Cause-effect relation between hyperfibrinogenemia and vascular disease

Abstract

Elevated plasma levels of fibrinogen are associated with the presence of cardiovascular disease, but it is controversial whether elevated fibrinogen causally imparts an increased risk, and as such is a true modifier of cardiovascular disease, or is merely associated with disease. By investigating a transgenic mouse model of hyperfibrinogenemia, we show that elevated plasma fibrinogen concentration IntroductionNumerous epidemiological studies have documented the association of elevated plasma fibrinogen levels with cardiovascular disease. [1][2][3][4][5][6][7] Cross-sectional prospective studies imply that elevated plasma fibrinogen levels are an independent and predictive parameter for increased risk of coronary artery disease, stroke, and peripheral vascular disease. The magnitude of the increase in fibrinogen levels correlates with the presence and severity of peripheral arterial disease, the extent of myocardial necrosis in infarcted patients, and cerebrovascular accidents. The disease risk associated with hyperfibrinogenemia is disproportionally augmented in those individuals with the highest fibrinogen levels, indicating a threshold effect. Notwithstanding its recognized value as a marker for the presence of cardiovascular disease, it remains controversial whether an elevated fibrinogen level itself imparts an increased risk, and therefore represents a true modifier of vascular disease, or is merely associated with disease. Fibrinogen production in the liver is regulated by cytokines and is greatly enhanced in the acute phase response to infection and other inflammatory processes. [8][9][10][11] It is therefore possible that moderately elevated fibrinogen levels simply report a state of inflammation associated with vascular disease. On the other hand, augmented fibrinogen levels, per se, could alter the hemodynamic properties of blood or enhance concentration driven enzyme-substrate interactions between thrombin, fibrinogen, and platelets, and thus lead to increased intravascular fibrin deposition and thrombosis. These views are not mutually exclusive, as augmentation of fibrinogen levels secondary to an inflammatory challenge could nevertheless amplify or accelerate the disease process. Moreover, fibrinogen and fibrin degradation products might in turn enhance the inflammatory aspect of vascular lesions by regulating cytokine production and leukocyte-endothelial interactions. [12][13][14][15][16][17] Recently described genetically altered mice with chronically increased plasma fibrinogen levels in the absence of underlying inflammation provide a novel experimental tool to investigate the cause-effect relationship between hyperfibrinogenemia and vascular disease. 18 The mutant mouse strain (hereafter referred to as Hifib mice) was derived by pronuclear oocyte microinjection of the entire mouse fibrinogen locus, including all 3 fibrinogen chains as well as several kilobases of flanking sequence. The added transgenic fibrinogen allele is inherited in a Mendelian fashion, and the mice were reported to exhibit...

Bivalent Binding to γA/γ′-Fibrin Engages Both Exosites of Thrombin and Protects It from Inhibition by the Antithrombin-Heparin Complex

“…Taken together, these findings support the concept that fibrin-bound thrombin contributes to the thrombogenic potential of thrombi (27,37).…”

Vascular Functions of the Plasminogen Activation System

“…By stabilizing intravascular fibrin, which often forms in response to vascular injury and which can be invaded by VSMCs and other cell types to form a neointima, PAI-1 may promote intimal hyperplasia. 7 Consistent with this hypothesis, hyperfibrinogenemic mice exhibit enhanced neointima formation after carotid artery ligation compared with wild-type mice, 50 and depletion of plasma fibrinogen by administration of ancrod reduces intimal hyperplasia in mice after carotid artery ligation. 51 However, ␣ 2 -antiplasmin deficiency, which promotes fibrinolysis in vivo, 32 has no effect on neointima formation in mice, 52 suggesting that stabilization of fibrin by PAI-1 and/or ␣ 2 -antiplasmin does not play an essential role in murine vascular remodeling.…”

Additive Value of Immunoassay-Measured Fibrinogen and High-Sensitivity C-Reactive Protein Levels for Predicting Incident Cardiovascular Events

“…9,28 In addition to its role as an inflammatory biomarker, fibrinogen is the predominant coagulation factor in blood plasma and plays an important role in platelet aggregation, fibrin formation, and plasma visosity. 29,30 Our findings suggest that plasma fibrinogen levels may reflect both an inflammatory and a prothrombotic state because the risk associated with higher fibrinogen levels was only partially accounted for by higher hs-CRP levels. Attenuation of the risk associated with fibrinogen after adjustment for hs-CRP, and vice versa, may be explained by potential confounding, or possible mediation, of some of the effect of fibrinogen via inflammation.…”