Euglobulin Fibrinolytic Activity Research Articles

Diurnal changes of fibrinolysis in patients with liver cirrhosis and esophageal varices.

Variceal bleeding, whose triggering mechanisms are largely unknown, occurs with a circadian rhythmicity, with 2 peaks, one greater, in the evening, and one smaller, in the early morning. We assessed some clotting and hemodynamic parameters, possibly involved in variceal hemorrhage, over a 24-hour period, at 4-hour intervals, in 16 patients with cirrhosis and esophageal varices and in 9 controls. At each time interval, tissue plasminogen activator (tPA) and tPA inhibitor-1 (PAI-1) antigens and activities and total euglobulin fibrinolytic activity were determined and portal-vein flow velocity, volume, and congestion index were measured by duplex-Doppler. Significant circadian rhythms were searched for by least-squares and cosinor methods. tPA activity showed a circadian rhythm in cirrhosis, with a peak of 2.85 times the trough value, calculated at 18:42, and remained over 2.5-fold until shortly after 22:00. Total fibrinolytic activity showed a similar pattern, which was statistically significant also in controls. tPA and PAI antigens also showed significant circadian rhythm both in controls and cirrhotics, with higher values in the morning. Among the portal hemodynamic parameters only the congestion index showed significant rhythmic changes and only in cirrhosis, with the highest values in the late evening, but with limited diurnal excursion (+/- 5.5%). In conclusion, we showed the existence of a circadian rhythm of fibrinolysis in cirrhosis, whose temporal distribution might suggest a role of fibrinolysis in variceal hemorrhage on the basis of the comparison to the known chronorisk of variceal bleeding.

Fibrinolytic activity in laparoscopic cholecystectomy.

The aim of this study was to examine the fibrinolytic activity in laparoscopic cholecystectomy (LC) to determine whether changes occur that might indicate a greater risk of thrombosis. The study was carried out in 20 patients who had undergone laparoscopic surgery for cholelithiasis without complications. The average age was 59.4 years (34-77 years). Seventy-five percent were women. The mean operating time was 70 minutes (35-120 minutes). Pneumoperitoneum at 14 mm Hg was maintained in all patients, and they were in 30 degrees reverse Trendelenburg position. Postoperative mobilization was obtained before 24 hours, and patients were discharged 48 hours after surgery. The control group was composed of 12 patients, evenly distributed by age, sex, and length of surgery, who had undergone Bassini herniorrhaphy without complications or relapses. The following hemostatic parameters were studied: plasma fibrinolytic activity (PFA), euglobulin fibrinolytic activity (EFA), tissue-type plasminogen activator (t-PA), fast-acting plasminogen activator inhibitor-1 (PAI-1), and D-dimer (D-D). Samples were obtained at the following times: (1) under basal conditions the day before surgery, (2) preoperatively, (3) at the end of surgery, (4) 24 hours after surgery, and (5) on the seventh day following surgery. No patient had clinical manifestations of thromboembolic disease immediately after surgery or during an average follow-up period of 16 months (range 15-18 months). Analysis of the results of global fibrinolysis showed that fibrinolytic activity was enhanced only in the postoperative period (third sample) of the LC patients. The fraction of euglobulins enhances fibrinolytic activity in both groups in the third sample with regard to the other determinations; the LC patients showed a higher degree of significance (p<0.005). A significant increase of postoperative t-PA in both groups was found, being more significant in the LC group (p<0.005). In the PAI-1 values, no significant differences existed between either determinations or groups. A significant increase in D-dimer (p<0.05) occurred in the immediate postoperative period (third sample) and 24 hours later (fourth sample), returning to normal basal values on the seventh day. No significant differences were found between the two groups. These results seem to indicate that LC produces an increase in the fibrinolytic activity in plasma as a result of the liberation of tissue plasminogen activator from the venous endothelium, which could indicate hypocoagulability during the immediate postoperative period and, therefore, signify less thrombotic risk for patients undergoing this procedure.

Hemostasis in normotensive and hypertensive men: results of the PROCAM study. The prospective cardiovascular Münster study.

