From the Research
Refractory thrombotic thrombocytopenic purpura (TTP) is defined as TTP that fails to respond adequately to standard first-line therapy with plasma exchange (PEX) and corticosteroids, characterized by persistent thrombocytopenia or lack of clinical improvement after 4-7 days of intensive plasma exchange treatment. This condition is a rare, potentially fatal hematologic disorder caused by a severe deficiency of ADAMTS13, a protease enzyme responsible for cleaving von Willebrand-factor (vWF) multimers 1. The underlying mechanism involves severe ADAMTS13 deficiency (typically <10% activity), usually due to autoantibodies that inhibit this enzyme, preventing it from cleaving von Willebrand factor and leading to widespread microvascular thrombosis.
Some key points to consider in the definition and management of refractory TTP include:
- Persistent thrombocytopenia (low platelet count below 150,000/μL) or lack of clinical improvement after 4-7 days of intensive plasma exchange treatment
- Disease exacerbation when attempting to taper PEX
- Early relapse within 30 days of stopping therapy
- Severe ADAMTS13 deficiency (typically <10% activity) due to autoantibodies
- Management typically requires escalation to second-line therapies such as rituximab, caplacizumab, cyclophosphamide, bortezomib, or consideration for splenectomy in select cases 2, 3.
The most recent and highest quality study on this topic is from 2022, which describes two cases of refractory TTP successfully managed with the addition of caplacizumab, an anti-von Willebrand factor immunoglobulin fragment that inhibits the interaction of vWF multimers with platelets 1. Other studies have also shown the effectiveness of second-line therapies such as rituximab and bortezomib in the treatment of refractory TTP 4, 3.
Early recognition of refractory status is crucial as mortality increases significantly without prompt treatment intensification. Therefore, it is essential to closely monitor patients with TTP and promptly escalate treatment if they fail to respond to first-line therapy.