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We compared hemostatic and fibrinolytic plasma markers in 41 patients having acute or subacute occlusion of lower limb arteries with 20 patients suffering stable peripheral arterial occlusive disease (PAOD). During occlusion, the amount of thrombin-antithrombin III (TAT) complex was five-fold higher compared with stable PAOD, being 16 micrograms/l [95% confidence interval (CI) 11-21 micrograms/l] vs 3 micrograms/l (95% CI 2-4 micrograms/l), p < 0.003. Similarly, D-dimer was over four-fold (p = 0.0001), while tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) antigens were about two-fold (p = 0.02 and p < 0.003, respectively) higher than in PAOD. Coagulation and fibrinolysis markers were increased most in patients with recent symptom onset, which mainly represented embolus rather than thrombosis. The marker levels assessing coagulation and fibrinolysis were related with myoglobin and CK, indicators of skeletal muscle damage. Finally, increased TAT, PAI-1 antigen, and myoglobin concentrations associated with poor outcome.

Objective: To assess the efficacy of arterial surgery in restoring ability to walk and working capacity., Design: Retrospective follow up study., Setting: Fourth Department of Surgery, Helsinki University Central Hospital., Subjects: 67 middle-aged patients (mean age 53 years) with chronic incapacitating ischaemia of the lower limb., Interventions: Arterial reconstruction., Main Outcome Measures: Clinical outcome, vascular laboratory assessments, mortality, morbidity, return to work, and retirement., Results: According to objective vascular laboratory criteria a primary positive effect was achieved in 63/67 (94%). Fourty-eight of the 65 surviving patients (74%) were free of symptoms on treadmill testing three months after the operation. Working capacity was restored in 41/50 of the patients not yet retired (82%). Three years postoperatively 77% of the surviving patients still fared objectively better than before operation. The 10-year survival rate was 67%. Fourteen of the 22 patients who died did so of cardiovascular diseases (64%). Advanced distal ischaemia (indicated by a preoperative ankle-brachial index of 0.5 or less) was associated with increased risk of death. Altogether 251 working years were achieved of the 435 that could have potentially been gained. The most common reason for retirement during follow up was progression of peripheral arterial disease in the lower limbs in 13/41 patients (32%). At the end of the study there were nine patients still working with potentially 73 working years left., Conclusion: These results indicate that arterial surgery can restore working capacity in middle aged patients with threatening or temporary invalidity. Long term outcome, especially mortality, is mostly affected by other signs of cardiovascular disease, whereas working capacity is dependent on a wider variety of factors.

Atherosclerosis is an inflammatory reaction to accumulated extracellular lipid in the arterial intima. Evidence from pathological studies indicate that there is constant deposition and lysis of fibrin within the atherosclerotic arterial wall. In patients with stable peripheral atherosclerosis, the functional severity of the disease is associated with circulating fibrinogen and degradation of cross-linked fibrin reflecting procoagulant activity in the blood-vessel wall interface, or in the wall itself. In atheromas the fibrinolytic activity is connected to macrophages, which can assemble in the plasminogen-plasmin system and generate plasmin-mediated pericellular proteolysis in tissues with inflammation. Plasmin capable of activating collagenase may therefore be a candidate for plaque rupture. The nature of the exposed vascular tissue, the inflammatory state, tissue-factor dependent thrombin generation and the degree of matrix degradation regulate platelet reactivity. Little is yet known about platelet adhesive functions in proteolyzed collagens that are the underlying substrate where platelets deposit during plaque rupture, the triggering event for thrombosis. Research in these areas is likely to improve the understanding of the thrombogenicity of atheromas when the tissue is suddenly exposed to blood.

Immunohistochemical studies of human atherosclerotic lesions have demonstrated the occurrence of fibrin deposition and its degradation in the arterial wall. We studied fibrinogen, the generation of thrombin, and the degradation of fibrin in 40 patients with stable peripheral arterial occlusive disease of varying severity, as assessed by the ankle/brachial pressure index and duplex ultrasonography and/or angiography. Circulating fibrinogen (functional and immunological), fibrinopeptide A, thrombin-antithrombin III complex, and D-dimer were measured. The severity of atherosclerosis was associated with both fibrinogen (both functional and immunological) and D-dimer (r = .57, P < .0002, and r = .57, P < .0001, respectively). Fibrinogen and D-dimer showed a significant positive correlation (r = .50, P < .001). Generation of thrombin was detected in 24 patients (60%) by fibrinopeptide A and levels of thrombin-antithrombin III complex. As a sign of coagulation activation and fibrinolysis, we found that thrombin-antithrombin III complex and the degradation of cross-linked fibrin were progressively associated with the extent of vascular disease. The plasmin-mediated fibrin breakdown contributed to increased levels of circulating fibrinogen, an established risk factor for thrombotic complications. The significant correlations between fibrinogen/D-dimer and the severity of atherosclerosis support previous pathological studies and imply that local degradation of cross-linked fibrin is involved in the progression of atherosclerosis.

