Info

Cell Gene

Haplotype

Location

Asian Saudi Arabia, Asia

Senegal West Africa Coast

Benin West Africa, Mediterranean

Bantu Central South Africa

Senegal/Bantu have Benin is the haplotype from Hgb F levels between the most seriously affected 5% and 20%/Benin patients <10%/Asian >20%

Asian Saudi Arabia, Asia

Senegal West Africa Coast

Benin West Africa, Mediterranean

Bantu Central South Africa

Senegal/Bantu have Benin is the haplotype from Hgb F levels between the most seriously affected 5% and 20%/Benin patients <10%/Asian >20%

Saudi Arabia and Asia; the Senegal haplotype, the west African coast; the Benin haplotype, West Africa; and the Mediterranean and Bantu haplotype, Central and South Africa (Table 8.1). Levels of hemoglobin F greater than 10% serve to lessen the clinical severity for sickle cell anemia patients.7

Pathophysiology of the Sickling Process

The beta chain has a carefully sequenced group of amino acids with glutamine or glutamic acid in the sixth position from the terminal end. If a person inherits the sickle gene, then valine is substituted for glutamic acid in the sixth position of the beta chain and the abnormal hemoglobin S is present in the person's red cells. Homozygous inheritance results in sickle cell disease, with most of the hemoglobin being hemoglobin S. Heterozygous inheritance results in sickle cell trait, in which hemoglobin S and hemoglobin A are present. The inheritance of one single abnormal amino acid means that the individual inherits hemoglobin S (a2P26glu^val) and sets in motion a myriad of events that alter the patient's quality of life and life span. Lives change when sickle cell disease is present, and the changes are dramatic and at times overwhelming. As we have already determined, it is essential for the hemoglobin in the red cells to remain soluble and pliable as the red cell passes through the oxygenated and deoxygenated rigors of circulation. Red cells possessing hemoglobin S as the majority hemoglobin are insoluble or rigid in areas of low oxygen concentration like the spleen, liver, kidneys, joints, and extremities. Instead of having a fluid hemoglobin content, hemoglobin S forms liquid tactoids or polymers of hemoglobin that appear as long, thin bundles of fibers under electron microscopy.8 Because of this, affected red cells become rigid and inflexible and form an irreversibly sickled cell (ISC) with a pointed projection. These misshapen and inflexible red cells obstruct small vessels and adhere to vascular endothelium, increasing the viscosity of the blood as circulation is slowed. Less oxygen is available to the tissues, the pH of the blood drops, and this combination of events quickly escalates the sickling process. Sickling is also induced by hypoxia, acidosis, dehydration, fever, and exposure to cold. Once red cells exit the spleen, they may return to the oxygenated environment of the lung and may be able to revert to the discoid shape or wheat shape (RSC). But for many hemoglobin S red cells, repeated sickling terminates their life span and they are trapped in the splenic graveyard. The extent to which a red cell will sickle depends on the amount of hemoglobin S, the amount of hemoglobin F, and the physiological conditions present that may advance sickling.

Clinical Considerations for Sickle Cell Anemia

Patients with sickle cell anemia are usually diagnosed through neonatal screening programs or between 6 months and 2 years of age. Prior to this time, red cells are protected from sickling with high levels of hemoglobin F, because the switch from the production of hemoglobin F to hemoglobin A occurs between 3 and 6 months of age. Young children will manifest with symptoms of chronic hemolytic anemia, failure to thrive, infection, or dactylitis, painful swelling of hands and feet by sickled cells in the microcirculation. Basic clinical considerations for sickle cell patients fall under five categories:

• Chronic hemolytic anemia

• Recurrent painful attacks

• Bacterial infections

• Deterioration of tissue and organ function

• Shortened life expectancy

Taken together, these conditions represent a complicated set of guideposts for medical management of a patient with sickle cell disease. Primary care physicians who treat sickle cell patients must be familiar with these particular complications. Each patient will have a unique presentation of their sickle state. Some will have a lifetime of complications and hospitalizations, and others will not be affected until later in life. Nevertheless, possessing hemoglobin S homozygously is not to be ignored or trivialized.

The Anemia

Most patients with sickle cell anemia have a chronic hemolytic process, characterized by a hypercellular

116 Part II • Red Cell Disorders bone marrow, red cells that live only 10 to 20 days,9 a marked reticulocytosis (8% to 12%), increased bilirubin, and cholelithiasis. The anemia is usually compensated with hematocrits in the range of 20% to 25%, and patients do well even with these low numbers. Complications occur in the form of aplastic anemia or splenic sequestration crisis. Acute aplastic anemia may develop as a result of infection, usually parvovirus, when the already overworked bone marrow simply fails to produce cells. The hematocrit may fall by 10% to 15% per day.10 Transfusion is essential because there is no backup therapy for bone marrow aplasia and death may occur without transfusion intervention.

