

In addition, there are myriad pleiotropic effects, such as increased adherence of sickle cells to endothelium, induction of red cell dehydration and irreversible sickled cell (ISC) status, autosplenectomy and urine concentration defects (Figure 14.5).

The primary events as well as the pleiotropic events are, in addition, affected by modifier or epistatic genes, which tend to be polymorphic, that is, different among individuals. The strong effect of all of these factors explains the great interpatient differences in the intensity of the phenotype: some patients are severely affected whilst others have only mild disease, and the majority span these two extremes.

Anemia is present in all cases, with an average hemoglobin concentration of 8.4 g/dl, reticulocytosis varying between 5 and 20%, dense cell fraction between 5 and 40%, increased white cells (10-20 x 109/L) and platelets in the upper limit of normal. Most of these features are modulated by the level of fetal hemoglobin (Hb F) in the sickle cells and the distribution function of the levels among red cells, since Hb F is het-

Fig. 14.5 Age-dependency of complications in sickle cell anemia

Reproduced from Davies SC, Oni L. (1997) Management of patients with sickle cell disease. British Medical Journal, 315, 656-60, with permission.

Pain Dactylitis Long bones Trunk

Sequestration Splenic Hepatic

Chest syndrome Mesenteric syndrome

Infection Pneumococcal Parvovirus Salmonella

Priapism

Upper airway obstruction Stroke

Subarachnoid hemorrhage Retinopathy

Gallstones Avascular necrosis Hyposthenuria

Delayed growth and development Leg ulcers

Chronic renal failure Chronic sickle lung

10 15 20 Age (years)

erogeneously expressed in reticulocytes and mature red cells. They are also modulated by the co-presence of a thalassemia (-a/aa and particularly -a/-a), a feature quite common among sickle cell anemia patients (between 20 and 50% of cases, according to age). Gender is also a factor; for example, in females sickle cell anemia is associated with higher Hb F concentrations, particularly when associated with the Senegal haplotype.

The kidneys are particularly affected in this disease: there is an increase in glomerular filtration rate early in life, as well as urinary concentration defect, papillary necrosis with hematuria, renal insufficiency and nephrotic syndrome (Plate 14.1). The lungs are the site of the acute chest syndrome that can be caused by infection (viral, bacterial and atypical organisms) as well as fat embolism. The latter gives the most se vere cases and has the highest mortality. This life-threatening complication may be arrested by exchange transfusion. Neurological complications also occur (for example, in children classical infarcts occur involving the major vessels) as well as small vessel infarcts. Some of these infarcts, particularly in the frontal lobe, have been associated with behavioral changes. The bones of patients with sickle cell anemia show a five-fold increase in red marrow and may suffer aseptic osteonecrosis, particularly at the site of terminal circulation (head of the femur and humerus) and also in the calcaneus. Peripheral reti-nopathy characterized by new vessel formation and choroidal infarcts is well recognized in patients with sickle cell disease. Patients with homozygous Hb SS, and some heterozygotes, may suffer hyphema secondary to eye trauma, since sickled cells cannot exit through the Schlemm canals (the vitreous is very deoxygenated). The spleen is partially ineffectual during the first decade of life and essentially disappears (autosple-nectomy), except in the co-presence of —a/—a thalassemia.

The liver can harbor bilirubin stones in the gall bladder as well as the common duct, but fortunately the patients have infrequent cholecystitis. They may also suffer hepatic crises, characterized by increase in serum bilirubin, abnormal liver functional tests, pain and a fall in hemoglobin. Thick bile, due to suspended bilirubinate crystals, can be a factor, as well as sequestration of red cells, a hypermacrophage erythrophagia (Kupffer cells).

The heart may be affected by cardiomyositis, leading to cardiac insufficiency and, in a small number of patients, small vessel obstruction. The lack of more vaso-occlusion in the heart may be the consequence of the very high perfusion pressure of coronary vessels as well as the squeezing effect of the ventricular contraction. Finally, the ankles are the site for leg ulcers in sickle cell anemia, and these may be painful and reduce the quality of life.

In sickle cell anemia, pregnancy poses a significant risk to the mother and newborn (lower birth weight). Previous protocols of exchange transfusion during pregnancy have been replaced by putting the patient into 'high risk track' obstetric care, involving frequent follow-ups, with good results and fewer complications.

The most devastating complication of sickle cell anemia is painful crisis. This involves pain in the extremities, joints, lower back, abdomen, cranium and parotid glands. The pain may be insidious or rapidly progressive, and may begin in one site and extend over time to others. It involves infarction of the circulation in marrow, bone or muscle, or a combination of these. Further studies have demonstrated that the decrease in dense sickle cells is actually preceded by a decrease in light-density sickle cells. The latter event might record light-density sickle cell adhesion while the subsequent decrease in dense cells reflects their trapping in vessels bedecked with adherent cells. Fever is usually present even in the absence of intercurrent infection. Precipitating factors include dehydration, fever, infection, emotional stress, interference with the vascular circulation of limbs, intense exercise and the use of cocaine.

Another very serious complication is pulmonary hypertension. In sickle cell anemia patients with this complication, the average systolic, diastolic and mean pulmonary artery pressures and mean pulmonary capillary wedge pressure were almost double those in sickle cell anemia patients without pulmonary hypertension. The mean level of pulmonary artery pressure was the best predictor of survival, and each increase of 10 mmHg was associated with a 1.7-fold increase in death rate. The median survival of patients with pulmonary hypertension is close to 2 years, which indicates that this is one of the worst complications in sickle cell anemia.

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