USMLE Step 1 Hematology Practice Questions
A ValueMD community study resource: original practice questions covering the core hematology concepts tested on USMLE Step 1.
Hematology on Step 1 rewards the ability to connect a CBC pattern or peripheral smear finding to the right diagnosis quickly. The 30 questions below are organized by topic so you can target a specific weak area or work through the set in order.
Educational note: these are original practice questions written for exam review, not a substitute for your course material or a clinical reference.
Anemias
1. A 40-year-old woman with longstanding rheumatoid arthritis has a mild normocytic anemia. Serum iron and TIBC are both low, while ferritin is elevated. What is the most likely explanation?
- A. Iron deficiency anemia
- B. Anemia of chronic disease
- C. Beta-thalassemia trait
- D. Sideroblastic anemia
Answer: B. Anemia of chronic disease is driven by hepcidin-mediated iron sequestration in inflammatory states. This produces low serum iron and low TIBC together with a normal or elevated ferritin, distinguishing it from iron deficiency, where TIBC is elevated and ferritin is low.
2. A 51-year-old woman reports fatigue and is found to have decreased vibratory sensation in her feet. Her MCV is 124 fL, reticulocyte count is low, and hypersegmented neutrophils are seen on smear. Which test should be ordered next?
- A. Serum ferritin
- B. Hemoglobin electrophoresis
- C. Serum B12 and folate levels
- D. HIV antibody test
Answer: C. Macrocytic anemia with hypersegmented neutrophils and peripheral neuropathy points to B12 deficiency, which affects both hematologic and neurologic systems (via impaired myelin synthesis), unlike isolated folate deficiency, which causes the same macrocytic anemia without the neurologic findings.
3. A 30-year-old woman has Hgb 11.1 g/dL, MCV 77 fL, mild reticulocytosis, and small round red cells lacking central pallor on smear, along with a palpable spleen tip. Which diagnosis best fits?
- A. Iron deficiency anemia
- B. Hereditary spherocytosis
- C. Sickle cell trait
- D. Thalassemia minor
Answer: B. Hereditary spherocytosis produces spherocytes (small, round cells without central pallor) due to a red cell membrane defect, along with splenomegaly and reticulocytosis from ongoing extravascular hemolysis in the spleen.
4. A patient has helmet cells (schistocytes) on peripheral smear along with thrombocytopenia and evidence of active infection. Which condition is most consistent with this finding?
- A. Beta-thalassemia
- B. Hereditary spherocytosis
- C. Microangiopathic hemolysis from sepsis/DIC
- D. Massive splenomegaly alone
Answer: C. Schistocytes form when red cells are mechanically sheared passing through fibrin strands in small vessels, classically seen in disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and other microangiopathic hemolytic processes, often triggered by severe infection.
5. A 13-year-old with chronic anemia has a hemoglobin electrophoresis showing 95% Hgb S. Which inheritance pattern and population association best fits sickle cell disease?
- A. Autosomal dominant, European ancestry
- B. Autosomal recessive, West African ancestry
- C. X-linked recessive, Middle Eastern ancestry
- D. Sporadic, no ancestry association
Answer: B. Sickle cell disease is autosomal recessive and is most prevalent in populations with West African ancestry, reflecting the historical selective advantage the sickle trait provided against malaria.
6. A young adult wants to reduce heavy alcohol use. Which MCV would most plausibly reflect alcohol-related macrocytosis in the absence of frank anemia?
- A. MCV of 55 fL
- B. MCV of 75 fL
- C. MCV of 85 fL
- D. MCV of 105 fL
Answer: D. Chronic alcohol use commonly produces a mild macrocytosis (elevated MCV) even without significant anemia, through direct toxic effects on erythropoiesis, distinct from the more pronounced macrocytosis seen in true B12 or folate deficiency.
7. A patient with a positive direct Coombs test and evidence of hemolysis is most consistent with which mechanism?
- A. Membrane defect causing spherocytosis
- B. Autoantibody bound directly to red cell surface antigens
- C. Mechanical shearing in small vessels
- D. Enzyme deficiency causing oxidative hemolysis
Answer: B. A positive direct Coombs (direct antiglobulin) test detects antibody or complement bound to the patient’s own red cells, confirming an autoimmune or alloimmune cause of hemolysis rather than a mechanical or enzymatic one.
Leukemias and Myeloproliferative Disorders
8. A 30-year-old man has a progressive cough, palpable spleen tip, WBC count of 67,000/microliter, and blasts with Auer rods on peripheral smear. What is the most likely diagnosis?
- A. Acute myelogenous leukemia
- B. Chronic lymphocytic leukemia
- C. Acute lymphoblastic leukemia
- D. Leukemoid reaction
Answer: A. Auer rods are needle-like cytoplasmic inclusions specific to myeloid blasts and are a hallmark finding of acute myelogenous leukemia, distinguishing it from acute lymphoblastic leukemia, which does not produce Auer rods.
