{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:08:08Z","timestamp":1789776488828,"version":"4.0.1"},"reference-count":45,"publisher":"American Society of Hematology","issue":"9","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Genetic variants within the fibrinogen A\u03b1 chain encoding the \u03b1C-region commonly result in hypodysfibrinogenemia in patients. However, the (patho)physiological consequences and underlying mechanisms of such mutations remain undefined. Here, we generated Fga270 mice carrying a premature termination codon within the Fga gene at residue 271. The Fga270 mutation was compatible with Mendelian inheritance for offspring of heterozygous crosses. Adult Fga270\/270 mice were hypofibrinogenemic with \u223c10% plasma fibrinogen levels relative to FgaWT\/WT mice, linked to 90% reduction in hepatic Fga messenger RNA (mRNA) because of nonsense-mediated decay of the mutant mRNA. Fga270\/270 mice had preserved hemostatic potential in\u00a0vitro and in\u00a0vivo in models of tail bleeding and laser-induced saphenous vein injury, whereas Fga\u2212\/\u2212 mice had continuous bleeding. Platelets from FgaWT\/WT and Fga270\/270 mice displayed comparable initial aggregation following adenosine 5\u2032-diphosphate stimulation, but Fga270\/270 platelets quickly disaggregated. Despite \u223c10% plasma fibrinogen, the fibrinogen level in Fga270\/270 platelets was \u223c30% of FgaWT\/WT platelets with a compensatory increase in fibronectin. Notably, Fga270\/270 mice showed complete protection from thrombosis in the inferior vena cava stasis model. In a model of Staphylococcus aureus peritonitis, Fga270\/270 mice supported local, fibrinogen-mediated bacterial clearance and host survival comparable to FgaWT\/WT, unlike Fga\u2212\/\u2212 mice. Decreasing the normal fibrinogen levels to \u223c10% with small interfering RNA in mice also provided significant protection from venous thrombosis without compromising hemostatic potential and antimicrobial function. These findings both reveal novel molecular mechanisms underpinning fibrinogen \u03b1C-region truncation mutations and highlight the concept that selective fibrinogen reduction may be efficacious for limiting thrombosis while preserving hemostatic and immune protective functions.<\/jats:p>","DOI":"10.1182\/blood.2021012537","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T19:56:27Z","timestamp":1639511787000},"page":"1374-1388","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":29,"title":["Hypofibrinogenemia with preserved hemostasis and\u00a0protection from thrombosis in mice with an <i>Fga<\/i>\u00a0truncation mutation"],"prefix":"10.1182","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5074-6423","authenticated-orcid":false,"given":"Woosuk S.","family":"Hur","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine,"},{"name":"Lineberger Comprehensive Cancer Center,"},{"name":"UNC Blood Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Paul","sequence":"additional","affiliation":[{"name":"UNC Blood Research Center, and"},{"name":"Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1481-3059","authenticated-orcid":false,"given":"Emma G.","family":"Bouck","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine,"},{"name":"UNC Blood Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar A.","family":"Negr\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine,"},{"name":"Lineberger Comprehensive Cancer Center,"},{"name":"UNC Blood Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3103-3318","authenticated-orcid":false,"given":"Jean-Marie","family":"Mwiza","sequence":"additional","affiliation":[{"name":"UNC Blood Research Center, and"},{"name":"Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren G.","family":"Poole","sequence":"additional","affiliation":[{"name":"Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly M.","family":"Cline-Fedewa","sequence":"additional","affiliation":[{"name":"Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily G.","family":"Clark","sequence":"additional","affiliation":[{"name":"UNC Blood Research Center, and"},{"name":"Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lih Jiin","family":"Juang","sequence":"additional","affiliation":[{"name":"Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Leung","sequence":"additional","affiliation":[{"name":"Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian J.","family":"Kastrup","sequence":"additional","affiliation":[{"name":"Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada;"},{"name":"Blood Research institute, Versiti, Milwaukee, WI; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana P.","family":"Ugarova","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Arizona State