The studies described herein demonstrate that γ′ fibrinogen and total fibrinogen are independent risk factors for cardiovascular disease. Further described herein is the unexpected finding that an elevated concentration of γ′ fibrinogen in combination with an elevated concentration of total fibrinogen is a significantly better predictor of cardiovascular disease risk than either marker alone. Thus, provided herein are methods of detecting a subject having cardiovascular disease, or at increased risk of developing a cardiovascular disease, by measuring both the concentration of γ′ fibrinogen and the concentration of total fibrinogen in a sample obtained from the subject.