Anemias

• Definition: anemia is a reduction in circulating red cell mass, operationalized in clinic as a hemoglobin or hematocrit below age-, sex-, and (per WHO) altitude- and pregnancy-adjusted norms. It is a sign, never a final diagnosis — every case demands a mechanism.
• Why it matters: oxygen delivery equals cardiac output × arterial oxygen content, and hemoglobin is the dominant term in content. Falling hemoglobin forces compensatory tachycardia and increased stroke volume, so anemia unmasks angina, precipitates decompensation in heart failure, and independently predicts worse outcomes in CKD, malignancy, and the perioperative period.
• A second reason it matters: in an adult without an obvious source, iron deficiency anemia is occult GI blood loss until proven otherwise — colorectal carcinoma is the diagnosis examiners want you to chase, not the anemia itself.

Epidemiology worth recalling

• Global burden: WHO estimates anemia affects roughly a quarter of the world's population, with iron deficiency the single largest contributor and the most common nutritional deficiency worldwide.
• Who gets iron deficiency: menstruating and pregnant women, toddlers fed excessive cow's milk, patients post-bariatric surgery or with celiac disease, and older adults with GI lesions. The AAP recommends universal hemoglobin screening at approximately 12 months of age with risk assessment; ACOG recommends screening for anemia in pregnancy, whereas the USPSTF has issued an I statement (insufficient evidence) for routine screening and supplementation in asymptomatic pregnant persons.
• Anemia of chronic disease/inflammation is the most common anemia among hospitalized patients and the second most common overall.
• Hemoglobinopathies cluster by ancestry: sickle cell disease occurs in roughly 1 in 365 Black or African American births in the US with sickle trait in about 1 in 13 (CDC); thalassemias predominate in Mediterranean, Middle Eastern, South Asian, and Southeast Asian populations; G6PD deficiency is X-linked and common in African, Mediterranean, and Asian males.

Decreased production — nutrient substrate lacking

• Iron deficiency: chronic blood loss (menorrhagia, GI malignancy, peptic ulcer, hookworm), malabsorption (celiac disease, atrophic gastritis, post-gastrectomy/bariatric surgery, chronic PPI use), or inadequate intake (toddlers on excess cow's milk).
• B12 (cobalamin) deficiency: pernicious anemia (autoimmune loss of parietal cells and intrinsic factor), ileal resection or Crohn disease, strict veganism, Diphyllobothrium latum, chronic metformin use.
• Folate deficiency: alcohol use disorder, pregnancy/lactation, hemolysis (increased turnover), and antifolate drugs — methotrexate, trimethoprim, phenytoin.

Decreased production — marrow or signal failure

• Anemia of inflammation: IL-6-driven hepcidin excess in infection, malignancy, rheumatoid arthritis, CKD.
• Erythropoietin deficiency: chronic kidney disease.
• Marrow infiltration or aplasia: leukemia, myeloma, metastases, myelodysplastic syndrome, parvovirus B19 (pure red cell aplasia), chloramphenicol, chemotherapy, radiation, benzene.

Increased destruction (hemolysis)

• Intrinsic: membrane (hereditary spherocytosis, PNH), enzyme (G6PD, pyruvate kinase), hemoglobin (sickle cell, thalassemia).
• Extrinsic: warm IgG autoimmune (SLE, CLL, methyldopa, penicillins), cold IgM (Mycoplasma, EBV), microangiopathic (TTP, HUS, DIC, mechanical valve), infection (malaria, Babesia), hypersplenism.

Non-modifiable risk factors

• Female sex and reproductive age; extremes of age; ancestry (hemoglobinopathy, G6PD); family history; inherited GI polyposis or hereditary hemorrhagic telangiectasia.

Modifiable risk factors

• Dietary inadequacy (vegan diet without B12 supplementation, iron-poor weaning diet), alcohol use, chronic NSAID/aspirin use, unaddressed heavy menstrual bleeding, hookworm exposure, and oxidant drug exposure in G6PD deficiency (dapsone, primaquine, nitrofurantoin, rasburicase, sulfonamides).
• Uncontrolled inflammatory disease and untreated CKD are modifiable in that treating the driver improves the anemia.

