Sickle Cello Disease
Sickle Cell Anemia
Definition Sickle cell anemia is an autosomal recessive disease caused by the substitution of the amino acid valine for glut-amine at the sixth position of the | -hemoglobin chain, which results in the production of HbS.
Epidemiology From 8% to 10% of African Americans and a lesser percentage of persons with eastern Mediterranean, Indian, or Saudi Arabian ancestry have the sickle (HbS) gene. Disease develops in persons who are homozygous for the sickle gene (HbSS), in whom 70% to 98% of hemoglobin is of the S type. About 0.2% of African Americans have sickle cell anemia. The fact that the sickle gene occurs in populations living in regions endemic for falciparum malaria suggests that sickle heterozy-gosity confers a protective advantage against malaria.
Restriction endonuclease analyses indicate that the sickle gene mutation probably arose spontaneously in at least five geographic locations. These variations are called Senegal, Benin, Central African Republic (or Bantu), Saudi-Asian, Cameroon, and Indian (which may be the same as the Saudi-Asian variant). These variants are important clinically because some variants are associated with higher output of y-globin chains (and thus higher HbF levels); others are associated more often with the gene for a-thalassemia-2 [see The Thalassemias, below]. Either of these associations may alleviate some aspects of the sickling process.
Pathophysiology Two major clinical features characterize sickle cell anemia: (1) chronic hemolysis and (2) acute, episodic vaso-occlusive crises that cause organ failure and account for most of the morbidity and mortality associated with the disease.
HbS liganded to oxygen or carbon monoxide shows near-normal solubility. When the molecule gives up its oxygen and changes to the deoxy S form, however, its solubility decreases. In an environment with reduced oxygen, HbS polymerizes into long tubelike fibers that induce erythrocytic sickling.32
The deoxyhemoglobin S polymer is in equilibrium with surrounding soluble molecules of deoxyhemoglobin S. An increase in the concentration of HbS, a decrease in pH, or an increase in the concentration of 2,3-BPG tends to stabilize the deoxy S form and enhances gelation.32 In addition, sickled erythrocytes retain the K+-Cl- cotransport function and have sufficient intracellular calcium to activate the Gardos efflux channel33 [see Control of Hydration and Volume, above]. These two mechanisms act together to produce a population of very dense sickled erythrocytes with MCHCs ranging up to 50 g/dl.33 HbF inhibits polymeriza-tion,33 so patients with high HbF values, such as those with the Saudi-Asian variant of sickle cell anemia, have milder disease.31 When hypoxemia and the MCHC reach a critical level, polymerization occurs after a variable delay33; this delay represents the period during which the deoxyhemoglobin S tetramers are slowly associating to form a nucleus. When the nucleus reaches a critical size, rapid, almost explosive gelation occurs. Free deoxyhemo-globin S tetramers rapidly attach to the nucleus to produce the long tubelike fibers that align to form parallel tubelike structures that distort the cell and produce the sickle shape [see Figure 5].
Figure 5 Sickle cell anemia is characterized by markedly distorted sickle cells, including elongated forms (a). Target cells (b) are seen in a variety of conditions, including hypochromia caused by iron deficiency, hemoglobinopathies such as HbC variants and the thalassemias, and liver disease. Cooley anemia (c), or ^-thalassemia major, is indicated by profound hypochromia, targeting, variation in size and shape of erythrocytes, and the presence of nucleated red cells.
Most cells in the venous circulation are not sickled. However, sickling will occur if the time to polymerization is shortened to less than 1 second or if RBCs become trapped in the microcircu-lation. Some RBCs contain polymerized sickle hemoglobin even in the arterial circulation. Another manifestation of membrane damage in sickle cells is the irreversibly sickled cell, which retains its sickle shape even when reoxygenated.34 Some of these poorly deformable RBCs are directly derived from a subpopula-tion of reticulocytes that are low in HbF30 and are removed predominantly in the reticuloendothelial system. The rapid removal of these young cells, as well as older, dense, rigid cells that cannot traverse the monocyte-macrophage system, results in chronic extravascular hemolysis.
