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

作者：Woosuk S. Hur, David S. Paul, Emma G. Bouck, Oscar Negrón, Jean-Marie Mwiza, Lauren G. Poole, Holly Cline-Fedewa, Emily G. Clark, Lih Jiin Juang, Jerry Leung, Christian J. Kastrup, Tatiana P. Ugarova, Alisa S. Wolberg, James P. Luyendyk, Wolfgang Bergmeier, Matthew J. Flick · 发表于：Blood · 年份：2021 · DOI：10.1182/blood.2021012537 · 被引用次数：27 · 研究领域：Blood properties and coagulation、Platelet Disorders and Treatments、Blood Coagulation and Thrombosis Mechanisms

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 fib...