HEM02 Anemia I Guide

MAPBig-picture map of anemia

Memory tool — microcytic causes

TAILS: Thalassemia, Anemia of chronic disease, Iron deficiency, Lead poisoning, Sideroblastic anemia.

LO 1Defining anemia

Q1. What does a normal red cell look like, and how is it removed?

Biconcave disc; made in marrow under EPO (from the kidney); average lifespan 120 days
Membrane: spectrin + actin lattice gives strength and flexibility. Shape changes with flow: fast arterial flow → asymmetric "slipper"; slow venous flow → symmetric "bullet"
Removal:
- Old (senescent) cells → eaten by macrophages
- Stiff (unpliable) cells → trapped in the spleen
Recycling: iron → stored, returned to marrow · porphyrin → bilirubin → bile · globin → amino acid pool

Q2. What is hemoglobin, and which types are normal?

Found only in RBCs. Carries O₂ from lungs → tissues and CO₂ + H⁺ from tissues → lungs
Heme = porphyrin ring with central ferrous iron (Fe²⁺), the O₂-binding site · Globin = protein chains
4 heme + 4 globin chains → one Hb carries up to 4 O₂

Hemoglobin	Chains	Adults	Newborns
HbA	α₂β₂	≈95%	≈20%
HbA1c	α₂β₂ + glucose	<3.5%	—
HbA2	α₂δ₂	<2.5%	<0.5%
HbF	α₂γ₂	<1%	≈80%

Memory tool

Fetal → adult: "Alpha always; gamma goes, becomes beta." Every normal Hb has α chains.

Trap

β-chain diseases (β-thalassemia, sickle cell) are silent at birth because the newborn runs on HbF (α₂γ₂), which needs no β chains. Symptoms start around 6 months as HbF falls.

Step 1

HbF binds 2,3-BPG less → higher O₂ affinity → pulls O₂ across the placenta. ↑ HbF is the goal of hydroxyurea in sickle cell.

Q3. So what exactly is anemia?

A reduction in the total number of red blood cells, or a reduction in the circulating red cell mass. In practice: a low Hb or Hct.

Normal balance	Value
Production vs loss	Under normal conditions, production = loss
RBC lifespan	110–120 days
Removed per day	≈1% of RBCs
Retics made per day	≈50,000 /µL of blood
Marrow reserve	Can raise output ≈5-fold in response to EPO

Q4. What are the only three ways to become anemic?

Decreased RBC production (iron, B12/folate lack, marrow failure, low EPO)
Increased RBC destruction (hemolysis: sickle cell, G6PD, spherocytosis, autoimmune)
Blood loss (acute bleeding, chronic GI or menstrual loss)

Analogy — the bathtub

Red cell mass is the water level. The faucet is the marrow (production); the drain is destruction; a crack in the tub is bleeding. Anemia means the faucet is too slow, the drain too fast, or the tub is leaking. The reticulocyte count tells you whether the faucet is working.

Trap

Right after a large acute bleed, Hb can still be normal because whole blood is lost (cells + plasma together). Judge acute blood loss by vital signs, not the first Hb.

In-house exam

Know the definition word for word in spirit: reduced total RBC number or circulating RBC mass, and the three causes: decreased production, increased destruction, blood loss.

ApplyLO 1 application questions

A1A healthy adult's marrow suddenly stops making red cells. Roughly what fraction of her red cells would be gone after 10 days?

About 10%. ≈1% of RBCs are removed each day (120-day lifespan), so a 10-day shutdown drops the mass ≈10%. That is why a brief stop (parvovirus B19) only matters when RBC survival is already short.

A2Which of the three mechanisms produces anemia with a high reticulocyte count?

Increased destruction (hemolysis) and blood loss: the marrow is healthy and speeds up. Decreased production gives a low reticulocyte count.

LO 2Classifying anemia

Q1. How do you classify anemia by mechanism?

Mechanism	What happens	Examples	Retics
Decreased production	Marrow lacks a building block, a signal, or working stem cells	Iron deficiency (hypoproliferative), B12/folate, CKD (↓ EPO), aplastic anemia, marrow infiltration	↓
Increased destruction	RBCs die before 120 days (hemolysis)	Sickle cell, thalassemia (partly), G6PD, hereditary spherocytosis, autoimmune	↑
Blood loss	Cells leave the body	Trauma, GI bleeding, heavy menses	↑ (after a few days)

Q2. How do you classify anemia by red cell size, and why is this the default?

