Correlation of in Vivo Clot Lysis with other Thrombolytic Variables Following Administration of abbokinase ®(Tissue Culture Urokinase), to Anesthetized Dogs

1979 ◽  
Author(s):  
D. Martin ◽  
J. Cain ◽  
J. Chmiel ◽  
S.E. El Masry
Keyword(s):  
Mathematical Model ◽  
Tissue Culture ◽  
Plasma Levels ◽  
Half Life ◽  
Clot Lysis ◽  
Lysis Time ◽  
Euglobulin Lysis Time ◽  
Anesthetized Dogs

An anesthetized dog model, using an extracorporeal loop containing an autologous radioactive clot, was utilized to test the effects of various doses of ABBOKINASE® on the rate of clot lysis and on plasma levels of urokinase, plasmin, antiplasmin, plasminogen and fibrinogen. The effects of ABBOKINASE® on hematocrit, euglobulin lysis time and125 I-clot lysis, in vitro, were also determined. Correlations were sought between plasma urokinase, plasmin, antiplasmin and the rate of clot lysis. Kinetic evaluations of half-lives of urokinase and plasmin and of the rate of regeneration of antiplasmin were made. Some of the conclusions reached were: 1) plasma fibrinogen does not decrease until antiplasmin is depleted and free plasmin appears in blood. 2) plasma urokinase levels are related to the dose infused and decrease with a half-life of about 8 minutes following infusion. 3) the rate of clot lysis in the loop is proportional to the dose of ABBOKINASE® over a defined range of doses and can be fitted to a mathematical model. 4) at lower doses, clot lysis occurs in the absence of measurable free plasmin.

The Effect of Erythropoietin on Platelet Function and Fibrinolysis in Chronic Renal Failure

1994 ◽  
Vol 17 (3) ◽  
pp. 141-145 ◽  
Author(s):  
D. Stenver ◽  
L. Jeppesen ◽  
B. Nielsen ◽  
J. Dalsgaard Nielsen ◽  
C. Hædersdal ◽  
...  
Keyword(s):  
Platelet Function ◽  
Clot Lysis ◽  
Platelet Activity ◽  
Platelet Factor ◽  
Human Erythropoietin ◽  
Lysis Time ◽  
Euglobulin Clot Lysis Time ◽  
Erythropoietin Treatment

The influence of erythropoietin therapy on platelet function and fibrinolysis was evaluated in 12 anemic hemodialysis patients. Six months of therapy with human erythropoietin (50 to 80 IU/kg initially) raised the hemoglobin level to 10.8 g/dl but did not increase platelet activity in vivo as measured by beta-thromboglobulin or platelet factor 4. There was no change in the platelet aggregation thresholds in vitro for ADP, adrenaline, thrombin or collagen during treatment. Platelet number and volume were also unaffected. Fibrinolytic activity intensified as erythropoietin treatment proceeded, with a fall of euglobulin clot lysis time and rise in the activity of t-PA. PAI-1 levels also showed a downward trend, without reaching significance. Thus erythropoietin treatment in modest doses does not seem to adversely influence the hemostatic system in patients on hemodialysis.

scholarly journals ‘In Vivo’ and ‘In Vitro’ Effects of Some Vasoactive Drugs on Platelet Function and on Coagulation/Fibrinolysis System

1977 ◽  
Author(s):  
A.G. Dettori ◽  
O. Ponari ◽  
C. Manotti ◽  
A. Megha ◽  
M. Pini
Keyword(s):  
Platelet Function ◽  
Vasoactive Drugs ◽  
Platelet Function Tests ◽  
Lysis Time ◽  
Low Concentrations ◽  
Euglobulin Lysis Time ◽  
In Vitro Effects ◽  
Induced Aggregation

