Coagulation and Fibrinolysis in Kidney Graft Rejection

Abstract

Coagulation system is currently considered an integrated part of innate immunity. Clotting activation in response to bacterial surface along with complement cascade priming represents the first line of defense against pathogens. In the last three decades, we learned that several coagulation factors, including factor II or thrombin and factor X, can interact with specific cell surface receptors activated by an unusual proteolytic mechanism and belonging to a novel class of G-protein-coupled receptors known as protease-activated receptors (PARs). PARs are expressed by a variety of cells, including monocytes, dendritic cells, and endothelial cells and may play a key role in the modulation of innate immunity and in the regulation of its interaction with the adaptive branch of the immune system. Also, the fibrinolytic system, in which activation is controlled by coagulation, can interact with innate immunity, and it is a key modulator of extracellular matrix deposition eventually leading to scarring and fibrosis. In the setting of kidney transplantation, coagulation and fibrinolytic systems have been shown to play key roles in the ischemia/reperfusion injury featuring delayed graft function and in the pathogenesis of tissue damage following acute and chronic rejection. In the present review, we aim to describe the mechanisms leading to coagulation and fibrinolysis activation in this setting and their interaction with the priming of the innate immune response and their role in kidney graft rejection.

Keywords: coagulation; fibrinolysis; graft function; innate immunity; protease-activated receptors.

Figure 1

Schematic representation of the coagulation cascade and the fibrinolytic system. In the coagulation cascade, the extrinsic pathway starts with tissue factor (TF) and activated factor VII (FVIIa). Tissue factor in physiological conditions is not in contact with the blood; however, damage of blood vessel structure can expose this membrane-associated glycoprotein to the blood, thus activating the extrinsic pathway of the coagulation cascade. TF can also be expressed by mononuclear cells or endothelial cells in response to inflammatory mediators. The TF/FVIIa complex promotes the activation of factor X (FXa). In the intrinsic pathway, negatively charged surfaces (such as phospholipids and polyphosphates from activated platelets) activate FXII, initiating a cascade leading to FXa. The common pathway FXa, along with the cofactor FVa, converts prothrombin (FII) to thrombin (FIIa). Finally, thrombin activates fibrinogen into fibrin and FXIIIa acts on fibrin strands to form a fibrin mesh. Regulation of coagulation activation occurs by three distinct natural anticoagulant pathways: AT (which blocks FXa and thrombin), TFPI (which inhibits the tissue factor–factor VIIa complex), and aPC (which proteolytically degrades factor Va and factor VIIIa). Natural regulators of the coagulation cascade are indicated in green: TFPI, AT, and aPC. Once the first thrombin is produced, it induces the propagation of the coagulation cascade (red arrows) but also a feedback regulation through aPC. In the fibrinolytic system, uPA and tPA catalyze the proteolysis of plasminogen into plasmin, which, in turn, degrades fibrin. Inhibition of the plasminogen system occurs by specific PAIs and by α2-AP at the level of plasmin.