Thrombotic Thrombocytopenic Purpura (TTP): Summary Points
Definition and Pathophysiology
TTP is a life-threatening thrombotic microangiopathy caused by severe deficiency (<10% activity) of ADAMTS13, resulting in microangiopathic hemolytic anemia, severe thrombocytopenia, and multiorgan ischemia from platelet-rich microthrombi. 1, 2
- Acquired (immune) TTP (iTTP) is caused by anti-ADAMTS13 autoantibodies and represents the most common form in adults 3, 4
- Congenital TTP (cTTP) results from biallelic ADAMTS13 gene mutations and typically presents in childhood or pregnancy 3, 4
- iTTP occurs approximately 2-fold more frequently in women 4
Clinical Presentation
The classic pentad (fever, neurologic abnormalities, thrombocytopenia with purpura, microangiopathic hemolytic anemia, and acute renal injury) is present in less than 7% of cases 5
- Thrombocytopenia and microangiopathic hemolytic anemia are the most consistent findings 1, 2
- Neuropsychiatric symptoms, renal dysfunction, and fever may be present but are not required for diagnosis 2
- End-organ ischemia and damage occur due to disseminated microvascular platelet-rich thrombi 4
Diagnostic Approach
ADAMTS13 activity below 10% is the internationally accepted diagnostic criterion for TTP, in addition to clinical findings of thrombocytopenia and non-immune hemolytic anemia. 1
Essential laboratory testing includes:
- Complete blood count showing severe thrombocytopenia 5
- Blood smear demonstrating schistocytes (microangiopathic hemolytic anemia) 5
- Elevated lactate dehydrogenase 5
- ADAMTS13 activity level and anti-ADAMTS13 antibody testing (though treatment should not be delayed awaiting results) 5, 3
- Complete metabolic panel, coagulation panel (typically normal in TTP), fibrinogen, D-dimer 5
- Troponin, HIV testing, urinalysis, pregnancy test as appropriate 5
Treatment Strategy
Immediate Management
Therapeutic plasma exchange (TPE) must be initiated immediately when TTP is suspected, as untreated TTP has a mortality rate exceeding 90%. 1, 2
- Daily TPE with fresh frozen plasma replacement is the cornerstone of treatment 3, 4
- TPE both supplements deficient ADAMTS13 and removes anti-ADAMTS13 autoantibodies in acquired TTP 1
- All patients require hematology consultation if available and hospital admission for treatment and close monitoring 5
First-Line Immunosuppression
Corticosteroids should be administered concurrently with TPE as first-line immunosuppressive therapy. 2, 3
- Corticosteroids suppress autoantibody production in iTTP 1
- Standard dosing or high-dose methylprednisolone can be used 3
Additional Front-Line Therapy
Rituximab (anti-CD20 monoclonal antibody at 375 mg/m² weekly × 4) is frequently added to initial therapy and is effective in newly diagnosed cases, refractory cases, and relapse prevention. 2, 3
Caplacizumab (anti-VWF nanobody) should be added to front-line therapy if available. 6, 2
- FDA-approved for treatment of acquired TTP in combination with plasma exchange and immunosuppressive therapy 6
- Administered as 11 mg IV bolus before first plasma exchange, followed by 11 mg subcutaneous daily after each plasma exchange, continuing for 30 days after cessation of daily plasma exchange 6
- Significantly reduces time to platelet count response and decreases TTP-related death, recurrence, and major thromboembolic events (12.7% vs 49.3% with placebo, p<0.0001) 6
- Reduces recurrence rate during overall study period (13% vs 38%) 6
Refractory or Relapsed TTP
For cases unresponsive to standard therapy, consider:
- Twice-daily plasma exchange 4
- Cyclosporine A 3, 4
- Cyclophosphamide 4
- Vincristine 4
- Bortezomib 3, 4
- N-acetylcysteine 3, 4
- Salvage splenectomy 4
Congenital TTP Management
Fresh frozen plasma transfusion is performed to supplement ADAMTS13 in patients with congenital TTP. 1
- Recombinant human ADAMTS13 is a promising emerging treatment for cTTP 2
Critical Pitfalls to Avoid
- Never delay TPE while awaiting ADAMTS13 results - initiate treatment immediately based on clinical suspicion, as untreated TTP is rapidly fatal 1, 2
- Do not confuse TTP with other thrombotic microangiopathies (atypical HUS, DIC, sepsis-related thrombocytopenia) - these require different management 6
- Recognize that the classic pentad is rarely complete; thrombocytopenia and hemolytic anemia alone should prompt consideration of TTP 5
- Monitor for caplacizumab-associated bleeding risk, particularly when combined with antiplatelet agents or anticoagulants 6
Long-Term Management
Long-term follow-up after acute episodes is critical to monitor for relapse, identify other autoimmune diseases, and evaluate psychophysical sequelae. 3, 4