Sickle cell anemia

I. What every physician needs to know.

Sickle cell disease is a term used to describe a variety of genotypes and disease states associated with the hemoglobin sickle cell (HbS) gene and the sickling of red blood cells (RBCs). The HbS gene develops from a mutation in the sixth codon of the beta-chain gene for hemoglobin, causing an adenine-to-thymine substitution at the nucleotide level and subsequently a glutamic acid-to-valine substitution at the amino acid level. The resulting HbS protein produces a hemoglobin molecule that has decreased solubility and increased viscosity during periods of deoxygenation, resulting in increased susceptibility to polymer formation and precipitation. These effects distort the RBC structure into the classic crescent (sickled) shape which markedly decreases its deformability. Additional changes include disordered cell volume control and increased adherence to vascular endothelium which also play a role in the pathophysiology of sickle cell disease.

Sickle cell anemia (HbSS disease) is characterized by homozygosity of the HbS gene, which is the most common genotype of the sickle cell diseases. Sickle cell anemia is clinically characterized by chronic hemolytic anemia and painful, recurrent vasooclussive crises that can have a variety of organ system complications that may lead to disability and increased mortality. Sickle cell trait and all other sickle cell disease genotypes are characterized by heterozygosity of the HbS gene and are of variable clinical severity.

II. Diagnostic Confirmation.

The diagnosis of sickle cell anemia (as well as the other sickle cell disease genotypes) is suspected by the clinical presentation (discussed separately) and confirmed by identifying the presence of the HbS protein by standard hemoglobin electrophoresis or thin layer isoelectric focusing, liquid chromatography, solubility testing, or direct DNA-based testing by polymerase chain reaction.

A. History Part I: Pattern Recognition.

The clinical symptoms of sickle cell anemia may develop as early as 6-12 months of age, the time when the circulating levels of fetal hemoglobin decrease. Nearly all patients develop symptoms within the first decade of life. The typical clinical presentation of sickle cell anemia in the adult is usually characterized by symptoms of chronic or acute on chronic hemolytic anemia; recurrent, painful vasooclusive crises; multi-organ damage from progressive, incremental microinfarctions to various tissues; and increased susceptibility to infection. Other related presentations may include depression, anxiety, and chronic pain behavior.

Patients with sickle cell anemia usually tolerate a chronic hemolytic anemia with baseline hemoglobin values of 6-10g/dL. While basic activities of daily living are usually well tolerated at this level of anemia, some patients may experience limitations and become symptomatic with exertional activities. The degree of anemia tolerated is also affected by shared cardiovascular and/or pulmonary comorbidities as well as other nutritional deficiencies (folate, vitamin B12, etc.) which may affect RBC production.

Acute symptomatic anemia, sometimes life-threatening, may develop in patients with concurrent infection with parvovirus B19 (resulting in aplastic crisis); in patients with co-existent G6PD deficiency; and in younger patients with rapidly progressive splenomegaly and splenic sequestration (splenic sequestration crisis). Acute symptomatic anemia may present with rapidly increasing fatigue, shortness of breath, decreased exercise tolerance, chest pain, palpitations, presyncopal symptoms, and/or syncope.

Many patients with sickle cell anemia have chronic pain that is mostly localized to the joints and long bones. Approximately half of patients with sickle cell anemia will experience intermittent exacerbations of pain of varying intensity, frequency, and duration. These exacerbations – termed vasoocclusive pain crises – occur when sickled RBCs obstruct the microcirculation of various capillary beds and cause ischemic injury to the organ involved, resulting in pain and possible organ dysfunction.

The pattern of pain in a given patient is usually consistent from crisis to crisis. A new or different pain should prompt investigation of alternative diagnoses. The pain may last several hours or several days. These vasoocclusive pain crises are exacerbated by factors that cause RBCs to adopt the sickled shape: hypoxemia including exposure to low oxygen tension with high-altitude travel; dehydration; pregnancy; infection; fever; acidosis; and rapid changes in temperature.

