Hemolytic Anemias

When RBCs are destroyed faster than they can be replaced

Anemia sorting hat · Microcytic · Macrocytic / Normocytic

Clinical Images

Sickle cell disease peripheral blood smear

📷 Sickle cells, target cells, polychromasia · tap to expand

Hereditary spherocytosis peripheral smear

📷 Spherocytes: small, round RBCs without central pallor · tap to expand

📷 Schistocytes: fragmented RBCs in MAHA / TTP · tap to expand

📷 Heinz bodies: oxidized Hgb in G6PD deficiency · tap to expand

Peripheral blood smear showing abnormal cells

📷 Peripheral smear: cell morphology guides hemolytic workup · tap to expand

🚨 Clinical Vignette

A 28-year-old woman presents with fatigue, jaundice, and dark urine. Labs show Hgb 8.2, elevated retic count (15%), and unconjugated hyperbilirubinemia. Her direct Coombs test is positive. There are no schistocytes on blood smear.

What type of hemolysis is occurring?

Extravascular hemolysis (most likely)

Intravascular hemolysis

Mixed pattern with more intravascular

Cannot determine from these findings

The Players: Globin, Haptoglobin & the Hb Family

Before the hemolysis labs make sense, know who's in the room. Globin lives inside the RBC. Haptoglobin patrols plasma. And not all hemoglobins are the same.

Hemoglobin Cheat Sheet

Name	Chains	Board Pearl
HbA	α₂β₂	Normal adult Hb. The Goal.
HbF	α₂γ₂	Fetal. Higher O₂ affinity. Hydroxyurea raises it.
HbA2	α₂δ₂	Elevated in beta-thalassemia (>3.5%).
HbS	α₂β^S₂	Sickle cell. Valine for glutamate at β6. Sticky when deoxygenated.
HbC	α₂β^C₂	Lysine for glutamate at β6. Ly-C-ne mnemonic.
HbH	β₄	Alpha-thal (3 gene loss). H = Heinz bodies · beta tetramers precipitate.
Hb Barts	γ₄	Alpha-thal (4 gene loss). Lethal · hydrops fetalis.

Walk Globin & Haptoglobin

Tap the blurred answer. Tap again for the next beat.

BEAT 1 OF 12

Teaching Drill

Instructor "I got a patient from the Mediterranean. HbA2 is 5%. What's the diagnosis?"

Student "Uh... Beta-Thalassemia?"

Instructor "WHICH ONE? Minor or Major? Don't say the family name, give me the person!"

Student "Beta-Thal Minor?"

Instructor "YES. Why is HbA2 high?"

Student "They can't make enough beta chains, so alpha pairs with delta instead?"

      Instructor
      "EXACTLY. Alpha is the popular girl at the prom. She wants Beta. If Beta didn't show up, she's going home with Delta (HbA2) or Gamma (HbF). She's not going home alone."
    

Instructor "BUT: if Alpha doesn't show up to the prom? THE PROM IS CANCELLED. No alpha, no life. That's Hydrops Fetalis."

Lab Differentiation: Thalassemia vs IDA

Lab	Thalassemia Blueprint	IDA Ingredients
Ferritin	Normal / High	Low · #1 early marker
TIBC	Normal	High (liver hunting for iron)
RDW	Normal (uniformly small)	High (mixed sizes)
RBC Count	High (compensatory)	Low / Normal
Mentzer Index	<13 suggests thal	>13 suggests IDA

Thalassemia Minor vs Major

Lab	Thal MINOR Trait	Thal MAJOR
RDW	Normal (uniformly small)	High (fragments everywhere)
RBC Count	High (compensatory)	Low (marrow failure + hemolysis)
Hemoglobin	Mild anemia (10-12)	Severe (<7)
Clinical	Asymptomatic / mild fatigue	Transfusion dependent

Teaching Drill

Attending "I got a kid here. MCV is 65. RDW is 11.5: it's beautiful! And he's got 6 million red cells. What's the diagnosis?"

Student "He's got a really high quality bone marrow?"

Attending "NO! HE'S ANEMIC! But look at the RDW. If the RDW is normal, are the cells mixed-size or same-size?"

Student "They're the same size. Uniformly small."

Attending "EXACTLY. And if they are all small, did they start out that way, or did they run out of iron halfway through?"

Student "They must have started that way. It's the blueprint."