9. A 64-year-old woman undergoing routine preoperative labs is incidentally found to have a WBC count of 26,000/microliter with many small, mature-appearing lymphocytes, no lymphadenopathy, and no organomegaly. What is the most likely diagnosis?
- A. Infectious mononucleosis
- B. Chronic lymphocytic leukemia
- C. Acute lymphocytic leukemia
- D. Cytomegalovirus infection
Answer: B. Chronic lymphocytic leukemia is often diagnosed incidentally in older adults with an asymptomatic lymphocytosis of small, mature-appearing lymphocytes, in contrast to the atypical, reactive lymphocytes seen in mononucleosis.
10. A 45-year-old plethoric man has headache, dizziness, and a bone marrow biopsy showing hypercellularity with all three cell lines increased. Which CBC pattern best fits this presentation?
- A. Hgb 20 g/dL, Hct 61%, MCV 92 fL
- B. Hgb 10 g/dL, platelet count 3,000/microliter
- C. Total lymphocyte count of 200/microliter
- D. WBC differential showing 15 eosinophils per 100 cells
Answer: A. Polycythemia vera involves panmyelosis (increased red cells, white cells, and platelets), and the markedly elevated hemoglobin and hematocrit reflect the erythrocytosis that drives the classic plethoric appearance and hyperviscosity symptoms.
11. A patient has a WBC count of 4,900/microliter with occasional teardrop-shaped red cells and a leukoerythroblastic differential (immature myeloid and nucleated red cells) on peripheral smear. Which diagnosis is most likely?
- A. Disseminated intravascular coagulation
- B. Hereditary spherocytosis
- C. Myelofibrosis
- D. Parvovirus infection
Answer: C. Myelofibrosis replaces the bone marrow with fibrous tissue, forcing extramedullary hematopoiesis and pushing immature myeloid precursors and nucleated red cells into the circulation, while the fibrotic marrow itself produces the characteristic teardrop-shaped red cells.
12. A patient presents with fever, purpuric skin hemorrhages, a low fibrinogen, thrombocytopenia, and a WBC differential dominated by promyelocytes. Which finding would you most expect to confirm the associated leukemia subtype?
- A. Numerous Auer rods with a t(15;17) translocation
- B. Philadelphia chromosome
- C. Terminal deoxynucleotidyl transferase (TdT) positivity
- D. Isolated eosinophilia
Answer: A. This presentation, promyelocyte predominance with DIC-like coagulopathy, is classic for acute promyelocytic leukemia (a subtype of AML), which carries the t(15;17) translocation and is notorious for triggering disseminated intravascular coagulation at presentation.
13. Which finding would most strongly suggest chronic myelogenous leukemia rather than a reactive leukemoid reaction?
- A. Toxic granulation in neutrophils
- B. Presence of the Philadelphia chromosome, BCR-ABL fusion
- C. Elevated leukocyte alkaline phosphatase
- D. Mild left shift with bandemia only
Answer: B. The Philadelphia chromosome (BCR-ABL fusion from a t(9;22) translocation) is the defining molecular marker of chronic myelogenous leukemia and is absent in a reactive leukemoid reaction, which instead typically shows elevated (not decreased) leukocyte alkaline phosphatase.
14. A 9-year-old boy has fatigue, pallor, and a CBC showing pancytopenia with a low WBC count and no lymphadenopathy or organomegaly. Bone marrow biopsy would most likely show which finding if this represents aplastic anemia rather than leukemia?
- A. Hypercellular marrow with blast predominance
- B. Hypocellular marrow with fatty replacement
- C. Marrow fibrosis with teardrop cells in circulation
- D. Marrow with sheets of plasma cells
Answer: B. Aplastic anemia is characterized by a hypocellular, fatty-replaced bone marrow producing pancytopenia, in contrast to acute leukemia, which produces a hypercellular marrow packed with blasts.
Lymphoma and Reactive Lymphoid Conditions
15. A lymph node biopsy shows bands of fibrosis, lacunar-type Reed-Sternberg variants, and focal necrosis. Which statement about this condition is FALSE?
- A. It typically affects young adults.
- B. Other lymph node groups may become involved over time.
- C. A monoclonal immunoglobulin spike is a typical associated finding.
- D. Staging often includes bone marrow evaluation.
Answer: C. This describes nodular sclerosis Hodgkin lymphoma. A monoclonal immunoglobulin spike is not a typical feature of Hodgkin lymphoma, it’s characteristic of plasma cell disorders like multiple myeloma, making that statement the false one among the answer choices.
16. A 19-year-old man has several weeks of pharyngitis, fever, lymphadenopathy, mild scleral icterus, and a positive monospot test. Which peripheral blood finding is most characteristic?