Size (MCV) comes free on every CBC and immediately narrows the list. It is the scheme used most often clinically.

Group	MCV	Core idea	Main causes
Microcytic	<70 fL	Normal DNA synthesis but too little hemoglobin (iron, heme or globin problem) → small, pale cells	Iron deficiency, thalassemias, sideroblastic, chronic disease
Normocytic	80–100 fL	Cells look normal; problem is number	Acute bleeding, sickle cell, chronic disease, marrow infiltration
Macrocytic	>100 fL	DNA synthesis lags (megaloblastic) or many big retics	B12, folate, alcohol, liver, MDS, hemolysis

Normal

RBC ≈ size of a lymphocyte nucleus
Central pallor ≈ ⅓ of the cell

Microcytic

Smaller than a lymphocyte nucleus
Big pale centers (hypochromic)

Macrocytic

Larger, often oval
Little central pallor

In-house exam

This course defines microcytic as MCV <70 fL. Use <70 on the block exam and <80 on boards.

Q3. How do size and mechanism fit together?

Size points to the cause; the reticulocyte count points to the mechanism. Use both.

Reticulocyte count = newborn RBCs; shows whether the marrow is answering the anemia
Low MCV + low retics → production problem (iron deficiency)
Normal MCV + high retics → destruction or bleeding (sickle cell, hemolysis)
High MCV + high retics → hemolysis (retics are big); high MCV + low retics → B12/folate, marrow problem

Step 1 — reticulocyte production index

The raw retic % is falsely high in anemia, so correct it: RPI = retic % × (patient Hct ÷ normal Hct) ÷ maturation time.

RPI >3 → marrow compensating (hemolysis, bleeding). RPI <2 → inadequate response (production problem).

ApplyLO 2 application questions

A1Hb 8, MCV 92, retics 9%, ↑ indirect bilirubin. Which group by size and by mechanism?

Normocytic, increased destruction (hemolysis). High retics and bilirubin show a working marrow and red cells breaking down.

A2Hb 9, MCV 64, retics 0.5%. Which group and mechanism?

Microcytic, decreased production. Think iron deficiency first.

LO 3Common causes by cell size

Q1. Why are some anemias microcytic, and which are the common ones?

Microcytic cells have normal DNA synthesis but too little hemoglobin. Precursors keep dividing while waiting for enough Hb, so they end up small and pale. Any defect in iron supply, heme synthesis or globin synthesis does it.

Cause	Defect	Key features
Iron deficiency	Not enough iron	Most common anemia; almost always microcytic with a high RDW; malnutrition or chronic blood loss
Thalassemias	Not enough globin	Usually microcytic (can be normocytic or macrocytic from hemolysis); normal RDW; target cells
Sideroblastic	Heme synthesis; iron trapped in erythroid precursors	Hereditary, MDS, lead, alcohol, drugs; ringed sideroblasts
Anemia of chronic disease	Iron trapped in marrow macrophages	Chronic inflammation; may be normocytic

In-house exam — clinical tips

Low Hb/Hct → look at the MCV. Low MCV → think iron deficiency first (RDW usually high).
Next, the smear: sickle cells → sickle cell anemia; target cells → thalassemia or sickle cell; RBC fragments → intravascular hemolysis.
Suspected iron deficiency in a child → treat; in an adult → confirm with iron studies.
No cause found and chronic disease or sideroblastic anemia suspected → bone marrow evaluation.

Q2. Which anemias are macrocytic?

Megaloblastic (vitamin B12 or folate deficiency): cells are large and oval; B12 is the most common cause
Chronic alcohol use
Aplastic anemia, myelodysplasia
Some hemolytic anemias (many large reticulocytes)
Decreased marrow function with low retics: drugs, toxins, liver and thyroid disease

Work-up: smear (megaloblastic changes?) + reticulocyte count. High retics → hemolysis or bleeding. Normal/low retics → consider marrow evaluation.

