A 46-year-old woman is referred with suspected TTP. She has had fatigue for months and numbness in both feet. Results: Hb 6.2 g/dL [62 g/L], MCV 109 fL, reticulocytes 0.8% (absolute 14 × 10^3/µL [14 × 10^9/L]), WBC 3.1 × 10^3/µL [3.1 × 10^9/L], platelets 64 × 10^3/µL [64 × 10^9/L], LD 4,900 U/L (reference 100-225 U/L), haptoglobin < 10 mg/dL [< 0.1 g/L], indirect bilirubin 2.4 mg/dL [41 µmol/L] (reference 0.2-0.8 mg/dL), DAT negative, and PT and APTT normal. The film shows hypersegmented neutrophils, oval macrocytes and 3% schistocytes. ADAMTS13 activity is 68%, and creatinine is 0.9 mg/dL [80 µmol/L]. The most likely diagnosis is:

Immune thrombotic thrombocytopenic purpura

Complement-mediated (atypical) HUS

An 8-month-old boy, exclusively breastfed, feeds poorly, has weak muscle tone and can no longer sit unsupported, as he could 2 months ago. His mother has followed a strict vegan diet for 6 years without supplements. Results: Hb 7.6 g/dL [76 g/L], MCV 98 fL (reference for age 70-86 fL), WBC 4.2 × 10^3/µL [4.2 × 10^9/L], platelets 110 × 10^3/µL [110 × 10^9/L] and hypersegmented neutrophils. Serum B12 is 85 pg/mL [63 pmol/L] (reference 200-900 pg/mL), folate is normal, and methylmalonic acid and homocysteine are both markedly raised. What is the most likely cause?

Maternal dietary B12 deficiency

Folate deficiency in the infant

Congenital intrinsic factor deficiency

A 22-year-old who inhales nitrous oxide recreationally has tingling legs, an MCV of 106 fL and a raised homocysteine. His serum B12 is low-normal. How does nitrous oxide cause this picture?

It oxidizes B12 and blocks methionine synthase

It causes autoimmune loss of parietal cells

It blocks B12-intrinsic factor uptake in the ileum

It inhibits dihydrofolate reductase in cells

The antibody test most specific for pernicious anemia is:

Anti-tissue transglutaminase IgA

Macrocytic anemias: megaloblastic and non-megaloblastic

19 ASCP MLS practice questions on Macrocytic anemias: megaloblastic and non-megaloblastic, part of Hematology. The first 19 are below; the first 5 with answers and explanations (tap Show answer after you have chosen), the rest in Learn with a free account.

