| First Author | Hur WS | Year | 2022 |
| Journal | Blood | Volume | 139 |
| Issue | 9 | Pages | 1374-1388 |
| PubMed ID | 34905618 | Mgi Jnum | J:330337 |
| Mgi Id | MGI:7262836 | Doi | 10.1182/blood.2021012537 |
| Citation | Hur WS, et al. (2022) Hypofibrinogenemia with preserved hemostasis and protection from thrombosis in mice with an Fga truncation mutation. Blood 139(9):1374-1388 |
| abstractText | Genetic variants within the fibrinogen Aalpha chain encoding the alphaC-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 approximately 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 approximately 10% plasma fibrinogen, the fibrinogen level in Fga270/270 platelets was approximately 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 approximately 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 alphaC-region truncation mutations and highlight the concept that selective fibrinogen reduction may be efficacious for limiting thrombosis while preserving hemostatic and immune protective functions. |
