Chapter 16: The Sickle Cell Diseases and Related Disorders

• The molecular biology of hemoglobinopathies is well understood, but clinical progress in treatment has been limited. The vast majority of hemoglobinopathies are the result of single-nucleotide substitutions in the α, β, δ, or γ chains within the hemoglobin (Hb) tetramer.

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

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

• The term sickle cell disorder describes states in which sickling of red cells occurs on deoxygenation, not the genotype (ie, Hb SS, S/beta thal, SE).

• Hb S homozygosity (Hb SS), Hb SC, sickle cell–β thalassemia, and Hb 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.

Hemoglobin Polymerization

• The Hb S mutation is the result of the substitution of valine for glutamic acid at position 6 in the β chain. Hb S polymerization is the central event in disease pathophysiology.

• 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 the endothelium.

• The sickling process is initially reversible, but repeated sickling and unsickling leads to irreversibly sickled cells because of 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 Hb concentration (mean cell hemoglobin concentration, MCHC), presence of Hb other than Hb S that may interfere with the rate or degree of polymerization of Hb S (eg, Hb F), blood oxygen tension, pH, temperature, and 2,3-biphosphoglycerate levels.

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

Other Pathways that are Key to the Pathophysiology of Sickle Cell Disease

• NO (nitric oxide) has vasodilatory, anti-inflammatory, and platelet aggregation effects. Chronic hemolysis releases free Hb into the circulation, which results in NO scavenging with consequent endothelial dysfunction and enhanced adhesion of sickled red cells.

• Several adhesion molecules and proinflammatory mediators (eg, tumor necrosis factor-alpha) are upregulated.

• Inflammatory stimuli lead to neutrophil, monocyte, and endothelial activation with increased white cell–red cell adhesion resulting in increased vaso-occlusion. Neutrophilia is an independent adverse prognostic factor in sickle cell anemia.

• Coagulation system is activated, and increased levels of tissue factor are present. Ischemia reperfusion injury with increased levels of reactive oxygen species occurs due to repeated vaso-occlusion followed by restoration of blood flow. Cation homeostasis is impaired because of red cell membrane injury, causing cellular dehydration and consequently increased intracellular Hb concentration. Some clinical findings such as isosthenuria in individuals with sickle cell trait are the result of this phenomenon. Abnormal adenosine signaling via the adenosine A2B receptor results in increased sickling, which may be key to clinical manifestations, such as priapism. Signaling through the adenosine A_2A receptor pathway of leukocytes and platelets results in an anti-inflammatory effect, which is being explored as a therapeutic strategy.

Inheritance

• Patients homozygous for the Hb S gene have inherited one gene from each parent. Because 8% of Americans of African ancestry have sickle trait, about 1 in 500 Americans of African descent are born with the Hb SS genotype.

• Occurrence of Hb SS disease can theoretically be prevented by detection of carriers and counseling regarding birth control or elective interruption of pregnancies with fetuses that are homozygous for Hb 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%. A geographic association with areas of high malaria prevalence has been determined to represent a lessened risk of developing falciparum malaria in heterozygotes. This enhanced resistance to malaria is considered the reason for the persistent high prevalence of the mutation, given the lethality of the homozygous state in Africans.

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

• High levels of Hb F 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 among 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. These occur with a frequency from almost daily to yearly; however, 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. Because red 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 and rarely in older children and adults with an enlarged spleen in sickle cell diseases, more likely in those other than Hb SS (eg, Hb SC). There is a sudden massive pooling of red 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. It is a leading cause of mortality from sickle cell disorders.

• 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. Pulmonary hypertension defined by right heart catheterization, elevated tricuspid regurgitant jet velocity of greater than or equal to 2.5 m/s and an elevated N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) level of greater than or equal to 160 pg/mL confer an increased mortality risk.

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

• Tachycardia and high-output cardiac (flow) murmurs are commonly seen, especially during vaso-occlusive episodes.

Central Nervous System

• Thrombotic 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. Older adults may have increased risk of hemorrhagic stroke.

• The best predictor for thrombotic 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 greater than 200 cm/s should be offered a chronic red cell transfusion program for primary stroke prevention. A strategy of switching to hydroxyurea after a year of transfusion along with phlebotomy to reduce iron overload appears to be noninferior to indefinite transfusion for primary stroke prevention. Silent brain infarcts, defined as an abnormal T2 signal on magnetic resonance imaging (MRI), begin in infancy and progress during childhood. They may occur despite chronic transfusion therapy. Neurocognitive decline secondary to anemia and hypoxemia occur even in those with a normal brain MRI.

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 Hb SS disease, whereas nocturnal enuresis is prevalent in approximately 30% of the adolescent sickle cell disease 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.

