What it is:Anemia isn't a single disease, it's a lab finding: hemoglobin below 13 g/dL in menor 12 g/dL in women(WHO cutoffs), reflecting either too few red cells or not enough hemoglobin packed into them. The oxygen-carrying capacity of blood drops, and everything downstream in the chapter is about figuring out why.
The core problem:Red cell production is a supply chain. You need raw material (iron), you need the machinery to assemble DNA fast enough to divide immature cells (B12 and folate), and you need a marrow that isn't being chemically suppressed (inflammation, chronic disease, marrow failure). Break any one link and you get anemia, but each break has a completely different fix.
What you do about it:Never treat "anemia." Treat the specific deficiency or process behind it. Giving iron to someone whose real problem is inflammation does nothing (and can be actively unhelpful); giving B12 to someone who's actually folate-deficient masks the diagnosis and lets neurologic damage progress.
Every anemia workup is really answering three questions in sequence: (1) Is the marrow trying?That's the reticulocyte count. (2) What size are the cells it's making?That's the MCV, macrocytic, microcytic, or normocytic. (3) What's actually missing or being blocked?That's ferritin, TIBC, B12, and folate. Learn this three-step funnel and you can reason through almost any anemia case instead of memorizing disconnected disease names.
Anemia gets sorted along two independent axes, and the exam trap is treating them as the same thing. One is mechanistic (what's actually broken in production), the other is descriptive (what the cells look like under the scope).
| Functional category | What's broken | Examples |
|---|---|---|
| Hypoproliferative | Marrow isn't making enough, either because it lacks raw material (cytoplasmic defect) or because it's being suppressed (stimulation problem) | Iron deficiency, thalassemia, sideroblastic anemia (cytoplasmic) · renal disease, inflammation, metabolic disease (stimulation) |
| Maturation disorder | Marrow has raw material but can't finish assembling the nucleus, so cells don't divide properly | Folate deficiency, vitamin B12 deficiency, refractory anemia |
| Hemorrhage / hemolysis | Production may be normal, but cells are being lost or destroyed faster than they're replaced | Blood loss, intravascular hemolysis, autoimmune disease, hemoglobinopathy, metabolic or membrane defects |
| Morphologic category | MCV | Usual cause |
|---|---|---|
| Microcytic | Small cells | Iron deficiency |
| Macrocytic | Large cells, MCV >100 fL | Vitamin B12 or folic acid deficiency |
| Normocytic | Normal-sized cells | Recent blood loss or chronic disease |
The functionalclassification tells you the mechanism (why production failed). The morphologicclassification tells you what you'll actually see first on a CBC (cell size). You use morphology to start the workup, then land on a functional diagnosis. They answer different questions, and a question that swaps one for the other is testing whether you know that.
The four anemias in this chapter each represent a different failure point in making red cells, and the treatment is always just replacing or fixing whatever failed.
Iron is the literal building block of heme, so when the supply runs out, the marrow keeps trying to make cells but can't finish loading them with hemoglobin. The result is small, pale cells. IDA develops from inadequate dietary intake, inadequate GI absorption, increased demand (pregnancy is the classic example), blood loss, or chronic disease. This is exactly why the fix is simple in concept: put iron back in the system, either through the gut or, if the gut can't be used, through a vein.
Both vitamins are required for DNA synthesis. Without them, the nucleus can't mature and divide on schedule even though the cytoplasm keeps growing, so you get large, immature-looking cells (macrocytic). Dietary deficiency, malabsorption, and inadequate utilization all cause this. B12 deficiency specifically from lack of intrinsic factor is called pernicious anemia. Folate deficiency has its own separate list of drivers: hyperutilization states like pregnancy, hemolytic anemia, malignancy, chronic inflammatory disease, long-term dialysis, burns, and growth spurts in adolescents and infants, plus drug effects, phenytoin reduces folate absorption and methotrexate directly antagonizes folate. This is exactly why replacing the missing vitamin (not a blood transfusion, not iron) fixes the maturation defect at its source.
AI covers both anemia of chronic disease and anemia of critical illness. It's a diagnosis of exclusion tied to malignant, infectious, or inflammatory processes, tissue injury, and release of proinflammatory cytokines. Unlike true iron deficiency, the iron isn't gone, it's present but functionally locked away and unavailable for making new red cells, which is exactly why serum iron is low but ferritin (the storage marker) is normal or even elevated. This is exactly why giving oral or IV iron to someone with pure AI doesn't work: the problem isn't a lack of iron, it's that inflammation is blocking access to the iron that's already there.
Elderly patients have reduced bone marrow reserve, so several minor, often-unrecognized problems (like mild nutritional deficiencies) can stack up and tip them into anemia in a way a younger marrow would compensate for. Pediatric anemia more often reflects a primary hematologic abnormality, and rapid growth spurts combined with dietary gaps raise the risk of IDA specifically in that population.
