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. 2025 Mar 19;104(3):1507–1514. doi: 10.1007/s00277-025-06318-w

Challenges in managing iTTP: insights into ADAMTS13 inhibitor boosting during caplacizumab therapy

Haruyuki Tanaka 1, Kazuya Sakai 2, Shusuke Tamura 3, Hiroya Shiwaku 3, Junko Nakamura 4, Yasunori Ueda 4, Seiya Bamba 5, Masashi Nishikubo 5, Yuya Nagai 5, Masanori Matsumoto 1,2,✉
PMCID: PMC12031809  PMID: 40105947

Abstract

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare but life-threatening disorder characterized by severe thrombocytopenia, hemolytic anemia, and end-organ ischemic damage. The introduction of caplacizumab, an anti-von Willebrand factor A1 nanobody, has revolutionized the treatment of patients with iTTP by preventing fatal thrombotic events and shortening the time to platelet normalization. Despite its benefits, caplacizumab does not address the challenge of anti-ADAMTS13 autoantibody production, posing a risk of ADAMTS13 inhibitor boosting and delayed recovery of ADAMTS13 activity. Here, we highlight three challenging cases from the Japanese TTP registry involving patients with iTTP who experienced severe ADAMTS13 inhibitor boosting. This delayed the recovery of ADAMTS13, and extended administration of caplacizumab while requiring additional therapeutic plasma exchange (TPE) and immunosuppressive therapy. All patients demonstrated delayed recovery of ADAMTS13 activity despite initial clinical improvement. Prolonged use of caplacizumab masked the persistence of ADAMTS13 inhibitors, emphasizing the need for close monitoring and timely interventions. Although recent proposals for TPE-free regimens show promise, our findings underscore that TPE remains essential for removing residual autoantibodies and preventing disease exacerbation in certain patients. Stratifying patients based on initial ADAMTS13 inhibitor titers and optimizing immunosuppressive strategies may help identify those at risk of severe inhibitor boosting. Further research is required to refine treatment protocols and ensure the safe withdrawal of caplacizumab while achieving sustained recovery of ADAMTS13 activity.

Keywords: Thrombotic thrombocytopenic purpura, ADAMTS13, Autoantibodies, Therapeutic plasma exchange, Caplacizumab

Introduction

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease characterized by severe thrombocytopenia, hemolytic anemia, and microthrombi-derived ischemic end-organ damage to the cardiovascular and neurological systems [1, 2]. The induction of therapeutic plasma exchange (TPE) using fresh frozen plasma (FFP) has greatly reduced the overall mortality rate in patients with TTP by removing anti-ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif, member 13) autoantibodies and highly platelet-adhesive von Willebrand factor (VWF) multimers, replenishing intact ADAMTS13 [3]. Nevertheless, up to 20% of patients encounter fatal outcomes in the very acute phase due to sudden cardiac arrest as a result of severe ischemic damage in the heart. Recently, the anti-VWF A1 nanobody, caplacizumab, was approved for faster normalization of platelet counts and prevention of fatal thrombotic events by interfering with the binding between VWF A1 and glycoprotein 1b expressed in platelets [4, 5]. Based on clinical trials and real-world data, caplacizumab, in conjunction with a standard regimen (TPE and immune suppressors), shortened the time to normalize platelet counts and significantly reduced the number of TPE procedures [6–10]. As a result, this groundbreaking drug has significantly enhanced the quality of life in patients and ensured their safety during acute-phase treatment.

Caplacizumab is not a curative treatment for patients with iTTP; rather, it serves as an anti-VWF therapy [11] that provides sufficient time for immunosuppressive agents, such as corticosteroids and rituximab, to eliminate antibody-producing cells. Hence, the withdrawal of caplacizumab with insufficient recovery of ADAMTS13 causes immediate TTP symptoms, which may lead to serious end-organ damage. The phase II clinical trial (TITAN study) underscored that the administration of caplacizumab should be extended until ADAMTS13 activity increases more than 10 to 20% [4]. According to the prescribing information of Cablivi® (Sanofi), the administration of caplacizumab could be extended for a maximum of 28 days beyond the 30 days after stopping TPE, guided by the level of ADAMTS13 activity. A research team in the UK and our group have previously reported that adding caplacizumab may delay ADAMTS13 recovery despite shortened periods of TPE [12, 13]. Saito et al. reported that patients with a higher titer of ADAMTS13 inhibitor at the first clinical presentation were likely to develop ADAMTS13 inhibitor boosting, whereas patients were free from any thrombotic events and thrombocytopenia [13]. Caplacizumab masks the production of anti-ADAMTS13 autoantibodies and the presence of ultra-large VWF multimers.

