Shortened FXII Clotting Protein May Play Key Role in HAE with Normal C1-inhibitor, Study Suggests

An abnormally short form of the clotting protein factor XII (FXII), caused by specific mutations in its gene, may lead to swelling episodes in hereditary angioedema (HAE) patients with normal C1-inhibitor activity, according to a study.

The study, “A Mechanism for Hereditary Angioedema with Normal C1-Inhibitor: An Inhibitory Regulatory Role for the Factor XII Heavy Chain,” appeared in the journal Blood.

The plasma proteins FXII and prekallikrein undergo reciprocal activation into the enzymes FXIIa and kallikrein. This process, called the contact activation pathway, is regulated by the complement C1-inhibitor (C1-INH), involved in the immune system.

Kallikrein mediates the release of bradykinin, implicated in inflammation as well as in blood vessel widening and permeability. Elevated kallikrein activity contributes to episodes of soft tissue swelling in HAE patients.

Although most HAE cases are caused by reduced plasma C1-INH activity, mutations in a specific spot (309) of FXII amino acid chain have been associated with this disease in patients with normal C1-INH activity.

Prior research showed that these alterations — which consist of replacing the amino acid threonine with lysine (Lys) or arginine (Arg) — create a new cleavage site in FXII that ultimately increases kallikrein and bradykinin generation.

Using a combination of experiments in lab-grown cells and mice, researchers in this study found that FXII with the Lys/Arg replacements is cleaved after amino acid 309 by enzymes generated during blood clotting. This resulted in a shortened protein, lacking the heavy chain portion of FXII — which is not associated with any enzymatic activity.

Kallikrein’s efficiency in activating this shorter FXII was 15 times greater than with the full-length FXII, which, in turn, accelerated kallikrein production. In human plasma and in mice, the accelerated activation of kallikrein and of the shorter FXII appeared to overwhelm the opposing function of C1-inhibitor, increasing the amount of bradykinin.

Then, in mice given human FXII with Lys/Arg at 309, the investigators found enhanced bradykinin release, secondary to the formation of shortened FXII and thrombin production. The effects were reproduced in mice with normal FXII, when an antibody targeting the missing region in the mutated FXII version was used.

“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 heavy chain,” the scientists wrote.