Fibrinolytic action on fresh human clots of whole body extracts and two semipurified fractions from Lonomia achelous caterpillar

The severe bleeding diathesis produced by intoxication with the venom of Lonomia achelous caterpillars is characterized by prolonged bleeding from superficial skin wounds as well as massive hemorrhage into body cavities. The aim of the present study was to evaluate the effect of the crude venom and its fibrinolytic fractions on in vitro lysis of whole blood clots. Venom fractions with fibrinolytic activity were obtained by gel filtration chromatography on Sephadex G75 using imidazole buffer, pH 7.4, at a flow rate of 24 ml/h. Four peaks with fibrinolytic activity were obtained by this method. The highest activity was found in the first two peaks (both peaks were used for the experiments). The results show that the caterpillar venom degraded the preformed clots at a slower rate than plasmin. In addition, plasma protease inhibitors of the fibrinolytic system (alpha 2-antiplasmin, alpha 2-macroglobulin, PAI, etc.) only weakly inhibited the lytic effect of the caterpillar venom. These characteristics, as well as the pattern of fibrinogen degradation products, the delay period on fibrin plate lysis and amidolytic activity on chromogenic substrate, reported previously, indicate that the caterpillar enzymes are different from plasmin and trypsin.     

Increased fibrinogen levels and acquired hypofibrinolysis in young adults with ischemic stroke

BACKGROUND AND PURPOSE: Elevated fibrinogen levels and abnormalities in the fibrinolytic system are related to the occurrence of cardiovascular events. However, the role of these factors in the evolution of cerebrovascular disease has received less attention, in particular in young stroke patients. The aim of this study was to evaluate possible abnormalities in plasma fibrinogen levels and the state of the fibrinolytic system in young adults with a first-ever ischemic stroke. METHODS: This study is based on 102 consecutive patients aged 18 to 44 years admitted between January 1991 and May 1996 as a result of a first ischemic stroke. Forty-one healthy controls were recruited. Evaluations of anthropometric/metabolic variables, plasma fibrinogen levels, and the fibrinolytic system were undertaken >/=3 months (mean, 5.4+/-2.0 months) after admission. RESULTS: Patients had lower tissue plasminogen activator activity and increased plasminogen activator inhibitor type 1 activity at baseline, as well as increased tissue plasminogen activator mass concentration both at baseline and after a venous occlusion test. Overall, there were no significant differences between the main etiologic subgroups regarding plasma fibrinogen levels and fibrinolytic variables. Baseline fibrinolytic variables were strongly correlated with body mass index, serum triglycerides, and cholesterol levels. After adjustments in multivariate models, fibrinogen levels and tissue plasminogen activator mass concentration both at baseline and after venous occlusion test remained significantly increased in patients. Logistic multiple regression analyses indicated that plasma fibrinogen was a strong predictor of ischemic stroke (odds ratio, 11.25; 95% CI, 3.27 to 38. 69). CONCLUSIONS: Increased fibrinogen levels and tissue plasminogen activator mass concentration are independently associated with ischemic stroke in young adults. Metabolic perturbations are closely interrelated with aberrations in tissue plasminogen activator and plasminogen activator inhibitor type 1 activity in these patients, findings consistent with an acquired hypofibrinolysis.     

Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease: effects of beta-adrenoreceptor blockers and angiotensin-converting enzyme inhibitors

