ArticleBlood2022
Hypofibrinogenemia with preserved hemostasis and protection from thrombosis in mice with an Fga truncation mutation.
Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 24 citations in OpenAlex.
- A scalable high-throughput platform for the discovery of intracellular and extracellular regulators of platelet migration.Blood advances · 2026Article
- The fibrinogen αC region promotes arterial thrombosis in the context of hypofibrinogenemia.Blood · 2026Article
- Depletion of Fibrinogen Suppresses Growth of Primary Tumors and Metastasis of Pancreatic Ductal Adenocarcinoma.Gastroenterology · 2026Article
- Preclinical safety and bleeding evaluation in swine for a small interfering RNA-lipid nanoparticle that prevents excess fibrinogen synthesis.Journal of thrombosis and haemostasis : JTH · 2026Article
- Recent Pathophysiological Insights Are Advancing the Treatment of Venous Thromboembolism.JACC. Basic to translational science · 2025Review
- Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD.Nature communications · 2024Article
- Regulation of fibrinogen synthesis.Thrombosis research · 2024Review
- RNA therapeutics to control fibrinolysis: review on applications in biology and medicine.Journal of thrombosis and haemostasis : JTH · 2024Review
- Article
- Protease-activated receptors and glycoprotein VI cooperatively drive the platelet component in thromboelastography.Journal of thrombosis and haemostasis : JTH · 2023Article
- Fbg αC 389-402 Enhances Factor XIII Cross-Linking in the Fibrinogen αC Region Via Electrostatic and Hydrophobic Interactions.Biochemistry · 2023Article
- Transglutaminase Activities of Blood Coagulant Factor XIII Are Dependent on the Activation Pathways and on the Substrates.Thrombosis and haemostasis · 2023Article
- Novel genetic regulators of fibrinogen synthesis identified by an in vitro experimental platform.Journal of thrombosis and haemostasis : JTH · 2023Article
- Elimination of fibrin polymer formation or crosslinking, but not fibrinogen deficiency, is protective against diet-induced obesity and associated pathologies.Journal of thrombosis and haemostasis : JTH · 2022Article
- Immunothrombosis and the Role of Platelets in Venous Thromboembolic Diseases.International journal of molecular sciences · 2022Review
- Fibrinogen and Factor XIII in Venous Thrombosis and Thrombus Stability.Arteriosclerosis, thrombosis, and vascular biology · 2022Review
- Hyperglycemia may increase deep vein thrombosis in trauma patients with lower limb fracture.Frontiers in cardiovascular medicine · 2022Article
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16 authors at 5 institutions in 3 countries.
Funding
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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