Chapter 17: The Sickle Cell Diseases and Related Disorders

• The molecular biology of these hemoglobinopathies is well understood, but clinical progress in treatment has been limited.

• Hemoglobin variants were initially designated by letter, but after the letters of the alphabet were exhausted, newly identified variants were named according to the place in which they were first found. If they had a particular feature previously described by a letter, the location was added as a subscript (e.g., Hb M_Saskatoon).

• In a fully characterized hemoglobin variant, the amino acid position and change is described in a superscript to the appropriate globin chain (e.g., Hb S, α₂ β₂^6Glu-Val).

• The term sickle cell disorder describes states in which sickling of red cells occurs on deoxygenation.

• Sickle cell anemia (Hb SS), hemoglobin SC, sickle cell–β thalassemia, and hemoglobin SD produce significant morbidity and are therefore designated sickle cell diseases. These diseases are marked by periods of relative well-being interspersed with episodes of illness, but the severity of clinical manifestations varies widely among patients. Generally, sickle cell anemia is the most severe, but there is considerable overlap in clinical behavior among these diseases.

• Hb E might be the most prevalent abnormal hemoglobin and is found principally in Burma, Thailand, Laos, Cambodia, Malaysia, and Indonesia.

Hemoglobin Polymerization

• The hemoglobin S mutation is the result of the substitution of valine for glutamic acid at position 6 in the β chain.

• Molecules of deoxyhemoglobin S have a strong tendency to aggregate and form polymers. Polymer formation alters the biophysical properties of the red cells, making them much less deformable and adherent to endothelium.

• The sickling process is initially reversible, but repeated sickling and unsickling leads to irreversibly sickled cells due to membrane damage.

• Sickle cells lead to vascular stasis, tissue damage, and increase in microvascular blood viscosity.

• Susceptibility to sickling is dependent on several factors including intracellular hemoglobin concentration, presence of hemoglobins other than hemoglobin S (e.g., Hg F), blood oxygen tension, pH, temperature, and 2,3-BPG levels.

• Cellular dehydration (such as in the hyperosmolar milieu in renal papillae) increases sickling by increasing the concentration of intracellular hemoglobin, and some of the clinical findings of sickle trait individuals, such as inability to concentrate urine and rarely hematuria, are to the result of this phenomenon.

• Some protection against sickling is conferred by elevated hemoglobin F levels; apparently a threshold phenomenon exists, so that there is no effect beneath a certain level of hemoglobin F.

• In the microvasculature, flow is affected by the rigidity of the sickled cells and adherence to the endothelium. Shear stresses in higher flow areas can break down the gel structure of hemoglobin S. Because the duration of hypoxia is also important, areas of vascular stasis (such as the spleen) with lower oxygen tension are particularly prone to vascular occlusion and infarction. Most patients with sickle cell anemia have splenic atrophy from multiple infarctions by early adulthood.

Nitric Oxide Scavenging and Other Factors Involved in Pathophysiology of Sickle Cell Disease

• NO (nitric oxide) has vasodilatory, antiinflammatory, and platelet aggregation effects.

• Chronic hemolysis with release of free hemoglobin into the circulation leads to scavenging of NO with endothelial dysfunction and increased sickle cell adherence.

• Several adhesion molecules and pro-inflammatory mediators (e.g., TNF-α) are up-regulated.

• Inflammatory stimuli lead to neutrophil, monocyte and endothelial activation with increased white cell-red cell adhesion resulting in increased vaso-occlusion.

• Coagulation system is also activated.

Inheritance

• Patients with sickle cell anemia are homozygous for the sickle hemoglobin gene and have inherited one gene from each parent. Because 8 percent of Americans of African ancestry have sickle trait, about 1 in 500 Americans of African descent are born with the sickle cell anemia genotype.

• Occurrence of sickle disease can theoretically be prevented by detection of carriers and counseling regarding birth control or elective interruption of pregnancies with fetuses that are homozygous from hemoglobin S.

• Although the sickle cell gene is found in a variety of areas (Middle East, Greece, India), its greatest prevalence is in tropical Africa, with heterozygote frequency as high as 40 percent. A geographic association with areas of high malaria prevalence suggests an advantage to individuals with sickle cell trait, and it appears that this advantage is enhanced resistance to falciparum malaria.

