Thrombosis from a prothrombin mutation conveying antithrombin resistance.

Abstract

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.

• Authors: Yuhri Miyawaki, Atsuo Suzuki, Junko Fujita, Asuka Maki, Eriko Okuyama, Moe Murata, Akira Takagi, Takashi Murate, Shinji Kunishima, Michio Sakai, Kohji Okamoto, Tadashi Matsushita, Tomoki Naoe, Hidehiko Saito, Tetsuhito Kojima
• Journal: The New England journal of medicine (N Engl J Med) Vol. 366 Issue 25 Pg. 2390-6 (Jun 21 2012) ISSN: 1533-4406 [Electronic] United States
• PMID: 22716977 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antithrombin Proteins
• antithrombin III-protease complex
• Antithrombin III
• Prothrombin
• Peptide Hydrolases

Topics

• Adolescent
• Antithrombin III (metabolism)
• Antithrombin Proteins (metabolism)
• Female
• Genotype
• Humans
• Male
• Peptide Hydrolases (metabolism)
• Point Mutation
• Prothrombin (genetics, metabolism)
• Sequence Analysis, DNA
• Thrombosis (genetics)
• Venous Thrombosis (genetics, metabolism)