Hypofibrinogenemia with preserved hemostasis and protection from thrombosis in mice with an Fga truncation mutation

Medientyp: E-Artikel

Titel: Hypofibrinogenemia with preserved hemostasis and protection from thrombosis in mice with an Fga truncation mutation

Beteiligte: Hur, Woosuk S.; Paul, David S.; Bouck, Emma G.; Negrón, Oscar A.; Mwiza, Jean-Marie; Poole, Lauren G.; Cline-Fedewa, Holly M.; Clark, Emily G.; Juang, Lih Jiin; Leung, Jerry; Kastrup, Christian J.; Ugarova, Tatiana P.; Wolberg, Alisa S.; Luyendyk, James P.; Bergmeier, Wolfgang; Flick, Matthew J.

Erschienen: American Society of Hematology, 2022

Sprache: Englisch

DOI: 10.1182/blood.2021012537

ISSN: 0006-4971; 1528-0020

Schlagwörter: Cell Biology ; Hematology ; Immunology ; Biochemistry

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Beschreibung: Abstract Genetic variants within the fibrinogen Aα chain encoding the αC-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 ∼10% 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 vitro and in vivo in models of tail bleeding and laser-induced saphenous vein injury, whereas Fga−/− mice had continuous bleeding. Platelets from FgaWT/WT and Fga270/270 mice displayed comparable initial aggregation following adenosine 5′-diphosphate stimulation, but Fga270/270 platelets quickly disaggregated. Despite ∼10% plasma fibrinogen, the fibrinogen level in Fga270/270 platelets was ∼30% 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−/− mice. Decreasing the normal fibrinogen levels to ∼10% 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 αC-region truncation mutations and highlight the concept that selective fibrinogen reduction may be efficacious for limiting thrombosis while preserving hemostatic and immune protective functions.

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