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

• Jak2^VF CH accelerated arterial thrombosis with a major role of increased young and more active Jak2^VF platelets.

• Jak2^VF platelets mediate thromboxane cross talk to WT platelets, suggesting a potentially beneficial effect of aspirin in JAK2^VF CH.

JAK2^V617F (JAK2^VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2^VF CH on arterial thrombosis and explored the underlying mechanisms. A meta-analysis of 3 large cohort studies confirmed the association of JAK2^VF with CVD and with platelet counts and adjusted mean platelet volume (MPV). In mice, 20% or 1.5% Jak2^VF CH accelerated arterial thrombosis and increased platelet activation. Megakaryocytes in Jak2^VF CH showed elevated proplatelet formation and release, increasing prothrombogenic reticulated platelet counts. Gp1ba-Cre–mediated expression of Jak2^VF in platelets (VFGp1ba) increased platelet counts to a similar level as in 20% Jak2^VF CH mice while having no effect on leukocyte counts. Like Jak2^VF CH mice, VFGp1ba mice showed enhanced platelet activation and accelerated arterial thrombosis. In Jak2^VF CH, both Jak2^VF and wild-type (WT) platelets showed increased activation, suggesting cross talk between mutant and WT platelets. Jak2^VF 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 Jak2^VF 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 Jak2^VF CH mice but not in WT control mice. This study shows accelerated arterial thrombosis and platelet activation in Jak2^VF CH with a major role of increased reticulated Jak2^VF platelets, which mediate thromboxane cross talk with WT platelets and suggests a potential beneficial effect of aspirin in JAK2^VF CH.