To underscore this issue in clinical practice, we analyzed patients treated with caplacizumab in our TTP registry. We extracted three challenging cases where the recovery of ADAMTS13 could not be achieved within the extended 58 days of caplacizumab administration because of severe ADAMTS13 inhibitor boosting [14], and additional TPE procedures were required to regulate the remaining anti-ADAMTS13 autoantibodies.

Materials and methods

We analyzed the data of patients with iTTP diagnosed using ADAMTS13 testing and treated with caplacizumab between 2022 and 2024 in the Japanese TTP registry. In total, 37 patients with their first episodes were eligible. Among them, three patients experienced severe ADAMTS13 inhibitor boosting and required a second TPE series to remove the remaining autoantibodies against ADAMTS13 from circulation.

This study was approved by the Ethics Committee of Nara Medical University and was conducted in accordance with the tenets of the Declaration of Helsinki. Based on the existing information, patients were provided with the opportunity to opt out of the study.

Case 1

A 38-year-old male presented with acute onset of altered levels of consciousness preceded by a 2-day history of nausea, fatigue, occipital headache, and petechiae. Upon arrival at the hospital, laboratory findings revealed thrombocytopenia (11 × 109/L), hemolytic anemia with schistocytes (hemoglobin [Hb]: 9.4 g/dL, total bilirubin: 3.1 mg/dL, and lactate dehydrogenase [LDH]: 1436 U/L), psychiatric symptoms, and fever, leading to a clinical diagnosis of TTP. Magnetic resonance imaging of the brain demonstrated an acute infarction in the left frontal lobe. Due to severe agitation, the patient was sedated with propofol and intubated in the intensive care unit (ICU). TPE was initiated on day 1, and caplacizumab was administered on day 2, resulting in an improvement in psychiatric symptoms. Subsequent extubation was performed on day 3. High-dose corticosteroid pulse therapy was initiated on day 3. By day 5, the platelet count of the patient had significantly increased to 182 × 109/L, allowing him to be transferred to the general ward. TPE was discontinued after six sessions, which were completed on day 6. ADAMTS13 testing confirmed the diagnosis of iTTP, with undetectable ADAMTS13 activity and a positive ADAMTS13 inhibitor (11.9 Bethesda Units/mL [BU/mL]) at the initial presentation.

Following the discontinuation of TPE, the titers of ADAMTS13 inhibitors significantly increased, accompanied by persistently undetectable ADAMTS13 activity. To address refractory iTTP, rituximab was administered in four weekly doses on days 19, 25, 33, and 40. Despite the addition of 500 mg of intravenous cyclophosphamide on day 50, ADAMTS13 activity remained below 10% in the presence of a positive ADAMTS13 inhibitor at approximately 2 BU/mL by day 66, the maximum allowable duration for caplacizumab administration under the health insurance policy. Consequently, a second course of TPE was initiated on day 61 and was continued till day 71 to eliminate residual ADAMTS13 inhibitors. Corticosteroid therapy was intensified to regulate auto-reactive T and B lymphocytes. Caplacizumab was subsequently discontinued following the removal of circulating ADAMTS13 inhibitors. Consequently, the patient required two vascular catheterizations during hospitalization. The patient was discharged on day 112. Outpatient follow-up continued with regular monitoring of ADAMTS13 activity and gradual steroid tapering. The entire clinical course of this case is presented as Fig. 1.

Fig. 1.

Fig. 1

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Overview of treatment and laboratory findings in the case 1. The patient finally required two sessions of TPE during the acute episode. The initial and peak level of ADAMTS13 inhibitor were 11.9 and 67.1 BU/mL, respectively. To control the production of ADAMTS13 inhibitor, additional rituximab and cyclophosphamide were used. The days means the days after admission to the institute. The ADAMTS13 inhibitor levels are presented on a logarithmic scale. Abbreviations; LDH, lactate dehydrogenase; BU, Bethesda units

Case 2

A 49-year-old female experienced exertional dyspnea one week before admission. On the day before admission, she noticed subcutaneous bleeding in her extremities, and laboratory tests in primary care medicine showed thrombocytopenia and anemia. Further evaluation at the referring hospital revealed jaundice, thrombocytopenia, anemia, and schistocytes on a peripheral blood smear, raising the suspicion of TTP, and the patient was transferred to our institution.

