Science review: role of coagulation protease cascades in sepsis

Abstract

Cellular signaling by proteases of the blood coagulation cascade through members of the protease-activated receptor (PAR) family can profoundly impact on the inflammatory balance in sepsis. The coagulation initiation reaction on tissue factor expressing cells signals through PAR1 and PAR2, leading to enhanced inflammation. The anticoagulant protein C pathway has potent anti-inflammatory effects, and activated protein C signals through PAR1 upon binding to the endothelial protein C receptor. Activation of the coagulation cascade and the downstream endothelial cell localized anticoagulant pathway thus have opposing effects on systemic inflammation. This dichotomy is of relevance for the interpretation of preclinical and clinical data that document nonuniform responses to anticoagulant strategies in sepsis therapy.

Figure 1

Cell surface coagulation complexes of the procoagulant and anticoagulant pathways. The coagulation pathways are initiated by tissue factor (TF), which serves as the allosteric activator of the enzyme coagulation factor VIIa (VIIa). The TF–VIIa complex binds substrate factor X (X) through multiple contacts at so-called exosites, leading to the formation of a fairly stable TF–VIIa–X complex in which substrate X is converted to product Xa. When Xa is released from this complex, it associates with the cofactor Va to form the Va-Xa (prothrombinase) complex, predominantly on activated platelets that expose procoagulant phospholipid binding sites for Va and Xa. The intrinsic factor VIIIa-IXa complex can generate additional Xa that further amplifies the burst of thrombin generation required for hemostasis. Cell surface receptor mediated events also govern activation of the anticoagulant protein C (PC) pathway, which is localized to endothelial cells. Thrombomodulin (TM) binds thrombin and switches the procoagulant properties of thrombin to anticoagulant functions. Endothelial PC receptor (EPCR) is the receptor for PC and activated protein C (APC), and promotes activation of PC by thrombin–thrombomodulin. When APC is released from EPCR, it can act as a systemic anticoagulant by cleaving cofactors Va and VIIIa on various cell types.

Figure 2

Coreceptor-dependent activation of protease-activated receptors (PARs) by coagulation proteases. Relevant signaling complexes are schematically represented and the target PARs are listed. In primary endothelial cells, activated protein C (APC) signaling is mediated through PAR1, whereas tissue factor (TF)-VIIa-Xa can signal when PAR1 is blocked, indicating signaling through PAR2. TF–VIIa inefficiently signals in endothelial cells [20,22].

Figure 3

Targets of anticoagulant therapy and their efficacy in providing anti-inflammatory benefit in sepsis. Anticoagulants (shown in red and boxed) showed preclinical efficacy in preventing lethality, whereas anticoagulant mechanisms (shown in blue and circled) failed to protect in sepsis. ATIII, antithrombin III; TF, tissue factor; TFPI, tissue factor pathway inhibitor.