The fibrinogen [gamma]A/[gamma]' isoform does not promote acute arterial thrombosis in mice

• Published in: Journal of thrombosis and haemostasis Vol. 12; no. 5; p. 680
• Main Authors: Walton, B L, Getz, T M, Bergmeier, W, Lin, F-C, Uitte de Willige, S, Wolberg, A S
• Format: Journal Article
• Language: English
• Published: Oxford Wiley Subscription Services, Inc 01.05.2014
• Subjects: Blood clots; Plasma; Thrombosis
• ISSN: 1538-7933; 1538-7836
• DOI: 10.1111/jth.12534

Summary Background 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: (A[alpha], B[beta], and [gamma])2. Alternative splicing of the [gamma] chain leads to a dominant form ([gamma]A/[gamma]A) and a minor species ([gamma]A/[gamma]'). Epidemiological studies have detected elevated [gamma]A/[gamma]' fibrinogen in patients with arterial thrombosis, suggesting that this isoform promotes thrombosis. However, in vitro data show that [gamma]A/[gamma]' is anticoagulant due to its ability to sequester thrombin and suggest its expression is upregulated in response to inflammatory processes. Objective To determine whether [gamma]A/[gamma]' fibrinogen is prothrombotic in vivo. Methods We separated [gamma]A/[gamma]A and [gamma]A/[gamma]' fibrinogen from human plasma-purified fibrinogen and determined the effects on in vitro plasma clot formation and on in vivo thrombus formation and circulating thrombin-antithrombin complexes in mice. Results and Conclusions Both [gamma]A/[gamma]A and [gamma]A/[gamma]' fibrinogen were cleaved by murine and human thrombin and were incorporated into murine and human clots. When [gamma]A/[gamma]A or [gamma]A/[gamma]' was spiked into plasma, [gamma]A/[gamma]A increased the fibrin formation rate to a greater extent than [gamma]A/[gamma]'. In mice, compared to controls, [gamma]A/[gamma]A infusion shortened the time to carotid artery occlusion, whereas [gamma]A/[gamma]' infusion did not. Additionally, [gamma]A/[gamma]' infusion led to lower levels of plasma thrombin-antithrombin complexes following arterial injury, whereas [gamma]A/[gamma]A infusion did not. These data suggest that [gamma]A/[gamma]' binds thrombin in vivo and decreases prothrombotic activity. Together, these findings indicate that elevated levels of [gamma]A/[gamma]A fibrinogen promote arterial thrombosis in vivo, whereas [gamma]A/[gamma]' does not. [PUBLICATION ABSTRACT]