The following cases and commentary, which focus on sickle cell disease, are excerpted from ACP's Medical Knowledge Self-Assessment Program (MKSAP 16). Part A of MKSAP 16 was released on July 31, and Part B on Feb. 1.
Case 1: Treat a pain crisis
A 29-year-old man is evaluated in the emergency department for dyspnea and diffuse severe pain in the arms, legs, back, and chest of 2 days' duration. He has sickle cell anemia and experiences painful episodes one to two times per year. He also has a history of acute chest syndrome and has known erythrocyte alloantibodies. In addition to increased fluid intake at home, he has been taking oral morphine sulfate, 30 mg twice daily, with no relief. He also takes folic acid.
On physical examination, temperature is 36.8°C (98.4°F), blood pressure is 153/65 mm Hg, pulse rate is 108/min, and respiration rate is 20/min. Oxygen saturation is 95% with the patient breathing ambient air. The patient is hunched over in pain, and he is diffusely tender to touch. Cardiopulmonary, abdominal, and neurologic examinations are normal.
Laboratory studies show hemoglobin 7.2 g/dL (72 g/L), leukocyte count 11,900/µL (11.9 × 109/L) with a normal differential, platelet count 199,000/µL (199 × 109/L), reticulocyte count 5.4%, and lactate dehydrogenase 420 units/L. The patient has alloantibodies to antigens C, E, and K on blood typing and screening.
In addition to intravenous hydration and incentive spirometry, which of the following is the most appropriate initial treatment?
A. Erythrocyte exchange transfusion
B. Erythrocyte transfusion
C. Intravenous meperidine
D. Intravenous morphine
Case 2: Worsening dyspnea, fever
A 21-year-old woman is admitted to the hospital with a sickle cell pain crisis. Over the next 48 hours, she develops worsening dyspnea, chest pain, and fever. She takes daily folic acid supplementation and morphine delivered by a patient-controlled analgesia device with bolus and demand infusions.
On physical examination, temperature is 38.0°C (100.4°F), blood pressure is 123/65 mm Hg, pulse rate is 118/min, and respiration rate is 22/min and labored. There is no jugular venous distention. Cardiopulmonary examination discloses decreased bilateral breath sounds at the lung bases, but no crackles or S3. There is no peripheral edema.
Laboratory studies show hemoglobin 6.2 g/dL (62 g/L), leukocyte count 6900/µL (6.9 × 109/L) with a normal differential, mean corpuscular volume 84 fL, platelet count 179,000/µL (179 × 109/L) and reticulocyte count 4.4%. Oxygen saturation is 86% with the patient breathing oxygen, 3 L/min by nasal cannula. Chest radiograph shows multilobar infiltrates not present on admission chest radiograph. An electrocardiogram demonstrates sinus tachycardia with no ST changes.
Broad-spectrum antibiotics are begun, incentive spirometry is initiated, and morphine is continued.
Which of the following is the most appropriate additional treatment?
A. Erythrocyte transfusion
B. Fluid bolus
Case 3: Finding the cause of pain
A 19-year-old man is admitted to the hospital with an acute pain crisis. He has sickle cell anemia and has developed macrocytic red cell indices over the past 6 months. He experiences pain crises two times per year. Medications are hydroxyurea and folic acid both started 9 months ago.
On physical examination, temperature is 36.7°C (98.0°F), blood pressure is 127/68 mm Hg, pulse rate is 108/min, and respiration rate is 17/min. BMI is 25. The patient has moderate pain in his upper and lower extremities. The remainder of the physical examination is normal.
Laboratory studies indicate a hematocrit of 21%, a hemoglobin level of 7.4 g/dL (74 g/L), and a mean corpuscular volume of 106 fL. A peripheral blood smear shows sickled erythrocytes and rare nucleated erythrocytes and macrocytes but is otherwise normal. A chest radiograph is normal.
Which of the following is the most likely cause of this patient's macrocytosis?