OBJECTIVES: To examine circadian changes in the sympathovagal balance, the activity of the renin-angiotensin system and hemostatic variables in patients with stable coronary artery disease, and the effects of beta-adrenoceptor blockade and angiotensin-converting enzyme inhibition. BACKGROUND: Sympathovagal balance and key components of the fibrinolytic system show circadian variability. The effects of beta-adrenergic blocking agents and angiotensin-converting enzyme inhibitors on these autonomic and hemostatic rhythms are not well defined. METHODS: Twenty patients with coronary artery disease underwent 24-h Holter monitoring for heart rate variability and blood sampling (6 hourly for 24 hours) after three consecutive treatment phases, (firstly with placebo, then bisoprolol, and finally quinapril). The effects on sympathovagal balance, hemostatic variables and the renin-angiotensin system activity were measured. RESULTS: The fibrinolytic capacity showed marked circadian variation at the end of the placebo phase (p = 0.002), plasminogen activator inhibitor-1 (PAI-1) activity peaking at 06.00 AM when tissue plasminogen activator (tPA) activity was at its nadir. Sympathovagal balance showed a sharp increase at approximately the same time but plasma renin activity did not rise until later in the day. Inspection of the 24-h profiles suggested that bisoprolol reduced sympathovagal balance and the morning peak of PAI-1 activity and antigen, with a small increase in tPA activity, although these changes were not significant. Quinapril produced a substantial rise in renin (p = 0.01) but did not significantly affect either PAI-1 or tPA. Sympathovagal balance was unaffected by quinapril. CONCLUSIONS: In patients with stable coronary artery disease, angiotensin-converting enzyme inhibition with quinapril does not affect either sympathovagal balance or the endogenous fibrinolytic system. Our data suggest that the sympathoadrenal system may modify fibrinolytic activity, judged by the response to beta-adrenoreceptor blockade with bisoprolol.     

Dimethyl sulfoxide-induced apoptosis in human leukemic U937 cells

The effects of two oral contraceptives, containing gestodene and either 20 micrograms or 30 micrograms ethinylestradiol, on hemostatic parameters was investigated in a six-month randomized study involving a total of 40 healthy women between the ages of 18 and 30 years. A large number of hemostatic parameters were measured, which were categorized as either pro-coagulatory, anti-coagulatory, profibrinolytic, anti-fibrinolytic or indicative of fibrin turnover. Additionally, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) were measured before and after venous occlusion and delta and ratio values calculated. Pro-coagulatory factors as well as reaction products reflecting in vivo coagulatory activity (thrombin-antithrombin III complex, prothrombin fragment 1 + 2) were found to increase. Among the anti-coagulatory parameters, only protein S concentration and protein S activity decreased, most notably in the 30 micrograms EE group. There was a corresponding increase in fibrinolytic activity reflected by reaction products of in vivo fibrinolysis (plasmin-antiplasmin 2-complex, fibrin-degradation products). Measurement of t-PA and PAI-1, before and after venous occlusion, revealed that the fibrinolytic response was more pronounced in the 20 micrograms EE group. There was also an increase in the threshold of fibrinolytic inhibition (ratio PAI-1) in both groups, which was less pronounced in the 20 micrograms EE group. Apart from isolated measurements, all parameters remained within their normal ranges and values returned to baseline in the follow-up cycle. It is concluded that both preparations had a balanced effect on the hemostatic system stimulating both pro-coagulant and fibrinolytic activity. No statistically significant differences were observed between the two groups; however, there was a trend towards greater fibrinolytic capacity in the 20 micrograms EE group.     

Effect of local exercise and vessel occlusion on fibrinolytic activity

Arterial occlusion of the upper limb did not affect the fibrinolytic activity in the venous blood of that limb; venous occlusion associated with venous distension resulted in a marked rise in activity. Local fibrinolytic activity was increased substantially by active exercise; passive exercise induced a smaller increase. Active exercise undertaken during arterial occlusion did not result in a rise in activator level. It is concluded from these results that blood flow into the venous system rather than accumulation of metabolites is responsible for the increased release of activator into the blood during local exercise and vessel occlusion.     

