A 3-year-old boy is brought to the physician because of a 1-week history of yellowish discoloration of his eyes and skin. He has had generalized fatigue and mild shortness of breath for the past month. Three weeks ago, he was treated for a urinary tract infection with antibiotics. His father underwent a splenectomy during childhood. Examination shows pale conjunctivae and jaundice. The abdomen is soft and nontender; there is nontender splenomegaly. Laboratory studies show: Hemoglobin 9.1 g/dL Mean corpuscular volume 89 μm3 Mean corpuscular hemoglobin 32 pg/cell Mean corpuscular hemoglobin concentration 37.8% Hb/cell Leukocyte count 7800/mm3 Platelet count 245,000/mm3 Red cell distribution width 22.8% (N=13%–15%) Serum Bilirubin Total 13.8 mg/dL Direct 1.9 mg/dL Lactate dehydrogenase 450 U/L Which of the following is the most likely pathophysiology of these findings?

Decreased spectrin in the RBC membrane

Deficient glucose-6 phosphate dehydrogenase

Decreased synthesis of alpha chains of hemoglobin

A 2-year-old girl with a history of SS-hemoglobin is brought to her pediatrician by her mother, who noted an abdominal mass. On exam, the girl's spleen is palpably enlarged, and her palms and conjunctiva are noted to be extremely pale. Serum haptoglobin levels are decreased. Which of the following is the most likely cause of this patient's symptoms?

Decreased red blood cell production

A 21-year-old college student is admitted to the emergency department with complaints of pharyngitis, headache, and a persistent, non-productive, dry, hacking cough. The patient complains of feeling tired and fatigued and denies fever/chills. On physical examination, her mucosa is pale. A complete blood count is remarkable for decreased hemoglobin. The physician suspects viral pneumonia, but the sputum culture tests come back with the following description: ‘fried-egg shaped colonies on sterol-containing media, and mulberry-shaped colonies on media containing sterols’. A direct Coombs test comes back positive. Which of the following statements is true regarding the complications associated with Mycoplasma pneumoniae?

Red blood cells bind to IgM in cold temperatures < 37°C (98.6°F)

It is similarly associated with systemic lupus erythematosus

The underlying mechanism is complement-independent.

Red blood cells bind to IgG in warm temperatures > 37°C (98.6°F)

It primarily causes intravascular hemolysis rather than extravascular hemolysis

A 25-year-old man of Mediterranean descent makes an appointment with his physician because his skin and sclera have become yellow. He complains of fatigue and fever that started at the same time icterus appeared. On examination, he is tachycardic and tachypneic. The oxygen (O2) saturation is < 90%. He has increased unconjugated bilirubin, hemoglobinemia, and an increased number of reticulocytes in the peripheral blood. What is the most likely diagnosis?

Hemolytic anemia caused by glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency)

Microcytic anemia caused by iron deficiency

Autoimmune hemolytic anemia (AIHA)

A 4-year-old boy is brought to the physician because of yellowish discoloration of his eyes and skin for 5 days. He has had generalized fatigue and mild shortness of breath over the past 2 months. Two weeks ago, he was treated for a urinary tract infection with antibiotics. His father has a history of undergoing a splenectomy in his childhood. Examination shows pale conjunctivae and jaundice. The abdomen is soft and nontender; the spleen is palpated 4 to 5 cm below the left costal margin. Laboratory studies show: Hemoglobin 9.9 g/dL Mean corpuscular volume 88 μm3 Mean corpuscular hemoglobin 31.7 pg/cell Mean corpuscular hemoglobin concentration 37.0% Hb/cell Leukocyte count 6600/mm3 Platelet count 233,000/mm3 Red cell distribution width 24.3% (N = 13–15) Serum Bilirubin Total 12.3 mg/dL Direct 1.8 mg/dL Lactate dehydrogenase 401 U/L Which of the following is the most likely cause of these findings?

Defective spectrin in the RBC membrane

Decreased synthesis of alpha chains of hemoglobin

Deficient glucose-6 phosphate dehydrogenase

A 55-year-old man comes to the physician because of progressive daytime sleepiness and exertional dyspnea for the past 6 months. Physical examination shows conjunctival pallor and several subcutaneous purple spots on his legs. His hemoglobin concentration is 8.5 g/dL, leukocyte count is 3,000/mm3, and platelet count is 16,000/mm3. Which of the following laboratory values is most likely to be increased in this patient?

Lactate dehydrogenase concentration

A 24-year-old woman, otherwise healthy, presents with a non-productive cough, sore throat, and myalgia. The patient reports that her symptoms started gradually 2 weeks ago and have not improved. She has no significant past medical history and no current medications. She is a college student and denies any recent overseas travel. The patient received the flu vaccine this year, and her 2-part PPD required for school was negative. She does not smoke, drink, or use recreational drugs. The patient denies being sexually active. The vital signs include: temperature 37.0°C (98.6°F), blood pressure 110/75 mm Hg, pulse 98/min, respirations 20/min, and oxygen saturation 99% on room air. On physical exam, the patient is alert and cooperative. The cardiac exam is normal. There are rales present bilaterally over both lung fields. The skin and conjunctiva are pale. The laboratory tests are pending. The chest X-ray is shown in the image. Which of the following laboratory findings would also commonly be found in this patient?

