25  Thrombotic Thrombocytopenic Purpura

Key Points
  • TTP: life-threatening TMA w/ ADAMTS13 <10% → uncleaved ULVWF → plt-rich microthrombi
  • Pentad (classic, rare all 5): thrombocytopenia, MAHA, fever, AKI, neuro
  • PLASMIC score ≥6: high prob ADAMTS13 <10%
  • Tx (acute): PLEX daily until plt >150K × 2d; steroids; caplacizumab; rituximab if refractory
  • Acquired TTP: anti-ADAMTS13 IgG antibodies (most cases)
  • Inherited TTP (Upshaw-Schulman): biallelic ADAMTS13 mutations → recombinant ADAMTS13

25.1 Clinical Presentation

25.1.1 Classic Pentad (Uncommon)

  • Thrombocytopenia: severe, often <10,000/μL
  • MAHA: schistocytes, ↑ LDH, ↓ haptoglobin, ↑ bilirubin, anemia
  • Renal dysfunction: variable; <HUS severity
  • Neuro: confusion, seizures, focal deficits, coma
  • Fever: ~50% only

25.1.2 Atypical Presentations

  • Rarely all 5; thrombocytopenia & MAHA usually together
  • Bleeding (mucosal, GI) in 1/3
  • Fatigue, weakness, abdominal pain, headache
  • Fulminant disease: rapid severe hemostasis & thrombosis

25.2 Diagnosis

25.2.1 Clinical Suspicion & Immediate Testing

  • DDx: TTP vs HUS, HELLP, DIC, scleroderma renal crisis, malignant HTN
  • Smear: schistocytes essential
  • Stat labs: CBC, coags (PT/INR, aPTT, fibrinogen), LDH, bili, Cr, haptoglobin, retic, BC

25.2.2 ADAMTS13 Testing

ADAMTS13 Interpretation
Activity Interpretation
<10% Immune TTP; check anti-ADAMTS13 IgG (sens ~96%)
10–40% Intermediate; r/o other TMAs or hereditary TTP
>40% Non-ADAMTS13 TMA (HUS, complement-mediated)
  • Inhibitor assay: >1.5 BU/mL = acquired inhibitor
  • Antigen: often severely ↓ in immune TTP
  • Don’t delay PLEX for results

25.3 Pathophysiology

25.3.1 Immune (Acquired) TTP

  • ADAMTS13 <10%: normally cleaves vWF ultralarge multimers
  • Loss of function: ↑ uncleaved multimers → abnormal plt aggregation → microthrombi
  • Anti-ADAMTS13 IgG: acquired auto-antibodies bind & inhibit
  • Triggers: viral (HIV, adenovirus), pregnancy, malignancy, drugs (ticlopidine, clopidogrel)
  • Mechanism: multimers bind plt GPIb/IX → consumption thrombocytopenia & mechanical hemolysis

25.3.2 Inherited (Upshaw-Schulman)

  • Biallelic ADAMTS13 mutations: rare; infancy/childhood onset
  • Persistent ↓ ADAMTS13: episodic thrombosis after triggers (infection, pregnancy)
  • Not PEX-responsive: genetic defect; require recombinant ADAMTS13

25.4 Treatment

25.4.1 First-Line: Plasma Exchange (PLEX)

  • Empiric PLEX: start ALL suspected TTP before confirmation
    • Mortality ~90% untreated vs ~5–10% w/ PLEX
  • Dosing: 1–1.5 plasma volumes (~40 mL/kg) daily
  • Duration: until plt ≥100,000/μL & LDH normal × 2 consecutive days
    • Typical 5–10 days
  • Monitoring: daily CBC, LDH, bili, Cr, retic
  • Bridge: FFP if PLEX unavailable; IVIG if delayed

25.4.2 Response Assessment

  • Platelet recovery: ~60–70% reach >100,000/μL in 3–7 days
  • Refractory (no response by day 5): escalate to rituximab ± caplacizumab

25.4.3 Adjunctive Agents

Steroids - Methylprednisolone 1 g × 3 days (acute), or - Prednisone 2–4 mg/kg/d (max 120 mg) × 5–7 days - Avoid prolonged use in children w/ life-threatening disease