Release of luteinizing hormone-releasing hormone from enzymatically dispersed rat hypothalamic explants is pulsatile

Impaired whole blood fibrinolytic activity (FA), measured by the dilute clot lysis time (DCLT), is associated with first episodes of ischaemic heart disease (IHD) in the Northwick Park Heart Study in men, especially under 55 years, and in women. In a community-based study to investigate possible determinants of the DCLT, and therefore to assess which fibrinolytic components might be predictors of first IHD events, we measured fibrinolytic variables in a sub-sample of 150 healthy adults (73 males, 77 females) randomly selected from a single general practice. Most of the variance in DCLT (68% in men, 63% in women) was explained by tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) activities. In multiple regression analysis there was a significant difference in the strength of the association of t-PA activity with DCLT in men compared to women (test for interaction p = 0.05), the association of t-PA activity with DCLT being significant in males but not in females. Plasma PAI-1 activity was strongly associated with DCLT in both sexes. There was no independent association of DCLT with plasma fibrinogen, t-PA antigen, other fibrinolytic inhibitors, body mass index, serum lipids or C-reactive protein. Plasma PAI-1 activity in females and both t-PA and PAI-1 activities in males are the main determinants of whole blood FA measured by DCLT. It is therefore likely that these modulators of the plasma fibrinolytic system are associated with the onset of first clinical episodes of IHD. Elevated levels of t-PA antigen were positively associated with DCLT after adjustment for age and sex and therefore indicate impaired rather than enhanced FA. Further studies of the association of FA with risk of IHD should include not only "global" measures but also assessment of t-PA and PAI-1 activities, particularly as our results suggest that their associations with IHD may differ in men and women.     

The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis

BACKGROUND AND OBJECTIVES: Intermittent pneumatic compression (IPC) is an effective form of deep vein thrombosis prophylaxis for general surgery patients. The antithrombotic effect of IPC is thought to be the result of increased venous velocity and stimulation of endogenous fibrinolysis. However, the mechanism of enhanced fibrinolytic activity and the relative effects on normal and postthrombotic veins have not been defined. The purposes of this study are 1) to quantify changes in fibrinolytic activity with IPC; 2) to study the mechanism of fibrinolytic enhancement with IPC; and 3) to evaluate whether postthrombotic patients have the same capacity for fibrinolytic enhancement with IPC as do normal subjects. METHODS: Twelve volunteers (6 normal and 6 postthrombotic) had 5 IPC devices applied for 120 minutes in random fashion, 1 per week x 5 weeks. The devices included single-chamber, sequential, foot, calf, and long-leg compression. Subjects had an indwelling antecubital venous cannula placed for blood drawn at baseline, 60, 120, and 180 minutes after IPC devices were applied. Global fibrinolytic activity (euglobulin fraction, fibrin plate assay), tissue plasminogen activator (tPA) antigen (Ag) and activity (Act), plasminogen activator inhibitor-1 (PAI-1) Ag and Act, alpha-2-antiplasmin-plasmin complexes, and von Willebrand factor (vWF) antigen were assayed. RESULTS: A striking elevation in fibrinolytic activity was noted at 180 minutes with all devices in normal subjects and postthrombotic patients (p = 0.01-0.0001); however, baseline and stimulated fibrinolytic activity was attenuated in postthrombotic patients (<0.03). The tPA-Act increased only in normal subjects (3.8 +/- 1.9%) (p = 0.057), despite a decrease in plasma tPA-Ag, which was observed in both normal subjects (-12.4 +/- 3.8%) (p = 0.009) and patients (-17.2 +/- 3.1%) (p = 0.001). PAI-1-Ag decreased in both normal subjects (-13.4 +/- 3.8%) (p = 0.007) and patients (-12.0 +/- 3.1%) (p = 0.013) with a marked reduction in PAI-1-Act in both normal subjects (p = 0.003) and patients (p = 0.004). There were no changes in vWF, and alpha-2-antiplasmin-plasmin complexes increased only in postthrombotic patients (p = 0.021). CONCLUSIONS: Stimulation of endogenous fibrinolytic activity occurs after IPC, both in normal subjects and postthrombotic patients; however, baseline and overall fibrinolytic response in postthrombotic patients is reduced. The mechanism of increased fibrinolytic activity is likely because of a reduction in PAI-1, with a resulting increase of tPA activity.     