On admission, the patient exhibited altered consciousness. The laboratory findings included severe thrombocytopenia (12 × 109/L), hemolytic anemia (Hb: 7.0 g/dL, total bilirubin: 5.0 mg/dL, and LDH: 1200 U/L), elevated high-sensitivity troponin I levels, undetectable haptoglobin levels, and the presence of schistocytes. A French Score of 2 further supported the strong suspicion of TTP. Subsequently, TPE and prednisolone (1 mg/kg) were administered on day 1. Caplacizumab was administered on the following day. The diagnosis of iTTP was established with an ADAMTS13 activity level of < 0.5% and an ADAMTS13 inhibitor titer of 13.5 BU/mL on day 1. The altered mental status and other clinical symptoms of the patient rapidly improved immediately after the initial treatment. The platelet count increased to 150 × 109/L on day 4, leading to the cessation of TPE on day 5.

Regular ADAMTS13 testing revealed that the ADAMTS13 inhibitor titer rapidly rebounded to 129.3 BU/mL, while the platelet count declined below 50 × 109/L. Rituximab was administered on days 15, 24, 29, and 36 to reduce antibody production; however, the ADAMTS13 inhibitor persisted at high levels, necessitating two additional doses of cyclophosphamide on days 29 and 47 for further immunosuppression. To accelerate antibody clearance, five additional sessions of TPE were performed before completing caplacizumab treatment on day 58 of post-TPE cessation (day 54–58 after initiation of treatment). After caplacizumab was discontinued, no recurrence of thrombocytopenia was observed. The ADAMTS13 inhibitor titers continued to decline, and ADAMTS13 activity demonstrated sustained recovery. The patient remained stable on a tapering regimen of prednisolone during outpatient follow-up. The entire clinical course of this case is presented as Fig. 2.

Fig. 2.

Fig. 2

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Overview of treatment and laboratory findings in the case 2. The patient finally required two sessions of TPE during the acute episode. The initial and peak level of ADAMTS13 inhibitor were 13.5 and 129.3 BU/mL, respectively. To control the production of ADAMTS13 inhibitor, additional rituximab and cyclophosphamide were used. The days means the days after admission to the institute. The ADAMTS13 inhibitor levels are presented on a logarithmic scale. Abbreviations; LDH, lactate dehydrogenase; BU, Bethesda units

Case 3

A 48-year-old female experienced fatigue, hematuria, and purpura in her extremities within one week of hospitalization. The patient noticed partial visual field loss, and laboratory testing in primary medicine showed thrombocytopenia and elevated LDH, leading to an emergency referral to our hospital on day 1. The laboratory findings revealed severe thrombocytopenia (9 × 109/L), hemolytic anemia (Hb: 9.2 g/dL, total bilirubin: 2.6 mg/dL, and LDH: 1661 U/L), and undetectable haptoglobin, leading to clinical diagnosis of iTTP. Although the troponin I (TnI) level was elevated to 0.141 ng/mL, no symptoms or electrocardiogram changes suggestive of acute coronary syndrome were observed. Similarly, no neurological deficits such as motor or sensory impairments or dysarthria were noted.

Treatment was initiated immediately in the ICU and included TPE, methylprednisolone 100 mg (1.5 mg/kg), and caplacizumab on the same day. Rituximab was administered without infusion reaction on day 2. Blood tests indicated an increased platelet count of 121 × 109/L, no schistocytes, and normalized hemolysis markers (LDH: 211 U/L, total bilirubin: 0.6 mg/dL). The TnI levels became negative in response to the initial treatment. A severe allergic reaction occurred in the patient with anaphylaxis due to FFP. TPE was discontinued on day 5 based on a sustained platelet count of 150 × 109/L. At this point, ADAMTS13 results from plasma samples drawn on day 1 revealed depleted ADAMTS13 activity < 0.5% and the presence of ADAMTS13 inhibitor (4.8 BU/mL), leading to the diagnosis of iTTP.

