Dilute Blood Clot Lysis Time Research Articles

The clearance of 125I-labelled fibrin from the subcutaneous tissue of limbs with lipodermatosclerosis.

The clearance of radioactive fibrin from the subcutaneous tissues has been measured in the rat and in the limbs of normal subjects, patients with varicose veins, and patients with lipodermatosclerosis. The animal experiments showed that the most effective way of producing a subcutaneous deposit of fibrin was by the simultaneous injection of labelled fibrinogen and thrombin. The clearance of these clots was delayed when fibrinolysis was depressed with epsilon-aminocaproic acid. Clearance of subcutaneous fibrin in man was significantly slower in the arms of patients with varicose veins and lipodermatosclerosis. Similarly clearance in the legs of patients with lipodermatosclerosis was significantly slower than that of the normal subjects and those with uncomplicated varicose veins. The clearance of fibrin from the legs of patients with lipodermatosclerosis was significantly slower than the clearance from their arms but there was no difference between arm and leg clearance in the normal subjects and those with uncomplicated varicose veins. The patients with lipodermatosclerosis had a significantly longer dilute blood clot lysis time. The inability to clear subcutaneous fibrin may be an aetological factor of lipodermatosclerosis.

AICF and DIC in Liver Cirrhosis: Expressions of a Hypercoagulable State

Liver cirrhosis is associated with a large spectrum of he-mostatic abnormalities that may contribute to abnormal microvascular bleeding (1). These include thrombocytopenia, platelet dysfunction, prolonged coagulation screening tests (APTT, PT, TT), decreased coagulation zymogens and co-factors, abnormal coagulation factors (hypocarboxylated factors X, IX, VII, II, dysfibrinogen), decreased natural anticoagulants (antithrombin III, protein C, protein S) and shortened euglobulin clot lysis time or dilute whole blood clot lysis time reflecting increased fibrinolysis (1). The mechanisms involved in these abnormalities are complex and incompletely understood. Thrombocytopenia is thought to be largely due to increased pooling of platelets in an enlarged spleen (hypersplenism), with decreased hepatic production of thrombopoietin as a possible contributor. Decreased coagulation zymogens, cofactors, and anticoagulants have been attributed to decreased synthesis and, to a lesser degree, increased third-spacing (e.g., ascites). Hyper-fibrinolysis appears to result largely from impaired clearance of plasminogen activators by the diseased liver. Because of the striking similarity between the hemostatic abnormalities seen in liver cirrhosis and those observed in disseminated intravascular coagulation (DIC), also called consumption coagulopathy, there has been a long and continued debate as to whether DIC is a common feature of, and an important contributor to, hemostatic failure in liver cirrhosis (2, 3, 4, 5, 6). The notion of a consumptive coagulopathy in liver cirrhosis was supported by earlier observations (7, 8, 9, 10, 11) that survival of radiolabeled platelets, fibrinogen, and plasminogen was shortened in some patients with liver cirrhosis, and, more importantly, shortened survival of fibrinogen, but not that of platelets or plasminogen, could be prolonged with administration of heparin (7, 8, 9, 10) and antithrombin III (ATIII) (11).

XR5118, a novel modulator of plasminogen activator inhibitor-1 (PAI-1), increases endogenous tPA activity in the rat

Summary XR5118, a diketopiperazine-based low molecular weight inhibitor of plasminogen activator inhibitor-1 (PAI-1) activity, was studied ex vivo and in vivo in the rat to determine whether inhibition of PAI-1 activity resulted in increased fibrinolysis and protection against thrombus formation. XR5118 reversed the inhibitory effects of human PAI-1 against tissue-type plasminogen activator (tPA), in an vitro amidolytic assay (S2251) with an IC50 value of 3.5 μM±0.19 μM (n=7). This activity was confirmed in in vitro fibrinolysis assays against both human and rat PAI-1 and, following intravenous administration to rats, XR5118 (1–5mg/kg) dose-dependently increased clot lysis in an ex vivo dilute blood clot lysis time (DBCLT) assay. At 5 mg/kg, XR5118 increased clot lysis by 41±1.6% (n=39, P

Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study

Summary Fibrinolytic activity (FA) was measured by dilute blood clot lysis time at entry to the Northwick Park Heart Study in 1382 white men aged 40-64, of whom 179 subsequently experienced episodes of ischaemic heart disease during a mean follow-up period of 16·1 years. There was a significant interaction between age and low FA (p=0·02) with respect to ischaemic heart disease: a difference of one standard deviation in FA was associated with a difference of about 40% in ischaemic heart disease risk (p= 0·002) in those aged 40-54 at entry. The FA association remained after adjusting for plasma fibrinogen. High fibrinogen concentrations themselves were also associated with ischaemic heart disease, as was high factor VII activity with fatal events. Low FA in younger men may exert a long-term influence by impairing the removal of fibrin deposits that contribute to atherogenesis. Low FA appears to be a leading determinant of ischaemic heart disease in younger men and methods of enhancing fibrinolytic activity, whether by life-style changes or pharmacologically, should be considered.

α2-Antiplasmin, Plasminogen Activator Inhibitor (PAI) and Dilute Blood Clot Lysis Time in Selected Disease States

This paper is an attempt to assess the relevance of the inhibitors of fibrinolysis for clot lysis in selected disease states and to discuss the mechanisms leading to acquired abnormal levels of such inhibitors. When compared to 20 control subjects the 30 hypertriglyceridemic patients (14 with type IIb and 16 with type IV) displayed significantly (p less than 0.001) increased plasma plasminogen activator inhibitor (PAI) activity (221 +/- 88% and 290 +/- 104% respectively; mean +/- SD), moderately (p less than 0.01) increased alpha 2 antiplasmin (alpha 2AP) level (112 +/- 11% and 115 +/- 16%) and accordingly an obviously prolonged dilute blood clot lysis time (DBCLT). Neither PAI activity and alpha 2AP level nor DBCLT were significantly different from controls in the 10 patients with hyperlipoproteinemia type IIa. The 18 patients with severe hepatic cirrhosis had low alpha 2AP level (59 +/- 19.7%) and accelerated clot lysis, while mean PAI activity (160 +/- 87%) was slightly (p less than 0.05) increased. In the 17 nephrotic patients alpha 2AP was increased (115 +/- 12%) while PAI activity was similar to controls and DBCLT rather shorter. Two liver secretion enzymes, namely serum cholinesterase and plasma protein C, were found to be decreased in cirrhotic patients, similar to control values in hyperlipoproteinemia type IIa and obviously increased in nephrotic patients as well as in hypertriglyceridemic subjects. The relevance of PAI and alpha 2AP for clot lysis was considered in relation to data in the literature concerning the behaviour of t-PA and factor XIII.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue-Type Plasminogen Activator (t-PA) and Dilute Blood Clot Lysis Time in Nephrotic Patients

When compared to normal weight normolipidemic control subjects, dilute blood clot lysis time was found to be obviously (p less than 0.001) prolonged in hypertriglyceridemic patients without proteinuria and slightly (p less than 0.05) accelerated in hyperlipidemic nephrotic patients in spite of their very high levels of plasma fibrinogen. As a result the ratio plasma fibrinogen (mg/dl) per clot lysis time (minutes) was 1.241 +/- 0.08 (X +/- SEM) in control subjects, 0.574 +/- 0.07 in hypertriglyceridemic patients and 2.69 +/- 0.172 in nephrotic patients. This finding suggesting that a larger amount of fibrin is rather readily dispersed from dilute blood clots of nephrotic patients was associated with higher levels of plasma t-PA:Ag (9.45 ng/ml +/- 1.18 in nephrotic patients versus 5.8 ng/ml +/- 1.23 in controls before venous occlusion and respectively 33.1 ng/ml +/- 3.83 versus 20.3 +/- 3.40 in controls after venous occlusion). Plasminogen activator activity of the euglobulins as assessed by the bovine fibrin-agarose plate was significantly higher in nephrotic patients only after venous occlusion. Plasma samples of nephrotic patients exerted a more potent inhibition of fibrinolysis in a urokinase activated system. This effect was, however, mainly due to the high levels of alpha 2 macroglobulin in nephrotic plasma which apparently have little influence on dilute blood clot lysis time.