Acute vasoocclusive pain crisis is the leading cause of emergency room visits and hospitalizations for patients with sickle cell disease. The vasoocclusive pain crises are characterized by severe pain in almost any organ or body part. The pain may be associated with constitutional symptoms such as malaise and fevers. Common systems, body parts, and organs affected by vasoocclusive ischemic injury include the following:

Musculoskeletal system (especially long bones of the extremities due to infarction of bone marrow; joints are also affected with the femoral and humeral heads at high-risk for osteonecrosis and subsequent collapse; dactylitis is usually seen in children)

Pulmonary system (acute chest syndrome; chronic symptoms associated with pulmonary hypertension including shortness of breath and decreased exercise tolerance)

Cardiac (myocardial infarction, heart failure, prolonged QT interval leading to arrhythmia)

Central nervous system (focal neurological deficits associated with ischemic and hemorrhagic strokes; transient ischemic attacks; seizures)

Eyes (proliferative retinopathy, retinal detachment, vitreous hemorrhage, retinal artery occlusion, orbital compression syndrome)

Integumentary system (leg ulcerations)

Renal (papillary necrosis, nephrotic syndrome, renal failure)

Genitourinary (priapism, infarction of the penis or clitoris)

Abdomen (pain secondary to vasocclusion of soft tissue and/or organs in the abdomen, especially the spleen; may also represent referred pain from outside the abdomen; reactive ileus is seen in some patients)

Acute chest syndrome may be characterized by chest pain, dyspnea, cough, hemoptysis, fever, chills, tachypnea, wheezing, hypoxemia, and/or leukocytosis with a pulmonary infiltrate on chest x-ray. It can develop as a result of vasoocclusive pain crisis, atelectasis, respiratory infection, in situ thrombosis, and/or bone marrow embolization. Patients with sickle cell anemia are at increased risk for developing pulmonary hypertension, resulting in right-sided heart failure and associated symptoms of shortness of breath, decreased exercise tolerance, volume overload, and presyncope. Those with pulmonary hypertension should be further screened for venous thromboembolism and sleep disorders as these conditions can worsen cardiopulmonary symptoms and function if left untreated.

Patients with sickle cell anemia may present with signs or symptoms of infection. The repeated, progressive obstruction, infarction, and damage of the spleen results in functional asplenia and eventual autosplenectomy with associated increased susceptibility to encapsulated bacterial organisms, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.

Areas of weakened, infarcted bone are also at risk for osteomylelitis in patients with sickle cell anemia, particularly with Salmonella, Staphylococcus, and gram-negative enteric bacilli. Finally, excessive bilirubin production from chronic hemolysis may result in cholelithiasis and associated increased risk for cholecystitis and cholangitis due to biliary obstruction; symptoms may include abdominal pain, nausea, vomiting, jaundice, and fevers.

B. History Part 2: Prevalence.

Sickle cell anemia is found most commonly in African Americans and, less frequently, in Middle Eastern, Eastern Mediterranean, and Central and South American populations. Over two million people in the United States carry the sickle cell (HbS) gene and about 70,000-100,000 are homozygous for the gene (have sickle cell anemia, HbSS disease). The male-to-female ratio is equal.

C. History Part 3: Differential diagnosis.

Sickle cell anemia (HbSS disease) must first be differentiated from sickle cell trait and other sickle cell disease genotypes, usually by hemoglobin electrophoresis and/or DNA-based testing. Sickle cell trait is defined by individuals carrying one HbS gene and one wild type (normal/HbA) gene for the beta-globin chain. Patients with sickle cell trait have a generally benign phenotype without anemia, increased risk for infection, or significant vasooclusive pain crises. Patients with sickle cell trait have a normal life expectancy.