Elevated cold agglutinin titers

Heinz bodies on peripheral smear

Low serum ferritin and serum iron

Schistocytes on peripheral smear

A 68-year-old woman comes to the physician because of increasing heartburn for the last few months. During this period, she has taken ranitidine several times a day without relief and has lost 10 kg (22 lbs). She has retrosternal pressure and burning with every meal. She has had heartburn for several years and took ranitidine as needed. She has hypertension. She has smoked one pack of cigarettes daily for the last 40 years and drinks one glass of wine occasionally. Other current medications include amlodipine and hydrochlorothiazide. She appears pale. Her height is 163 cm (5 ft 4 in), her weight is 75 kg (165 lbs), BMI is 27.5 kg/m2. Her temperature is 37.2°C (98.96°F), pulse is 78/min, and blood pressure is 135/80 mm Hg. Cardiovascular examination shows no abnormalities. Abdominal examination shows mild tenderness to palpation in the epigastric region. Bowel sounds are normal. The remainder of the examination shows no abnormalities. Laboratory studies show: Hemoglobin 10.2 g/dL Mean corpuscular volume 78 μm Mean corpuscular hemoglobin 23 pg/cell Leukocyte count 9,500/mm3 Platelet count 330,000/mm3 Serum Na+ 137 mEq/L K+ 3.8 mEq/L Cl- 100 mEq/L HCO3- 25 mEq/L Creatinine 1.2 mg/dL Lactate dehydrogenase 260 U/L Alanine aminotransferase 18 U/L Aspartate aminotransferase 15 U/L Lipase (N < 280 U/L) 40 U/L Troponin I (N < 0.1 ng/mL) 0.029 ng/mL An ECG shows normal sinus rhythm without ST-T changes. Which of the following is the most appropriate next step in the management of this patient?

24-hour esophageal pH monitoring

Hemolytic anemias for USMLE Step 3: High-Yield Internal Medicine Lessons

Overview - Red Cell Roulette

Premature destruction of red blood cells (RBCs) when bone marrow compensation is overwhelmed. RBC lifespan falls below the normal 100-120 days.
Classification:
- Location: Intravascular (within vessels) vs. Extravascular (spleen, liver).
- Etiology: Inherited (e.g., spherocytosis) vs. Acquired (e.g., autoimmune, MAHA).
Key Labs: ↑LDH, ↑unconjugated bilirubin, ↑reticulocyte count.

⭐ Haptoglobin is a key marker; it binds free Hb. A sharp ↓ in haptoglobin is highly specific for intravascular hemolysis.

Blood smear: schistocytes, polychromasia, and nucleated RBCs

Intrinsic Defects - Born to Lyse

Membrane Defect: Hereditary Spherocytosis (HS)
- Autosomal dominant defect in RBC membrane proteins (spectrin, ankyrin).
- Causes loss of membrane surface area → spherocytes (↑ MCHC) → splenic sequestration.
- Presents with splenomegaly, jaundice; diagnosed with osmotic fragility test.
- Risk of aplastic crisis with Parvovirus B19.
Enzyme Defects
- G6PD Deficiency (X-linked): ↓ NADPH production impairs defense against oxidative stress.
  - Triggers: Sulfa drugs, fava beans, infections.
  - Smear shows Heinz bodies and bite cells. 📌 "Bite into some Heinz ketchup."
- Pyruvate Kinase Deficiency (AR): ↓ ATP production → rigid RBCs → extravascular hemolysis.

⭐ In G6PD deficiency, enzyme assays may be falsely normal during an acute hemolytic episode because older, deficient RBCs are hemolyzed first, leaving a younger population of cells.

Bite cell formation and appearance in peripheral smear

Extrinsic Insults - Acquired Annihilation

Immune-Mediated (Coombs Positive)
- Warm AIHA: IgG-mediated; optimal at core body temp. Causes: SLE, CLL, drugs (e.g., α-methyldopa). Labs show spherocytes & +Direct Coombs (anti-IgG).
- Cold Agglutinin Disease: IgM-mediated; optimal <37°C. Causes: Mycoplasma pneumoniae, EBV. Labs show RBC agglutination & +Direct Coombs (anti-C3).
Microangiopathic Hemolytic Anemia (MAHA)
- RBC fragmentation in small vessels → Schistocytes ("helmet cells").
- Causes: TTP, HUS, DIC, HELLP syndrome, malignant hypertension.

⭐ The TTP classic pentad is Fever, Anemia (MAHA), Thrombocytopenia, Renal failure, and Neurologic symptoms (FAT RN). It's caused by deficient ADAMTS13 activity.

Other Causes
- Infections: Malaria, Babesia.
- Mechanical Trauma: Prosthetic heart valves, March hemoglobinuria.

Clinical Approach - The Hemolysis Hunt

Initial Labs: Suspect hemolysis with anemia + ↑ LDH, ↑ indirect bilirubin, and ↓ haptoglobin.
Reticulocyte Count: Expect ↑ reticulocytes (>2%), indicating bone marrow compensation.

⭐ Haptoglobin is the most sensitive indicator for intravascular hemolysis. Its levels are depleted as it binds free hemoglobin released from lysed RBCs.

High‑Yield Points - ⚡ Biggest Takeaways

Intravascular hemolysis presents with hemoglobinuria; extravascular with jaundice & splenomegaly.

Universal labs: ↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin.

G6PD deficiency: oxidative stress (sulfa drugs, fava beans) triggers hemolysis; see Heinz bodies & Bite cells.

Hereditary Spherocytosis: AD inheritance, spherocytes, ↑ MCHC, positive osmotic fragility test.

Sickle Cell Anemia: AR inheritance, vaso-occlusive crises, Howell-Jolly bodies (autosplenectomy).

AIHA: diagnosed via Direct Coombs test (IgG for warm, C3 for cold).

PNH: complement-mediated hemolysis with a high risk of thrombosis.

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