A. Cobalamin deficiency
D. Sickle cell anemia
Case 4: Recent hospitalization and surgery
A 34-year-old woman is evaluated for increasing bone pain, dyspnea, and fatigue of 2 days' duration. The patient has sickle cell anemia. She was hospitalized 7 days ago for an elective cholecystectomy for which she received 2 units of AB-negative and C antigen-negative, leukodepleted erythrocytes. The operation was uneventful, and she was discharged to home in 24 hours. Current medications are hydroxyurea and folic acid. A preoperative type and screen indicated the patient was AB-negative with alloantibodies to antigen C.
On physical examination, the patient is in obvious pain. Temperature is 37.4°C (99.4°F), blood pressure is 146/85 mm Hg, pulse rate is 116/min, and respiration rate is 12/min. The patient has jaundice. The cardiopulmonary and neurologic examinations are normal. Laboratory studies are below.
Which of the following laboratory findings would best explain this patient's current clinical presentation?
A. Antineutrophil antibodies
B. HLA antibodies
C. IgA deficiency
D. New alloantibodies
Case 5: Teenager with fatigue
A 15-year-old boy is evaluated in the emergency department for the subacute onset of fatigue, shortness of breath, and lethargy. He has a 2-week history of fever and arthralgia, which has improved over the past week. Medical history is significant for sickle cell anemia (Hb SS). He has had infrequent pain crises and no history of stroke or acute chest syndrome. He recently had contact with a sick cousin. His immunizations are up to date, and he takes folic acid, 2 mg/d.
On physical examination, temperature is 35.7°C (96.4°F), blood pressure is 96/55 mm Hg, pulse rate is 114/min, and respiration rate is 22/min. He has pallor and pale sclerae and appears lethargic. There is no rash. Other than tachycardia, the cardiopulmonary examination is normal. There is no lymphadenopathy or splenomegaly, and chest radiograph is normal. Lab studies show:
Which of the following is the most likely diagnosis?
A. Aplastic crisis
B. Hyperhemolytic crisis
C. Megaloblastic crisis
D. Splenic sequestration crisis
Case 6: Pregnant patient in pain
A 22-year-old woman is evaluated in the emergency department for a 2-day history of pain in her arms, legs, and back, but she notes no fever, shortness of breath, or chills. The patient has sickle cell anemia and is 29 weeks pregnant. She rarely has more than one to two painful crises per year, and they are often managed at home. Her only medication is folic acid.
On physical examination, temperature is 37.0°C (98.6°F), blood pressure is 110/63 mm Hg, pulse rate is 96/min, and respiration rate is 16/min. BMI is 22. The patient is in obvious distress from pain and is diffusely tender to touch. She has a gravid uterus. Cardiopulmonary, abdominal, and neurologic examinations are normal.
Laboratory studies indicate a hemoglobin level of 7.4 g/dL (74 g/L) and a leukocyte count of 6800/µL (6.8 × 109/L). Urinalysis is normal. The chest radiograph is normal.
Which of the following is the most appropriate treatment?
Answers and critique
Correct answer: D. Intravenous morphine.
The most appropriate initial treatment is intravenous morphine. This patient has sickle cell anemia and presents with a severe painful episode. No reliable physical or laboratory findings are useful surrogate markers for excluding vasoocclusion; therefore, treatment is based on reported symptoms. Consensus guidelines and expert opinion guide the management of acute painful episodes in sickle cell disease. Management of an uncomplicated painful episode generally includes hydration, nonopioid and opioid analgesia, and incentive spirometry. Morphine and hydromorphone are the opioid analgesics of choice.
Erythrocyte transfusion and exchange transfusion are not indicated for uncomplicated painful episodes but would be indicated in the acute management of stroke and acute chest syndrome. Unless transfusion is absolutely indicated, it should be avoided given the presence of this patient's multiple alloantibodies, which could increase the risk for a delayed hemolytic transfusion reaction. If transfusion were necessary, phenotypically matched erythrocytes would be indicated to minimize this risk.
Meperidine use is avoided in most patients, including those with sickle cell disease, because of its short half-life and low seizure threshold and no benefit over morphine or hydromorphone.
- Management of an uncomplicated painful episode in a patient with sickle cell disease generally includes hydration, nonopioid and opioid analgesia such as morphine and hydromorphone, and incentive spirometry.
Correct answer: A. Erythrocyte transfusion.