All other sickle cell disease genotypes contain at least one HbS gene and one non-wild type gene (beta-globin chain variant). These diseases are of variable clinical severity and include the following:

HbS/C disease

HbS/E disease

HbS/alpha thalassemia

HbS/beta-(+) thalassemia

HbS/beta-0 thalassemia (severe disease severity similar to HbSS disease)

HbS/hereditary persistence of fetal hemoglobin (HbS/HPFH) (asymptomatic or very mild disease severity)

Other rare combinations of HbS with other abnormal hemoglobin genes

Additional diagnoses may mimic the various clinic presentations of sickle cell anemia, including:

Acute or chronic anemia of alternative etiology

Aortic disease

Gaucher disease

Hemoglobin CC disease

Hemolytic anemia

Legg-Calve-Perthes disease

Leukemia

Macroglobulinemia

Osteomyelitis

Polycythemia vera

Pulmonary embolism

Rheumatoid arthritis

Sepsis

Septic arthritis

Systemic lupus erythematosus

Talc emboli

Valvular heart disease

D. Physical Examination Findings.

Physical examination findings are variable. Fever is a non-specific finding in adults with sickle cell anemia and may accompany vasoocclusive pain crisis in the absence of true infection. Higher-grade temperatures, however, are more suggestive of infection. Tachycardia and hypotension may be a sign of septic shock, splenic sequestration crisis, or aplastic crisis. Tachypnea and signs of respiratory distress may be secondary to acute chest syndrome, pneumonia, heart failure, and/or pulmonary hypertension.

Ocular examination should identify patients with scleral icterus, conjunctival pallor, and signs of retinopathy. Examination of the neck should focus on evaluating for meningeal signs (neck stiffness, positive Brudzinski or Kernig signs, etc.). Examination of the cardiovascular and pulmonary systems may reveal signs of heart failure (audible S3, pulmonary rales, elevated jugular venous pressure, positive hepatojugular reflux, ascites, lower extremity edema) and/or pulmonary hypertension (widely split S2, loud P2, parasternal heave, diastolic murmur suggestive of pulmonary regurgitation).

Pulmonary examination may reveal an area of consolidation concerning for pneumonia and/or acute chest syndrome. Abdominal examination may identify hepatosplenomegaly, however, in adults, the spleen is usually absent and non-palpable. Right upper quadrant tenderness and/or a positive Murphy’s sign may be suggestive of cholecystitis. Musculoskeletal examination may reveal swelling, warmth, and tenderness to palpation of the extremities and joints. Range of motion may be limited in afflicted joints. Chronic infarction of bones and joints may result in various structural and/or functional musculoskeletal abnormalities, including: immobile, non-functional, and/or dysmorphic appearance of the shoulder or hip joints; shortened digits; and/or kyphoscoliosis. Signs and symptoms of secondary osteoarthritis may also develop at afflicted joints.

Synovitis and joint effusions are the result of infarction of adjacent synovium, bone, and bone marrow. Leg ulcerations may be evident on integumentary examination and evidenced by pallor, erythema, edema, or frank ulceration of the extremity. Significant erythema and/or discharge may be signs of bacterial superinfection. Focal neurological deficits may be a sign of stroke.

E. What diagnostic tests should be performed?

N/A

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

A sickling test can be used for screening purposes when the diagnosis is suspected but uncertain. The sickling test will detect the presence of the HbS gene, but it cannot differentiate between sickle cell anemia (homozygous for the HbS gene), sickle cell trait, or one of the other sickle cell genotypes (which are heterozygous for the HbS gene). The diagnosis of sickle cell anemia (HbSS disease) is confirmed on the basis of hemoglobin electrophoresis. Most adult patients with sickle cell anemia born in the United States however will already carry the diagnosis since it is part of the newborn screening program. Additional laboratory studies may be helpful but are not necessary to confirm the diagnosis.

Complete blood count (CBC) will reveal anemia (hemoglobin 6-10 g/dL), leukocytosis (typically <20,000 cells/uL) with predominant neutrophilia, and thrombocytosis. Reticulocyte count is usually high but may vary depending on the degree of concurrent hemolysis and other concurrent disease processes which may alter bone marrow production. Lactate dehydrogenase (LDH) may be increased and haptoglobin decreased, also depending on the level of hemolysis. Fractionated bilirubin measurement may reveal an unconjugated hyperbilirubinemia. Erythrocyte sedimentation rate (ESR) is usually low unless another condition, such as infection, is present that may elevate ESR. The peripheral blood smear will reveal the characteristic sickled, crescent-shaped RBCs, elongated RBCs, target cells, and Howell-Jolly bodies. Additional baseline laboratory studies may include an assessment of renal function, hepatobiliary function, and pulmonary function.