The greater than normal cardiovascular risk of hypertensive patients could be partly due to an impairment of hemostatic balance found in such individuals. To examine the relationship between hemostatic variables and blood pressures in 1950 apparently healthy male participants in the prospective cardiovascular Münster study aged 40-65 years. Blood pressure and other variables were determined, including fibrinogen level, coagulation factor VII clotting activity, protein C level, antithrombin III level, plasminogen activator inhibitor-1 level, euglobulin fibrinolytic activity, and von Willebrand factor level. Age-adjusted mean values of coagulation factor VII clotting activity, plasminogen activator inhibitor-1 level, antithrombin III level, and protein C level in hypertensives and borderline hypertensives were significantly higher than those in normotensive men (e.g. for hypertensive versus normotensive men, coagulation factor VII clotting factor activity 111.5 versus 106.1%, plasminogen activator inhibitor-1 level 5.05 versus 3.22 arbitrary units/ml, and protein C level 111.1 versus 107.0%, P < 0.05-0.01). For most of the hemostatic variables we found positive bivariate correlations to blood pressure (P < or = 0.05). Exceptions were von Willebrand factor level (no correlation to blood pressure), and euglobulin fibrinolytic activity (a negative correlation to systolic blood pressure and no correlation to diastolic blood pressure). Significance persisted in the multiple logistic regression analysis with the exception of the relationships between systolic and diastolic blood pressures and fibrinogen level as well as euglobin fibrinolytic activity after adjustment for age. After adjustment for age and body mass index significance for relationships between systolic blood pressure and coagulation factor VII clotting activity as well as protein C level was also lost. We conclude that the greater than normal cardiovascular risk of hypertensive patients is partly due to an imbalance in hemostasis.

The increase of plasminogen activator inhibitor activity is associated with graft occlusion in patients undergoing aorto-coronary bypass surgery.

Early graft occlusion is a common complication in patients undergoing aorto-coronary bypass surgery. Both mechanical and haemostatic factors play a role in the pathogenesis of thrombotic occlusion. Several studies have demonstrated a relationship between fibrinolytic activity and venous or arterial thrombosis. We undertook this study to evaluate the possible contribution of the fibrinolytic system to postoperative occlusion in patients undergoing aorto-coronary bypass graft (CABG). A venous occlusion (VO) test was performed preoperatively in 82 patients undergoing revascularization procedures. Before and after VO the euglobulin fibrinolytic activity and tissue type plasminogen activator (t-PA) activity and antigen were measured. Plasminogen activator inhibitor (PAI) activity and antigen and fibrinogen were also assessed in the preocclusion sample. An angiography performed 10d postoperatively showed graft occlusion in 23% of patients. Patients with graft occlusion had significantly higher preoperative PAI activity than patients without occlusion (P < 0.001). Reduced fibrinolytic response and t-PA capacity was also observed in the group of patients with graft occlusion (P < 0.03 and P < 0.02 respectively). We found a reduced preoperative fibrinolytic response, mainly related to high plasma PAI activity in patients with postoperative graft occlusion. These results suggest that increased PAI activity might have a predictive value for early thrombosis in patients undergoing CABG.

Fibrinolytic response in subjects with hypertriglyceridemia and low HDL cholesterol

