In this video lecture, Dr. Flora Peyvandi discusses:
- The evolution of treatment for immune TTP from plasma exchange alone to a triple regimen including immunosuppression and caplacizumab.
- The importance of timely therapy initiation and ADAMTS13 monitoring in guiding both acute management and relapse prevention.
- The recognition of TTP as a chronic disease requiring long-term follow-up and multidisciplinary care to address relapses and organ complications.
Dr. Flora Peyvandi is professor of Internal Medicine at the University of Milan, Italy and director of the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center of the Milan Policlinic Hospital, Italy. Her research started with molecular and biochemical characterization of coagulation disorders aiming at the development of novel treatment for the affected patients. Her research continued with the understanding of the microvascular dysfunctions in order to implement/develop and standardize innovative diagnostic and therapeutic strategies.
Since many years, Dr. Peyvandi has been participating in clinical, educational and research activities of different European and International scientific societies and patients’ organizations. She served as President of the International Society of Thrombosis and Haemostasis and President of the Executive Committee of the European Association for Haemophilia and Allied Disorders. She is currently advisor on the European Agency of Medicine and member of the Technical Health Committee of the Italian Ministry of Health. Her clinical, teaching and research experience combined with her life in different countries, led her to familiarize with patient management, scientific projects and educational systems of different parts of the world.
(Video Lecture Summary)
Introduction
In this lecture, Dr. Peyvandi provides a detailed overview of the evolution of therapeutic strategies for acquired thrombotic thrombocytopenic purpura. She highlights how treatment has shifted from the historical reliance on plasma exchange alone toward a combined approach that integrates immunosuppression and novel targeted therapies. Her discussion emphasizes both the evidence supporting current practice and the continuing challenges of relapse prevention and long-term patient management.
Plasma Exchange as the Foundations of Therapy
The modern management of immune-mediated TTP began with the introduction of daily plasma exchange, which dramatically reduced mortality compared to the pre-treatment era. Plasma exchange works by physically removing ultra-large von Willebrand factor multimers and simultaneously eliminating circulating anti-ADAMTS13 autoantibodies. At the same time, donor plasma restores functional ADAMTS13 activity. Dr. Peyvandi stresses that timing is critical. Initiating plasma exchange immediately after diagnosis is associated with markedly better outcomes, whereas even a twenty-four-hour delay significantly worsens prognosis. This early intervention remains the cornerstone of treatment and provides the foundation upon which other therapies are layered.
The Role of Immunosuppression
Because acquired TTP is mediated by inhibitory autoantibodies, plasma exchange must be combined with immunosuppressive therapy to address the underlying immune process. Corticosteroids are the standard first-line addition. Although randomized trials comparing plasma exchange alone with plasma exchange plus steroids have not been conducted, extensive clinical experience supports the superiority of combination therapy. International guidelines strongly recommend the addition of corticosteroids for both acute episodes and relapses. Italian guidelines further advise maintaining full-dose corticosteroid treatment until ADAMTS13 activity reaches thirty percent, followed by tapering over a maximum of three weeks.
Rituximab has also become an important component of management. While the greatest benefit appears to be in preventing relapse rather than improving immediate outcomes, observational data and widespread use demonstrate its effectiveness in downregulating antibody production. There remains debate about the optimal timing of rituximab initiation, with practice differing between starting at the first acute episode or deferring to remission. At the time of recent guideline development, evidence was still limited, and recommendations therefore remain conditional.
Caplacizumab and the Triple Regimen
The advent of caplacizumab has transformed the treatment landscape. This nanobody targets the A1 domain of von Willebrand factor, preventing platelet adhesion and thereby halting microthrombus formation. Caplacizumab offers the unique advantage of rapidly normalizing platelet counts and reducing organ damage, buying crucial time for immunosuppressive therapies to take effect. Clinical trials, though relatively small given the rarity of the disease, demonstrated consistent benefits in accelerating platelet recovery and lowering the risk of exacerbations. Importantly, however, caplacizumab does not correct the fundamental immunological defect and must therefore be used in conjunction with plasma exchange and immune suppression.
Dr. Peyvandi notes that timing again plays a critical role. Delayed initiation of caplacizumab is associated with poorer outcomes, and real-world evidence underscores the importance of introducing this therapy as early as possible. Current consensus supports the routine use of caplacizumab alongside plasma exchange and corticosteroids, forming a triple regimen that represents the modern standard of care.
The Importance of ADAMTS13 Monitoring
A central theme of the lecture is the necessity of careful monitoring of ADAMTS13 activity. This enzyme level not only confirms the diagnosis but also guides ongoing treatment decisions. Persistently low ADAMTS13 activity after clinical remission signals a high risk of relapse. In such cases, rituximab or other immunosuppressive therapies may be warranted even in the absence of acute symptoms. Guidelines recommend frequent monitoring in the first months after an acute episode, then at gradually extended intervals if the patient remains stable. Weekly monitoring during the first month is considered standard, with adjustments for those whose enzyme activity begins to decline.
This approach reflects the recognition that TTP should not be viewed solely as an episodic emergency but rather as a chronic disorder requiring long-term surveillance. ADAMTS13 activity functions as both a diagnostic tool and a prognostic marker, shaping decisions about when to initiate, continue, or discontinue specific therapies.
Long-Term Management and Complications
Dr. Peyvandi emphasizes that survival from acute TTP is only the beginning of patient care. Many individuals face a high risk of relapse, particularly within the first three years after the initial episode. Relapse risk correlates strongly with persistently low ADAMTS13 activity, but other triggers such as infection, surgery, pregnancy, and certain medications may also precipitate recurrence. Preventive strategies, including prophylactic immunosuppression in high-risk patients, are increasingly integrated into clinical practice.
Beyond relapse, long-term complications are a growing concern. Patients who experience repeated microvascular thrombosis may develop permanent organ damage, with the brain, heart, kidney, and liver being particularly vulnerable. Neurocognitive difficulties, emotional disorders such as depression and anxiety, and an elevated risk of cardiovascular events have all been documented. These findings reinforce the importance of treating TTP as a chronic disease requiring multidisciplinary follow-up. Collaboration with cardiology, neurology, and maternal-fetal medicine specialists is particularly important in tailoring care to the needs of individual patients.
Conclusion
In conclusion, Dr. Peyvandi frames the management of immune TTP as a paradigm that has shifted from a two-part regimen of plasma exchange and corticosteroids toward a comprehensive three-part strategy that incorporates caplacizumab. Early and aggressive intervention is vital, with treatment ideally initiated immediately upon clinical suspicion rather than awaiting confirmatory test results. ADAMTS13 monitoring plays a pivotal role in both acute and long-term management, guiding decisions about immunosuppressive therapy and identifying patients at risk of relapse. Finally, the recognition that TTP is a chronic disease with significant long-term sequelae underscores the need for lifelong monitoring and multidisciplinary care.