📋 Key Information Summary
- TTP is a medical emergency — untreated mortality exceeds 90%; early plasma exchange (PEX) reduces mortality to 10–20%.
- Thrombotic microangiopathy (TMA) driven by severe ADAMTS13 deficiency (activity <10%) leading to ultra-large von Willebrand factor (vWF) multimer accumulation and microvascular thrombosis.
- The classic pentad — thrombocytopenia, microangiopathic haemolytic anaemia (MAHA), renal impairment, neurological features, and fever — is present in its entirety in <10% of patients; do not wait for all five features before initiating PEX.
- A presumptive diagnosis of TTP should be made whenever MAHA and thrombocytopenia are present without another obvious cause (e.g., DIC, HUS, HELLP).
- Therapeutic plasma exchange (PEX) is first-line treatment — removes autoantibodies and ultra-large vWF multimers while replacing ADAMTS13 enzyme.
- Caplacizumab (anti-vWF nanobody) reduces time to platelet normalisation and TTP-related death/organ failure; PBS Authority Required listing in Australia.
- Rituximab (anti-CD20) is second-line for refractory/relapsing TTP and increasingly used as upfront adjunctive therapy in high-risk patients.
- ADAMTS13 activity <10% with positive anti-ADAMTS13 IgG confirms acquired TTP; a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) assay turnaround is typically 5–7 days in Australia.
- The PLASMIC score or French score can risk-stratify patients for probable severe ADAMTS13 deficiency while awaiting results.
- Congenital TTP (Upshaw–Schulman syndrome) requires fresh frozen plasma infusions rather than PEX and is managed with a haematologist.
- Relapse occurs in 30–50% of acquired TTP; maintenance rituximab and serial ADAMTS13 monitoring guide pre-emptive therapy.
- ATSI Australians have higher TMA incidence and face barriers to timely PEX access — early retrieval coordination via RFDS is essential.
Introduction & Australian Epidemiology
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) characterised by severe deficiency of the von Willebrand factor (vWF)-cleaving protease ADAMTS13. Inadequate cleavage of ultra-large vWF multimers results in widespread platelet-rich microthrombi, consumptive thrombocytopenia, and mechanical haemolysis of red blood cells.
TTP accounts for approximately 15–20% of all TMA presentations in Australian tertiary centres. The incidence of acquired TTP in Australia is estimated at 3–11 cases per million per year, with a female predominance (approximately 3:1) and peak incidence in the 30–50-year age group. Aboriginal and Torres Strait Islander peoples may have a higher burden of TMA-related illness, partly driven by higher rates of autoimmune comorbidities and delayed access to specialist care in remote settings.
Acquired TTP is autoimmune, driven by inhibitory IgG autoantibodies against ADAMTS13. Congenital TTP (Upshaw–Schulman syndrome, OMIM #274150) is rare, autosomal recessive, and accounts for <5% of cases. Triggers for acquired TTP include pregnancy, autoimmune disease (particularly SLE), infections, and certain medications (e.g., ticlopidine, clopidogrel — rare).
Time-critical diagnosis: Delay in initiating plasma exchange beyond 24–48 hours of presentation significantly increases mortality. If MAHA + thrombocytopenia are present with no other clear cause, start PEX immediately — do not wait for ADAMTS13 results.
Pathogenesis — ADAMTS13 Deficiency
ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) is a zinc metalloprotease synthesised predominantly by hepatic stellate cells. Its physiological role is to cleave ultra-large (UL) vWF multimers secreted by endothelial cells into smaller, less thrombogenic forms.
Mechanism of Acquired (Autoimmune) TTP
- IgG autoantibodies (predominantly IgG1 and IgG4) bind ADAMTS13, causing functional inhibition and/or accelerated clearance via the reticuloendothelial system.
- ADAMTS13 activity falls to <10% of normal, resulting in accumulation of UL-vWF multimers in the microvasculature.