Step 1

Megaloblastic = hypersegmented neutrophils (≥6 lobes) + oval macrocytes. B12 deficiency adds ↑ methylmalonic acid and neuro signs; folate does not. (Full detail in Anemia II.)

Q3. What should I think of with a normocytic anemia?

Acute bleeding
Sickle cell disease
Anemia of chronic disease
Myelophthisic (infiltrative) marrow: metastatic tumor, myelofibrosis, infection in children
Primary hematologic malignancy (leukemia, lymphoma) crowding out normal marrow

Normocytic, normochromic anemia usually needs a bone marrow evaluation; normocytic + high retics → work up like hemolysis.

Trap

Iron deficiency (small cells) + B12/folate deficiency (big cells) can average to a normal MCV with a very high RDW (celiac disease, malnutrition, after gastric bypass).

ApplyLO 3 application questions

A1A 4-year-old with pica has an MCV of 62. Before giving iron, which other microcytic cause should a basophilic-stippled smear make you consider?

Lead poisoning (a sideroblastic cause). Pica is common to both.

A2An MCV of 112 with a reticulocyte count of 12%. Most likely group of causes?

Hemolysis (or recovery from bleeding): large reticulocytes raise the MCV.

LO 4Red cell indices

Q1. What does each number on the CBC mean?

Index	Definition	How it is used
Hemoglobin (Hb)	Hb concentration in blood (g/dL)	Defines anemia
Hematocrit (Hct)	% of blood volume that is RBCs	Defines anemia; ≈ 3 × Hb
MCV	Average volume of a red cell (fL)	Size → micro / normo / macro; guides the differential
MCH	Average mass of Hb per red cell (pg)	Low in hypochromic cells; rarely used
MCHC	Average concentration of Hb in a volume of packed RBCs	Low in iron deficiency; ↑ in spherocytosis; rarely used
RDW	Degree of variation in size (and shape)	Low = uniform cells · high = many sizes (iron deficiency)

In-house exam

The MCV and RDW are the two indices that matter most. MCH and MCHC are included for completeness. A bone marrow biopsy is NOT an initial test for isolated anemia; MCV, RDW and the smear guide you.

Memory tool

MCV = size. RDW = variety. "V" for volume, "W" for width of the size spread.

Q2. How do MCV and RDW together separate the microcytic anemias?

	RDW normal	RDW high
MCV low	Thalassemia trait (uniform small cells)	Iron deficiency (old normal + new small cells)
MCV normal	Chronic disease, acute bleed	Mixed iron + B12/folate deficiency; early deficiency
MCV high	Aplastic anemia, liver disease	B12/folate deficiency

Step 1 — Mentzer index

MCV ÷ RBC count (millions/µL). <13 → thalassemia trait (many small cells, RBC count normal or high). >13 → iron deficiency (fewer cells).

Q3. Which smear shapes point to which disease?

Shape	Points to
Pencil (elongated) cells	Iron deficiency
Target cells	Hemoglobinopathies (thalassemias, sickle cell)
Spherocytes	Autoimmune hemolytic anemia, hereditary spherocytosis
Schistocytes (fragments)	Microangiopathy, intravascular hemolysis
Sickle cells	Sickle cell anemia

Step 1

Target cells: "HALT," said the hunter to his target → HbC, Asplenia, Liver disease, Thalassemia.

ApplyLO 4 application questions

A1Two patients have MCV 68. Patient A: RBC 3.9 million, RDW 19%. Patient B: RBC 5.8 million, RDW 13%. Which is which?

A: Mentzer 68 ÷ 3.9 ≈ 17 (>13) + high RDW → iron deficiency. B: 68 ÷ 5.8 ≈ 11.7 (<13) + normal RDW → thalassemia trait.

A2A resident orders a bone marrow biopsy as the first test for a mild isolated anemia. Better first steps?

CBC indices (MCV, RDW), reticulocyte count and a peripheral smear. Marrow biopsy is often not helpful for isolated anemia.

LO 5Signs and symptoms

Q1. What symptoms does any anemia cause?

All come from less O₂ delivered to tissues plus the body's compensation:

Fatigue, weakness, dizziness, headache
Shortness of breath and chest pain on exertion (angina if coronary disease)
Palpitations, tachycardia, flow murmur

Step 1

Compensation: ↑ cardiac output (can cause high-output heart failure in severe chronic anemia), ↑ 2,3-BPG (right shift → easier O₂ unloading), ↑ EPO.

