Thrombosis from a prothrombin mutation conveying antithrombin resistance.
We identified a novel mechanism of hereditary thrombosis associated with antithrombin resistance, with a substitution of arginine for leucine at position 596 (p.Arg596Leu) in the gene encoding prothrombin (called prothrombin Yukuhashi). The mutant prothrombin had moderately lower activity than wild-type prothrombin in clotting assays, but the formation of thrombin-antithrombin complex was substantially impaired. A thrombin-generation assay revealed that the peak activity of the mutant prothrombin was fairly low, but its inactivation was extremely slow in reconstituted plasma. The Leu596 substitution caused a gain-of-function mutation in the prothrombin gene, resulting in resistance to antithrombin and susceptibility to thrombosis.
Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yuhri
Y
Miyawaki
Atsuo
A
Suzuki
Junko
J
Fujita
Asuka
A
Maki
Eriko
E
Okuyama
Moe
M
Murata
Akira
A
Takagi
Takashi
T
Murate
Shinji
S
Kunishima
Michio
M
Sakai
Kohji
K
Okamoto
Tadashi
T
Matsushita
Tomoki
T
Naoe
Hidehiko
H
Saito
Tetsuhito
T
Kojima
D000293:Adolescent; D000990:Antithrombin III / Q000378:metabolism; D058833:Antithrombin Proteins / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010447:Peptide Hydrolases / Q000378:metabolism; D017354:Point Mutation; D011516:Prothrombin / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013927:Thrombosis / Q000235:genetics; D020246:Venous Thrombosis / Q000235:genetics* / Q000378:metabolism
D058833:Antithrombin Proteins; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D011516:Prothrombin; D010447:Peptide Hydrolases