Jak2 V617F clonal hematopoiesis promotes arterial thrombosis via platelet activation and cross talk.

Autor:	Liu W; Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY., Pircher J; Department of Cardiology, Medical Clinic I, University Hospital, Ludwig Maximilian University, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Schuermans A; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.; Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium., Ul Ain Q; Department of Cardiology, Medical Clinic I, University Hospital, Ludwig Maximilian University, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Zhang Z; Department of Cardiology, Medical Clinic I, University Hospital, Ludwig Maximilian University, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Honigberg MC; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.; Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA., Yalcinkaya M; Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY., Nakao T; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.; Cardiology Division, Brigham and Women's Hospital, Boston, MA.; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Pournamadri A; Biomedical Informatics Graduate Training Program, Stanford University, Stanford, CA., Xiao T; Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY., Hajebrahimi MA; Department of Cardiology, Medical Clinic I, University Hospital, Ludwig Maximilian University, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Wasner L; Department of Cardiology, Medical Clinic I, University Hospital, Ludwig Maximilian University, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Stegner D; Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.; Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany., Petzold T; Department of Cardiology, Medical Clinic I, University Hospital, Ludwig Maximilian University, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Natarajan P; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.; Department of Medicine, Harvard Medical School, Boston, MA., Massberg S; Department of Cardiology, Medical Clinic I, University Hospital, Ludwig Maximilian University, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Tall AR; Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY., Schulz C; Department of Cardiology, Medical Clinic I, University Hospital, Ludwig Maximilian University, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Wang N; Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Apr 11; Vol. 143 (15), pp. 1539-1550.
DOI:	10.1182/blood.2023022260
Abstrakt:	Abstract: JAK2 V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2VF CH on arterial thrombosis and explored the underlying mechanisms. A meta-analysis of 3 large cohort studies confirmed the association of JAK2VF with CVD and with platelet counts and adjusted mean platelet volume (MPV). In mice, 20% or 1.5% Jak2VF CH accelerated arterial thrombosis and increased platelet activation. Megakaryocytes in Jak2VF CH showed elevated proplatelet formation and release, increasing prothrombogenic reticulated platelet counts. Gp1ba-Cre-mediated expression of Jak2VF in platelets (VFGp1ba) increased platelet counts to a similar level as in 20% Jak2VF CH mice while having no effect on leukocyte counts. Like Jak2VF CH mice, VFGp1ba mice showed enhanced platelet activation and accelerated arterial thrombosis. In Jak2VF CH, both Jak2VF and wild-type (WT) platelets showed increased activation, suggesting cross talk between mutant and WT platelets. Jak2VF platelets showed twofold to threefold upregulation of COX-1 and COX-2, particularly in young platelets, with elevated cPLA2 activation and thromboxane A2 production. Compared with controls, conditioned media from activated Jak2VF platelets induced greater activation of WT platelets that was reversed by a thromboxane receptor antagonist. Low-dose aspirin ameliorated carotid artery thrombosis in VFGp1ba and Jak2VF CH mice but not in WT control mice. This study shows accelerated arterial thrombosis and platelet activation in Jak2VF CH with a major role of increased reticulated Jak2VF platelets, which mediate thromboxane cross talk with WT platelets and suggests a potential beneficial effect of aspirin in JAK2VF CH. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
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