The focus of the Mackman laboratory is a protein called tissue factor (TF). This transmembrane receptor is the primary cellular activator of the coagulation protease cascades (Figure 1). TF is expressed constitutively on perivascular cells and initiates clot formation. After vascular injury, factor VIIa (FVIIa) binds TF and the complex initiates the clotting cascade by cleavage of FX to FXa and FIX to FIXa. Subsequent amplification of the clotting cascade by the intrinsic pathway produces large amounts of thrombin that cleave fibrinogen, activate FXIII and activate platelets. Tissue factor pathway inhibitor (TFPI) and activated protein C (APC) act to attenuate the clotting response.
Figure 1: Blood Coagulation Cascade
Coagulation and inflammation are linked through activation of protease-activated receptors (PARs) (Figure 2). Activation of the clotting cascade leads to the generation of proteases that can cleave and activate PARs. PAR-1 is activated by thrombin and FXa, PAR-3 and PAR-4 are activated by thrombin, and PAR-2 is activated by FVIIa and FXa. This allows cross-talk between coagulation and inflammation.
Figure 2: Activation of protease-activated receptors (PARs)