The sickle cell syndromes are caused by a mutation in the β-globin gene that changes the sixth amino acid from glutamic acid to valine. HbS (α2β26 Glu→Val) polymerizes reversibly when deoxygenated to form a gelatinous network of fibrous polymers that stiffen the RBC membrane, increase viscosity, and cause dehydration due to potassium leakage and calcium influx (Fig. 127-3). These changes also produce the sickle shape. Sickled cells lose the pliability needed to traverse small capillaries. They possess altered “sticky” membranes that are abnormally adherent to the endothelium of small venules. These abnormalities provoke unpredictable episodes of microvascular vasoocclusion and premature RBC destruction (hemolytic anemia). Hemolysis occurs because the spleen destroys the abnormal RBC. The rigid adherent cells clog small capillaries and venules, causing tissue ischemia, acute pain, and gradual end-organ damage. This venoocclusive component usually dominates the clinical course. Prominent manifestations include episodes of ischemic pain (i.e., painful crises) and ischemic malfunction or frank infarction in the spleen, central nervous system, bones, joints, liver, kidneys, and lungs (Fig. 127-3).
Pathophysiology of sickle cell crisis.
Several sickle syndromes occur as the result of inheritance of HbS from one parent and another hemoglobinopathy, such as β thalassemia or HbC (α2β26 Glu→Lys), from the other parent. The prototype disease, sickle cell anemia, is the homozygous state for HbS (Table 127-2).
TABLE 127-2Clinical Features of Sickle Hemoglobinopathies ||Download (.pdf) TABLE 127-2Clinical Features of Sickle Hemoglobinopathies
|Condition ||Clinical Abnormalities ||Hemoglobin Level, g/L (g/dL) ||MCV, fL ||Hemoglobin Electrophoresis |
|Sickle cell trait ||None; rare painless hematuria ||Normal ||Normal ||HbS/A: 40/60 |
|Sickle cell anemia ||Vasoocclusive crises with infarction of spleen, brain, marrow, kidney, lung; aseptic necrosis of bone; gallstones; priapism; ankle ulcers ||70–100 (7–10) ||80–100 || |
|S/β° thalassemia ||Vasoocclusive crises; aseptic necrosis of bone ||70–100 (7–10) ||60–80 || |
|S/β+ thalassemia ||Rare crises and aseptic necrosis ||100–140 (10–14) ||70–80 ||HbS/A: 60/40 |
|Hemoglobin SC ||Rare crises and aseptic necrosis; painless hematuria ||100–140 (10–14) ||80–100 || |
Clinical Manifestations of Sickle Cell Anemia
Most patients with sickling syndromes suffer from hemolytic anemia, with hematocrits from 15 to 30%, and significant reticulocytosis. Anemia was once thought to exert protective effects against vasoocclusion by reducing blood viscosity. However, natural history and drug therapy trials suggest that an increase in the hematocrit and feedback inhibition of reticulocytosis might be beneficial, even at the expense of increased blood viscosity. The role of adhesive reticulocytes in vasoocclusion might account for these paradoxical effects.
Granulocytosis is common. The white count can fluctuate substantially and unpredictably during and between painful crises, infectious episodes, and other intercurrent illnesses.
Vasoocclusion causes protean manifestations. Intermittent episodes of vasoocclusion in connective and musculoskeletal structures produce ischemia manifested by acute pain and tenderness, fever, tachycardia, and anxiety. These recurrent episodes, called painful crises, are the most common clinical manifestation. Their frequency and severity vary greatly. Pain can develop almost anywhere in the body and may last from a few hours to 2 weeks. Repeated crises requiring hospitalization (>3 episodes per year) correlate with reduced survival in adult life, suggesting that these episodes are associated with accumulation of chronic end-organ damage. Provocative factors include infection, fever, excessive exercise, anxiety, abrupt changes in temperature, hypoxia, or hypertonic dyes.
Repeated microinfarction can destroy tissues having microvascular beds prone to sickling. Thus, splenic function is frequently lost within the first 18–36 months of life, causing susceptibility to infection, particularly by pneumococci. Acute venous obstruction of the spleen (splenic sequestration crisis), a rare occurrence in early childhood, may require emergency transfusion and/or splenectomy to prevent trapping of the entire arterial output in the obstructed spleen. Occlusion of retinal vessels can produce hemorrhage, neovascularization, and eventual detachments. Renal papillary necrosis invariably produces isosthenuria. More widespread renal necrosis leads to renal failure in adults, a common late cause of death. Bone and joint ischemia can lead to aseptic necrosis, especially of the femoral or humeral heads; chronic arthropathy; and unusual susceptibility to osteomyelitis, which may be caused by organisms, such as Salmonella, rarely encountered in other settings. The hand-foot syndrome is caused by painful infarcts of the digits and dactylitis. Stroke is especially common in children; a small subset tends to suffer repeated episodes. Stroke is less common in adults and is often hemorrhagic. A particularly painful complication in males is priapism, due to infarction of the penile venous outflow tracts; permanent impotence is a frequent consequence. Chronic lower leg ulcers probably arise from ischemia and superinfection in the distal circulation.