Caplacizumab - Anti-vWF nanobody - ↓ Thrombotic events; may shorten PLEX duration

Fostamatinib - Syk kinase inhibitor (oral) - For chronic immune TTP; reduces plt consumption - Dose: 100 mg BID (some 150–200 mg BID)

25.4.4 Refractory TTP (Salvage)

  • Rituximab: anti-CD20; use if PEX/upfront failure
  • Cyclophosphamide/vincristine: limited prospective data
  • Third-line: mycophenolate, azathioprine, eculizumab
  • Rare: splenectomy post-PEX failure

25.4.5 Pediatric TTP

  • Shiga toxin–mediated (HUS): supportive care; avoid aggressive PLEX
  • Immune TTP: TPO-RAs preferred; avoid upfront rituximab/caplacizumab
  • Bleeding mgmt: transfuse if severe; avoid prophylactic plt transfusions
  • Splenectomy: select refractory cases; limited efficacy data

25.4.6 Severe Bleeding (Emergency)

  • IV methylprednisolone: 30 mg/kg (max 1 g/d) × 3 days, or IVIG 1 g/kg
  • Anti-D Ig: caution (thrombosis risk in TTP)
  • Off-label: ε-aminocaproic acid; TPO-RAs (limited data)

25.5 Drug-Induced TTP (DITP)

25.5.1 Pathophysiology

  • Myelosuppressive agents (quinine, quinidine) via immune ± nonimmune pathways
  • Quinine-type: bind drug hapten → immune complex → GPIIb/IIIa & complement activation
  • Ticlopidine-type: drug as neo-antigen; persist after drug cessation
  • Penicillins/cephalosporins: ADCC & complement activation

25.5.2 Testing & Diagnosis

  • Clinical: temporal drug exposure (1–2 wks new; hours if prior)
  • Lab: DITP-specific antibody detection; drug-dependent plt activation assays (reference lab)
  • ELISA: semi-quantitative; gold standard indirect (plt count, LTA)

25.5.3 Management

  • Stop offending agent: essential; patient counseling
  • Timeline: plt recovery 1–2 wks post-discontinuation
  • Support: transfuse if bleeding/high-risk; PEX rarely effective; IVIG less studied
  • Prolonged avoidance: some drugs (ticlopidine, quinine) require extended monitoring

25.6 Special Populations

25.6.1 Pregnancy & Postpartum

  • Onset: peripartum; risk ↑ weeks 1–4 postpartum
  • Distinguish from HELLP: ADAMTS13 testing essential; ↓ ADAMTS13 = TTP
  • Tx: PLEX if ADAMTS13-mediated TTP
  • Delivery: doesn’t alter TTP (unlike HELLP)
  • Neonatal: rare transplacental maternal antibody transfer

25.6.2 Elderly

  • Comorbidities: CV disease, renal dysfunction limit PLEX tolerance
  • Drug review: ↑ risk offending drugs (ticlopidine, NSAIDs)
  • Escalation: third-line agents more readily considered

25.7 PLASMIC Score (Pretest Probability ADAMTS13 <10%)

PLASMIC Score
Variable 1 Point
Platelet <30,000/μL ✓
LDH ≥2.5× ULN ✓
Age ≥60 yr ✓
Schistocytes present ✓
MAHA (bili ≥2 mg/dL, negative Coombs) ✓
Infection preceding ✓
Cancer a/w thrombocytopenia ✓

Interpretation: - ≥6: ~95% prob ADAMTS13 <10% - 5: ~60% prob - ≤4: ~5% prob

25.8 Clinical Pearls

Tip

Pearl 1: Empiric PLEX is standard of care for ALL suspected TTP—do NOT wait for ADAMTS13 results. Delay increases mortality; start immediately & confirm diagnosis post-initiation.

Tip

Pearl 2: ADAMTS13 <10% w/ anti-ADAMTS13 IgG = immune TTP. Normal ADAMTS13 in TMA → r/o complement-mediated, Shiga toxin, drug-induced.

Tip

Pearl 3: Refractory TTP (no plt recovery day 3–5) → escalate to rituximab ± caplacizumab. Consider alternative diagnoses & secondary causes in slow responders.