The behavior of the fibrinolytic system during long-term orthopedic immobilization]

Our previous experimental studies on rats motionless for 7 to 60 days in special devices limiting their movements revealed a significantly increased activity of the fibrinolytic system (Groza, Artino) due to the "detention stress" rather then to the immobilization. Starting from these studies we have tried to observe the behaviour of the fibrinolytic system during long-term orthopedic immobilization (7-28 days) on patients having different injuries of the lower limb and submitted to orthopedic therapy (with or without osteosynthesis) to which an anticoagulant preventive treatment was added (heparin or low-molecular-weight substitutes such as Clivarine, Fraxiparine). We studied on 23 patients (11 male and 12 female) motionless for 14, 21, 28 days the plasma fibrinolytic activity (PFA) through euglobulin lysis time (ELT). Clinical investigation revealed that PFA did not change significantly during long-term orthopedic immobilization regardless of the duration of immobilization (14,21,28 days). Rosenfeld et al. (1994) described in healthy volunteers on bedrest for 36 hours an increase of PFA beginning at 24 hours of immobilization, this variation being capable of preventing stasis effects. Our results suggest that preventive anticoagulant therapy properly given during immobilization prevents thromboembolic events.     

Uremic medium increases cytokine-induced PAI-1 secretion by cultured endothelial cells

The overall fibrinolytic activity is depressed in patients with chronic renal failure where a prothrombotic state is described, thereby enhancing the risk of vascular occlusive events. The mechanism responsible for fibrinolysis derangement has not yet been elucidated. To evaluate the effect of the uremic environment on the fibrinolytic activity of endothelial cells, we studied plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) production by human umbilical vein endothelial cells (HUVEC) in culture, exposed either to uremic or normal sera, before and after cytokine stimulation. Twenty uremics were studied: 11 were on conservative dietary treatment and nine were on maintenance hemodialysis. Eight healthy subjects served as controls. Before cytokine stimulation, no difference in the HUVEC supernatant concentration of t-PA and PAI-1 was found among the groups studied. After stimulation with interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, the HUVEC supernatant levels of PAI-1 in the uremics were higher than in the controls, whereas the supernatant levels of t-PA did not differ. Our data provide evidence that uremic serum, in concert with IL-1 or TNF-alpha, can enhance PAI-1 secretion by endothelial cells, thereby depressing the fibrinolytic system. This impaired endothelial fibrinolytic response to hypercoagulation could favor vascular events, which are the major cause of morbidity and mortality in patients with chronic uremia.     

Tissue markers as predictors of postoperative adhesions

BACKGROUND: Postoperative adhesion formation has been associated with a decreased capacity to degrade intra-abdominally deposited fibrin. Adhesions, once lysed, have a high propensity for reformation. This study tested the hypothesis that patients with a high propensity for adhesion formation as well as adhesion tissue had a reduced fibrinolytic capacity. METHODS: Peritoneal biopsies were taken during abdominal surgery from 21 patients who had previously undergone operation; previously formed adhesion tissue was sampled from ten of these patients. Adhesion formation was scored. The fibrinolytic capacity of peritoneum was determined in tissue extracts. RESULTS: At the time of opening of the abdominal cavity, levels of plasminogen activator inhibitor (PAI) type 1 (P = 0.009) and tissue-type plasminogen activator (tPA)/PAI complex (P = 0.008) were increased in peritoneal samples from patients with severe adhesions compared with those in samples from patients with less severe adhesions. Adhesion tissue similarly had reduced fibrinolytic capacity as judged by a decrease in tPA activity (P = 0.005) and an increase in PAI-1 level (P = 0.01), reflected in an increased level of tPA/PAI complex (P = 0.008) compared with unaffected peritoneum. CONCLUSION: These observations demonstrate reduced fibrinolytic capacity in peritoneal tissue in patients with a greater propensity for development of adhesions and likewise in adhesion tissue. This suggests that components of the fibrinolytic system may be used as markers of an increased risk of adhesion development.     

