Skip to content

Add your earlier progress to your account?

From before you signed in, this browser has:

Which plan do you want to keep?

You answered the plan questions before you signed in, and those answers don't match the plan saved on your account.

SettingSaved planNew answers

Study progress is waiting to be saved

Macrocytic anemias

15 min

Skills you'll build4 skills
  • Tell vitamin B12 from folate deficiency with methylmalonic acid and homocysteine
  • Recognize a raised MCV caused by a high reticulocyte count
  • Recognize a vitamin B12 deficiency pattern from the CBC, film, and B12 result
  • Recognize polychromatophilic cells as young red cells on a Wright-stained film

At the bench: Relate red cell indices and morphology to the anemia workup

Try first

Try first

A patient's homocysteine is elevated and methylmalonic acid is elevated. Which deficiency does this support?

Keep going to see the reasoning.

Right. Keep going to follow the reasoning.

Keep going to see the reasoning.

Keep going to see the reasoning.

Get the idea

Use the explanation to check your first decision.

Megaloblastic and nonmegaloblastic macrocytosis

Megaloblastic anemia comes from impaired DNA synthesis and delayed nuclear maturation. It often produces an MCV from about 100 to 150 fL, oval macrocytes, marked anisocytosis, and hypersegmented neutrophils.1 The International Council for Standardization in Haematology defines hypersegmentation as at least one neutrophil with six or more lobes, or more than 3% of neutrophils with five lobes, out of 100 examined.2 Nonmegaloblastic causes include reticulocytosis, liver disease, hypothyroidism, marrow disease and medication effect. They more often produce round macrocytes without hypersegmentation and an MCV nearer 100 to 110 fL.1

Reticulocytes and the MCV

Reticulocytes are larger than mature red cells, so hemolysis, recovery after hemorrhage, or a response to effective treatment can raise the MCV without megaloblastic change.1 Round macrocytes and a raised reticulocyte count without hypersegmented neutrophils distinguish this regenerative pattern from a megaloblastic one.1

Polychromasia and the reticulocyte count

Polychromatophilic cells on a Wright-stained film are young reticulocytes, slate blue-gray from residual ribosomal RNA.3 They show that marrow output has reached the blood. A film impression cannot measure how many there are. The reticulocyte count and its production index quantify the response.3

Vitamin B12 and folate testing

Macro-ovalocytes and hypersegmented neutrophils support megaloblastic change but do not identify its cause, since folate deficiency and myelodysplasia can produce the same morphology.4 A low vitamin B12, with methylmalonic acid when B12 is indeterminate, supports B12 deficiency. Homocysteine rises with either B12 or folate deficiency and cannot distinguish them.4 Many laboratories treat a total B12 below about 200 to 250 pg/mL as subnormal, though the exact decision limit is assay-dependent.4

Follow the bench demonstration

Sources for this step
References
  1. Keohane EM, Preston MM, Mirza KM, Walenga JM, eds. Rodak's Hematology: Clinical Principles and Applications. 7th ed. Elsevier; 2025. Accessed September 26, 2026. https://www.us.elsevierhealth.com/rodaks-hematology-9780323936507.html
  2. Palmer L, Briggs C, McFadden S, et al. ICSH recommendations for the standardization of nomenclature and grading of peripheral blood cell morphological features. Int J Lab Hematol. 2015;37(3):287-303. doi:10.1111/ijlh.12327
  3. College of American Pathologists. 2026 Hematology, Clinical Microscopy, and Body Fluids Glossary. 2026. Accessed September 26, 2026. https://www.cap.org/wp-content/uploads/documents/2026-Heme-Glossary-FINAL.pdf
  4. National Institutes of Health, Office of Dietary Supplements. Vitamin B12: Fact Sheet for Health Professionals. Updated April 2, 2026. Accessed September 26, 2026. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/

Watch one

Read each decision and its explanation.

A patient's CBC shows hemoglobin 8.4 g/dL, MCV 118 fL, WBC 3.1 × 10³/µL, and platelets 98 × 10³/µL. The film shows oval macrocytes and a neutrophil with 6 nuclear lobes. The reticulocyte count is 0.6%, below the reference interval. Vitamin B12 is 150 pg/mL, and methylmalonic acid is elevated. Interpret the pattern.

