Jak2VF clonal hematopoiesis promotes arterial thrombosis via increased production of activated Jak²VF platelets and cross-talk to wild type platelets

Joachim Pircher (München)1, W. Liu (New York)2, A. Schuermans (Cambridge)3, Q. Ul Ain (München)1, Z. Zhang (München)1, T. Petzold (München)1, P. Natarajan (Cambridge)3, S. Massberg (München)1, A. Tall (New York)2, C. Schulz (München)1, N. Wang (New York)2

1LMU Klinikum der Universität München Medizinische Klinik und Poliklinik I München, Deutschland; 2Columbia University Irving Medical Center New York, USA; 3Broad Institute of Harvard and MIT Cambridge, USA


Clonal hematopoiesis of indeterminate potential (CHIP), a stem cell mutation driven clonal expansion of haematopoietic derived blood cells emerged as independent cardiovascular risk factor. JAK2V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD) and was associated with early onset myocardial infarction. In this study we assessed the impact of Jak2VF CH on arterial thrombosis and explored the underlying mechanisms.

A meta-analysis of three large cohort studies confirmed the association of JAK2VF CHIP with CVD and demonstrated that JAK2VF was the strongest driver mutation associated with coronary artery disease. Individuals with JAK2VF CHIP showed increased platelet counts, adjusted mean platelet volume (MPV) and platelet distribution width (PDW) indicating increased platelet production. In a mouse model of Jak2VF CH 20% or 1.5% Jak2VF mutated cells increased platelet activation and adhesion ex vivo and accelerated arterial thrombosis in vivo. Jak2VF CH further led to increased formation of platelet-leukocyte-hetero-aggregates, a marker of thromboinflammation. A similar phenotype was observed in Gp1ba-Cre mediated expression of Jak2VF in platelets (VFGp1ba) indicating that platelet dependent mechanisms are sufficient for the prothrombotic effects. Bone marrow imaging of thrombopoiesis revealed megakaryocytes with accelerated proplatelet formation and release in Jak2VF CH and resulted in elevated counts of hyper-reactive reticulated platelets. Interestingly, in Jak2VF CH, both Jak2VF and wild type (WT) platelets were more activated, suggesting cross-talk between mutant and WT platelets. Mechanistically, in Jak2VF platelets COX-1 and COX-2 were upregulated particularly in young platelets, which were increased in Jak2VF CH. Additionally, Jak2VF platelets showed increased expression of NOX2, cPLA2 activation and thromboxane A2 production. Consequently, as compared to controls, conditioned media from activated Jak2VF platelets induced greater activation of WT platelets that was reversed by a thromboxane receptor antagonist. Low-dose aspirin reduced carotid artery thrombosis in vivo in VFGp1ba and Jak2VF CH mice but not in WT control mice.

This study shows accelerated arterial thrombosis and platelet activation in Jak2VF CH, where increased platelet production results in elevated hyper-reactive reticulated Jak2VF platelets, which mediate thromboxane cross-talk to WT platelets. The results suggest a potential beneficial effect of aspirin in JAK2VF CHIP.

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