However, the patient developed severe ADAMTS13 inhibitor boosting immediately after the termination of TPE, with undetectable ADAMTS13 activity (peak 143.1 BU/mL on day 12). To control the production of anti-ADAMTS13 autoantibodies, intravenous cyclophosphamide (IVCY) at 500 mg was administered on days 40 and 55. The administration of caplacizumab was extended with a single TPE on day 63 owing to health insurance limitations. Post-TPE, ADAMTS13 activity briefly increased, and the inhibitor titer decreased, but these reversed shortly thereafter, indicating the presence of residual inhibitors. The additional TPE session was necessary but was limited because the patient had severe allergic reactions. TPE was performed on days 70 and 73. IVCY caused transient neutropenia (180/µL) on day 74, which was managed with granulocyte colony-stimulating factor (75 µg/day) from day 74 to 76. Subsequent leukocytosis coincided with elevated LDH levels, which likely reflected this response. Finally, ADAMTS13 activity reached 44.9%, and the inhibitor titer was undetectable, and caplacizumab was discontinued on day 76. The patient was discharged on day 82 and underwent outpatient follow-up. The entire clinical course of this case is presented as Fig. 3.

Fig. 3.

Fig. 3

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Overview of treatment and laboratory findings in the case 3. The patient finally required two sessions of TPE during the acute episode. The initial and peak level of ADAMTS13 inhibitor were 4.8 and 143.1 BU/mL, respectively. Based on the clinical judgment of the treating physicians, upfront rituximab was used as high risk of refractory TTP. To control the production of ADAMTS13 inhibitor, cyclophosphamide was added. The days means the days after admission to the institute. The ADAMTS13 inhibitor levels are presented on a logarithmic scale. Abbreviations; LDH, lactate dehydrogenase; BU, Bethesda units; G-CSF, granulocyte colony-stimulating factor

Results and discussions

The initiation of caplacizumab-combined therapy has shown that patients with iTTP are protected from fatal thrombotic events and can stop TPE procedures earlier. In the pre-caplacizumab era, certain patients experienced sudden cardiac arrest due to fatal arrhythmia within one week of treatment [15]. Even survivors required prolonged TPE sessions via an inserted catheter until most of the anti-ADAMTS13 autoantibodies were removed, followed by the recovery of ADAMTS13 activity. In addition, severe allergic reactions owing to FFP, catheter-related complications, and post-traumatic stress disorder due to extreme mental stress from prolonged TPE procedures usually hinder the completion of TPE, which is needed to restore ADAMTS13 activity by removing autoantibodies in circulation. Rituximab was administered to eliminate CD20-positive autoantibody-producing cells, resulting in shorter hospital stays and longer relapse-free intervals during remission [16–18]. However, upfront rituximab use is yet to be approved in certain countries, including Japan, where rituximab can be administered to patients who relapsed and had refractory iTTP. Moreover, it takes approximately two weeks for its therapeutic effects to become evident. As rituximab cannot prevent acute TTP-related death in vulnerable patients, caplacizumab has been widely regarded by clinicians as a “game changer” in the treatment of patients with iTTP. Caplacizumab facilitates faster normalization of platelet counts, reduces mortality by preventing further microthrombi in the vasculature, shortens hospital stays due to fewer TPE sessions, and enables home infusion therapy. Real-world data from several countries, including France [8], UK [6], Germany [9, 19], Spain [20], Italy [10] and Japan [21], and previous clinical trials have confirmed the efficacy and safety of caplacizumab in the treatment of patients with iTTP.

In 2023, however, a research group in the UK reported that significantly delayed normalization of ADAMTS13 activity was observed in a few patients treated with caplacizumab-containing regimens [12]. Patients treated with caplacizumab achieved ADAMTS13 activity > 30% at a median of 31 days after TPE compared with 11.5 days in those not treated with caplacizumab. Failure to reach ADAMTS13 activity > 30% within 30 + 28 days was six times more likely with caplacizumab. Subsequently, our group consolidated the theory that caplacizumab may delay ADAMTS13 recovery despite earlier platelet count recovery and fewer sessions of TPE procedures among patients in Japan [13]. The caplacizumab group experienced significantly delayed normalization of ADAMTS13 activity (42 vs. 23 days to achieve ≥ 10% activity, P = 0.014) compared with the non-caplacizumab group. Higher levels of inhibitors and anti-ADAMTS13 IgG were sustained during the treatment. Indeed, it has been reported that persistent inhibitors interfere with ADAMTS13 recovery in the pre-caplacizumab era [22, 23]. Reduced frequency of TPE and delayed administration of rituximab were suggested as contributing factors. Patients with higher ADAMTS13 inhibitor titers in the caplacizumab group developed ADAMTS13 inhibitor boosting more frequently than those in the non-caplacizumab group, suggesting that patients need to monitor ADAMTS13 parameters closely and require more sessions of TPE to remove the remaining anti-ADAMTS13 autoantibodies. In Japan, the use of rituximab upfront is generally not approved by their health insurance system. Hence, a delay in the administration of rituximab may potentially lead to further delays in ADAMTS13 recovery, although there were no significant differences in ADAMTS13 recovery between earlier and later rituximab administration in our previousstudy [13].