Three substances widely used as vasoactive drugs are known to have an inhibiting effect on platelet aggregation ‘in vitro’. We investigated the changes induced on thrombelastogram, routine clotting tests, euglobulin lysis time (ELT), platelet count, aggregation, and adhesiveness by i, v. administration of these drugs to man. The same indices were also studied ‘in vitro’ by adding comparable concentrations of the substances to human blood or plasma.Aminophilline did not produce any significant variation in ADP-or collagen-induced aggregation either ‘in vitro’ (50 to 200 μg/ml) or ‘in vivo’ (240 mg). A trend to disaggregation was seen only in a few cases. Shorter ELT were found 30 and 120 minutes after injection.A papaverine derivative (Metaverinum, 150 mg) showed a similar ‘in vivo’ pattern: minor changes in platelet function tests and a moderate activation of fibrinolysis were seen. The drug acted ‘in vitro’ as a powerful inhibitor of aggregation (from 30 µg/ml)while fibrinolysis was only activated at the highest concentration (120 µg/ml).Bencyclan, capable of inhibiting platelet function ‘in vitro’ at very low concentrations (0.25µM) did not show similar effects ‘in vivo’ (50 mg) apart from a reduced platelet adhesiveness to glass.

Clot Lysis in a Perfusion System

1966 ◽  
Vol 15 (01/02) ◽  
pp. 205-219
Author(s):  
C. A Bouvier ◽  
J Gruendlinger ◽  
S Berthoud
Keyword(s):  
Aminocaproic Acid ◽  
Clot Lysis ◽  
Fibrin Gel ◽  
Standard Size ◽  
Lysis Time ◽  
Therapeutic Thrombolysis ◽  
And Diffusion ◽  
Diffusion Problems

SummaryMost information on clot lysis is derived from in vitro methods whereby various components of the clotting and fibrinolytic systems are mixed before an actual clot is formed. This situation bears little relationship to thrombolysis in vivo. Therefore several techniques have been recently proposed, in which pre-formed clots are exposed to the effects of active agents by contact and diffusion rather than by intimate mixing prior to clotting. We describe an apparatus whereby a perfusion is delivered at controlled rates to clots of standard size and volume formed in calibrated tubes. The composition of the clots can be varied as well as the rate of perfusion and the content of perfusate. The surface of contact between the fluid and the fibrin gel is kept constant throughout and the clot-perfusate relationship is as close as possible to the in vivo situation during thrombolytic therapy. Under these conditions clot lysis by Streptokinase appears as a linear function of time, and the rate of lysis is directly related to kinase concentration. Since the clot intrinsic plasminogen-proactivator content is sufficient to ensure lysis, the lysis time finally depends upon the rate of diffusion of the kinase into the gel. Inhibition obtained with various amounts of E-aminocaproic acid incorporated to the clots or added to the perfusion fluid also suggests that diffusion problems are of major importance in physiological and therapeutic thrombolysis.

A Comparison of Pentosan Polysulphate and Heparin II: Effects of Subcutaneous Injection

1982 ◽  
Vol 47 (02) ◽  
pp. 109-113 ◽  
Author(s):  
A-M Fischer ◽  
R E Merton ◽  
N A Marsh ◽  
S Williams ◽  
P J Gaffney ◽  
...  
Keyword(s):  
Subcutaneous Injection ◽  
Factor Xa ◽  
Coagulation System ◽  
Clot Lysis ◽  
Lysis Time ◽  
At Iii ◽  
Euglobulin Clot Lysis Time ◽  
Pentosan Polysulphate

SummaryA comparison has been made between the effects of pentosan polysulphate (SP54) and mucosal heparin following subcutaneous injection in man. Unlike heparin, pentosan polysulphate has relatively little effect in vivo as measured by anti-factor Xa clotting assay and none by an anti-Xa amidolytic assay (S-2222). However, pentosan polysulphate is at least as potent as heparin on a weight basis in producing activation of lipoprotein lipase, shortening of the euglobulin clot lysis time and impairing the generation of factor Xa. Our data indicate that pentosan polysulphate has more marked effects in vivo than in vitro, that the action of the drug on clotting is mediated mainly via an At III-independent pathway, and that its effects are not confined to the coagulation system.

