MKSAP quiz on sickle cell disease


Case 1: Acute pain episode

A 23-year-old man is admitted to the hospital with an acute vaso-occlusive pain episode. He reports pain in his back and legs with no respiratory or abdominal symptoms and rates his pain 10/10. Medical history is significant for homozygous sickle cell anemia (Hb SS). He has vaso-occlusive pain episodes approximately every 2 months. He typically receives erythrocyte transfusions for symptomatic anemia one to three times per year. Medications are folic acid and hydroxyurea.

On physical examination, temperature is 37.2°C (99.0°F), blood pressure is 115/70 mm Hg, pulse rate is 96/min, and respiration rate is 20/min. Oxygen saturation is 96% breathing ambient air. Scleral icterus is observed. A grade 2/6 early systolic murmur is heard at the base of the heart. Lungs are clear. No hepatosplenomegaly or tenderness is noted on abdominal examination.

Laboratory studies show a hemoglobin level of 7 g/dL (70 g/L), a mean corpuscular volume of 110 fL, and a serum creatinine level of 0.4 mg/dL (35.4 µmol/L).

A chest radiograph is normal.

Hydration and incentive spirometry are initiated.

Which of the following analgesic regimens is most appropriate for this patient?

A. As-needed ketoprofen and morphine
B. As-needed morphine
C. Scheduled meperidine
D. Scheduled morphine

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Case 2: Dyspnea and fatigue

A 24-year-old woman is evaluated in the emergency department for dyspnea on exertion and severe fatigue. Medical history is significant for sickle cell anemia, with a hospital admission for acute chest syndrome last year. She reports that her 4-year-old son had a high fever 1 week ago. She takes stable doses of hydroxyurea and a folic acid supplement.

On physical examination, she appears breathless and pale. Temperature is 38.4°C (101.1°F), blood pressure is 95/61 mm Hg, pulse rate is 104/min, and respiration rate is 14/min. Scleral icterus is observed. Lungs are clear. Cardiac examination reveals tachycardia with a prominent flow murmur.

Laboratory studies show hemoglobin 3.4 g/dL (34 g/L), leukocyte count 14,000/µL (14 × 109/L), platelet count 222,000/µL (222 × 109/L), and reticulocyte count 0.1% of erythrocytes.

Which of the following is the most likely cause of this patient's findings?

A. Cytomegalovirus
B. Epstein-Barr virus
C. Influenza A virus
D. Parvovirus B19

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Case 3: Pregnant patient

A 24-year-old woman with hemoglobin SS sickle cell disease is evaluated in the emergency department for lower extremity and back pain of 24 hours' duration. She is 24 weeks pregnant. She reports the pain is similar to her usual vasoocclusive pain located in her legs and low back but is not sufficiently relieved by morphine taken at home. She experiences pain episodes approximately two to three times per year, which she often manages at home. Medical history is otherwise unremarkable. Her only other medication is a folic acid supplement.

On physical examination, the patient appears uncomfortable and pale, with slight scleral icterus. She is afebrile, blood pressure is 120/70 mm Hg, pulse rate is 110/min, and respiration rate is 24/min and unlabored. Oxygen saturation is 94% breathing ambient air. Cardiac examination reveals regular heart sounds with a grade 2/6 systolic murmur. The lungs are clear to auscultation.

Laboratory studies show hemoglobin of 5.9 g/dL (59 g/L) from a prepregnancy baseline of 7-8 g/dL (70-80 g/L) and levels during pregnancy of 6-7 g/dL (60-70 g/L), as well as alanine aminotransferase 35 U/L, aspartate aminotransferase 32 U/L, and creatinine 0.7 mg/dL (35.4 µmol/L).

Fetal examination reveals no fetal distress.

Which of the following is the most appropriate treatment?

A. Erythrocyte transfusion
B. Exchange transfusion
C. Hydroxyurea
D. Intravenous fluids and narcotic analgesics

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Case 4: Right upper quandrant pain

A 23-year-old man is admitted to the hospital for severe right upper quadrant pain of 2 days' duration. Medical history is significant for homozygous sickle cell anemia (Hb SS). His only medication is folic acid.