From insult to small, pale cells (microcytic)

• Hemoglobin synthesis requires heme (iron + protoporphyrin) and globin chains. When iron, heme synthesis, or globin production fails, erythroid precursors undergo extra divisions while waiting for hemoglobin to accumulate — the result is a smaller cell with less pigment, hence low MCV and low MCHC with hypochromia.
• In iron deficiency the sequence is stereotyped: storage iron depletes (ferritin falls) → the liver upregulates transferrin (TIBC rises, saturation falls) → only then does hemoglobin fall. This is why ferritin drops before the MCV does.
• In lead toxicity, inhibition of ALA dehydratase and ferrochelatase blocks heme assembly; lead also inhibits rRNA degradation, leaving ribosomal aggregates seen as basophilic stippling.

From insult to large cells (macrocytic)

• B12 and folate feed the methionine synthase and thymidylate synthase reactions. Without them, dTTP is scarce, uracil is misincorporated, and DNA replication stalls while cytoplasmic RNA and protein synthesis continue — nuclear–cytoplasmic asynchrony. Precursors grow large, many die in the marrow (ineffective erythropoiesis, giving indirect hyperbilirubinemia and a strikingly high LDH), and neutrophil nuclei over-segment.
• B12 uniquely serves methylmalonyl-CoA mutase; its failure accumulates methylmalonic acid, which disrupts myelin synthesis in the dorsal columns and lateral corticospinal tracts — subacute combined degeneration. Folate deficiency spares this pathway, which is exactly why it spares the neurologic exam.

Hemolysis

• Intravascular lysis spills free hemoglobin, saturating haptoglobin (which falls), producing hemoglobinemia, hemoglobinuria, and hemosiderinuria. Extravascular lysis occurs in splenic cords, giving splenomegaly, jaundice, and pigment gallstones without hemoglobinuria.

Why symptoms appear

• Reduced oxygen content triggers 2,3-BPG rise (right-shifted curve), tachycardia, and increased stroke volume; flow becomes turbulent, producing a systolic flow murmur. When compensation is exhausted, subendocardial ischemia and high-output failure follow.

Symptoms common to all anemias (reduced oxygen-carrying capacity)

• Fatigue, exertional dyspnea, lightheadedness: inadequate tissue oxygen delivery; severity tracks with rate of onset more than absolute hemoglobin — chronic anemia at 7 g/dL may be better tolerated than acute loss to 9 g/dL.
• Pallor: best appreciated in conjunctivae, palmar creases, and nail beds, which are less affected by skin pigmentation.
• Tachycardia, wide pulse pressure, systolic ejection flow murmur: compensatory high-output state.
• Angina, claudication, or decompensated heart failure: anemia unmasking fixed arterial stenosis — an ominous finding in older patients.

Findings that name the mechanism

• Iron deficiency: pica (ice = pagophagia), koilonychia (spoon nails), angular cheilitis, restless legs. Plummer-Vinson syndrome — dysphagia from esophageal webs plus atrophic glossitis in an iron-deficient woman.
• B12 deficiency: symmetric distal paresthesias, loss of vibration and proprioception, ataxia with a positive Romberg, spastic weakness with upgoing toes, and cognitive change. Stems name a strict vegan, a patient after ileal resection or bariatric surgery, or an older woman with vitiligo and hypothyroidism (pernicious anemia's autoimmune company).
• Hemolysis: scleral icterus, dark (cola-colored) urine, splenomegaly, and leg ulcers; cold agglutinin patients report acrocyanosis after cold exposure following a Mycoplasma or EBV infection.
• G6PD deficiency: an African American or Mediterranean male with sudden back pain, jaundice, and dark urine days after a sulfa drug, nitrofurantoin, primaquine, or fava beans.
• Sickle cell disease: a child or young adult with severe bone/back/chest pain crises, dactylitis in infancy, priapism, and functional asplenia (Howell-Jolly bodies).
• Marrow failure: anemia accompanied by infection and bleeding — pancytopenia points to aplastic anemia, leukemia, or MDS rather than a nutrient deficiency.

Step 1 — CBC with indices, peripheral smear, reticulocyte count

• Confirm anemia, then use MCV to branch and the absolute reticulocyte count (or reticulocyte production index) to separate hypoproliferative marrow from appropriate response to hemolysis or bleeding.
• The RDW helps: iron deficiency raises it (mixed population), while thalassemia trait classically keeps it near normal. The Mentzer index (MCV ÷ RBC count) below ~13 favors thalassemia trait; above ~13 favors iron deficiency.

