Thrombotic thrombocytopenic purpura is an uncommon syndrome characterised by:
- fever
- microangiopathic haemolytic anaemia
- thrombocytopenia
- neurologic and renal abnormalities
Thrombotic thrombocytopenic purpura (TTP) (immune TTP), a potentially fatal clinical syndrome, is primarily caused by autoantibodies against the von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13 (2):
- in general, severe deficiency of plasma ADAMTS13 activity (<10 IU/dL) with or without detectable inhibitory autoantibodies against ADAMTS13 supports the diagnosis of TTP if a patient presents with thrombocytopenia and microangiopathic hemolytic anemia (i.e. schistocytes, elevated serum lactate dehydrogenase, decreased hemoglobin and haptoglobin) without other known etiologies that cause thrombotic microangiopathy (TMA)
TTP often follows infection or in women, oral contraception or pregnancy
TTP is a critical medical condition requiring immediate transfer for treatment (1):
- 50% of patients require intensive care admission and without treatment, the mortality in acute TTP is >90%.
TTP results from a deficiency of the enzyme ADAMTS 13, required for Von Willebrand factor (vWF) cleavage
- severely reduced enzyme levels are caused either by a genetic abnormality or through their destruction by antibodies (immune TTP) (iTTP)
- deficiency of the ADAMTS13 enzyme results in insufficient processing of the large vWF clotting factor which unravels during passage through the microcirculation leading to platelet aggregation and multi-organ microvascular thrombosis involving neurological, cardiac, gastro-intestinal and renal disease
- occlusion of small vessels also causes a fragmentation haemolysis (microangiopathic haemolytic anaemia) and platelet consumption resulting in thrombocytopenia
- with severely low ADAMTS13 activity (<10%), large multimers of vWF accumulate and bind platelets, forming microvasculature thromboses that cause ischemic organ injury (eg, myocardial infarction and stroke) (3)
The incidence of iTTP is higher in adults than children, females than males , and Black compared with non-Black individuals (3).
Prompt differentiation of TTP from other causes of TMA is crucial for the initiation of an appropriate therapy to reduce morbidity and mortality.
Management
- plasma infusion is often sufficient for prophylaxis or treatment of hereditary TTP due to ADAMTS13 mutations
- prompt initiation of therapy with therapeutic plasma exchange, corticosteroids, and rituximab improves survival with iTTP from almost zero to approximately 93% (3):
- treatment with therapeutic plasma exchange, corticosteroids, and rituximab is associated with 30-day survival rates of more than 90%
- caplacizumab, a synthetic small antibody (nanobody) that blocks platelet binding to vWF, administered concurrently with immunosuppression and therapeutic plasma exchange and continued until ADAMTS13 recovery, reduces the time to normalization of platelet count and decreases the risk of early recurrence
Monitoring ADAMTS13 activity in survivors and initiation of rituximab for those with low ADAMTS13 activity reduces the risk of clinical relapse (3).
Notes
- normal to moderately reduced plasma ADAMTS13 activity (>20 IU/dL) in a similar clinical context supports an alternative diagnosis such as atypical hemolytic uremic syndrome (aHUS) or other types of TMA
Reference:
- NHS England (October 2022).Rituximab treatment for acute TTP: Clinical Commissioning Policy
- Saha M, McDaniel JK, Zheng XL. Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics. J Thromb Haemost. 2017 Oct;15(10):1889-1900.
- Pishko AM, Li A, Cuker A. Immune Thrombotic Thrombocytopenic Purpura: A Review. JAMA. 2025;334(6):517–529.