On physical examination, temperature is 37.8°C (100.0°F), blood pressure is 115/70 mm Hg, pulse rate is 100/min, and respiration rate is 24/min. Oxygen saturation is 98% breathing ambient air. Palpation confirms a tender right upper quadrant. The remainder of the examination is normal.

Laboratory studies reveal a hemoglobin level of 7.5 g/dL (75 g/L) and a platelet count of 415,000/µL (415 × 109/L).

Abdominal ultrasonography confirms a diagnosis of cholecystitis, and a laparoscopic cholecystectomy is planned before hospital discharge.

In addition to antibiotics, which of the following is the most appropriate preoperative management?

A. Erythrocyte exchange transfusion to a target hemoglobin S of less than 30%
B. Erythrocyte transfusion to a hemoglobin level of 10 g/dL (100 g/L)
C. Erythrocyte transfusion to a hemoglobin level of 12 g/dL (120 g/L)
D. Erythrocyte transfusion for symptomatic anemia

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Case 5: Return to the ED

A 23-year-old woman is evaluated in the emergency department for profound shortness of breath, which developed earlier in the day. She reports no chest pain but feels very weak. Medical history is significant for homozygous sickle cell anemia (Hb SS). She was evaluated in the emergency department 1 week ago for symptomatic anemia; she received a transfusion of 2 units of packed red blood cells, her hemoglobin level increased to 8.5 g/dL (85 g/L), and she was sent home. Her only medication is folic acid.

On physical examination, she appears pale and weak. Temperature is 37.1°C (98.8°F), blood pressure is 100/60 mm Hg, pulse rate is 110/min, and respiration rate is 32/min. Oxygen saturation is 96% breathing ambient air. Scleral icterus is noted. Cardiac examination reveals a grade 3/6 early systolic murmur at the base of the heart. Lungs are clear. Abdominal palpation reveals no hepatosplenomegaly.

Laboratory studies show hemoglobin 3.5 g/dL (35 g/L), platelet count 415,000/µL (415 × 109/L), reticulocyte count 8% of erythrocytes, total bilirubin 7.7 mg/dL (132 µmol/L), and lactate dehydrogenase 650 U/L.

Which of the following is the most likely diagnosis?

A. Aplastic crisis
B. Delayed hyperhemolytic transfusion reaction
C. Hepatic sequestration crisis
D. Splenic sequestration crisis

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Answers and commentary

Case 1

Correct answer: D. Scheduled morphine.

The most appropriate pain regimen for this patient is scheduled morphine. Pain is the most common complication of sickle cell disease (SCD) and may be the initial presenting symptom in patients who subsequently develop more severe complications, such as acute chest syndrome (ACS) or multiorgan failure. Patients commonly have musculoskeletal symptoms, but vaso-occlusion can occur in any organ system. No reliable physical or laboratory findings serve as useful surrogate markers for excluding vaso-occlusion; therefore, managing a painful episode in SCD is based on symptoms. Management of an uncomplicated painful episode includes hydration, nonopioid and opioid analgesia, and incentive spirometry to avoid ACS. Morphine and hydromorphone are the opioid analgesics of choice. During hospitalization, opioid analgesia is most effectively delivered by regularly scheduled opioid administration or by patient-controlled analgesia pumps that include a basal rate and a demand option.

Meperidine is generally avoided because of its short half-life and lowered seizure threshold.

NSAIDs such as ketoprofen may be useful in the outpatient management of a painful vaso-occlusive crisis in patients with stable kidney function, but are probably inadequate as single agents for patients with severe pain requiring hospitalization. In addition, randomized studies have demonstrated no benefit of adding an NSAID to an opioid for the treatment of acute vaso-occlusive crisis in hospitalized patients.

Key point

  • During hospitalization, opioid analgesia is most effectively delivered by regularly scheduled opioid administration or by patient-controlled analgesia pumps.

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Case 2

Correct answer: D. Parvovirus B19.