The combination of hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) appears to be an excessively high risk factor for coronary artery disease (CAD). In the Helsinki study, both coronary events and mortality were decreased by gemfibrozil, especially in subjects with low HDL-C and high triglycerides (TG). On the other hand, it is known that high levels of TG can be associated with high levels of circulating plasminogen activator inhibitor (PAI), which is also a possible risk factor for CAD. The aim of the present study was to see: 1) whether the combination of low HDL-C and high TG is associated with a more impaired fibrinolytic response than in either isolated condition, and 2) whether gemfibrozil administration can improve fibrinolysis in patients with both high TG and low HDL-C. Twelve non-obese, non-diabetic subjects (eight men, four women; mean age 55 +/- 13 yrs) with low HDL-C (< 35 mg/dL men; < 45 mg/dL women) and high TG (mean 253.6 +/- 42.6 mg/dL) entered the study (Group A). Additionally fourteen comparable subjects with normal HDL-C were also investigated (Group B), plus 12 comparable subjects with isolated low HDL-C (Group C). Ten healthy people served as the control group. The following plasma fibrinolytic parameters were measured: tissue plasminogen activator antigen, PAI antigen and activity, euglobulin fibrinolytic activity (EFA) on fibrin plates, plasminogen and alpha-2-antiplasmin activities. All except the latter two values were also measured after venous occlusion (vo). In baseline conditions, patients in Groups A and B had higher EFA values before vo and higher PAI-1 antigen and alpha-2-antiplasmin levels after vo than those of controls or the subjects in Group C. The relationship between PAI antigen and PAI activity and TG was not confirmed in our population (n = 48). We also saw no interference due to HDL-C, while there was a significant relationship between EFA before vo and both TG and cholesterol. After gemfibrozil treatment (600 mg bid for 12 weeks), the lipid profiles of subjects with high TG and low HDL-C were significantly improved. There was also a slight reduction of PAI activity after vo, while the PAI-1 antigen had decreased significantly from baseline after vo (56.3 +/- 13 ng/mL before vo; 48.4 +/- 21 ng/mL after vo; P = 0.04). The higher risk of CAD in patients with low HDL-C and high TG might be in part related to impairment of fibrinolysis, which occurs in patients with isolated high TG. The close relationship existing between both TG and cholesterol levels and fibrinolytic activity confirm the key role of this latter process in the development of CAD.

Effect of deamino-8-D-arginine desmopressin in uremic bleeding.

ObjectivesThis study is designed to evaluate the clinical outcome of uremic bleeding treated with DDAVP. DDAVP was given intravenously in nine ESRD patients who had undergone A/V fistula surgery and showed oozing of the operation site for more than one hour.MethodsHemostasis was observed by removing the blood from the wound site with a piece of filter paper for 3 hours after DDAVP administration. vWF, t-PA antigen, t-PA activity, total fibrinolytic activity in euglobulin fraction, fibrinopeptide A and FDP were measured before and after DDAVP administration.ResultsCessation of the oozing did not occur within 3 hours after DDAVP administration in all of the cases. vWF levels and t-PA antigen were significantly increased after DDAVP administration peaked at 30 min for vWF and 60 min for t-PA antigen. t-PA activity increased in 6 cases and euglobulin fibrinolytic activity increased in 7 cases, respectively. These values fell towards pre-administration levels 120 min after the administration. There was no difference in fibrinopeptide A levels before and after DDAVP administration. FDP became positive in 4 cases after DDAVP administration.ConclusionDDAVP increased both vWF and t-PA levels and cessation of the oozing from post-operative AV-fistula wounds did not occur within 3 hours after DDAVP administration in all of the cases. These results suggest that the effect of DDAVP should be reassessed in the treatment of uremic bleeding.

Alterations of fibrinolytic activity in human during and after hyperbaric oxygen exposure.

To clarify the stage of fibrinolytic activation by hyperbaric oxygen (HBO) exposure, we examined its alterations in human during and after the HBO exposure. Eight healthy female volunteers breathed oxygen at 284 kPa (2.8 atmospheres absolute). Blood samples were collected before compression, shortly after compression to the pressure 284 kPa, shortly before the start of decompression, shortly after decompression, and then again 3 hours after decompression. We estimated the euglobulin fibrinolytic activity (EFA) and, the activities and antigens of both tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). The PAI-1 activity and PAI-1 antigen showed significant decrease after compression to a pressure 284 kPa, before the start of decompression, and after decompression. The EFA level and t-PA activity rose significantly shortly after decompression, and 3 hours later returned on baseline. These findings suggest that fibrinolytic activity is elicited after HBO rather than during HBO.