Optimization of the nutrient medium for Actinomyces spheroides--producer of proteolytic enzymes with fibrinolytic activity

Optimization of the medium for growing Actinomyces spheroides producing proteolytic exoenzymes with the fibrinolytic activity was performed by the method of mathematical planning. The composition of the medium is as follows (%): glucose 7.1, sodium citrate, trisubstituted, 0.48; (NH4)2SO4, 0.15; MgSO4, 0.575; KH2PO4, 0.2; ZnSO4, 0.001; FeSO4, 0.002. The fibrinolytic activity of the cultural broth on this medium is three times as high as on the initial medium (7142 units). Changes in the ratio between components of the medium lead to changes in the ratio between the fibrinolytic and caseinolytic activities. Therefore, Act. spheroides, strain 1, produces exoenzymes which differ by their substrate specificity. The ratio between the fibrinolytic and caseinolytic activities of the complex on the optimized medium is twice as high as on the initial medium.     

Three cases of tuberculosis after heart transplantation in Spain

The fibrinolytic capacity of patients with acute myocardial infarction (AMI) is known to be impaired. The primary regulatory element of the fibrinolytic system is plasminogen activator inhibitor (PAI). It has been previously observed that there are 2 peaks in the plasma PAI level of AMI patients at 4h and 16h after thrombolytic therapy with recombinant tissue plasminogen activator (rtPA). Lanoteplase/SUN9216 is a mutant tPA with a biological half-life longer than that of rtPA. Thrombolytic therapy with mutant tPA or rtPA was carried out consecutively in 21 patients with AMI (8 patients as the mutant tPA group, and 13 patients as the rtPA group). The recanalization time of the mutant tPA group was significantly faster than that of the rtPA group (16.1 +/- 3.9 min vs 39.6 +/- 4.8 min, p<0.01). The PAI activity at 4h after the initiation of thrombolysis was significantly lower in the mutant tPA group than in the rtPA group (8.74 +/- 5.46IU/L vs 26.74 +/- 3.35 IU/L, p<0.01). There was a one mild peak in serial plasma PAI activity levels 24h after the initiation of thrombolysis. The results suggest that thrombolytic therapy with mutant tPA reduced the impairment of fibrinolytic capacity. The mutant tPA gives faster recanalization and lower PAI activity after successful thrombolysis, compared with rtPA.     

Effects on platelet aggregation and fibrinolytic activity during upright posture and exercise in healthy men

The circadian variation of acute myocardial infarction suggests that daily activities such as assuming the upright posture and performing different daily activities may trigger the onset of coronary thrombosis. Such triggering may result from unfavorable alterations in the balance between the prothrombotic and antithrombotic properties of the blood. The present study compares the effects of 2 common daily activities, assuming the upright posture and exercise, on platelet aggregation and fibrinolytic activity. In healthy male subjects, assuming the upright posture in the morning significantly increased platelet aggregation and produced only a moderate increase in fibrinolytic activity within 10 minutes. These changes were still present after 90 minutes in the upright posture. Supine posture for 45 minutes resulted in levels of fibrinolytic activity and platelet aggregation comparable to that observed before initially assuming the upright posture in the morning. Return to the supine posture for 45 minutes resulted in levels of fibrinolytic activity and platelet aggregation comparable to that observed before the initial assumption of upright posture. The changes recurred when upright posture was taken later in the day. Exercise did not increase platelet aggregation to levels beyond that produced by the upright posture, but was associated with a marked increase in fibrinolytic activity. Thus, exercise and upright posture produce distinctive alterations in the thrombogenic potential of the blood that may influence the timing of clinical vascular events.     

Fluctuation formula for elastic constants

To clarify the physiological role played by neutrophil lysosomal protease in cultured human umbilical vein endothelial cells (HUVEC), we studied the effects of cathepsins B and D released from activated polymorphonuclear leukocytes on the fibrinolytic system in HUVEC. Cathepsins B and D reduced the antigens of tissue-type plasminogen activator, and they increased both the antigens and the activity of plasminogen activator inhibitor-1. These results suggest that cathepsins B and D are involved in the thrombotic tendency, since they inhibited the fibrinolytic system in cultured HUVEC.     