University, Tempe, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2845-2303","authenticated-orcid":false,"given":"Alisa S.","family":"Wolberg","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine,"},{"name":"UNC Blood Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Luyendyk","sequence":"additional","affiliation":[{"name":"Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1211-8861","authenticated-orcid":false,"given":"Wolfgang","family":"Bergmeier","sequence":"additional","affiliation":[{"name":"UNC Blood Research Center, and"},{"name":"Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5034-3162","authenticated-orcid":false,"given":"Matthew J.","family":"Flick","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine,"},{"name":"Lineberger Comprehensive Cancer Center,"},{"name":"UNC Blood Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"2","key":"2022030316214806400_B1","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/rth2.12183","article-title":"Fibrinogen \u03b1C domain: its importance 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response in\u00a0vivo","volume":"113","author":"Flick","year":"2004","journal-title":"J Clin Invest."},{"issue":"2","key":"2022030316214806400_B22","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1097\/MBC.0b013e32833678d5","article-title":"Identification and functional characterization of a novel nonsense mutation in FGA accounting for congenital afibrinogenemia in six Egyptian patients","volume":"21","author":"Abdel Wahab","year":"2010","journal-title":"Blood Coagul Fibrinolysis."},{"issue":"6","key":"2022030316214806400_B23","first-page":"1483","article-title":"A frameshift mutation in the human fibrinogen Aalpha-chain gene (Aalpha(499)Ala frameshift stop) leading to dysfibrinogen San Giovanni Rotondo","volume":"86","author":"Margaglione","year":"2001","journal-title":"Thromb Haemost."},{"issue":"3","key":"2022030316214806400_B24","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s004390100469","article-title":"Molecular analysis of the fibrinogen gene cluster in 16 patients with congenital afibrinogenemia: novel truncating mutations in the FGA and FGG genes","volume":"108","author":"Neerman-Arbez","year":"2001","journal-title":"Hum Genet."},{"issue":"1","key":"2022030316214806400_B25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1046\/j.1365-2141.1996.4681007.x","article-title":"Fibrinogen Lincoln: a new truncated alpha chain variant with delayed clotting","volume":"93","author":"Ridgway","year":"1996","journal-title":"Br J Haematol."},{"issue":"1","key":"2022030316214806400_B26","first-page":"88","article-title":"Dysfibrinogenemia (fibrinogen Wilmington) due to a novel Aalpha chain truncation causing decreased plasma expression and impaired fibrin polymerisation","volume":"96","author":"Brennan","year":"2006","journal-title":"Thromb Haemost."},{"issue":"4","key":"2022030316214806400_B27","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.thromres.2013.08.010","article-title":"Nonsense-mediated mRNA decay 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polymerization, albeit more subtle than anticipated from the analogous proteolytic fragment X","volume":"37","author":"Gorkun","year":"1998","journal-title":"Biochemistry."},{"key":"2022030316214806400_B36","doi-asserted-by":"crossref","first-page":"e68761","DOI":"10.7554\/eLife.68761","article-title":"Fibrinogen \u03b1C-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis","volume":"10","author":"McPherson","year":"2021","journal-title":"eLife."},{"issue":"7","key":"2022030316214806400_B37","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1111\/jth.14148","article-title":"Abrogating fibrinolysis does not improve bleeding or rFVIIa\/rFVIII treatment in a non-mucosal venous injury model in haemophilic rodents","volume":"16","author":"Stagaard","year":"2018","journal-title":"J Thromb Haemost."},{"issue":"22","key":"2022030316214806400_B38","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1182\/bloodadvances.2018024851","article-title":"Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice","volume":"2","author":"Stagaard","year":"2018","journal-title":"Blood Adv."},{"issue":"18","key":"2022030316214806400_B39","doi-asserted-by":"crossref","first-page":"4953","DOI":"10.1182\/blood-2010-11-316885","article-title":"Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice","volume":"117","author":"Machlus","year":"2011","journal-title":"Blood."},{"issue":"32","key":"2022030316214806400_B40","doi-asserted-by":"crossref","first-page":"19288","DOI":"10.1074\/jbc.271.32.19288","article-title":"Identification of the alpha chain lysine donor sites involved in factor XIIIa fibrin cross-linking","volume":"271","author":"Sobel","year":"1996","journal-title":"J Biol 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