Acute chest syndrome is a distinctive manifestation characterized by chest pain, tachypnea, fever, cough, and arterial oxygen desaturation. It can mimic pneumonia, pulmonary emboli, bone marrow infarction and embolism, myocardial ischemia, or in situ lung infarction. Acute chest syndrome is thought to reflect in situ sickling within the lung, producing pain and temporary pulmonary dysfunction. Often it is difficult or impossible to distinguish among other possibilities. Pulmonary infarction and pneumonia are the most frequent underlying or concomitant conditions in patients with this syndrome. Repeated episodes of acute chest pain correlate with reduced survival. Acutely, reduction in arterial oxygen saturation is especially ominous because it promotes sickling on a massive scale. Chronic acute or subacute pulmonary crises lead to pulmonary hypertension and cor pulmonale, an increasingly common cause of death as patients survive longer. Considerable controversy exists about the possible role played by free plasma HbS in scavenging nitrogen dioxide (NO2), thus raising pulmonary vascular tone. Trials of sildenafil to restore NO2 levels were terminated because of adverse effects.
Chronic subacute central nervous system damage in the absence of an overt stroke is a distressingly common phenomenon beginning in early childhood. Modern functional imaging techniques have pinpointed circulatory dysfunction due to a likely CNS sickle vasculopathy; these changes correlate with an array of cognitive and behavioral abnormalities in children and young adults. It is important to be aware of these often subtle changes because they can complicate clinical management or be misinterpreted as “difficult patient” behaviors.
Sickle cell syndromes are remarkable for their clinical heterogeneity. Some patients remain virtually asymptomatic into or even through adult life, while others suffer repeated crises requiring hospitalization from early childhood. Patients with sickle thalassemia and sickle-HbE tend to have similar, slightly milder symptoms, perhaps because of the ameliorating effects of production of other hemoglobins within the RBC. Hemoglobin SC disease, one of the more common variants of sickle cell anemia, is frequently marked by lesser degrees of hemolytic anemia and a greater propensity for the development of retinopathy and aseptic necrosis of bones. In most respects, however, the clinical manifestations resemble sickle cell anemia. Some rare hemoglobin variants actually aggravate the sickling phenomenon.
The clinical variability in different patients inheriting the same disease-causing mutation (sickle hemoglobin) has made sickle cell disease the focus of efforts to identify modifying genetic polymorphisms in other genes that might account for the heterogeneity. The complexity of the data obtained thus far has dampened the expectation that genome-wide analysis will yield individualized profiles that predict a patient's clinical course. Nevertheless, a number of interesting patterns have emerged from these modifying gene analyses. For example, genes affecting the inflammatory response or cytokine expression appear to be modifying candidates. Genes that affect transcriptional regulation of lymphocytes may also be involved.
Clinical Manifestations of Sickle Cell Trait
Sickle cell trait is often asymptomatic. Anemia and painful crises are rare. An uncommon but highly distinctive symptom is painless hematuria often occurring in adolescent males, probably due to papillary necrosis. Isosthenuria is a more common manifestation of the same process. Sloughing of papillae with urethral obstruction has been reported, as have isolated cases of massive sickling or sudden death due to exposure to high altitudes or extremes of exercise and dehydration. Avoidance of dehydration or extreme physical stress should be advised.
Sickle cell syndromes are suspected on the basis of hemolytic anemia, RBC morphology (Fig. 127-4), and intermittent episodes of ischemic pain. Diagnosis is confirmed by hemoglobin electrophoresis, mass spectroscopy, and the sickling tests already discussed. Thorough characterization of the exact hemoglobin profile of the patient is important, because sickle thalassemia and hemoglobin SC disease have distinct prognoses or clinical features. Diagnosis is usually established in childhood, but occasional patients, often with compound heterozygous states, do not develop symptoms until the onset of puberty, pregnancy, or early adult life. Genotyping of family members and potential parental partners is critical for genetic counseling. Details of the childhood history establish prognosis and need for aggressive or experimental therapies. Factors associated with increased morbidity and reduced survival include more than three crises requiring hospitalization per year, chronic neutrophilia, a history of splenic sequestration or hand-foot syndrome, and second episodes of acute chest syndrome. Patients with a history of cerebrovascular accidents are at higher risk for repeated episodes and require partial exchange transfusion and especially close monitoring using Doppler carotid flow measurements. Patients with severe or repeated episodes of acute chest syndrome may need lifelong transfusion support, using partial exchange transfusion, if possible.
