The main and original finding of this longitudinal observation of elderly patients with chronic critical limb ischaemia is the association of elevated plasma fibrinogen with the relative risk of death. Mortality doubled for each standard deviation above the mean and increased in a graded manner with each tertile increase in fibrinogen, indicating that a specific threshold effect is lacking. The data strengthen fibrinogen's role as a predictor of mortality and are consistent with results obtained in stable claudicants [ 8, 10], geriatric patients [ 22], subjects with coronary artery disease [ 23] and even men [ 24, 25] and women [ 7] without obvious disease upon commencement of follow-up. Thus, our results confirm [ 16–18] the ominous implications for life expectancy of the appearance of resting pain and/or trophic lesions in previously uncomplicated peripheral arterial occlusive disease patients. However, protracted observation also showed lack of uniformity in the disease course of this group of critical limb ischaemia patients. In fact, an early period of exceedingly rapid accrual of mainly cardiovascular deaths was followed by a later phase in which demises occurred at a progressively slower rate and were less frequently due to cardiovascular causes. The reasons for such heterogeneous behaviour, unrecognized in previous follow-ups limited to 1 year or less [ 16–18], are unclear. In this regard, it is noteworthy that, of all the potential prognostic factors considered, elevated fibrinogen was the only parameter distinguishing the subset of patients with a more aggressive disease evolution. One might hypothesize that the existence of abnormal fibrinogen predated the development of critical limb ischaemia, perhaps as a consequence of a more advanced and progressive atherosclerotic process in these patients [ 6, 26]. However, this possibility is unlikely, firstly because fibrinogen levels were independent of ABI, a surrogate measure of systemic atherosclerosis [ 27] and haemodynamic severity of regional disease [ 21], and secondly, because the distribution of coronary, cerebrovascular and myocardial disease upon admission did not differ markedly between those who died during the following years and those who did not. Lack of differences linked to diabetes, age and sex is not surprising, as it concurs with findings in the general elderly population [ 28–30]. Interestingly enough, in the univariate analysis, fibrinogen showed a statistically significant positive association with serum creatinine, suggesting some link with worsening renal function. However, as no data are available for conditions less extreme than end-stage renal failure [ 31], we cannot speculate on this potentially interesting finding. Furthermore, other frequent correlates of fibrinogen, such as cholesterol, triglycerides, BP and smoking [ 28, 29], showed distributions independent of the outcome. Thus, the impact of those biological factors previously shown in both stable claudicants [ 4, 5] and healthy elderly populations [ 28–30] was probably overcome by stronger stimuli in our patients, particularly in the subgroup with the most progressive and unfavourable course of disease. Fibrinogen, an acute-phase protein [ 32], may respond to inflammatory stimuli triggered by the drastically reduced tissue oxygenation typical of chronic critical limb ischaemia [ 33], especially if complicated by sepsis and necrosis. Normalization of fibrinogen after successful vascular surgery of critically ischaemic limbs [ 34] implies that tissue ischaemia may indeed stimulate hepatic fibrinogen synthesis, possibly through interleukin-6 produced by activated monocytes [ 32]. The positive correlation with leucocyte levels is consistent with such a hypothesis, although the present evidence cannot be considered conclusive, as similar trends have been reported in elderly subjects unaffected by peripheral vascular disease [ 28, 29]. The influence of reactive components on fibrinogen is also consistent with the lower baseline haematocrit in those patients who died during the subsequent follow-up, as inflammatory processes depress haematopoiesis in a manner roughly proportional to the duration and severity of disease [ 35]. Similar inferences can be drawn from the tendency towards decreasing packed-cell volume with increasing fibrinogen values, an association opposite to that reported in uncomplicated subjects [ 36] and in contrast with conceptions of haematocrit as a prognostic predictor positively related to clinical events [ 36, 37]. However, even non-specific fibrinogen stimulation might still be a relevant chain in the link of events eventually leading to death, for example by compromising organ perfusion through increased blood viscosity [ 38] or by activating thrombosis [ 39]. On the other hand, the possibility that elevated fibrinogen levels may be a consequence, rather than a cause, of disease cannot be discounted. The nature of such an association will be clarified only by selective pharmacological lowering of fibrinogen.
In conclusion, plasma fibrinogen levels were found to be an independent predictor of early cardiovascular death in elderly peripheral arterial occlusive disease patients with critical limb ischaemia, in whom fibrinogen stimulation, perhaps related to inflammatory processes consequent to drastically impaired limb perfusion, may have contributed to the development of clinical events. However, further trials, possibly using specific fibrinogen inhibitors, are needed to confirm the precise mechanisms involved.