Abstract
Platelet activation is a hallmark of antiphospholipid syndrome (APS). However, the mechanisms through which antiphospholipid antibodies activate platelets and the optimal way to inhibit this pathophysiology are still not fully understood. Extracellular adenosine, produced by the ectoenzyme CD73, activates cell-surface receptors to increase intracellular cyclic adenosine monophosphate (cAMP), raising the threshold for platelet activation. Here, we found that platelets from patients with APS exhibited lower CD73 activity and cAMP content than healthy controls. Platelet activation, as measured by the surface expression of CD62P and activated αIIbβ3, was negatively correlated with CD73 activity and cAMP content. Exposing healthy platelets to APS patient immunoglobulin G (IgG) in vitro significantly reduced CD73 activity and intracellular cAMP while simultaneously increasing activation markers. We identified critical roles for FcγRIIa, phospholipase C, and the Akt signaling pathway in platelet activation by APS IgG. We also tested whether various agents that boost intracellular cAMP could blunt APS IgG-induced platelet activation. Agonism of the adenosine 2A receptor (A2AR) and inhibition of phosphodiesterase 3 (PDE3) were both highly effective in this regard. In summary, a dysregulated adenosinergic axis appears to potentiate APS platelets for prothrombotic activation by antiphospholipid antibodies. A2AR agonists and PDE3 inhibitors may be useful strategies for restoring platelet homeostasis in APS.