Thrombotic Thrombocytopenic Purpura (TTP)
TTP is a life-threatening thrombotic microangiopathy caused by severe deficiency (<10%) of ADAMTS13, resulting in microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia from disseminated microvascular platelet-rich thrombi. 1, 2
Pathophysiology
TTP results from ADAMTS13 deficiency, which prevents cleavage of ultra-large von Willebrand factor multimers, leading to spontaneous platelet aggregation and microvascular thrombosis throughout the body. 2, 3
The acquired form (iTTP) accounts for approximately 95% of cases and is caused by autoantibodies against ADAMTS13, while the remaining 5% are congenital (cTTP) due to biallelic ADAMTS13 gene mutations. 2, 4, 5
iTTP occurs approximately 2-fold more frequently in women and typically presents in adulthood, whereas cTTP often manifests in childhood or during pregnancy. 2, 4
Clinical Manifestations
The classic pentad (microangiopathic hemolytic anemia, thrombocytopenia, neurological abnormalities, renal dysfunction, and fever) is not required for diagnosis—most patients present with only thrombocytopenia and hemolysis. 1
Hematologic Features
Microangiopathic hemolytic anemia with schistocytes on peripheral smear, elevated LDH, elevated indirect bilirubin, decreased haptoglobin, and negative direct antiglobulin test (Coombs test). 1, 5
Severe thrombocytopenia (typically <30,000/μL) resulting from platelet consumption in forming microthrombi, with reticulocytosis as a compensatory response to hemolysis. 1, 3
Organ Involvement
Neurological manifestations are most common and include confusion, headache, visual disturbances (blurred vision or visual field defects), sensorimotor deficits, and altered consciousness. 1, 6
Renal dysfunction presents with elevated creatinine, though typically less severe than in hemolytic uremic syndrome (HUS). 1
Cardiac ischemia and abdominal pain may occur depending on the organs affected by microvascular thrombosis. 6
Diagnostic Approach
Severely deficient ADAMTS13 activity (<10%) confirms TTP diagnosis and must be measured urgently when thrombotic microangiopathy is suspected. 1
Essential Laboratory Findings
Presence of hemolysis with schistocytes immediately excludes isolated immune thrombocytopenia (ITP) and mandates consideration of thrombotic microangiopathy. 1
Normal coagulation studies (PT, aPTT, fibrinogen) are critical for excluding disseminated intravascular coagulation (DIC), which would show prolonged PT/APTT and elevated INR. 1
Differential Diagnosis
HUS typically presents with more severe renal dysfunction than TTP and usually follows acute gastrointestinal illness with bloody diarrhea (especially E. coli O157 infection). 1, 7
Malignant hypertension-associated thrombotic microangiopathy can be differentiated by severe blood pressure elevation with advanced retinopathy, and ADAMTS13 activity remains normal or only mildly reduced. 1
Drug-induced thrombocytopenia (from heparin, quinidine, sulfonamides) does not cause microangiopathic hemolytic anemia with schistocytes. 1
PLASMIC Score
- The PLASMIC score can determine the probability of low ADAMTS13 in hospitalized patients with thrombocytopenia and hemolysis to identify those who could benefit from early TTP-specific treatment while awaiting ADAMTS13 results. 3
Treatment
First-line therapy for acute TTP includes immediate daily plasma exchange with fresh frozen plasma replacement, corticosteroids, and rituximab—treatment must be initiated urgently when TTP is suspected, even before ADAMTS13 results are available. 2, 3, 4
Standard Therapy
Daily therapeutic plasma exchange supplies deficient ADAMTS13 and removes autoantibodies, improving survival from less than 10% to approximately 80-90%. 2, 6
Immunosuppression with corticosteroids and the humanized anti-CD20 monoclonal antibody rituximab targets ADAMTS13 autoantibodies. 2, 4
Caplacizumab (CABLIVI)
Caplacizumab is an anti-von Willebrand factor antibody fragment that inhibits the interaction between von Willebrand factor multimers and platelets, added to standard treatment for beneficial effects without immunosuppressive effects. 7, 3, 4
In the HERCULES trial, caplacizumab resulted in shorter time to platelet count response and significantly lower rates of TTP-related death, recurrence, or major thromboembolic events (12.7% vs 49.3%, p<0.0001) during the treatment period. 7
The FDA-approved dosing is 11 mg IV bolus before the first plasma exchange, followed by 11 mg subcutaneous daily after plasma exchange completion, continuing for 30 days after cessation of daily plasma exchange. 7
Refractory Cases
- For refractory or unresponsive TTP, more intensive therapies include twice-daily plasma exchange, pulses of cyclophosphamide, vincristine, cyclosporine A, N-acetylcysteine, bortezomib, or salvage splenectomy. 2, 4
Prognosis and Follow-Up
The proportion of patients with TTP recurrence in the overall study period was lower with caplacizumab (13%) compared to placebo (38%, p<0.001). 7
Long-term follow-up is crucial to identify occurrence of other autoimmune diseases, control relapses, and evaluate psychophysical sequelae. 2, 4
In patients who experienced TTP relapse after caplacizumab discontinuation, ADAMTS13 activity levels were <10% at the end of treatment, indicating persistent underlying immunological disease. 7
Critical Pitfalls
Delaying plasma exchange while awaiting ADAMTS13 results is potentially fatal—when clinical probability is high, plasmapheresis must be initiated immediately. 3
Traditional anticoagulant and antiplatelet strategies are generally not effective in TTP patients, despite the predominance of thrombotic manifestations. 6
Overlooking TTP in patients with neurological symptoms can delay diagnosis, as neurological manifestations may be attributed to other causes. 1