- Under high shear stress (particularly arteriolar), UL-vWF unfolds and recruits platelets via glycoprotein Ibα (GPIbα), forming platelet-rich microthrombi.
- These thrombi mechanically fragment red blood cells (schistocytes), producing MAHA.
- Consumptive thrombocytopenia results from platelet incorporation into microthrombi.
- End-organ ischaemia produces the clinical features: brain (neurological symptoms), kidney (renal impairment), and systemic (fever).
Congenital TTP (Upshaw–Schulman Syndrome)
- Biallelic mutations in the ADAMTS13 gene (chromosome 9q34) lead to absent or severely reduced ADAMTS13 protein.
- Typically presents in neonatal period or early childhood with jaundice, thrombocytopenia, and haemolysis — often triggered by intercurrent infection.
- No autoantibodies detected; genetic testing confirms the diagnosis.
- Managed with prophylactic plasma infusions (10–15 mL/kg every 2–3 weeks) to supply exogenous ADAMTS13.
Distinguishing TTP from Other TMAs
| Feature | TTP | HUS (typical/complement) | DIC |
|---|---|---|---|
| ADAMTS13 activity | <10% | Normal or mildly reduced | Normal |
| Platelets | Very low (often <30) | Low–moderate | Low |
| Renal failure | Mild–moderate | Severe (hallmark) | Variable |
| Schistocytes | Present | Present | May be present |
| Coagulation screen | Normal (PT/APTT) | Normal | Prolonged PT/APTT |
| First-line treatment | Plasma exchange | Supportive ± eculizumab | Treat underlying cause |
Clinical Pentad & Presentation
The traditional pentad of TTP comprises five clinical features. However, the complete pentad is present in only 5–10% of patients at presentation. Most patients present with the triad of thrombocytopenia, MAHA, and non-specific neurological symptoms. A high index of suspicion is required.
Component 1
Thrombocytopenia
Platelet count often <30 × 10⁹/L at presentation. Petechiae, purpura, mucosal bleeding, and menorrhagia are common. Purpura may be the presenting feature.
Present in ~100% of cases
Component 2
Microangiopathic Haemolytic Anaemia
Haemoglobin typically <100 g/L. Elevated LDH (often >1000 U/L), unconjugated bilirubin, reticulocytosis, low haptoglobin. Schistocytes on peripheral blood film.
Present in ~100% of cases
Component 3
Neurological Features
Fluctuating symptoms: confusion, headache, aphasia, visual disturbance, seizures, focal deficits. May be transient. Brain MRI usually normal acutely.
Present in ~60% of cases
Component 4
Renal Impairment
Usually mild (eGFR >30). Severe renal failure is uncommon and should prompt consideration of complement-mediated HUS. Proteinuria and microscopic haematuria may occur.
Present in ~25–50% of cases
Component 5
Fever
Low-grade fever without identifiable infectious source. May be absent in many patients.
Present in ~25% of cases
Do not wait for the complete pentad. Any patient presenting with unexplained thrombocytopenia and MAHA (schistocytes on blood film, elevated LDH, low haptoglobin) should be treated as TTP until proven otherwise. Initiate urgent plasma exchange — mortality doubles for every 24 hours of delay.
Predisposing Factors & Triggers
- Female sex (3:1 female predominance, likely oestrogen-related immune modulation)
- African ancestry (higher autoantibody prevalence; relevant in multicultural Australian populations)
- Systemic lupus erythematosus and other autoimmune conditions
- Pregnancy (especially 2nd and 3rd trimester — must differentiate from pre-eclampsia/HELLP)
- HIV infection
- Drugs: ticlopidine, clopidogrel (rare), quinine, ciclosporin
- Bone marrow transplantation
Investigations
Laboratory confirmation of TTP requires demonstration of thrombocytopenia, MAHA (with schistocytes), and critically, severe ADAMTS13 deficiency. While awaiting ADAMTS13 results (typically 5–7 working days in Australian reference laboratories), treatment must not be delayed.