      Attending
      "RIGHT. This is Thalassemia Minor. In Thal Major the cells are so broken up that the RDW goes high (fragments everywhere). But in Minor, the factory is just making smaller-than-normal cars, all coming off the same line."
    

Memory Hook

Globin = the globe holding heme iron in place. Haptoglobin = hapto (to fasten) + globin → it fastens to free globin chains before the kidneys pay the price.

Board Hook

Low haptoglobin points hardest toward intravascular hemolysis. Extravascular? The spleen eats the whole RBC before hemoglobin reaches plasma, so haptoglobin may stay normal. Never use haptoglobin alone to rule out extravascular hemolysis.

The Big Picture: Reticulocytosis = Hemolytic Anemia

A high reticulocyte count screams hemolytic anemia. It's NOT a bone marrow problem. The bone marrow is overproducing because red blood cells are being destroyed faster than normal in the periphery.

From the Attending

Hemolysis is one lab tuple and two questions.

The lab tuple

Reticulocytes up LDH up Indirect bilirubin up Haptoglobin down

Question 1: where is the RBC destroyed? Intravascular means haptoglobin can be undetectable, with hemoglobinuria or hemosiderinuria. Think PNH, mechanical shear, severe AIHA, or transfusion reaction.

Extravascular pattern Spleen and liver macrophages eat whole RBCs. The stem gives jaundice plus splenomegaly: hereditary spherocytosis, sickle cell disease, warm AIHA, thalassemia.

Question 2: immune or non-immune? Direct Coombs positive means immune: warm IgG or cold IgM.

Coombs negative Non-immune: membrane, enzyme, hemoglobin, mechanical, or infection.

Lab tuple → site → mechanism. That is the whole flowchart.

Normal RBC lifespan: 120 days

In hemolytic anemias: days to weeks

The bone marrow responds by:

• Releasing immature RBCs (reticulocytes) before they're fully mature
• Increasing RBC production up to 6-8x normal
• This hyperproliferation = elevated reticulocyte count

Memory Hook

High retic count = marrow is FIGHTING BACK against peripheral destruction. It's not failing→it's trying too hard because enemies are everywhere.

Which Diseases Cause Which Type?

Primarily Extravascular:

Hereditary Spherocytosis → osmotic fragility, bursts in hypotonic saline
Hereditary Elliptocytosis → structural RBC defect
Sickle Cell Disease → vaso-occlusion + splenic infarction
HbC Disease → RBC damage
Pyruvate Kinase Deficiency → RBC fragility
Warm Agglutinin Hemolytic Anemia (IgG antibodies, positive direct Coombs)

Intravascular + Extravascular (Both):

G6PD Deficiency → oxidative stress + hemolysis in oxidative crises
Cold Agglutinin Disease → IgM-mediated

Primarily Intravascular:

PNH → complement-mediated
Microangiopathic Hemolytic Anemia (MAHA) → TTP, HUS, DIC
Malaria → parasite destruction

🔍 Crime Scene Investigation: Where Are The RBCs Being Destroyed?

Sort each clue by where the RBC is being destroyed. No dragging: tap the scene that owns the clue.

0 / 8 sorted

Hemoglobinuria Dark red urine means free hemoglobin reached the kidney.

Hemoglobinemia Pink serum means hemoglobin spilled into plasma.

Schistocytes / helmet cells Fibrin or hardware shredded RBCs inside vessels.

Very low haptoglobin Free hemoglobin consumed the plasma cleanup protein.

Splenomegaly Macrophages are removing whole RBCs in the spleen.

Unconjugated hyperbilirubinemia Macrophages process heme into bilirubin after eating RBCs.

Jaundice Bilirubin rises while RBCs are cleared by reticuloendothelial organs.

Hemosiderin in urine Renal tubular cells handled filtered hemoglobin and shed iron pigment.

Blood vessels

Free hemoglobin spills into plasma, urine, and kidney tubules.

Spleen / liver

Macrophages eat whole RBCs before hemoglobin floods plasma.

Memory Hook

INTRAVASCULAR = hemoglobin escapes into blood and urine: hemoglobinuria, hemosiderinuria, pink serum, very low haptoglobin.

EXTRAVASCULAR = organs do the cleanup: jaundice plus splenomegaly, often without dramatic urinary hemoglobin.