The patient has parvovirus B19 infection. She has chronic hemolytic anemia due to sickle cell anemia and presents with severe anemia and a completely inadequate reticulocyte response 1 week after being exposed to a child with a febrile illness, which was likely caused by parvovirus B19. Hydroxyurea could lead to worsening anemia in a patient with sickle cell anemia but would not cause the acute signs or symptoms found in this patient. A subsequent bone marrow examination would demonstrate pure red cell aplasia (PRCA). Parvovirus has a tropism for erythrocyte precursors and is a known cause of aplastic crisis in patients with underlying sickle cell disease (SCD). Immune competent patients and those without chronic hemolysis have a milder hematologic response to parvovirus infection and are more likely to recover spontaneously.

Cytomegalovirus could cause constitutional symptoms and could trigger a painful crisis, but it is not associated with direct destruction of erythrocyte precursors. Cytomegalovirus may cause retinitis, gastroenteritis, or hepatitis in an immunocompromised patient, none of which are seen in this patient. Adults with SCD are functionally asplenic.

Epstein-Barr virus is unlikely owing to its lack of association with PRCA. However, viral illnesses are the frequent underlying causes that precipitate vaso-occlusive crises or acute chest syndrome in patients with SCD.

Influenza A virus is an unlikely diagnosis because the patient has no typical symptoms. Although influenza A could cause severe viral pneumonia and could lead to acute chest syndrome, its association with PRCA is not strong.

Key Point

  • Parvovirus B19 infection can cause acquired pure red cell aplasia in an otherwise functionally asplenic patient with sickle cell disease.

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Case 3

Correct answer: D. Intravenous fluids and narcotic analgesics.

This patient should receive intravenous fluids and narcotic analgesics. She is experiencing a vaso-occlusive pain episode that does not differ greatly from those she typically experiences. Because no reliable physical findings or laboratory markers can objectively establish the vaso-occlusion, the diagnosis of vaso-occlusive pain is based on subjective reports by the patient. She has no signs of acute chest syndrome (ACS) (no fever or hypoxia [oxygen saturation >90% breathing room air]) or other end-organ damage (her creatinine and aminotransferase levels are normal). No randomized studies have been conducted on the effectiveness or harms of standard therapy for vaso-occlusive crisis during pregnancy. Expert opinion recommends this patient should receive the same treatment as nonpregnant patients with sickle cell disease, which includes rest, relaxation, warmth, NSAIDs (which are considered safe before 30 weeks' gestation), oral and intravenous hydration, and narcotic analgesia. Narcotics are safe to use during pregnancy, and she will benefit from hydration, which will theoretically correct any dehydration contributing to the vaso-occlusive episode.

Because neither the patient nor the fetus is displaying symptoms of anemia (significant shortness of breath, dizziness, and chest pain in the mother or fetal distress), transfusion is not indicated. The patient's hemoglobin level is slightly lower now than her prepregnancy baseline; however, neither transfusion nor exchange transfusion is indicated in asymptomatic patients without signs of end-organ damage. Neither has been shown to decrease maternal morbidity or mortality during pregnancy, but both would predispose the patient to iron overload and erythrocyte antibody production. Transfusion would be appropriate to treat symptomatic anemia or signs of end-organ involvement (stroke symptoms, kidney failure, ACS, hepatic involvement).

Hydroxyurea therapy results in decreased mortality in hemoglobin SS sickle cell anemia and is indicated in patients with recurrent painful episodes, ACS, and symptomatic anemia. However, because of its potential teratogenicity, hydroxyurea should not be administered during pregnancy. Proper contraception before hydroxyurea initiation should be discussed with the nonpregnant patient.

Key Point

  • Expert opinion recommends that pregnant patients should receive the same treatment for acute vaso-occlusive crisis as nonpregnant patients with sickle cell disease.

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Case 4

Correct answer: B. Erythrocyte transfusion to a hemoglobin level of 10 g/dL (100 g/L).

