Beyond Coagulation: Fibrinogen as a Cause of Cardiovascular Surgical Disease Mark S. Sumeray, 1 Hugh E. Montgomery, 1 and Stephen E. Humphries 2 1 Hatter Institute for Cardiovascular Studies and 2 Department of Cardiovascular Genetics, University College London School of Medicine, London, UK Summary. Fibrinogen is generally considered to be an im- portant mediator of clot formation. However, its effects on clots and perhaps other more direct effects may also make it a powerful mediator in the genesis and progression of atheromatous disease. Indeed, raised ~brinogen levels may pose as great a cardiovascular risk as classical risk factors such as elevated blood pressure or cholesterol levels. The plasma ~brinogen level of any given individual, and its associated cardiovascular risk, is dependent upon an inter- action between environmental and intrinsic (genetic) fac- tors. Most environmental factors associated with elevated ~brinogen levels are also potent cardiovascular risk factors (e.g., cigarette smoking). Less is known of the role played by genetic factors. However, as research into the genotypic in_uences on both basal and “stimulated” ~brinogen pro- duction continues, high-risk groups may be identi~ed that may bene~t from therapeutic intervention aimed at lower- ing plasma ~brinogen. Cardiovasc Drugs Ther 1998:12 Key Words. ~brinogen, risk factor, cardiovascular disease Fibrinogen and Cardiovascular Disease For many years ~brinogen has been considered to have a major role as a coagulation factor. The role played by thrombin in triggering the conversion of soluble ~bri- nogen molecules to insoluble ~brin, with the sub- sequent formation of a ~brin gel and clot, is well known. Fibrinogen is also an essential cofactor in platelet ag- gregation, and experimental and epidemiological stud- ies [1] have shown that the degree of platelet aggre- gability is determined, in part, by plasma ~brinogen levels. At low shear rates, ~brinogen bridges glycopro- tein IIb/IIIa receptors, causing aggregation by a direct ligand effect. Fibrinogen levels may thus correlate with blood coagulability, a concept supported by the ~ndings of the large ECAT Angina Pectoris Study [2]. This association of ~brinogen levels with blood coagu- lability may have important clinical consequences, and those prone to higher ~brinogen levels may be espe- cially prone to thromboembolic events. However, in addition to in_uencing the development of thromboembolic disease, ~brinogen may also medi- ate the development and progression of atheroma, and may play a role in the genesis of both acute and chronic coronary disease. Perhaps more intuitively, a sudden rise in coagulability and viscosity associated with a rise in ~brinogen concentration might predispose to acute coronary thrombosis and to the development of an un- stable coronary syndrome. However, elevated ~brino- gen level may in theory also contribute to the patho- genesis of coronary disease over years. Fibrinogen possesses all the features of a potent atherogenic factor. Once produced, both ~brinogen and its breakdown products can penetrate the vascular wall and is found in human aortic intima, where levels relate to those found in the plasma [3]. Indeed, ~brino- gen and ~brin degradation products (FDPs) are found at high concentrations within the edematous plaque intimal space. Either alone [3], or as components of mural microthrombi [3], they may promote athero- genesis [4] by increasing vascular permeability and collagen synthesis [5], and endothelial injury [3], and by promoting smooth muscle cell proliferation and mi- gration [3], as well as providing a scaffold for VSMC migration [6]. Fibrin and its products also bind throm- bin within the lesion, leading to recruitment of more ~brin in a positive feedback loop. Additionally, the ac- cumulation of lipid in intimal plaques may also be re- lated to the presence of ~brinogen. The high af~nity of lipoprotein a (Lp(a)) for ~brin has been demonstrated [7], and the ability of Lp(a) to displace plasminogen in vitro may explain its apparent atherogenicity. In addi- tion, because ~brinogen is a long molecule, high plasma levels cause a signi~cant increase in blood viscosity [8], and this may be clinically important, especially down- stream of a moderate or severe arterial stenosis. Address for correspondence: Dr. Hugh Montgomery, Hatter In- stitute for Cardiovascular Research, UCH, Grafton Way, London WC1E6DB, UK. Received 4 March 1997; receipt/review time 3 months; accepted 4 June 1997. 261 Cardiovascular Drugs and Therapy 1998;12:261–265 © Kluwer Academic Publishers. Boston. Printed in U.S.A.