Major substrates cleaved by thrombin and their functional impact on coagulation, thrombosis or inflammation
| Thrombin substrates . | Action . | Role . |
|---|---|---|
| Fibrinogen | Cleavage of fibrinogen to fibrin | *Prothrombotic: blood clot formation and stability |
| FV | Activation of FV (Fva) | †Procoagulant: enhances thrombin generation through +ve feedback loop |
| FVIII | Activation of FVIII (FVIIIa) | †Procoagulant: increases thrombin generation through +ve feedback loop |
| FXI (cofactor PolyP) | Activation of FXI (FXIa) | †Procoagulant: upregulates thrombin generation through +ve feedback |
| FXIII (cofactor calcium, fibrin) | Activation of FXIII (FXIIIa) | *Prothrombotic: active XIIIa acts on fibrin to cross-link polymers to form insoluble fibrin polymers |
| ADAMTS13 | Inactivation of ADAMTS13 | *Antithrombotic: proteolysis ablates activity against purified VWF |
| GPV (cofactor GPIbα) | Cleavage of GPV subunit of VWF receptor GPIb/V/IX | *Negative regulation of platelet activation |
| PARs | Limited cleavage of protease-activated receptors, initiating subsequent G protein–mediated signaling events | *Prothrombotic: platelet activation via PAR1 and PAR4 |
| ‡Proinflammatory: endothelial PAR1, leading to upregulation of chemokine expression, adhesion molecules (ICAM-1, P-selectin) | ||
| ‡Proinflammatory: monocyte PAR1, increased expression of proinflammatory cytokines (TNF, IL-1, IL-6, MCP-1) | ||
| Protease nexin 1 (PN-1) | Inhibitor of thrombin activity, FXa and FXIa activity132 | †Anticoagulant: expressed in monocytes, platelets and vascular cells. PN-1 is primarily localized at the cell surface as a result of the high affinity of PN-1 for GAGs. Active and heparin-bound PN-1 is secreted during platelet activation and efficiently inhibits thrombin, thereby inhibiting fibrin formation, thrombin-induced platelet activation, and amplification of thrombin generation in vitro. |
| Protein C (in complex with TM and EPCR) | Activation of protein C–APC | †Anticoagulant: inactivation of FVa and FVIIIa |
| ‡Anti-inflammatory/cytoprotective: via PAR1 signaling | ||
| TAFI (and cofactor TM, GAGs) | Activation of TAFI-TAFIa | §Inhibitor of fibrinolysis. TAFIa downregulates fibrinolysis by the removal of C-terminal lysines from fibrin. As a consequence, the binding of plasminogen and t-PA to the fibrin clot is inhibited. |
| ‡Anti-inflammatory: generation of proinflammatory mediators (bradykinin and complement factor C5a) | ||
| Inter-a-inhibitor (IaI) heavy chain 1 (HC1) | Cleavage of IaI HC1–associated hyaluronan (HA) matrices133 | ‡Thrombin cleavage of HC1 dissolves the inflammatory matrix (HA:HC) generated during inflammation as a consequence of covalent modification of HA with the HC of IaI. This leads to a reduction in leukocyte adhesion. |
| C5 (C5 convertase) | Cleavage of C5 (R947), generating the intermediates C5T and C5bT134,135 | ‡Proinflammatory: thrombin partners with C5 convertases during terminal complement pathway activation through the formation of C5bT and possibly C5T, leading to assembly of a functional membrane attack complex responsible for destroying damaged cells and pathogens |
| Thrombin substrates . | Action . | Role . |
|---|---|---|
| Fibrinogen | Cleavage of fibrinogen to fibrin | *Prothrombotic: blood clot formation and stability |
| FV | Activation of FV (Fva) | †Procoagulant: enhances thrombin generation through +ve feedback loop |
| FVIII | Activation of FVIII (FVIIIa) | †Procoagulant: increases thrombin generation through +ve feedback loop |
| FXI (cofactor PolyP) | Activation of FXI (FXIa) | †Procoagulant: upregulates thrombin generation through +ve feedback |
| FXIII (cofactor calcium, fibrin) | Activation of FXIII (FXIIIa) | *Prothrombotic: active XIIIa acts on fibrin to cross-link polymers to form insoluble fibrin polymers |
| ADAMTS13 | Inactivation of ADAMTS13 | *Antithrombotic: proteolysis ablates activity against purified VWF |
| GPV (cofactor GPIbα) | Cleavage of GPV subunit of VWF receptor GPIb/V/IX | *Negative regulation of platelet activation |
| PARs | Limited cleavage of protease-activated receptors, initiating subsequent G protein–mediated signaling events | *Prothrombotic: platelet activation via PAR1 and PAR4 |
| ‡Proinflammatory: endothelial PAR1, leading to upregulation of chemokine expression, adhesion molecules (ICAM-1, P-selectin) | ||
| ‡Proinflammatory: monocyte PAR1, increased expression of proinflammatory cytokines (TNF, IL-1, IL-6, MCP-1) | ||
| Protease nexin 1 (PN-1) | Inhibitor of thrombin activity, FXa and FXIa activity132 | †Anticoagulant: expressed in monocytes, platelets and vascular cells. PN-1 is primarily localized at the cell surface as a result of the high affinity of PN-1 for GAGs. Active and heparin-bound PN-1 is secreted during platelet activation and efficiently inhibits thrombin, thereby inhibiting fibrin formation, thrombin-induced platelet activation, and amplification of thrombin generation in vitro. |
| Protein C (in complex with TM and EPCR) | Activation of protein C–APC | †Anticoagulant: inactivation of FVa and FVIIIa |
| ‡Anti-inflammatory/cytoprotective: via PAR1 signaling | ||
| TAFI (and cofactor TM, GAGs) | Activation of TAFI-TAFIa | §Inhibitor of fibrinolysis. TAFIa downregulates fibrinolysis by the removal of C-terminal lysines from fibrin. As a consequence, the binding of plasminogen and t-PA to the fibrin clot is inhibited. |
| ‡Anti-inflammatory: generation of proinflammatory mediators (bradykinin and complement factor C5a) | ||
| Inter-a-inhibitor (IaI) heavy chain 1 (HC1) | Cleavage of IaI HC1–associated hyaluronan (HA) matrices133 | ‡Thrombin cleavage of HC1 dissolves the inflammatory matrix (HA:HC) generated during inflammation as a consequence of covalent modification of HA with the HC of IaI. This leads to a reduction in leukocyte adhesion. |
| C5 (C5 convertase) | Cleavage of C5 (R947), generating the intermediates C5T and C5bT134,135 | ‡Proinflammatory: thrombin partners with C5 convertases during terminal complement pathway activation through the formation of C5bT and possibly C5T, leading to assembly of a functional membrane attack complex responsible for destroying damaged cells and pathogens |