Therapeutic modulation of coagulation processes in sepsis. This illustration highlights some of the therapeutic targets of various anticoagulant approaches trialed in sepsis. (1) Inhibiting the procoagulant and proinflammatory functions of thrombin and FXa was initially trialed through the use of unfractionated heparin (UFH) or low-molecular-weight heparins (LMWHs). (2) Restoring the circulating plasma levels of ATIII has also been trialed via the infusion of recombinant human ATIII. Bolstering the anticoagulant and anti-inflammatory properties of endothelial cells has been attempted through the administration of recombination APC (3), recombinant human TM (rhTM) (4), or TFPI (5). Despite heparins, APC, ATIII, and TFPI having unique pharmacological profiles, acting at distinct points in the coagulation cascade, and possessing additional pharmacological activities independent of their anticoagulant effects, their potential clinical benefits have been undermined by bleeding complications. Improved understanding of the structural regions of APC responsible for anti-inflammatory properties (6a) and cytoprotective properties (6b), independent of anticoagulant effects, has facilitated the generation of recombinant mutants of APC with potentially fewer bleeding side effects (6a-b).