• The manifestations of all sickle cell diseases are sufficiently similar that they are discussed together here.

• High levels of fetal hemoglobin protect against sickling for the first 8 to 10 weeks of life; thereafter, the manifestations of sickle cell disease may become apparent.

• There is great variability between affected individuals, but many patients are in good health most of the time.

• In children, most problems are related to pain, infection, or inflammation. In adults, clinical manifestations are likely to be more chronic, related to organ damage.

Crises

• Vaso-occlusive or painful crises are the most common manifestation, occurring with a frequency from almost daily to yearly while some affected individuals never have a painful crisis. Tissue hypoxia and infarction can occur anywhere in the body. It is important to carefully evaluate the patient to distinguish between painful crises and pain caused by another process.

• Aplastic crises occur when erythropoiesis is suppressed. As red blood cell survival is greatly shortened in sickle cell disease, even temporary reduction in erythropoiesis is rapidly manifested by a dramatic fall in blood hemoglobin concentration. Infection (most notably parvovirus B19) usually causes this type of crisis, but it may also result from folic acid deficiency, which is of particular concern during pregnancy.

• Sequestration crises occur in infants or rarely in older children, and in the occasional adult with an enlarged spleen. There is a sudden massive pooling of red blood cells in the spleen; this can cause hypotension and even death.

• Hyperhemolytic episodes occur uncommonly as a result of enhanced hemolysis in certain conditions, such as resolution phase of vaso-occlusive crisis where irreversibly sickled red cells are rapidly destroyed.

Other Clinical Manifestations

Cardiopulmonary System

• The "acute chest syndrome" consists of fever, leukocytosis, and a new pulmonary infiltrate. Infections or pulmonary fat microembolization are the two common causes of the acute chest syndrome.

• Chronic pulmonary hypertension is another common manifestation in adult sickle cell disease patients. The likely reasons are NO scavenging, increased reactive oxygen species, increased arginase activity, and increased platelet activation.

• Asthma, abnormal pulmonary function tests, and airway hyperreactivity are other pulmonary presentations.

• In vaso-occlusive crisis, tachycardia and high-output cardiac (flow) murmurs are commonly seen.

Central Nervous System

• Strokes occur more commonly in children, usually without warning. Risk is highest during first decade of life. Recurrence is common (in at least two-thirds), usually within 3 years.

• The best predictor for stroke risk is an increased blood flow velocity in major intracranial arteries on transcranial Doppler (TCD) ultrasound.

• Patients with two abnormal readings defined as TCD velocities > 200 cm/sec should be offered a chronic red cell transfusion program for primary stroke prevention.

Genitourinary System

• The environment of the renal medulla (hyperosmolar, hypoxic) predisposes to sickling. Hyposthenuria, papillary necrosis, and hematuria are commonly present.

• Priapism is most commonly seen in hemoglobin SS disease, while nocturnal enuresis is prevalent in approximately 30 percent of the adolescent sickle cell population.

• The prevalence of microalbuminuria and proteinuria increases with age. Infants with sickle cell disease have glomerular hyperfiltration. This may evolve into microalbuminuria, proteinuria, and to chronic kidney disease/end-stage renal disease in some.

Musculoskeletal System

• Young children with hemoglobin SS tend to be short. Puberty is delayed, but growth occurs in late adolescence and adults are of normal size.

• Erythroid hyperplasia in the marrow results in widening of the medullary spaces and thinning of the cortex. The vertebral bodies may show biconcavities on the upper and lower surface (codfish spine).

• Bone infarctions can be followed by periosteal reaction and areas of osteosclerosis. Dactylitis occurs in children, usually up to 4 years of age, probably related to avascular necrosis. In adults, avascular necrosis occurs chiefly in the femoral and humeral heads; joint replacement is occasionally required.

Spleen

• In hemoglobin SS disease, splenomegaly (but poor splenic function) in childhood is followed by repeated infarction, leaving a small fibrotic spleen in the adult (auto-splenectomy). However, splenomegaly usually persists in patients with hemoglobin SC, SE, or sickle β-thalassemia.