Step 2 — mechanism-specific confirmation

• Iron studies: ferritin is the single most useful test — a low ferritin (conventionally under about 30 ng/mL, with values under ~15 essentially diagnostic) confirms iron deficiency. Transferrin saturation is low and TIBC high. Because ferritin is an acute-phase reactant, in inflammation use transferrin saturation and, if needed, soluble transferrin receptor, which is elevated in true iron deficiency and normal in anemia of inflammation.
• B12 and folate levels; when B12 is borderline, methylmalonic acid and homocysteine are the tiebreakers — both elevated in B12 deficiency, only homocysteine in folate deficiency. Anti-intrinsic factor antibody supports pernicious anemia.
• Hemolysis panel: elevated LDH, elevated indirect bilirubin, low haptoglobin, reticulocytosis. Then the direct antiglobulin (Coombs) test — positive means immune-mediated; negative sends you to the smear for spherocytes, schistocytes, bite cells, or sickle forms.
• Hemoglobin electrophoresis or HPLC for sickle cell and thalassemia (universal newborn screening in the US identifies sickle disease). A G6PD enzyme assay can be falsely normal during acute hemolysis because the deficient old cells have already lysed — repeat weeks later.
• Bone marrow biopsy is the gold standard when pancytopenia, blasts, dysplasia, or unexplained hypoproliferative anemia is present, per ASH and NCCN (MDS) evaluation pathways.

Step 3 — find the cause, not just the label

• Iron deficiency in an adult male or postmenopausal woman warrants bidirectional endoscopy (ACG recommendation) to exclude GI malignancy.

Immediate stabilization

• Hemodynamically unstable bleeding: two large-bore IVs, type and crossmatch, activate the massive transfusion protocol with balanced product ratios, and control the source. Resuscitate the bleeding, not the number.
• Transfusion threshold: AABB recommends a restrictive strategy, transfusing at a hemoglobin around 7 g/dL in most hospitalized hemodynamically stable adults and around 8 g/dL in patients undergoing cardiac or orthopedic surgery or with pre-existing cardiovascular disease. Liberal transfusion confers no benefit and adds risk.

First-line, by mechanism

• Oral iron salts (ferrous sulfate) for iron deficiency; give with vitamin C on an empty stomach and separate from PPIs, calcium, and tea. Evidence supports once-daily or alternate-day dosing over divided doses because each dose raises hepcidin and blunts the next absorption. Reticulocytosis in about a week confirms response; continue several months after hemoglobin normalizes to refill stores.
• Parenteral iron (ferric carboxymaltose, iron sucrose) when oral iron fails, is not tolerated, or absorption is impaired — malabsorption, IBD, dialysis, or late pregnancy.
• Cobalamin replacement, parenteral when malabsorption or neurologic disease is present; folic acid for folate deficiency.
• Anemia of CKD: KDIGO advises correcting iron deficiency first, then erythropoiesis-stimulating agents, deliberately not targeting normal hemoglobin — targets above roughly 11.5 g/dL increase stroke and thrombosis.
• Autoimmune hemolytic anemia: corticosteroids first line, then rituximab or splenectomy; transfuse when life-threatening despite crossmatch difficulty.
• Sickle cell disease: hydroxyurea is disease-modifying (NHLBI and ASH guidance); crises are managed with hydration and prompt opioid analgesia per the ASH acute pain guideline, plus penicillin prophylaxis and pneumococcal vaccination in children and transcranial Doppler screening with chronic transfusion for stroke prevention. Allogeneic transplant — and now FDA-approved gene therapies — are curative options.

Contraindicated / avoid

• Folate alone in B12 deficiency (corrects the anemia, lets neuropathy progress); ESAs targeting normal hemoglobin; oxidant drugs in G6PD deficiency; empiric iron without finding the bleeding source.

Of the anemia itself

• High-output heart failure and demand ischemia: chronic severe anemia forces sustained tachycardia and increased stroke volume; signals include new angina, an S3, or pulmonary edema in a patient whose hemoglobin has drifted low. Emergency.
• Subacute combined degeneration in B12 deficiency: dorsal column and corticospinal demyelination. Deficits present for months may be irreversible even after repletion — this is why delay in diagnosis is the tested error.
• Developmental and cognitive impairment in iron-deficient infants and toddlers, partly irreversible.
• Pigment gallstones and aplastic crisis in chronic hemolysis; parvovirus B19 transiently shuts off erythropoiesis and, in a patient with a shortened red cell lifespan, causes an abrupt hemoglobin drop with an absent reticulocyte count.
• Sickle-specific emergencies: acute chest syndrome (new infiltrate with fever/hypoxia — leading cause of death, treat with antibiotics, oxygen, and exchange transfusion), splenic sequestration in young children (rapidly enlarging spleen with shock), overwhelming encapsulated-organism sepsis from functional asplenia, and stroke. All are emergencies.
• Thrombosis in paroxysmal nocturnal hemoglobinuria and in warm autoimmune hemolytic anemia.

