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Misfolded proteins activate Factor XII in humans, leading to kallikrein formation without initiating coagulation
Coen Maas, … , Bonno N. Bouma, Martijn F.B.G. Gebbink
Coen Maas, … , Bonno N. Bouma, Martijn F.B.G. Gebbink
Published August 21, 2008
Citation Information: J Clin Invest. 2008;118(9):3208-3218. https://doi.org/10.1172/JCI35424.
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Research Article

Misfolded proteins activate Factor XII in humans, leading to kallikrein formation without initiating coagulation

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Abstract

When blood is exposed to negatively charged surface materials such as glass, an enzymatic cascade known as the contact system becomes activated. This cascade is initiated by autoactivation of Factor XII and leads to both coagulation (via Factor XI) and an inflammatory response (via the kallikrein-kinin system). However, while Factor XII is important for coagulation in vitro, it is not important for physiological hemostasis, so the physiological role of the contact system remains elusive. Using patient blood samples and isolated proteins, we identified a novel class of Factor XII activators. Factor XII was activated by misfolded protein aggregates that formed by denaturation or by surface adsorption, which specifically led to the activation of the kallikrein-kinin system without inducing coagulation. Consistent with this, we found that Factor XII, but not Factor XI, was activated and kallikrein was formed in blood from patients with systemic amyloidosis, a disease marked by the accumulation and deposition of misfolded plasma proteins. These results show that the kallikrein-kinin system can be activated by Factor XII, in a process separate from the coagulation cascade, and point to a protective role for Factor XII following activation by misfolded protein aggregates.

Authors

Coen Maas, José W.P. Govers-Riemslag, Barend Bouma, Bettina Schiks, Bouke P.C. Hazenberg, Henk M. Lokhorst, Per Hammarström, Hugo ten Cate, Philip G. de Groot, Bonno N. Bouma, Martijn F.B.G. Gebbink

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Figure 4

FXII-dependent activation of FXI, as measured by chromogenic assay in vitro, is not stimulated by misfolded protein aggregates.

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FXII-dependent activation of FXI, as measured by chromogenic assay in vi...
Conversion of the chromogenic substrate Pefachrome XIa3371 in the presence of 1 nM FXII, 10 nM FXI, and 30 nM HK was measured. As a control, either FXII or FXI was omitted from the experiments. Although 2.5 μg/ml DXS-500k induced activation of FXIa in an FXII-dependent manner, as expected, misfolded protein aggregates of BSA-AGE (A), Hb-AGE (B), or FP13 (C) could not induce significant activation of FXI above buffer background at any concentration tested. Concentrations of these proteins up to 500 μg/ml were tested and found inactive (data not shown). The values in the graphs represent the mean ± SEM of duplicate determinations performed within 1 representative experiment of at least 3.

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