Hemoglobinopathies and Thalassemias



Hemoglobinopathies and Thalassemias


Paul L. Martin



The genetic, molecular, and biochemical characteristics of human hemoglobin are well known. The genes for the polypeptide chains of hemoglobin are located on chromosomes 11 and 16, and their DNA sequences have been determined. Each of the alpha and beta chains of adult hemoglobin consists of approximately 150 amino acids. The single amino acid substitution in these chains that causes each abnormal hemoglobin syndrome can be identified and located. Although more than 400 types of abnormal human hemoglobins have been characterized, only a few of them are prevalent.

Hemoglobin variants are identified by hemoglobin electrophoresis, a technique that usually permits a specific genotypic diagnosis. The thalassemias are associated with decreased production of the normal polypeptide chains of hemoglobin. The thalassemias are quantitative rather than qualitative abnormalities of hemoglobin.


SICKLE CELL DISEASE AND TRAIT

The gene for sickle cell hemoglobin (Hb S) is not exclusively African, although a broad periequatorial sickle cell belt is found in Africa. The sickle gene was introduced into the Western Hemisphere from Africa by the slave trade during the sixteenth through the eighteenth centuries. In the United States, sickling disorders are particularly prevalent in the South and in the urban North, reflecting the demographics of the African American population. In Latin America, relatively high frequencies are seen in the Caribbean, Panama, Guyana, and Brazil, but not in Mexico and most of South America. A high incidence of sickle genes, apparently resulting from independent mutational events, is found in Italy, Greece, the Middle East, and India.


Pathophysiology

In Hb S, a valine residue is substituted for the usual glutamic acid in the chains of the hemoglobin molecule. When Hb S becomes deoxygenated, polymerization occurs, with the formation of long, crystalline tactoids. These ultimately form elongated, sickled erythrocytes. Sickled erythrocytes have markedly shortened survival, and they can obstruct small blood vessels and can cause distal tissue ischemia and necrosis.

Heterozygosity for a sickle gene has a benign clinical course. Approximately 8% of African Americans have the trait. The sickle gene is thought to confer a degree of resistance to falciparum malaria during infancy in endemic areas. The erythrocytes in sickle trait contain only 30% to 40% Hb S, and sickling does not occur under physiologic conditions. Rarely, hypoxia resulting from shock or from flying at high altitudes in an unpressurized aircraft may produce vasoocclusive phenomena. Unexpected death has also been observed in military recruits during the extreme exertion of basic training. Spontaneous hematuria, usually from the left kidney, and mild hyposthenuria also occur. Anemia or hemolysis should not be attributed to the sickle trait.

In persons homozygous for the sickle gene, sickle cell anemia is a severe, chronic hemolytic anemia. The clinical course is marked by episodes of pain caused by occlusion of small blood vessels by the spontaneously sickled erythrocytes. These events have traditionally been called crises (Table 290.1).








TABLE 290.1. CLINICAL CRISES SEEN IN PATIENTS WITH SICKLE CELL DISEASE






























Crisis Designation Cause Treatment
Pain crisis Vaso-occlusion of small vessels, frequently Hydration, narcotics
Hand-foot syndrome (dactylitis) Infarcts of small bones in hands, frequently seen in infancy Hydration, narcotics
Sequestration crisis Acute trapping of red cells in spleen, causing an abrupt fall in blood volume and red cell mass Transfusion, often exchange transfusion, oxygen and splenectomy as last resort
Acute chest crisis Vasoocclusion of pulmonary vessels leading to an often severe pulmonary process Hydration, oxygen, narcotics, antibiotics, positive-pressure ventilation if necessary
Acute hemolytic crisis Rapid and unpredictable increase in hemolysis leading to rapid fall in hemoglobin Transfusion, oxygen, exchange transfusion may be necessary
Aplastic crisis Infection with parvovirus B19 causing severe reticulocytopenia Transfusion if necessary



Clinical Manifestations

Manifestations of sickle cell disease usually do not appear until the second 6 months of life, coincident with the postnatal decrease in fetal hemoglobin (Hb F) and an increase in Hb S. The hemolytic process is evident by 6 months of age.

The painful or vasoocclusive crises are the most frequent clinical symptoms. Symmetric, painful swelling of the hands and feet (i.e., hand-foot syndrome) caused by infarction of the small bones of the hands and feet may be the initial manifestation of sickle cell anemia in infancy. Older patients may have painful involvement of the larger bones and joints and severe abdominal pain resembling acute surgical conditions. Strokes may leave permanent paralysis as well as more subtle neurologic damage. Extensive pulmonary consolidation occurs, and it is difficult to differentiate infarction from pneumonia. Vasoocclusive crises usually are not associated with changes in the hematologic picture at baseline.

A second type of crisis, seen only in young infants and children, is called the sequestration crisis. Large amounts of blood become pooled in the abdominal organs. The spleen becomes massively enlarged, and signs of circulatory collapse develop rapidly. If volume replacement is given, much of the sequestered blood is remobilized. The sequestration crisis is an important cause of death in infants with sickle cell disease.

The third well-characterized type of crisis is the aplastic crisis, which results from erythroblast maturation arrest caused by parvovirus B19 infection (see Chapter 192). Parvovirus B19 causes generally a brief, self-limited illness in patients with sickle cell disease. Rarely, it can persist for weeks, but generally it resolves in a few days, although the reticulocytopenia may persist for several weeks in some patients.

In addition to these acute crises, various clinical signs and symptoms result from chronic severe hemolytic anemia and vasoocclusive disease. Impairment of liver function contributes to the jaundice of these patients. Gallstones can occur in children as young as 3 years. Renal function is progressively impaired by diffuse glomerular and tubular fibrosis, resulting in hyposthenuria and polyuria.

As many as 30% of children with sickle cell anemia develop pneumococcal sepsis during the first 5 years of life. The increased risk is a result of functional hyposplenia and low levels of specific serum antibodies. Increased susceptibility to Salmonella osteomyelitis is also a feature of sickle cell disease.

By middle childhood, most patients are underweight, and puberty is delayed, particularly in boys. Chronic leg ulcers are common in adolescence and early adult life. The median life span for patients with sickle cell disease ranges from 40 to 60 years. Causes of death include infection, acute chest crisis, and stroke.


Laboratory Findings

Hemoglobin levels range from 5 to 9 g/dL. Peripheral blood smears show irreversibly sickled cells, a finding almost diagnostic of homozygous sickle cell disease (Fig. 290.1). The reticulocyte count ranges from 5% to 15%, and nucleated erythrocytes and Howell-Jolly bodies are usually observed. The total leukocyte count is elevated (12,000 to 20,000/μL), with a predominance of neutrophils. The platelet count is increased, and the sedimentation rate is slow. Other changes include abnormal liver function test results, hyperbilirubinemia, and diffuse hypergammaglobulinemia. The bone marrow shows erythroid hyperplasia.

Diagnostic studies to demonstrate Hb S include the sickle cell preparation and hemoglobin solubility studies. However, hemoglobin electrophoresis is more conclusive and is necessary for a precise diagnosis. After infancy, the erythrocytes of patients with sickle cell anemia contain approximately 90% Hb S, 2% to 10% Hb F, and a normal amount of Hb A2; they do not contain Hb A.

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Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Hemoglobinopathies and Thalassemias

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