Trap

Speed matters more than depth. A slow drop (iron deficiency, thal trait) can reach a very low Hb with few symptoms; a fast drop of the same size is poorly tolerated.

Q2. What do you see on exam?

Pallor of skin and mucous membranes, best seen in the conjunctiva, palms and palmar creases, and nail beds.

Palmar pallor

Pale palm and creases next to a normal hand

Conjunctival pallor

Pull down the lower lid; pale inner rim

Q3. Which findings hint at a specific cause?

Finding	Think
Jaundice, splenomegaly, dark urine	Hemolysis
Pica, koilonychia, blue sclera	Iron deficiency
Bony deformities, hepatosplenomegaly in a child	β-thalassemia major
Pain crises, leg ulcers	Sickle cell disease
Neuropathy, glossitis	B12 deficiency

In-house exam

A complete history and physical exam are the most valuable tools in diagnosing anemia; clinical suspicion guides which tests to order.

ApplyLO 5 application questions

A1A 70-year-old with Hb 7 reports chest pressure walking upstairs. Why?

Less O₂-carrying capacity + higher heart rate raise myocardial O₂ demand → demand ischemia (exertional angina).

A2A fatigued patient with anemia has yellow sclerae and a palpable spleen tip. Which mechanism?

Increased destruction (hemolysis): bilirubin from broken-down heme; spleen working hard.

LO 6Iron deficiency anemia

Q1. How does the body normally handle iron?

Protein	Role	Lab meaning
Ferritin	Stores iron in cells; hepatocytes (liver) and macrophages (spleen, marrow, muscle)	Serum ferritin tracks body iron stores; also rises with inflammation
Transferrin	Plasma iron carrier; protects tissues from free iron; delivers to cells with transferrin receptors (marrow, liver, muscle)	Measured as TIBC; normally ≈33% saturated
Hemosiderin	Clumps of degraded ferritin; storage iron	Brown-yellow pigment on H&E
Free iron	Toxic; makes free radicals	Why it is always bound

Step 1

Fe²⁺ enters via DMT1 and leaves the enterocyte via ferroportin. Hepcidin (made by the liver, ↑ by IL-6 in inflammation) degrades ferroportin → iron trapped in enterocytes and macrophages = anemia of chronic disease. Vitamin C helps absorption.

Q2. Who gets iron deficiency, and why? (causes by age)

The most common cause of anemia; most common in toddlers, adolescent girls and women of childbearing age. Four mechanisms, often more than one at once:

Mechanism	Examples
Inadequate intake	Infants on a milk-only diet; picky toddlers; elderly with restricted diets or poor dentition; vegetarians
Impaired absorption	Tea, wine, bran/high-fiber diets; drugs that raise gastric pH (PPIs); duodenal surgery or resection; celiac disease; some infections
Increased requirement	Growing children, pregnancy, menstruating women, blood donors
Chronic blood loss	GI tract (peptic ulcer, gastritis, colon carcinoma), heavy menses

Patient	Most likely cause
Infant / toddler	Diet (milk) + rapid growth
Premenopausal woman	Menstrual loss (GI cancer in only ≈1%)
Man or postmenopausal woman	Occult GI blood loss → GI cancer found in 8–10%
Adult >65	Colon or other GI carcinoma until proven otherwise

High yield

In every adult with iron deficiency, consider occult GI blood loss and look with endoscopy and/or colonoscopy. Dual pathology (upper + lower GI) is found in 1–10%, especially in older patients.

Step 1

Right-sided colon cancer → occult bleeding → iron deficiency anemia in an older adult.

Q3. What clinical clues are unique to iron deficiency?

General anemia symptoms (fatigue) plus clues from iron's role in many enzymes:

Koilonychia

Thin, brittle, spoon-shaped nails

Pica: craving inert things (ice, chalk, dirt, starch). Craving ice = pagophagia, very suggestive
Blue sclera: thin sclera (rarely seen)
Children: motor and mental developmental delay

Step 1

Also: restless legs, glossitis, angular cheilitis, and Plummer-Vinson syndrome (iron deficiency + esophageal webs + dysphagia).