Following endothelial injury, monocytes attach to the subendothelium and penetrate into the vessel wall, forming macrophage/foam cells by accumulating lipids. Macrophages release various products such as interleukins, complement factor fragments, tumour necrosis factors, oxidized cholesterol, and oxygen free radicals, leading to further endothelial injury and cytolysis. Platelets at the site of vascular injury, monocytes, endothelial cells, and smooth muscle cells release mitogenic factors which stimulate smooth muscle cell proliferation and migration. This smooth muscle cell proliferation, together with organization of thrombus and extracellular matrix synthesis, leads to the development of atheromatous plaques. Macrophages, by releasing proteases such as collagenase and elastase, form an abscess in the plaque which is covered by a thin fibrous cap. When this cap ruptures, a local thrombus is formed and depending upon the degree and duration of thrombus, and the degree of collateral development the fate of this thrombotic process is determined.

We report the effects of monitored smoking cessation on adrenergic regulation in chronic smokers. The beta 2 adrenoceptor density of mononuclear leukocytes (MNLs) and plasma catecholamines was analyzed before cessation and 2, 3, and 8 weeks after cessation. We found a progressive increase in beta-adrenoceptor density after smoking cessation. During smoking the beta-adrenoceptor density was 1.456 +/- 83 (mean +/- SEM) binding sites per cell (n = 10), whereas 3 weeks after cessation the density was 1,774 +/- 157 sites per cell (n = 10; p less than 0.05), and at 8 weeks, 1,900 +/- 227 sites per cell (n = 8; p less than 0.05), representing an overall increase of 23%. Smoking cessation had no effect on binding affinity nor on lymphocyte subgroup distribution. The density of MNL cell beta-adrenoceptors in age-matched nonsmoking men was higher, at 1,896 +/- 271 sites per cell, than that of the chronic smokers before cessation, 1,419 +/- 117 sites per cell (n = 14; p less than 0.01). Plasma epinephrine decreased as a result of cessation from 0.36 pmol/ml (0.26-0.44, 95% confidence interval; baseline) to 0.26 pmol/ml (0.20-0.32) at 8 weeks (p less than 0.05), and norepinephrine decreased from 2.09 pmol/ml (1.38-2.80) to 1.69 pmol/ml (1.14-2.24; p = 0.06). We conclude that stopping smoking progressively increases beta 2-adrenoceptor density on MNL cells. Eight weeks after cessation the adrenoceptor density reaches the corresponding level of nonsmokers. These reversible changes in adrenergic regulation after smoking cessation may be associated with the relatively rapid reduction in cardiovascular disease risk among ex-smokers.

A prospective controlled study of 144 patients with peripheral obstructive arterial disease was undertaken to evaluate the efficacy of acetylsalicylic acid (ASA) treatment (250 mg daily) on the outcome after lower limb arterial surgery which mainly involved endarterectomy. By random enrollment, 2 groups of 72 patients were formed after the surgery. Patients with ASA treatment for 3 months, starting from the seventh postoperative day, were compared with patients who were not treated with ASA. The patients in both groups had similar characteristics as to sex ratio, age, concomitant diseases, preoperative arm-ankle systolic blood pressure index, and type and primary success of the reconstruction. Forty-seven of the ASA-treated and 48 of the untreated patients reported to continue cigarette smoking. Postoperative ASA-treatment protected against local adverse events which occurred in 15 patients (21%) of the ASA-treated group compared with 31 patients (43%) of the untreated group (p less than 0.01). Among heavy smokers (greater than 15 cigarettes/day) the efficacy of antiplatelet treatment was not detectable. These results imply that, in patients with peripheral arterial disease, ASA prevents platelet interaction to endarterectomized and atherosclerotic lower limb arteries thereby affecting the subsequent risk of occlusion; however, heavy cigarette smoking, which is very common among patients with peripheral arterial disease, counteracts the local antithrombotic potency of ASA.