Hepatobiliary System

• About one-third of sickle cell disease patients will manifest hepatic dysfunction of multifactorial origin.

• Sickle cell–induced cholestasis can be very serious and even fatal, although exchange transfusion has been reported as an effective treatment.

• Hepatitis may develop from transfusions, usually in regions in which testing for hepatitis B and C virus in blood is not performed fastidiously.

• The liver, sometimes chronically enlarged, can also enlarge transiently during a painful crisis.

• Gallstones are seen in 50 to 75 percent of adults; they have been seen in children as young as 6 years of age. Although there is some debate, patients with asymptomatic cholelithiasis probably should not be subjected to surgery.

Iron Overload

• Organ effects from iron overload is being recognized increasingly in adults with sickle cell disease; it develops in patients who have been transfused repeatedly.

Eye

• Neovascularization occurs after obstruction of retinal vessels, resulting in a proliferative retinopathy; however, spontaneous regression can occur in up to 60 percent of cases. Laser coagulation can prevent this complication. This is more common in hemoglobin SC disease than in hemoglobin SS disease.

Leg Ulcers

• Leg ulcers occur with varying frequency in adults and are related to multiple factors (low blood hemoglobin concentration, brisk hemolysis, stasis). They typically occur on lower extremity with the medial malleolus area being more likely affected than the lateral malleolus.

Infection

• Children less than 5 years of age are susceptible to infection by encapsulated organisms due to functional asplenia.

Pregnancy

• Complications to mother include increased frequency sickle cell painful crises, preeclampsia, and infections.

• Complications to fetus include miscarriage, intrauterine growth restriction, preterm birth, low birth weight, and stillbirth and newborn death.

• Oral contraceptives may slightly increase the risk of thromboembolism, but this is less of a risk than pregnancy.

Laboratory Features

• The hemoglobin level is usually between 5 and 11 g/dL. Anemia is normochromic and normocytic, but considerable variation in red cell size and shape is noted. Sickled cells and target cells are seen on the blood film; reticulocytosis is almost always present (see Fig. 17–1).

• Leukocytosis and thrombocytosis are common, even in patients without acute problems; these may be caused by a reactive marrow along with demargination of peripheral leukocytes, and possibly contributed by functional asplenia.

• Modest elevations in whole body iron burden are common; however, hemochromatosis is rare.

• Hemoglobin electrophoresis is utilized to detect hemoglobin S. Hemoglobins A₂ and often F are particularly increased in patients with sickle cell–β thalassemia; however, many laboratories cannot accurately measure hemoglobins A₂ in the presence of hemoglobin S. Despite high levels of hemoglobin F at birth, electrophoresis can detect hemoglobin S in the newborn.

• Prenatal diagnosis is performed by examining DNA from a chorionic villus biopsy or from cells obtained at amniocentesis.

Nonspecific Measures

• The administration of folic acid may be useful. Pneumococcal vaccine should be given to children and to those adults who have not received it. Penicillin prophylaxis is administered up to the age of 6 years. Infections should be identified and treated early.

Specific Measures

• Hydroxyurea

  — Chronic administration at a starting dose of 15 mg/kg per day has been shown to decrease the incidence of painful crises, and should therefore be considered for patients with frequent and severe crises; therapy may be associated with improved survival, and this agent is underutilized in sickle cell disease. The precise mechanism of the hydroxyurea effect is uncertain. It was used initially to increase red cell hemoglobin F, but this does not occur in most sickle cells in treated patients and is quantitatively modest. The drug decreases the neutrophil concentration in the blood. Neutrophils play a key role in fostering sickle cell crisis. Both effects may play a role. Other agents are being studied that can encourage the switch from beta to gamma hemoglobin chains, resulting in higher hemoglobin F in the cells.

• Allogeneic hematopoietic stem cell transplantation

  — Only curative treatment for sickle cell disease, but because of the attendant risks, including death, it is suitable only for carefully selected patients with an HLA-matched donor.

• Red cell transfusion

  — Used frequently in sickle cell disease to increase hemoglobin concentration and to decrease the proportion of sickle cells in the blood. Chronic red cell transfusion therapy has been conclusively demonstrated to prevent strokes. See Chap. 91 for considerations of chronic red cell transfusion therapy.

