Thrombosis from a prothrombin mutation conveying antithrombin resistance

N Engl J Med. 2012 Jun 21;366(25):2390-6. doi: 10.1056/NEJMoa1201994.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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