Are We Entering a New Era in Treatment of Thrombotic Microangiopathy?

Acquired thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening event resulting from systemic microvascular thrombosis leading to profound thrombocytopenia, hemolytic anemia, and organ failure of varying severity (1). Acquired immune TTP (iTTP) is caused by a severe deficiency of a disintegrant and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) due to the presence of inhibitory autoantibody anti-cysteine-spacer antibody or other antibodies directed against other domains of ADAMTS13 such as thrombospondin type 1 doamain, and C-terminal domains. This process further contributes to the accumulation of ultra large von Willebrand factor (vWF) multimers, which bind to platelets and induce aggregation (2). Advancements in the management of iTTP over the past three decades have dramatically transformed the management and outcome of this previously fatal disease. A 90% mortality rate of thrombotic microangiopathy (TMA) in the 1980s has been reduced to approximately 10% in 2024 alone (3).

The groundbreaking TITAN (Study to Assess Efficacy and Safety of Anti-von Willebrand Factor [vWF] Nanobody in Patients With Acquired Thrombotic Thrombocytopenic Purpura [aTTP]) study using caplacizumab, an anti-vWF-humanized single variable domain immunoglobulin, showed promising results in the management of iTTP (Nanobody and Nanobodies [Ablynx NV] target the A1 domain of the vWF, which prevents interaction with the platelet glycoprotein Ib-IX-V receptor). Caplacizumab with a plasma exchange showed accelerated resolution of TTP and platelets stabilization; however, it produced a higher bleeding risk (4). Later, HERCULES (Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura) and post-HERCULES (Follow-Up Study for Patients Who Completed Study ALX0681-C301) studies showed similar outcomes (5, 6). Other treatments like recombinant ADAMTS13 (rADAMTS13), N-acetyl cysteine, and anfibatide, which inhibits platelet aggregation by binding to glycoprotein Ib and inhibiting its interaction with vWF, have been tested in animal models and showed efficacious results; however, they were only seen in case reports (7). Based on these studies, an expert panel for the International Society on Thrombosis and Haemostasis released 11 comprehensive recommendations on TTP in 2018. For a first acute episode and relapses of iTTP, the panel made a strong recommendation for adding corticosteroids to therapeutic plasma exchange (TPE) and a conditional recommendation for adding rituximab and caplacizumab (8).

iTTP treatment with TPE may lead to a prolonged hospital stay, including multiple sessions of daily TPE and the associated costs of plasma, equipment, nursing care, and medical supervision. Recently, Kühne and colleagues evaluated the treatment of acute iTTP with caplacizumab and immunosuppression without TPE in comparison with management with TPE, caplacizumab, and immunosuppression (9). The main objective of the retrospective study was to reduce the therapeutic burden without compromising the overall clinical outcome or patient safety. In the study, the authors used the Austrian Thrombotic Microangiopathy Registry and the German REACT-2020 TTP registry. A total of 42 patients with acute iTTP who received a TPE-free treatment regimen of immunosuppression and upfront caplacizumab were compared with a control group of 59 patients with iTTP who received frontline treatment with caplacizumab, in addition to TPE and immunosuppression. Clinical outcomes were evaluated based on daily complete blood count, serum chemistry, and ADAMTS13 activity testing done weekly. Subsequent initiation of TPE was based on a missing increase in platelet count, a worsening clinical condition, or new organ damage. Time-to-platelet count normalization was considered the primary outcome, and key secondary outcomes included clinical response, clinical exacerbation, refractory TTP, TTP-related deaths, and the time-to-platelet count doubling.

The parameters of the initial clinical presentation—duration and dose of caplacizumab—and the use of rituximab within 72 hours did not differ between the two groups, except for a significantly higher initial lactate dehydrogenase level in the TPE group (median, 703 vs 1052 U/L; p < 0.01). The primary outcome time-to-platelet count normalization was not significantly different between TPE-free and TPE-based management. Clinical exacerbations occurred in two patients (4.8%) in the TPE-free cohort and in nine patients (15.3%) in the TPE cohort. Exacerbations in the TPE-free cohort were linked to concomitant cytomegalovirus, active HIV and hepatitis B virus coinfection, concomitant antiplatelet antibodies in association with an ovarian teratoma, and multiple platelet transfusions before the correct diagnosis of TTP was made and early termination of caplacizumab before ADAMTS13 remission was acquired. In the TPE group, refractory TTP was observed due to active diseases that may have impaired the platelet count response, namely, the diagnosis of pancreatic cancer, pneumonic sepsis, and aspiration pneumonia. There was no significant difference in the time-to-platelet count doubling between the two cohorts with a median time of 1 day in both cohorts. Reported time to recovery of ADAMTS13 activity to 20% or more after treatment initiation was shorter in the TPE-free cohort. The duration of hospital stay was significantly shorter in the TPE-free cohort, and fewer patients were admitted to the intensive care unit. Complications were observed in 11 patients (26.2%) in the TPE-free group and 16 patients (27.1%) in the TPE group, excluding complications of iTTP.

To our knowledge, the study by Kühne et al. (9) is the largest real-world cohort with acute iTTP, managed by anti-VWF treatment and omitting TPE. Due to the retrospective nature of the study, selection bias, such as the tendency to recruit patients with milder iTTP symptoms for TPE-free management, may be present in the current study, but differences in initial lactate dehydrogenase levels did not show any differences in primary outcome based on stratified analysis. In most instances, exacerbations were attributed to the early termination of caplacizumab when ADAMTS13 activity remained below 10%. This highlights that the ADAMTS13-guided approach is successful in acute iTTP management with caplacizumab.

There are many other ongoing studies for treatment of iTTP. The MAYARI (Caplacizumab and Immunosuppressive Therapy Without Firstline Therapeutic Plasma Exchange in Adults With Immune-Mediated Thrombotic Thrombocytopenic Purpura) trial (10) is an open-label, single-group, phase III multicenter trial of caplacizumab with immunosuppressive therapy without frontline use of TPE for iTTP. The study is aiming to recruit 61 adult patients with recurrent iTTP confirmed by low ADAMTS13 activity and absence of signs or symptoms consistent with other TMA syndromes such as atypical hemolytic uremia syndrome. The primary objective of the study is to find the proportion of participants achieving remission without TPE.

The assessment of safety and efficacy for rADAMTS13 as a treatment for iTTP is the objective of another study (A Study of TAK-755 [rADAMTS13] With Little to No Plasma Exchange [PEX] Treatment in Adults With Immune-Mediated Thrombotic Thrombocytopenic Purpura) (11). In this phase II study, 40 adult patients with de novo or recurrent iTTP are given random, two dose levels of intravenous rADAMTS13 for the acute treatment period combined with immunosuppressive therapy. The primary outcome in this trial is incidence of adverse events over a 12-week period.

Despite potential limitations arising from the retrospective design and possible selection bias, the key findings from the study by Kühne et al. (9) suggest that caplacizumab without TPE is efficacious in controlling TMA and achieving a clinical response in acute iTTP. In addition to the short-term control of microvascular thrombosis and subsequent organ damage, the modified treatment regimen was efficacious in achieving ADAMTS13 remission and allows for the cessation of anti-VWF medication with caplacizumab. Kühne et al. (9) showed efficacy and safety of a TPE-free approach in patients with iTTP. This can be the beginning of a TPE-free era in the treatment of iTTP.