Overview of the multiple opposing effects of polyP and APC on inflammation and coagulation. The proinflammatory (top left) and procoagulant (top right) effects of polyP provide multiple head-to-head confrontations with the cytoprotective (bottom left) and anticoagulant (bottom right) activities of APC. Amplification by polyP of proinflammatory effects by histones or HMGB1 that require RAGE and P2Y₁ are inhibited by APC’s cytoprotective effects that require PAR1 and EPCR.^1,3,7  Furthermore, APC directly inactivates histones, whereas histones inhibit the generation of APC by the thrombin-thrombomodulin complex (IIa-TM).^2,8  PF4 secreted by platelets inhibits polyP but enhances APC generation by the thrombin-thrombomodulin complex.^7,9  PolyP also mediates numerous procoagulant effects that include stimulation of factor V (FV) activation by thrombin (IIa) and factor Xa (FXa), inhibition of TFPI function, stimulation of FXI activation by thrombin, and inhibition of fibrinolysis.⁶  Procoagulant effects of polyP are counteracted by anticoagulant effects of APC that involve proteolysis of FVa to inactive FVa (FVai). Consequent to FVa inactivation, APC alleviates FVa-dependent inhibition of TFPI by polyP, eliminates FVa as cofactor for FXI activation by thrombin, and promotes fibrinolysis.^6,7,10  Not shown are the activation of the contact system resulting in the generation of bradykinin by long-chain polyP and the inactivation of HMGB1 by the thrombin-thrombomodulin complex.^3,6  Green arrows indicate stimulation/activation; red arrows indicate inhibition/inactivation.