Residual Plasminogen Activator Inhibitor Activity After Venous Stasis as a Criterion for Hypofibrinolysis: A Study in 83 Patients With Confirmed Deep Vein Thrombosis

Abstract In eighty-three patients with confirmed deep vein thrombosis, the fibrinolytic system was studied before and after a 10-minute venous occlusion. Blood was collected at least 3 months after the last acute episode, and PAI-1 antigen and activity, as well as tissue-type plasminogen activator (t-PA) antigen, urokinase-type plasminogen activator (u-PA) antigen, and fibrinolytic activity were measured in these samples. During venous stasis, plasminogen activator inhibitor (PAI) activity decreased in almost all patients (81 of 83), from a median value of 8.2 to 2.9 U/mL (P less than .001, Wilcoxon signed-rank test). Because PAI-1 antigen augmented from a median value of 16 to 19.2 ng/mL (P less than .001), the decline in PAI activity was attributed to an increase in t-PA antigen from a median value of 10 to 21.7 ng/mL (P less than .001). Neutralization of PAI activity thus reflects the patient's capacity to overcome basal inhibitory potential through t-PA release. Based on residual PAI activity after 10-minute stasis, patients were classified as good or bad responders (PAI activity below detection limit, ie, less than or equal to 1.0 and greater than 1.0 U/ml, respectively). Good responders had a significantly higher fibrinolytic response after stasis than bad responders (median euglobulin clot lysis time 60 v 180 minutes; dilute whole blood clot lysis time 60 v 120 minutes; fibrinolytic activity on fibrin plates 7.7 v 0 U/mL). Furthermore, good responders, as compared with bad responders, had higher t-PA release (median 16.5 v 11.5 ng/mL), lower basal PAI activity (median 4.8 v 11.2 U/mL), and lower basal PAI-1 (median 11 v 21 ng/mL) and u-PA antigen (median 7.9 v 9.0 ng/mL, P less than .02). Hypofibrinolysis, as defined by the inability of released t-PA to overcome PAI-1 basal inhibitory potential, was observed in 45 of 83 patients (54%) and resulted either from an insufficient release of t-PA or from an increased basal PAI activity.

Residual plasminogen activator inhibitor activity after venous stasis as a criterion for hypofibrinolysis: a study in 83 patients with confirmed deep vein thrombosis

In eighty-three patients with confirmed deep vein thrombosis, the fibrinolytic system was studied before and after a 10-minute venous occlusion. Blood was collected at least 3 months after the last acute episode, and PAI-1 antigen and activity, as well as tissue-type plasminogen activator (t-PA) antigen, urokinase-type plasminogen activator (u-PA) antigen, and fibrinolytic activity were measured in these samples. During venous stasis, plasminogen activator inhibitor (PAI) activity decreased in almost all patients (81 of 83), from a median value of 8.2 to 2.9 U/mL (P less than .001, Wilcoxon signed-rank test). Because PAI-1 antigen augmented from a median value of 16 to 19.2 ng/mL (P less than .001), the decline in PAI activity was attributed to an increase in t-PA antigen from a median value of 10 to 21.7 ng/mL (P less than .001). Neutralization of PAI activity thus reflects the patient's capacity to overcome basal inhibitory potential through t-PA release. Based on residual PAI activity after 10-minute stasis, patients were classified as good or bad responders (PAI activity below detection limit, ie, less than or equal to 1.0 and greater than 1.0 U/ml, respectively). Good responders had a significantly higher fibrinolytic response after stasis than bad responders (median euglobulin clot lysis time 60 v 180 minutes; dilute whole blood clot lysis time 60 v 120 minutes; fibrinolytic activity on fibrin plates 7.7 v 0 U/mL). Furthermore, good responders, as compared with bad responders, had higher t-PA release (median 16.5 v 11.5 ng/mL), lower basal PAI activity (median 4.8 v 11.2 U/mL), and lower basal PAI-1 (median 11 v 21 ng/mL) and u-PA antigen (median 7.9 v 9.0 ng/mL, P less than .02). Hypofibrinolysis, as defined by the inability of released t-PA to overcome PAI-1 basal inhibitory potential, was observed in 45 of 83 patients (54%) and resulted either from an insufficient release of t-PA or from an increased basal PAI activity.