- A. Eosinophilia
- B. Atypical lymphocytosis
- C. Isolated thrombocytosis
- D. Increased band neutrophils
Answer: B. Infectious mononucleosis (Epstein-Barr virus) classically produces a striking atypical lymphocytosis, reflecting reactive, activated CD8-positive T cells responding to EBV-infected B cells, rather than a true leukemic proliferation.
17. A cervical lymph node biopsy from a child with a recent sore throat and runny nose shows well-defined paracortical follicles with reactive germinal centers. What does this pattern most likely represent?
- A. Metastatic carcinoma
- B. Reactive lymphoid hyperplasia
- C. Follicular lymphoma
- D. Multiple myeloma involvement
Answer: B. Prominent reactive germinal centers in an enlarged lymph node in the setting of a recent upper respiratory infection is the classic appearance of reactive (benign) lymphoid hyperplasia, not a malignant process.
Coagulation and Platelet Disorders
18. A 62-year-old man has declining renal function, proteinuria, and a large monoclonal gamma spike on serum protein electrophoresis. Which additional finding would be LEAST expected in this condition?
- A. Elevated BUN and creatinine
- B. Hypercalcemia
- C. Normocytic anemia
- D. Marked eosinophilia
Answer: D. This presentation describes multiple myeloma, which classically causes renal impairment, hypercalcemia (from bone destruction), and normocytic anemia. Marked eosinophilia is not a typical feature of multiple myeloma.
19. A patient with fever, purpura, thrombocytopenia, and schistocytes on smear, along with a low fibrinogen and elevated D-dimer, most likely has which condition?
- A. Immune thrombocytopenic purpura
- B. Disseminated intravascular coagulation
- C. Hereditary spherocytosis
- D. Iron deficiency anemia
Answer: B. DIC consumes both platelets and clotting factors (lowering fibrinogen) while generating fibrin strands that shear red cells into schistocytes, producing this combination of thrombocytopenia, coagulopathy, and microangiopathic hemolysis.
20. Which of the following is most useful for distinguishing immune thrombocytopenic purpura from disseminated intravascular coagulation?
- A. Platelet count alone
- B. Fibrinogen and D-dimer levels
- C. Presence of any bleeding symptoms
- D. Hemoglobin level
Answer: B. Both conditions can cause thrombocytopenia and bleeding, but DIC additionally consumes clotting factors, producing a low fibrinogen and elevated D-dimer, findings that are typically normal in isolated immune thrombocytopenic purpura.
Reactive and Secondary Blood Count Changes
21. A WBC differential shows 13% eosinophils. Which of the following would NOT typically explain this finding?
- A. Ascaris lumbricoides infection
- B. Extrinsic (allergic) asthma
- C. Corticosteroid therapy
- D. Hypersensitivity pneumonitis
Answer: C. Corticosteroids typically suppress eosinophil counts rather than raise them, while parasitic infection, allergic asthma, and hypersensitivity pneumonitis are all classic causes of true eosinophilia.
22. A 61-year-old smoker with a hilar lung mass and bone metastases develops easy bruising, moon facies, and truncal obesity despite overall weight loss. Which hematologic finding would this presentation most likely produce?
- A. Eosinophilia
- B. Neutrophilia
- C. Lymphopenia
- D. Polycythemia
Answer: C. This describes paraneoplastic ectopic ACTH production causing Cushing syndrome. Endogenous or exogenous glucocorticoid excess characteristically causes lymphopenia (along with neutrophilia in many cases), reflecting glucocorticoid-induced lymphocyte redistribution and apoptosis.
23. A dehydrated marathon runner has an elevated hematocrit on routine labs with no other CBC abnormality. What is the most likely explanation?
- A. True polycythemia vera
- B. Relative (spurious) polycythemia from hemoconcentration
- C. Chronic myelogenous leukemia
- D. Secondary polycythemia from chronic hypoxia
Answer: B. Dehydration reduces plasma volume without changing the actual red cell mass, producing an artificially elevated hematocrit and hemoglobin concentration, distinct from true polycythemia (either primary, as in polycythemia vera, or secondary to chronic hypoxia).
24. A 69-year-old man has chronic back pain, weight loss, and a leukoerythroblastic blood picture (immature myeloid cells and nucleated red cells) without fever. What is the most likely underlying cause?
- A. Hemolytic anemia
- B. Chronic lymphocytic leukemia
- C. Metastatic carcinoma infiltrating the bone marrow
- D. Previous splenectomy
Answer: C. A leukoerythroblastic picture in an older adult with bone pain and weight loss, without infection, strongly suggests marrow infiltration by metastatic carcinoma (myelophthisic process), which pushes immature and nucleated cells into the peripheral circulation.
Infection-Associated Hematologic Findings
25. Which infectious agent is most associated with triggering autoimmune hemolytic anemia through molecular mimicry or cold agglutinin formation?
