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

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 Fga^270/270 mice were hypofibrinogenemic with ∼10% plasma fibrinogen levels relative to Fga^WT/WT mice, linked to 90% reduction in hepatic Fga messenger RNA (mRNA) because of nonsense-mediated decay of the mutant mRNA. Fga^270/270 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 Fga^WT/WT and Fga^270/270 mice displayed comparable initial aggregation following adenosine 5′-diphosphate stimulation, but Fga^270/270 platelets quickly disaggregated. Despite ∼10% plasma fibrinogen, the fibrinogen level in Fga^270/270 platelets was ∼30% of Fga^WT/WT platelets with a compensatory increase in fibronectin. Notably, Fga^270/270 mice showed complete protection from thrombosis in the inferior vena cava stasis model. In a model of Staphylococcus aureus peritonitis, Fga^270/270 mice supported local, fibrinogen-mediated bacterial clearance and host survival comparable to Fga^WT/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.