Overview
TTP and HUS (Thrombotic Microangiopathies)
Topic Overview
Summary
Thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS) are thrombotic microangiopathies (TMAs) characterised by microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, and organ dysfunction. TTP is caused by ADAMTS13 deficiency and predominantly affects the brain. HUS predominantly affects the kidneys and is often triggered by Shiga toxin-producing E. coli. TTP is treated with plasma exchange; HUS is managed with supportive care (typical) or eculizumab (atypical).
Key Facts
- TMA triad: MAHA + thrombocytopenia + organ dysfunction
- TTP pentad: MAHA + thrombocytopenia + neurological symptoms + renal impairment + fever (rarely all 5)
- TTP mechanism: ADAMTS13 deficiency → ultra-large VWF multimers → platelet microthrombi
- HUS mechanism: Shiga toxin (typical) or complement dysregulation (atypical)
- Treatment: TTP — plasma exchange; aHUS — eculizumab; tHUS — supportive
- DO NOT transfuse platelets (fuels microthrombosis)
Clinical Pearls
MAHA + thrombocytopenia = TMA until proven otherwise — send ADAMTS13 immediately
TTP mortality untreated: Over 90%; with plasma exchange: Under 20%
Do NOT transfuse platelets in TTP — it "adds fuel to the fire"
Why This Matters Clinically
TTP and aHUS are fatal without treatment. Recognising the blood film (schistocytes) and initiating plasma exchange or eculizumab urgently saves lives.
Visual Summary
Visual assets to be added:
- Blood film showing schistocytes
- TTP vs HUS comparison table
- ADAMTS13 pathway diagram
- TMA management algorithm
Epidemiology
TTP
- Incidence: 2-6 per million/year
- Peak age: 30-50 years
- Female predominance
HUS
- Typical HUS (tHUS): Children, post-diarrhoeal (E. coli O157:H7)
- Atypical HUS (aHUS): All ages; complement-mediated
Causes/Triggers
| Condition | Trigger/Cause |
|---|---|
| TTP (acquired) | Autoantibody to ADAMTS13 |
| TTP (congenital) | ADAMTS13 gene mutation (Upshaw-Schulman) |
| Typical HUS | Shiga toxin-producing E. coli (O157:H7) |
| Atypical HUS | Complement dysregulation (genetic or acquired) |
| Secondary TMA | Pregnancy, malignancy, HIV, drugs (quinine, cyclosporin) |
Pathophysiology
TTP — ADAMTS13 Deficiency
- ADAMTS13 normally cleaves ultra-large VWF multimers
- Deficiency → ultra-large VWF persists
- Platelet adhesion and aggregation → microthrombi
- Microvascular occlusion → organ ischaemia (brain, kidney)
- RBCs sheared by fibrin strands → haemolysis + schistocytes
HUS — Typical (Shiga Toxin)
- Infection with Shiga toxin-producing E. coli
- Toxin binds Gb3 receptors (high in kidney)
- Endothelial damage → microthrombi
- Predominantly renal injury
HUS — Atypical (Complement)
- Uncontrolled alternative complement pathway activation
- Endothelial damage → microthrombi
- Systemic + renal involvement
Clinical Presentation
TTP
| Feature | Frequency |
|---|---|
| Thrombocytopenia | 100% |
| MAHA | 100% |
| Neurological symptoms | 60-70% (confusion, seizures, stroke) |
| Renal impairment | 50% (usually mild) |
| Fever | 30% |
Typical HUS
Atypical HUS
Red Flags
| Finding | Significance |
|---|---|
| Schistocytes on film | MAHA — TMA |
| Platelet count under 30 | Severe |
| Neurological symptoms | TTP — urgent plasma exchange |
| AKI requiring dialysis | HUS |
Bloody diarrhoea (prodrome) — 5-10 days before
Common presentation.
Abdominal pain
Common presentation.
Acute kidney injury (often severe, dialysis-requiring)
Common presentation.
Thrombocytopenia, MAHA
Common presentation.
Children most commonly affected
Common presentation.
