Bleeding diathesis in mice lacking JAK2 in platelets.

Abstract

The tyrosine kinase JAK2 is a critical component of intracellular JAK/STAT cytokine signaling cascades that is prevalent in hematopoietic cells, such as hematopoietic stem cells and megakaryocytes (MKs). Individuals expressing the somatic JAK2 V617F mutation commonly develop myeloproliferative neoplasms (MPNs) associated with venous and arterial thrombosis, a leading cause of mortality. The role of JAK2 in hemostasis remains unclear. We investigated the role of JAK2 in platelet hemostatic function using Jak2fl/fl Pf4-Cre (Jak2Plt-/-) mice lacking JAK2 in platelets and MKs. Jak2Plt-/- mice developed MK hyperplasia and splenomegaly associated with severe thrombocytosis and bleeding. This notion was supported by failure to occlude in a ferric chloride carotid artery injury model and by a cremaster muscle laser-induced injury assay, in which Jak2Plt-/- platelets failed to form stable thrombi. Jak2Plt-/- platelets formed thrombi poorly after adhesion to type 1 collagen under arterial shear rates. Jak2Plt-/- platelets spread poorly on collagen under static conditions or on fibrinogen in response to the collagen receptor GPVI-specific agonist, collagen-related peptide (CRP). After activation with collagen, CRP, or the CLEC-2 agonist rhodocytin, Jak2Plt-/- platelets displayed decreased α-granule secretion and integrin αIIbβ3 activation or aggregation, but showed normal responses to thrombin. Jak2Plt-/- platelets had impaired intracellular signaling when activated via GPVI, as assessed by tyrosine phosphorylation. Together, the results show that JAK2 deletion impairs platelet immunoreceptor tyrosine-based activation motif signaling and hemostatic function in mice and suggest that aberrant JAK2 signaling in patients with MPNs affects GPVI signaling, leading to hemostatic platelet function.

• Authors: Nathan Eaton, Saravanan Subramaniam, Marie L Schulte, Caleb Drew, David Jakab, Sandra L Haberichter, Hartmut Weiler, Hervé Falet
• Journal: Blood advances (Blood Adv) Vol. 5 Issue 15 Pg. 2969-2981 (08 10 2021) ISSN: 2473-9537 [Electronic] United States
• PMID: 34342643 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• Platelet Membrane Glycoproteins
• Jak2 protein, mouse
• Janus Kinase 2

Topics

• Animals
• Blood Platelets
• Disease Susceptibility
• Hemorrhage
• Hemostasis
• Janus Kinase 2 (genetics)
• Mice
• Mice, Knockout
• Platelet Activation
• Platelet Membrane Glycoproteins
• Thrombocytosis