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Fibrin(ogen): friend and foe
A
B
Figure 1. Possible mechanisms linking fibrinogen with cardiovascular diseases. (A) Potential contributions of high levels of plasma fibrinogen to cardiovascular dis- eases. (B) Effects of structural variations in fibrinogen. This figure was prepared using BioRender.com. MMP-2: matrix metalloprotease 2.
fibrin(ogen) can interact with red blood cells, mediating erythrocyte sedimentation and blood viscosity, while also permitting red blood cells to attach to thrombi. Besides contributing to thrombus size, structure, and stability, red blood cells can alter fibrin network organization, suppress plasmin generation and reduce clot permeability, possibly delaying fibrinolysis and prolonging clot resolution, which may contribute to CVD.48 Fibrinogen is also a selective matrix metalloproteinase 2 (MMP-2) inhibitor. High plas- ma fibrinogen levels could lead to MMP-2 insufficiency in humans. As this enzyme is vital for healthy organ devel- opment and repair, excessive MMP-2 inhibition could result in arthritic and cardiac disorders similar to those seen in patients with MMP-2 gene deficiency.56
There is, therefore, a potential clinical interest in fibrino- gen-lowering drugs for the prevention and/or treatment of CVD. However, some studies have not found a link between high plasma fibrinogen levels and disease. While several single nucleotide polymorphisms have been asso- ciated with elevated fibrinogen, the analysis of 24 inde- pendent genome-wide significant single nucleotide poly- morphisms in 28 European ancestry cohorts, including 91,323 individuals, did not support a causal relationship between plasma fibrinogen and CVD events.57 A more recent Mendelian randomization study using genetic vari- ants to uncover evidence for a causal relationship between fibrinogen as a modifiable risk factor, and CVD events as an outcome, came to similar conclusions.58 After account- ing for horizontal pleiotropy, the effect of fibrinogen on CVD is likely to be small and so resolving any causal effect
will require further analysis using larger sample sizes. Structural variability in fibrinogen can be linked to CVD. Increased plasma fibrinogen γ’ concentration is associated with the risk of myocardial infarction and other thrombotic states.59 Epidemiological data suggest decreased levels of γ’ may be associated with venous thrombosis, due to the capacity of γ’ to counteract a com- mon risk factor for venous thrombosis i.e. plasma activat- ed protein C resistance.60 However, increased levels of fib- rinogen γ’ are associated with arterial thrombosis. This has been attributed to the capacity of the γ’ chain to mod- ulate the fibrin clot architecture toward a more thrombot- ic fibrin network.61 Whether γ’ is causal in this disease or a consequence of increased inflammation is not clear, and further studies are necessary to evaluate the hemostatic properties of fibrinogen γ’ depending on the disease type. Nevertheless, haplotype data are concordant: a haplotype which shows decreased fibrinogen γ’ levels was associat- ed with an increased risk of venous but not arterial thrombosis in different studies.62,63 By contrast, a haplo- type linked to increased γ’ was associated with arterial thrombosis, although contradictory results have been
reported.64,65
Fibrinogen variants found in congenital dysfibrinogene-
mia can contribute to CVD in different ways (Figure 1B). These include elevated levels of free thrombin resulting from impaired binding to fibrinogen, or altered strength, structure and stability of the fibrin clot, prompting embolization or compromised fibrinolysis.38 In particular, patients carrying dysfibrinogenemic mutations which sig-
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