Sickle cell anemia. The elongated and crescent-shaped red blood cells seen on this smear represent circulatingirreversibly sickled cells. Target cells and a nucleated red blood cell are also seen.
TREATMENT Sickle Cell Syndromes
Patients with sickle cell syndromes require ongoing continuity of care. Familiarity with the pattern of symptoms provides the best safeguard against excessive use of the emergency room, hospitalization, and habituation to addictive narcotics. Additional preventive measures include regular slit-lamp examinations to monitor development of retinopathy; antibiotic prophylaxis appropriate for splenectomized patients during dental or other invasive procedures; and vigorous oral hydration during or in anticipation of periods of extreme exercise, exposure to heat or cold, emotional stress, or infection. Pneumococcal and Haemophilus influenzae vaccines are less effective in splenectomized individuals. Thus, patients with sickle cell anemia should be vaccinated early in life.
The management of an acute painful crisis includes vigorous hydration, thorough evaluation for underlying causes (such as infection), and aggressive analgesia administered by a standing order and/or patient-controlled analgesia (PCA) pump. Morphine (0.1–0.15 mg/kg every 3–4 h) should be used to control severe pain. Bone pain may respond as well to ketorolac (30–60 mg initial dose, then 15–30 mg every 6–8 h). Inhalation of nitrous oxide can provide short-term pain relief, but great care must be exercised to avoid hypoxia and respiratory depression. Nitrous oxide also elevates O2 affinity, reducing O2 delivery to tissues. Its use should be restricted to experts. Many crises can be managed at home with oral hydration and oral analgesia. Use of the emergency room should be reserved for especially severe symptoms or circumstances in which other processes, e.g., infection, are strongly suspected. Nasal oxygen should be used as appropriate to protect arterial saturation. Most crises resolve in 1–7 days. Use of blood transfusion should be reserved for extreme cases: transfusions do not shorten the duration of the crisis.
No tests are definitive to diagnose acute painful crisis. Critical to good management is an approach that recognizes that most patients reporting crisis symptoms do indeed have crisis or another significant medical problem. Diligent diagnostic evaluation for underlying causes is imperative, even though these are found infrequently. In adults, the possibility of aseptic necrosis or sickle arthropathy must be considered, especially if pain and immobility become repeated or chronic at a single site. Nonsteroidal anti-inflammatory agents are often effective for sickle cell arthropathy.
Acute chest syndrome is a medical emergency that may require management in an intensive care unit. Hydration should be monitored carefully to avoid the development of pulmonary edema, and oxygen therapy should be especially vigorous for protection of arterial saturation. Diagnostic evaluation for pneumonia and pulmonary embolism should be especially thorough, since these may occur with atypical symptoms. Critical interventions are transfusion to maintain a hematocrit >30, and emergency exchange transfusion if arterial saturation drops to <90%. As patients with sickle cell syndrome increasingly survive into their fifth and sixth decades, end-stage renal failure and pulmonary hypertension are becoming increasingly prominent causes of end-stage morbidity. A sickle cell cardiomyopathy and/or premature coronary artery disease may compromise cardiac function in later years. Sickle cell patients have received kidney transplants, but they often experience an increase in the frequency and severity of crises, possibly due to increased infection as a consequence of immunosuppression.
The most significant advance in the therapy of sickle cell anemia has been the introduction of hydroxyurea as a mainstay of therapy for patients with severe symptoms. Hydroxyurea (10–30 mg/kg per day) increases fetal hemoglobin and may also exert beneficial effects on RBC hydration, vascular wall adherence, and suppression of the granulocyte and reticulocyte counts; dosage is titrated to maintain a white cell count between 5000 and 8000/μL. White cells and reticulocytes may play a major role in the pathogenesis of sickle cell crisis, and their suppression may be an important side benefit of hydroxyurea therapy.
Hydroxyurea should be considered in patients experiencing repeated episodes of acute chest syndrome or with more than three crises per year requiring hospitalization. The utility of this agent for reducing the incidence of other complications (priapism, retinopathy) is under evaluation, as are the long-term side effects. To date, however, minimal risk of bone marrow dyscrasias or other neoplasms has been documented. Hydroxyurea offers broad benefits to most patients whose disease is severe enough to impair their functional status, and it may improve survival. HbF levels increase in most patients within a few months.