Essential & Urgent Investigations
Essential
Full Blood Count (FBC) with Film
Thrombocytopenia (platelets typically <30 × 10⁹/L), anaemia with elevated reticulocyte count. Peripheral blood film — ≥2 schistocytes per high-power field is strongly suggestive of TMA. MBS Item 65060.
Essential
Haemolysis Markers
Elevated LDH (>1000 U/L typical), elevated unconjugated bilirubin, low haptoglobin (<0.1 g/L), elevated reticulocyte count. Direct antiglobulin test (DAT/Coombs) is typically negative in TTP (positive DAT should suggest alternative diagnosis). MBS Items 66548, 66551.
Essential
Coagulation Screen (PT, APTT, Fibrinogen)
Normal or near-normal in TTP. Prolonged PT/APTT with low fibrinogen suggests DIC rather than TTP. MBS Item 65095.
Essential
Renal Function & Electrolytes
Creatinine, eGFR, urea, electrolytes. Severe renal failure (<15 mL/min) is uncommon in TTP and should prompt reconsideration of complement-mediated HUS. MBS Item 66509.
Essential
ADAMTS13 Activity & Inhibitor Assay
Functional ADAMTS13 activity (<10% confirms TTP), anti-ADAMTS13 IgG (inhibitor detection). Sent to reference laboratory — turnaround 5–7 days in most Australian centres. Do not delay treatment while awaiting results. State reference labs: SA Pathology (Adelaide), Royal Prince Alfred (Sydney), Royal Melbourne (Melbourne).
Available
Blood Cultures
Exclude sepsis/DIC. Two sets from different sites before commencing antibiotics if infection suspected.
Available
Stool Shiga Toxin / E. coli O157
Exclude STEC-HUS, particularly in children or after bloody diarrhoea. PCR-based stool assay available at public health labs.
Available
Complement Studies (C3, C4, Factor H, Factor I)
Consider if atypical HUS suspected (ADAMTS13 >10%, severe renal failure). Genetic complement panel via reference laboratory.
Referral
Brain MRI
If focal neurological deficits, seizures, or altered consciousness. Often normal in acute TTP; white matter lesions may be seen. Exclude stroke.
Available
ADAMTS13 Genetic Testing
For suspected congenital TTP (Upshaw–Schulman syndrome). Sequencing of ADAMTS13 gene. Performed at specialised genomic labs. MBS genomic testing may be available under Medicare-funded panels.
Risk-Stratification Scores
While awaiting ADAMTS13 results, clinical scoring systems help estimate the probability of severe ADAMTS13 deficiency and guide early treatment decisions.
PLASMIC Score
| Parameter | Points |
|---|---|
| Platelet count <30 × 10⁹/L | 1 |
| Haemolysis (reticulocytes >2.5%, haptoglobin undetectable, indirect bilirubin >2 mg/dL) | 1 |
| No active cancer | 1 |
| No stem-cell or solid organ transplant | 1 |
| MCV <90 fL | 1 |
| INR <1.5 | 1 |
| Creatinine <2.0 mg/dL (176 µmol/L) | 1 |
Interpretation: Score ≥5 → high probability of severe ADAMTS13 deficiency (PPV ~84%). Score 0–4 → low probability. A high PLASMIC score in the setting of MAHA and thrombocytopenia should strongly support immediate PEX initiation.
Risk Stratification & Severity Scoring
Standard Risk
First Episode, No Major Organ Failure
Isolated thrombocytopenia and MAHA. No significant neurological deficit, no cardiac ischaemia, platelet nadir >20 × 10⁹/L.
Treatment: PEX + corticosteroids. Consider caplacizumab if platelet nadir <20 or high PLASMIC score.
High Risk
Refractory or Severe Features
Platelet count not recovering after 3–5 days of daily PEX, worsening neurological features, troponin elevation, or clinical deterioration despite treatment.
Treatment: Escalate to twice-daily PEX. Add rituximab. Add caplacizumab if not already started. ICU consultation.