🔬 RBC Mugshot Gallery: Suspect Lineup

Click each suspect to reveal their name and criminal record (clinical significance).

Immature RBC

Reticulocyte

Immature RBC with residual RNA

MCC Healthy Marrow Response

•

Nuclear Remnant

Howell-Jolly Body

Nuclear fragment in RBC

MCC Splenectomy
Also: hemolytic anemia

●

Dense Sphere

Spherocyte

Aged/damaged RBC, lost surface area

MCC Hereditary Spherocytosis
Also: autoimmune hemolytic anemia

◐

Oval Shape

Elliptocyte

Structurally abnormal oval RBC

MCC Hereditary Elliptocytosis

✂

Fragmented

Schistocyte

RBC sheared by fibrin strands

MCC TTP/DIC/MAHA
Intravascular hemolysis

💧

Squeezed Shape

Tear Drop Cell

RBC squeezed through damaged BM

MCC Hemolytic Anemia
Also: BM fibrosis (myelofibrosis)

⊙

Bullseye

Target Cell

More central Hb staining, excess membrane

MCC Iron Deficiency
Also: thalassemia, liver disease

●○

Inclusion

Heinz Body

Precipitated hemoglobin (oxidative damage)

MCC G6PD Deficiency

✿

Spiky

Acanthocyte

RBC with lipid-coated spicules

MCC Hyperlipidemia
Also: abetalipoproteinemia

The Coombs Test: Who Killed The RBCs?

From the Attending

Direct Coombs (DAT) = "are antibodies stuck to the patient's RBCs RIGHT NOW?" Tests the patient's RBCs with anti-IgG / anti-C3 reagent. Positive = autoimmune hemolysis (warm AIHA, cold AIHA, drug-induced). Indirect Coombs (IAT) = "are antibodies floating in the patient's plasma waiting to attack donor RBCs?" Used for crossmatch, prenatal Rh testing. Boards mnemonic: Direct = on the cells (in vivo), Indirect = in the plasma (in vitro). Warm AIHA = IgG, spleen-mediated, lupus/CLL/methyldopa/penicillin. Cold AIHA = IgM, intravascular, mycoplasma/EBV/idiopathic.

The Coombs test detects antibodies involved in hemolysis. Two versions, two questions:

🔴 Direct Coombs (DAT)

Detects antibodies DIRECTLY ON RBC surface

Warm Agglutinin (IgG)

Most common autoimmune hemolytic anemia. IgG binds at 37°C. Extravascular hemolysis in spleen.

Cold Agglutinin (IgM)

IgM binds at cold temps. RBCs clump in cold. Follows infection or lymphoma. Intravascular hemolysis.

Hemolytic Disease of Newborn

Screen babies for maternal antibodies on their RBCs (Rh incompatibility, ABO mismatch).

🧬 Indirect Coombs (IAT)

Detects antibodies IN THE PLASMA (not on RBCs)

Transfusion Compatibility

Screen donor blood to detect antibodies against recipient RBCs (pre-transfusion testing).

Hemolytic Disease of Newborn

Screen MOTHER for antibodies that will cross placenta and attack fetal RBCs (Rh incompatibility).

Alloimmunization

Detect if patient developed antibodies to donor antigens (after transfusions, pregnancy).

Memory Hook

DIRECT = RBCs with bullseyes on them (antibodies STUCK to RBCs)
→ Used to screen BABIES for hemolytic disease

INDIRECT = Free-floating antibodies (antibodies FLOATING in plasma)
→ Used to screen MOM for hemolytic disease

Non-Immune Hemolytic Anemias

Positive direct Coombs means immune-mediated. Negative direct Coombs = consider these:

From the Attending

Non-immune hemolysis maps to the RBC layer that broke.

Membrane Hereditary spherocytosis: spectrin / ankyrin defect. PNH: anchor proteins lost, complement attacks CD55/CD59-deficient cells.

Enzyme G6PD: oxidative stress makes Heinz bodies and bite cells. Triggers: sulfa, nitrofurantoin, primaquine, fava beans, infection. Pyruvate kinase: chronic ATP failure.

Hemoglobin Sickle cell disease: HbS polymerization. Thalassemias: chain imbalance.

Mechanical MAHA from TTP, HUS, DIC, or HELLP makes schistocytes. Also prosthetic valve and march hemoglobinuria.