The antitumor drug 5-azacytidine was the first agent found to elevate HbF. It never achieved widespread use because of concerns about acute toxicity and carcinogenesis. However, low doses of the related agent 5-deoxyazacytidine (decitabine) can elevate HbF with more acceptable toxicity.
Bone marrow transplantation can provide definitive cures but is known to be effective and safe only in children. Clinical trials studying partially myeloablative conditioning regimens (“mini” transplants) are likely to support more widespread use of this modality in older patients. Prognostic features justifying bone marrow transplant are the presence of repeated crises early in life, a high neutrophil count, or the development of hand-foot syndrome. Children at risk for stroke can now be identified through the use of Doppler ultrasound techniques. Prophylactic exchange transfusion appears to substantially reduce the risk of stroke in this population. Children who do suffer a cerebrovascular accident should be maintained for at least 3–5 years on a program of vigorous exchange transfusion, as the risk of second strokes is extremely high.
Gene therapy for sickle cell anemia is being intensively pursued, but no safe measures are currently available. The development of newer methods of direct gene correction in situ (e.g., zinc finger nucleases, or “CRISPR” [clustered regularly interspaced short palindromic repeats] technology) could well find clinical use in these patients. Experimental methods of derepressing HbF by interfering with Bcl11a are also being explored.
Amino acid substitutions that reduce solubility or increase susceptibility to oxidation result in unstable hemoglobins that precipitate, forming inclusion bodies injurious to the RBC membrane. Representative mutations are those that interfere with contact points between the α and β subunits (e.g., Hb Philly [β35Tyr→Phe]), alter the helical segments (e.g., Hb Genova [β28Leu→Pro]), or disrupt interactions of the hydrophobic pockets of the globin subunits with heme (e.g., Hb Köln [β98Val→Met]) (Table 127-3). The inclusions, called Heinz bodies, are clinically detectable by staining with supravital dyes such as crystal violet. Removal of these inclusions by the spleen generates pitted, rigid cells that have shortened life spans, producing hemolytic anemia of variable severity, sometimes requiring chronic transfusion support. Splenectomy may be needed to correct the anemia. Leg ulcers and premature gallbladder disease due to bilirubin loading are frequent stigmata.
TABLE 127-3Representative Abnormal Hemoglobins with Altered Synthesis or Function ||Download (.pdf) TABLE 127-3Representative Abnormal Hemoglobins with Altered Synthesis or Function
|Designation ||Mutation ||Population ||Main Clinical Effectsa |
|Sickle or S ||β6Glu→Val ||African ||Anemia, ischemic infarcts |
|C ||β6Glu→Lys ||African ||Mild anemia; interacts with HbS |
|E ||β26Glu→Lys ||Southeast Asian ||Microcytic anemia, splenomegaly, thalassemic phenotype |
|Köln ||β98Val→Met ||Sporadic ||Hemolytic anemia, Heinz bodies when splenectomized |
|Yakima ||β99Asp→His ||Sporadic ||Polycythemia |
|Kansas ||β102Asn→Lys ||Sporadic ||Mild anemia |
|M Iwata ||α87His→Tyr ||Sporadic ||Methemoglobinemia |
Unstable hemoglobins occur sporadically, often by spontaneous new mutations. Heterozygotes are often symptomatic because a significant Heinz body burden can develop even when the unstable variant accounts for only a portion of the total hemoglobin. Symptomatic unstable hemoglobins tend to be β-globin variants, because sporadic mutations affecting only one of the four α globins alleles would generate only 20–30% abnormal hemoglobin.
HEMOGLOBINS WITH ALTERED OXYGEN AFFINITY
High-affinity hemoglobins (e.g., Hb Yakima [β99Asp→His]) bind oxygen more readily but deliver less O2 to tissues at normal capillary Po2 levels (Fig. 127-2). Mild tissue hypoxia ensues, stimulating RBC production and erythrocytosis (Table 127-3). In extreme cases, the hematocrits can rise to 60–65%, increasing blood viscosity and producing typical symptoms (headache, somnolence, or dizziness). Phlebotomy may be required. Typical mutations alter interactions within the heme pocket or disrupt the Bohr effect or salt-bond site. Mutations that impair the interaction of HbA with 2,3-BPG can increase O2 affinity because 2,3-BPG binding lowers O2 affinity.
Low-affinity hemoglobins (e.g., Hb Kansas [β102Asn→Lys]) bind sufficient oxygen in the lungs, despite their lower oxygen affinity, to achieve nearly full saturation. At capillary oxygen tensions, they lose sufficient amounts of oxygen to maintain homeostasis at a low hematocrit (Fig. 127-2) (pseudoanemia). Capillary hemoglobin desaturation can also be sufficient to produce clinically apparent cyanosis. Despite these findings, patients usually require no specific treatment.