Because of the extreme sensitivity of sickling to the local environment, attention has been focused on cellular factors. The extreme hyperosmolality of the renal medulla (1,200 mOsm) dehydrates RBCs and raises the MCHC. Consequently, sickling sufficient to abolish the renal medullary concentrating ability may occur even in patients who have only the sickle trait.
Sickle Crisis and Ischemic Infarction
Sickle crisis is a potentially life-threatening vaso-occlusive complication of sickle disease. The initiating event in the sickle crisis is not known, nor is it clear why some patients have severe crises and others do not.
Clusters of increasingly rigid sickle cells will occlude the mi-crovasculature in the followng circumstances: (1) the pH falls, deoxygenation increases, or the MCHC rises; (2) nitric oxide production decreases or nitric oxide is trapped and removed by free hemoglobin in plasma35; (3) microvascular disease is present; or (4) capillary transit time is prolonged. Thrombosis may also play a role in sickle occlusion. There is some disorganization of the membrane phospholipid bilayer, with phosphatidylserine moving to the outer leaflet, possibly enhancing the thromboembolic manifestations of sickle disease.36 In sickle cell anemia, there also appears to be an increase in circulating endothelial cells, which abnormally express tissue factor and may provide an additional basis for thromboembolism.
Blockage leads to ischemic infarction, the release of inflammatory cytokines, and an amplifying sequence of stasis-induced occlusion, which may progress to sickle crisis. Portal circulations in which oxygen tension is low, such as those in the liver or the kidney, are at particular risk for occlusion.
Risk factors predisposing to painful crises include a hemoglobin level greater than 8.5 g/dl, pregnancy, cold weather, and a high reticulocyte count. Nocturnal hypoxemia is an important risk factor in children.38 Conversely, the low hematocrit in sickle cell anemia reduces blood viscosity and is protective. Sickle cell patients also characteristically have a high plasma fibrinogen level, which enhances the aggregation of already rigid erythrocytes and increases viscosity, particularly at the low shear rates encountered in the microcirculation.39 Sickled RBCs also have a greater tendency to adhere to endothelial cells than do normal RBCs.40 The role of leukocytes in this adhesion process is becoming clearer. Adminstration of G-CSF has led to sickle crises and even death.41,42 Granulocyte-macrophage CSF (GM-CSF) has caused similar crises. The severity of sickle disease appears to parallel the level of the WBC count, and WBC cell-adhesion molecules seem to be critical to sickle vaso-occlusion.
Diagnosis of Sickle Cell Disease
In the past, the diagnosis of sickle cell anemia was usually made on the basis of clinical manifestations occurring in childhood; the affected child was seen to have limitation in exercise tolerance, shortness of breath, tachycardia, frequent severe infections, and episodes of very painful dactylitis. Currently, many cases are identified on screening tests, which may be prompted by the diagnosis in a family member or performed as a routine neonatal procedure; in California and many other states, every fetal cord blood sample is examined by high-performance liquid chromatography (HPLC). Rarely, the disorder is diagnosed in adult life, occasionally during a first pregnancy, when prenatal screening reveals anemia. The general symptoms are limited exercise tolerance, exertional dyspnea, painful crises, bouts of jaundice, and even biliary colic.
