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Blood. 2018 Dec 27. pii: blood-2018-06-860270. doi: 10.1182/blood-2018-06-860270. [Epub ahead of print]

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

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Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, United States.
Department of Biomedical Engineering, School of Medicine, Oregon Health & Sciences University, Portland, OR, United States.
Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH, United States.
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States;


The plasma proteins factor XII (FXII) and prekallikrein 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. While most HAE cases are due to 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 factor XIa), 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 (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 heavy chain that normally limits PK activation in plasma.

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