Lipoprotein(a) Levels and Fibrinolytic Activity in Patients with Nephrotic Syndrome

Recently there has been a renewed interest in the possibility that lipoprotein(a)--Lp(a)--may be important in the pathogenesis of thrombosis-related disease. In nephrotic syndrome, hyperlipidemia is a common finding, and thrombosis is a major complication. With this regard, if Lp(a) levels increase concomitantly with low-density lipoprotein and/or very-low-density lipoprotein levels in nephrotic syndrome, this may be considered a thrombogenic factor. To probe this possibility and to corroborate the relationship between Lp(a) and fibrinolytic profiles, we measured the Lp(a) levels in patients with nephrotic syndrome (n = 43), in patients with chronic glomerulonephritis with less proteinuria than in nephrotic syndrome (n = 28), and in healthy controls (n = 50) and observed the relation between Lp(a) levels and tissue-type plasminogen activator (t-PA) activity, euglobulin fibrinolytic activity, and t-PA antigen. The Lp(a) levels were significantly higher in the patients with nephrotic syndrome as compared with both patients with chronic glomerulonephritis and healthy controls (p < 0.001). There was a direct correlation with serum cholesterol level (r = 0.780; p = 0.0001), triglyceride level (r = 0.445; p = 0.0001), and urine protein level (r = 0.675; p = 0.0001) and a reverse correlation with serum albumin levels (r = 0.566; p = 0.0001). The Lp(a) levels showed a reverse correlation with t-pA activity (r = 0.627; p = 0.0001), total fibrinolytic activity in euglobulin fraction (r = 0.458; p = 0.0001), and t-PA activity divided by the t-PA antigen (r = 0.567; p = 0.0001), but no correlation with t-PA antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrinolytic changes in malignant ascites

Fibrinolytic activity and inhibitory activity was measured in 36 malignant ascites and 20 cirrhotic ascites using euglobulin fibrinolytic activity, fibrin autography, reverse fibrin autography and quantitation of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor type-1 (PAI-1) antigen by ELISA method. Fibrin autography demonstrated fibrinolytic bands at Mr of 100 kD, 70 kD, 62 kD and 55 kD. The 70 kD band was the predominant one. Reverse fibrin autography showed a single fibrinolysis-resistant band at Mr of 40 kD. t-PA was the predominant fibrinolytic protein in ascites and its concentration was 1.5 to 2 times that in plasma (p<0.005). u-PA, t-PA and PAI-1 antigen concentrations were significantly increased in malignant ascites over cirrhotic ascites (p<0.001, p<0.001, p<0.0001). However, the difference in euglobulin fibrinolytic activities was not statistically significant between the two groups. The sensitivity, specificity and accuracy of PAI-1 antigen at the cut-off point of>4.5 ng/ml in diagnosis of malignant ascites were comparable or better to conventional parameters, but those of t-PA antigen and u-PA antigen were not. In conclusion, we observed that fibrinolytic profiles in malignant ascites differ from those in cirrhotic ascites and measurement of PAI-1ag, could be helpful to differentiate malignant and benign ascites.

Heterogeneous mechanisms responsible for reduced fibrinolytic capacity in patients with a history of venous thrombosis

