What Causes Thrombotic Thrombocytopenic Purpura (TTP)
TTP is caused by severe deficiency of the ADAMTS13 enzyme, which occurs either through autoimmune destruction (acquired/immune-mediated TTP) or through inherited genetic mutations (congenital TTP). 1, 2, 3
Primary Mechanism
- ADAMTS13 deficiency is the fundamental cause of TTP, resulting in accumulation of ultra-large von Willebrand factor multimers that trigger platelet aggregation and microvascular thrombosis 2, 3, 4
- When ADAMTS13 activity falls below 10%, the von Willebrand factor remains in its elongated active form, causing uncontrolled platelet activation and aggregation in arterioles and capillaries 5, 4
Acquired (Immune-Mediated) TTP
This is the most common form in adults:
- Anti-ADAMTS13 autoantibodies develop and inhibit or accelerate clearance of the ADAMTS13 enzyme 1, 2, 3
- Occurs approximately 2-fold more frequently in women 2
- The first acute episode typically occurs during adulthood 2
Secondary Triggers for Acquired TTP
- Immune checkpoint inhibitors (ICIs) can trigger acquired TTP by upregulating the immune system and generating anti-ADAMTS13 antibodies 6
- Pregnancy can unmask or trigger acquired TTP 2
- Other autoimmune conditions may coexist with or trigger TTP 2
Congenital (Hereditary) TTP
- Biallelic mutations in the ADAMTS13 gene cause inherited ADAMTS13 deficiency 2, 3
- Typically presents in childhood, though can manifest during pregnancy in previously undiagnosed cases 2, 3
- This form is rare compared to acquired TTP 2
Critical Diagnostic Distinction
TTP must be distinguished from other causes of thrombocytopenia and microangiopathic hemolytic anemia:
- Hemolytic uremic syndrome (HUS) presents with more severe renal dysfunction and typically follows acute gastrointestinal illness, whereas TTP has more prominent neurological features and less severe renal involvement 7, 5
- 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 5
- Drug-induced thrombocytopenia (from heparin, quinidine, sulfonamides) does not cause microangiopathic hemolytic anemia with schistocytes 7, 8
Common Pitfall
Do not delay plasma exchange while waiting for ADAMTS13 results if clinical suspicion is high—TTP is rapidly fatal without treatment, and ADAMTS13 testing takes several days 4. The PLASMIC score can help determine probability of severe ADAMTS13 deficiency in hospitalized patients with thrombocytopenia and hemolysis to identify those requiring immediate TTP-specific treatment 4.