Caplacizumab as a single agent without plasma exchange in relapsed and refractory thrombotic thrombocytopenic purpura: A systematic review. Free

Caplacizumab is an anti-von Willebrand factor nanobody that has transformed the treatment landscape of thrombotic thrombocytopenic purpura (TTP), particularly when used with plasma exchange (PEX). However, data on its efficacy in the absence of PEX remain limited.

Methods:

We systematically reviewed PubMed, Embase, and MEDLINE through April 2025 to identify studies evaluating caplacizumab as a second-line agent in relapsed or refractory immune-mediated TTP without concomitant PEX. Case reports, case series, observational studies, and trials were included. Studies involving concurrent PEX were excluded.

Results:

The Covidence search yielded 1,036, of which 37 studies met the inclusion criteria. These studies include 13 case reports, 5 case series, and eight retrospective observational or cohort studies. Additionally, there are three clinical trials, two modeling/simulation studies, and one real-world multicenter retrospective study. Time to platelet recovery ranged from 1-5 days; themedian time to recovery is 3.5 days. Caplacizumab was most commonly used in refractory TTP (9 cases) and in relapsed TTP (3 cases), including presentations with neurological symptoms, pregnancy, and SLE. It was also frequently administered when plasma exchange was contraindicated or refused—this included 3 Jehovah's Witness patients, 2 Jewish patients, 2 cases of patient refusal, and 2 cases of anaphylaxis to plasma exchange. In 3 cases, it was initiated in patients with suspected iTTP pending ADAMTS13 confirmation. Other indications included severe or life-threatening presentations such as organ failure or intracranial hemorrhage (3 cases), and clinical trial settings evaluating safety and efficacy (2 cases). One study described the general use in acute TTP. In one series of six women with relapsed TTP, platelet counts normalized after a median of 3.5 days without needing PEX. Similarly, in a cohort of 14 patients treated without PEX due to severe comorbidities or patient refusal, no relapses or exacerbations were observed following caplacizumab initiation. Organ function improved alongside platelet recovery. Favorable responses to caplacizumab without PEX were seen in pregnant patients with TTP (n=2), Jehovah's Witnesses and Jewish patients refusing blood products (n=3), patients with refractory TTP despite prior rituximab and steroids, and those with coexisting HIV, CMV, or hepatitis infections. Several reports demonstrated reversal of neurologic symptoms, renal dysfunction, and cardiac injury following caplacizumab initiation. Favorable outcomes were observed in pregnant patients, those with HIV, autoimmune disorders, and CMV infection, though some comorbidities predicted failure of monotherapy. Most patients tolerated caplacizumab well. However, rare but serious bleeding events, including intracranial hemorrhage, were reported, particularly in those with prior ischemic infarcts or trauma. Volker et al. (2022) demonstrated that early use of caplacizumab (within 72 hours of diagnosis) in relapsed cases reduced mortality (absolute risk reduction 2.87%) and refractory disease (relative risk reduction 59%) without PEX (Number Needed to Treat = 35). In cases where patients were refractory to initial PEX, caplacizumab use only or combined with corticosteroids and rituximab resulted in clinical turnaround, suggesting its utility as salvage therapy. Studies emphasized the importance of early initiation and individualized duration based on ADAMTS13 activity recovery. Even when caplacizumab was started late in the hospital course (e.g., day 10), platelet response was seen with a median of 3.5 days, suggesting potential benefit despite delayed administration.

Conclusion:

This first systematic synthesis focuses on caplacizumab without plasma exchange in relapsed and refractory TTP, where PEX is contraindicated or unavailable. Our findings suggest that caplacizumab, with or without steroids and rituximab, can achieve rapid clinical and hematologic remission in select patients, offering a potentially life-saving option. These findings reinforce the evolving treatment landscape where plasma exchange may no longer be the default. These results support ongoing trials like the MAYARI study and underscore the need for updated treatment guidelines reflecting caplacizumab as the first-line therapy for TTP.