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

Clonal hematopoiesis of indeterminate potential (CHIP), a stem cell mutation driven clonal expansion of haematopoietic derived blood cells emerged as independent cardiovascular risk factor. JAK2^V617F (JAK2^VF) 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 Jak2^VF CH on arterial thrombosis and explored the underlying mechanisms.

A meta-analysis of three large cohort studies confirmed the association of JAK2^VF CHIP with CVD and demonstrated that JAK2^VF was the strongest driver mutation associated with coronary artery disease. Individuals with JAK2^VF CHIP showed increased platelet counts, adjusted mean platelet volume (MPV) and platelet distribution width (PDW) indicating increased platelet production. In a mouse model of Jak2^VF CH 20% or 1.5% Jak2^VF mutated cells increased platelet activation and adhesion ex vivo and accelerated arterial thrombosis in vivo. Jak2^VF 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 Jak2^VF 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 Jak2^VF CH and resulted in elevated counts of hyper-reactive reticulated platelets. Interestingly, in Jak2^VF CH, both Jak2^VF and wild type (WT) platelets were more activated, suggesting cross-talk between mutant and WT platelets. Mechanistically, in Jak2^VF platelets COX-1 and COX-2 were upregulated particularly in young platelets, which were increased in Jak2^VF CH. Additionally, Jak2^VF platelets showed increased expression of NOX2, cPLA2 activation and thromboxane A2 production. Consequently, as compared to controls, conditioned media from activated Jak2^VF 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 Jak2^VF CH mice but not in WT control mice.

This study shows accelerated arterial thrombosis and platelet activation in Jak2^VF CH, where increased platelet production results in elevated hyper-reactive reticulated Jak2^VF platelets, which mediate thromboxane cross-talk to WT platelets. The results suggest a potential beneficial effect of aspirin in JAK2^VF CHIP.