An acutely ill patient with sickle cell anemia presenting with signs/symptoms of worsening anemia, vasoocclusive pain crisis, and/or infection may benefit from the following laboratory studies, depending on the clinical presentation:

CBC with differential (baseline leukocytosis with neutrophilia is typical for patients with chronic sickle cell anemia, but profound elevations [>20,000 cells/uL] may be suggestive of true infection; leukopenia in the setting of worsening anemia may suggest parvovirus infection)

Reticulocyte count (usually high, but may be low in patients with parvovirus infection)

Hepatobiliary panel with fractionated bilirubin

Urinalysis

Blood and urine cultures

Wound cultures

Arterial blood gas

Secretory phospholipase A2 (laboratory marker closely associated with present or impending acute chest syndrome)

Cardiac enzymes (troponin I, CK-MB)

Brain natriuretic peptide

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The following diagnostic imaging studies may be helpful in evaluating a patient with sickle cell anemia. Chest imaging (plain film or non-contrast computed tomography [CT] of the chest) is important in evaluating patients with acute respiratory symptoms. Abdominal ultrasound or CT imaging evaluating the kidneys, spleen, and the hepatobiliary system may be helpful in evaluating patients with renal dysfunction, liver dysfunction (including signs of obstruction, cholecystitis, or cholangitis), or any other abdominal symptoms.

Skeletal plain films of painful extremities and joints are helpful in evaluating for osteonecrosis and osteomyelitis. Magnetic resonance imaging (MRI) is more useful in identifying osteonecrosis of the humeral and femoral heads, as well as distinguishing osteonecrosis from osteomyelitis. CT and nuclear imaging studies using technetium-99m are helpful in detecting osteonecrosis. Nuclear imaging studies using indium-111 tagged white blood cells (WBCs) may be helpful in diagnosing osteomyelitis.

Transcranial Doppler ultrasonography is used in children and adolescents to identify those at higher risk for stroke. MRI is used in patients with suspected stroke. Electroencephalogram (EEG) may be helpful in the diagnosis of seizure activity. Electrocardiogram (ECG) may be considered if there is concern for cardiac pathology. Transthoracic echocardiography, 6-minute walk, and cardiopulmonary exercise testing may be helpful in evaluating patients with suspected pulmonary hypertension.

III. Default Management.

The basic management principles of sickle anemia focus on rapidly identifying and treating acute exacerbations and complications of the disease (mainly vasooclusive pain crises, acute anemia, and infection); managing chronic pain; and preventing long-term complications of the disease.

A. Immediate management.

Vasooclusive pain crisis

Vasooclusive pain crisis is usually managed with aggressive oral versus intravenous fluid hydration on the order of 3-4 liters per day; oral versus parenteral analgesia; incentive spriometry; and supplemental oxygen when hypoxemia is present. Opiates help achieve the best pain control in vasoocclusive pain crisis and dosing must be individualized. The use of parenteral opiates will help gain adequate pain control quickly and effectively during the initial presentation. Patient controlled analgesia may sometimes be necessary.

Adjunctive use of ketorolac can help achieve pain control and minimize the total dose of opioids used. Patients can be converted to oral opiates after 24-48 hours with a regimen consisting of immediate-acting and/or sustained-release opiates tapered over the ensuing few days. Meperidine should be avoided in patients with sickle cell disease secondary to accumulation of toxic metabolites which can induce seizure activity.

Acute chest syndrome

Acute chest syndrome is treated with: broad-spectrum antibiotics (third-generation cephalosporin plus azithromycin; or equivalent coverage for Streptococcus pneumoniae and atypical respiratory organisms); supplemental oxygen; incentive spirometry; analgesia; and bronchodilators. Simple or exchange transfusion may also be considered to decrease blood viscosity and increase oxygen delivery. Antibiotic coverage may change based on sputum and blood culture results. Analgesic regimens should minimize or avoid, if possible, opiates that may suppress respiratory drive. Adjunctive use of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) may be beneficial in this regard. The use of systemic corticosteroids has been studied and shown to prevent deterioration in acute chest syndrome; however, these patients had higher readmission rates.

