HaematologyTier 2Disease (DEADMAN)

Thrombotic thrombocytopenic purpura

Description

Thrombotic microangiopathy from severe ADAMTS13 deficiency (<10%)
- Platelet-VWF microthrombi in high-shear arterioles/capillaries -> MAHA + consumptive thrombocytopenia + ischaemic organ injury
Haematological emergency - untreated mortality >90%

Two forms


Immune (iTTP)	~95%	Anti-ADAMTS13 IgG (inhibitory or clearing). Adults
Congenital (cTTP, Upshaw-Schulman)	~5%	Biallelic ADAMTS13 mutations. Neonatal jaundice, childhood, or unmasked by first pregnancy

Target organs are those with the highest shear: brain, heart, kidney, gut, pancreas
- Renal failure is usually mild - severe renal failure points to HUS/aHUS instead

Incidence ~2-6 per million/yr
F>M ~2-3:1; median onset 40s
Over-represented in people of African ancestry (~9x) - *HLA-DRB1\11** association
Congenital ~5% of cases; presents in childhood or at first pregnancy

ADAMTS13 cleaves ultra-large VWF multimers at Tyr1605-Met1606 in the A2 domain
- Cleavage site exposed only by shear-induced unfolding of VWF
Synthesis: liver (hepatic stellate cells) is the main source
- Also renal podocytes + tubular epithelium; platelets and endothelium make a biologically active form
dec ADAMTS13 -> ULVWF multimers persist as strings anchored to endothelium
- -> spontaneous platelet adhesion at high shear
- -> occlusive platelet-rich (not fibrin-rich) microthrombi
- -> RBC fragmentation across strands = schistocytes, plus platelet consumption
Coagulation cascade is not activated -> normal PT/APTT/fibrinogen - the point of difference from DIC

Triggers of an acute episode

Pregnancy (2nd/3rd trimester, postpartum), infection, pancreatitis, surgery, obesity
Drugs: ticlopidine, clopidogrel (antibody-mediated)

Deficiency is necessary but not sufficient

cTTP patients sit at <10% activity between episodes yet remain well until a second hit (inflammation, complement activation, pregnancy)

MAHA + thrombocytopenia with no other explanation = TTP until disproven. Do not wait for ADAMTS13 before treating

The pentad - historical, not a checklist

Thrombocytopenia | MAHA | Neurological (headache, confusion, seizure, focal deficit, coma) | Renal impairment | Fever
*All five in only ~10%* - waiting for the pentad means treating a patient who is already dying
Neurological features fluctuate; cardiac involvement (troponin rise ~50%) is a leading cause of sudden death

Laboratory

Schistocytes on film, polychromasia, nucleated RBC
Platelets often <30 x10^9/L - typically far lower than in other TMAs
inc LDH (haemolysis + tissue ischaemia), undetectable haptoglobin, inc unconjugated bilirubin, inc retics
DAT negative (positive DAT -> AIHA/Evans, not TTP)
PT, APTT, fibrinogen normal - abnormal = DIC
Creatinine normal or mildly raised
ADAMTS13 activity <10% confirms - send before plasma exchange
- Anti-ADAMTS13 IgG / inhibitor titre separates immune from congenital
- Activity <10% with no antibody -> genotype for cTTP

PLASMIC score - pre-test probability while ADAMTS13 is pending

1 point each; 6-7 = high risk, proceed to plasma exchange


PL	Platelets <30 x10^9/L
A	Haemolysis: retics >2.5%, OR undetectable haptoglobin, OR indirect bilirubin >20.5 micromol/L
S	No active cancer
M	No solid organ or stem cell transplant
I	MCV <90 fL
C	INR <1.5
C	Creatinine <176.8 micromol/L

Differential of a TMA

	Discriminator
STEC-HUS	Children <5, bloody diarrhoea at 1-2 days, TMA at 5-7 days. Renal failure dominates
aHUS	Uncontrolled alternative complement pathway. Renal-predominant, ADAMTS13 normal -> eculizumab/ravulizumab
DIC	Prolonged PT/APTT, low fibrinogen, high D-dimer
Drug-induced TMA	Calcineurin inhibitors, gemcitabine, VEGF inhibitors, quinine
Transplant-associated TMA / disseminated malignancy	Malignancy often with a leucoerythroblastic film
HELLP / pre-eclampsia	LFTs, hypertension, proteinuria; resolves with delivery
Mechanical haemolysis (prosthetic valve)	*Platelet count normal*
Malignant hypertension, HIV, SLE/APS, scleroderma renal crisis	Context

Axis: disease phase. Treat on suspicion before the diagnosis is confirmed, then direct remission therapy by ADAMTS13.

A. Acute immune TTP

1. Therapeutic plasma exchange (TPE) - within 4-8 h. The single life-saving intervention
- Removes autoantibody + ULVWF, replaces ADAMTS13
- Replacement fluid must be FFP (or cryo-poor plasma) - albumin supplies no ADAMTS13
- 1-1.5 plasma volumes daily until platelets >150 x10^9/L for 2 consecutive days, then taper
- No immediate access -> FFP infusion as a temporising measure while arranging urgent transfer. Never a substitute
2. Corticosteroid - methylprednisolone 1 g IV daily x3, or prednisolone 1 mg/kg
3. Rituximab 375 mg/m2 weekly x4 - upfront, not on failure
- Reduces relapse and shortens the TPE course
- Give after the TPE session, or it is exchanged straight back out
4. Caplacizumab - anti-VWF A1 nanobody, blocks GPIb-VWF binding
- 10 mg IV load, then 10 mg SC daily; continue >=30 days beyond TPE cessation and until ADAMTS13 recovers
- Faster platelet normalisation, fewer exacerbations, less refractory disease (HERCULES)
- ISTH 2025 focused update reviewed the newer data and retained the conditional recommendation - conditional on cost/access, not on doubt about efficacy
- Bleeding is the main toxicity; withhold before invasive procedures
Folate; VTE prophylaxis once platelets >50

*Do not transfuse platelets*

B. Refractory or exacerbating

Twice-daily TPE, higher-dose corticosteroid
Bortezomib (kills long-lived plasma cells), cyclophosphamide, ciclosporin, vincristine
Splenectomy in truly refractory disease

C. Congenital TTP

Plasma infusion (FFP or intermediate-purity factor VIII concentrate) - TPE unnecessary, there is no antibody to remove
Recombinant ADAMTS13 (apadamtase alfa) - on-demand and prophylactic; the preferred replacement where available
Prophylaxis every 2-3 weeks if recurrent events; intensify through pregnancy

D. Remission and relapse prevention

Serial ADAMTS13 activity at every follow-up visit
- Falling activity precedes clinical relapse -> pre-emptive rituximab at <10-20%, before cytopenia appears
Response terms: clinical response (platelets >150 x2 days, LDH <1.5x ULN); ADAMTS13 remission = activity >=50-60%
Pregnancy: high relapse risk - plan with a TTP service, ADAMTS13 each trimester

Untreated mortality >90%; with plasma exchange ~10-20%
Deaths are early - cardiac (arrhythmia, infarction) and neurological, usually within days
Exacerbation = recurrence within 30 days of stopping TPE; relapse = after 30 days
Relapse in ~30-50% of immune TTP, most within 2 years -> lifelong follow-up

Long-term morbidity is under-recognised

Neurocognitive impairment (memory, concentration), depression, headache - despite "full" haematological recovery
Hypertension, CKD, stroke
Excess long-term mortality vs the general population
Persistently low ADAMTS13 in remission = strongest relapse predictor

Monitor

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