Factor XI is a substrate for oxidoreductases: enhanced activation of reduced FXI and its role in antiphospholipid syndrome thrombosis.
Factor XI (FXI), a disulfide-linked covalent homodimer, circulates in plasma, and upon activation initiates the intrinsic/consolidation phase of coagulation. We present evidence that disulfide bonds in FXI are reduced to free thiols by oxidoreductases thioredoxin-1 (TRX-1) and protein disulfide isomerase (PDI). We identified that Cys362-Cys482 and Cys118-Cys147 disulfide bonds are reduced by TRX-1. The activation of TRX-1-treated FXI by thrombin, FXIIa or FXIa was significantly increased compared to non-reduced FXI, indicating that the reduced factor is more efficiently activated than the oxidized protein. Using a novel ELISA system, we compared the amount of reduced FXI in antiphospholipid syndrome (APS) thrombosis patients with levels in healthy controls, and found that APS patients have higher levels of reduced FXI. This may have implication for understanding the contribution of FXI to APS thrombosis, and the predisposition to thrombosis in patients with elevated plasma levels of reduced FXI.
Department of Immunology, Allergy and Infectious Diseases, St. George Hospital, University of New South Wales, Sydney, Australia. bill.giannakopoulos@unsw.edu.au
Bill
B
Giannakopoulos
Lu
L
Gao
Miao
M
Qi
Jason W
JW
Wong
Demin M
DM
Yu
Panayiotis G
PG
Vlachoyiannopoulos
Harry M
HM
Moutsopoulos
Tatsuya
T
Atsumi
Takao
T
Koike
Philip
P
Hogg
Jian C
JC
Qi
Steven A
SA
Krilis
D000328:Adult; D000368:Aged; D016736:Antiphospholipid Syndrome / Q000097:blood* / Q000150:complications / Q000201:enzymology; D001777:Blood Coagulation; D016022:Case-Control Studies; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005172:Factor XI / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D015956:Factor XIIa / Q000378:metabolism / Q000494:pharmacology; D015945:Factor XIa / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D019704:Protein Disulfide-Isomerases / Q000097:blood*; D013879:Thioredoxins / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood* / Q000150:complications / Q000201:enzymology
D004220:Disulfides; C491203:TXN protein, human; D013879:Thioredoxins; D005172:Factor XI; D015945:Factor XIa; D015956:Factor XIIa; D013917:Thrombin; D019704:Protein Disulfide-Isomerases; D003545:Cysteine