The clinical appearance of the patient and a blood smear showing sickled cells, holly leaf cells, and erythrocytes with Howell-Jolly bodies are fairly suggestive of sickle cell anemia. Howell-Jolly bodies represent cytoplasmic remnants of nuclear chromatin that are normally removed by the spleen. Platelet and WBC counts are usually high. Unless an aplastic crisis is in progress, causing a virtual absence of normoblasts, the marrow shows erythroid hyperplasia. Diagnosis is confirmed by performing a sickle preparation: a drop of blood is incubated with fresh 2% sodium metabisulfite, and the proportion of sickle cells is measured immediately and then 1 hour later. Commercial testing sets such as Sickledex rely on the relative insolubility of HbS in 1.0 M phosphate buffers to make the diagnosis. The most definitive tests for sickle cell anemia, however, are hemoglobin electrophoresis or HPLC, which indicate the relative percentages of HbS and HbF. All of these tests are also useful in screening family members for sickle cell trait. Patients who are heterozygous for both the HbS gene and the | -thalassemia gene may appear to be homozygous for HbS. Other varieties of sickling hemoglobin are observed very infrequently. DNA-based methods can also be used to pinpoint the specific genetic abnormality and to identify the subpopulations from which the patient descend-ed31; further description and information on diagnostic testing is available online at http://www.geneclinics.org. Persons with sickle cell anemia and a-thalassemia have higher hemoglobin levels, lower reticulocyte counts, a lower MCHC, a lower MCV, and less-dense RBCs than persons who have sickle cell anemia alone. Such patients may have increased life expectancy and perhaps a different pattern of manifestations of veno-occlusive com-plications.45 The combination of G6PD deficiency and sickle cell anemia has neither beneficial nor harmful effects.
Management of Sickle Cell Disease
Sickle crisis Standard conservative management of sickle crisis centers on rest, hydration, and analgesia. In demonstrably acidotic patients, mild alkalinization should be induced by administration of a bicarbonate solution, which is prepared by addition of an ampule of sodium bicarbonate to 1 L of either 5% dextrose in water or half-normal saline. The bicarbonate solution should be infused at a rate of 5 to 7 ml/kg/hr for the first 4 hours and at 4 ml/kg/hr for the next 20 hours. The role of supplemental oxygen in patients with normal arterial oxygen tension (PaO2) and no cardiopulmonary problems is untested.
Pain management Pain [see 11:XIV Pain] is the major concern for 10% to 20% of patients with sickle cell anemia. Avascu-lar necrosis of bone marrow produces excruciating pain that can last as long as 8 to 10 days. The need for pain relief sometimes results in habituation or addiction. Because there are few objective ways to monitor the sickle crisis, the physician may not know whether a demand for narcotics is a manifestation of drug-seeking behavior.
The patient who has sickle cell anemia should be provided with oral analgesics for use at home in an attempt to abort the pain crisis at its onset. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen (500 mg ) and ketorolac (10 mg), can be used initially. If NSAIDs alone are not sufficient, they can be followed by a narcotic-analgesic combination, such as hy-drocodone and acetaminophen or oxycodone and aspirin. Adjuvants such as oral diphenhydramine (50 mg) or lorazepam (1 to 2 mg) may calm the patient and perhaps antagonize the actions of released histamine.48 If these measures, perhaps repeated every 6 hours, do not control the pain, the patient usually requires parenteral treatment. Care from the patient’s regular physicians is far preferable to reliance on unfamiliar providers in emergency departments.48 The patient needs rapid evaluation for possible infection, acute chest syndrome, bone infarction, and other complications, and the pain should be treated either with 10 mg of intravenous morphine along with 50 mg of intramuscular diphenhydramine every 2 hours or with 4 mg of intramuscular hydromorphone along with 50 mg of intramuscular diphenhydramine every 2 hours. If there is no pain relief or inadequate pain relief 30 minutes after the first dose, 50% of the initial dose of opiates can be administered; the respiratory rate should be monitored closely, particularly if it approaches 10 respirations a minute. Some units have used patient-controlled analgesia with good results. It is important to continue to administer par-enteral analgesia at regular intervals and to provide increased doses for breakthrough pain. The patient will probably need a laxative and may need an antiemetic, such as prochlorperazine (10 mg p.o. or I.M.). If the patient responds, home therapy with oral controlled-release morphine, such as MS Contin, is usually effective. If pain continues for more than 8 to 12 hours, the patient will probably need to be hospitalized to receive extended therapy with increased doses of analgesia and parenteral fluids, along with observation.48