Abnormal response to venous stasis is a frequent finding in patients with previous venous thrombosis. The factors studied to explain the response of the fibrinolytic system to venous occlusion (VO) have included tissue plasminogen activator (t-PA), PAI antigen and activity measurements as additional tests to the conventional euglobulin fibrinolytic activity. However, there is no consensus on the definition of an abnormal response. In order to further investigate the clinical relevance and the definition of good and bad responders (GR, BR), we have used a 10 min VO test in 109 patients with well documented venous thromboembolic events. Hematocrit, euglobulin clot lysis time (ECLT), diluted whole blood lysis time (DWBLT), tissue plasminogen activator (t-PA ag), fibrinolytic activity of euglobulins on fibrin plates (EFA), activity of the t-PA inhibitor (PAI act), a complete study of haemostasis, and a platelet count were performed before and after VO. Clinical characteristics did not reveal a significant difference between GR and BR. Among these 109 patients, 46 patients had a GR according to our previous definition (residual PAI≤2 U/ml). In this subgroup, results are homogeneous in the various fibrinolytic tests used. In the 63 remaining patients, results are heterogeneous: in 28 patients a BR was observed whatever the test used and could be attributed to a high basal PAI act in 17 cases, or a poor t-PA release in 11 cases. In the remaining 35 cases, interpretation of results is difficult: in 16 patients the anomaly of the t-PA-PAI balance coexists with a satisfactory response of global fibrinolytic activity judged on the ECLT after VO (≤90 min) or on the EFA after VO (t-PA>2 U/l). This discordance may be linked to a compensating activity of another pathway of the fibrinolytic system. In 19 cases the discordances remain unexplained. In these subgroups of BR, clinical characteristics were not clearly different. However, the subgroup ‘concordant BR’ seems to be more frequently associated with recurrences or familial thrombotic tendency. This work underlines the difficulties of clinical interpretation of hypofibrinolysis testing. Global tests (ECLT, DWBLT) and EFA are not only dependent on the t-PA-PAI balance but also on the contact phase and u-PA course. Combinations of tests and a better understanding of the multiple pathways involved will be necessary if we wish to prospectively identify patients at significant risk of thrombosis.

Lipoprotein(a) levels and fibrinolytic activity in patients with nephrotic syndrome

Recently there has been a renewed interest in the possibility that lipoprotein(a)--Lp(a)--may be important in the pathogenesis of thrombosis-related disease. In nephrotic syndrome, hyperlipidemia is a common finding, and thrombosis is a major complication. With this regard, if Lp(a) levels increase concomitantly with low-density lipoprotein and/or very-low-density lipoprotein levels in nephrotic syndrome, this may be considered a thrombogenic factor. To probe this possibility and to corroborate the relationship between Lp(a) and fibrinolytic profiles, we measured the Lp(a) levels in patients with nephrotic syndrome (n = 43), in patients with chronic glomerulonephritis with less proteinuria than in nephrotic syndrome (n = 28), and in healthy controls (n = 50) and observed the relation between Lp(a) levels and tissue-type plasminogen activator (t-PA) activity, euglobulin fibrinolytic activity, and t-PA antigen. The Lp(a) levels were significantly higher in the patients with nephrotic syndrome as compared with both patients with chronic glomerulonephritis and healthy controls (p < 0.001). There was a direct correlation with serum cholesterol level (r = 0.780; p = 0.0001), triglyceride level (r = 0.445; p = 0.0001), and urine protein level (r = 0.675; p = 0.0001) and a reverse correlation with serum albumin levels (r = 0.566; p = 0.0001). The Lp(a) levels showed a reverse correlation with t-pA activity (r = 0.627; p = 0.0001), total fibrinolytic activity in euglobulin fraction (r = 0.458; p = 0.0001), and t-PA activity divided by the t-PA antigen (r = 0.567; p = 0.0001), but no correlation with t-PA antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin Levels and Fibrinolytic Activity in Patients with End-Stage Renal Disease

Considering that PAI-1 is an important factor modulating the systemic fibrinolytic activity, the abnormal insulin metabolism frequently seen in end-stage renal disease (ESRD) may cause decreased fibrinolytic activity in concert with PAI-1. To study this possibility, we measured insulin levels and compared it with the fibrinolytic profiles in ESRD patients. Fasting blood sugar, insulin, and C peptide levels were higher in ESRD patients than in the control group. In the ESRD patients, the insulin levels showed a positive correlation with C peptide (r = 0.612, p = 0.0001), fasting blood sugar (r = 0.334, p = 0.044), and PAI-1 antigen (r = 0.474, p = 0.0001) and a reverse correlation with euglobulin fibrinolytic activity (r = 0.5, p = 0.005), but no correlation with t-PA antigen. The euglobulin fibrinolytic activity showed a reverse correlation with PAI-1 antigen (r = 0.289, p = 0.0144), but no correlation with t-PA antigen. Our results suggest that abnormal insulin metabolism and/or insulin resistance, which occur frequently in ESRD, may play an important role in the decrease in systemic fibrinolytic activity by the regulation of the PAI-1 concentration.