This patient should receive an erythrocyte transfusion to a target hemoglobin level of 10 g/dL (100 g/L). He has homozygous sickle cell anemia (Hb SS) and must undergo laparoscopic cholecystectomy, a surgical procedure of low to moderate risk. Patients requiring surgery should undergo transfusion before their procedure to avoid complications. Transfusion to a hemoglobin level of 10 g/dL (100 g/L) has been shown to be equivalent to exchange transfusion for low- to medium-risk surgeries. The recent TAPS study showed that, for this surgical risk group, significantly more clinically important complications occurred in the group that did not receive preoperative transfusion (39%) than the group that did receive transfusion (15%). Significantly more serious events were also recorded in the nontransfusion group (30%) than in the transfusion group (3%), most of which were acute chest syndrome (ACS). Erythrocyte transfusions must be given with care in patients with sickle cell disease, because these transfusions are associated with iron overload. In some patients, “hyperhemolysis” occurs because of alloimmune responses to erythrocyte antigens, which leads to a delayed transfusion reaction characterized by hyperbilirubinemia and anemia. Additionally, erythrocyte transfusions that result in hemoglobin levels greater than 10 g/dL (100 g/L) can increase blood viscosity and potentially cause thrombotic complications.

Several multicenter studies have documented the clinical efficacy of transfusion to 10 g/dL (100 g/dL) compared with the more aggressive strategy of exchange transfusion targeting a hemoglobin S level of 30%. Transfusion and exchange transfusion are associated with similar serious surgery-related complications and ACS, but transfusion is associated with fewer transfusion-related complications and exposure to less blood.

Key Point

  • Patients with sickle cell disease undergoing low- to moderate-risk surgery should receive erythrocyte transfusion, which has been shown to be equivalent to exchange transfusion, targeting a hemoglobin level of 10 g/dL (100 g/L) before the procedure to avoid complications.

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Case 5

Correct answer: B. Delayed hyperhemolytic transfusion reaction.

This patient has delayed hyperhemolytic transfusion reaction (DHTR). Chronic transfusion in patients with sickle cell disease (SCD) can lead to iron overload, alloimmunization, and an increased risk for DHTR. DHTR is caused by an amnestic response of a preformed erythrocyte alloantibody after re-exposure to an erythrocyte antigen outside the ABO system. Additionally, an autoimmune component could be worsening the hemolysis. Following transfusion, a 1% to 1.6% chance exists of developing these antibodies. DHTR may then occur after re-exposure with subsequent transfusion. Clinical findings, which typically develop approximately 2 to 19 days after erythrocyte transfusion, include anemia, reticulocytosis, jaundice, a significant decrease in hemoglobin level, and increases in hemolytic markers such as lactate dehydrogenase and bilirubin levels, although many patients will be asymptomatic. Patients with SCD may present with a worsening pain crisis. Hemolysis is typically extravascular, and life-threatening complications are rare. Treatment is supportive. Subsequent transfusions should be minimized but not withheld when indicated, such as in situations of severely symptomatic anemia and multiorgan failure.

Transient 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 identified by anemia and lack of reticulocytosis. Parvovirus B19 infection is a viral syndrome characterized by malaise, fever, and arthralgia; 25% of patients are asymptomatic.

A rare complication of SCD is hepatic sequestration crisis, characterized by large numbers of erythrocytes becoming trapped in the liver. Patients may develop acute anemia, reticulocytosis, hypovolemia, and distributive shock. Prominent symptoms include right upper quadrant pain, hepatomegaly, and anemia. The patient has none of these manifestations.

Splenic sequestration crisis occurs when splenic pooling of erythrocytes causes an acute anemia with reticulocytosis and a rapidly enlarging spleen. Patients may develop hypotension and shock. This condition is found primarily in children who have functional spleens that have not been subjected to multiple infarctions and subsequent development of fibrotic atrophy. This adult patient does not have splenomegaly. Splenic sequestration crisis is not the most likely diagnosis for anemia following a transfusion.

Key Point

  • Delayed hyperhemolytic transfusion reaction can occur several days after transfusion and is diagnosed by a significant decrease in the hemoglobin level with reticulocytosis and concomitant increases in the bilirubin and lactate dehydrogenase levels.