Fluid hydration should be performed judiciously to avoid volume overload which may worsen pulmonary function. The role of corticosteroids in the treatment of acute chest syndrome remains controversial. Patients with severe hypoxemia or respiratory failure may require higher level of care in an intensive care unit.

Priapism

Priapism is treated with hydration, analgesia, and possible simple versus exchange transfusion. These patients may require urological consultation if symptoms persist for more than 2-4 hours. Urological intervention may include penile aspiration, irrigation of the corpus cavernosum with a saline solution containing epinephrine, and possible surgical shunting.

Leg ulcerations

Leg ulcerations are treated with rest, leg elevation, wet-to-dry dressing changes, zinc oxide occlusive dressing (Unna boot), and possible antibiotics (if bacterial superinfection is suspected), debridement, and/or split-thickness skin grafts for poorly healing ulcerations.

Osteonecrosis

Osteonecrosis is treated with analgeisia, local heat, non-weight bearing activity, physical and occupational therapy, and possible arthroplasty. Orthopedic surgery consultation may be necessary. Interventional radiology consultation may be necessary for possible bone tissue sampling in the setting of osteomyelitis.

Indications for blood transfusion

Indications for blood transfusion in patients with sickle cell anemia include the following: acute symptomatic anemia; severe acute anemia secondary to aplastic crisis, splenic sequestration crisis, or hyperhemolytic crisis; acute ischemic stroke; acute chest syndrome; acute multiorgan system failure believed to be secondary to vasoocclusive disease; severe infection with symptomatic anemia; and severe cases of priapism that do not resolve with conservative measures. Transfusion may also be beneficial in female patients with a complicated pregnancy (those with preeclampsia, eclampsia, twin pregnancy, previous perinatal mortality, acute renal failure, sepsis, bacteremia, severe anemia, acute chest syndrome, hypoxemia, anticipated surgery with general anesthesia, etc.), as well as patients with chronic kidney disease and preoperative patients undergoing general anesthesia.

The goal of transfusion is to reduce the HbS concentration to less than 30%-60% and raise the hemoglobin concentration to about 10 g/dL, but not greater 12 g/dL. Patients with hemoglobin concentrations less than 10 g/dL may benefit from simple blood transfusion while patients with hemoglobin greater than 10 g/dL may require exchange transfusion. Erythrocytapheresis may be available at some institutions.

The treatment of acute stroke, heart failure, myocardial infarction, pulmonary hypertension, ophthalmologic complications, osteomyelitis, and renal disease in patients with sickle cell anemia does not differ from the general population. Expert consultation with a hematologist, neurologist, cardiologist, pulmonologist, nephrologist, orthopedic surgeon, and/or ophthalmologist may be necessary depending on the clinical presentation and initial diagnostic work-up. Furthermore, consultation with social workers, case managers, physical and occupational therapists, substance abuse counselors, pain management specialists, and psychiatrists may be necessary depending on the clinical situation.

B. Physical Examination Tips to Guide Management.

Frequent evaluation of pain control is advised in a patient with sickle cell anemia hospitalized with vasooclusive pain crisis. Attention should be made to the adequacy of pain control as well as to side-effects of opiate administration, mainly over-sedation.

In patients with comorbid conditions such as heart failure, chronic kidney disease, and/or liver disease, attention should be closely paid to volume status on physical examination (to avoid fluid overload) if they are receiving aggressive intravascular and/or oral hydration therapy. Close monitoring of respiratory status and continuous pulse oximetry are recommended in patients with, or at-risk for, acute chest syndrome. Scheduled, frequent neurologic testing by nursing staff is helpful in following patients with suspected or confirmed stroke or seizure activity.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

The following laboratory tests and studies may be helpful in monitoring the patient’s response to and/or adjusting management, depending on the clinical presentation: CBC with differential and reticulocyte count (especially in patients with a presentation of acute on chronic anemia); renal function; hepatobiliary panel; and arterial blood gas (especially in patients with acute chest syndrome).

