Evaluating the Role of Janus Kinase Pathways in Platelet Homeostasis Using a Systems Modeling Approach.

ABSTRACT

Maintaining platelet homeostasis is important to avoid spontaneous bleeding and organ damage. Thrombopoietin, the primary regulator of platelet production, is affected by and acts in part via Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-mediated mechanisms. Interleukin-6 is also partly responsible for inducing thrombopoietin production via the JAK-STAT pathway. Although current understanding suggests that JAK2 is a primary mediator of platelet regulation, the emerging data show that a JAK1-specific inhibitor resulted in the modulation of platelet numbers following dosing. To gain a mechanistic understanding, a model describing platelet regulation based on known physiology and JAK-STAT pathways was built. The model provides a tool to coalesce biological understanding of platelet physiology and an in silico experimental platform to explore drug effects on platelet homeostasis. In this article, we explain the model construction and demonstrate the use of JAK-inhibitor programs as informing probes of the physiology, gaining insights on dosing paradigms that avoid platelet-related safety concerns.