Critical
Organ Failure / Life-Threatening
Seizures, coma, myocardial infarction/ischaemia (TTP-related), mesenteric ischaemia, major haemorrhage. Multi-organ dysfunction.
Treatment: ICU admission. Aggressive PEX (twice daily). Rituximab + caplacizumab. Consider adjunctive bortezomib or cyclophosphamide if refractory.
Referral threshold: All patients with suspected TTP should be managed in consultation with a clinical haematologist at a centre with plasma exchange capability. In regional/remote Australia, urgent retrieval via the Royal Flying Doctor Service (RFDS) to the nearest PEX-capable centre is essential — do not delay transfer for ADAMTS13 results.
Management — Plasma Exchange, Rituximab & Caplacizumab
Immediate Management (First 24 Hours)
1
Suspect TTP
Unexplained thrombocytopenia + MAHA (schistocytes, elevated LDH, low haptoglobin). Initiate haematology referral immediately.
2
Send ADAMTS13 — Do NOT Wait
Collect blood for ADAMTS13 activity and inhibitor assay. Transport urgently to reference laboratory. Begin treatment before results are available.
3
Start Plasma Exchange
1.0–1.5 × plasma volume daily using fresh frozen plasma (FFP) as replacement. Continue daily until platelet count >150 × 10⁹/L for ≥2 consecutive days.
4
Initiate Corticosteroids
Methylprednisolone 1 g IV daily × 3 days, then prednisolone 1 mg/kg/day PO (max 80 mg), taper over 3–4 weeks.
5
Consider Caplacizumab
If platelet nadir <30 × 10⁹/L or high PLASMIC score. 11 mg IV loading dose (pre-PEX), then 11 mg SC daily for 30 days post-PEX cessation.
6
Supportive Care
Avoid platelet transfusions (unless life-threatening haemorrhage — may worsen thrombosis). Anticoagulation as per standard VTE prophylaxis. Monitor troponin, neurological status.
Therapeutic Plasma Exchange (PEX)
PEX remains the cornerstone of TTP treatment and should be initiated within 4–8 hours of clinical suspicion. PEX performs three critical functions simultaneously:
- Removes pathogenic anti-ADAMTS13 autoantibodies
- Removes ultra-large vWF multimers
- Replaces functional ADAMTS13 enzyme via donor FFP
| Parameter | Detail |
|---|---|
| Volume exchanged | 1.0–1.5 × calculated plasma volume daily |
| Replacement fluid | Fresh frozen plasma (FFP) or cryoprecipitate-poor plasma (cryo-poor FFP — preferentially used in some centres) |
| Frequency | Daily until platelet count >150 × 10⁹/L for ≥2 consecutive days and LDH normalised |
| Taper | After initial response: reduce to alternate days, then twice weekly, then cease over 1–2 weeks |
| Refractory definition | No platelet count improvement after 5–7 days of daily PEX — escalate: twice-daily PEX + rituximab |
| Venous access | Large-bore central venous catheter (e.g., Mahurkar dialysis catheter) inserted by experienced operator |
Plasma infusion is NOT a substitute for PEX. If PEX is not immediately available (e.g., remote/regional setting), commence FFP infusion (15–30 mL/kg) as a temporising measure while arranging emergency retrieval. PEX is still required as soon as possible.
Caplacizumab (Cablivi®)
Caplacizumab is a humanised anti-vWF A1-domain nanobody that blocks the interaction between UL-vWF multimers and platelet glycoprotein Ibα (GPIbα), preventing microthrombus formation independently of ADAMTS13 reconstitution.
Caplacizumab
Cablivi® · Anti-vWF nanobody
Adult dose (Day 1)
11 mg IV bolus ≥15 minutes before first PEX (or immediately after if already on PEX)
Adult dose (maintenance)
11 mg SC once daily, administered ≥2 hours after completion of each PEX session
Duration
Continue for 30 days after cessation of daily PEX. Extend if underlying ADAMTS13 activity remains <10%
Paediatric dose
Not established. Limited data in patients <18 years. Specialist consultation required.
