Hemolytic Anemias

Recognizing hemolysis and where it happens

The universal hemolysis panel. Any hemolysis raises LDH (released from lysed cells), indirect (unconjugated) bilirubin, and reticulocytes (marrow compensation), and lowers haptoglobin, which binds free hemoglobin and is cleared with it. Haptoglobin is the single most useful screen. A peripheral smear then localizes the cause.

Intravascular hemolysis. RBCs lyse inside vessels (complement attack, mechanical shearing), releasing hemoglobin into plasma: haptoglobin plummets, and hemoglobinemia, hemoglobinuria (red-brown urine) and later hemosiderinuria follow. Chronic urinary losses can cause iron deficiency.

Extravascular hemolysis. Splenic macrophages remove abnormal or antibody-coated RBCs. Heme becomes unconjugated bilirubin, causing jaundice and pigment gallstones, urinary urobilinogen rises, and the working spleen enlarges. Haptoglobin is less affected and there is no hemoglobinuria.

Intrinsic red cell defects

Hereditary spherocytosis (membrane). Defects in ankyrin, spectrin, band 3 or protein 4.2 (usually autosomal dominant) weaken the membrane skeleton, so RBCs lose membrane, become spheres, and are trapped and destroyed EXTRAvascularly in the spleen. Findings are spherocytes, high MCHC, increased osmotic fragility or abnormal EMA-binding test, a negative Coombs test, splenomegaly, jaundice and gallstones; parvovirus B19 can cause an aplastic crisis. Splenectomy treats the anemia, after which Howell-Jolly bodies appear because no spleen remains to pit them out.

G6PD deficiency (enzyme). In this X-linked disorder, common in African and Mediterranean populations, the HMP shunt makes too little NADPH, so glutathione cannot neutralize oxidants. Triggers (fava beans, infections, dapsone, primaquine, sulfa drugs, nitrofurantoin) cause episodic hemolysis. Oxidized hemoglobin precipitates as Heinz bodies; splenic macrophages pit them out, leaving BITE cells. Check G6PD activity weeks after an acute episode, because the surviving young cells have enzyme and can give a falsely normal result.

Pyruvate kinase deficiency (enzyme). This autosomal recessive defect lowers ATP, so RBCs cannot maintain their shape and are cleared EXTRAvascularly: chronic hemolytic anemia from birth. Upstream 2,3-BPG rises, shifting the O₂ curve RIGHT and improving tissue O₂ delivery.

Sickle cell disease (hemoglobin). A β-globin point mutation substitutes valine for glutamate at position 6, creating HbS, which polymerizes when deoxygenated (worse with hypoxia, dehydration and acidosis). Sickled cells cause both intravascular and extravascular hemolysis plus vaso-occlusive crises. Repeated splenic infarction leads to autosplenectomy, leaving Howell-Jolly bodies and risk from encapsulated organisms. Hydroxyurea raises HbF, which reduces sickling. In HbC, lysine replaces glutamate at the same position, producing target cells and milder hemolysis.

Thalassemias (hemoglobin). Reduced globin-chain synthesis (α from gene deletions, β from point mutations) causes microcytic anemia with target cells, extravascular hemolysis and ineffective erythropoiesis. β-Thalassemia raises HbA₂ and HbF; severe forms cause a crew-cut skull and hepatosplenomegaly.

Immune hemolysis and the Coombs test

Warm autoimmune hemolytic anemia (AIHA). IgG antibodies active at 37 °C coat RBCs; splenic macrophages remove bits of membrane, creating spherocytes, and destroy cells EXTRAvascularly. The direct Coombs test is positive with anti-IgG. Associations are SLE, CLL and drugs (α-methyldopa, penicillin). Warm = IgG ("warm weather, wear IgG"). Glucocorticoids are first-line therapy.

Cold agglutinin disease. IgM binds RBCs in cool peripheral blood and fixes complement: cells are lysed intravascularly or coated with C3b and removed by hepatic macrophages (extravascular). The direct Coombs test is positive for C3. Hemolysis and acrocyanosis of the ears and fingers worsen with cold exposure. Associations are Mycoplasma pneumoniae, EBV (infectious mononucleosis), CLL and Waldenström macroglobulinemia. Avoiding cold is central, and splenectomy helps little because clearance is hepatic.

Direct vs indirect Coombs. The direct antiglobulin test (DAT) adds anti-human globulin to the patient's washed RBCs; agglutination shows antibody or complement already ON the cells, as in autoimmune hemolysis. The indirect Coombs test mixes the patient's serum with reagent RBCs to detect free antibody in the serum, as in blood typing and crossmatching and Rh antibody screening in pregnancy. Direct = on the cell; indirect = in the serum.

Mechanical and acquired hemolysis

Microangiopathic hemolytic anemia (MAHA). RBCs shear on fibrin strands in small vessels or on abnormal surfaces, producing SCHISTOCYTES (helmet cells) and intravascular hemolysis with low haptoglobin and high LDH. Causes are DIC, TTP/HUS, HELLP syndrome, malignant hypertension, and mechanical prosthetic heart valves.

Paroxysmal nocturnal hemoglobinuria (PNH). An acquired PIGA mutation in a hematopoietic stem cell blocks synthesis of the GPI anchor, so blood cells lack the complement regulators CD55 (DAF) and CD59. Complement lyses the RBCs intravascularly, classically noticed as dark morning urine, and the Coombs test is negative. The triad is hemolysis, pancytopenia and VENOUS THROMBOSIS, often at unusual sites such as the hepatic veins (Budd-Chiari). Flow cytometry showing absent CD55/CD59 is diagnostic. Eculizumab, an anti-C5 antibody, blocks terminal complement; because it raises the risk of meningococcal infection, patients are vaccinated first. PNH is associated with aplastic anemia.

PNH's leading cause of death is thrombosis, not anemia.

Let the smear name the anemia

• Spherocytes: hereditary spherocytosis or warm AIHA; the Coombs test separates them (negative vs positive).
• Bite cells and Heinz bodies: G6PD deficiency.
• Schistocytes (helmet cells): microangiopathic or mechanical hemolysis (DIC, TTP/HUS, prosthetic valves).
• Target cells: thalassemia or HbC.
• Sickled cells with Howell-Jolly bodies: sickle cell disease after autosplenectomy.