Methemoglobin is generated by oxidation of the heme iron moieties to the ferric state, causing a characteristic bluish-brown muddy color resembling cyanosis. Methemoglobin has such high oxygen affinity that virtually no oxygen is delivered. Levels >50–60% are often fatal.
Congenital methemoglobinemia arises from globin mutations that stabilize iron in the ferric state (e.g., HbM Iwata [α87His→Tyr], Table 127-3) or from mutations that impair the enzymes that reduce methemoglobin to hemoglobin (e.g., methemoglobin reductase, NADP diaphorase). Acquired methemoglobinemia is caused by toxins that oxidize heme iron, notably nitrate and nitrite-containing compounds, including drugs commonly used in cardiology and anesthesiology.
DIAGNOSIS AND MANAGEMENT OF PATIENTS WITH UNSTABLE HEMOGLOBINS, HIGH-AFFINITY HEMOGLOBINS, AND METHEMOGLOBINEMIA
Unstable hemoglobin variants should be suspected in patients with nonimmune hemolytic anemia, jaundice, splenomegaly, or premature biliary tract disease. Severe hemolysis usually presents during infancy as neonatal jaundice or anemia. Milder cases may present in adult life with anemia or only as unexplained reticulocytosis, hepatosplenomegaly, premature biliary tract disease, or leg ulcers. Because spontaneous mutation is common, family history of anemia may be absent. The peripheral blood smear often shows anisocytosis, abundant cells with punctate inclusions, and irregular shapes (i.e., poikilocytosis).
The two best tests for diagnosing unstable hemoglobins are the Heinz body preparation and the isopropanol or heat stability test. Many unstable Hb variants are electrophoretically silent. A normal electrophoresis does not rule out the diagnosis. Mass spectroscopy or direct gene analysis will provide a definitive diagnosis.
Severely affected patients may require transfusion support for the first 3 years of life, because splenectomy before age 3 is associated with a significantly higher immune deficit. Splenectomy is usually effective thereafter, but occasional patients may require lifelong transfusion support. After splenectomy, patients can develop cholelithiasis and leg ulcers, hypercoagulable states, and susceptibility to overwhelming sepsis. Splenectomy should thus be avoided or delayed unless it is the only alternative. Precipitation of unstable hemoglobins is aggravated by oxidative stress, e.g., infection and antimalarial drugs, which should be avoided where possible.
High-O2 affinity hemoglobin variants should be suspected in patients with erythrocytosis. The best test for confirmation is measurement of the P50. A high-O2 affinity hemoglobin causes a significant left shift (i.e., lower numeric value of the P50); confounding conditions, e.g., tobacco smoking or carbon monoxide exposure, can also lower the P50.
High-affinity hemoglobins are often asymptomatic; rubor or plethora may be telltale signs. When the hematocrit approaches 60%, symptoms of high blood viscosity and sluggish flow (headache, lethargy, dizziness, etc.) may be present. These persons may benefit from judicious phlebotomy. Erythrocytosis represents an appropriate attempt to compensate for the impaired oxygen delivery by the abnormal variant. Overzealous phlebotomy may stimulate increased erythropoiesis or aggravate symptoms by thwarting this compensatory mechanism. The guiding principle of phlebotomy should be to improve oxygen delivery by reducing blood viscosity and increasing blood flow rather than restoration of a normal hematocrit. Phlebotomy-induced modest iron deficiency may aid in control.
Low-affinity hemoglobins should be considered in patients with cyanosis or a low hematocrit with no other reason apparent after thorough evaluation. The P50 test confirms the diagnosis. Counseling and reassurance are the interventions of choice.
Methemoglobin should be suspected in patients with hypoxic symptoms who appear cyanotic but have a Pao2 sufficiently high that hemoglobin should be fully saturated with oxygen. A history of nitrite or other oxidant ingestions may not always be available; some exposures may be inapparent to the patient, and others may result from suicide attempts. The characteristic muddy appearance of freshly drawn blood can be a critical clue. The best diagnostic test is methemoglobin assay, which is usually available on an emergency basis.
Methemoglobinemia often causes symptoms of cerebral ischemia at levels >15%; levels >60% are usually lethal. Intravenous injection of 1 mg/kg of methylene blue is effective emergency therapy. Milder cases and follow-up of severe cases can be treated orally with methylene blue (60 mg three to four times each day) or ascorbic acid (300–600 mg/d).