Bradykinin: Inflammatory Product of the Coagulation System

Abstract

Episodic and recurrent local cutaneous or mucosal swelling are key features of angioedema. The vasoactive agents histamine and bradykinin are highly implicated as mediators of these swelling attacks. It is challenging to assess the contribution of bradykinin to the clinical expression of angioedema, as accurate biomarkers for the generation of this vasoactive peptide are still lacking. In this review, we will describe the mechanisms that are responsible for bradykinin production in hereditary angioedema (HAE) and the central role that the coagulation factor XII (FXII) plays in it. Evidently, several plasma parameters of coagulation change during attacks of HAE and may prove valuable biomarkers for disease activity. We propose that these changes are secondary to vascular leakage, rather than a direct consequence of FXII activation. Furthermore, biomarkers for fibrinolytic system activation (i.e. plasminogen activation) also change during attacks of HAE. These changes may reflect triggering of the bradykinin-forming mechanisms by plasmin. Finally, multiple lines of evidence suggest that neutrophil activation and mast-cell activation are functionally linked to bradykinin production. We put forward the paradigm that FXII functions as a 'sensor molecule' to detect conditions that require bradykinin release via crosstalk with cell-derived enzymes. Understanding the mechanisms that drive bradykinin generation may help to identify angioedema patients that have bradykinin-mediated disease and could benefit from a targeted treatment.

Keywords: Angioedema; Bradykinin; D-dimer; Factor XII; HAE; Histamine; Plasmin.

Fig. 1

Overview of coagulation, contact activation and fibrinolysis. The coagulation cascade is initiated by either tissue factor (TF) or FXIIa. Positive feedback by thrombin (FIIa) accelerates coagulation. The end-product of coagulation is fibrin, cross-linked by factor XIII. Fibrin is degraded by plasmin. During this process, D-dimer, an important clinical biomarker for thrombosis, is generated. Fibrinolysis is started when tPA bound to fibrin, or uPA expressed on the endothelium, converts plasminogen into plasmin. Contact activation starts with the activation of FXII that will eventually lead to bradykinin release and vascular leakage. C1-INH is the most important inhibitor of contact activation and a weak inhibitor of plasmin. Anti-thrombin (AT) inhibits coagulation and α2-antiplasmin inhibits plasmin; complexes between enzymes and these inhibitors can be measured in plasma as biomarkers for contact activation, coagulation and fibrinolysis. PAI-1 inhibits plasminogen activation via inhibition of tPA and uPA. TAFI modulates plasminogen to prevent activation. Abbreviations: TF tissue factor, FXIIa activate factor XII, PK plasma prekallikrein, KK kallikrein, HMWK high molecular weight kininogen, BK bradykinin, C1-INH C1 inhibitor, AT anti-thrombin, α2AP α2-anti-plasmin, TAFI thrombin activatable fibrinolysis inhibitor, PAI plasminogen activator inhibitor, tPA tissue plasminogen activator, uPA urokinase plasminogen activator

Fig. 2

Proposed model: increased plasma coagulation parameters secondary to increased vascular permeability and extravascular coagulation. Bradykinin binds to its receptors on endothelial cells. Increased vascular permeability allows extravasation of coagulation factors. Tissue factor expressed in the extravascular space can initiate coagulation. In the absence of any injury, the forming fibrin lattice is continuously degraded by plasmin. Subsequently, D-dimer formed in the extra vascular space dissipates into the blood stream. Abbreviations: TF tissue factor, FII factor II, BK bradykinin