Q4. Which tests confirm it, and what do they show?

Labs

↓ Hb, ↓ Hct
↓ MCV (microcytic)
↑ RDW (many sizes)
↓ Serum iron (iron bound to transferrin)
↑ TIBC (more transferrin, hungry for iron)
↓ Serum ferritin (empty stores) — key test
↓ transferrin saturation

Iron deficiency smear: small pale red cells of varying size and pencil cells — Small, pale cells; anisocytosis; pencil cells

Smear: microcytic, hypochromic, marked anisocytosis/poikilocytosis, pencil cells
Marrow iron stores: absent

	Iron deficiency	Chronic disease	Thal trait	Hemochromatosis
Serum iron	↓	↓	Normal	↑
TIBC	↑	↓	Normal	↓
Ferritin	↓	↑	Normal	↑
RDW	↑	Normal	Normal	—

In-house exam

Classic item: heavy menses from fibroids, MCV 68, ferritin 5, TIBC 500 → smear shows poikilocytosis (variation in shape) with small pale cells. Distractors: schistocytes (intravascular hemolysis), spherocytes (hereditary spherocytosis), sickle cells, dacrocytes (marrow fibrosis).

Trap

Ferritin is an acute-phase reactant. Inflammation can push it into the normal range even with low stores.

Q5. In what order does iron run out?

1 Storage (ferritin) empties → 2 Circulating iron (transferrin) falls → 3 Cells get smaller, then fewer → anemia

Anemia appears only after stores are depleted. Treatment refills in reverse: circulating iron first (Hb normalizes), stores last.

Q6. How is it treated?

Oral or parenteral iron; transfusion if severe
Marrow response (↑ retics) in about 10 days
Find and treat the cause; rule out malignancy in adults
Follow up; infection, inflammation or cancer can blunt the response

Trap

A normal Hb does not mean treatment is finished. Keep giving iron until the storage compartment (ferritin) is refilled.

ApplyLO 6 application questions

A1A 27-year-old woman has fatigue and a new craving to chew ice. Best next step?

Order serum ferritin. Pagophagia points to iron deficiency; confirm with iron studies in an adult. Not electrophoresis, GI cancer screening or marrow biopsy first.

A2A 69-year-old man has Hb 9.3 and MCV 67 with no obvious bleeding. After confirming iron deficiency, what must be done?

Endoscopy/colonoscopy to find occult GI blood loss; GI cancer is found in 8–10% of men and postmenopausal women.

A3A patient on long-term omeprazole develops a microcytic anemia. Mechanism?

Higher gastric pH → less conversion to absorbable Fe²⁺ → impaired absorption.

LO 7Thalassemias

Q1. What is a thalassemia, and how is it different from sickle cell?

Inherited quantitative disorders of hemoglobin: decreased or absent synthesis of α or β globin chains
Result: less normal Hb + shortened RBC survival
Sickle cell is qualitative: a normal amount of an abnormal globin
Common in Mediterranean, African and Southeast Asian populations

	α-thalassemia	β-thalassemia
Gene	2 α genes on chromosome 16 (4 total)	1 β gene on chromosome 11 (2 total)
Usual defect	Gene deletions	Point mutations (>100) affecting RNA synthesis, processing or stability
Excess chain	β (or γ in the fetus)	α

Memory tool

Alpha: 4 genes on chromosome 16 (4 × 4 = 16). Beta: 2 genes on chromosome 11. Alpha is usually a deletion; beta is usually a point mutation.

Q2. Why does missing one chain make red cells die?

Iron overload: the body senses too few RBCs and absorbs more iron (plus transfusions), though iron is not the problem
Extramedullary hematopoiesis in spleen and liver; more common in β

Q3. How do α-thalassemias scale with the number of deleted genes?

Genes deleted	Condition	Result
1	Silent carrier	No anemia
2	α-thalassemia trait	Mild microcytic anemia
3	HbH disease (β₄)	Moderate to severe anemia
4	Hydrops fetalis (Hb Barts, γ₄)	Incompatible with life

Step 1

α-trait cis deletion (both on one chromosome; Asian ancestry) → offspring at risk of hydrops; trans deletion (African ancestry) → less risk. Two-gene deletion has a normal electrophoresis.