Alteration of sickle cell pathophysiology A clearer understanding of the kinetics of sickling suggests some future prospects for the therapy of sickle cell anemia. Decreasing the MCHC should diminish gelation. An approach that attempts to block the Ca2+-dependent K+ efflux (Gardos channel) [see Control of Hydra-tion and Volume, above] has been tested in a sickle mouse model and shows promise in preventing RBC dehydration.49,50
Therapies to interfere with sickling are being actively pursued. The presence of 20% to 30% HbF in sickle RBCs markedly delays gelation, so a mechanism that would switch on the genes that control fetal hemoglobin synthesis and thus lessen the severity of sickle disease appears feasible.51,52 Hydroxyurea produces an increase in F reticulocyte and HbF levels. In a phase III trial, patients treated with hydroxyurea (starting dosage, 15 mg/kg/day) had fewer painful crises, admissions for crisis, and episodes of acute chest syndrome, as well as required fewer transfusions, than patients given a placebo.53 There was no effect on stroke; however, after 8 years of follow-up, mortality was reduced by 40%.54 The beneficial effect of hydroxyurea accrued after about 8 weeks of therapy and was accompanied by an increase in MCV and an increase in the proportion of F cells; in addition, there was a decrease in neutrophils and a decrease in sickle RBC adhesion to en-dothelial cells.55 Trials are also being conducted with butyrate, which can increase y-chain production, thereby increasing HbF levels and interfering with gelation.56,57 Demethylating agents such as 5-azacytidine and decitabine can also increase HbF to therapeutically useful levels. Because sickle cells adhere abnormally to the endothelium, attempts have been made to block adhesion; thus far, these efforts have not proved useful.
Inflammatory cytokines appear to play an important role in the sickle crisis, as evidenced by the fact that a predictor of success in hydroxyurea therapy is a decrease in the WBC count.54,55 Other investigators are studying the possible vasodilatory role of nitric oxide.
Sibling-donor allogeneic bone marrow transplantation can result in cure or can lead to a substitution of sickle trait for sickle cell anemia. Bone marrow transplantation resulted in apparent cure in 15 of 22 carefully selected patients; there were two deaths (9%), and the remaining five patients had complications such as graft failure. Of the 22 patients, 12 had a history of stroke, five had a history of recurrent episodes of acute chest syndrome, and five had recurrent painful crises.
Long-term transfusion therapy Long-term transfusion therapy has been found to prevent stroke.59 Some investigators have shown that preventive transfusions reduce or eliminate pain crisis, episodes of acute chest syndrome, bacterial infection, and hospitalization.60,61 Other authors, however, warn against the dangers of iron overload,62,63 transfusion hepatitis, problems with venous access, and RBC alloimmunization.64 Further studies may clarify the role of long-term transfusion therapy.
Complications and Their Management
Skeletal problems Aseptic necrosis (osteonecrosis) of the femoral head occurs in about 10% of patients, particularly those who also have a-thalassemia. Arthroplasty has been relatively ineffective, partly because of the presence of adjacent hard bone, which interferes with the placement of the prosthesis, and because of the increased risk of infection.
Cardiopulmonary problems Cardiac complications associated with anemia are the result of a large increase in cardiac output. Such complications include chamber enlargement, car-diomegaly, left ventricular hypertrophy, and flow murmurs.66 Acute myocardial infarction has occurred in relatively young adults who do not have coronary disease.67 The incidence of pulmonary hypertension is unknown, but its presence markedly shortens survival.
