Hemolytic anemias are tested every year on USMLE Step 1. The questions repeat the same patterns: jaundice with unconjugated bilirubin, a drug or infection that triggers hemolysis, how the disease is inherited and what the blood smear shows. Start with the table, then try the 10 questions.
Hemolytic anemias at a glance
Disease
Inheritance
Smear and key clue
G6PD deficiency
X-linked recessive
Heinz bodies and bite cells; hemolysis after primaquine, sulfa drugs, dapsone, fava beans or infection
Pyruvate kinase deficiency
Autosomal recessive
Echinocytes (burr cells); low ATP; hemolysis from birth
Spherocytes; high MCHC; positive osmotic fragility test
Lab pattern of any hemolysis: high unconjugated (indirect) bilirubin, high LDH, high reticulocyte count, low haptoglobin, and more urobilinogen in the urine. There is no bilirubin in the urine.
Question 1: Yellow eyes with normal liver tests
A 21-year-old college student notices yellow color in the whites of her eyes. She has felt dizzy and weak for 3 days. She has no pain or fever, and her stool color is normal. The abdomen is soft with no tenderness and no enlarged organs. Liver enzymes are normal, and unconjugated (indirect) bilirubin is high. What is the most likely cause?
A. Hepatocellular disease B. Hemolysis C. Gallstones D. Obstructive jaundice E. Pancreatic cancer
Correct answer: B. Hemolysis
Jaundice with high unconjugated bilirubin, normal liver enzymes and no pain points to hemolysis. Red cells break down faster than the liver can conjugate the bilirubin. The dizziness and weakness come from anemia. Gilbert syndrome can give a similar picture, but without anemia.
Why the other options are wrong:
Hepatocellular disease raises liver enzymes and usually both types of bilirubin.
Gallstones, obstructive jaundice and pancreatic cancer raise conjugated bilirubin and alkaline phosphatase, often with pale stool and dark urine.
Question 2: Jaundice with a family history of G6PD deficiency
A 20-year-old exchange student from Greece notices yellow discoloration of his eyes 2 days ago. Several family members have hemolytic anemia due to G6PD deficiency. Which of the following findings is most likely?
A. Increased unconjugated bilirubin in the plasma B. Increased bilirubin in the urine C. Increased conjugated bilirubin in the plasma D. Clay-colored stool E. Very low urine urobilinogen
Correct answer: A. Increased unconjugated bilirubin in the plasma
Hemolysis delivers more bilirubin to the liver than it can conjugate, so unconjugated bilirubin rises in the plasma. Unconjugated bilirubin is bound to albumin and is not water-soluble, so it does not pass into the urine (this is called acholuric jaundice). More bilirubin reaches the gut, so urine urobilinogen goes up.
Why the other options are wrong:
Bilirubin in the urine and high conjugated bilirubin are seen in liver disease or bile duct obstruction.
Clay-colored stool means bile is not reaching the gut (obstruction).
Urine urobilinogen is increased in hemolysis, not decreased.
Question 3: Dark urine after malaria treatment
A 45-year-old man is treated for malaria. A few days later he develops fatigue, poor appetite and dark urine. Urinalysis is positive for urobilinogen and negative for bilirubin. Total bilirubin is 4.3 mg/dL (mostly unconjugated), hemoglobin is 8.5 g/dL and hematocrit is 30%. Which antimalarial drug most likely caused this?
A. Atovaquone B. Chloroquine C. Doxycycline D. Primaquine
Correct answer: D. Primaquine
This is hemolysis in G6PD deficiency. G6PD makes NADPH, which keeps glutathione in its reduced form to protect red cells from oxidants. Without it, oxidant drugs damage hemoglobin (Heinz bodies), and the spleen removes the damaged parts (bite cells). Primaquine is a classic trigger. Others are sulfonamides, dapsone, nitrofurantoin, rasburicase, fava beans and infections. Test for G6PD deficiency before giving primaquine.
Why the other options are wrong:
Atovaquone, chloroquine and doxycycline are not typical triggers of hemolysis in G6PD deficiency.
Question 4: Anemia after antibiotics in a young boy
A 2-year-old boy from Egypt develops anemia after taking antibiotics for an ear infection. One of his brothers had anemia at the same age. His parents receive a list of foods and drugs to avoid. What is the inheritance pattern of this condition?
A. Autosomal dominant B. Autosomal recessive C. X-linked recessive D. Mitochondrial E. Multifactorial
Correct answer: C. X-linked recessive
This is G6PD deficiency, the most common red cell enzyme defect in the world. It is X-linked recessive, so it mainly affects boys, and it is common in Africa, the Mediterranean region and the Middle East. Carriers have some protection against malaria. Sulfonamide antibiotics are a common trigger in children.
Why the other options are wrong:
Autosomal dominant: hereditary spherocytosis.
Autosomal recessive: sickle cell disease, thalassemia and pyruvate kinase deficiency.
Mitochondrial and multifactorial inheritance do not fit an affected boy and brother with a drug trigger.