The Spleen

This organ bears the burden of the sickle process. Many patients will have an initial splenomegaly, but by 5 to 6 years of age,11 this organ drastically changes. Functional asplenia occurs within the first 2 years as the spleen loses its ability to clear abnormalities from red cells. Howell-Jolly bodies and other inclusions are evident in the peripheral smear, and there is increased incidence of severe infections, due to the weakened immune function of the spleen. Repeated infarctions and congestion of the spleen will lead to autosplenectomy, producing a fibrosed and shriveled organ. This scarred organ is dysfunctional, lacking the basic and most important splenic functions. Two consequences may develop: overwhelming sepsis and splenic sequestration. In an historical study performed in 1986, the incidence of infection dropped 85% with the use of oral penicillin compared with a placebo study in patients of the same age range.12 Streptococcus pneumoniae infections are especially grave in this age group, yet other encapsulated organisms, such as Haemophilus influenzae and Neisseria meningitidis, pose serious hazards. Acute splenic sequestration is most often a complication of young children. The onset is sudden, as large volumes of blood pool in the spleen. Distention of the abdomen and hypovolemic shock occur because of the rapid pooling. Recovery is not guaranteed as often the condition goes unrecognized and treatment is delayed.

The Lungs

Sickling can occur in any organ of the body, yet the lungs are particularly susceptible to occlusions in the microenvironment of the pulmonary space. During the course of disease, patients may experience clinical lung conditions that are chronic or acute. Often, minute pulmonary infarctions may go undetected, but over time these may lead to impaired pulmonary function and pulmonary hypertension in 20% to 40% of patients, which carries a high risk of death.13 Children with sickle cell anemia are 100 times more susceptible to pneumonia than are other members of the pediatric population.14 Acute chest syndrome is characterized by fever, chest pain, hypoxia, and pulmonary infiltrates. These patients are critically ill with an average hospital-ization of 10 days. Older patients tend to have a more severe course of disease. Multiple causes are suggested, including pneumonia and other infectious agents and possible fat embolism, although pulmonary infarction underlies each of these possibilities. Acute chest syndrome represents the leading cause of death and hospi-talization in patients with sickle cell disease and should be considered in any sickle individual who is admitted for pain.15

Vaso-occlusive Episodes and Complications

Painful crisis is the trademark of patients with sickle cell disease. In African cultures, the descriptive words associated with this condition translate as "body biting" or "body chewing."16 Tissue infarctions and sickling in small vessels produce several painful target points. Patients do not experience crisis episodes on a daily basis; for the most part they are able to live reasonably normal lives. Yet, several features may predispose to a crisis event including fever, dehydration, cold, and stress. When a crisis occurs, the pain is described as gnawing, throbbing, and overwhelming with few moments of relief. If the crisis is centered in the bones, patients experience tenderness, warmth, and swelling and some bone necrosis. Infarctions at the joint level lead to swelling, pain, and loss of mobility. What may also result from joint infarction and poor circulation in the limbs are large, pitting ulcers that are slow to heal and difficult to treat. The pain of sickle cell crisis is intense and unrelenting and only temporarily relieved by analgesics. Clinicians may need to reevaluate the protocols and analgesics necessary for pain management in the child and adult sickle population, with a goal of providing some relief and comfort.17

Priapism, Retinopathy, and Stroke

Priapism, an unfortunate complication of vaso-occlu-sion, is the persistent painful erection of the penis that usually occurs around 15 years of age, the age of puberty. The condition may persist for hours, days, or even weeks with analgesics and sedation as the main course of treatment. Repeated episodes may resolutely alter sexual activity or the desire for sexual activity and lead to erectile dysfunction. There is a high incidence of priapism in males with sickle cell anemia, 35%, yet this complication needs additional attention in the overall management of this disease.18

Retinopathy refers to the ophthalmological complications that sickle patients experience resulting from sickling lesions and stasis of small blood vessels during the course of their disease. These may begin at 10 years of age and can include retinal detachment, retinal lesions, and possibly blindness.19 Eye assessments need to be conducted regularly for sickle cell patients, so that appropriate treatment can be initiated and implemented.

Strokes are an infrequent complication of sickle cell anemia, affecting only 7% of children, yet they may yield serious and unpredictable setbacks to this patient group. Young patients who experience a stroke may have some degree of paralysis, coma, or seizure.20 Preventive measures include identifying children at risk through transcranial Doppler imaging, which may disclose the narrowing of arteries causing a blockage and hypoxia to the brain.21 An additional strategy is to maintain hemoglobin S levels close to 30% through transfusion therapy. This method has been shown to reduce the recurrence of strokes or prevention of firsttime events from 80% to 10%.22

Disease Management and Prognosis

Although sickle cell anemia was first described by Dr. Herrick in 1910, interest in sickle cell disease was sluggish and progress for patients with sickle cell anemia was tentative at best. Two events have signaled a significant advance in the disease profile: the passage of the national Sickle Cell Anemia Control Act of1972 and the establishment of the Cooperative Study of Sickle Cell Disease (CSSCD) in 1979 under the auspices of the National Heart, Lung, and Blood Institute. The study aims to provide a central database to analyze treatment trends, social issues faced by patients, and disease data. Several key issues have been gleaned from 16 years of data23:

1. Hospital visits are not the norm and are used only for crisis emergencies.

2. From 5% to 10% of patients account for 40% to 50% of hospital visits.

3. The average age of death for men was 42 years, and women, 48 years.

4. Longer-lived patients had a higher level of hemoglobin F.

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