Interactions between the innate immune and blood coagulation systems

Abstract

Blood coagulation and inflammation are universal responses to infection and there is crosstalk between inflammation and coagulation that can either amplify or dampen the responses. Loss of appropriate interactions between these systems probably contributes to morbidity and mortality in infectious diseases. For instance, inflammatory cytokines and leukocyte elastase can downregulate natural anticoagulant proteins that help to maintain endothelial-cell integrity, control clotting, inhibit vasoactive peptides and dampen leukocyte infiltration into the vessel wall. This Review will summarize our current understanding of the mechanisms involved in the crosstalk between these two important systems.

Figure 1

The function of membranes and cofactors in blood coagulation. The enzymes associate with cofactors on membrane surfaces. Factor VIIa associates with tissue factor (TF) to activate either factor X or factor IX. Factor IXa associates with factor VIIIa to activate factor X. Factor Va associates with factor Xa to activate prothrombin (Pro). Thrombin (T) associates with thrombomodulin (TM) to activate protein C (PC) and the activated protein C (APC) complexes with protein S (S) to inactivate factors Va and VIIIa, thereby blocking the coagulation cascade.

Figure 2

The impact of inflammatory mediators on the regulation of coagulation. Inflammatory mediators, such as TNF-α or endotoxin, can effect the changes indicated. An upward arrow indicates increases in levels and a downward arrow indicates decreases. Abbreviations: α₁-AT, α₁ antitrypsin; EPCR, endothelial-cell protein C receptor; PAI-1, plasminogen activator inhibitor-1; TNF-α, tumor necrosis factor-α.

Figure 3

Thrombin is a multifunctional enzyme. Thrombin generates procoagulant, anticoagulant, inflammatory and mitogenic responses. These responses shift the hemostatic balance. Abbreviations: CD40L, CD40 ligand; EC, endothelial cell; IL-6, interleukin-6; MCP-1, macrophage chemotactic protein-1; PAF, platelet activating factor; PDGF, platelet-derived growth factor; PMNs, polymorphonucleocytes; TGF-β, transforming growth factor-β. Reproduced with permission from Ref. .

Figure 4

Antithrombin binds to heparin-like glycosaminoglycans, such as those on syndecan 4. Binding induces a conformational chance in antithrombin (AT). Thrombin (T) and some other coagulation enzymes react preferentially with the bound AT. In the case of T this requires T binding to the glycosaminoglycan (syndecan 4). Once T binds to the inhibitor, major conformational changes occur that lead to the release of the complex . In the absence of T, AT binding to the glycosaminoglycan leads to cell signaling, increasing prostacyclin (PGI₂) formation and decreasing NF-κB activation.

Figure 5

Thrombin binding to TM involves anion-binding exosite 1 on thrombin (shown as a strip through the middle of thrombin) and EGF domains 4 to 6 on TM. A chondroitin sulfate moiety on TM increases the affinity for thrombin but is not required for function. This chondroitin sulfate interacts with anion-binding exosite 2 on thrombin, a second, basic area near the heparin-binding site. The lectin domain of TM inhibits leukocyte adhesion and the MAP kinase pathway. Other functions of TM require the presence of different EGF domains. Domains 1–6 stimulate fibroblast growth; domains 3–6 are required for TAFI activation; domains 4–6 are required for PC activation; and thrombin-clotting activity is blocked by domains 5–6. The activation of PC to APC by the thrombin–TM complex is enhanced by binding of PC to EPCR through its gla domain . Abbreviations: APC, activated protein C; EGF, epidermal growth factor; EPCR, endothelial-cell protein C receptor; MAP, mitogen-activated protein; PC, protein C; TAFI, thrombin activatable fibrinolysis inhibitor; TM, thrombomodulin.

Figure 6

The EPCR molecule with a portion of the PC Gla domain and a lipid molecule. In the EPCR (yellow ribbon), two α-helices and an eight-stranded β-sheet create a groove that is filled with phospholipid (the space filling blue balls in the center). Binding of Ca²⁺ ions (magenta spheres) to the PC Gla domain (green ribbon) exposes the N-terminal ‘omega’ loop, which in the absence of EPCR interacts with the phospholipid surfaces on the membrane. There do not appear to be direct interactions between the PC Gla domain and the lipid molecule located in the groove of the EPCR. The model of the complex consists of residues 7–177 of the rsEPCR and the first 33 residues of the PC Gla domain. Abbreviations: EPCR, endothelial-cell protein C receptor; PC, protein C.