Haematopoiesis, iron and the megaloblastic anaemias

How bone marrow makes blood cells, what growth factors steer it, and how lack of iron, vitamin B12 or folate leads to anaemia.

Updated Nov 12, 2026

The bone marrow replaces billions of blood cells every day from a small pool of stem cells, guided by growth factors such as erythropoietin and G-CSF. Production also needs raw materials, above all iron, vitamin B12 and folate. This page explains the lineages and growth factors used as drugs, how the body absorbs and recycles iron, and the biochemistry behind megaloblastic anaemia and its tests.

Key points

Pluripotent stem cells give rise to committed progenitors, steered by lineage-specific growth factors: erythropoietin for red cells, G-CSF and GM-CSF for granulocytes, thrombopoietin for platelets.
Erythropoietin is made mainly by the kidney in response to low oxygen, through the HIF pathway; kidney failure causes anaemia from its lack.
The body has no active way to excrete iron, so absorption in the duodenum is the control point; the liver hormone hepcidin blocks the iron exporter ferroportin.
Vitamin B12 and folate are both needed for DNA synthesis; lack of either makes large, immature red cells (megaloblastic anaemia).
Methylmalonic acid rises in B12 deficiency but not in folate deficiency; homocysteine rises in both.
Folic acid can correct the anaemia of B12 deficiency but not its nerve damage, which may become permanent.

Lineages and growth factors

Stem cells in the marrow both renew themselves and give rise to progenitors that commit to one lineage. Progenitors are named by the colonies they form in culture (for example CFU-E for red cells and CFU-GM for granulocytes and macrophages). Growth factors are glycoproteins that drive survival and multiplication of these progenitors; several have become drugs.

Erythropoietin: main regulator of red cell progenitors. Low oxygen stabilises HIF, which switches on the erythropoietin gene in the kidney. Drugs: epoetin alfa and darbepoetin alfa; HIF prolyl hydroxylase inhibitors raise the body's own production.
G-CSF (filgrastim, pegfilgrastim): raises neutrophil counts after chemotherapy and mobilises stem cells for collection. GM-CSF (sargramostim) acts more broadly.
Thrombopoietin: drives megakaryocytes and platelets; receptor agonists such as romiplostim and eltrombopag are used in immune thrombocytopenia.
Interleukins such as IL-3, IL-6 and IL-11 and stem cell factor act earlier and on several lineages.

Erythropoiesis-stimulating agents: benefits and limits

Epoetin and darbepoetin treat anaemia from chronic kidney disease, some chemotherapy and zidovudine, and reduce transfusions. Pushing haemoglobin up to normal raised the risk of stroke, heart attack, heart failure and thrombosis, and in some cancers was linked to tumour progression and shorter survival. Labels therefore aim for the lowest level that avoids transfusion. Iron deficiency, inflammation and infection make these drugs work poorly, so iron status is checked first.

Iron: absorption, transport and storage

Most body iron sits in haemoglobin, and old red cells are recycled by macrophages, so daily needs are small. Losses are not regulated, so balance is controlled at absorption. In the duodenum, dietary ferric iron is reduced to ferrous iron and taken up by the transporter DMT1; haem iron from meat is taken up separately and much more efficiently. Iron leaves the gut cell, and macrophages, through ferroportin, is reoxidised and travels bound to transferrin to the marrow, where cells take it up through transferrin receptors. Spare iron is stored as ferritin. Hepcidin, made by the liver when iron is high or during inflammation, binds ferroportin and causes its destruction, shutting the exit door.

Low hepcidin (deficiency, active erythropoiesis): absorption rises. Inherited low hepcidin action causes haemochromatosis.
High hepcidin (inflammation, chronic disease): iron is trapped in macrophages and absorption falls, causing the anaemia of inflammation; oral iron works poorly there.
Vitamin C helps absorption of non-haem iron; phytates, tannins in tea, calcium, antacids and proton pump inhibitors reduce it.
Frequent oral doses raise hepcidin and may reduce the fraction absorbed from later doses, one reason for interest in alternate-day regimens.
Groups at risk include infants, adolescent girls, menstruating and pregnant women, and people with gut bleeding, including from intestinal parasites common in tropical regions.

Megaloblastic anaemia: the biochemistry

Folate in its reduced forms carries one-carbon units needed to make thymidylate and purines, so DNA synthesis slows when it is lacking while cytoplasm keeps growing: cells become large with immature nuclei, and neutrophils hypersegment. Vitamin B12 links to folate at one enzyme: methionine synthase uses methylcobalamin to move a methyl group from methyltetrahydrofolate to homocysteine, making methionine and freeing tetrahydrofolate. Without B12, folate gets stuck as methyltetrahydrofolate, the folate trap, and the cell behaves as if folate-deficient. B12 (as deoxyadenosylcobalamin) is also the cofactor of methylmalonyl-CoA mutase, which has nothing to do with folate.

Diagnosis and treatment principles

Homocysteine rises in both B12 and folate deficiency, because both are needed by methionine synthase.
Methylmalonic acid rises in B12 deficiency only, and is the more sensitive marker of tissue B12 lack.
B12 absorption needs stomach acid, intrinsic factor from parietal cells and the terminal ileum; causes of deficiency include pernicious anaemia, gastrectomy, ileal disease, strict vegan diets, and long use of metformin or acid suppressants.
Folate deficiency comes from poor diet, alcohol, pregnancy, haemolysis and drugs such as methotrexate, trimethoprim and some antiepileptics. Fortification and folic acid before conception reduce neural tube defects.
Giving folic acid alone in B12 deficiency bypasses the trap and improves the blood count, but nerve and spinal cord damage continues. B12 status is therefore checked before folate treatment; B12 is given by injection when absorption is impaired, or orally in high amounts.

Test yourself

Think of the answer, then tap the question to see it.

How does low oxygen increase red cell production?

Hypoxia stabilises HIF, which switches on erythropoietin production in the kidney; erythropoietin drives red cell progenitors in the marrow.

How does hepcidin control iron, and why does oral iron work poorly in inflammation?

Hepcidin destroys ferroportin, the iron exit channel of gut cells and macrophages; inflammation raises hepcidin, so little oral iron is absorbed.

What is the folate trap?

Without vitamin B12, methionine synthase stops, so folate accumulates as methyltetrahydrofolate and cannot return to the forms used for DNA synthesis.

Which test separates B12 deficiency from folate deficiency?

Methylmalonic acid: high in B12 deficiency, normal in folate deficiency. Homocysteine is high in both.

Why is giving folic acid alone risky in B12 deficiency?

It can correct the anaemia and hide the diagnosis while nerve and spinal cord damage progresses and may become irreversible.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Epoetin Alfa, Injection: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); Filgrastim Injection: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); Methylmalonic Acid (MMA) Test: MedlinePlus Medical Test (MedlinePlus (U.S. National Library of Medicine), 2026).

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