A novel therapeutic approach incorporating TPE-free therapy in combination with caplacizumab and immunosuppressive treatment was recently proposed based on clinical experiences in patients who were either intolerant of FFP or declined FFP [24–26]. Kühne et al. retrospectively analyzed data from 42 patients with iTTP in Austria and Germany treated with a TPE-free regimen, omitting TPE if the platelet count increased after the first caplacizumab dose [27]. Outcomes were compared with those in 59 patients who received standard TPE-based treatment. The key findings showed that the time to platelet normalization (3 vs. 4 days, P = 0.31) was comparable among patients in both groups, and there were no significant differences in response, exacerbations, refractoriness, or mortality, suggesting that caplacizumab and immunosuppression alone rapidly controlled thrombotic microangiopathy. Furthermore, an international phase III clinical study (MAYRI) is currently underway to evaluate the feasibility of a TPE-free regimen in patients with iTTP. We speculate that once the efficacy and safety of a TPE-free regimen are established, conventional TPE will lose its relevance.

However, as discussed in this study, a few patients are exposed to an underlying risk of severe ADAMTS13 inhibitor boosting, which requires the physical removal of autoantibodies from the circulation. Theoretically, even if all ADAMTS13-specific B-cells are eliminated by immunosuppressors, including rituximab, the preexisting IgG-autoantibody against ADAMTS13 will not be cleared, and its half-life is generally estimated to be approximately three weeks [28]. One plasma volume of TPE is expected to remove 63.2% of pathogenic substances in plasma [29]. It has not been demonstrated whether exogenous ADAMTS13 can trigger further antibody production against ADAMTS13 since FFP is a commonly used replacement fluid as a source of functional ADAMTS13. In response to the query about why a subset of patients who receive caplacizumab experience delayed antibody clearance or severe ADAMTS13 inhibitor boosting, we hypothesize that the variability in the reactivity of ADAMTS13-specific T-lymphocytes in the acute phase may contribute to this phenomenon. Specifically, exposure to ADAMTS13 present in FFP might activate T-lymphocytes to different extents, leading to excessive autoantibody production by B-lymphocytes in some cases. Shin et al. reported that a higher percentage of plasmablasts in circulating B-cells was associated with higher anti-ADAMTS13 IgG and lower ADAMTS13 antigen levels in at acute iTTP presentation [30]. At least three of our patients should have undergone additional TPE procedures and earlier administration of additional immunosuppressants to eliminate a source of autoantibodies. Thus, even in the caplacizumab era, a few patients seem to require additional TPE based on ADAMTS13 inhibitor titers. Of course, this original research cited only a small number of cases across Japan; however, it alerts us that TPE will remain a cornerstone in certain patients who are at the risk of severe ADAMTS13 inhibitor boosting. Further investigation is needed to find a way to stratify each potential risk to develop ADAMTS13 inhibitor boosting (e.g., an initial titer of ADAMTS13 inhibitor).

Acknowledgements

Dr. Hidekazu Azumi, Dr. Kenki Saito, and Dr. Atsushi Hamamura performed the ADAMTS13 tests in this study. The authors also thank all physicians for sending the data and samples of the Japanese patients with iTTP.

Author contributions

H. T. and K. S. interpreted the data and drafted the manuscript. S.T., H.S., J.N., Y.U., S.B., M.N., and Y.N. treated the patients and collected clinical and blood samples. M. M. provided advice regarding the analysis. All authors critically reviewed the manuscript.

Funding

This study was financially supported by research grants from the Ministry of Health, Labor, and Welfare of Japan (20FC1024 to M.M.).

Data availability

As for clinical data, please contact mmatsumo@naramed-u.ac.jp.

Declarations

Competing interests

K. S. received speaker fees from Sanofi and participated on the advisory boards for Takeda. Y. U. received speaker fees from Sanofi. M.M. provided consultancy services for Takeda, Alexion Pharma, and Sanofi; received speaker fees from Takeda, Alexion Pharma, Asahi Kasei Pharma, and Sanofi; and received research funding from Alexion Pharma, Chugai Pharmaceutical, Asahi Kasei Pharma, and Sanofi.

Consent to publish

Not applicable.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

As for clinical data, please contact mmatsumo@naramed-u.ac.jp.

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