In this video lecture, Dr. Paul Knoebl discusses:
- How caplacizumab and rituximab, combined with ADAMTS13 monitoring, allow safe and effective management of immune TTP without routine plasma exchange.
- The role of recombinant ADAMTS13 as the new standard of care for congenital TTP, replacing plasma infusions with a more targeted and practical therapy.
- How ongoing trials and future innovations including novel antibodies, enzyme variants, gene therapy, and mRNA delivery are reshaping TTP care toward a fully plasma-free paradigm.
Paul Knoebl, MD Paul Knoebl is Senior Physician at the Division of Haematology and Haemostatis at the Medical University of Vienna in Vienna, Austria. He has a training in internal medicine and has specialized on hematology/oncology and intensive care medicine. Prof. Knoebl has many years of clinical experience in treating all kinds of blood disorders, including stem cell transplantation, and he is also an experienced intensive care physician. His scientific interests are focused on clinical and basic research on blood coagulation, fibrinolysis, endothelial cell function, haemophilia, diabetes mellitus, haematologic malignancies, intensive care medicine, thrombotic microangiopathy and coagulation lab techniques. He has authored and co-authored over 200 scientific articles and book chapter publications, and serves as a reviewer and section editor for several important medical journals. Prof. Knoebl has conducted a variety of clinical trials as principal investigator or co-investigator and has served as a member of steering committees or data safety monitoring boards for several projects. He is a member of several organization such as: International Society on Thrombosis and Hemostasis; Society on Thrombosis and Hemostasis Research (GTH); Austrian Society of Internal Medicine; Austrian Society of Hematology and Oncology.
(Video Lecture Summary)
Introduction
Dr. Paul Knoebl outlines a contemporary, plasma-free approach to managing thrombotic thrombocytopenic purpura, rooted in the pathophysiology clarified around 2000 and refined through the last quarter century of clinical progress. The core message is that in immune TTP, caplacizumab for rapid control of microvascular thrombosis and timely immunosuppression for restoration of ADAMTS13 activity permit safe care without routine plasma exchange in experienced centers. In congenital TTP, recombinant ADAMTS13 concentrates have supplanted plasma as targeted replacement therapy. The talk contrasts these strategies with historical plasma-based care, explains a practical bedside algorithm, and reviews outcomes from a plasma-free cohort.
Pathophysiology and Therapeutic Logic
Immune TTP results from autoantibodies that bind ADAMTS13, block its activity, and alter its conformation. Congenital TTP arises from biallelic ADAMTS13 mutations that cause severe enzyme deficiency. In either case, ultra-large von Willebrand factor multimers persist, unfold under high shear, and recruit platelets to form strings that seed disseminated microthrombi. Neutrophil extracellular traps, hemolysis, and organ injury follow, threatening the brain, heart, and kidneys. Treatment must accomplish two distinct aims. The immediate aim is to halt ongoing microthrombosis and stabilize organs, which is tracked by a rising platelet count and improving injury markers. The definitive aim is to achieve ADAMTS13 remission, since activity above roughly 10 percent markedly reduces the risk of exacerbation and early relapse even if levels are not fully normal.
Why Move Beyond Plasma Exchange
Plasma exchange can remove autoantibodies, immune complexes, ultra-large multimers, inflammatory mediators, and neutrophil extracellular traps while providing exogenous ADAMTS13 and physiologic von Willebrand factor. Yet it is invasive and symptomatic rather than disease modifying. Central venous access, blood group typing, daily large-volume plasma replacement, machine time, and specialized staff are required. Risks include citrate effects, allergic reactions, line complications, infection, and immunogenicity. Efficacy is imperfect in a subset, with delayed responses, exacerbations despite daily sessions, refractory courses, and occasional deaths. Immediately after exchange, ADAMTS13 levels may remain low, leaving patients vulnerable. These limitations motivate strategies that suppress autoimmunity and neutralize von Willebrand factor mediated platelet capture without defaulting to plasma.
Plasma-Free Tools in Immune TTP
Two agents are foundational. Caplacizumab is a nanobody that binds the A1 domain of von Willebrand factor and competes with platelet GP1b binding. This immediately interrupts platelet string formation and prevents new microthrombi. Clinically it produces rapid platelet increases, with normalization by about three to five days on median and by one week in nearly all patients, and it improves organ injury markers. Exacerbations decline sharply and resource use falls, at the cost of a higher rate of usually mucocutaneous bleeding. Caplacizumab does not correct the autoimmune process or restore ADAMTS13 activity, so it must be paired with immunosuppression. Rituximab depletes B cells and is widely used off label in TTP. Response rates are high. It shortens time to remission, reduces hospital days, and lowers relapse and mortality rates. Together, caplacizumab protects patients during the period when rituximab has not yet restored ADAMTS13, and rituximab delivers the durable immunologic reset that achieves enzyme recovery.
