{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T11:35:56Z","timestamp":1740137756801,"version":"3.37.3"},"reference-count":56,"publisher":"Georg Thieme Verlag KG","issue":"05","funder":[{"name":"OMRF"},{"name":"National Heart, Lung, and Blood Institute of the National Institutes of Health","award":["HL101917"],"award-info":[{"award-number":["HL101917"]}]},{"name":"National Heart, Lung, and Blood Institute of the National Institutes of Health","award":["HL062565"],"award-info":[{"award-number":["HL062565"]}]},{"name":"The General Program of National Natural Science Foundation of China","award":["81870107"],"award-info":[{"award-number":["81870107"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A patient with hematuria in our clinic was diagnosed with urolithiasis. Analysis of the patient's plasma clotting time indicated that both activated partial thromboplastin time (52.6\u2009seconds) and prothrombin time (19.4\u2009seconds) are prolonged and prothrombin activity is reduced to 12.4% of normal, though the patient exhibited no abnormal bleeding phenotype and a prothrombin antigen level of 87.9%. Genetic analysis revealed the patient is homozygous for prothrombin Y510N mutation. We expressed and characterized the prothrombin-Y510N variant in appropriate coagulation assays and found that the specificity constant for activation of the mutant zymogen by factor Xa is impaired approximately fivefold. Thrombin generation assay using patient's plasma and prothrombin-deficient plasma supplemented with either wild-type or prothrombin-Y510N revealed that both peak height and time to peak for the prothrombin mutant are decreased; however, the endogenous thrombin generation potential is increased. Further analysis indicated that the thrombin mutant exhibits resistance to antithrombin and is inhibited by the serpin with approximately 12-fold slower rate constant. Protein C activation by thrombin-Y510N was also decreased by approximately 10-fold; however, thrombomodulin overcame the catalytic defect. The Na+-concentration-dependence of the amidolytic activities revealed that the dissociation constant for the interaction of Na+ with the mutant has been elevated approximately 20-fold. These results suggest that Y510 (Y184a in chymotrypsin numbering) belongs to network of residues involved in binding Na+. A normal protein C activation by thrombin-Y510N suggests that thrombomodulin modulates the conformation of the Na+-binding loop of thrombin. The clotting defect of thrombin-Y510N appears to be compensated by its markedly lower reactivity with antithrombin, explaining patient's normal hemostatic phenotype.<\/jats:p>","DOI":"10.1055\/a-1549-6407","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T23:04:25Z","timestamp":1626217465000},"page":"679-691","source":"Crossref","is-referenced-by-count":1,"title":["Antithrombin Resistance Rescues Clotting Defect of Homozygous Prothrombin-Y510N Dysprothrombinemia"],"prefix":"10.1055","volume":"122","author":[{"given":"Yeling","family":"Lu","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States"},{"name":"Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno O.","family":"Villoutreix","sequence":"additional","affiliation":[{"name":"INSERM 1141, NeuroDiderot, Universit\u00e9 de Paris, H\u00f4pital Robert-Debr\u00e9, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2479-0249","authenticated-orcid":false,"given":"Indranil","family":"Biswas","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiulan","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuefeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alireza R.","family":"Rezaie","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States"},{"name":"Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2021,9,5]]},"reference":[{"issue":"09","key":"ref1","doi-asserted-by":"crossref","first-page":"5153","DOI":"10.1073\/pnas.77.9.5153","article-title":"Cloning and analysis of a cDNA coding for bovine prothrombin","volume":"77","author":"R T MacGillivray","year":"1980","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"07","key":"ref2","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1016\/S0021-9258(18)61503-0","article-title":"Activation of human prothrombin by human prothrombinase. 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