Renal adjustment
None required (no renal metabolism)
Hepatic adjustment
Not formally studied; use with caution in severe hepatic impairment
Key side effects
Bleeding (epistaxis, gingival, mucocutaneous), headache, injection-site reactions. Monitor for major haemorrhage.
PBS status
Authority Required
Key trial
HERCULES trial (NEJM 2019) — reduced TTP-related death, recurrence, and major thromboembolic events.
Rituximab
Rituximab depletes CD20+ B lymphocytes, reducing anti-ADAMTS13 autoantibody production. Used for refractory, relapsing, or high-risk acquired TTP.
Rituximab
MabThera® / Riximyo® · Anti-CD20 monoclonal antibody
Dose
375 mg/m² IV weekly × 4 weeks (Days 1, 8, 15, 22)
Administration
Administer ≥4 hours after PEX (PEX removes the drug). Delay next dose if PEX ongoing, or give on non-PEX day.
Indication
Refractory TTP (platelets not recovering after ≥5 days PEX). Relapsing TTP. Upfront in high-risk patients (ADAMTS13 <5%, severe organ involvement).
Onset of effect
7–14 days (B-cell depletion). ADAMTS13 recovery typically 2–3 weeks.
Paediatric dose
375 mg/m² IV weekly × 4 weeks. Dose cap of 1000 mg per infusion.
Renal adjustment
None required
Hepatic adjustment
None required; monitor for HBV reactivation
Key side effects
Infusion reactions (premedicate with paracetamol, antihistamine, corticosteroid). Risk of progressive multifocal leukoencephalopathy (PML) — rare. Hepatitis B reactivation — screen HBsAg/anti-HBc prior.
PBS status
Restricted Benefit
Corticosteroids
Methylprednisolone (IV) → Prednisolone (PO)
Solu-Medrol® → Panafcortelone® · Corticosteroid
Induction dose
Methylprednisolone 1 g IV daily × 3 days
Maintenance
Prednisolone 1 mg/kg/day PO (max 80 mg), taper over 3–4 weeks
Renal adjustment
None; monitor glucose in renal impairment
PBS status
✔ PBS General Benefit
Refractory TTP — Second-Line & Salvage Options
| Agent | Mechanism | Dose | Notes |
|---|---|---|---|
| Rituximab (if not yet used) | Anti-CD20 B-cell depletion | 375 mg/m² IV weekly × 4 | Standard second-line; response in 80–90% refractory cases |
| Bortezomib | Proteasome inhibitor — targets plasma cells | 1.3 mg/m² SC/IV Days 1, 4, 8, 11 (21-day cycle) | Case-series evidence. Effective when rituximab fails. Specialist-only. PBS authority may be needed. |
| Cyclophosphamide | Alkylating agent — broad immunosuppression | 500–1000 mg/m² IV single dose or monthly | Rarely used; for multiply-refractory TTP. Haematology/oncology supervision required. |
| Vincristine | Microtubule inhibitor | 2 mg IV weekly × 4 | Historical salvage option; limited evidence. Use only when other options exhausted. |
| Splenectomy | Removes antibody-producing and vWF-clearing organ | N/A — surgical | Last resort for multiply-refractory TTP. Limited to case series. |
Monitoring During Treatment
- Platelet count: Daily until >150 × 10⁹/L for ≥2 days, then taper PEX frequency.
- LDH: Daily during active treatment — should fall with platelet recovery.
- FBC, haemolysis markers: Daily during PEX, then 2–3 times weekly during taper.
- ADAMTS13 activity: Repeat at Day 7–14, then monthly for 6–12 months to guide rituximab maintenance and detect impending relapse.
- Troponin: Baseline and if chest pain/dyspnoea — TTP-related myocardial microthrombi cause elevated troponin without epicardial coronary disease.
- Neurological status: Serial neurological examinations; fluctuations are common and may indicate active disease.