Sulfa / fava / infection plus bite cells = G6PD, the X-linked oxidative kill.

Drugs That Cause Hemolytic Anemia

These bind to RBCs or cause immune responses, triggering hemolysis:

• Penicillins & Cephalosporins → hapten mechanism (drug binds RBC, antibodies attack)
• Sulfonamides → immune complex formation
• Alpha-Methyldopa → induces anti-RBC antibodies (classic board trap)
• PTU → thyroid drug, immune-mediated
• Antimalarials → especially in G6PD patients
• Dapsone → oxidative hemolysis

Memory Hook

Patient on alpha-methyldopa for HTN presents with hemolytic anemia + positive direct Coombs?
CLASSIC BOARD TRAP. The drug induced antibodies against the patient's own RBCs (warm IgG-type). Stop the drug, hemolysis resolves slowly.

The Villains: Flip to Diagnose

Five hemolytic anemias. Each one has a signature. Tap each card.

🧬

G6PD Deficiency

Oxidative crisis

tap to learn

G6PD Deficiency

X-linked recessive. African American males. Coombs NEGATIVE (not immune-mediated).

Triggers: Dapsone, sulfonamides, antimalarials, fava beans, infection.

Smear: Heinz bodies (oxidized Hgb precipitates), bite cells (splenic macrophages chewing out Heinz bodies).

Rule: Heinz bodies + bite cells + oxidative trigger = G6PD.

🔴

Hereditary Spherocytosis

Spectrin/ankyrin defect

tap to learn

Hereditary Spherocytosis

Autosomal dominant (mostly). Defect in spectrin or ankyrin → RBC loses membrane → becomes sphere.

Coombs NEGATIVE. Smear: small round RBCs without central pallor (spherocytes).

Osmotic fragility test: spheres lyse in hypotonic saline faster than normal.

Rule: Spherocytes + osmotic fragility + Coombs negative = hereditary spherocytosis.

🌙

Sickle Cell Disease

HbS homozygous

tap to learn

Sickle Cell Disease (HbSS)

Beta-globin mutation (Glu → Val at position 6). HbS polymerizes under low O2, acidosis, dehydration.

Coombs NEGATIVE. Extravascular + intravascular hemolysis. Smear: sickle cells, target cells, Howell-Jolly bodies (after auto-splenectomy).

Rule: Sickle cells + vaso-occlusive crises + functional asplenia = sickle cell.

🩸

TTP

ADAMTS13 deficiency

tap to learn

Thrombotic Thrombocytopenic Purpura

ADAMTS13 deficiency → ultra-large vWF multimers → platelet clumping in microvessels → mechanical shearing of RBCs.

Pentad: MAHA + thrombocytopenia + fever + renal failure + neuro changes.

Rule: Schistocytes + thrombocytopenia + Coombs NEGATIVE = MAHA (TTP/HUS).

🔥

Autoimmune HA

Coombs positive

tap to learn

Autoimmune Hemolytic Anemia

Warm (IgG, 37°C): Extravascular. Associated with SLE, CLL, alpha-methyldopa. Coombs POSITIVE.

Cold (IgM, 4°C): Intravascular. After EBV/Mycoplasma. Agglutination in cold extremities. Complement activation.

Rule: Positive DAT (direct Coombs) = immune-mediated. Stop there. Coombs tells you everything.

Coombs Decision Tree: Intrinsic vs Extrinsic

One test. Every time. Click each node for the reasoning.

Patient has hemolytic anemia (high retic, elevated indirect bili). Run Direct Coombs Test (DAT).

The DAT is step one in every hemolytic workup. It detects antibodies or complement proteins DIRECTLY ON the RBC surface. A positive result means immune-mediated destruction. Negative means intrinsic RBC defect or mechanical shearing.

DAT POSITIVE

Immune-Mediated Hemolysis (Extrinsic). Antibody on RBC confirmed.

Positive DAT = something coated those RBCs. Now ask: IgG (warm) or IgM (cold)? Warm agglutinin (IgG) reacts at 37°C and causes extravascular hemolysis in the spleen. Cold agglutinin (IgM) reacts at 4°C and causes intravascular hemolysis with complement activation.

Warm (IgG)

Warm agglutinin AIHA. Check for SLE, CLL, drugs (alpha-methyldopa).