Influence of oral intake of retinoids on the human plasma fibrinolytic system

Retinoic acid and some of its derivatives cause a specific induction of tissue-type plasminogen activator (t-PA) synthesis in cells cultured in vitro as well as in experimental animals. In the present study we have evaluated the effect of the oral intake of β-carotene and of isotretinoin (13-cis-retinoic acid) or acitretinoin (acitretin) on the human fibrinolytic system. In the placebo-controlled cross-over β-carotene study 18 healthy volunteers received β-carotene at a dose of 250 mg/day for 4 days. Euglobulin fibrinolytic activity (EFA) was 0.98±0.47 U/ml (mean±SD, n=18) and 0.79±0.26 U/ml before and after intake, respectively. t-PA antigen values in plasma were 5.0±1.8 ng/ml and 3.9±1.4 ng/ml, respectively. PAW activity levels were 12±15 and 13±13 ng/ml, respectively. Paired t-test analysis on values before and after intake could not reveal any significant difference. In the prospective retinoid study plasma was obtained from 12 patients (with acne-related or psoriasis-related skin disorders) before and 1 month after daily oral intake of 20 to 60mg isotretinoin (13-cis-retinoic acid) or acitretinoin (acitretin). In these patients mean values (±SD) for EFA were 2.9±4.8 and 3.0±5.7 U/ml before and during treatment, respectively; t-PA antigen values were 2.6±1.3 and 3.3±1.6 ng/ml before and during treatment, respectively and values of 4.4±4.0 and 6.1±6.4 ng/ml were found for PAI-1 activity before and during treatment, respectively. Paired t-test analysis revealed a significant increase (p=0.027) in t-PA antigen during therapy. No changes were observed in EFA or PAI-1 activity. In conclusion, these results suggest that the retinoids isotretinoin and acitretinoin, but not β-carotene, can have a minor but significant influence on circulating t-PA antigen in human plasma. The present data indicate that, in an effort to modulate pharmacologically the fibrinolytic potential in plasma, it may be interesting to perform further in vivo studies with other retinoids, showing in vitro a more potent t-PA inducing activity relative to their PAI-1 inducing activity.

Protease activities, as well as plasminogen activators, contribute to the "lytic" state during orthotopic liver transplantation.

High levels of tissue plasminogen activator (t-PA) have been reported to be the main component of the high fibrinolytic activity measured in patients during orthotopic liver transplantation. However, a previous study of our group suggested that specific t-PA may not completely account for the massive fibrinolytic activities recorded. In the present study we investigated the fibrinolytic patterns in 10 consecutive liver cirrhosis patients undergoing OLT. Euglobulin fibrinolytic activity, measured either on physiologic (fibrin plates) or amidolytic substrates, increased as expected during anhepatic and reperfusion phases, but largely exceeded the specific activity of t-PA, as proved by quenching procedures using anti-t-PA antibodies. The presence of plasmin- and trypsin-like amidolytic activities was detected in native plasmas at the end of anhepatic and reperfusion phases, together with decreased levels of protease inhibitors, especially alpha 1 Antitrypsin. In conclusion, the hyperfibrinolytic pattern recorded in the central OLT phases is not only attributable to an increased t-PA concentration, and is better described as a complex "lytic" state also including the presence of free proteases (plasmin- and trypsin-like), with limited participation of u-PA. Although t-PA increase is probably the main mechanism of stimulation of the fibrinolytic system during OLT, actual and not just potential proteolytic activities can be found in this condition independent of the occurrence of major hemorrhagic complications.