The most appropriate treatment is erythrocyte transfusion. An uncomplicated painful episode is often the initial presenting symptom for patients with sickle cell disease who subsequently develop more severe complications, such as acute chest syndrome or multiorgan failure. This patient meets the criteria for the acute chest syndrome, which includes identification of a new infiltrate on chest radiograph that includes at least one segment and one or more of the following: chest pain; temperature less than 38.5°C (101.3°F); tachypnea, wheezing or cough or labored breathing; and hypoxia relative to baseline. Management includes empiric broad-spectrum antibiotics, supplemental oxygen, pain medication to diminish chest splinting, and avoidance of overhydration. Bronchodilators may be helpful in patients with concomitant reactive airways disease. Erythrocyte transfusion is indicated if hypoxia persists despite supplemental oxygen as in this patient. Erythrocyte exchange transfusion may be preferred if the hypoxia continues to progress.
A fluid bolus is not indicated in this patient because she is not hypovolemic or hypotensive, although maintenance fluid should be continued.
Furosemide may be helpful in those patients who are hypervolemic, but there is no clinical evidence to support this diagnosis in this patient. Furosemide-induced hypovolemia should be avoided because it can lead to increased sickling.
Hydroxyurea is effective in decreasing the incidence of acute chest syndrome but is not indicated for treatment in the acute setting.
- Management of acute chest syndrome in patients with sickle cell disease includes empiric broad-spectrum antibiotics, supplemental oxygen, pain medication, avoidance of overhydration, bronchodilators as needed, and erythrocyte transfusion for persistent hypoxia despite supplemental oxygen.
Correct answer: B. Hydroxyurea.
Hydroxyurea has been shown to decrease the incidence of painful crises in patients with sickle cell anemia. Hydroxyurea is an RNA-reductase inhibitor that causes macrocytosis because of its effect on DNA synthesis. In fact, adherence to hydroxyurea therapy can be confirmed by identification of an increased mean corpuscular volume (MCV). Patients with sickle cell anemia who are not treated with hydroxyurea typically have a normal MCV, and the hemoglobin abnormality does not in and of itself lead to increased cell volumes.
Clinical manifestations and findings of cobalamin deficiency include glossitis, weight loss, macroovalocytes and hypersegmented polymorphonuclear cells on the peripheral blood smear, and hemolysis; neurologic findings may also occur. This patient's presentation is not suggestive of cobalamin deficiency. In addition, although cobalamin deficiency is associated with macrocytosis, cobalamin deficiency typically takes years to manifest, and this patient's MCV increased over several months.
The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and a variable rate of transformation to acute myeloid leukemia. The incidence of MDS increases with age. Patients have signs and symptoms referable to a specific cytopenia (most often megaloblastic anemia) and bone marrow findings showing a hypercellular marrow with dyserythropoiesis. Alcohol abuse and nutritional deficiencies, especially vitamin B12 and folate deficiencies, may be associated with similar findings, and, therefore, must be excluded. This patient has no signs or symptoms of myelodysplasia, such as leukopenia, thrombocytopenia, or other abnormalities on the peripheral blood smear, and myelodysplasia would be uncommon in a young patient.
- Hydroxyurea, an RNA-reductase inhibitor used to decrease the incidence of painful crises in sickle cell disease, causes macrocytosis because of its effect on DNA synthesis.
Correct answer: D. New alloantibodies.
The presence of new alloantibodies would best explain this patient's current clinical presentation. She has sickle cell anemia and has received a blood transfusion in the past week. This patient's severe pain crisis occurring 5 to 10 days after a receiving a transfusion is classic for a delayed hemolytic transfusion reaction (DHTR). Her clinical course, including jaundice, an elevated indirect bilirubin level, and a hemoglobin level lower than her recent value, combined with a type and screen demonstrating the presence of a new alloantibody, would be most characteristic of a DHTR. Because this patient has a known alloantibody against the C antigen, she is at risk for further alloantibody formation and subsequent delayed hemolytic transfusion reaction, which occurs commonly in patients with sickle cell anemia.