Question 5: G6PD deficiency and a baby girl
A woman is found on genetic testing to carry one defective G6PD gene on one X chromosome. Her husband has a normal X chromosome. She is pregnant with a girl. Which of the following is most likely true for the baby?
A. 100% chance of having the disease B. 50% chance of having the disease C. No chance of being a carrier D. 50% chance of being a carrier
Correct answer: D. 50% chance of being a carrier
The father gives his only X chromosome (normal) to every daughter. The mother gives either her normal X or her affected X, each with a 50% chance. So the daughter has a 50% chance of being a carrier and will not usually have the disease. (Rarely, a carrier girl can have mild symptoms because of uneven X-inactivation, called lyonization.)
Why the other options are wrong: A daughter cannot have the full disease unless she receives an affected X from both parents. She has a real chance of being a carrier, so “no chance” is wrong.
Question 6: Spiky red cells
Echinocytes are red blood cells with small, evenly spaced, spiky projections. Their presence in the blood is characteristic of which enzyme deficiency?
A. Citrate synthase B. Glucose-6-phosphate dehydrogenase C. Glycogen synthase D. Pyruvate kinase
Correct answer: D. Pyruvate kinase
Pyruvate kinase deficiency is an autosomal recessive defect in the last step of glycolysis. Red cells have no mitochondria and depend on glycolysis for ATP. Without ATP, the membrane pumps fail, the cells become rigid and spiky (echinocytes), and the spleen destroys them. It causes hemolytic anemia from early childhood.
Why the other options are wrong:
G6PD deficiency shows Heinz bodies and bite cells, not echinocytes.
Citrate synthase is a Krebs cycle enzyme; red cells have no Krebs cycle.
Glycogen synthase deficiency affects glycogen storage in the liver and muscle, not red cells.
Question 7: Why sickle cell is common in some populations
Which of the following best explains why sickle cell disease is more common in people of African descent?
A. Genetic drift B. Increased gene flow C. Increased mutation rate D. Natural selection
Correct answer: D. Natural selection
People with sickle cell trait (one copy of the HbS gene) are protected against severe falciparum malaria but do not get sickle cell disease, which needs two copies. In areas where malaria is common, carriers survive and have children more often, so the gene stays common. This is natural selection through heterozygote advantage. The same idea applies to G6PD deficiency and thalassemia.
Why the other options are wrong:
Genetic drift is a random change in gene frequency, mostly in small populations.
Gene flow is the movement of genes between populations through migration.
The HbS mutation does not occur more often in these populations; it is kept there by selection.
Question 8: Sudden pale child with sickle cell disease
Which virus most likely causes aplastic crisis in a patient with sickle cell disease?
A. Hepatitis C virus B. Herpes simplex virus C. Parvovirus B19 D. Rotavirus
Correct answer: C. Parvovirus B19
Parvovirus B19 infects and kills red cell precursors in the bone marrow, which stops red cell production for about a week. Healthy people hardly notice, but in sickle cell disease and other hemolytic anemias, red cells live only a short time, so hemoglobin falls very fast. The key lab finding is a very low reticulocyte count. Treatment is supportive with blood transfusion.
Why the other options are wrong:Hepatitis C, herpes simplex and rotavirus do not target red cell precursors.
Question 9: The spleen in sickle cell disease
Which of the following is a major complication of sickle cell disease?
A. Autosplenectomy B. Cerebral hemorrhage C. Liver failure D. Kidney failure
Correct answer: A. Autosplenectomy
Repeated sickling in the spleen causes many small infarcts, and by adulthood the spleen is small, scarred and non-functional: autosplenectomy. These patients are at high risk of infection with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) and Salmonella osteomyelitis. They need vaccines and, in young children, daily penicillin.
Why the other options are wrong:
Sickle cell disease more often causes ischemic stroke in children, not cerebral hemorrhage as the main complication.
Kidney problems (papillary necrosis, inability to concentrate urine) and liver problems occur but are not the classic answer.
Question 10: Blood smear in sickle cell disease
Which of the following is likely to be seen on the blood smear of an adult with sickle cell disease?
A. Bite cells B. Howell-Jolly bodies C. Schistocytes D. Spherocytes
Correct answer: B. Howell-Jolly bodies
Because of autosplenectomy, the spleen can no longer remove nuclear fragments from red cells. These fragments stay in the cells as Howell-Jolly bodies. They are also seen after surgical splenectomy.
Why the other options are wrong:
Bite cells are typical of G6PD deficiency.
Schistocytes (fragmented cells) are seen in TTP, HUS, DIC and mechanical heart valves.
Spherocytes are seen in hereditary spherocytosis and warm autoimmune hemolytic anemia.
Key takeaways
Hemolysis: high unconjugated bilirubin, high LDH and reticulocytes, low haptoglobin; no bilirubin in the urine.
G6PD deficiency: X-linked recessive; bite cells and Heinz bodies; triggers include primaquine, sulfa drugs, dapsone, fava beans and infection.
Pyruvate kinase deficiency: autosomal recessive; echinocytes; low ATP.
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Written and reviewed by Dr. Ray Makar, MD, dermatologist with 20 years of clinical practice. Last reviewed: November 2026. For exam preparation only, not medical advice.
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