Cigarette smoking is a strong but avoidable risk factor for development of cardiovascular disease and its acute complications. Intermittent claudication is most strikingly associated with smoking. The link between smoking and occlusive peripheral arterial disease is dose-dependent and can be broken by cessation of smoking. The risk of chronic as well as acute limb ischemia is then decreased in conservatively treated patients and also in those with reconstructive arterial surgery. Heavy smoking seems to abolish the positive effect of adjuvant antiplatelet medication. Cessation of smoking is a cornerstone in the management of occlusive peripheral arterial disease at any stage.

Smoking is per se a major risk factor in cardio-vascular diseases. It causes atherosclerosis and blockage particularly in the aorta and the leg arteries. The components of tobacco smoke damage the endothelium, increase arterial contractility, and accelerate the formation of plaque therein. The mechanisms of the effect of smoking on the genesis of atherothrombotic diseases have been studied in inter alios identical twins where the one smokes and the other does not. Smoking activates the sympathetic nerves and affects their regulation. Tobacco smokers show signs of activated thrombocyte function and increased sensitivity to vasoconstriction, which provokes a counter-reaction in the arterial walls. The observations emphasize the importance of vaso-active agents for the development and complications of atherosclerosis.

The formation of an arterial thrombus is a dynamic process that depends upon the characteristics of blood flow, the triggering substrate, and the blood components. We have developed and characterized a sensitive and specific computer-assisted nuclear scintigraphic method to study the dynamics of platelet deposition on severely damaged vessels both in vitro and in vivo in nonstenotic and stenotic flow conditions. Heparinized pig blood with Indium-111-labeled platelets was perfused for 50 minutes. Method variability in both static and flowing conditions was evaluated by Indium-111-labeled transferrin and Indium-111-labeled platelets. Positive scintigrams were obtained mainly in the presence of severe high grade stenoses on a thrombogenic substrate. Since the method is highly sensitive, computer-assisted axial dependence analysis was performed on the scintigraphic images to locate the thrombotic accumulation with respect to the area of the stenosis and to monitor the dynamic changes in platelet accumulation over time. Both in vitro and in vivo the highest level of platelet deposition occurred at the apex of the 80% stenosis, where embolization could be usually detected after 30 minutes of perfusion. This study is the first to assess the dynamics of thrombus growth in nonparallel flow streamlines such as are encountered in stenotic vessels. This method provides a new experimental tool with which to study factors affecting thrombus formation and stability.

Three hundred and twelve patients with peripheral arterial disease were followed up for 8 3/4 years or more (maximum 11 3/4 years) to assess the natural history of the disease and factors determining its outcome. Of the 312 patients, 188 (69%) died during the follow-up, 68% of the deaths having cardiovascular causes. The 10-year relative cumulative survival rate was 0.61 for males and 0.48 for females. The role of smoking as a risk factor could not be analysed without bias. In addition to known risk factors diabetes mellitus, cerebrovascular disease and coronary heart disease, the degree of peripheral arterial disease itself also proved to be a risk factor among men. The expected life lost for men with intermittent claudication was 20%, but 44.3% for men with advanced lower limb ischaemia (p less than 0.01). This difference could not be explained by the well-known association of advanced ischaemia and diabetes mellitus. The present results therefore suggest that the state of advanced ischaemia indicates larger involvement of the whole of the arterial tree and predicts fatal cardiovascular events among these patients.

After reconstructive arterial surgery 190 patients with peripheral arterial disease of lower limbs (PAD) were followed up for three years in a prospective manner to assess the effects of smoking habits on the outcome. 173 patients (91%) were smokers at presentation. 48 patients reported to have given up smoking during the study. Exsmokers could not be included in the analysis, however, due to differences in the severity of PAD, age, sex ratio, type of operation and other risk factors. Current moderate (MS) (less than 15 cigarettes/day, N = 45) and heavy smokers (HS) (greater than or equal to 15, N = 80) were comparable groups. The three-year relative cumulative survival rates among male HS and MS were 0.40 and 0.65 (p less than 0.05), respectively. HS died mostly of cardiovascular causes. Major amputation was needed in 21% of HS compared to only 2% in MS (p less than 0.001). The present results show a strong association with heavy smoking, cardiovascular mortality and severe local adverse events. Thus, arterial thrombogenity appears to be enhanced by continued heavy smoking in patients with peripheral atherosclerosis.

