In this video lecture, Dr. Paul Coppo discusses:
- The limitations of plasma exchange and steroids alone, and how refractoriness and exacerbations historically impacted outcomes.
- The complementary roles of rituximab and caplacizumab in preventing early refractoriness and relapse.
- How ADAMTS13 monitoring and preemptive rituximab have transformed long-term relapse prevention.
Dr. Paul Coppo is professor of Haematology at Sorbonne University in Paris. He heads the French reference center for thrombotic microangiopathies (CNR-MAT) and the department of lymphoid malignancies in Saint-Antoine hospital (Paris, France), involved in the management of rare lymphoid malignancies and other immuno-hematological diseases. He is member of the team Immunopathology and Immuno-intervention (Equipe 16, INSERM UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne University).
Dr Coppo received his medical degree from Sorbonne University in 2003 and completed his residency at Saint-Antoine Hospital. He completed his PhD in the Laboratory of Dr Vainchenker (Institut Gustave Roussy, Villejuif) in 2006. Paul Coppo set up ex-nihilo the CNR-MAT, which is a resourse center for the diagnosis and the management of thrombotic microangiopathies. The works of his team include clinical trials and translational research works which have been published in Blood, Leukemia, Lancet Haematology, Haematologica and the Journal of Thrombosis and Haemostasis.
(Video Lecture Summary)
Introduction
In this lecture, Dr. Coppo addresses the challenge of preventing refractoriness and relapse in autoimmune thrombotic thrombocytopenic purpura (iTTP). He begins by situating current approaches in their historical context. Standard therapy with daily plasma exchange combined with corticosteroids dramatically improved survival, from nearly zero before its introduction to more than 85 percent in the modern era. Yet significant unmet needs persisted, as up to 40 percent of patients experienced exacerbations and about 10 percent remained refractory. These patients often required prolonged therapy, faced increased treatment-related complications, and carried an elevated risk of death. Dr. Coppo outlines how subsequent innovations—particularly the addition of rituximab and caplacizumab—have reshaped management strategies to address these gaps.
Refractoriness and the Limits of Historical Therapy
Refractoriness refers to a failure of platelet counts and clinical symptoms to improve despite adequate treatment, while exacerbations describe worsening after an initial partial response. In the plasma exchange and steroid era, these phenomena exposed patients to extended courses of treatment and high complication rates. Rituximab was introduced to target the autoimmune basis of the disease by depleting B cells and reducing production of anti-ADAMTS13 antibodies. Rituximab shortened the course of therapy for slow responders and helped prevent early relapses. However, its onset of action is delayed by roughly two weeks, leaving patients vulnerable in what Dr. Coppo describes as the “danger zone.” Thus, while rituximab provided durable protection, it was not sufficient to address acute refractoriness or the risk of immediate clinical deterioration.
Caplacizumab as Complementary Therapy
The introduction of caplacizumab marked a turning point. As a nanobody targeting the A1 domain of von Willebrand factor, it blocks the interaction between von Willebrand factor and platelets, preventing the formation of microthrombi. Clinical trials such as TITAN and HERCULES demonstrated faster platelet recovery and significantly fewer deaths, cases of refractoriness, and exacerbations among patients treated with caplacizumab compared with controls. Importantly, caplacizumab acts precisely during the period when rituximab is not yet effective, making the two therapies complementary. Real-world studies confirmed these results, showing mortality reduced to around 1 percent and dramatic decreases in refractoriness and exacerbations when caplacizumab was added to plasma exchange and immunosuppression. Treatment duration varies: about half of patients achieve sufficient ADAMTS13 recovery within a month, while others require longer therapy, underscoring the importance of individualized monitoring.
Preventing Long-Term Relapse
Relapse remains a major concern, as up to one third of survivors experience recurrence within ten years. Relapse severity is unpredictable, ranging from indolent to fatal, and cannot be inferred from prior episodes. Historically, there was no reliable way to anticipate relapse, but discovery of ADAMTS13 deficiency transformed this landscape. Low ADAMTS13 activity during remission is a strong predictor of clinical relapse. Preemptive rituximab in patients with severe ADAMTS13 deficiency but no overt clinical relapse has proven effective in preventing progression. Studies show that without treatment, most of these patients will relapse, whereas rituximab stabilizes ADAMTS13 activity and prevents clinical events.
Recent insights into ADAMTS13 conformation add another layer of predictive value. Patients with an “open” conformation, typically associated with anti-ADAMTS13 antibodies, remain at higher risk even if their activity levels appear normal. This opens the door to earlier detection of relapse risk. Despite these advances, about 15 percent of patients are refractory to rituximab and another group require repeated infusions due to recurrent relapses. For such cases, newer anti-CD20 antibodies like obinutuzumab, along with other immunosuppressive strategies including cyclosporine, azathioprine, mycophenolate, or even splenectomy, may be considered.
Conclusion
Dr. Coppo concludes that refractoriness and relapse, once common, have become rare in the modern management of iTTP. Caplacizumab effectively prevents refractoriness at the acute stage, while rituximab prevents relapse for 12 to 18 months by sustaining ADAMTS13 recovery. Long-term follow-up is essential, with regular monitoring of ADAMTS13 activity to identify patients at risk of relapse and to guide preemptive therapy. For those who cannot tolerate rituximab or remain refractory, next-generation therapies offer alternative strategies. iTTP, once marked by high mortality, can now be managed effectively through timely use of these complementary agents and careful long-term surveillance.