Is urinary infection a risk factor for ischemic cerebrovascular disease?

The hypothesis is put forward that urinary infection is a risk factor for ischemic cerebrovascular disease (ICVD). Bacteriuria exceding 10 5 units/ml actiually occurred in 68% of the patients with ICVD while a similar number of bacteria was detected only in 12% of the age-matched control subjects. An increased concentration of circulating immune complexes was found in infected patients but the investigated hemostatic variables (plasma fibrinogen and factor VIII related antigen, platelet count and adhesivenes as well as dilute blood clot lysis time) did not significantly differ from patients with ICVD but no urinary infection. Although circulating immune complexes are able to cause endothelial lesions, further investigations on the hemostatic balance are required in order to substantiate the above mentioned hypothesis.

The Pathogenesis of Accelerated Fibrinolysis in Liver Cirrhosis: A Critical Role for Tissue Plasminogen Activator Inhibitor

AbstractThe pathogenesis of accelerated fibrinolysis in liver cirrhosis was investigated by comparing the results of specific assays for tissue plasminogen activator (tpa) antigen, tpa activity, tpa inhibitor, and alpha-2 plasmin inhibitor (a2PI) in 12 patients with cirrhosis and markedly accelerated fibrinolysis (dilute whole blood clot lysis time (DWBCLT) < two hours), in nine patients with cirrhosis and moderately accelerated fibrinolysis (DWBCLT two to four hours), and in nine patients with cirrhosis and normal fibrinolysis (DWBCLT > four hours). Mean tpa antigen was markedly increased in all three groups, but no correlation was observed between overall fibrinolytic activity as measured by the DWBCLT and the level of tpa antigen. In contrast, there was a significant correlation between overall fibrinolytic activity and tpa activity and an equally significant correlation between fibrinolytic activity and decreased tpa inhibition. Mean a2PI activity was significantly lower than normal in groups 1 and 2 but was normal in group 3. The pathogenesis of accelerated fibrinolysis in liver cirrhosis thus appears to depend critically on the capacity of plasma inhibitors to inhibit increased circulating tpa antigen. Reduced a2PI also appears to play a role.

The pathogenesis of accelerated fibrinolysis in liver cirrhosis: a critical role for tissue plasminogen activator inhibitor

The pathogenesis of accelerated fibrinolysis in liver cirrhosis was investigated by comparing the results of specific assays for tissue plasminogen activator (tpa) antigen, tpa activity, tpa inhibitor, and alpha-2 plasmin inhibitor (a2PI) in 12 patients with cirrhosis and markedly accelerated fibrinolysis (dilute whole blood clot lysis time (DWBCLT) less than two hours), in nine patients with cirrhosis and moderately accelerated fibrinolysis (DWBCLT two to four hours), and in nine patients with cirrhosis and normal fibrinolysis (DWBCLT greater than four hours). Mean tpa antigen was markedly increased in all three groups, but no correlation was observed between overall fibrinolytic activity as measured by the DWBCLT and the level of tpa antigen. In contrast, there was a significant correlation between overall fibrinolytic activity and tpa activity and an equally significant correlation between fibrinolytic activity and decreased tpa inhibition. Mean a2PI activity was significantly lower than normal in groups 1 and 2 but was normal in group 3. The pathogenesis of accelerated fibrinolysis in liver cirrhosis thus appears to depend critically on the capacity of plasma inhibitors to inhibit increased circulating tpa antigen. Reduced a2PI also appears to play a role.

Platelet aggregation and coagulation factors in insulin dependent diabetics with and without microangiopathy.

