What is the management for Thrombotic Thrombocytopenic Purpura (TTP)?

Management of Thrombotic Thrombocytopenic Purpura (TTP)

Immediate therapeutic plasma exchange (TPE) is the cornerstone of TTP management and must be initiated emergently upon clinical suspicion, as untreated TTP has a mortality rate exceeding 90%, which TPE reduces to 10-20%. 1, 2

Critical Distinction: TTP vs ITP

• TTP must be distinguished from Immune Thrombocytopenic Purpura (ITP) - this is a life-or-death distinction, as ITP is treated with corticosteroids and immunosuppression while TTP requires plasma exchange 3
• TTP presents with thrombocytopenia, microangiopathic hemolytic anemia (MAHA) with schistocytes on peripheral smear, and severe ADAMTS13 deficiency (<10% activity) 4, 1, 2
• Platelet transfusions are contraindicated in TTP as they can worsen microvascular thrombosis, whereas they are used in ITP 5

First-Line Treatment Protocol

Immediate Therapeutic Plasma Exchange

• Initiate daily TPE (1.0-1.5 plasma volumes) immediately upon clinical suspicion - do not wait for ADAMTS13 results, as delays increase mortality 1, 2
• Continue daily TPE until platelet count normalizes (>150 × 10⁹/L) for at least 2 consecutive days AND LDH normalizes 6, 2
• TPE removes anti-ADAMTS13 autoantibodies and replaces deficient ADAMTS13 enzyme 1, 2

Concurrent Immunosuppression

• Add high-dose corticosteroids (prednisone 1 mg/kg/day or methylprednisolone 1 g IV daily for 3 days) from day 1 alongside TPE 4, 2
• Rituximab (375 mg/m² weekly for 4 weeks) should be added upfront in all patients, not reserved for refractory cases, as it significantly reduces relapse rates and improves outcomes 4, 2, 7

High-Dose Plasma Infusion Alternative

• If TPE is unavailable emergently, high-dose plasma infusion (25-30 mL/kg/day) can be used as a temporizing measure 6
• Major caveat: 42% of patients (8/19) required switch to TPE due to fluid overload or inadequate response 6
• This is a bridge therapy only - arrange urgent transfer to a facility with TPE capability 6

Refractory TTP Management

Refractory TTP is defined as failure to achieve platelet count >50 × 10⁹/L or 50% reduction in LDH after 4-7 days of daily TPE. 4

Escalation Algorithm for Refractory Disease

Step 1: Intensify Plasma Exchange

• Increase to twice-daily TPE (1.5 plasma volumes per session) 4, 2, 7
• Continue for 3-5 days before declaring treatment failure 4

Step 2: Add Rituximab (if not already given)

• Administer rituximab 375 mg/m² weekly × 4 doses 4, 2, 7
• Response typically occurs within 1-2 weeks 4

Step 3: Pulse Immunosuppression

• Cyclophosphamide: 500-1000 mg/m² IV every 2-4 weeks for 2-4 doses 4, 2, 7
• Vincristine: 1.4-2 mg IV weekly for 4 weeks 4, 2, 7
• Cyclosporine A: 2.5-3 mg/kg/day divided twice daily 4, 2, 7

Step 4: Salvage Splenectomy

• Reserved for desperate cases unresponsive to all medical therapies 4, 2, 7
• Removes major site of anti-ADAMTS13 antibody production 4

Emerging Therapies

Caplacizumab

• Anti-von Willebrand factor nanobody that prevents platelet-VWF binding and microthrombi formation 1, 2
• Rapidly normalizes platelet counts but does not address underlying ADAMTS13 deficiency 1
• Must be used in conjunction with TPE and immunosuppression, not as monotherapy 1

Other Promising Agents

• N-acetylcysteine: Cleaves VWF multimers, reducing microthrombi 4, 2, 7
• Bortezomib: Proteasome inhibitor targeting antibody-producing plasma cells 4, 2, 7
• Recombinant ADAMTS13: Enzyme replacement for congenital TTP 4, 1, 2

Relapse Prevention

Persistent severe ADAMTS13 deficiency (<10% activity) during clinical remission predicts high relapse risk (40% of patients). 2, 7

• Monitor ADAMTS13 activity monthly for first 6 months, then every 3 months 2, 7
• Preemptive rituximab (375 mg/m² weekly × 4) should be administered if ADAMTS13 activity remains <10% despite clinical remission 7
• Continue long-term follow-up indefinitely, as relapses can occur years later 2

Critical Pitfalls to Avoid

• Never delay TPE to wait for ADAMTS13 results - clinical suspicion alone warrants immediate treatment 1, 2
• Never give platelet transfusions in suspected TTP unless life-threatening bleeding with concurrent severe thrombocytopenia 5, 4
• Do not use IVIg or anti-D in TTP - these are ITP treatments that are ineffective and potentially harmful in TTP 3, 5
• Avoid abrupt discontinuation of TPE - taper frequency (daily → every other day → twice weekly) based on sustained platelet and LDH normalization 2
• High-dose plasma infusion causes fluid overload in 32% of patients - monitor closely and have low threshold to switch to TPE 6