Primed to Understand Fibrinogen in Cardiovascular Disease.

Abstract

Fibrinogen is a 340-kDa glycoprotein that circulates in healthy humans at 2 to 4 mg/mL; however, fibrinogen is an acute phase protein synthesized in the liver, and its circulating levels can exceed 7 mg/mL during acute inflammation. Elevated fibrinogen levels are associated with increased risk of incident cardiovascular disease (CVD).1,2 Healthy mice infused with unfractionated human fibrinogen and subjected to FeCl3-mediated carotid artery injury have a shortened time to vessel occlusion and increased resistance of thrombi to acute thrombolysis, suggesting that elevated fibrinogen independently contributes to thrombosis.3,4 See accompanying article on page 2700 of the December 2015 issue Fibrinogen is composed of two sets of three polypeptide chains: Aα, Bβ, and γ. Alternative splicing of the γA chain leads to synthesis of a γ′ chain containing a unique 20-amino acid sequence at the C terminus. Between 8% and 15% of circulating fibrinogen in healthy individuals contains a γ′ chain (γA/γ′). Cross-sectional and retrospective studies have associated elevated circulating levels of the γA/γ′ isoform with increased incidence of coronary artery disease,5 myocardial infarction,6 and ischemic stroke.7–9 The observation that some patients have an increased γ′-to-total fibrinogen ratio7–11 suggests that γA/γ′ fibrinogen is not simply a biomarker for increased total fibrinogen. Together with data from in vitro …