- A. Mycoplasma pneumoniae
- B. Parvovirus B19
- C. Plasmodium species
- D. Babesia species
Answer: A. Mycoplasma pneumoniae infection classically triggers cold agglutinin formation (IgM antibodies against the I red cell antigen), producing autoimmune hemolytic anemia, distinct from parvovirus B19, which instead causes transient marrow suppression (aplastic crisis) rather than hemolysis.
26. A patient with sickle cell disease develops a sudden drop in hemoglobin and a very low reticulocyte count during a febrile illness. Which infectious agent is the classic cause of this aplastic crisis?
- A. Epstein-Barr virus
- B. Parvovirus B19
- C. Cytomegalovirus
- D. Mycoplasma pneumoniae
Answer: B. Parvovirus B19 infects erythroid progenitor cells directly, temporarily halting red cell production. In patients with a shortened red cell lifespan from an underlying hemolytic condition like sickle cell disease, this produces a sudden, severe aplastic crisis.
27. A newborn is found to be hydropic with significant anemia and elevated bilirubin shortly after birth. Which mechanism is most likely responsible?
- A. Hereditary spherocytosis inherited from an affected parent
- B. Rh alloimmunization causing hemolytic disease of the newborn
- C. Iron deficiency from poor maternal nutrition
- D. Physiologic jaundice of the newborn
Answer: B. Hydrops fetalis with severe anemia and hyperbilirubinemia in a newborn is classically caused by Rh alloimmunization, in which maternal IgG antibodies cross the placenta and destroy fetal Rh-positive red cells, producing severe hemolysis in utero.
Putting It Together
28. A 51-year-old man on new antihypertensive medication still has epigastric burning pain. His CBC shows a low MCV (75 fL) with a normal platelet count and no other abnormality. What is the most cost-effective next test?
- A. Hemoglobin electrophoresis
- B. Serum haptoglobin
- C. Stool guaiac test
- D. Urinalysis
Answer: C. A microcytic anemia in a patient with ongoing epigastric pain raises concern for chronic GI blood loss, most efficiently screened for first with a stool guaiac test before moving to more specialized or expensive studies.
29. A patient has an isolated finding of sickled erythrocytes on peripheral smear. Which clinical scenario best fits this finding?
- A. A young adult with severe abdominal and bone pain during a vaso-occlusive crisis
- B. A patient with recent parvovirus B19 infection alone
- C. A patient with chronic atrophic gastritis
- D. A patient with Wilson’s disease and ascites
Answer: A. Sickled erythrocytes on a peripheral smear, especially accompanied by severe pain, are the classic finding of a vaso-occlusive sickle cell crisis, in which deoxygenated hemoglobin S polymerizes and distorts red cell shape.
30. A patient with chronic hemolysis and gallstones is found to have an elevated indirect (unconjugated) bilirubin with a normal direct bilirubin. What does this pattern most directly reflect?
- A. Impaired bile duct drainage
- B. Increased red cell breakdown exceeding the liver’s conjugation capacity
- C. Primary liver cell dysfunction
- D. Decreased albumin production
Answer: B. Chronic hemolysis increases the load of unconjugated bilirubin delivered to the liver faster than it can be conjugated and excreted, raising indirect bilirubin while direct (conjugated) bilirubin stays normal, and the excess bilirubin also predisposes to pigment gallstones.
Frequently Asked Questions
What’s the fastest way to distinguish anemia of chronic disease from iron deficiency anemia? Both can be microcytic or normocytic, but anemia of chronic disease shows a low TIBC alongside low serum iron, while iron deficiency shows a high TIBC with low iron. Ferritin is also typically low in iron deficiency but normal or elevated in anemia of chronic disease, since ferritin is an acute-phase reactant.
How do I remember which conditions cause Auer rods versus TdT positivity? Auer rods are specific to myeloid blasts and point to acute myelogenous leukemia. TdT (terminal deoxynucleotidyl transferase) is a marker of lymphoblasts and points to acute lymphoblastic leukemia instead. If a vignette mentions Auer rods, think myeloid; if it mentions TdT, think lymphoblastic.
What’s the difference between direct and indirect Coombs tests? The direct Coombs (direct antiglobulin) test detects antibody or complement already bound to a patient’s own red cells, confirming autoimmune hemolysis. The indirect Coombs test detects antibodies in a patient’s serum that could bind to red cells, which is more relevant for pretransfusion compatibility testing and prenatal Rh screening.
Why does dehydration cause a falsely elevated hematocrit? Hematocrit measures the proportion of blood volume occupied by red cells. Dehydration reduces the plasma (liquid) portion of blood without changing the actual number of red cells, so the same red cell mass now makes up a larger percentage of a smaller total blood volume, artificially raising the hematocrit without reflecting true polycythemia.
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