Q4. What does β-thalassemia major look like?

Two abnormal β genes (homozygous). Appears in infancy / early childhood as HbF falls: poor feeding, failure to thrive, pallor.

Labs and smear

Hb very low: 2.5–6 g/dL
↓ MCV; microcytic, hypochromic
Target cells, nucleated RBCs
Retics ↑ but lower than expected
↑ HbF (and HbA2)
Serum iron normal to high
Diagnosis: Hb electrophoresis + quantitation of HbA, HbA2, HbF

From severe anemia → ↑ EPO

Erythroid hyperplasia in many bones → skull and facial deformities ("chipmunk" face, "crew-cut" skull X-ray)
Impaired bone growth
Hepatosplenomegaly (sequestration + extramedullary hematopoiesis)
Cachexia

Maxillofacial bone overgrowth in thalassemia major

Facial bone expansion

Marrow expands into maxilla and skull

Child with thalassemia major and a large abdomen

Hepatosplenomegaly

Big liver and spleen, poor growth

Enlarged spleen, child's face and skull X-ray in thalassemia

Spleen · face · skull

"Hair-on-end" skull from marrow expansion

Iron overload

Brown hemosiderin in liver → secondary hemochromatosis

Iron overload and treatment

Iron from increased absorption + transfusions → secondary hemochromatosis: heart, liver, pancreas, joints
Untreated: fatal. Treat with transfusions + iron chelation; bone marrow transplant can cure
Leading cause of death: congestive heart failure (cardiac iron)

In-house exam

Classic stem: a young child of Mediterranean (Italian/Sicilian) descent, poor appetite, underweight, hepatosplenomegaly, Hb 6, hypochromic microcytic smear, normal serum iron, retics 10%, marrow with erythroid hyperplasia and ↑ iron. Answer: imbalance of α and β globin chains.

Step 1

An adolescent with lifelong anemia, delayed puberty, hyperglycemia, ↑ TSH and ferritin ≈700 = β-thalassemia with transfusion iron overload hitting pancreas, pituitary and thyroid. Chelators: deferoxamine, deferasirox.

Q5. How is β-thalassemia minor different from iron deficiency?

One abnormal gene (trait). More common; mild, often asymptomatic microcytic anemia; mild erythroid hyperplasia. The point is to not mistake it for iron deficiency: treatment differs and genetic counseling matters.

Feature	β-thal minor	Iron deficiency
MCV	↓ (very low for how mild the anemia is)	↓
RBC count	Normal or ↑	↓
RDW	Normal	↑
Mentzer	<13	>13
Iron studies	Normal	↓ iron, ↓ ferritin, ↑ TIBC
Smear	Target cells, basophilic stippling	Pencil cells, anisocytosis
Electrophoresis	↑ HbA2 (>3.5%)	Normal
Iron therapy	Not helpful (can harm)	Cures

Hemoglobin electrophoresis bands: normal, beta-thal trait, beta-thal major, sickle trait, sickle disease — Electrophoresis: normal, β-thal trait, β-thal major, sickle trait, sickle disease

ApplyLO 7 application questions

A1A 10-month-old is fussy and eating poorly; Hb 6, hepatosplenomegaly, target cells, normal serum iron, retics 10%. Cause?

Imbalance of α and β globin chains (β-thalassemia major). Symptoms start as HbF wanes after ~6 months.

A2A healthy 24-year-old Greek man has Hb 12.1, MCV 63, RBC 5.9 million, normal RDW and ferritin. Next test and what to avoid?

Hb electrophoresis (expect ↑ HbA2 → β-thal trait). Mentzer ≈10.7. Do not give iron; offer partner testing and counseling.

A3A transfusion-dependent 19-year-old with β-thal major develops dyspnea and edema. Most likely cause of death in this disease?

Congestive heart failure from cardiac iron overload (secondary hemochromatosis).

LO 8Sickle cell anemia

Q1. What is the genetic defect, and who is affected?