A Pragmatic Plasma-Free Algorithm
For suspected immune TTP, platelet transfusions are avoided. Diagnostic samples for TTP and mimics are drawn at presentation. Caplacizumab 10 mg is administered intravenously as the first dose, steroids are started, and clinically stable patients are monitored on a regular ward. The team prepares for plasma exchange but does not start it. Blood group typing and plasma ordering proceed without thawing, machines and staff are put on standby, and no central line is placed. Four to six hours after the first caplacizumab dose, platelets and organ parameters are reassessed. If platelets are rising and organ function is improving, the patient continues on a plasma-free pathway with daily 10 mg caplacizumab subcutaneously and early rituximab, using any standard dosing schedule. Education for home caplacizumab administration is arranged. Discharge follows once platelets normalize and organ injury is controlled, often within a few days. Weekly ADAMTS13 testing guides therapy in the outpatient setting, and caplacizumab is stopped once ADAMTS13 rises above 10 percent. Long-term follow up with monthly ADAMTS13 checks is recommended. If platelets do not rise after the initial dose, the team searches for remediable causes such as viral infections or medication errors. Plasma exchange can then be layered in, with caplacizumab given after each session, and exchange stopped after platelets exceed 150, followed by continued daily caplacizumab.
Outcomes with a Plasma-Free Strategy
Using this approach, the Vienna group treated 42 immune TTP episodes without plasma exchange and compared them with 95 episodes managed with caplacizumab plus plasma exchange, steroids, and rituximab. Groups were comparable by French severity score, with somewhat lower lactate dehydrogenase levels in the plasma-free cohort. Time to platelet normalization was the same with or without plasma exchange, indicating that exchange did not add speed to clinical stabilization when caplacizumab was used. Time to ADAMTS13 recovery was significantly shorter without plasma exchange, with a median of 25 days compared with 37 days, suggesting a more direct path to enzyme remission, although the study was not powered for definitive proof. There were no TTP-related deaths in the plasma-free cohort, hospital stays were shorter, and fewer patients required intensive care. Four patients with delayed platelet increases transitioned to combined plasma exchange and caplacizumab for brief courses, two due to active viral infections, one due to prior platelet transfusion before diagnosis, and one with antiplatelet antibodies who never achieved a fully normal platelet count. Median caplacizumab duration and total dose were lower without plasma exchange, around 20 days, and nearly all patients received rituximab upfront.
Managing the Risk Window Before ADAMTS13 Recovery
Median time to ADAMTS13 recovery after treatment start is about one month, but some patients require several months. During this window, exacerbation risk persists if von Willebrand factor mediated platelet capture is not blocked. Continuing caplacizumab through the period of low ADAMTS13 activity prevents exacerbations. If caplacizumab is stopped at clinical remission while ADAMTS13 remains under 10 percent, roughly one third of patients experience exacerbation or relapse. When caplacizumab is stopped after ADAMTS13 rises above 10 percent, exacerbations were not observed in this experience. The principle is practical. Platelet normalization signals that the microangiopathy has been controlled, but the enzyme has not necessarily recovered, so therapy should be guided by ADAMTS13 activity rather than by platelet count alone.
Congenital TTP and Recombinant ADAMTS13
For congenital TTP, recombinant ADAMTS13 has transformed care. Phase 3 and extension data show higher post-infusion ADAMTS13 activity, longer time above the 10 percent threshold, approximately fivefold greater overall exposure, no TTP events on treatment, and no severe treatment related adverse events. Importantly, neutralizing antibodies were not observed in congenital deficiency. Regulatory approvals in the United States and Europe now support use as standard of care. Dosing is 40 units per kilogram as a small intravenous injection that is suitable for home therapy. Compared with plasma infusions every one to two weeks, which deliver non-specific plasma components and carry frequent side effects while failing to prevent breakthrough events reliably, recombinant ADAMTS13 is targeted, efficient, and practical for long-term prophylaxis or on-demand use during triggers.
Requirements for Safe Plasma-Free Management
A plasma-free pathway depends on rapid access to ADAMTS13 activity assays, reliable supply of caplacizumab and rituximab, and team experience with TTP. The service must be ready to pivot quickly to plasma exchange in the small minority of patients who fail to show an early laboratory response or who have correctable impediments to platelet recovery. Patient instruction for home caplacizumab and structured follow up with frequent ADAMTS13 testing are essential to maintain safety and conserve resources.
Ongoing Trials and Future Directions
Prospective trials are now testing plasma-free care. The MAYARI study has completed enrollment of patients treated with caplacizumab and rituximab without plasma exchange, with results pending. The VITA study is evaluating recombinant ADAMTS13 for immune TTP without plasma exchange and is ongoing. Beyond these, new immunomodulatory options are under study, including alternative anti-CD20 and anti-CD38 antibodies, bispecific antibodies, and cellular approaches that are being repurposed for autoimmunity. Modified ADAMTS13 variants designed to evade autoantibody binding, enzymes that cleave ultra-large von Willebrand factor multimers, gene therapy, lipid-encapsulated messenger RNA delivery, and platelet surface delivery of recombinant ADAMTS13 are being explored. These efforts suggest that the field is moving toward targeted, durable strategies that minimize invasive procedures and broaden outpatient care.
Conclusion
Dr. Paul Knoebl argues that both immune and congenital TTP can be managed without plasma in centers with rapid diagnostics, access to key biologics, and multidisciplinary expertise. In immune disease, caplacizumab provides immediate protection from microthrombi while early immunosuppression restores ADAMTS13. Therapy is continued until ADAMTS13 activity surpasses a protective threshold, which prevents exacerbations and supports outpatient pathways. In congenital disease, recombinant ADAMTS13 delivers precise, home-based replacement with favorable safety and reliability. Plasma remains a contingency rather than a default. With ongoing trials and emerging therapies, the management paradigm is shifting toward plasma-free care that reduces risk, shortens hospitalization, and improves quality of life for people living with TTP.