Medicine chapters
TTP and HUS
Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome are thrombotic microangiopathies that cause low platelets, fragmented red cells and organ damage, with normal clotting tests.
- TTP: autoantibodies against ADAMTS13 leave ultra-large vWF multimers that clump platelets in small vessels; classic pentad = fever, low platelets, MAHA, neurological signs, renal impairment; mainly adult women.
- HUS: classic triad = MAHA, low platelets, acute kidney injury; usually children after bloody diarrhoea from E. coli O157 (Shiga toxin); atypical HUS is complement-driven.
- Both have schistocytes, high LDH, and normal PT/APTT and fibrinogen (unlike DIC). TTP: urgent plasma exchange (+ steroids, rituximab, caplacizumab), no platelet transfusion; typical HUS: supportive care/dialysis; atypical HUS: eculizumab.
On this page
Overview
TTP and HUS are the two main thrombotic microangiopathies (TMA). In both, platelet-rich microthrombi form in small vessels. This causes:
- Thrombocytopenia (platelets used up in clots).
- Microangiopathic haemolytic anaemia (MAHA): red cells are sliced as they pass the clots, giving schistocytes.
- Organ ischaemia: mainly brain in TTP and kidney in HUS.
Unlike DIC, the coagulation cascade is not activated, so the clotting tests are normal. Both are medical emergencies.
Pathophysiology
TTP
- Endothelium releases von Willebrand factor (vWF) as very large chains (ultra-large multimers), which are very "sticky" for platelets.
- Normally the plasma enzyme ADAMTS13 (a metalloproteinase) cuts these into smaller multimers.
- In TTP, ADAMTS13 is severely deficient, so ultra-large vWF persists and grabs platelets → widespread platelet microthrombi.
| TTP type | Cause |
|---|---|
| Acquired (immune) | IgG autoantibody against ADAMTS13; most adult cases |
| Congenital (Upshaw-Schulman) | Mutations in the ADAMTS13 gene; presents in childhood or in pregnancy |
| Secondary triggers | Pregnancy, oral contraceptives, SLE, HIV and other infections, cancer, drugs (ticlopidine, clopidogrel, quinine, ciclosporin) |
HUS
- Typical (diarrhoea-associated, D+) HUS: Shiga toxin (verotoxin) from E. coli O157:H7 (or Shigella dysenteriae) is absorbed from the gut and binds a receptor (Gb3) on kidney endothelium. The toxin stops protein synthesis and damages endothelial cells → microthrombi mainly in the kidney.
- Source: undercooked beef, contaminated food, milk or water, contact with cattle.
- Atypical HUS (aHUS): uncontrolled alternative complement pathway from mutations or antibodies affecting complement factor H, factor I, CD46 (MCP) or C3. Triggers: pregnancy, infections, drugs (ciclosporin, tacrolimus, cisplatin, mitomycin C), malignant hypertension.
- Pneumococcal HUS: neuraminidase exposes the hidden Thomsen (T) antigen on cells; avoid plasma products.
Clinical features: the pentad and triad
| Feature | TTP | HUS |
|---|---|---|
| Thrombocytopenia (purpura, bleeding) | Yes (often severe) | Yes |
| MAHA (pallor, jaundice) | Yes | Yes |
| Neurological signs (headache, confusion, fits, stroke, fluctuating focal signs, coma) | Prominent | Less common |
| Renal impairment | Usually mild | Prominent: acute kidney injury, oliguria, hypertension |
| Fever | Yes | Less typical |
| Prodrome | None typical | Bloody diarrhoea a few days before (typical HUS) |
| Typical patient | Adult, more often women | Young child |
TTP pentad = "FAT RN": Fever, Anaemia (MAHA), Thrombocytopenia, Renal impairment, Neurological signs. HUS = the same minus fever and neurology: MAHA + low platelets + kidney failure.
The full pentad is present in only a minority of TTP patients. Do not wait for all five; MAHA plus thrombocytopenia without another cause is enough to start treatment.
Investigations
| Test | TTP / HUS finding |
|---|---|
| Full blood count | Anaemia, thrombocytopenia (often very low in TTP) |
| Blood film | Schistocytes (fragmented red cells, helmet cells); polychromasia |
| Reticulocytes | Raised |
| LDH | Markedly raised (haemolysis and tissue ischaemia); used to monitor response |
| Bilirubin | Raised (unconjugated) |
| Haptoglobin | Low |
| Direct Coombs test | Negative (not immune haemolysis) |
| PT, APTT, fibrinogen | Normal (key difference from DIC) |
| D-dimer | Normal or mildly raised |
| Urea, creatinine | Raised (marked in HUS) |
| Urinalysis | Haematuria, proteinuria |
| ADAMTS13 activity | Severely reduced in TTP; anti-ADAMTS13 antibody in acquired TTP (take blood before plasma exchange) |
| Stool culture / Shiga toxin PCR | E. coli O157 in typical HUS |
| Complement studies, genetics | In atypical HUS |
| Others | Pregnancy test, HIV, autoantibodies (SLE), troponin, CT/MRI brain if neurological signs |
Schistocytes + low platelets + normal clotting tests = thrombotic microangiopathy (TTP/HUS). Schistocytes + low platelets + abnormal clotting + low fibrinogen = DIC.