Point mutation in codon 6 of the β-globin gene (A → T) → valine replaces glutamic acid → HbS
Autosomal recessive; a qualitative hemoglobinopathy
More common with ancestry from sub-Saharan Africa, Cuba, South/Central America, Saudi Arabia, India, Turkey, Greece, Italy
US: ≈72,000 with SS disease; 1 in 500 African American births; 1 in 1,000–1,400 Hispanic American births; ≈2 million with trait

	Sickle cell trait (HbAS)	Sickle cell disease (HbSS)
HbS	≈40% of Hb	≈100%
Symptoms	Usually none	Hemolysis, vaso-occlusion, organ damage
MCV	Normal	Usually normocytic; Hb 5–9 g/dL

Step 1

Trait protects against falciparum malaria (heterozygote advantage). Trait can still cause renal medullary carcinoma and microscopic hematuria/isosthenuria.

Q2. What makes a red cell sickle?

On deoxygenation, HbS molecules aggregate and polymerize → long, narrow cells; viscous, sticky cytoplasm
Reversible at first; repeated cycles → irreversibly sickled cells with membrane damage
Factors that increase sickling:
- Amount of HbS (SS ≫ trait)
- Intracellular dehydration (↑ HbS concentration)
- Longer exposure to low O₂ tension

Peripheral smear with sickle cells and target cells — Sickle cells and target cells

Step 1

Sickling triggers: hypoxia, acidosis, dehydration, high altitude, infection, cold.

Q3. What are the three arms of sickle cell pathophysiology?

In-house exam

A child with sickle cell, abdominal and hip pain: the mechanism is ischemia. Infection and inflammation trigger sickling; adhesion molecules make sickled cells stick and occlude vessels → micro-thrombi → infarction.

Q4. Which organs are damaged, and how?

Organ	Complication
Spleen	Autosplenectomy: repeated infarcts → small fibrous spleen → infections with encapsulated bacteria (pneumococcus). Sequestration crisis in young children with intact spleens: rapid enlargement, hypovolemia, shock
Bone	Avascular necrosis; pain crises
Lung	Acute chest syndrome: fever, cough, chest pain, hypoxia; an emergency, often triggered by infection
Brain	Stroke
Kidney	Renal disease, renal failure
Skin	Leg ulcers
Other	Liver, penis (priapism); gallstones; impaired growth and development

Autosplenectomy

Shrunken, scarred spleen

Leg ulcer

Peripheral vaso-occlusion

Course: ↑ infection risk, pain crises, growth impairment. Survival ≈90% at age 20, ≈50% into the fifth decade.

Step 1

Asplenia → Howell-Jolly bodies, target cells; vaccinate (pneumococcal, Hib, meningococcal) and give penicillin prophylaxis in children.
Salmonella osteomyelitis; dactylitis (painful hand/foot swelling) in infants; renal papillary necrosis.
Parvovirus B19 → aplastic crisis.

Q5. How is it diagnosed?

Clinical suspicion → CBC and indices → peripheral smear (sickle cells, target cells)
Hemoglobin electrophoresis confirms: HbS has a distinct migration pattern

Hemoglobin electrophoresis gel for normal adult, newborn, sickle disease, sickle trait and HbSC — Electrophoresis: normal adult, newborn, sickle cell disease, sickle trait, HbSC

Q6. How is it treated?

Treatment	How it works
Hydroxyurea	Shifts production back toward HbF, which does not sickle; fewer pain crises
Voxelotor	Inhibits HbS polymerization
Crizanlizumab	Blocks P-selectin (cell adhesion)
Bone marrow transplant	Replaces the "factory" → cells with HbAA
Gene therapy	Corrects or bypasses the defect

High yield

Hydroxyurea ↑ HbF. This is the single most tested treatment fact for sickle cell disease.

ApplyLO 8 application questions

A1An 11-year-old has fever, severe leg pain and fatigue after a recent chest cold, with similar past episodes. Diagnosis?

Sickle cell disease (vaso-occlusive crisis triggered by infection).

A2A 12-year-old with sickle cell has Howell-Jolly bodies on smear. What happened to his spleen, and which organisms threaten him?

Autosplenectomy (infarcted, fibrotic spleen) → infections with encapsulated bacteria such as S. pneumoniae.

A3A sickle cell patient develops fever, cough, chest pain and hypoxia with a new infiltrate. What is it?

Acute chest syndrome: sickled cells occlude pulmonary vessels; a medical emergency.