Question 1 · Hard
A 46-year-old woman is referred with suspected TTP. She has had fatigue for months and numbness in both feet. Results: Hb 6.2 g/dL [62 g/L], MCV 109 fL, reticulocytes 0.8% (absolute 14 × 10^3/µL [14 × 10^9/L]), WBC 3.1 × 10^3/µL [3.1 × 10^9/L], platelets 64 × 10^3/µL [64 × 10^9/L], LD 4,900 U/L (reference 100-225 U/L), haptoglobin < 10 mg/dL [< 0.1 g/L], indirect bilirubin 2.4 mg/dL [41 µmol/L] (reference 0.2-0.8 mg/dL), DAT negative, and PT and APTT normal. The film shows hypersegmented neutrophils, oval macrocytes and 3% schistocytes. ADAMTS13 activity is 68%, and creatinine is 0.9 mg/dL [80 µmol/L]. The most likely diagnosis is:
1. AImmune thrombotic thrombocytopenic purpura
2. BSevere vitamin B12 deficiency
3. CComplement-mediated (atypical) HUS
4. DAcute erythroid leukemia
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Answer: B · Severe vitamin B12 deficiency
Pancytopenia with oval macrocytes, hypersegmented neutrophils and numb feet points to vitamin B12 deficiency. In severe megaloblastic anemia, fragile red cell precursors die in the marrow and some circulating cells fragment, so LD can be extremely high, haptoglobin absent and schistocytes present, a picture that mimics a thrombotic microangiopathy. The low reticulocyte count is the key difference: the marrow is failing to respond, whereas the peripheral destruction of TTP brings a raised count. An ADAMTS13 activity of 68% excludes TTP, and the normal creatinine argues against HUS. Serum B12 and methylmalonic acid confirm the diagnosis, and plasma exchange is not needed.
- A: ADAMTS13 activity is 68%, and TTP brings a raised reticulocyte count.
- C: Creatinine is normal, so there is no kidney injury to suggest HUS.
- D: Acute erythroid leukemia would show erythroid blasts; numb feet and hypersegmented neutrophils point to B12.
Question 2 · Hard
An 8-month-old boy, exclusively breastfed, feeds poorly, has weak muscle tone and can no longer sit unsupported, as he could 2 months ago. His mother has followed a strict vegan diet for 6 years without supplements. Results: Hb 7.6 g/dL [76 g/L], MCV 98 fL (reference for age 70-86 fL), WBC 4.2 × 10^3/µL [4.2 × 10^9/L], platelets 110 × 10^3/µL [110 × 10^9/L] and hypersegmented neutrophils. Serum B12 is 85 pg/mL [63 pmol/L] (reference 200-900 pg/mL), folate is normal, and methylmalonic acid and homocysteine are both markedly raised. What is the most likely cause?
1. ATranscobalamin II deficiency
2. BFolate deficiency in the infant
3. CCongenital intrinsic factor deficiency
4. DMaternal dietary B12 deficiency
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Answer: D · Maternal dietary B12 deficiency
Megaloblastic anemia with hypersegmented neutrophils, a low B12 and raised methylmalonic acid and homocysteine show true vitamin B12 deficiency, and the loss of skills reflects its effect on the developing nervous system. A baby's B12 comes from stores built up before birth and from breast milk, and both are low when the mother has eaten no animal foods for years without supplements. Such infants typically present at about 4 to 12 months, as here. Transcobalamin II deficiency presents in the first months with a normal serum B12, because most measured B12 is bound to haptocorrin. Folate is normal, and congenital intrinsic factor deficiency is rare and usually presents after the first year; the mother should also be tested and treated.
- A: Transcobalamin II deficiency usually shows a normal serum B12 and presents in the first months.
- B: Folate is normal, and the raised methylmalonic acid points to B12.
- C: Congenital intrinsic factor deficiency is rare and usually presents after the first year.
Question 3 · Hard
A 22-year-old who inhales nitrous oxide recreationally has tingling legs, an MCV of 106 fL and a raised homocysteine. His serum B12 is low-normal. How does nitrous oxide cause this picture?
1. AIt oxidizes B12 and blocks methionine synthase
2. BIt causes autoimmune loss of parietal cells
3. CIt blocks B12-intrinsic factor uptake in the ileum
4. DIt inhibits dihydrofolate reductase in cells
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Answer: A · It oxidizes B12 and blocks methionine synthase
Nitrous oxide oxidizes the cobalt atom in cobalamin, which inactivates the B12-dependent enzyme methionine synthase. Homocysteine builds up and folate is trapped as methyltetrahydrofolate, so DNA synthesis and the nervous system both suffer. The serum B12 can be normal or only slightly low because the assay also measures the inactive vitamin, so homocysteine and methylmalonic acid are better markers. Frequent recreational use can cause subacute combined degeneration in young people.
- B: Autoimmune loss of parietal cells is the cause of pernicious anemia.
- C: Nitrous oxide acts on B12 already in the body, not on its absorption.
- D: Dihydrofolate reductase is inhibited by methotrexate, not nitrous oxide.
Question 4 · Medium
The antibody test most specific for pernicious anemia is:
1. AAnti-tissue transglutaminase IgA
2. BAnti-parietal cell antibody
3. CAntinuclear antibody
4. DAnti-intrinsic factor antibody
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Answer: D · Anti-intrinsic factor antibody
Anti-intrinsic factor antibodies are found in only about half of patients with pernicious anemia, but they are very rarely present without it, so a positive result is close to diagnostic. Anti-parietal cell antibodies are more sensitive but also occur in other autoimmune diseases and in many healthy older people. A raised gastrin and low pepsinogen I support autoimmune gastritis. These tests are done after B12 deficiency has been shown.
- A: Anti-tTG IgA is a screen for celiac disease, which mainly affects iron and folate absorption.
- B: Anti-parietal cell antibody is more sensitive but much less specific.