The presence of antibodies against recipient neutrophils present in donor plasma is known to cause transfusion-related acute lung injury (TRALI), which may mimic noncardiogenic pulmonary edema, including radiographic evidence of pulmonary edema and pulmonary infiltrates. Patients may also have fever and hypotension. This constellation of symptoms and findings is not consistent with this patient's presentation, which is most characteristic of a pain crisis. In addition, TRALI occurs during or soon after a transfusion, and this patient's symptoms were delayed several days after the transfusion.
Platelet refractoriness is an inappropriately low increment in the platelet count following a transfusion, generally defined as an increment of less than 10,000/µL (10 × 109/L). HLA alloimmunization can cause platelet refractoriness, but this patient did not receive platelets, and HLA alloimmunization would not explain her current symptoms.
Anaphylaxis during blood transfusion can rarely occur in patients with a severe IgA deficiency, but this patient did not experience anaphylaxis.
- Clinical symptoms of delayed hemolytic transfusion reaction typically develop approximately 5 to 10 days after erythrocyte transfusion and include anemia, jaundice, and fever and a worsening pain crisis in patients with sickle cell disease.
Correct answer: A. Aplastic crisis.
The most likely diagnosis is aplastic crisis. This patient with sickle cell anemia has an acute worsening of his chronic anemia. His recent viral syndrome, which presented with fever and arthralgia, is consistent with parvovirus B19 infection. Aplastic crisis can occur when patients with chronic hemolytic anemia and shortened erythrocyte survival are infected with parvovirus B19, which leads to suppression of erythrocyte production. His recent contact with a sick cousin and the very low reticulocyte count are also highly suggestive of parvovirus B19 infection. Confirmation may be obtained by demonstrating IgM antibodies against parvovirus B19 or polymerase chain reaction studies detecting parvovirus B19 DNA.
Hyperhemolytic crisis is characterized by a sudden worsening of sickle cell anemia with reticulocytosis. This complication is rare, and its cause is unknown.
Megaloblastic crisis refers to an acquired anemia occurring in patients with increased folate demands such as those with chronic hemolysis, and rarely, pregnant patients, children with accelerated growth, or the elderly. Although a low reticulocyte count may be consistent with a megaloblastic crisis, this condition would be unlikely to occur so acutely after a viral illness and would be very unlikely in a patient who takes chronic folic acid replacement.
Splenic sequestration crisis is the result of splenic vasoocclusion and splenic pooling of erythrocytes, causing a rapid drop in hemoglobin concentration, reticulocytosis, and a rapidly enlarging spleen. Splenic sequestration is also often accompanied by left upper-quadrant pain and splenomegaly and would not be characterized by a very low reticulocyte count.
- Aplastic crisis can occur when patients with chronic hemolytic anemia and shortened erythrocyte survival are infected with parvovirus B19, which leads to suppression of erythrocyte production.
Correct answer: D. Morphine.
The most appropriate treatment is morphine. The pregnancy-related mortality rate in women with sickle cell anemia is between 0.5% and 2%. Because of the associated increased fetal morbidity and maternal mortality, pregnancy in women with sickle cell disease should be managed by a team of medical personnel, including an obstetrician, internist, and hematologist. The incidence of pain crises in patients with sickle cell anemia is increased in pregnancy. Patients with painful crises present with severe pain in the arms, legs, chest, abdomen, and back and are managed with hydration, supplemental oxygen in the setting of hypoxia, and opiate analgesics such as morphine, which is not known to be teratogenic.
Hydroxyurea is contraindicated in pregnancy because of teratogenic effects when used in the first trimester. It should be stopped at least 3 months before conception whenever possible. Although case reports of successful pregnancies in women taking hydroxyurea have been published, there are currently no guidelines concerning the management of patients who become pregnant while taking this drug; therefore, discontinuation of this agent seems advisable.
NSAIDs are typically not used in pregnancy, and ketorolac is a pregnancy class C drug that is potentially teratogenic, based on animal studies.
Meperidine is contraindicated in the treatment of pain because of its tendency to induce seizures owing to the accumulation of normeperidine.
- Morphine is the therapy of choice for the long-term treatment of pain in all patients, including pregnant women, with sickle cell anemia and painful crises.