IDSmear and image ID

Image 1 — smear

Iron deficiency: small, pale cells; varied sizes; pencil cells.

Image 2 — smear

β-thalassemia major: hypochromic microcytes, target cells, nucleated RBCs.

Image 3 — smear

Sickle cell disease: sickled and target cells.

Image 4 — smear

Macrocytic red cells (larger than a lymphocyte nucleus).

Image 5 — nails

Koilonychia → iron deficiency.

Image 6 — face

Maxillofacial marrow expansion → β-thalassemia major.

Image 7 — liver

Brown hemosiderin → iron overload (secondary hemochromatosis).

Image 8 — spleen

Autosplenectomy in sickle cell disease.

MCQExam-style questions

Score: 0 / 0

1A 27-year-old woman has increasing fatigue and a new craving to chew ice chips. What is the most appropriate next step?

2An 11-year-old boy has fever, severe leg pain and fatigue a few weeks after a chest cold. He has had similar pain before, which he blamed on soccer. Most likely diagnosis?

3A 10-month-old boy feeds poorly, is at the 10th percentile and has hepatosplenomegaly. Hb 6 g/dL, normal serum iron, retics 10%; marrow shows erythroid hyperplasia and increased iron. Most likely cause?

4A 10-year-old girl with sickle cell anemia and several past pneumonias has severe left upper quadrant and left hip pain. Hb 7 g/dL. The pain is most likely caused by:

5A 42-year-old woman with fibroids and heavy periods has Hb 9.5, MCV 68, ferritin 5, transferrin saturation 10%, TIBC 500. Most likely peripheral smear finding?

6A 12-year-old with lifelong pain crises has Hb 11.2 and electrophoresis showing 93% HbS, 6% HbF, 1% HbA2. Hydroxyurea helps him. Its benefit comes mainly from an increase in:

7A 17-year-old girl with lifelong fatigue has not entered puberty; she has hepatosplenomegaly, Hb 9.1, MCV 66, target cells, glucose 144, TSH 6.2 and ferritin 679. A mutation in which gene is most likely?

8Two patients have MCV 66. Which pair of findings best supports thalassemia trait over iron deficiency?

9A 70-year-old man has new iron deficiency anemia and no symptoms other than fatigue. Which is the most important next step?

10Why is a child with β-thalassemia major well at birth?

11A 7-year-old with sickle cell disease is admitted with pneumococcal sepsis. Which change most explains his risk?

12Which iron study pattern fits iron deficiency?

!Numbers that differ between in-house and Step 1

Item	In-house	Step 1 / board review
Microcytic cutoff	MCV <70 fL	MCV <80 fL
HbA in adults	≈95% (also 95–97%)	≈97%
HbA2 in adults	<2.5% (also <3.5%)	2–3.5%; >3.5% = β-thal trait
RBC lifespan	110–120 days	≈120 days; 60–90 days in neonates
Target cells	Thalassemias, sickle cell	HALT: HbC, Asplenia, Liver disease, Thalassemia
Most common macrocytic cause	B12 deficiency	Megaloblastic (B12, folate), alcohol
Reticulocyte normal	≈1%	0.5–1.5%; use RPI

Anemia I

Learning objectives

MAPBig-picture map of anemia

LO 1Defining anemia

ApplyLO 1 application questions

LO 2Classifying anemia

Normal

Microcytic

Macrocytic

ApplyLO 2 application questions

LO 3Common causes by cell size

ApplyLO 3 application questions

LO 4Red cell indices

ApplyLO 4 application questions

LO 5Signs and symptoms

Palmar pallor

Conjunctival pallor

ApplyLO 5 application questions

LO 6Iron deficiency anemia

Koilonychia

Labs

ApplyLO 6 application questions

LO 7Thalassemias

Labs and smear

From severe anemia → ↑ EPO

Facial bone expansion

Hepatosplenomegaly

Spleen · face · skull

Iron overload

Iron overload and treatment

ApplyLO 7 application questions

LO 8Sickle cell anemia

Autosplenectomy

Leg ulcer

ApplyLO 8 application questions

IDSmear and image ID

MCQExam-style questions

!Numbers that differ between in-house and Step 1

✓Rapid review