What the patient feels depends heavily on how fast the anemia developed, plus their age and cardiovascular status. The same hemoglobin number can look completely different in a healthy 25-year-old versus someone with underlying heart disease.
| Onset | Typical symptoms |
|---|---|
| Acute | Cardiopulmonary symptoms dominate: palpitations, angina, light-headedness, shortness of breath |
| Chronic | Weakness, fatigue, headache, orthopnea, dyspnea on exertion, vertigo, faintness, cold sensitivity, pallor |
Severity of symptoms does not reliably track with degree of anemia. A slow, chronic drop lets the body compensate, so someone can be profoundly anemic and still feel only mildly off, while an acute drop of the same magnitude can look like a cardiac emergency.
Folate deficiency anemia is not associated with neurologic symptoms.B12 deficiency is. If a question gives you numbness, paresthesias, or psychiatric changes alongside macrocytic anemia, the answer is B12, not folate, and it's worth acting fast since neurologic damage from B12 deficiency can outlast the hematologic recovery.
Anemia is frequently a sign of something else going on underneath, so working it up quickly matters. Initial evaluation is a CBC, a reticulocyte index, and a stool exam for occult blood.
The earliest and most sensitive change is a decreased serum ferritin(the storage marker), read alongside decreased transferrin saturation and increased total iron-binding capacity (TIBC). Hemoglobin, hematocrit, and RBC indices tend to stay normal until IDA is fairly advanced, which is exactly why ferritin catches it first.
MCV climbs above 100 fL. From there, B12 and folate levels separate the two causes.
| Test | Diagnostic cutoff |
|---|---|
| Vitamin B12 | <200 pg/mL (148 pmol/L), combined with compatible peripheral smear and symptoms |
| RBC folate | <150 ng/mL (340 nmol/L), a better indicator than serum folate |
| Serum folate | <2 ng/mL (4.5 nmol/L), less reliable than RBC folate |
Also a diagnosis of exclusion, and you have to actively consider coexisting iron or folate deficiency before landing here. The lab signature that separates it from IDA is the key testable point.
Both have low serum iron, which is why they get confused. The tell is ferritin and TIBC move in opposite directions. In IDA: ferritin low, TIBC high. In AI: ferritin normal-to-high, TIBC low. Bone marrow in AI actually shows plenty of iron sitting there, it's just not accessible, and the peripheral smear looks normocytic rather than microcytic.
Elderly patients get a CBC with peripheral smear and reticulocyte count, plus whatever additional labs the picture suggests, to pin down the etiology. Pediatric diagnosis requires age- and sex-adjusted normal ranges rather than adult cutoffs.
Across every anemia in this chapter, the goals are the same three things: return hematologic parameters to normal, restore normal function and quality of life, and prevent long-term complications.How you get there depends entirely on which deficiency or process you're correcting, which is why the rest of this document is organized by cause, not by one generic "anemia" protocol.
| Route | Regimen |
|---|---|
| Oral (first-line) | Soluble ferrous iron salts, not enteric-coated, not slow/sustained release, at 150-200 mg elemental iron/day in 2-3 divided doses. Continue 3-6 months after Hb normalizes to fully replete iron stores and prevent relapse. |
| Parenteral | Reserve for iron malabsorption, intolerance of oral iron, or nonadherence. Dose (mg) = whole blood Hb deficit (g/L) × body weight (kg) × 0.22 |
Enteric-coated and sustained-release formulations pass through the duodenum, which is where iron actually gets absorbed, before the coating dissolves. A gentler-seeming formulation can end up delivering less usable iron. Plain, immediate-release ferrous salts are the ones proven to work.
| Iron salt | % elemental iron | Common formulations (elemental iron provided) |
|---|---|---|
| Ferrous sulfate | 20% | 60-65 mg/324-325 mg tablet · 44 mg/5 mL elixir · 15 mg/1 mL solution |
| Ferrous gluconate | 12% | 38 mg/325 mg tablet · 28-29 mg/240-246 mg tablet |
| Ferrous fumarate | 33% | 66 mg/200 mg tablet · 106 mg/324-325 mg tablet |
| Ferric maltol | 100% | 30 mg/30 mg |
Iron absorbs best from meat, fish, and poultry. Administer oral iron at least 1 hour before mealssince food blunts absorption, but if that causes intolerable GI upset, giving it with food (accepting somewhat lower absorption) is a reasonable tradeoff to keep the patient adherent.