TTP/HUS versus DIC
| Feature | TTP | HUS | DIC |
|---|---|---|---|
| Platelets | Low | Low | Low |
| Schistocytes | Yes | Yes | Yes |
| PT / APTT | Normal | Normal | Prolonged |
| Fibrinogen | Normal | Normal | Low |
| D-dimer | Normal/slightly up | Normal/slightly up | High |
| Main organ | Brain | Kidney | Many |
| Key cause | ADAMTS13 deficiency | Shiga toxin / complement | Sepsis, obstetric, trauma, cancer |
Management
TTP
- Urgent plasma exchange (plasmapheresis), started as soon as TTP is suspected, daily until the platelet count recovers. It:
- removes the anti-ADAMTS13 antibody and ultra-large vWF, and
- replaces ADAMTS13 (in the donor plasma).
If exchange is delayed, give FFP infusion as a stop-gap (FFP and cryoprecipitate both contain ADAMTS13).
- Corticosteroids (pulsed IV methylprednisolone) to reduce antibody.
- Rituximab (anti-CD20) is now commonly used early in acquired TTP and reduces relapse.
- Caplacizumab: a nanobody against vWF that blocks its binding to platelet GPIb; speeds platelet recovery.
- Stop triggering drugs; manage pregnancy-associated cases with obstetric input.
- Folic acid; red cell transfusion if needed; aspirin/LMWH thromboprophylaxis once platelets recover.
- Monitor with platelet count and LDH.
- Congenital TTP: regular plasma infusion (or recombinant ADAMTS13).
Platelet transfusion is contraindicated in TTP (except for life-threatening bleeding) because it "feeds the fire" and can worsen thrombosis.
Prognosis: untreated TTP is fatal in up to 90%; with plasma exchange mortality falls to about 10%. Relapses occur, especially with persistently low ADAMTS13.
Typical (Shiga toxin) HUS
- Supportive care: careful fluid and electrolyte balance, blood pressure control, nutrition, red cell transfusion if needed.
- Dialysis for severe acute kidney injury; most children recover renal function.
- Plasma exchange is not beneficial in typical HUS.
- Avoid antibiotics and antimotility drugs in suspected E. coli O157 diarrhoea: they increase the risk of HUS.
- Long-term: some develop hypertension, proteinuria or chronic kidney disease, so follow up.
Atypical HUS
- Eculizumab (monoclonal antibody against C5) is the main treatment; it blocks the terminal complement pathway. Vaccinate against meningococcus first (risk of Neisseria infection).
- Plasma exchange or infusion is often started until the diagnosis is clear.
- Liver transplant can cure factor H or I mutations (these proteins are made in the liver).
- Recurrence after kidney transplant is common without complement blockade.
TTP → plasma exchange; typical HUS → supportive care and dialysis; atypical HUS → eculizumab.
Aetiology summary
| Condition | Main causes |
|---|---|
| TTP | Anti-ADAMTS13 autoantibody; congenital ADAMTS13 mutation; pregnancy, OCP, SLE, HIV, ticlopidine/clopidogrel, cancer |
| Typical HUS | E. coli O157:H7 Shiga toxin; Shigella |
| Atypical HUS | Complement factor H/I/CD46 mutations or antibodies; pregnancy, drugs (ciclosporin, tacrolimus, chemotherapy), malignant hypertension |
| Pneumococcal HUS | Streptococcus pneumoniae (T antigen exposure) |
Expect: the five features of the TTP pentad and the three of HUS; a child with bloody diarrhoea then oliguria, pallor and petechiae (typical HUS from E. coli O157); a young woman with fever, confusion, purpura and anaemia with schistocytes (TTP); ADAMTS13 and ultra-large vWF multimers; normal PT/APTT and fibrinogen separating TTP/HUS from DIC; negative Coombs test and high LDH; plasma exchange as the treatment of choice for TTP and avoidance of platelet transfusion; supportive care and dialysis for typical HUS and no antibiotics for O157; eculizumab for atypical HUS; and drug causes such as clopidogrel, ticlopidine and ciclosporin.
Quick revision
- TMA = low platelets + MAHA (schistocytes) + organ damage; clotting tests normal.
- TTP: ADAMTS13 deficiency (autoantibody) → ultra-large vWF → platelet clots.
- TTP pentad: fever, anaemia (MAHA), thrombocytopenia, renal, neurological.
- HUS triad: MAHA, thrombocytopenia, AKI; child after E. coli O157 bloody diarrhoea.
- Labs: high LDH, low haptoglobin, negative Coombs, normal PT/APTT/fibrinogen.
- TTP: urgent plasma exchange, steroids, rituximab, caplacizumab; no platelets.
- Typical HUS: supportive care, dialysis; avoid antibiotics and antimotility drugs.
- Atypical HUS: complement; eculizumab (vaccinate against meningococcus).
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pathoma: Fundamentals of Pathology).
FAQ
What is ADAMTS13?
It is a plasma enzyme that cuts large von Willebrand factor chains into smaller pieces; when it is missing or blocked, large vWF chains cause platelet clots, producing TTP.
How do you tell TTP from DIC on blood tests?
Both have low platelets and schistocytes, but in TTP the PT, APTT and fibrinogen are normal, whereas in DIC the clotting times are prolonged, fibrinogen is low and D-dimer is high.
Why are platelet transfusions avoided in TTP?
Transfused platelets can be pulled into new microthrombi, worsening organ damage, so they are given only for life-threatening bleeding.
Should a child with E. coli O157 diarrhoea get antibiotics?
Generally no, because antibiotics and antimotility drugs increase the chance of developing haemolytic uraemic syndrome.
What is the treatment of atypical HUS?
Eculizumab, an antibody that blocks complement C5, after meningococcal vaccination; plasma exchange is often used until the diagnosis is confirmed.