Of treatment

• Oral iron: constipation, dark stools, nausea — the usual reason for nonadherence. IV iron: infusion reactions and rare anaphylaxis; some formulations cause hypophosphatemia.
• Transfusion: acute hemolytic reaction from ABO mismatch (fever, flank pain, hemoglobinuria — stop the transfusion immediately, an emergency), TRALI (hypoxemia with bilateral infiltrates, normal filling pressures), TACO (volume overload), febrile nonhemolytic and allergic reactions, alloimmunization complicating future crossmatch, and iron overload with cardiomyopathy and endocrinopathy in chronically transfused thalassemia or sickle patients — treated with chelation.
• ESAs: hypertension, thrombosis, and increased mortality when hemoglobin is normalized (KDIGO and FDA labeling).
• Hydroxyurea: myelosuppression requiring counts monitoring.
• Repletion effect: aggressive B12 or iron repletion can precipitate hypokalemia as potassium is consumed by brisk erythropoiesis.

• Iron deficiency in an adult male or postmenopausal woman = colon cancer until excluded. The single best next step is bidirectional endoscopy (ACG), not another iron panel. Do not settle for "poor diet."
• Ferritin falls first, MCV falls last. The earliest lab abnormality in iron deficiency is depleted stores; a normal MCV never excludes it. Conversely, ferritin is an acute-phase reactant — in a patient with active inflammation, use transferrin saturation.
• Give folate alone to a B12-deficient patient and the anemia corrects while the neuropathy marches on. Always check B12 before repleting folate. Methylmalonic acid elevated = B12; homocysteine alone = folate.
• Hypersegmented neutrophils are the smear buzzword for megaloblastic anemia; basophilic stippling for lead (and thalassemia); bite cells and Heinz bodies for G6PD; schistocytes for microangiopathy; spherocytes for hereditary spherocytosis or warm AIHA — the DAT/Coombs test is what separates those last two.
• A high LDH with a low haptoglobin and reticulocytosis means hemolysis; the next test is the direct antiglobulin test to sort immune from non-immune.
• Microcytosis with a normal or high ferritin and a near-normal RDW in a patient of Mediterranean or Southeast Asian ancestry is thalassemia trait, not iron deficiency — the classic distractor is prescribing iron, which is useless and risks overload.
• Transfuse to a restrictive threshold (AABB): around 7 g/dL for most stable inpatients, around 8 g/dL with cardiovascular disease or after cardiac/orthopedic surgery. The distractor is transfusing an asymptomatic patient at 9 g/dL.
• In sickle cell disease, hydroxyurea is the disease-modifying drug (it raises HbF); an abrupt hemoglobin drop with no reticulocytes is parvovirus B19 aplastic crisis, whereas a drop with reticulocytosis and a big spleen is sequestration.

• Anemia = Hgb <12 g/dL (women) or <13.5 g/dL (men) or hematocrit <36-39%
• Classified by MCV: microcytic (<80), normocytic (80-100), macrocytic (>100)
• Reticulocyte count differentiates bone marrow response (elevated = adequate response; low = marrow failure)
• Most common causes globally: iron deficiency, anemia of chronic disease, B12/folate deficiency
• Severity correlates with symptoms: fatigue/dyspnea at Hgb 7-8, cardiac complications <6 g/dL

• Iron deficiency: Fatigue, pallor, dyspnea, pica (ice/dirt), glossitis; microcytic, hypochromic
• B12 deficiency: Paresthesias, ataxia, dementia ("megaloblastic madness"), glossitis; macrocytic + neurologic
• Folate deficiency: Similar to B12 but NO neurologic symptoms; associated with pregnancy/malnutrition
• Hemolytic anemia: Jaundice, dark urine, splenomegaly, elevated LDH/bilirubin, low haptoglobin
• Anemia of chronic disease: Mild-moderate anemia (Hgb 8-11) in infection, malignancy, autoimmune disease

• B12 vs. Folate confusion: Both cause macrocytic anemia, but ONLY B12 deficiency causes neurologic symptoms (paresthesias, ataxia, dementia)—folate does NOT; distinguish with serum methylmalonic acid (↑ in B12 deficiency)
• Anemia of chronic disease vs. iron deficiency: Both can be microcytic; key differentiator is ferritin (low in iron deficiency, normal/elevated in chronic disease) and ↑hepcidin in chronic disease
• Reticulocyte count misinterpretation: A "low" absolute reticulocyte count in anemic patient = marrow failure; must calculate absolute count, not just percentage