Available parenteral options: iron dextran, sodium ferric gluconate, iron sucrose, ferumoxytol, ferric derisomaltose, ferric pyrophosphate citrate, and ferric carboxymaltose. These have similar efficacy to each other but differ in molecular size, pharmacokinetics, bioavailability, and adverse effect profiles, which is why product selection is individualized rather than one-size-fits-all.
| Situation | Regimen |
|---|---|
| No neurologic symptoms | Oral cobalamin 1 mg daily. Effective even in pernicious anemia, because an alternate absorption pathway works independently of intrinsic factor. |
| Neurologic symptoms present | Parenteral acts faster: IM cyanocobalamin 1000 mcg daily × 1 week, then weekly × 1 month, then monthly for maintenance. Switch to daily oral once symptoms resolve. |
| Pernicious anemia | Continue vitamin B12 for life, since the underlying intrinsic-factor defect never resolves. |
It's tempting to assume pernicious anemia requiresinjections since the problem is intrinsic factor. It doesn't. High-dose oral B12 gets absorbed passively at a low rate regardless of intrinsic factor status, so it still works, it's just slower to build up. Parenteral therapy earns its place when symptoms (especially neurologic ones) need a faster response, not because oral therapy is ineffective.
Oral folic acid 1 mg daily for 4 monthsis usually sufficient, as long as the underlying cause can be corrected. If malabsorption is driving the deficiency, dosing increases to 1-5 mg daily. Parenteral folic acid exists but is rarely necessary since oral absorption of folate isn't intrinsic-factor dependent the way B12 is.
Never treat macrocytic anemia with folic acid alone until B12 deficiency is ruled out. Folic acid can correct the hematologic picture in a B12-deficient patient while doing nothing to stop the neurologic damage, effectively masking the real diagnosis while the nervous system keeps deteriorating.
Treatment is less specific than for the deficiency anemias, and the priority is correcting whatever reversible process is driving it.
Reserve iron therapy for a confirmed, established IDA. Iron is not effectivewhen inflammation is present, because the problem isn't an empty iron supply, it's inflammation blocking access to iron that's already there. Giving iron anyway doesn't correct the anemia and just adds unnecessary iron exposure.
| Option | Use |
|---|---|
| RBC transfusion | Effective, but reserve for episodes of inadequate oxygen transport and Hb of 7-8 g/dL (70-80 g/L) |
| Epoetin alfa | 50-100 units/kg three times weekly (initial) |
| Darbepoetin alfa | 0.45 mcg/kg once weekly (initial) |
ESA response is often impaired in AI, and supplementing iron, cobalamin, and folic acid alongside an ESA may improve response.
Watch for increases in blood pressure, nausea, headache, fever, bone pain, and fatigue. Hb must be monitored during ESA therapy: an increase above 12 g/dL, or a rise of more than 1 g/dL every 2 weeks, is associated with increased mortality and cardiovascular events. Correcting anemia too fast with an ESA is a real harm, not just a lab curiosity.
In anemia of critical illness specifically, parenteral iron is often used, but it carries a theoretical risk of infection that's worth weighing given the patient's overall clinical state.
| Population | Key point |
|---|---|
| Infants 9-12 months | Ferrous sulfate 3-6 mg/kg/day elemental iron, divided once or twice daily between meals, for 4 weeks. Responders continue an additional 2 months to replace storage iron pools. Folic acid dose is 1 mg daily; B12 dosing is titrated to clinical and lab response. |
| Elderly | Reduced bone marrow reserve means several minor, often-unrecognized problems can combine to cause anemia that a younger marrow would have compensated for. |
| Pediatric, general | Anemia more often reflects a primary hematologic abnormality; rapid growth spurts plus dietary deficiency raise IDA risk specifically. |
Each anemia has its own expected recovery timeline, and knowing it tells you when to worry that the diagnosis or therapy is wrong.
| Anemia | Expected timeline | Watching for |
|---|---|---|
| IDA | Modest reticulocytosis within days; Hb rise visible at 2 weeks; Hb normal by 2 months | Reevaluate the patient if reticulocytosis doesn't occur. Continue iron until stores are replenished and ferritin normalizes, which can take up to 12 months. |
| Megaloblastic (B12) | Symptoms improve within days; reticulocytosis in 3-5 days; Hb starts rising about 1 week in, normalizes in 1-2 months | Neurologic symptoms improve more slowly, or may be irreversible, but should not keep progressing once therapy starts |
| Megaloblastic (folate) | Reticulocytosis in 3-5 days; Hct rises within 2 weeks, normalizes within 2 months | Same reticulocyte timeline as B12, but no expected neurologic recovery curve since folate deficiency doesn't cause neuro symptoms |
| ESA therapy | Reticulocytosis within a few days | Iron, TIBC, transferrin saturation, and ferritin at baseline and periodically. Discontinue if no clinical response after 8 weeks. |
| Pediatric iron therapy | Recheck at 4-8 weeks | Hb, Hct, and RBC indices; check weekly in premature infants specifically |