- Bleeding: Particularly on caplacizumab — monitor for epistaxis, gingival bleeding, GI bleeding. Hold caplacizumab for platelet count >50 × 10⁹/L with active bleeding.
- Immunoglobulin levels: After rituximab — monitor IgG monthly; IVIg replacement if IgG <4 g/L with recurrent infections.
When to Stop PEX
- Platelet count >150 × 10⁹/L for ≥2 consecutive days AND LDH normalised — begin PEX taper.
- Taper: alternate day × 3 sessions, then twice weekly × 2 sessions, then cease.
- Caplacizumab continues for 30 days after last daily PEX.
- If platelets fall during taper → increase PEX frequency back to daily.
Special Populations
Pregnancy
TTP vs HELLP differentiation
TTP typically presents in 2nd trimester; HELLP in 3rd trimester. ADAMTS13 activity <10% favours TTP. Delivery does not resolve TTP (unlike HELLP).
PEX
Safe in pregnancy. Continue until delivery and postpartum if TTP persists. Coordinate with obstetric and haematology teams.
Rituximab
Avoid in pregnancy if possible (Category D — crosses placenta, causes neonatal B-cell depletion). Use if life-threatening refractory TTP. Vaccinate infant live vaccines deferred until 6 months post-last dose.
Caplacizumab
Limited data in pregnancy. Avoid unless benefits clearly outweigh risks.
Paediatrics
Congenital TTP (Upshaw–Schulman)
First-line: FFP infusion 10–15 mL/kg every 2–3 weeks (not PEX in stable patients). PEX for acute crises.
Acquired TTP in children
Rare. PEX (dose adjusted for weight), corticosteroids. Rituximab 375 mg/m² IV weekly × 4 (max 1000 mg/infusion). Caplacizumab — insufficient paediatric data.
Differential diagnosis
In children, STEC-HUS is far more common than TTP. Always test stool for Shiga toxin before diagnosing TTP in paediatric patients.
Elderly
Diagnostic challenges
Cancer-associated TMA and drug-induced TMA more common in elderly patients. Ensure thorough malignancy workup (especially pancreatic, gastric, prostate).
PEX complications
Higher risk of line-related complications (DVT, pneumothorax), fluid overload, and citrate-related hypocalcaemia. Monitor ionised calcium during PEX.
Caplacizumab
Higher bleeding risk in elderly. Careful risk-benefit assessment. No dose adjustment required.
Renal Impairment
Severe renal failure uncommon in TTP
If eGFR <15 or dialysis-dependent, reconsider complement-mediated HUS. ADAMTS13 >10% strongly suggests alternative TMA.
PEX in CKD
No contraindication. Avoid citrate anticoagulation in severe hepatic failure — use heparin anticoagulation for PEX circuit.
Caplacizumab
No renal dose adjustment needed — not renally metabolised.
Hepatic Impairment
ADAMTS13 synthesis
Severe liver disease may independently reduce ADAMTS13 levels. Interpret results with caution — ADAMTS13 <10% in liver disease may not indicate TTP.
Rituximab
Screen for hepatitis B (HBsAg, anti-HBc) prior to initiation. Lamivudine prophylaxis if HBsAg+ or isolated anti-HBc+. Monitor LFTs.
Immunocompromised
HIV-associated TTP
TTP occurs at higher CD4 counts in HIV. PEX + ART initiation. Lower threshold for rituximab. Opportunistic infection screening essential.
Post-transplant TMA
Differentiate drug-related (tacrolimus, ciclosporin) TMA from de novo TTP. ADAMTS13 testing critical. Reduce calcineurin inhibitor dose. PEX if ADAMTS13 <10%.
Aboriginal and Torres Strait Islander Health Considerations
Aboriginal and Torres Strait Islander Health
Thrombotic microangiopathies, including TTP, present particular challenges for Aboriginal and Torres Strait Islander communities. The following considerations are essential for equitable management.
📚 References
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