A mechanism for hereditary angioedema with normal C1 inhibitor: an inhibitory regulatory role for the factor XII heavy chain

Abstract

The plasma proteins factor XII (FXII) and prekallikrein (PK) undergo reciprocal activation to the proteases FXIIa and kallikrein by a process that is enhanced by surfaces (contact activation) and regulated by the serpin C1 inhibitor. Kallikrein cleaves high-molecular-weight kininogen (HK), releasing the vasoactive peptide bradykinin. Patients with hereditary angioedema (HAE) experience episodes of soft tissue swelling as a consequence of unregulated kallikrein activity or increased prekallikrein activation. Although most HAE cases are caused by reduced plasma C1-inhibitor activity, HAE has been linked to lysine/arginine substitutions for Thr309 in FXII (FXII-Lys/Arg309). Here, we show that FXII-Lys/Arg309 is susceptible to cleavage after residue 309 by coagulation proteases (thrombin and FXIa), resulting in generation of a truncated form of FXII (δFXII). The catalytic efficiency of δFXII activation by kallikrein is 15-fold greater than for full-length FXII. The enhanced rate of reciprocal activation of PK and δFXII in human plasma and in mice appears to overwhelm the normal inhibitory function of C1 inhibitor, leading to increased HK cleavage. In mice given human FXII-Lys/Arg309, induction of thrombin generation by infusion of tissue factor results in enhanced HK cleavage as a consequence of δFXII formation. The effects of δFXII in vitro and in vivo are reproduced when wild-type FXII is bound by an antibody to the FXII heavy chain (HC; 15H8). The results contribute to our understanding of the predisposition of patients carrying FXII-Lys/Arg309 to angioedema after trauma, and reveal a regulatory function for the FXII HC that normally limits PK activation in plasma.

Factor XII in PMM2-CDG patients: role of N-glycosylation in the secretion and function of the first element of the contact pathway.

“…importantly, no PMM2-CDG patient neither from our cohort nor from the literature has ever developed angioedema to our knowledge. These data support recent studies showing the key role of the N-terminal domain of FXII in the activation of this molecule [30]. However, we must remember that most PMM2-CDG patients have not been exposed to the triggering factors that cause angioedema in carriers of the p.Thr309Lys mutation (pregnancy, oral contraceptives…) [31], and on the other hand that marked edemas were already reported in CDG patients [32][33][34][35][36].…”

Impaired control of the contact system in hereditary angioedema with normal C1‐inhibitor

“…This facilitates conversion of FXII protein into its active form FXIIa, which can in turn generate active kallikrein and bradykinin leading to angioedema. Ivanov et al have recently demonstrated that factor XII with Lys/Arg substitutions for Thr309 can be cleaved by thrombin and factor XIa generating the truncated species δFXII, which in turn activates kallikrein. In ANGPT1‐HAE, the mechanism of angioedema implies that this mutation could impair the interaction of angiopoietin‐1 with its endothelial membrane receptor TIE2, leading to a vascular leakage and angioedema .…”

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

“…FXII molecules with the variant adopt an open or relaxed conformation which facilitates the access of PKa and plasmin to their FXII-activating moieties and also exposes cryptic proteolytic targets for thrombin which are normally concealed and not accessible in the compact conformation of FXII ( de Maat and Maas, 2016 ). Moreover, the cleavage of FXII Thr 328Lys by thrombin leads to enhanced activation of the contact system and bradykinin-mediated angioedema ( Ivanov et al, 2019 ).…”