STEPTRACKERHEMATOLOGY | PATHOLOGY + IMMUNOLOGY | HIGH-YIELD REVIEW

Immune & Microangiopathic Hemolysis

Normal red cells destroyed from outside — by antibodies, by fibrin strands and valves, or by infection.

FOCUS ON
Warm AIHA is IgG, splenic, with spherocytes (SLE, CLL, drugs). Cold agglutinin disease is IgM + complement (Mycoplasma, EBV, lymphoma). The direct Coombs test proves the immune cause. Schistocytes mean mechanical shearing: TTP, HUS, DIC, HELLP, malignant hypertension, valves. Rh disease affects the second pregnancy.
DISORDER
MECHANISM
CAUSES
CLUE
Warm AIHA
IgG, 37 °C
IgG-coated RBCs are nibbled by splenic macrophages → spherocytes → extravascular hemolysis.
Idiopathic, SLE, CLL, other lymphomas, drugs (methyldopa)
Direct Coombs ⁺ for IgG · steroids, rituximab, splenectomy
Cold agglutinin disease
IgM, cold
IgM binds in cool extremities and fixes complement → C3b-coated cells cleared by liver; some intravascular lysis.
Mycoplasma pneumoniae, EBV (mono), Waldenström, CLL, other lymphomas
Acrocyanosis, RBC clumping on smear; Coombs ⁺ for C3 only · keep warm, rituximab
Paroxysmal cold hemoglobinuria
biphasic IgG
Donath-Landsteiner IgG binds in the cold, then fixes complement on rewarming → intravascular lysis.
Children after a viral illness
Hemoglobinuria after cold exposure
Drug-induced immune hemolysis
Hapten (drug binds RBC), immune complex, or true autoantibody.
Penicillin/cephalosporins (hapten), quinine (complex), methyldopa (autoantibody)
Stop the drug
Hemolytic disease of fetus & newborn
Maternal IgG crosses the placenta and coats fetal RBCs.
Rh (anti-D): sensitized in 1st pregnancy, severe in 2nd · ABO: O mothers, 1st pregnancy, mild
Hydrops, jaundice, kernicterus · RhoGAM at 28 weeks and after delivery
Microangiopathic (MAHA)
small vessels
RBCs are sliced by fibrin strands in microthrombi.
TTP, HUS, DIC, HELLP, malignant hypertension, scleroderma renal crisis
Schistocytes (helmet cells), ↓ platelets
Macroangiopathic
large vessels
Turbulence and shear across abnormal or artificial valves.
Mechanical valves, severe aortic stenosis
Schistocytes; iron deficiency from urinary loss
Infection-related
Parasites rupture RBCs; toxins lyse membranes.
Malaria (cyclic fevers), Babesia (ticks, asplenia), Clostridium perfringens (lecithinase)
Ring forms; Maltese cross (Babesia)
Hypersplenism
Enlarged spleen traps and destroys cells.
Portal hypertension, infiltrative diseases
Mild anemia + thrombocytopenia + big spleen

Mechanism — the antibody decides the site

IgG (warm)Fc receptors
→
Splenic macrophageBites membrane
→
SpherocyteExtravascular
IgM (cold)Fixes complement
→
C3bLiver Kupffer cells
→
Full MACIntravascular lysis

Direct Coombs: anti-IgG or anti-C3 added to the patient's RBCs → agglutination means the cells are already coated.

Warm vs cold AIHA

FEATURE
WARM
COLD
Antibody
IgG
IgM
Temperature
Body temperature
< 30 °C (extremities)
Coombs
IgG ± C3
C3 only
Site
Spleen
Liver ± intravascular
Smear
Spherocytes
Agglutination
Causes
SLE, CLL, drugs
Mycoplasma, EBV, lymphoma
Treatment
Steroids first
Avoid cold; rituximab

How it's tested

COMMON CONFUSIONSpherocytes with a positive Coombs test mean warm AIHA. Spherocytes with a negative Coombs test mean hereditary spherocytosis.
THE TRAPRh disease rarely harms a first baby, because anti-D IgG forms only after sensitization at the first delivery. ABO disease can affect the first baby but is mild.
YOUR APPROACHHemolysis confirmed → Coombs (immune or not) → antibody type (IgG/IgM) → cause. Coombs negative with schistocytes → find the microthrombi or valve.

If you see… think…

SLE or CLL with spherocytes, IgG Coombs ⁺ → warm AIHA
Mycoplasma pneumonia, then hemolysis and blue fingertips → cold agglutinin disease
Infectious mono with hemolysis → cold agglutinins
Child with dark urine after playing in snow → paroxysmal cold hemoglobinuria
Rh-negative mother, second baby with hydrops → anti-D HDFN
Type O mother, first baby jaundiced → ABO HDFN
Schistocytes + low platelets → MAHA (TTP, HUS, DIC)
Mechanical valve + schistocytes + low ferritin → valve hemolysis, urinary iron loss
Asplenic patient after a tick bite, Maltese-cross forms → Babesia