Management of Complications

• Patients in vascular crises should be kept warm and given adequate hydration and pain control; oxygen may be beneficial only for hypoxic patients. The period of crisis usually resolves in hours to days. Hydroxyurea therapy (see "Specific Measures," above) may be considered for prevention or decreased frequency of recurrences.

• Patients undergoing anesthesia are at increased risk for a crisis and should be observed closely for development of hypoxia or acidosis, which could precipitate a crisis.

• The acute chest syndrome is a life-threatening complication, and exchange transfusions or red cell transfusions appear beneficial.

• Because strokes in children are a recurring complication, vigorous therapy of children who have had this complication is recommended. A regular transfusion program is instituted to reduce hemoglobin S levels below 30 percent. Hematopoietic stem cell transplantation can be considered for children with an HLA-matched sibling.

• Priapism, if recent, should be treated immediately by rapid hydration, red cell transfusion, and analgesia for a short period of observation, while awaiting an urgent urologic consultation. If unsuccessful, urologic intervention, usually by injection of a dilute solution of epinephrine into the corpus cavernosum, can be performed. This approach has a high frequency of success and preserves penile function. Surgical procedures, such as shunts, should be avoided if at all possible. Maintenance therapy with an oral α-adrenergic blocker, such as phenylephrine, can be used.

• Patients should be closely watched during pregnancy; prophylactic transfusions have been given, but it is doubtful whether they are of benefit. Low birth weight and increased fetal loss are probably related to placental vascular occlusions.

• Bed rest, elevation, and zinc sulfate dressings are used to treat leg ulcers. A transfusion program or skin grafting can enhance healing. Often, they are quite resistant to therapeutic measures and require a long time to heal.

• In sickle cell trait, less than half of the hemoglobin in each red blood cell is hemoglobin S (approximately 40%) and the rest is normal hemoglobin, principally A. This effectively protects against sickling except under special circumstances, such as severe hypoxia or the hyperosmolarity encountered in the renal circulation.

• Numerous anecdotal reports suggest that sickle cell trait may be injurious, but the morbidity and mortality are extremely low and difficult to quantitate.

• A slightly higher incidence of concentrating defect, hyposthenuria, hematuria, and pulmonary embolus has been documented in persons with sickle cell trait.

• Glutamic acid in the sixth position of the β chain is replaced by lysine in hemoglobin C.

• In the homozygous state, most of the hemoglobin in the cell is hemoglobin C, the red blood cells are more rigid than normal, and intracellular crystals of hemoglobin C are found; target cells are numerous. In addition, a population of spherocytes is a characteristic finding.

• In Americans of African descent, the prevalence of the heterozygous state (hemoglobin C trait), which is asymptomatic, is approximately 2 percent.

• Splenomegaly and mild hemolytic anemia are almost always present in the homozygous state. Some patients develop bilirubin gallstones.

• No treatment is required and the prognosis is excellent.

• These hemoglobin variants have normal solubility but migrate like hemoglobin S on electrophoresis.

• The highest prevalence is in northwest India (2 to 3%).

• The heterozygous state as well as the homozygotes are asymptomatic with normal red cell indices.

• Hemoglobin SD occurs rarely and presents as severe sickle cell disease. Hemoglobin D-β thalassemia is also rare.

• A β-chain mutation (β^26Glu-Lys) results in hemoglobin designated hemoglobin E. Some of the hemoglobin E mRNA undergoes alternative splicing, giving rise to a thalassemia-like picture.

• This is a relatively common abnormal hemoglobin in Southeast Asia.

• Hemoglobin E trait is asymptomatic, but mild microcytosis occurs.

• In association with β thalassemia, a moderate anemia and splenomegaly are present; splenectomy may be considered in this setting.

• Homozygous patients have been described; they have microcytosis and mild anemia.

• Many other abnormal hemoglobins have been described; most are uncommon and of no clinical significance. Others can produce cyanosis because of a low oxygen affinity, erythrocytosis because of a high oxygen affinity, or a hemolytic anemia because of instability. These are described in Chaps. 18, 19, and 29.