Dietary effects on circadian fluctuation in human blood coagulation factor VII and fibrinolysis

Six healthy male volunteers were served 4 strictly controlled isoenergetic diets differing in fat (20% or 50% of energy) and fiber contents (2 or 4 g/MJ) for periods of 2 days. The diets were served in random order with at least 5 days separating each diet period. Blood samples for determination of factor VII clotting activity using human (FVIIc) and bovine thromboplastin (MIN), and for assessment of factor VII antigen (FVIIag), tissue-plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1) antigen, PAI activity, t-PA and euglobulin fibrinolytic activity, and triglyceride and insulin levels were collected regularly on the second day of each diet period. The high-fat diets resulted in significantly increased postprandial MIN levels (peak values: 131% vs. 95%, P < 0.01), and higher postprandial FVIIbt/FVIIag ratios (peak values: 1.42 vs. 1.16, P < 0.01) compared with the low-fat diets. Fibrinolytic variables were not affected by the dietary changes and consistently showed characteristic U-shaped (t-PA and PAI-1 antigen, PAI activity), or inverted U-shaped (t-PA and euglobulin fibrinolytic activity) circadian patterns with troughs and peaks, respectively, at 17:30-21:30 h. The dietary fiber content had no significant influence on any of the measured variables. Our findings indicate that high-fat diets may increase blood thrombogenicity by virtue of augmented postprandial activation of factor VII.

The Effect of Tranexamic Acid on the Fibrinolytic System During Anaphylaxis in Rabbits; The Importance of the Fibrinolytic System During Anaphylaxis

We previously reported (Shimaya et al. (1992) Enzyme, 46, 204) that a rapid and strong increase of plasminogen activator (PA) was induced during anaphylaxis, and that the main plasma fibrinolytic enzyme which increased in the anaphylaxis group was shown to be tissue-type plasminogen activator (t-PA). Anaphylaxis was induced in rabbits by giving BSA after t-AMCHA injection. 44% of those rabbits died within 3 h after BSA injection. In the dead group, the euglobulin fibrinolytic activity (EFA) could not be detected by the plasminogen-rich fibrin plate method and the t-PA activity, using the natural substrate plasminogen, did not rise significantly reaching a peak at 10–15 min. However, the EFA and t-PA activity increased significantly in the surviving group. A significant prolongation of the activated partial thromboplastin time (AFTT) and the prothrombin time (PT) was observed during anaphylaxis in both groups. These findings suggest that increased PA activity during anaphylaxis is an important defense mechanism against the rapid increase in the blood coagulation system.

Fibrinolytic Activity in End-Stage Renal Disease

Recently, we described that in the physiologic state, urokinase concentration is higher in the renal vein than in the renal artery which suggests that the kidney is the essential organ providing urokinase to the systemic circulation. In end-stage renal disease (ESRD) patients, urokinase provided by the kidney may be decreased, and this might be the cause of decreased systemic fibrinolytic activity seen in ESRD. To study this possibility, we measured fibrinolytic profiles including urokinase, tissue plasminogen activator (t-PA) and fibrinolytic activity in the euglobulin fraction of ESRD patients and compared the results with those of two control groups consisting of renal transplantation patients and age- and sex-matched healthy controls. The euglobulin fibrinolytic activity was 92.2 +/- 14.8 BAU in the ESRD group, 108.7 +/- 13.5 BAU in the kidney transplantation (KT) group and 101.5 +/- 8.0 BAU in the healthy control group. Although it was lower in the ESRD than in the KT (p < 0.005) and the healthy control group (p < 0.005), there was no difference between the KT and the healthy control group. t-PA antigen was 1.2 +/- 1.3 ng/ml in the ESRD group, 3.5 +/- 1.7 ng/ml in the KT group and 3.1 +/- 2.1 ng/ml in the healthy control group. It was lower in the ESRD compared to the KT (p < 0.001) and the healthy control group (p < 0.001) but there was no difference between the KT and the healthy control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of t-PA Synthesis with intravenous bolus injection of vitamin A palmitate in vitamin a deficient rats