Interaction of N-methyl-anthraniloyl-labelled porcine apolipoprotein A-I with porcine lecithin: cholesterol acyltransferase: an energy transfer study

In an 8-month strictly controlled dietary study of 16 healthy young men, the long-term effect of a low-fat (26% of energy) high-fiber (4.5 g/MJ) diet on cardiovascular risk markers of the hemostatic system was assessed. Fasting blood sampling was performed during a 4-week baseline period and then monthly during the intervention. A matched control group of 16 men on habitual diets was also monitored. Median fibrinolytic activity of tissue-type plasminogen activator (t-PA) in plasma was significantly elevated (twofold to fourfold) by the experimental diet. A significant increase in the systemic fibrinolytic activity of the euglobulin fraction of plasma was also observed. Median plasma factor VII coagulant activity (F VIIc) was depressed by 5-10% during the first 2 months and the last month of the study period. The dietary change did not significantly affect plasma levels of fibrinogen, t-PA antigen, or plasminogen activator inhibitor type I antigen. In conclusion, young men who were switched from a typical Danish diet high in saturated fat to a low-fat/high-fiber diet showed a permanent increase in plasma fibrinolytic activity and a biphasic decrease in F VIIc. The dietary change thus had a favorable effect on cardiovascular risk markers of the hemostatic system.     

Stroke prevention screening program

The authors observed 49 patients aged 65-83 years with benign prostatic hyperplasia (BPH) before and after adenomectomy. It was found that prognosis of hemorrhagic complications of adenomectomy in early and late postoperative period demands a comprehensive assessment of coagulation and anticoagulation systems (fibrinolytic activity, first of all), ultrasound investigation (size of BPH), blood count and urinalysis (absence of residual inflammation of the urinary tract). Postoperative severe hemorrhage was observed in patients with changes in several parameters. It also was related to size of BPH and preoperative fibrinolytic activity. Early postoperative hemorrhages were more frequent than late (34.6% against 10%, respectively). 17 patients had micro- or macrohematuria, 2 patients developed massive blood loss. All the hemorrhagic patients had preoperative hemostasis disorders manifesting primarily as enhanced fibrinolytic activity and reduced fibrinogen concentrations.     

Serial changes of plasma plasminogen activator inhibitor activity in acute myocardial infarction: difference between thrombolytic therapy and direct coronary angioplasty

The fibrinolytic system is impaired in patients with acute myocardial infarction (AMI). The primary regulatory element of fibrinolytic activity is plasminogen activator inhibitor (PAI). There are no reports, however, on the serial changes of PAI activity after thrombolysis or coronary angioplasty in patients with AMI undergoing emergency coronary angiography. This study was designed to examine the difference in the change of fibrinolytic activity between patients with AMI who underwent thrombolytic therapy with recombinant tissue-plasminogen activator (rTPA) and those who underwent direct percutaneous coronary angioplasty (PTCA). We measured the serial changes of PAI activity and tissue plasminogen activator (TPA) antigen after rTPA therapy or direct PTCA. Twenty-two patients received emergency coronary angiography and were treated with rTPA intravenously. Twenty patients underwent direct PTCA. Plasma PAI activity levels were increased on admission and further increased within 24 hours in patients treated with rTPA and in those treated with direct PTCA. In the thrombolysis group, there were two peaks in plasma PAI activity levels (IU/ml) at 4 hours (27.0 +/- 2.9) and at 16 hours (25.6 +/- 2.5) after the initiation of rTPA infusion. However, in the direct PTCA group, there was one peak of PAI activity (IU/ml) at 16 hours (23.9 +/- 2.7) after the initiation of direct PTCA. In conclusion, the PAI activity has two peaks in the thrombolysis group and one peak in the direct PTCA group.     

