Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation.
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.
Maas
Coen
C
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
Govers-Riemslag
José W P
JW
Bouma
Barend
B
Schiks
Bettina
B
Hazenberg
Bouke P C
BP
Lokhorst
Henk M
HM
Hammarström
Per
P
ten Cate
Hugo
H
de Groot
Philip G
PG
Bouma
Bonno N
BN
Gebbink
Martijn F B G
MF
D000327:Adsorption; D001777:Blood Coagulation; D002942:Circular Dichroism; D005172:Factor XI / Q000378:metabolism; D005174:Factor XII / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007610:Kallikreins / Q000737:chemistry*; D007616:Kaolin / Q000737:chemistry; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013997:Time Factors
D007616:Kaolin; D005174:Factor XII; D005172:Factor XI; D007610:Kallikreins