The fibrinogen γA/γ′ isoform does not promote acute arterial thrombosis in mice. (May 2014)

• Record Type: Journal Article
• Authors: Walton, B. L.; Getz, T. M.; Bergmeier, W.; Lin, F.‐C.; Uitte de Willige, S.; Wolberg, A. S.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 12:Number 5(2014:May)
• Page Start: 680
• Page End: 689
• Publication Date: 2014-05
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.12534
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth12534-abs-0001"> <title>Summary</title> <sec id="jth12534-sec-0001" sec-type="section"> <title>Background</title> <p>Elevated plasma fibrinogen is associated with arterial thrombosis in humans and promotes thrombosis in mice by increasing fibrin formation and thrombus fibrin content. Fibrinogen is composed of six polypeptide chains: (Aα, Bβ, and γ)<sub>2</sub>. Alternative splicing of the γ chain leads to a dominant form (γA/γA) and a minor species (γA/γ′). Epidemiological studies have detected elevated γA/γ′ fibrinogen in patients with arterial thrombosis, suggesting that this isoform promotes thrombosis. However, <italic>in vitro</italic> data show that γA/γ′ is anticoagulant due to its ability to sequester thrombin and suggest its expression is upregulated in response to inflammatory processes.</p> </sec> <sec id="jth12534-sec-0002" sec-type="section"> <title>Objective</title> <p>To determine whether γA/γ′ fibrinogen is prothrombotic <italic>in vivo</italic>.</p> </sec> <sec id="jth12534-sec-0003" sec-type="section"> <title>Methods</title> <p>We separated γA/γA and γA/γ′ fibrinogen from human plasma‐purified fibrinogen and determined the effects on <italic>in vitro</italic> plasma clot formation and on <italic>in vivo</italic> thrombus formation and circulating thrombin–antithrombin complexes in mice.</p> </sec> <sec id="jth12534-sec-0004" sec-type="section"> <title>Results and Conclusions</title> <p>Both γA/γA and γA/γ′ fibrinogen were cleaved by murine and human thrombin and were incorporated into murine and human clots. When γA/γA or γA/γ′ was spiked into plasma, γA/γA increased the fibrin formation rate to a greater extent than γA/γ′. In mice, compared to controls, γA/γA infusion shortened the time to carotid artery occlusion, whereas γA/γ′ infusion did not. Additionally, γA/γ′ infusion led to lower levels of plasma thrombin–antithrombin complexes following arterial injury, whereas γA/γA infusion did not. These data suggest that γA/γ′ binds thrombin <italic>in vivo</italic> and decreases prothrombotic activity. Together, these findings indicate that elevated levels of γA/γA fibrinogen promote arterial thrombosis <italic>in vivo</italic>, whereas γA/γ′ does not.</p> </sec> </abstract>