While it remains unproven whether any of these mechanisms are actually at play in situ, given all the available data it seems likely that higher fibrinogen may well not only reflect the low-grade inflammation caused by the atherothrombosis, but also participate in that process, allowing it to proceed at a faster rate. This “positive feedback” is illustrated in Figure 1.
Along with their work in clotting, Meade and colleagues were also the first to propose that deficiencies in fibrinolysis might also be associated with CVD and that levels of these factors might predict future CVD events. In this same vein, others have demonstrated that levels of the major plasma antifibrinolysis protein, plasminogen activator inhibitor-1 (PAI-1), are elevated in those with existing clinical CVD and did offer some risk prediction for future secondary CVD events.’ However, this finding, like those in the coagulation system, was not always confirmed in future studies. It has been suggested that the degree of predictive power may be a function of the adjustment done for other variables, since PAI-1 levels are associated with inflammation, plasma lipid levels, and, most strongly, with adiposity and insulin levels. These factors are all CVD risk factors in their own right, and it remains uncertain whether the concept of fibrinolytic capacity is valid and in fact a predisposing risk factor for arterial disease. Sobel invoked a possible role for PAI-1 in the arterial wall, where it may play more of a role than in blood. Plaques particularly prone to rupture and that precipitate relatively large thrombus formation are characterized by minimal cellularity, among other factors. Migration of cells into the plaque region is likely to require collagenase activity, which is in turn provided by plasmin-mediated activation of collagenase zymogens. PAI-1 in the wall may inhibit plasmin formation and contribute to a lack of cellularity and resultant instability. there
Figure 1. The complex interplay of atherothrombotic disease with inflammation and clotting. Inflammation and the proinflammatory cytokines, eg, IL-6, are increased by a variety of mechanisms in atherothrombosis. In addition, there is activation of the coagulation system, with subsequent activation of fibrinolysis, leading to a complex interplay. An example concerns the feedback control of fibrinogen levels. The use of fibrinogen in clotting, including the increased clotting of atherosclerotic progression, results in the production of FDPs. FDPs are bound by monocytes, which in turn increase production of IL-6. This IL-6 acts via the endocrine system to increase the hepatic synthesis of fibrinogen. As discussed in the text, increased plasma fibrinogen may feedback in a positive manner, increasing the likelihood of atheroprogression. In addition, other causes of inflammation feed into this system, such as chronic infections and diabetes. Also, the elaboration of proinflammatory cytokines is affected by an individual’s capacity for inflammatory response, such as the extent of visceral adiposity. A wide variety of genetic influences are easily conceived, and as we have recently observed, increased IL-6 itself may accelerate the atherothrombotic process, possibly acting as a potent cell growth regulator, an activator of monocytes and/or other cells, an amplifier of the innate immune response exacerbating uptake of lipid particles by macrophage, or by other potential mechanisms. The plasma proteins affected by IL-6, such as CRP, fibrinogen, and others, may also directly participate in the atherothrombotic process to make it worse. Adapted with permission. ICAM = intracellular adhesion molecule; HDL = high-density lipoprotein.