title: Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice.
abstract: Epidemiologic studies have correlated elevated plasma fibrinogen (hyperfibrinogenemia) with risk of cardiovascular disease and arterial and venous thrombosis. However, it is unknown whether hyperfibrinogenemia is merely a biomarker of the proinflammatory disease state or is a causative mechanism in the etiology. We raised plasma fibrinogen levels in mice via intravenous infusion and induced thrombosis by ferric chloride application to the carotid artery (high shear) or saphenous vein (lower shear); hyperfibrinogenemia significantly shortened the time to occlusion in both models. Using immunohistochemistry, turbidity, confocal microscopy, and elastometry of clots produced in cell and tissue factor-initiated models of thrombosis, we show that hyperfibrinogenemia increased thrombus fibrin content, promoted faster fibrin formation, and increased fibrin network density, strength, and stability. Hyperfibrinogenemia also increased thrombus resistance to tenecteplase-induced thrombolysis in vivo. These data indicate that hyperfibrinogenemia directly promotes thrombosis and thrombolysis resistance and does so via enhanced fibrin formation and stability. These findings strongly suggest a causative role for hyperfibrinogenemia in acute thrombosis and have significant implications for thrombolytic therapy. Plasma fibrinogen levels may be used to identify patients at risk for thrombosis and inform thrombolytic administration for treating acute thrombosis/thromboembolism.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Kellie R
authors.initials: KR
authors.lastname: Machlus
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Cardenas
authors.forename: Frank C
authors.initials: FC
authors.lastname: Church
authors.forename: Alisa S
authors.initials: AS
authors.lastname: Wolberg
mesh_terms: D000818:Animals; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D002712:Chlorides / Q000633:toxicity; D004195:Disease Models, Animal; D004351:Drug Resistance; D005290:Ferric Compounds / Q000633:toxicity; D005340:Fibrinogen / Q000008:administration & dosage / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation; D012307:Risk Factors; D012501:Saphenous Vein / Q000187:drug effects / Q000293:injuries; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000097:blood* / Q000188:drug therapy* / Q000209:etiology
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D005340:Fibrinogen; C024555:ferric chloride