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Review
. 2021 Jun;60(3):348-356.
doi: 10.1007/s12016-021-08837-6. Epub 2021 May 6.

Blood Clotting and the Pathogenesis of Types I and II Hereditary Angioedema

Steven de Maat  1 , Kusumam Joseph  2 , Coen Maas  1 , Allen P Kaplan  3
Affiliations
Review

Blood Clotting and the Pathogenesis of Types I and II Hereditary Angioedema

Steven de Maat et al. Clin Rev Allergy Immunol. 2021 Jun.

Abstract

The plasma contact system is the initiator of the intrinsic pathway of coagulation and the main producer of the inflammatory peptide bradykinin. When plasma is exposed to a negatively charged surface the two enzymes factor XII (FXII) and plasma prekallikrein (PK) bind to the surface alongside the co-factor high molecular weight kininogen (HK), where PK is non-covalently bound to. Here, FXII and PK undergo a reciprocal activation feedback loop that leads to full contact system activity in a matter of seconds. Although naturally occurring negatively charged surfaces have shown to be involved in the role of the contact system in thrombosis, such surfaces are elusive in the pathogenesis of bradykinin-driven hereditary angioedema (HAE). In this review, we will explore the molecular mechanisms behind contact system activation, their assembly on the endothelial surface, and their role in the HAE pathophysiology.

Keywords: Angioedema; Bradykinin; Coagulation; Contact activation.

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Conflict of interest statement

CM has been a speaker for Shire/Takeda. SdM declares no conflict of interest. APK is a consultant/lecturer for CSL Behring, BioCryst, and Pharming.

Figures

Fig. 1
Fig. 1
The mechanism of bradykinin formation in types I and II HAE and sites of inhibition by C1-INH. The steps include autoactivation of FXII, conversion of prekallikrein (PK) to kallikrein (PKa), the PKa “feedback” for rapid activation of FXII, and cleavage of HK to liberate BK. Further cleavage of FXIIa by PKa yields FXIIf (βFXIIa) which loses its ability to activate FXII but gains the ability to activate C1r and to a lesser degree C1s, thereby further depleting C4 and cleaving (activating) C2 during attacks of swelling
Fig. 2
Fig. 2
Assembly of the contact system on the surface of endothelial cells. Abbreviations: FXII; factor XII, PK; plasma prekallikrein, HK; high molecular weight kininogen, uPAR; urokinase plasminogen activator receptor, CK1; cytokeratin 1, gC1qR; receptor for globular heads of C1q
Fig. 3
Fig. 3
Plasma kallikrein (PKa) as a clotting factor. Abbreviations: FXII factor XII, FXIIa activated FXII, PK plasma prekallikrein, PKa activated plasma kallikrein, HK high molecular-weight kininogen, FXI Factor XI, FXIa activated FXI, FIX Factor IX, FIXa activated FIX. RBC red blood cell, TAT-complex thrombin-antithrombin complex
See this image and copyright information in PMC

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