Abnormalities of platelet aggregation and coagulation have been reported in insulin dependent diabetes mellitus (IDDM), although there is controversy concerning their relationship to microangiopathy. We have studied platelet function and haemostasis in 55 patients with IDDM, 23 without, 14 with mild (background retinopathy) and 18 with severe (proliferative retinopathy, or background retinopathy plus proteinuria) complications. Studies were done on 2 occasions 8 weeks apart and the results compared with 28 control subjects. There was evidence of increased in vivo platelet aggregation in the diabetic group v controls shown by raised values of beta-thromboglobulin (61 +/- 42, mean +/- SD, v 18 +/- 14 micrograms/ml, p less than 0.001), platelet factor 4 (62 +/- 76 v 14 +/- 11 micrograms/ml, p less than 0.01), and platelet micro-aggregates (20 +/- 16 v 12 +/- 11%, p less than 0.01). There was no significant difference in fibrinogen and fibrinopeptide A levels, nor in 'in vitro' tests of platelet aggregation between the groups. Dilute whole blood clot lysis time was increased in the diabetic group v controls (6.4 +/- 2.6 v 4.8 +/- 0.5 hours, respectively, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The rabbit as a model for studies of fibrinolysis

When compared to man, the rabbit shows marked prolongation of the dilute whole blood clot lysis time and an attenuated increase in plasminogen activator (PA) after the infusion of desmopressin (DDAVP). The levels of specific components of the plasma fibrinolytic system of the rabbit were compared to those in human plasma to ascertain their role in the differences between species. PA activity and plasminogen levels were similar in the two species. Anti-plasmin and plasminogen activator inhibitor (PAI) activity were lower in the rabbit than in man. The rabbit PAI, apparently similar to that described in man, was not increased by DDAVP infusion. The disparity between man and rabbit with respect to the lysis times of dilute blood clots and response to DDAVP cannot be explained by differences in functional plasma levels of inhibitors or activators of the fibrinolytic system.

In Vitro Effect of p-Chlormercuribenzoate upon Dilute Blood Clot Lysis Time in Hyperlipemia

SummaryIn comparison to values obtained in normal-weight normolipenic controls, dilute blood clot lysis time was found to be prolonged in resting and exercised patients with endogenous hypertriglyceridemia. Lysis time was also prolonged in overweight subjects with only slightly increased serum lipids but it was not significantly changed in type II-a hyperlipoproteinemia. An obvious acceleration of clot lysis was noted in patients with decompensated cirrhosis of the liver. Inclusion of p-chlormercuribenzoate (PCMB) into the diluted blood clot caused an acceleration of lysis time. This effect was particularly obvious with hypertriglyceridemic blood and minimal with blood obtained from cirrhotic patients. Addition of various amounts of heat-defibrinated plasma to blood from cirrhotic patients caused a proportional prolongation of clot lysis time and this effect was greatly diminished in the presence of PCMB. Similar amounts of serum had a much lesser effect than defibrinated plasma. Inhibition of fibrin cross-linking by PCMB was confirmed by sodium dodecylsulfate polyacrylamide gel electrophoresis.The present data complete previous observations concerning a higher plasma factor XIII activity in type II-b and type IV hyperlipoproteinemia and suggest that an increased crosslinking of fibrin might partially explain the deficient thrombolysis of hypertriglyceridemic patients.

Effects of some benzodiazepine derivatives on fibrinolysis and serum lipids in normolipidaemic rats and in humans

The effects of diazepam, chlordiazepoxide, lorazepam and bipotassium chlorazepate on the dilute blood-clot lysis time in normolipidaemic rats and in humans were investigated. Diazepam in small doses induced in acutely treated rats an acceleration of fibrinolysis. At the same time chlordiazepoxide was ineffective, while lorazepam and bipotassium chlorazepate delayed the lysis time. Large doses of diazepam were less effective than small ones, while chlordiazepoxide was more active when larger doses were used. Lorazepam had an inhibitory effect when administered in large doses. In contrast to the lowering effect exhibited by small doses of bipotassium chlorazepate, larger doses were found to produce a slight acceleration of lysis time. In subacutely treated rats, both small and large doses were found to activate fibrinolysis, with the exception of large doses of bipotassium chlorazepate which proved to be inhibitory. Only minor changes in serum lipids (total cholesterol and triglycerides) were observed in normolipidaemic rats treated with the compounds mentioned above. Acceleration of clot lysis but no significant changes in serum lipids or of plasma fibrinogen were noted in 13 healthy human volunteers given therapeutic doses of diazepam.

The Effect of Plasma Fibrinogen Levels on Measures of Fibrinolytic Activity

It has been claimed that lysis time methods may be inappropriate as measures of fibrinolytic activity on the grounds that they are largely determined by plasma fibrinogen levels. The dilute blood clot lysis time (DBCLT) has therefore been measured in 103 subjects; fibrinolytic activity (expressed as 100/DBCLT) has been compared with the fibrin plate area (FPA) lysed by the euglobulin fraction, the latter method being, of course, virtually independent of plasma fibrinogen. Plasma fibrinogen levels have also been measured; they ranged from 167 to 416 mg%. Results have been analysed by the technique of multiple regression. The incorporation of plasma fibrinogen levels in the regression equation relating 100/DBCLT to FPA does not result in a significant increase in the proportion of the variance in 100/DBCLT that can be explained. It is concluded that there is no evidence that DBCLT is influenced by plasma fibrinogen levels within the physiological range.

Dilute blood clot lysis time and electrophoretic lipoprotein fractions in a population sample of healthy Romanians

Serum total lipids and cholesterol, electrophoretically determined lipoprotein concentrations, serum pseudocholinesterase and dilute blood clot lysis time were determined in 630 healthy subjects (287 men and 343 women) aged 20–60, working in the food industry. A high incidence of over-weight was noted ranging from 22.4% in women aged 20–40 to 58.7% in men aged 41–60. Over-weight subjects presenting higher levels of serum cholesterol, total lipids and of the pre-beta electrophoretic fraction also had a higher pseudo-cholinesterase activity and a more delayed clot lysis time than normal-weight subjects matched as to age and sex. When the material was divided into quintiles for pre-beta- and beta-lipoproteins, a highly significant delay of fibrinolysis was noted in the fourth and fifth quintiles for pre-beta-lipoproteins, but no significant changes of lysis time occurred with increasing concentrations of beta-lipoproteins. Possible explanations of the abovementioned findings are briefly discussed.

Idiopathic recurrent superficial thrombophlebitis: treatment with fibrinolytic enhancement.

Sixteen patients with idiopathic recurrent superficial thrombophlebitis were shown to have a defect of blood and tissue fibrinolytic activity. After six months' treatment with stanozolol their mean dilute blood clot lysis time and plasma fibrinogen fell significantly and the mean fibrin plate lysis area increased. Attacks of thrombophlebitis stopped completely in 13 patients, though five patients later suffered recurrences and phenformin had to be added to their treatment. Fibrinolytic enhancement with stanozolol seems to be effective in this previously intractable condition, and regular blood studies will indicate which patients also need phenformin.

Blood and vein-wall fibrinolytic activity in health and vascular disease.

The resting blood fibrinolytic activity of 120 normal subjects and 294 patients with various forms of vascular disease was assessed by measuring the dilute blood clot lysis time and fibrin plate lysis area before and after 10 minutes of venous congestion. The tissue fibrinolytic activity of several of these subjects was assessed in vein biopsy specimens. The results suggested that there was a correlation between blood and tissue fibrinolytic activity and that certain venous diseases, particularly recurrent superficial thrombophlebitis and venous liposclerosis, were associated with a deficiency of blood and tissue fibrinolytic activity.

The effect of oxpentifylline (Trental') on fibrinolytic activity and plasma fibrinogen levels

Twenty healthy volunteers were treated for 3 months with oxpenifylline (200 mg 3-times a day) or a placebo in a controlled double-blind randomized trial. The volunteers taking the oxpenifylline showed a significant increase in their fibrinolytic activity, as assessed by the dilute blood clot lysis time and fibrin plate lysis area, and a significant reduction in their plasma fibrinogen levels. No change was found in the control group. These findings suggest that oxpentifylline may be valuable in the treatment of small vessel occlusive disease associated with lowered fibrinolytic activity and raised fibrinogen levels.