IgG binds at body temperature. Destruction happens in spleen (extravascular). Secondary causes: SLE (most common systemic cause), CLL, alpha-methyldopa, penicillin (hapten). Treatment: steroids first, then rituximab or splenectomy if refractory.

Cold (IgM)

Cold agglutinin disease. After EBV or Mycoplasma. Intravascular + complement.

IgM activates complement, causing intravascular hemolysis. Classic triggers: EBV (anti-i antibody) and Mycoplasma pneumoniae (anti-I antibody). Also lymphoma. Labs: hemoglobinuria, very low haptoglobin. Keep patient warm. Rituximab works well.

DAT NEGATIVE

Non-Immune Hemolysis (Intrinsic or Mechanical). Look at the smear.

Negative DAT means no antibodies coating RBCs. Now look at the peripheral smear. The smear morphology is your next decision gate. Schistocytes = mechanical. Spherocytes = hereditary spherocytosis. Sickle cells = HbSS. Bite cells + Heinz bodies = G6PD.

Schistocytes present

MAHA: TTP vs HUS vs DIC. Check platelets + renal function.

Schistocytes = RBCs shredded by fibrin strands in microthrombi. TTP: ADAMTS13 deficient, fever, neuro. HUS: E. coli O157:H7, children, renal failure dominant, no neuro. DIC: underlying sepsis/cancer, prolonged PT/PTT, low fibrinogen. Treatment is disease-specific.

No schistocytes

Intrinsic RBC defect: G6PD vs HS vs Sickle Cell. Match the smear + trigger.

G6PD: bite cells + Heinz bodies + oxidative trigger. Hereditary spherocytosis: spherocytes + osmotic fragility + family history. Sickle cell: sickle forms + target cells + Howell-Jolly bodies (functional asplenia). PNH: dark morning urine + unusual thrombosis + CD59 absent on flow cytometry.

🎯

The one-second rule: Positive Coombs = immune (extrinsic). Negative Coombs = intrinsic or mechanical. Then use the smear to ID which one. That's the entire algorithm.

Decision Tree: Hemolytic Anemia Workup

Labs suggest hemolysis (low haptoglobin, elevated LDH, elevated indirect bili, elevated retics). Click each branch to follow the workup.

From the Attending

Workup order matters. (1) Confirm hemolysis with the lab tuple. (2) Smear + DAT in parallel. Smear identifies the morphology (spherocytes, schistocytes, sickle, bite cells, target cells, agglutination). DAT splits immune from non-immune. (3) Reflex tests by morphology. Spherocytes + DAT positive = warm AIHA. Spherocytes + DAT negative = hereditary spherocytosis (EMA binding test). Schistocytes = TMA workup (ADAMTS13, Shiga, DIC panel). Sickle cells = Hgb electrophoresis. Bite cells = G6PD activity (assay AFTER acute crisis · falsely normal during). Wrong order → wasted labs. Smear is cheaper than every send-out panel; let it pick what to send.

Labs suggest hemolysis: low haptoglobin, elevated LDH, elevated indirect bilirubin, elevated reticulocytes. Next step?

Check peripheral smear

Schistocytes

MAHA: check TTP (pentad: fever + thrombocytopenia + MAHA + AKI + neuro, low ADAMTS13) vs HUS (MAHA + AKI + diarrhea, Shiga toxin E. coli) vs DIC (prolonged PT/aPTT + low fibrinogen)

Spherocytes

Hereditary spherocytosis (osmotic fragility test, high MCHC, splenomegaly) or AIHA. Confirm with DAT.

Sickle cells

Sickle cell disease: HbSS. Sickling, vaso-occlusive crisis, avascular necrosis. Hemoglobin electrophoresis confirms.

Target cells

Thalassemia, liver disease, or HbC. Check hemoglobin electrophoresis and liver function tests.

Direct antiglobulin test (DAT)

DAT positive

Immune-mediated: warm AIHA (IgG, anti-RBC abs, treat with steroids) vs cold agglutinin disease (IgM, Mycoplasma/EBV, cold avoidance) vs drug-induced hemolysis.

DAT negative

Non-immune: G6PD (oxidative stress trigger, bite cells, Heinz bodies) vs PNH (CD55/CD59 absent, flow cytometry) vs mechanical (prosthetic valve).

Board Walkthrough

25 original clinical vignettes. One at a time, shuffled, never repeats. Right-click or long-press to cross out. Double-tap to highlight.

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