D. Long-term management.

Education

Education in identifying and preventing disease exacerbation is strongly encouraged.

Chronic pain management

Chronic pain management is achieved with sustained-release opiates, acetaminophen, and NSAIDs; immediate-acting opiates may also be necessary for breakthrough pain. Meperidine should be avoided secondary to increased seizure risk. Tricyclic antidepressants may be helpful in reducing the perception of pain, thereby reducing the dose of opiates needed, and in treating underlying depression. Additional treatment options for chronic pain include:

Acupuncture

Hypnosis

Physical and occupational therapy

Transcutaneous electric nerve stimulation

Hydroxyurea

Hydroxyurea is the only FDA-approved therapy for sickle cell anemia. Hydroxyurea is used in select patients with sickle cell anemia to increase the level of fetal hemoglobin (limiting the sickling of RBC) and decrease circulating leukocytes (reducing neutrophil adherence). Patients in whom treatment with hydroxyurea may be indicated include those with a history of acute chest syndrome, those with frequent vasoocclusive pain crises and/or history of other severe vasoocclusive episodes, and those with ongoing severe symptomatic anemia. Hydroxyurea has been associated with reduced hospitalization, frequency of pain crises, and mortality in patients with sickle cell anemia. Hydroxyurea should be prescribed in consultation with a hematologist. Avoid hydroxyurea in pregnant patients because it is a potential teratogen.

Chronic anemia

In the absence of other cardiovascular or pulmonary comorbidities, anemia is usually well tolerated in sickle cell patients. Folate is often prescribed to prevent the development of megaloblastic anemia. Menstruating women should be screened and treated for concurrent iron deficiency anemia.

Chronic prophylactic transfusion programs

Chronic prophylactic transfusion programs are in place for primary stroke prevention in patients identified as high-risk for stroke by transcranial Doppler screening programs during childhood and adolescence. They are also recommended for secondary prevention following a stroke.

Allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation is the only potentially curable option that is available for sickle cell patients at this time. It is an evolving therapy that continues to be under investigation, particularly in regard to the efficacy of this treatment over time. Patients who may benefit from bone marrow transplantation are those who continue to have severe symptoms despite treatment with hydroxyurea and blood transfusions.

Additional long-term management strategies are currently being investigated:

Gene therapy (has the potential for a cure)

Allogeneic bone marrow transplantation

Butyrate infusion therapy

Erythropoietin

Selectin-blocking therapies

Nitric oxide administration and other direct chemical inhibitors of polymerization

Phosphodiesterase type 5 inhibitors in the prevention of recurrent priapism

Prophylactic anticoagulation

Topical GM-CSF in the treatment of leg ulcerations

E. Common Pitfalls and Side-Effects of Management

Patients with sickle cell anemia may experience complications related to multiple blood transfusions, including alloimmunization, iron overload, and infection. Iron overload can result in heart and liver failure. Iron overload is treated with iron chelation therapy. Treatment with hydroxyurea may result in leukopenia and thrombocytopenia; patients require frequent blood testing to monitor for these effects. Pain medication addiction and abuse are also sometimes seen in patients with chronic pain secondary to sickle cell disease.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

All medications, including opiates, should be renally dosed. NSAIDs should be minimized or avoided in patients with renal dysfunction, depending on the degree of renal impairment. Meperidine should be avoided in patients with sickle cell disease, especially those with concomitant renal dysfunction, because the accumulation of toxic metabolites can induce seizure activity. The degree and rate of intravascular and/or oral hydration therapy may be limited in patients with end-stage renal disease. ACE inhibitors should be used in those patients with microalbuminemia.

B. Liver Insufficiency.

All medications, including opiates, should be dosed based on hepatic function.

C. Systolic and Diastolic Heart Failure

The degree and rate of intravascular and/or oral hydration therapy may be limited in patients with heart failure.