Decreased fibrinolytic activity in porcine-to-primate cardiac xenotransplantation

BACKGROUND: One major barrier to successful xenotransplantation is acute vascular rejection, a process pathologically characterized by microvascular thrombosis and diffuse fibrin deposition in transplant blood vessels. This pathologic picture may result from a disturbance in the coagulant or fibrinolytic pathways that regulate normal vascular patency. This study evaluated the regulation of fibrinolytic activity defined by tissue plasminogen activator and plasminogen activator inhibitor-1 as it may exist in the setting of acute vascular rejection. MATERIALS AND METHODS, RESULTS: Serial biopsies from cardiac xenotransplants evaluated by immunofluorescence microscopy demonstrated progressive decreases in tissue plasminogen activator and increases in plasminogen activator inhibitor-1. In vitro studies measuring fibrinolytic activity of cell culture medium from porcine aortic endothelial cells stimulated with human serum or autologous porcine serum revealed that human serum triggered as much as 93% increase in antifibrinolytic activity. CONCLUSIONS: These findings demonstrate that porcine vascular endothelial cells change toward an antifibrinolytic state following stimulation with human xenoreactive antibodies and complement. The shift is at least partly explained by an increased ratio of plasminogen activator inhibitor-1 to tissue plasminogen activator, and is at least in part mediated by the activation of complement. This increased antifibrinolytic activity may contribute to the thrombotic diathesis seen in acute vascular rejection in pig-to-primate xenografts.     

Eighteen-level analysis of vertebral rotation following Harrington-Luque instrumentation in idiopathic scoliosis

Accelerated atherosclerosis is the leading cause of death in patients with non-insulin-dependent diabetes mellitus (NIDDM). Impaired endogenous fibrinolytic activity may accelerate atherosclerosis by exposing vascular luminal wall surfaces to persistent and recurrent thrombi and clot-associated mitogens. This study was conducted to further characterize endogenous fibrinolysis in lean and obese nondiabetic subjects and in NIDDM patients and to identify mechanisms responsible for the alterations identified. Obese and diabetic subjects had threefold elevations of plasma concentrations of plasminogen activator inhibitor type 1 (PAI-1) compared with values in lean control subjects. Despite the lack of significant differences in plasma concentrations of tissue-type plasminogen activator in the obese and diabetic subjects, both basal and stimulated endogenous fibrinolytic activities were decreased. The decreases were associated with increased activity of PAI-1 in plasma, in turn correlated with increased concentrations of immunoreactive insulin and C-peptide. These results are consistent with our previous observations demonstrating direct stimulatory effects of insulin and its precursors on cellular expression of PAI-1 in vitro and observations by others demonstrating decreased basal fibrinolytic activity in NIDDM patients. Impaired endogenous fibrinolytic activity could lead to prolonged or recurrent exposure of luminal surfaces of vessel walls to microthrombi and clot-associated mitogens that may accelerate atherosclerosis in hyperinsulinemic subjects.     

Insulin resistance syndrome and fibrinolytic activity: the northern Sweden MONICA study

BACKGROUND: Many studies have, in small and highly selected study populations, described how cardiovascular risk factors tend to cluster in subjects with insulin resistance. Recently, interest has focused on possible relationships between this insulin resistance syndrome and fibrinolysis, and the role of triglycerides in this association. The present study addresses these issues in a general population. METHODS: A subsample of participants in the population-based Northern Sweden MONICA (MONItoring of trends and determinants in CArdiovascular diseases) Study, consisting of 353 men and 403 women in the 25-64 year age range, was investigated. Insulin resistance was estimated indirectly from the fasting levels of insulin and glucose. Fibrinolytic activity was measured both as plasminogen activator inhibitor type 1 (PAI-1) activity and tissue plasminogen activator ((t)PA) activity. RESULTS: Insulin resistance was highly correlated with those cardiovascular risk factors that have been associated with the insulin resistance syndrome, and to the measures of fibrinolytic activity. Subjects in the upper tertile of insulin resistance had a PAI-1 activity that was three times higher than that of the lower third men and twice as high in women. There was a strong interaction between insulin resistance and serum triglycerides. Low versus high levels of both variables together were associated with a fivefold difference in PAI-1 activity in men and a threefold difference in women. The (t)PA activity was inversely correlated to both insulin resistance and serum triglycerides. CONCLUSIONS: In a general population, the 'insulin resistance syndrome' is closely associated with low fibrinolytic activity. Serum triglyceride levels interact with insulin resistance to predict fibrinolytic activity.