Clinical Examination
General
- Pallor (anaemia)
- Jaundice (haemolysis)
- Petechiae, bruising (thrombocytopenia)
Neurological
- Confusion
- Focal deficits
- Seizures
Abdominal
- Tenderness (diarrhoeal illness)
Investigations
Blood Tests
| Test | Finding |
|---|---|
| FBC | Low platelets; low Hb |
| Blood film | Schistocytes (fragmented RBCs) |
| LDH | Markedly elevated |
| Haptoglobin | Low or undetectable |
| Bilirubin | Elevated (unconjugated) |
| Reticulocyte count | Elevated |
| Coombs test | Negative (distinguishes from AIHA) |
| U&E, creatinine | AKI |
| ADAMTS13 activity | Under 10% = TTP |
Stool Culture
- Shiga toxin or E. coli O157:H7 (typical HUS)
Complement Studies (aHUS)
- C3, C4, factor H, factor I, CFB
- Genetic testing
PLASMIC Score
- Predicts likelihood of ADAMTS13 under 10%
Classification & Staging
Types of TMA
| Type | Key Features |
|---|---|
| TTP (acquired) | ADAMTS13 under 10%; neurological predominance |
| TTP (congenital) | ADAMTS13 gene mutation |
| Typical HUS | Post-Shiga toxin; children; renal predominance |
| Atypical HUS | Complement-mediated; any age |
| Secondary TMA | Pregnancy, malignancy, drugs, HIV |
Management
TTP — Emergency Plasma Exchange
| Treatment | Details |
|---|---|
| Plasma exchange (PEX) | First-line; daily until platelet recovery |
| Steroids | Methylprednisolone 1g IV daily x3, then prednisolone |
| Rituximab | Refractory or relapsing TTP |
| Caplacizumab | Anti-VWF nanobody; speeds remission |
Do NOT transfuse platelets (worsens microthrombosis) — only if life-threatening bleeding or procedure
Typical HUS
| Treatment | Details |
|---|---|
| Supportive care | IV fluids, dialysis if needed |
| Avoid antibiotics | May increase Shiga toxin release |
| No plasma exchange | Not effective |
Atypical HUS
| Treatment | Details |
|---|---|
| Eculizumab | Anti-C5 monoclonal antibody; highly effective |
| Meningococcal vaccination | Before eculizumab (risk of meningococcal infection) |
| Plasma exchange | May be used while awaiting eculizumab |
Secondary TMA
- Treat underlying cause (stop drug, deliver baby, treat malignancy)
Complications
Of TMA
- Stroke
- MI
- AKI (may need long-term dialysis)
- Death
Of Treatment
- Line complications (PEX)
- Transfusion reactions
- Infection (eculizumab increases meningococcal risk)
Prognosis & Outcomes
TTP
- Untreated mortality: Over 90%
- With PEX: Under 20%
- Relapse risk: 20-50% (reduced with rituximab)
Typical HUS
- Mortality: 3-5%
- Most recover renal function
- Some develop CKD
Atypical HUS
- Without treatment: High mortality, ESRD
- With eculizumab: Excellent outcomes
Evidence & Guidelines
Key Guidelines
- BCSH Guideline on TTP (2019)
- BSH Guideline on Diagnosis and Management of TTP
Key Evidence
- Plasma exchange is life-saving in TTP
- Eculizumab is highly effective in aHUS
- Caplacizumab reduces time to remission in TTP
Patient & Family Information
What is TTP/HUS?
TTP and HUS are rare blood clotting disorders. They cause tiny blood clots to form in small blood vessels, which can damage organs like the brain and kidneys.
Symptoms
- Tiredness and feeling weak (anaemia)
- Bruising or bleeding
- Confusion or headaches (TTP)
- Reduced urine output (HUS)
Treatment
- TTP: Plasma exchange (a treatment to filter your blood)
- HUS: Supportive care or a medication called eculizumab
Resources
References
Primary Guidelines
- Scully M, et al. British Society for Haematology guideline on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2019;184(4):542-558. PMID: 30512199
Key Trials
- Peyvandi F, et al. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura (HERCULES). N Engl J Med. 2019;380(4):335-346. PMID: 30625070
- Legendre CM, et al. Terminal complement inhibitor eculizumab in atypical hemolytic–uremic syndrome. N Engl J Med. 2013;368(23):2169-2181. PMID: 23738544