Fig. 1.

The role of the plasma kallikrein-kinin system on thromboinflammation. (1) Upon endothelial damage, platelets are activated through the binding of the GPIb-V-IX to vWF, or GPVI to exposed collagen. (2) Activated platelets release polyphosphates which activate FXII. (3) FXIIa activates FXI, (4) leading to the subsequent activation of thrombin. (5) Thrombin facilitates the enzymatic cleavage of fibrinogen to fibrin, forming and stabilizing the thrombus. (6) The contact-kinin pathway itself is initiated by FXIIa, which cleaves PPK into PK. (7) PK subsequently acts on KNG, inducing the release of the proinflammatory peptide hormone BK. (8) Consequently, BK binding to its endothelial bradykinin receptor 1 and 2 initiates several inflammatory signaling cascades resulting in breakdown of tight junction proteins and edema formation. (9) Activation of the complement system leads to cleavage of the key molecule C3 into C3a and C3b. (10) Subsequently, C5 is cleaved into C5a and C5b, (11) resulting in the formation of the MAC on endothelial cells and platelets. (12) The MAC induces the release of nanoparticles that enhance the proteolytic formation of thrombin by FVa, initiating coagulation. (13) In parallel, large amounts of ATP and Ca²⁺ are released which phosphorylate C3b and attenuates proteolytic cleavage of C3b. (14) Thrombin also promotes the conversion of C3 and C5 to their effector molecules (C3a, C3b, C5a, C5b) and promotes complement activation. (15) Subsequently, C3a and C5a are capable of enhancing the inflammatory response as well as platelet activation. Abbreviations: ATP, adenosinetriphosphat; B1/2R, bradykinin receptor 1/2; FXII, factor XII; GP, Glycoprotein; KNG, high-molecular-weight-kininogen; MAC, membrane attack complex; P, phosphorylation; PK, plasma kallikrein; polyP, polyphosphates; PPK, plasma prekallikrein; vWF, von Willebrand factor. Created with BioRender.com