Musculoskeletal System

• Young children with Hb 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, because hematopoietic marrow is still present in the bones of the hand and feet. In adults, avascular necrosis occurs chiefly in the femoral and humeral heads. About 50% of adults with sickle cell anemia will have femoral head avascular necrosis by age 33. Chronic transfusion and hydroxyurea do not impact incidence of avascular necrosis; joint replacement is needed in advanced cases. Osteopenia, osteoporosis and fractures of long bones are prevalent and likely under-reported.

Spleen

• In Hb SS disease, splenomegaly (but poor splenic function) in childhood is followed by repeated infarction, leaving a small fibrotic spleen in the adult (autosplenectomy). However, splenomegaly usually persists in patients with Hb 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 (hepatic sequestration crisis).

• Gallstones are seen in 50% to 75% 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 are being recognized increasingly in adults with sickle cell disease; they develop in patients who have been transfused repeatedly (see Chap. 9).

Eye

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

Leg Ulcers

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

Infection

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

Pregnancy

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

• Complications to the 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. Given insufficient data, contraception advice is similar to that of the non–sickle cell disease population. Routine transfusion has not been shown to be beneficial; transfusion should be undertaken for Hg of less than 6 g/dL, given an increased risk of abnormal fetal oxygenation and fetal death reported in the non–sickle cell disease population.

Laboratory Features

• The Hg 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 (Figure 16–1).

• 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 by functional asplenia.

• Elevation in whole body iron burden is common; however, clinically significant hemochromatosis is rare.

• Hb electrophoresis is utilized to detect Hb S. Hb A₂ and often Hb F are particularly increased in patients with sickle cell–β thalassemia; however, many laboratories cannot accurately measure Hb A₂ in the presence of Hb S. Despite high levels of Hb F at birth, electrophoresis can detect Hb 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 5 years. Penicillin prophylaxis beyond age 5 may be considered in patients with a surgical splenectomy and those with recurrent pneumococcal infections. Infections should be identified and treated early.

Specific Measures

• Hydroxyurea

  — Chronic administration at a starting dose of 15 mg/kg orally per day has been shown to decrease the incidence and severity of painful crises. Therefore, it should be considered for patients with frequent and severe crises or occurrence of other disease manifestations, including acute chest syndrome. Therapy is associated with improved survival, and this agent is underutilized in sickle cell disease patients. Therapy may be safely given to infants as young as 6 months of age. The dose may be escalated to 35 mg/kg with careful monitoring of blood counts; caution should be exercised in those with renal failure. The drug is held during pregnancy, although no teratogenic or leukemogenic effect has been observed to date. The precise mechanism of the hydroxyurea effect is uncertain. It was used initially to increase red cell Hb 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 β to γ Hb chains, resulting in higher Hb F in the cells.

• Allogeneic hematopoietic stem cell transplantation

  — This is the only curative treatment for sickle cell disease, but because of the attendant risks, including death, it is suitable only for carefully selected patients with a human leukocyte antigen (HLA)–matched donor.

• Red cell transfusion

  — This treatment is 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).

  — Transfusions for chronic asymptomatic anemia or routine vaso-occlusive episodes should be avoided.

  — Typical indications include acute chest syndrome, stroke prevention or treatment, aplastic and sequestration crises, multiorgan failure, and transfusion prior to surgery.

Management of Complications

• Patients in vascular crises should be kept warm and given adequate hydration and pain control; oxygen is beneficial only for hypoxic patients. Overhydration should be avoided. 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. Transfusion has been shown to decrease the risk of clinically significant complications.

• The acute chest syndrome is a life-threatening complication, and exchange transfusions or red cell transfusions appear beneficial along with adequate pain control, bronchodilators, antibiotics (include coverage of atypical organisms), and incentive spirometry.

• 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 Hb S levels below 30%. 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. Transfusion should follow general guidelines for sickle cell disease; prophylactic transfusions are undertaken for Hg of less than 6 g/dL.

• 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. Iron overload is managed by iron chelators: desferrioxamine given subcutaneously at a dose of 25 to 40 mg/kg per day or deferasirox given orally at a dose of 20 to 40 mg/kg per day. Auditory and ophthalmologic examinations should be performed at least annually while on iron chelation therapy; because deferasirox carries a risk of renal failure and hepatic damage, hepatic and renal function should be monitored closely.

• In sickle cell trait, less than half of the Hb in each red blood cell is Hb S (approximately 40%) and the rest is normal Hb, 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 quantify.

• Individuals with sickle cell trait are at increased risk of sudden death and splenic infarction under severe environmental conditions. Hyposthenuria, renal papillary necrosis causing microscopic or gross hematuria, and rarely renal medullary carcinoma can be seen. There is an increased risk of venous thromboembolism as well.

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

• In the homozygous state, most of the Hb in the cell is Hb C, the red blood cells are more rigid than normal, and intracellular crystals of Hb 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 (Hb C trait), which is asymptomatic, is approximately 2%.

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

• The highest prevalence is in northwest India (2%–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. Hb D-β thalassemia is also rare.

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

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

• Hb 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 Hg molecules 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. 17, 18, and 27.