Lamya Garabet1, Carola E Henriksson2, María Luisa Lozano3, Waleed Ghanima4, James Bussel5, Ellen Brodin6, María Piedad Fernández-Pérez7, Constantino Martínez7, Rocío González-Conejero7, Marie-Christine Mowinckel8, Per Morten Sandset9. 1. Multidisciplinary Laboratory Medicine and Medical Biochemistry, Akershus University Hospital, Norway; Department of Research, Østfold Hospital Trust, Norway; Institute of Clinical Medicine, University of Oslo, Norway. Electronic address: lamyagarabet@hotmail.com. 2. Institute of Clinical Medicine, University of Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital, Norway. 3. Hospital JM Morales Meseguer, Centro Regional de Hemodonacion, IMIB-Arrixaca, Murcia, Spain; Grupo de investigación CB15/00055 del Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. 4. Department of Research, Østfold Hospital Trust, Norway; Institute of Clinical Medicine, University of Oslo, Norway. 5. New York Presbyterian Hospital, Weill Cornell, United States. 6. Department of Haematology, Akershus University Hospital, Norway. 7. Hospital JM Morales Meseguer, Centro Regional de Hemodonacion, IMIB-Arrixaca, Murcia, Spain. 8. Research Institute of Internal Medicine, Oslo University Hospital, Norway; Department of Haematology, Oslo University Hospital, Norway. 9. Institute of Clinical Medicine, University of Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital, Norway; Department of Haematology, Oslo University Hospital, Norway.
Abstract
INTRODUCTION: Patients with immune thrombocytopenia (ITP) are at increased risk of thrombosis, which seems to be further enhanced by treatment with thrombopoietin-receptor-agonists (TPO-RAs). The underlying mechanisms of thrombosis in ITP are not fully understood. Endothelial cell activation and neutrophil extracellular traps (NETs) play important roles in thrombosis, however, their roles in ITP itself, or in TPO-RA-treatment, have not yet been fully explored. We aimed to investigate whether endothelial cell activation and NETs are involved in the hypercoagulable state of ITP, and whether TPO-RA-treatment enhances endothelial cell activation and NET formation. MATERIAL AND METHODS: We measured markers of endothelial cell activation including intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and thrombomodulin in 21 ITP patients, and E-selectin in 18 ITP patients. Markers of NET formation, citrullinated histone H3-DNA (H3Cit-DNA) and cell-free DNA (cfDNA), were measured in 15 ITP patients. All markers were measured before, and 2 and 6 weeks after initiation of TPO-RA-treatment in ITP patients, and in matched controls. RESULTS: Higher levels of ICAM-1, thrombomodulin, and H3Cit-DNA were found in ITP patients, both before and after TPO-RA-treatment, compared with controls. No differences were found for VCAM-1, E-selectin or cfDNA. TPO-RA-treatment did not further increase markers of endothelial cell activation or NET formation. CONCLUSIONS: This study showed that ITP patients have increased endothelial cell activation and NET formation, both of which may contribute to the intrinsic hypercoagulable state of ITP. TPO-RA-treatment, however, did not further increase endothelial cell activation or NET formation indicating that other drug-associated prothrombotic mechanisms are involved.
INTRODUCTION:Patients with immune thrombocytopenia (ITP) are at increased risk of thrombosis, which seems to be further enhanced by treatment with thrombopoietin-receptor-agonists (TPO-RAs). The underlying mechanisms of thrombosis in ITP are not fully understood. Endothelial cell activation and neutrophil extracellular traps (NETs) play important roles in thrombosis, however, their roles in ITP itself, or in TPO-RA-treatment, have not yet been fully explored. We aimed to investigate whether endothelial cell activation and NETs are involved in the hypercoagulable state of ITP, and whether TPO-RA-treatment enhances endothelial cell activation and NET formation. MATERIAL AND METHODS: We measured markers of endothelial cell activation including intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and thrombomodulin in 21 ITPpatients, and E-selectin in 18 ITPpatients. Markers of NET formation, citrullinated histone H3-DNA (H3Cit-DNA) and cell-free DNA (cfDNA), were measured in 15 ITPpatients. All markers were measured before, and 2 and 6 weeks after initiation of TPO-RA-treatment in ITPpatients, and in matched controls. RESULTS: Higher levels of ICAM-1, thrombomodulin, and H3Cit-DNA were found in ITPpatients, both before and after TPO-RA-treatment, compared with controls. No differences were found for VCAM-1, E-selectin or cfDNA. TPO-RA-treatment did not further increase markers of endothelial cell activation or NET formation. CONCLUSIONS: This study showed that ITPpatients have increased endothelial cell activation and NET formation, both of which may contribute to the intrinsic hypercoagulable state of ITP. TPO-RA-treatment, however, did not further increase endothelial cell activation or NET formation indicating that other drug-associated prothrombotic mechanisms are involved.
Authors: Nichola Cooper; Ivy Altomare; Mark R Thomas; Phillip L R Nicolson; Steve P Watson; Vadim Markovtsov; Leslie K Todd; Esteban Masuda; James B Bussel Journal: Ther Adv Hematol Date: 2021-04-30
Authors: Vivianne S Nelson; Anne-Tess C Jolink; Sufia N Amini; Jaap Jan Zwaginga; Tanja Netelenbos; John W Semple; Leendert Porcelijn; Masja de Haas; Martin R Schipperus; Rick Kapur Journal: Cells Date: 2021-11-19 Impact factor: 6.600
Authors: Philip Smith; Axel Rosell; Maria Farm; Maria Bruzelius; Katherina Aguilera Gatica; Nigel Mackman; Jacob Odeberg; Charlotte Thålin Journal: PLoS One Date: 2022-07-28 Impact factor: 3.752