- C: Antinuclear antibody screens for systemic autoimmune disease, not pernicious anemia.
Question 5 · Medium
Which drug commonly raises the MCV by slowing DNA synthesis, even when serum B12 and folate are normal?
1. AFerrous sulfate
2. BWarfarin
3. CIsoniazid
4. DHydroxyurea
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Answer: D · Hydroxyurea
Hydroxyurea inhibits ribonucleotide reductase, the enzyme that makes the deoxyribonucleotides needed for DNA, so red cell precursors divide more slowly and grow larger. A rising MCV is expected in patients who take it, for example in sickle cell disease, and is used as a rough check that they take the drug. Zidovudine, azathioprine and methotrexate also raise the MCV. Serum B12 and folate stay normal, and no vitamin treatment is needed.
- A: Iron therapy corrects microcytosis; it does not cause macrocytosis.
- B: Warfarin is an anticoagulant and does not raise the MCV.
- C: Isoniazid interferes with vitamin B6 and can cause a sideroblastic anemia, often microcytic.
Question 6 · Medium
Red cell folate reflects tissue folate stores better than serum folate does, because red cell folate:
1. AReflects folate over recent months
2. BRises within hours of a folate-rich meal
3. CIs not lowered by vitamin B12 deficiency
4. DIs unaffected by a recent transfusion
Answer and explanation in LearnFree account
Question 7 · Hard
A 55-year-old man has Hgb 11.8 g/dL (118 g/L), MCV 108 fL, RDW 13.9%, platelets 112 × 10^3/µL (112 × 10^9/L), round macrocytes and target cells, no hypersegmented neutrophils, normal serum B12 and red cell folate, and a GGT three times the upper limit. The most likely cause of the macrocytosis is:
1. AAlcohol use and liver disease
2. BEarly pernicious anemia
3. CMyelodysplastic syndrome
4. DDietary folate deficiency
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Question 8 · Easy
What is the basic defect in megaloblastic anemia?
1. AImpaired iron transport
2. BImpaired heme synthesis
3. CImpaired DNA synthesis
4. DImpaired globin synthesis
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Question 9 · Easy
After intake stops, body folate stores in a healthy adult usually last about:
1. A2 to 3 weeks
2. B3 to 4 months
3. C1 to 2 years
4. D3 to 5 years
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Question 10 · Medium
Which red cell finding on the film favors a megaloblastic cause of macrocytosis over alcohol use or liver disease?
1. ARound macrocytes
2. BTarget cells
3. COval macrocytes
4. DStomatocytes
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Question 11 · Easy
Intrinsic factor, which the ileum needs to absorb vitamin B12, is secreted by:
1. AGastric chief cells
2. BParietal cells of the stomach
3. CIleal enterocytes
4. DPancreatic acinar cells
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Question 12 · Hard
A 68-year-old woman has numb feet, an MCV of 117 fL and hypersegmented neutrophils. Her serum B12 is within the reference interval, but methylmalonic acid and homocysteine are both raised and anti-intrinsic factor antibody is positive. What best explains the B12 result?
1. AFolate deficiency with normal B12 status
2. BRecent folic acid supplements
3. CHypothyroidism causing the macrocytosis
4. DAntibody interference in the B12 assay
Answer and explanation in LearnFree account
Question 13 · Hard
Megaloblastic anemia caused by vitamin B12 deficiency is treated with folic acid alone. What is the expected result?
1. ABlood counts and nerve damage both improve
2. BNeither the blood counts nor the nerves improve
3. CNerve damage improves but the anemia persists
4. DCounts improve while nerve damage progresses
Answer and explanation in LearnFree account
Question 14 · Hard
A 66-year-old man with jejunal diverticula has a macrocytic anemia with hypersegmented neutrophils. Serum B12 is low and methylmalonic acid is raised, but serum folate is above the reference interval. Gastrin is normal and gastric antibodies are negative. What is the most likely cause?
1. AAutoimmune pernicious anemia
2. BSmall-bowel bacterial overgrowth
3. CMyelodysplastic syndrome
4. DDietary folate deficiency
Answer and explanation in LearnFree account
Question 15 · Hard
In untreated severe pernicious anemia with Hgb 6.4 g/dL (64 g/L), which other set of results is expected?
1. AHigh retic, normal LD, normal haptoglobin
2. BHigh retic, high LD, low haptoglobin
3. CLow retic, normal LD, normal haptoglobin
4. DLow retic, very high LD, low haptoglobin
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Question 16 · Medium
After acute blood loss or hemolysis, an MCV of 104 fL with a reticulocyte count of 9% (0.09), polychromasia and no hypersegmented neutrophils is best explained by:
1. AA high number of reticulocytes
2. BVitamin B12 malabsorption
3. CEarly myelodysplastic syndrome
4. DFolate deficiency from blood loss
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Question 17 · Medium
Which finding points to vitamin B12 deficiency rather than folate deficiency?
1. AOval macrocytes with a high MCV
2. BA raised serum homocysteine
3. CLoss of vibration sense in the feet
4. DHypersegmented neutrophils
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Question 18 · Hard
In a patient with megaloblastic anemia, the set of results that fits folate deficiency without B12 deficiency is:
1. AMMA normal, homocysteine raised, B12 normal
2. BMMA raised, homocysteine normal, B12 normal
3. CMMA raised, homocysteine raised, B12 low
4. DMMA normal, homocysteine normal, B12 low
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Question 19 · Medium
Hypersegmented neutrophils (six or more lobes) on a blood film most suggest which condition?
1. APelger-Huët anomaly
2. BVitamin B12 or folate deficiency
3. CBacterial infection with a left shift
4. DIron deficiency
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Macrocytic anemias: megaloblastic and non-megaloblastic

