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

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: ADAMTS13; Autoantibodies; Caplacizumab; Therapeutic plasma exchange; Thrombotic thrombocytopenic purpura.

Fig. 1

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

Fig. 2

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

Fig. 3

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