The Red Cell Under Attack
Acquired hemolytic anemia — distinguishing immune destruction (AIHA) from mechanical fragmentation (MAHA), with the Coombs test as the fork in the road.
A specialised, fragile vessel
To carry maximum oxygen, the red cell sacrifices everything else. It has no nucleus, no mitochondria, no ribosomes — it cannot repair itself. It simply survives on what it was built with, for about 120 days, before the spleen retires it.
Lifespan
120 days · ~5 million circulations
Cargo
Hemoglobin — pure O₂ transport
Stripped down
No nucleus · no mitochondria · no ribosomes
Disposal
Splenic macrophage system
Hereditary vs acquired
Every hemolytic anemia is either an inside job — a defective blueprint the cell was born with — or an outside attack from a hostile environment. This whole part is about the outside attack.
Hereditary · intrinsic
The defective blueprint — covered in Part 3.
- Hemoglobin: sickle cell, thalassemia
- Membrane: spherocytosis
- Enzymes: G6PD deficiency
Acquired · extrinsic
The hostile environment — this part.
- Immune: antibodies (AIHA)
- Mechanical: microangiopathy (MAHA)
- Toxins / infection: malaria, drugs
Extravascular vs intravascular
Where the cell dies decides the clinical signature. Retired gently by macrophages in the spleen — or ruptured violently inside the vessel.
Extravascular · the spleen
- Spleen / liver (macrophages)
- Heme → bilirubin → jaundice
- The slow, gentle route
Intravascular · the vessel
- Inside the blood vessels
- Hemoglobinemia & hemoglobinuria
- The violent route
The hemolysis lab panel
Four markers confirm that cells are being destroyed faster than normal — a marrow racing to compensate, and the debris of burst cells in the blood.
Haptoglobin drops most sharply in intravascular hemolysis — it is the clean-up crew for free hemoglobin, and it runs out.
Decoding urine colour
Dark urine is non-specific. Three very different processes look similar in the cup. Tap a tube.
Hemoglobinuria
Free hemoglobin / hemosiderin — the fingerprint of intravascular hemolysis.
Key insight — high urobilinogen is a specific pointer toward hemolytic anemia.
Autoimmune hemolysis (AIHA)
The body produces antibodies against its own red-cell surface antigens. One test cracks the case.
| Presentation | Dyspnea, abdominal pain |
| Hb | 7.3 g/dL |
| Reticulocytes | 16% |
| Haptoglobin | <8 mg/dL — undetectable |
| Direct Coombs | Positive (+) |
Agglutination on the smear
Antibodies bridge cells into clumps — the visual hint that the immune system is the attacker.
Warm vs cold antibodies
Two temperatures, two antibody classes, two destruction sites. Toggle between them.
Antibody
IgG — small monomer
Site
Extravascular — spleen
Associations
SLE (lupus), CLL, drugs (penicillin)
Antibody
IgM — large pentamer
Site
Intravascular — fixes complement
Associations
Mycoplasma, mononucleosis, lymphoma
The Coombs test
The antiglobulin test detects antibodies against red cells — either already stuck to the cell, or floating free in the serum. Switch between the two.
- Patient’s red cells are already coated with IgG in vivo.
- Add anti-human globulin (Coombs reagent).
- Reagent bridges the coated cells → agglutination.
Detects antibody attached to the cell.
- Antibodies float free in the patient’s serum.
- Add donor red cells & incubate — antibodies bind.
- Add anti-human globulin → agglutination.
Detects antibody floating in the serum.
The microspherocyte
In warm AIHA the spleen doesn’t swallow the cell whole — it takes bites. Each bite costs membrane, and the cell rounds up until it can’t squeeze through anymore.
Antibody coats the cell
IgG decorates the red-cell membrane.
Macrophage takes a “bite”
Splenic macrophages nibble the coated membrane.
Surface area is lost
The cell becomes a rigid sphere (lowest surface-to-volume ratio).
Trapped & destroyed
The rigid sphere can’t pass splenic sinusoids → extravascular death.
Microangiopathy (MAHA)
Here the antibodies are innocent — Coombs is negative. The cells are being physically shredded as they force past strands of fibrin in small vessels.
| Presentation | Severe headache, abdominal pain |
| Hb | 7.3 g/dL |
| Platelets | 50 — thrombocytopenia |
| Direct Coombs | Negative (−) |
| Smear | Schistocytes |
Fibrin strands shred the cell
Physical destruction of red cells in the small vessels.
The schistocyte
The fragment is the signature of MAHA — a helmet or triangle, sliced by shear force. Its presence forces three diagnoses to the front.
Morphology
- Fragmented shapes
- Result of high shear forces slicing the cell
Differential — the deadly trio
Thrombotic thrombocytopenic purpura · hemolytic uremic syndrome · disseminated intravascular coagulation. Schistocytes + low platelets demand you rule these out now.
TTP: the molecular scissors
Von Willebrand factor comes off the vessel wall as ultra-long, ultra-sticky multimers. Normally an enzyme — ADAMTS13 — trims them to safe lengths. In TTP an antibody blocks the scissors. Toggle it.
ADAMTS13 deficiency → large vWF → platelet consumption & red-cell fragmentation.
The pentad & the one rule
The classic pentad
Urgent management
- Gold standard: plasma exchange (PEX) — removes antibody, replaces ADAMTS13
- Adjunct: immunosuppression (steroids, rituximab)
Giving platelets in TTP feeds the micro-thrombi and worsens the thrombosis. Plasma exchange first.
The diagnostic algorithm
The smear plus the Coombs test separates the immune attack from the mechanical one.
↑ retics · ↑ LDH · ↓ haptoglobin
warm IgG · cold IgM
rule out TTP / HUS / DIC
The smear + Coombs test separate the immune from the mechanical.
End of Part 2. Next: the inside job — hereditary defects of membrane, enzyme, and cargo.
Part 3 · Hereditary hemolysis →