Revisiting clinical response and refractoriness in immune thrombotic thrombocytopenic purpura
Abstract
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.
Article Details
Authors (39)
Lucas Kühne
1Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Thomas Osterholt
1Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Maximilian Suer
1Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Sadrija Cukoski
1Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Ralph Wendt
Christian Pfrepper
4Division of Hemostaseology, Department of Hematology, Cellular Therapy, Hemostaseology and Infectiology, University of Leipzig Medical Centre, Leipzig, Germany
Sirak Petros
4Division of Hemostaseology, Department of Hematology, Cellular Therapy, Hemostaseology and Infectiology, University of Leipzig Medical Centre, Leipzig, Germany
Ulf Schönermarck
5Nephrology Division, Department of Medicine IV, University Hospital LMU Munich, Munich, Germany
Anke von Bergwelt-Baildon
5Nephrology Division, Department of Medicine IV, University Hospital LMU Munich, Munich, Germany
Jessica Kaufeld
6Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
Anja Gäckler
7Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Kristina Schönfelder
7Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Felix S. Seibert
Matthias Masla
9Department of Internal Medicine and Nephrology, Herz-Jesu-Hospital Münster-Hiltrup, Münster-Hiltrup, Germany
Jörn Bramstedt
10Medizinische Klinik II Sektion Nephrologie, Klinikum Bremerhaven Reinkenheide, Bremerhaven, Germany
Vedat Schwenger
11Department of Nephrology, Klinikum Stuttgart, Stuttgart, Germany
Evelyn Seelow
12Department of Nephrology and Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
Anja Mühlfeld
13Division of Nephrology, Department of Medicine, Uniklinik RWTH Aachen, Aachen, Germany
Martin Bommer
14Alb-Fils-Klinikum Göppingen, Klinik für Hämatologie, Onkologie, Infektiologie und Palliativmedizin, Göppingen, Germany
Tilmann Schmidt
15Section of Nephrology, Clinic and Policlinic of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany
Marcus Brand
16General Internal Medicine and Emergency Department, Nephrology, Hypertension and Rheumatology, University Hospital Münster, Münster, Germany
Victor Walendy
17Department of Internal Medicine II, Universitätsmedizin (Halle), Medical Faculty of the Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
Lena Schulte-Kemna
18Division of Nephrology, University Hospital Ulm, Ulm, Germany
Johannes Thaler
19Division of Hematology and Hemostasis, Department of Medicine 1, Medical University of Vienna, Vienna, Austria
Kathrin Eller
20Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
Johannes Ruhe
21Department of Internal Medicine III, Nephrology, University Hospital Jena, Jena, Germany
Wolfram J. Jabs
22Department of Nephrology, Vivantes Klinikum im Friedrichshain, Berlin, Germany
Saban Elitok
23Department of Nephrology and Endocrinology, Ernst von Bergmann Hospital Potsdam, Potsdam, Germany
Christina Hart
24Department of Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
Felix Eisinger
25Department of Diabetology, Endocrinology, and Nephrology, University of Tübingen, Tübingen, Germany
Martin Nitschke
26Division of Nephrology, Department of Internal Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany
Lars Grasshoff
26Division of Nephrology, Department of Internal Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany
Wolfgang Miesbach
University Hospital Frankfurt, Frankfurt, Germany
Fedai Özcan
28Department of Nephrology, Klinikum Dortmund, Universität Witten Herdecke, Dortmund, Germany
Dennis A. Eichenauer
29Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, University of Cologne, Cologne, Germany
Jan Menne
30Department of Nephrology, Klinikum Region Hannover, Hannover, Germany
Paul Knöbl
19Division of Hematology and Hemostasis, Department of Medicine 1, Medical University of Vienna, Vienna, Austria
Linus A. Völker
1Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Paul T. Brinkkoetter
1Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany