Fibrinolytic capacity of arm and leg veins after femoral shaft fracture and acute myocardial infarction.

The local fibrinolytic activity generated in the leg and arm veins during venous occlusion (fibrinolytic capacity) and the systemic fibrinolytic activity were measured at intervals in 11 patients after fracture of the femoral shaft and in 11 patients after acute myocardial infarction. In both groups the fibrinolytic capacity of the leg veins and the systemic fibrinolytic activity were significantly reduced two days after the onset of tissue injury. The fibrinolytic capacity of the arm veins was not altered. These results provide a possible explanation for the predilection of venous thrombosis for the leg veins after accidental trauma and acute myocardial infarction.     

Disorders in the release of plasminogen activators

Impairment of the release of plasminogen activator has been looked for in patients with a predisposition to vascular disease or venous thrombosis. In normal people the fibrinolytic activity of the blood rises sharply after strenuous physical exercise or after the administration of certain drugs, among which DDAVP. These measures fail to elicit a normal response in many of these patients. In most cases this turned out to be due to a high level of a circulating plasminogen activator inhibitor which suppresses the rise in fibrinolytic activity. Release of activator can only be demonstrated reliably by the assay of t-PA-antigen. An impaired release appears to be very rare and in the experience of the author it occurs with some regularity only in patients with terminal renal insufficiency.     

Immunoradiometric determination of blood/tissue plasminogen activators in thrombophilia

Immunoradiometric determination of the blood/tissue plasminogen activator was in plasma from patients before and after response to venous occlusion, infusion of DDAVP or exercise. The raise in the level of plasminogen activator was most pronounced after venous occlusion. In patients who earlier had had verified thrombosis the levels of plasminogen activator compared to normals did not show any significant difference.     

Effect of ethyloestrenol on fibrinolysis in the vessel wall.

Forty-nine patients with decreased fibrinolytic activity in the vessel walls or a decreased release mechanism, or both, were treated with ethyloestrenol for three to 17 months. Forty-five of the patients had had recurrent, phlebographically verified, deep venous thrombosis (DVT) and four had arterial thrombosis. Ethyloestrenol 8 mg/day was given to 31 patients and 4 mg/day was given to 12. The remaining six patients had been treated with a combination of phenformin and ethloestrenol. The phenformin was withdrawn but they were kept on ethyloestrenol 8 mg/day. Another 15 patients with a normal fibrinolytic system--four with recurrent DVT and 11 with severe arteriosclerosis--were given ethyloestrenol 8 mg/day. The spontaneous fibrinolytic activity, local fibrinolytic activity during standardised venous occlusion of the arms, and fibrinolytic activity of the vessel walls increased significantly after treatment with ethyloestrenol 8 mg/day for three months. No further increase occurred after three months, and ethyloestrenol 4 mg/day had no effect. No values rose significantly in the patients with a normal fibrinolytic system. One patient suffered a recurrence within three months of treatment, before the fibrinolytic system became normal. In one patient the fibrinolytic defect reappeared after 10 months in spite of continued treatment. Two of the three women of fertile age developed irregular cycles and intermenstrual bleeding, which disappeared when the treatment was withdrawn. No other side effects were observed.     

Deep venous thrombosis of the arm: a study of coagulation and fibrinolysis.

Sixty consecutive patients with phlebographically verified deep venous thrombosis of the upper arm were studied for disorders of coagulation and fibrinolysis. No appreciable increase in abnormalities of the factor VIII complex, antithrombin III, or inhibitors of activators of fibrinolysis were found. A decreased fibrinolytic defence mechanism, evident either as a deficient release capacity of fibrinolytic activators from the vein during stasis or as decreased fibrinolytic activity in the vein wall as determined histochemically, was found in 26 out of 53 patients studied (49%). It is concluded that deep venous thrombosis of the upper arm is a multifactorial disease. An impaired fibrinolytic defence mechanism is one of the factors that may be of pathogenetic importance.     

Normal tissue plasminogen activator and plasminogen activator inhibitor activity in plasma from patients with type 1 diabetes mellitus.

The fibrinolytic system was investigated in 38 patients (21 males and 17 females) affected by type 1 diabetes mellitus (18 free from complications, 10 with retinopathy, and 10 with autonomic neuropathy) and in 8 healthy controls. Two separate fibrinolysis-stimulating tests were done: standardized venous occlusion and 1-desamino-8-D-arginine vasopressin infusion. Plasma tissue plasminogen activator antigen and activity and plasma plasminogen activator inhibitor activity were measured. All the patients were in good metabolic control (mean HbA1c 7.4%, range 6.1-8.0%). No significant differences were observed either between the diabetic patients and the control subjects, nor among the subgroups of diabetic patients. The fibrinolytic system is probably not involved in type 1 diabetes mellitus.     

Status of fibrinolysis in systemic lupus erythematosus

In patients with systemic lupus erythematosus (SLE) both a haemorrhagic diathesis and a tendency to thrombosis of the venous and arterial vessels can be observed. In the course of the disease, thrombosis of the leg or pelvic veins developed in 20 per cent of 188 patients. The levels of alpha 2-plasmin inhibitor, plasminogen, fibronectin and of factor VIII complex were increased in patients with SLE compared with a control group. Fifty per cent of the patients showed no increase in fibrinolytic activity after venous occlusion measured with the fibrin plate method. This suggests a reduced fibrinolytic capacity in SLE probably caused by alteration of the endothelial cells through immune complex vasculitis. In addition, the lupus anticoagulant and an acquired antithrombin III deficiency in nephrotic syndrome in SLE are to be considered thrombophilic mechanisms. In the individual case there is an overlapping of hyper- and hypocoagulability.     

Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor.

Fibrinolytic components after venous occlusion and concentrations of tissue plasminogen activator inhibitor were studied in 100 consecutive patients with confirmed recurrent deep vein thrombosis or pulmonary embolism. After 20 minutes of venous occlusion the fibrinolytic response was decreased in 33 patients, as measured both amidolytically with S-2251 and on fibrin plates. Two different mechanisms responsible for the poor fibrinolytic response could be distinguished. Twenty two of the patients in whom the response was poor released normal amounts of tissue plasminogen activator antigen, as assayed by immunoradiometric assay, but had appreciably increased concentrations of tissue plasminogen activator inhibitor. The 11 other patients in whom the response was poor had both low tissue plasminogen activator activities and low tissue plasminogen activator antigen concentrations but normal concentrations of tissue plasminogen activator inhibitor. The results show not only that defective synthesis or release of tissue plasminogen activator may be important in the pathogenesis of venous thrombosis but also that a large group of patients with thrombosis have an increased concentration of the inhibitor to tissue plasminogen activator.     

Response of fibrinolytic activity to venous occlusion.

Resting fibrinolytic activity and the response of the fibrinolytic system to venous occlusion were studied in a group of healthy middle-aged men. All subjects showed increased fibrinolytic activity but of varying degrees. There was a linear relationship between resting and occluded levels of fibrinolytic activity but many subjects with lower levels of fibrinolytic activity showed an anomalous response. Responses over the expected level were more common than unexpectedly low levels of response. Fibrinogen and plasminogen concentrations were inversely correlated with fibrinolytic activity.     

Increased tissue-plasminogen activator (t-PA) levels in patients under oral anticoagulant therapy

The fibrinolytic system was investigated in 30 patients under oral anticoagulant therapy, and in 23 control patients not receiving oral anticoagulants. Patients under oral anticoagulant therapy had significantly higher tissue-plasminogen activator (t-PA) antigen levels than patients in the control group. Mean t-PA levels before venous occlusion were 18.4 ng/ml in the anticoagulated patients vs. 7.9 ng/ml in the control patients (p less than 0.001). After venous occlusion for 10 minutes, t-PA levels were 45.0 ng/ml in the anticoagulated patients and 24.2 ng/ml in the control patients (p less than 0.01). Plasminogen activator inhibitor (PAI) capacity was not significantly different in the two groups before venous occlusion (VO) but differed slightly (p less than 0.05) after VO. The net decrease in euglobulin lysis time (ELT) after venous occlusion (= ELT before VO - ELT after VO), indicating the relative potency of the fibrinolytic activity in blood, was also significantly higher in the anticoagulated patients (median 240 min vs. 125 min, p less than 0.001). These data indicate that oral anticoagulant therapy increases the fibrinolytic activity in blood, and thus may have an additional therapeutic effect in addition to anticoagulation.     

Flow cytometric analysis of peroxidative activity in granulocytes from coronary and peripheral blood in acute myocardial ischemia and reperfusion in dogs: protective effect of methionine.

BACKGROUND: Methionine has shown protective effects in experimental models of myocardial infarction and is highly reactive to oxidative compounds produced by polymorphonuclear leukocytes (PMN), which in turn have been associated with myocardial damage. We have investigated the effect of methionine administration on spontaneous leukocyte peroxidative activity in myocardial ischemia and reperfusion. METHODS: In anesthetized dogs, with coronary occlusion (90 min) and reperfusion (90 min), PMN activation was measured by flow cytometric determination of H(2)O(2) with dihydrorhodamine 123, and correlated to hemodynamic parameters and infarct presence. To assess a possible direct effect of methionine, H(2)O(2) and superoxide were measured by flow cytometry in dog leukocyte suspensions following in vitro stimulation with f-MLP. RESULTS: PMN peroxidative activity in saline-treated dogs increased significantly after coronary occlusion and after reperfusion. These changes were greater in coronary venous blood than in femoral blood. Methionine administration (150 mg/kg, i.v.) before occlusion totally suppressed PMN activation, both after occlusion and reperfusion. CONCLUSIONS: PMN are promptly activated in myocardial ischemia, and methionine administration prevents such activation. However, methionine has no direct effect on spontaneous peroxidative activity, and f-MLP induced peroxidative activity. These in vivo effects of methionine, may additionally contribute to explain its protective role in experimental -788-877-7QQ8-8-7-88-8-8778--8Q78-----8--8-Q-7-Q7----- --------------8888 888888-7777777777777777777777777777777----------------888888888888888888 8877777--87--------8-----------------7-8888-887-----------8----8-8-87777 7777777------------------------------------------------------T7OW     

Fibrinolytic effect of a particular glycosaminoglycan (endoglycan) per os on normals and in patients with chronic artery disease.

Endoglycan, a heparan-dermatan sulphate association, is a highly purified heparinoid extracted from porcine intestinal mucosa. The aim of our study was to investigate the fibrinolytic system in a group of healthy controls and vascular disease patients, before and after endoglycan administration "per os". All the patients had a reduced basal fibrinolytic activity. The tests carried out were PT, PTT, FDP, Euglobulin Lysis Time (ELT), fibrinogen, plasminogen, alpha 2-antiplasmin, alpha 2-macroglobulin and t-PA activity assayed with a chromogenic method. After endoglycan administration, we have shown a significant shortening of ELT with complete normalization during the treatment. A fibrinogen decrease and either plasminogen or alpha 2-antiplasmin increase was seen. This was shown in normals too, however to a lesser extent. During therapy most of the healthy subjects, but only some patients, showed increased t-PA levels. Before and during treatment, significantly higher t-PA levels were seen in the control group as compared to the patients group. Reduced t-PA release was seen in our vascular disease patients. In conclusion, endoglycan "per os" appears to exert a stimulatory effect on the fibrinolytic system.     

The Pathogenesis of Human Myocardial Infarction

Coronary arteriography, dissection of the coronary arteries and histopathological examination of the heart were carried out in 150 autopsies to study the effect of coronary narrowing and occlusion, of the presence of collaterals, and of coronary artery predominance on the development of myocardial infarction. The thrombosis rate was related to the severity of coronary sclerosis. The development of collaterals was not enhanced by coronary sclerosis and occlusion, and collaterals did not protect the myocardium against reinfarction. Coronary occlusion was regularly demonstrable in recent myocardial infarct cases. The association of atrial and posterior ventricular infarcts was explained by occlusion of their common arterial branch. The interdependence between coronary sclerosis, thrombosis and myocardial infarction in human autopsy material emphasizes the importance of mural coronary artery disease in the genesis of coronary occlusion and myocardial infarction, and it is at variance with statistical data and experimental results.     

Fibrinolytic activity of prostacyclin and iloprost in patients with peripheral arterial disease

We studied the effects of prostacyclin (PGI2) and its stable analog, iloprost, on blood fibrinolytic activity in 33 patients with peripheral arterial disease. Ten subjects (group A) received three 5-hour infusions of iloprost on three consecutive days. The remaining 23 patients received three different 5-hour infusions (placebo, iloprost 2 ng/kg/min, PGI2 5 ng/kg/min). Tissue plasminogen activator (t-PA), total plasma fibrinolytic activity and euglobulin clot lysis time (ECLT) were determined in patients before and after each infusion, both in freely flowing blood samples and following 10 min venous occlusion. In patients of group A, ECLT at rest was significantly shortened after all three iloprost infusions (on average by about 5-11%). First and third infusions produced also shortening of ECLT after venostasis (by 21 and 32%). Statistically significant rise in t-PA activity (by about 68% on average) accompanied only the first infusion. In patients of the group B iloprost provoked significant fall in ECLT at rest (by about 19% on average) only. PGI2 shortened ECLT both at rest and after venous occlusion (by about 17% and 20% on average, respectively) and led to a rise in t-PA activity after venous occlusion by about 33% on average. Our results indicate that prostacyclin and its stable analog, iloprost, enhance fibrinolytic activity in man by releasing or facilitating the release of tissue plasminogen activator from the vessel wall.     

Fibrinolytic activity of prostacyclin and iloprost in patients with peripheral arterial disease

We studied the effect of prostacyclin /PGI₂/ and its stable analog, iloprost, on blood fibrinolytic activity in 33 patients with peripheral arterial disease. Ten subjects /group A/ received three 5-hour infusions of iloprost on three consecutive days. The remaining 23 patients received three different 5-hour infusions /placebo, iloprost 2 ng/kg/min, PGI₂ 5 ng/kg/min/. Tissue plasminogen activator /t-PA/, total plasma fibrinolytic activity and euglobulin clot lysis time /ECLT/ were determined in patients before and after each infusion, both in freely flowing blood samples and following 10 min venous occlusion. In patients of group A, ECLT at rest was significantly shortened after all three iloprost infusions /on average by about 5–11%/. First and third infusions produced also shortening of ECLT after venostasis /by 21 and 32%/. Statistically significant rise in t-PA activity /by about 68% on average/ accompanied only the first infusion. In patients of the group B iloprost provoked significant fall in ECLT at rest /by about 19% on average/ only. PGI₂ shortened ECLT both at rest and after venous occlusion /by about 17% and 20% on average, respectively/ and led to a rise in t-PA activity after venous occlusion by about 33% on average. Our results indicate that prostacyclin and its stable analog, iloprost, enhance fibrinolytic activity in man by releasing or facilitating the release of tissue plasminogen activator from the vessel wall.     

Internal synchronization of the main 0.1-Hz rhythms in the autonomic control of the cardiovascular system

Synchronization parameters of 0.1-Hz rhythms isolated from the heart rate and the oscillations of the blood volume in microcirculatory vessels were studied in 12 healthy subjects and 32 patients with acute myocardial infarction. Recordings of the electrocardiogram and the pulsogram from the distal phalanx of the index finger, as well as mechanical recording of respiration with the body in a horizontal position, were performed. In patients with myocardial infarction, the recordings were performed during the first three to five days and the third week after the infarction. Synchronization was tested by plotting phase differences and calculating the total percentage of phase synchronization. Synchronization parameters of 0.1-Hz rhythms were high in healthy subjects. In patients with acute myocardial infarction, synchronization of 0.1-Hz rhythms was considerably poorer. The data obtained suggest that the studied 0.1-Hz rhythms are two independent oscillatory processes that are synchronized in healthy subjects. However, this interaction may be disturbed in cardiovascular pathologies, e.g., myocardial infarction.     

Prolonged antidiuresis by 1-desamino-8-D-arginine vasopressin (DDAVP): correlation to its plasma levels and nephrogenous cyclic AMP production

In an attempt to clarify the mechanism responsible for the prolonged effect of DDAVP (1-desamino-8-D-arginine vasopressin), plasma levels of DDAVP and nephrogenous cyclic AMP were determined in patients with diabetes insipidus after a single intranasal administration of 10 micrograms of DDAVP. Plasma DDAVP levels were uniformly elevated within 30 min, and showed a peak ranging from 5.6 to 25.0 pg/ml between 30 and 120 min. The subsequent time-course of plasma DDAVP differed however, from patient to patient, and was irregular in most of them. In all of the patients whose plasma DDAVP dropped below 1.0 pg/ml, antidiuresis was still observed. Although the mean basal level of nephrogenous cyclic AMP in patients with diabetes insipidus was not significantly different from that in control subjects, the administration of DDAVP resulted in a 2-fold increase. A negative correlation between nephrogenous cyclic AMP and free water clearance was obtained. These results suggest that the long-acting nature of DDAVP may be attributed, in addition to its gradual absorption from nasal mucosa and slow metabolic clearance, to a higher or persistent biological activity at the receptor site in the kidney and that a nearly physiological level of antidiuretic hormone may cause de novo synthesis of cyclic AMP in the kidney and exert its biological action.     

Fluctuation of thrombin-antithrombin III complex in patients with acute myocardial infarction: influence of low-dose heparin administration.

The haemostatic parameters were studied within 14 days of acute myocardial infarction (AMI) in 103 patients randomly allocated into a group receiving low-dose heparin or into a group treated without anticoagulants. Patients with isotopic evidence of deep vein thrombosis were excluded from the analysis. An important formation of thrombin-antithrombin III complex (TAT) in the plasma was detected in the early stage of the disease. It was accompanied by an activation of plasma intrinsic fibrinolysis (IF), an elevation of fibrinogen and its degradation products (FDP) and a reduction of extrinsic plasma fibrinolytic activity (EF) together with normal levels of factor X, antithrombin III (AT III), protein C and alpha-2-antiplasmin. Sequentially studies periods of the disease revealed a diminution of TAT complex concentration in the plasma on the seventh day of AMI together with a rise of the both plasma fibrinolytic activities (IF, EF) as well as an elevation of fibrinogen and its degradation products, returning to the initial values on the 14 day of AMI. In the patients treated with heparin the augmentation of TAT complex in the plasma was prolonged until the fifth day of AMI. Moreover, heparin administration was connected with significantly higher levels of AT III and protein C along with a lower concentration of factor X and FDP on the seventh day of the disease. The fluctuation of fibrinolytic activities (IF, EF) in the plasma was heparin-independent. The present results indicate that low-dose heparin treatment modulates the plasmatic fluctuation of TAT complex as well as factor X, AT III and protein C levels in patients with acute myocardial infarction.     

Prophylaxis of recurrent venous thrombosis with long-term enhancement of fibrinolysis.

The effects of 6 months' combined therapy with phenformin and an anabolic steroid were compared in patients with thrombophlebitis migrans (12 patients) and those with superficial thrombophlebitis (15 patients). In both groups of patients an increase in blood fibrinolytic activity, and "capacity" decrease in platelet adhesiveness, plasma fibrinogen, blood lipids, beta lipoproteins as well as serum cholesterol level were found. A statistically significant decrease in frequency of inflammations in patients with thrombophlebitis migrans occurred. In these patients a return of the previously low "fibrinolytic capacity" to normal values was observed. It seems that prolonged activation of fibrinolysis by means of phenformin and an anabolic steriod may be of value in the prophylaxis of venous thrombosis especially thrombophlebitis migrans.     

Co-activation of platelets by prolactin or leptin--pathophysiological findings and clinical implications.

Platelet activation is involved in the pathogenesis of atherosclerosis and venous thromboembolism, and might therefore be a possible link between the two entities. Prolactin and leptin have recently been recognized as potent co-activators of ADP-dependent platelet aggregation or P-selectin expression, and are therefore suspected as additional risk factors for both arterial and venous thrombosis. There are clinical situations that have a known association with higher prolactin or leptin levels (pregnancy, obesity or anti-psychotic therapy) and increased risk of thromboembolic events. We compared the impact of both hormones on platelet activation in vitro and in vivo, indicating that prolactin has a stronger effect on platelet activation as leptin in vitro and in vivo. We have also demonstrated that prolactin levels are increased in so called idiopathic thrombosis, and that conversely, patients with prolactinoma have an increased frequency of thrombosis during the hyperprolactinemic state, in a retrospective analysis. Moreover, we have demonstrated increased prolactin values in stroke and myocardial infarction. Prospective studies have yet to be performed to give this theory its final confirmation. The involvement of hormonal factors in platelet aggregation and venous or arterial thrombosis may have important clinical implications such as for risk stratification of patients with venous and arterial thrombosis or new therapeutic options such as decreasing pro-coagulant hormone levels in certain risk situations.