Revisiting clinical response and refractoriness in immune thrombotic thrombocytopenic purpura

ABSTRACT: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening condition. Caplacizumab substantially shortens the time to clinical response, yet delayed platelet count recovery is occasionally observed, raising concerns about iTTP refractoriness. This retrospective multicenter study analyzed 204 acute iTTP episodes reported to the German REACT (Retrospective Evaluation of Acquired Thrombotic Thrombocytopenic Purpura in Caplacizumab-Treated Patients) 2020 and ATMAR (Austrian Thrombotic Microangiopathy Registry) registries, all treated with caplacizumab. Refractoriness was assessed using the 2017 International Working Group criteria and the more stringent definition by the French Reference Center for Thrombotic Microangiopathies. We evaluated time to platelet recovery and presence of confounding clinical conditions, potentially accounting for persistent thrombocytopenia, in all episodes. By day 5 after caplacizumab initiation, 171 of 204 patients (83.8%) achieved a clinical response, and the remaining 33 of 204 (16.2%) showed at least a doubling of the platelet count. Only 3 patients (1.5%) met laboratory criteria for refractoriness. In all cases, plausible alternative causes were present (eg, missed doses, infection). No patient was refractory without a confounding factor. In 8 of 204 patients (3.9%) we observed a markedly prolonged thrombocytopenia (≥10 days) and identified confounding conditions in all cases. In the stratified Cox model, the presence of alternative causes of thrombocytopenia was the only independent determinant of delayed platelet count normalization (hazard ratio, 0.16; 95% confidence interval, 0.09-0.28; P< .001). In the context of caplacizumab-based therapy, true refractoriness is rare. Delayed platelet count recovery is predominantly attributable to concomitant clinical conditions. Careful clinical assessment and context-sensitive interpretation of treatment response before escalating iTTP-specific therapy may avoid unnecessary treatment intensification and associated risks.