Hematology, Oncology & Immunology · Topic 2 of 26

Hemolytic Anemia

Hematology · hemolysis

Hemolytic Anemia

Hemolysis = anemia with reticulocytosis, high LDH and indirect bilirubin, low haptoglobin; the smear and the direct Coombs test point to the cause.

Key numbers

Warm AIHA: prednisone 1 mg/kg/dayprednisone 1 mg/kg/day

01 · Defined byHigh LDH, indirect bilirubin; low haptoglobin

Hemolysis = anemia with reticulocytosis, raised LDH and indirect (unconjugated) bilirubin, and low haptoglobin; urine urobilinogen rises. Jaundice and splenomegaly may accompany it.

02 · Defined byPositive direct Coombs = immune hemolysis

The direct antiglobulin (Coombs) test detects IgG or complement (C3) on the patient's red cells; a positive test points to immune hemolysis — autoimmune, drug-induced, or a transfusion reaction.

03 · Look forSchistocytes with low platelets: exclude TTP now

Schistocytes with thrombocytopenia mean microangiopathic hemolysis (TTP, HUS, DIC, HELLP); send ADAMTS13 activity at once, because untreated TTP is over 90% fatal and needs plasma exchange without waiting for results.

What it is

Core idea

Extravascular hemolysis happens in spleen and liverMost pathologic hemolysis is extravascular: macrophages in the spleen and liver remove antibody-coated or abnormal red cells, producing spherocytes, splenomegaly and indirect hyperbilirubinemia without hemoglobinuria.

Causes & risk factors

Why it happens

Drug-induced immune hemolysis: stop the drugDrugs cause immune hemolysis — cephalosporins and penicillins, methyldopa, quinine, sulfonamides, fludarabine; withdrawing the drug is the treatment, with glucocorticoids or IVIG as second-line.

G6PD deficiency: oxidant trigger, bite cellsG6PD deficiency (X-linked, mostly men) causes episodic Coombs-negative hemolysis after infection, DKA or oxidant drugs — dapsone, primaquine, rasburicase, sulfonamides, nitrofurans, methylene blue — or fava beans; smear shows bite cells and Heinz bodies.

Presentation

What you'll see

Intravascular hemolysis: hemoglobinuria, very low haptoglobinIntravascular hemolysis (ABO-incompatible transfusion, microangiopathy, mechanical valve, clostridial toxin) causes hemoglobinemia, hemoglobinuria (dipstick blood-positive without RBCs on microscopy), hemosiderinuria and very low haptoglobin.

Do right now

In this order

First moves

Smear and reticulocyte count come first

→

Positive direct Coombs = immune hemolysis

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Schistocytes with low platelets: exclude TTP now

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Never withhold transfusion in life-threatening AIHA

Why each step

Smear and reticulocyte count come firstThe peripheral smear and reticulocyte count are the key tests: spherocytes suggest extravascular hemolysis (autoimmune or hereditary spherocytosis); schistocytes suggest mechanical intravascular hemolysis (microangiopathy or valve).

Positive direct Coombs = immune hemolysisThe direct antiglobulin (Coombs) test detects IgG or complement (C3) on the patient's red cells; a positive test points to immune hemolysis — autoimmune, drug-induced, or a transfusion reaction.

Schistocytes with low platelets: exclude TTP nowSchistocytes with thrombocytopenia mean microangiopathic hemolysis (TTP, HUS, DIC, HELLP); send ADAMTS13 activity at once, because untreated TTP is over 90% fatal and needs plasma exchange without waiting for results.

Never withhold transfusion in life-threatening AIHATransfuse symptomatic, rapidly worsening autoimmune hemolysis even when no fully compatible unit can be found: panagglutinins make crossmatching difficult, but transfusion is life-saving until immunosuppression works.

Management

Orders

Warm AIHA: prednisone 1 mg/kg/day must knowWarm autoimmune hemolytic anemia (IgG, most common form) is treated first with prednisone 1 mg/kg daily, tapered slowly once counts stabilize; rituximab is second-line (often added early when severe), then splenectomy or immunosuppressants.

Folate and vaccines in chronic hemolysisChronic hemolysis consumes folate — give folic acid. Before splenectomy, vaccinate against pneumococcus, Haemophilus influenzae and meningococcus, ideally at least 2 weeks ahead.

Red flags & don'ts

Avoid harm

Hemolysis with low reticulocytes is an emergency complicationHemolysis with an inappropriately low reticulocyte count (renal failure, infection, marrow failure) causes rapidly severe anemia and needs prompt transfusion.

Give VTE prophylaxis in warm AIHA complicationVenous thromboembolism is common in warm autoimmune hemolytic anemia (cold agglutinin disease also raises thrombotic risk); keep hospitalized patients on pharmacologic VTE prophylaxis.

The rules

Know these

G6PD level can be falsely normal acutelyDuring and just after a hemolytic episode the G6PD assay can be falsely normal (young reticulocytes are rich in G6PD); repeat it weeks later. Screen high-risk patients before rasburicase, which is contraindicated in G6PD deficiency.

Warm AIHA or cold agglutinin disease?

Commonly confused

Antibody	IgG, reacts at 37 °C
Direct Coombs	IgG, with or without C3
Associations	Idiopathic, SLE, CLL or lymphoma, drugs
First-line	Prednisone 1 mg/kg/day; rituximab next
Steroids and splenectomy	Both can work

Commonly confused

Tell apart

Spherocytes: Coombs separates AIHA from spherocytosisSpherocytes with increased osmotic fragility occur in both hereditary spherocytosis and autoimmune hemolytic anemia; the direct Coombs test is positive in AIHA and negative in hereditary spherocytosis.

More detail

Reference

Show 5 reference facts

A positive direct Coombs test without autoimmunity can reflect transfusion within 3 months (alloantibodies, delayed hemolytic reaction), IVIG, RhD immune globulin or daratumumab; about 5% of AIHA is Coombs-negative.

Paroxysmal nocturnal hemoglobinuria: Coombs-negative intravascular hemolysis with dark morning urine, thrombosis and cytopenias; diagnose by flow cytometry for the PNH clone.

Cold agglutinins clump unwarmed samples, giving a spuriously high MCV and low hemoglobin on automated counts; rewarming the tube corrects the values.

Infections cause hemolysis by red-cell invasion (malaria, babesiosis, Bartonella), toxins (Clostridium perfringens, Shiga toxin in HUS) or antibodies (mycoplasma, EBV).

In valvular (turbulent-flow) hemolysis, keeping the hematocrit above 30% reduces hemolysis, and iron is replaced when chronic hemosiderinuria causes iron deficiency.

Pearl

Spherocytes plus a positive Coombs = autoimmune; schistocytes plus low platelets = a microangiopathy until TTP is excluded.

Sources · Merck Manual Professional — Overview of Hemolytic Anemia · Merck Manual Professional — Autoimmune Hemolytic Anemia · Merck Manual Professional — Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency · Merck Manual Professional — Microangiopathic Hemolytic Anemia (rev. Apr 2026) · Merck Manual Professional — Evaluation of Anemia (table: Characteristics of Common Anemias) · Merck Manual Professional — Thrombotic Thrombocytopenic Purpura (TTP) · Starter sheet built from the verified AGACNP fact map (facts reviewed 2026-10-15).