  1. Check the MCV. At 118 fL it is macrocytic, within the range megaloblastic anemia often produces.

    The MCV classifies the anemia before further testing.

  2. Review the film. Oval macrocytes and a neutrophil with 6 lobes both support megaloblastic change.

    Hypersegmentation and oval macrocytes together support the megaloblastic pattern.

  3. Check the other cell lines. The WBC count and platelet count are both reduced, consistent with megaloblastic hematopoiesis affecting more than one lineage.

    Megaloblastic change can lower more than one cell line, and the CBC shows whether it has.

  4. Check the reticulocyte count. At 0.6% it is inappropriately low for this degree of anemia, consistent with impaired DNA synthesis.

    An adequate marrow response would show reticulocytosis, and this pattern shows the opposite.

  5. Check the B12 and methylmalonic acid. B12 is low and methylmalonic acid is elevated, which supports B12 deficiency as the cause.

    Morphology cannot identify the cause. The biochemical results identify it.

The pattern fits megaloblastic macrocytic anemia from vitamin B12 deficiency. Macro-ovalocytes, a hypersegmented neutrophil, reduced WBC and platelet counts, an inappropriately low reticulocyte count, a low B12, and an elevated methylmalonic acid are all consistent.

Practice this skill

Your turn

Problem 1 of 3 · Hints available

Which paired blood-film findings most strongly support megaloblastic hematopoiesis?

Incorrect. These findings suggest membrane or immune processes and do not define the megaloblastic pattern.

Incorrect. These findings support impaired hemoglobin assembly, including iron restriction or thalassemia.

Correct. The paired findings support delayed nuclear maturation from impaired DNA synthesis. Biochemical confirmation is still needed.

Hint
  1. Consider the two listed findings together.
  2. A finding of impaired hemoglobin synthesis points to a microcytic process.
  3. The megaloblastic pattern needs biochemical confirmation even when the film fits it.

Review Macrocytic anemia patterns

Problem 2 of 3 · Hints available

A patient recovering from acute blood loss has MCV 106 fL, a reticulocyte count of 8%, and a markedly elevated absolute reticulocyte count. The film shows round macrocytes and no hypersegmented neutrophils. What explains the raised MCV?

Megaloblastic change produces oval macrocytes and hypersegmented neutrophils, and the reticulocyte count would be inappropriately low. Neither fits here.

Called reticulocyte macrocytosis megaloblastic

Reticulocytes are larger than mature red cells, so a brisk response after bleeding or hemolysis raises the MCV. Polychromasia, a raised reticulocyte count, and round macrocytes without hypersegmented neutrophils separate it from megaloblastic change, which shows oval macrocytes and an inappropriately low reticulocyte count.

Reticulocytes are larger than mature red cells. A brisk response after bleeding raises the MCV, and round macrocytes without hypersegmentation fit this regenerative pattern.

Cold agglutinins falsely raise the MCV by clumping red cells, but here the reticulocyte count and film already explain the macrocytosis.

Hint
  1. Compare the size of a reticulocyte with a mature red cell.
  2. Check the film for the specific findings that support megaloblastic change.

Review Nonmegaloblastic macrocytosis and spurious results

Problem 3 of 3 · On your own

A patient's homocysteine is mildly elevated and methylmalonic acid is within its reference interval. Which deficiency does this best support?

Homocysteine rises with either vitamin B12 or folate deficiency, so an elevated homocysteine cannot identify B12 deficiency.

Used homocysteine to separate B12 from folate deficiency

Homocysteine rises in both vitamin B12 and folate deficiency, so it cannot separate them. Methylmalonic acid rises in B12 deficiency and is the more specific marker, although kidney impairment and age also raise it.

Methylmalonic acid is the more specific marker for B12 deficiency and is normal here. A normal methylmalonic acid with an elevated homocysteine favors folate deficiency.

Serum folate and B12 testing, interpreted with these two markers, narrow the cause. A marrow biopsy is not the routine next step for this question.

Review Vitamin B12 and folate

Use it

Read the case evidence, then make each decision. The step is complete without it.