A 22-year-old who inhales nitrous oxide recreationally has tingling legs, an MCV of 106 fL and a raised homocysteine. His serum B12 is low-normal. How does nitrous oxide cause this picture?

The antibody test most specific for pernicious anemia is:

Which drug commonly raises the MCV by slowing DNA synthesis, even when serum B12 and folate are normal?

Red cell folate reflects tissue folate stores better than serum folate does, because red cell folate:

What is the basic defect in megaloblastic anemia?

After intake stops, body folate stores in a healthy adult usually last about:

Which red cell finding on the film favors a megaloblastic cause of macrocytosis over alcohol use or liver disease?

Intrinsic factor, which the ileum needs to absorb vitamin B12, is secreted by:

A 68-year-old woman has numb feet, an MCV of 117 fL and hypersegmented neutrophils. Her serum B12 is within the reference interval, but methylmalonic acid and homocysteine are both raised and anti-intrinsic factor antibody is positive. What best explains the B12 result?

Megaloblastic anemia caused by vitamin B12 deficiency is treated with folic acid alone. What is the expected result?

A 66-year-old man with jejunal diverticula has a macrocytic anemia with hypersegmented neutrophils. Serum B12 is low and methylmalonic acid is raised, but serum folate is above the reference interval. Gastrin is normal and gastric antibodies are negative. What is the most likely cause?

In untreated severe pernicious anemia with Hgb 6.4 g/dL (64 g/L), which other set of results is expected?

After acute blood loss or hemolysis, an MCV of 104 fL with a reticulocyte count of 9% (0.09), polychromasia and no hypersegmented neutrophils is best explained by:

Which finding points to vitamin B12 deficiency rather than folate deficiency?

In a patient with megaloblastic anemia, the set of results that fits folate deficiency without B12 deficiency is:

Hypersegmented neutrophils (six or more lobes) on a blood film most suggest which condition?