Retinoic acid and vitamin A palmitate induce tissue-type plasminogen activator (t-PA) synthesis in cultured human umbilical vein endothelial cells (HUVEC) in vitro without alteration of plasminogen activator inhibitor-] (PAI-1) synthesis. Therefore the effect of intravenous bolus injection of water-miscible vitamin A palmitate on the blood fibrinolytic system was investigated in normal and vitamin A deficient rats. In 5 normal rats, injection of 200000 IU/kg of vitamin A palmitate did not induce a significant increase in euglobulin fibrinolytic activity, t-PA antigen and PAI activity in plasma nor of t-PA and PAI-1 mRNA in the heart within 240 min after injection. In groups of 3–6 vitamin A deficient rats, injection of 200000IU/kg of vitamin A palmitate induced a significant increase in t-PA antigen in plasma (1.9-fold after 60 min and 2.9-fold after 120 min), but no significant increase in plasma euglobulin fibrinolytic activity. A 2-fold increase in PAI activity was observed 90 min after injection of both vitamin A palmitate as well as of its solvent, suggesting that this induction was non-specific. The increase in t-PA antigen coincided with a significant increase in t-PA mRNA in heart tissue: 2.3-fold after 60 min and 4.3-fold after 120 min. PAI-1 mRNA in heart tissue increased 3.6-fold 90 min after injection with vitamin A palmitate but, surprisingly, not after injection of solvent. It is concluded that intravenous bolus injection of vitamin A palmitate induces a specific increase of t-PA mRNA in the heart and of t-PA antigen secretion in plasma of vitamin A deficient rats.

Tissue plasminogen activator, plasminogen activator inhibitor, and other parameters of fibrinolysis in the early stages of taurocholate acute pancreatitis in rats.

It is well known that fibrinolytic activity in the early stages of acute experimental pancreatitis (AEP) as assessed by euglobulin lysis time (ELT) is depressed. The aim of this study was to evaluate changes in the fibrinolytic system in the early stages of taurocholate AEP in rats. Tissue plasminogen activator (t-PA) activity, plasminogen activator inhibitor 1 (PAI-1) activity, plasminogen, alpha 1 proteinase inhibitor (alpha 1 PI), alpha 2 antiplasmin (alpha 2 AP), antithrombin III (AT III), fibrinogen, and ELT were measured 0.5, 1, 3, and 6 h after the induction of taurocholate AEP in rats, as well as in sham-operated animals and the control group, which was not submitted to any operation. T-PA activity decreased significantly after 3 and 6 h of AEP; PAI activity had a time course reverse to t-PA and was parallel to alpha 1 PI activity. ELT was slightly prolonged after 0.5, 1, and 3 h, whereas alpha 2 AP activity and plasminogen levels increased significantly; AT III activity was increased after 1 h in comparison to control group. Sham operation caused nonsignificant changes in fibrinolysis. Increase of PAI activity and decrease of t-PA could be a reasonable explanation for inhibited plasma euglobulin fibrinolytic activity noted in the early period of AEP.

Effect of nerve block on t-PA release by venous occlusion

In order to investigate the influence of neural blockade on tissue plasminogen activator (t-PA) release by venous occlusion, we compared the increase in t-PA and fibrinolytic activity in the euglobulin fraction initiated by cubital venous occlusion (100 mmHg for 10 min), in pre-neural block and post-neural block states, in 7 cases. In all patients, the supra-clavicular approach was used to obtain a brachial plexus block and venous occlusion was achieved at the cubital levels on the ipsilateral arm. The euglobulin fibrinolytic activity before venous occlusion was 100.9±27.5 BAU in the pre-nerve block state and 102.7±29.4 BAU in the post-nerve block state (p>0.5). The t-PA antigen level before venous occlusion was 3.5±1.2ng/ml in the pre-nerve block state and 4.0±1.0 ng/ml in the post-nerve block state (p>0.05). The increase in the euglobulin fibrinolytic activity after venous occlusion was 18.0±16.7 BAU in the pre-nerve block state, and 18.3±15.6 BAU in the post-nerve block state (p>0.5). The increase in the t-PA antigen levels after venous occlusion was 3.0±2.0 ng/ml in the pre-nerve block state and 3.0±2.1ng/ml in the post-nerve block state (p>0.5). These findings suggest that the peripheral nervous system does not exert any influence on t-PA release during venous occlusion.