  • A man on the medical ward is recovering 5 days after a large upper gastrointestinal bleed, now hemodynamically stable.
  • His hemoglobin has risen from 7.2 to 9.8 g/dL since the day of the bleed, without transfusion.
  • The film shows round macrocytes and frequent polychromatophilic cells, with no hypersegmented neutrophils.
  • Homocysteine is mildly elevated. Methylmalonic acid is within its reference interval.
  • He has no history of alcohol use, liver disease, or thyroid disease.
TestResultPreviousReference intervalFlag
Hemoglobin9.8 g/dL Low5 days ago: 7.2 g/dL7.2 g/dL5 days ago13.5–17.5 g/dL13.5–17.5Low
MCV101 fL High5 days ago: 89 fL89 fL5 days ago76–100 fL76–100High
WBC11.0 × 10³/µL High5 days ago: 9.8 × 10³/µL9.8 × 10³/µL5 days ago3.6–10.6 × 10³/µL3.6–10.6High
Platelets480 × 10³/µL High5 days ago: 260 × 10³/µL260 × 10³/µL5 days ago150–450 × 10³/µL150–450High
Reticulocytes, relative6.5 % High5 days ago: 1.2 %1.2 %5 days ago0.5–2.5 %0.5–2.5High
Reticulocytes, absolute260 × 10³/µL High5 days ago: 55 × 10³/µL55 × 10³/µL5 days ago20–115 × 10³/µL20–115High

Specimen: H 6, L 10, I 2. Serum and EDTA specimens drawn together this morning.

Decision 1 of 3

What do the polychromatophilic cells on the film show, and can their number on the film substitute for the reticulocyte count?

Polychromatophilic cells are young reticulocytes, but a film impression cannot measure how many there are. The reticulocyte count and its production index quantify the response.

Treated polychromasia as a direct reticulocyte count

Polychromatophilic cells are young reticulocytes that stain slate blue-gray. A film impression cannot measure how many there are. Estimating the response from the film misstates marrow output, which the reticulocyte count and production index quantify.

Polychromasia shows that marrow output has reached the blood. The reticulocyte count, 6.5% and markedly elevated in absolute terms, quantifies that response.

Polychromasia indicates a marrow response to any cause of anemia, including this recent hemorrhage. It cannot distinguish hemolysis from a brisk response to blood loss.

Review Red-cell morphology on the stained film

Decision 2 of 3

What explains the raised MCV in this case?

Megaloblastic change would show oval macrocytes, hypersegmented neutrophils, and an inappropriately low reticulocyte count. This film and count show the opposite.

Called reticulocyte macrocytosis megaloblastic

Reticulocytes are larger than mature red cells, so a brisk response after bleeding or hemolysis raises the MCV. Polychromasia, a raised reticulocyte count, and round macrocytes without hypersegmented neutrophils separate it from megaloblastic change, which shows oval macrocytes and an inappropriately low reticulocyte count.

Reticulocytes are larger than mature red cells. The markedly elevated absolute reticulocyte count and round macrocytes without hypersegmentation fit a regenerative response to the recent bleed.

Nothing in the history or results points to liver disease, and the reticulocyte response already explains the macrocytosis.

Review Nonmegaloblastic macrocytosis and spurious results

Decision 3 of 3

Given the mildly elevated homocysteine and the normal methylmalonic acid, does this patient need further vitamin B12 workup right now?

Homocysteine rises with either B12 or folate deficiency and cannot point to B12 deficiency specifically. The normal methylmalonic acid argues against it.

Used homocysteine to separate B12 from folate deficiency

Homocysteine rises in both vitamin B12 and folate deficiency, so it cannot separate them. Methylmalonic acid rises in B12 deficiency and is the more specific marker, although kidney impairment and age also raise it.

The film and reticulocyte count already explain the macrocytosis as regenerative. A normal methylmalonic acid argues against B12 deficiency as an additional cause.

Here the CBC, film, and reticulocyte count already give a sufficient explanation. Testing is chosen by the pattern in each case.

Review Vitamin B12 and folate

The reticulocyte response explains the raised MCV. A markedly elevated absolute reticulocyte count and round macrocytes without hypersegmentation fit a regenerative macrocytosis, and a normal methylmalonic acid, the specific marker, argues against vitamin B12 deficiency.

For reference

Sources checked