Acute pulmonary complications are a major cause of morbidity and mortality; such complications include local infection, vascular occlusions in the pulmonary vessels (both in situ thrombosis and embolism), and pulmonary fat embolism from ischemic marrow fat necrosis.69 A large study of acute chest syndrome found that adult patients were afebrile but had shortness of breath, chills, and pain in the chest and in at least one extremity.70 Infarctions of the thoracic vertebrae contribute substantially to the pain.64 Physical examination frequently shows no abnormal chest findings. In one study, the PaO2 was found to be low, averaging 71 mm Hg but falling below 60 mm Hg in 25% of patients. In this study, the death rate in adults was 4.3%; death was preceded by a lower hemoglobin value, a higher WBC count, and multilobe involvement. Autopsy of 16 cases showed that nine patients had pulmonary embolism and fat emboli and possibly 20% had bacterial infections. In patients with acute chest syndrome and pulmonary infection, the most common infecting organism was Chlamydia pneumoniae (30%), followed by Mycoplasma pneumoniae (21%), respiratory syncytial virus (10%), Staphylococcus aureus (4%), and Streptococcus pneumoniae (3%).71
Usually, therapy for acute chest syndrome should include incentive spirometry,64 antimicrobial therapy for patients with evidence of infection, the cautious use of analgesia, aggressive fluid replacement, and consideration of bronchoalveolar lavage to identify microbial infection or the fat-laden macrophages of fat emboli. Meticulous monitoring is required; repeat measurements of oxygenation should be made, and transfusions should be performed when clinically necessary. One of the most important benefits of hydroxyurea therapy is its ability to reduce the frequency of acute chest syndrome.53,72 Children may also need supplementary penicillin prophylaxis.73
Hepatobiliary disease Cholelithiasis occurs in 30% to 70% of patients, some of whom exhibit signs and symptoms of chole-cystitis.74 There are conflicting data regarding frequency of cholecystitis or obstruction of the common bile duct.74,75 If cholecystec-tomy is to be done, one should wait until the painful crisis is over. Transfusions should be given to raise the hemoglobin to 10 g/dl before surgery, if necessary, and the procedure should be done laparoscopically.74
Hepatic complications include congestive hepatopathy secondary to heart failure and viral hepatitis from frequent transfusions. Sickling in the liver can also produce hepatopathy. Often, serum bilirubin levels exceed 30 mg/dl in patients with intra-hepatic cholestasis, and coagulation abnormalities may lead to hemorrhagic complications and death.
Renal and urologic complications Water loss as a result of an inability to concentrate urine may enhance the sickling process. The extremely hypertonic milieu of the renal medulla induces severe sickling and destruction of the vasa recta. Hema-turia and papillary necrosis ensue. These complications are also observed in patients with sickle trait and in those who have sickle cell-hemoglobin C disease. The defect in renal concentrating ability appears to depend on the amount of HbS polymer contained in cells and is thus less severe in patients who also have a-thalassemia variants.76
Complications include renal tubular acidosis, hyperkalemia, and proteinuria. Treatment with enalapril reduces proteinuria, suggesting the presence of a component of glomerular capillary hypertension.77 Renal failure, in association with worsening anemia, contributes to the death of about one fifth of patients older than 40 years who have homozygous sickle disease.
Priapism is an extraordinarily painful complication of sickle cell anemia and may result in impotence.78 A United Kingdom study reported a good response in 13 of 18 patients treated for priapism with the alpha-adrenergic agonist etilefrine; however, this agent is not available in the United States.
Neurologic disorders Neurologic complications of sickle cell disease include stroke, subarachnoid hemorrhage, and isolated functional losses that suggest a focal occlusion. The patho-genesis of occlusion of the large cerebral arteries is probably different from that of the microvascular occlusive events that occur in hypoxic capillary beds. The most likely underlying causes are damage to the vascular endothelium, followed by extensive inti-mal proliferation and then thrombosis of the damaged vascular bed.45 In a multi-institutional study of 4,082 patients, the prevalence of cerebrovascular accidents (CVAs) was 4% to 5%; the incidence was 0.61 per 100 patient-years.80 Of the CVAs, 54% were infarcts, 34% were hemorrhagic in nature, 11% were transient ischemic attacks (TIAs), and 1% had both infarctive and hemor-rhagic features. Of the patients who survived, the recurrence rate of CVA was 14%. Mortality was 11%. Virtually all patients who died had hemorrhagic CVAs.