A study with ten identical twin pairs discordant for cigarette smoking for over 20 years was undertaken to evaluate the effect of smoking on platelet alpha 2-adrenoceptor binding ([3H]-yohimbine) and prostacyclin (IloprostR) sensitivity. Since plasma catecholamines, adrenaline and noradrenaline were increased in smokers (3.95 +/- 0.7 vs 2.26 +/- 0.1 pmol/ml, p less than 0.05) at rest, the objective of an acute additional adrenergic discharge by physical exercise was to uncover possible tachyphylaxis. Aggregation of adrenaline-stimulated platelets was significantly reduced in smokers after exercise and the refractoriness appeared to be maintained for 15 and 30 min afterwards. However, the densities of binding sites for the radioligand were not markedly different between the study groups at rest or after exercise. The binding affinity decreased after exercise in both groups. Adrenaline-stimulated platelets responded to prostacyclin by inhibiting aggregation and activating cAMP production equally in smokers and nonsmokers implying a preserved sensitivity to prostacyclin. Although smoking introduces long-term sympathoadrenergic effects, it does not alter alpha 2-adrenoceptor binding in platelets. Thus, the present data support a theory that smoking mediates its effects by platelet to vessel wall interaction and vasoactivity, rather than directly changing the properties of adrenoceptor in platelet or the coupling to adenylate cyclase.

Plasma renin activity (PRA) and aldosterone concentration were measured before and during submaximal exercise in 10 male monozygotic twin pairs who were discordant for smoking. In nine twin pairs PRA was higher in the smoker both at rest and during exercise. The mean PRA was 99% higher at rest and 84% higher during exercise than in nonsmokers. Plasma aldosterone levels were higher at rest in seven smokers and during exercise in eight smokers compared with the respective nonsmokers. The mean aldosterone level at rest was 23% and during exercise 40% higher in the smokers than in the nonsmokers. Chronic smoking induces increased PRA, which results in increased aldosterone formation, presumably via enhanced generation of angiotensin II. This may partly explain the greater vasoconstrictive reactivity typical of the arteries of chronic smokers.

The effects of the lipid-lowering drug gemfibrozil on platelet reactivity at rest and during submaximal exercise were investigated in 10 patients with serum cholesterol levels greater than 270 mg/dl. No significant changes were observed in platelet reactivity at rest after gemfibrozil treatment. However, a marked decrease in platelet reactivity was seen in almost all patients treated with gemfibrozil during exercise. The adrenaline concentration necessary to induce secondary aggregation increased in eight patients during exercise after gemfibrozil and in two after placebo treatment. When adenosine diphosphatase (2 to 4 mumol/L) was used to induce aggregation, 5-hydroxytryptamine (serotonin) and thromboxane B2 secretion by platelets decreased by 35% and 67%, respectively, during exercise in patients treated with gemfibrozil. The area under the aggregation curve decreased by 28% during exercise after gemfibrozil. No significant changes occurred in these variables during exercise after placebo. Thus, gemfibrozil seems to have antiplatelet effects that might have importance in the prevention of acute complications of atherosclerosis in patients with hypercholesterolemia.

The mechanism by which atherosclerotic disease is induced by cigarette smoking has not yet been identified unequivocally. Chronic cigarette smoking and the generation of vasoactive prostanoids and the size of carotid atherosclerotic plaques were studied in nine pairs of identical male twins discordant for smoking for over 20 years. The urinary excretion of 2,3-dinor-thromboxane B2 (thromboxane B2 metabolite) of the smoking twin was significantly higher (on average 1.8 times higher) in every pair and that of 2,3-dinor-6-keto-prostaglandin F1 alpha (prostacyclin metabolite) was significantly higher (on average 1.3 times higher) in eight of the nine pairs. The ratio of excretion of these metabolites was significantly higher, being 4.0 (95% confidence interval 2.7 to 5.4) among the smokers compared with 2.9 (2.1 to 3.8) among the non-smokers, thus favouring a mechanism of vasoconstriction. Excretion of the thromboxane B2 metabolite was related to the urinary concentrations of nicotine metabolites. Atherosclerotic plaques detected by ultrasonography in the carotid arteries were significantly larger among smokers but did not correlate with the urinary excretion of prostacyclin and thromboxane B2 metabolites or intensity of smoking. Smoking was concluded to induce activation of platelets by an effect mediated by nicotine. The increased prostacyclin production, on the other hand, suggested a compensatory mechanism for the general vasoconstrictive properties of cigarette smoking.