Thrombosis from a Prothrombin Mutation Conveying Antithrombin Resistance
- 21 June 2012
- journal article
- case report
- Published by Massachusetts Medical Society in New England Journal of Medicine
- Vol. 366 (25), 2390-2396
- https://doi.org/10.1056/nejmoa1201994
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.This publication has 16 references indexed in Scilit:
- A novel ENG mutation causing impaired co-translational processing of endoglin associated with hereditary hemorrhagic telangiectasiaThrombosis Research, 2012
- Down-regulation of PROS1 Gene Expression by 17β-Estradiol via Estrogen Receptor α (ERα)-Sp1 Interaction Recruiting Receptor-interacting Protein 140 and the Corepressor-HDAC3 ComplexPublished by Elsevier BV ,2010
- Structure of the antithrombin–thrombin–heparin ternary complex reveals the antithrombotic mechanism of heparinNature Structural & Molecular Biology, 2004
- Molecular Dissection of Na+ Binding to ThrombinPublished by Elsevier BV ,2004
- Identification of protein Sα gene mutations including four novel mutations in eight unrelated patients with protein S deficiencyBritish Journal of Haematology, 2004
- A common mutation, Arg457→Gln, links prothrombin deficiencies in the Puerto Rican populationJournal of Thrombosis and Haemostasis, 2003
- Rational engineering of activity and specificity in a serine proteaseNature Biotechnology, 1997
- An allosteric switch controls the procoagulant and anticoagulant activities of thrombin.Proceedings of the National Academy of Sciences of the United States of America, 1995
- The refined 1.9‐Å X‐ray crystal structure of d‐Phe‐Pro‐Arg chloromethylketone‐inhibited human α‐thrombin: Structure analysis, overall structure, electrostatic properties, detailed active‐site geometry, and structure‐function relationshipsProtein Science, 1992
- [14] ThrombinMethods in Enzymology, 1976