In a prospective study in which transcranial Doppler ultra-sonography was used to pinpoint children at risk for stroke, treatment with standard care or transfusion therapy (to reduce the HbS concentration to < 30%) resulted in only one CVA, compared with 10 CVAs and one intracerebral hematoma in the 65 control subjects (P < 0.002). The trial was terminated early.59 The success of this trial raises many serious questions about the necessity of ultrasonographic devices for successful management; the optimum duration of transfusion therapy; the inevitable consequences of transfusional hemochromatosis [see ^-Thalassemia major (Cooley anemia), below] and the necessity for ethnically matched blood to minimize allotransfusion reaction; the willingness of patients and families to accept transfusion therapy; and the role of allogeneic bone marrow transplantation as a potential alternative.59,81 The risk of recurrent cerebrovascular events is increased in patients receiving long-term transfusion therapy who have multiple cerebral collateral vessels as a result of moyamoya disease (hazard ratio, 2.40).82
Ocular complications The major ocular problems associated with sickle cell anemia are retinopathy, vitreous hemorrhage, and neovascularization. Annual ophthalmologic evaluations are recommended. The efficacy of laser photocoagulation in treating sickle-induced ocular changes is currently being investigated.
Dermatologic complications Poorly healing leg ulcers can be an important cause of morbidity in patients with sickle cell anemia. The degree of anemia does not seem to correlate with the presence or severity of these ulcers, but incompetence of venous valves and the resulting venous insufficiency have been associated with ulceration.83 Standard management includes de-bridement, control of local infection, use of wet-dry dressings, and possibly RBC transfusion. Local treatment with GM-CSF enhances healing, perhaps by stimulating the local growth of macrophages.84 GM-CSF can be either injected perilesionally or added topically to the wound, but the more successful application method involves the subcutaneous injection of 100 Mg of GM-CSF in each of four sites circumferentially around the ulcer at a distance of 5 mm from its edge (resulting in a total dose of 400 Mg in the wound). In some circumstances, one treatment sufficed, whereas in others, weekly treatments for 4 to 12 weeks were necessary. This therapy has not been approved by the Food and Drug Administration.
Aplastic crisis Aplastic crisis rapidly lowers hemoglobin and hematocrit levels and produces reticulocytopenia, as it does in any chronic hemolytic state. Parvovirus infection has been found to cause aplastic crisis,7 as has bone marrow necrosis.
Susceptibility to infections Patients with sickle cell anemia are hyposplenic and exhibit complement system abnormalities. Deficient serum opsonizing activity for Salmonella organisms may confer an increased susceptibility to those infections, including osteomyelitis.
Anesthesia complications The hypoxemia and vascular stasis that may occur during general anesthesia enhance sickling and may lead to a sickle crisis in the postoperative period. In an analysis of almost 4,000 patients, 12 deaths were associated with 1,079 procedures, and there were more complications after regional anesthesia than after general anesthesia.86 A simple transfusion program to raise the hemoglobin level to 10 g/dl was as effective as more aggressive preoperative programs in reducing the rate of complications.
Pregnancy and contraception The dangers of pregnancy for women with sickle disease include pulmonary problems and an increased incidence of urinary tract infection, hematuria, pre-eclampsia, and maternal death. Presumably, pelvic hypoxemia and the vascular overload associated with pregnancy lead to enhanced sickling, with its attendant complications. Vaso-occlusion in the placenta may account for fetal death and low birth weight.
Experienced clinicians differ in their approach to the pregnant patient with sickle disease. Some advocate only meticulous conservative care, whereas others recommend prophylactic transfusions. A controlled study has indicated that there is no advantage to the use of prophylactic transfusions.
Chorionic villus sampling (which can provide DNA for analysis in the first trimester of pregnancy), DNA amplification techniques, and probes that identify the specific nucleotide change of sickle cell anemia can give a relatively safe and very reliable prenatal diagnosis.
Oral contraceptives may pose a special hazard to women with sickle cell anemia, because they have been associated with a slight increase in the incidence of stroke, venous thromboembolism, and myocardial infarction. However, the emerging evidence that daily use of oral contraceptives containing less than 50 mg of synthetic estrogens is relatively safe suggests that patients with sickle disease can take such medication with reasonable confidence. The use of the Norplant implantable contraceptive device is another alternative for some patients. In any event, pregnancy or abortion in sickle disease carries significant risk.