Effect of a Selective Thrombin Inhibitor MCI-9038 on Fibrinolysis In Vitro and In Vivo

1986 ◽  
Vol 56 (01) ◽  
pp. 028-034 ◽  
Author(s):  
Y Tamao ◽  
T Yamamoto ◽  
R Kikumoto ◽  
H Hara ◽  
J Itoh ◽  
...  
Keyword(s):  
Cell Injury ◽  
Factor Xiiia ◽  
Thrombin Inhibitor ◽  
Clot Lysis ◽  
Plasma Clot ◽  
Lysis Time ◽  
Combined Use ◽  
Lower Effect

SummaryThe effect of a selective thrombin inhibitor, (2R, 4R)-4-methyl-1- [N2- [(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfo-nyl]-L-arginyl]-2-piperidinecarboxylic acid (MCI-9038), on the fibrinolysis induced by t-PA and u-PA was studied in vitro and in vivo. MCI-9038 remarkably reduced the lysis time of the plasma clot generated by the addition of calcium chloride to the plasma at the concentration ranging from 0.01 to 0.3 μM. Heparin also reduced the plasma clot lysis time with a lower effect than MCI-9038. The fibrin crosslinkage in the plasma clot was inhibited by MCI-9038 or heparin. MCI-9038 potently inhibited the factor XIIIa generation from factor XIII by thrombin.The effect on the in vivo thrombolysis was studied on the arterial thrombosis generated by the endothelial cell injury of the rabbit carotid artery by acetic acid. t-PA dissolved the thrombi with the infusion at 0.96 mg/kg over 2 h without a significant activation of a systemic fibrinolysis. u-PA dissolved the thrombi with the infusion at 180,000 and 360,000 IU/kg over 2 h. At a dose of 0.48 mg/kg t-PA or 90,000 IU/kg u-PA, the thrombi were not dissolved, but the combined use of MCI-9038 at 1.2 mg/kg over 2 h effectively dissolved the thrombi. Thus, combination of MCI-9038 with plasminogen activators accelerated thrombolysis of an experimental thrombosis in rabbits.

Effect of Heparin on Lysis of Fibrinogen/Fibrin

1979 ◽  
Author(s):  
R. Chakrabarti
Keyword(s):  
Clot Lysis ◽  
In Vitro Tests ◽  
Human Fibrinogen ◽  
Lysis Time ◽  
Small Doses ◽  
Before And After ◽  
Opposing Effects ◽  
Vitro Effect

The incubation of citrated human plasma with small doses of streptokinase or urokinase for 30 minutes does not result in any appreciable loss of recoverable fibrinogen in the plasma. However, the addition of heparin before incubation causes a loss of fibrinogen which is dependent on the dose of heparin added. This in vitro effect has been confirmed in plasma from patients before and after receiving 5-7, 500 units of heparin intravenously. It is possible that the loss of fibrinogen is due to the interaction of heparin with the inhibitors of fibrinolysis. To study this, in vitro tests were performed in a purified system (i.e. without inhibitors), using plasminogen-rich human fibrinogen and urokinase. These tests revealed that the addition of heparin to the fibrinogen before it wae clotted with thrombin in the presence of urokinase shortened clot lysis times. On the other hand, the addition of heparin prolonged the lysis time of a preforaed clot by urokinase. These results imply that the loss of fibrinogen originally observed was not due to an interaction of heparin with inhibitors. The results indicate that heparin augments or retards fibrinolysis by urokinase depending on whether the heparin is present before or after fibrinogen is converted to fibrin. If opposing effects of heparin on fibrinolysis are confirmed in vivo, it will be necessary to distinguish carefully between its use prophylactically and therapeutically, especially if used in association with a thrombolytic agent.

scholarly journals Solulin increases clot stability in whole blood from humans and dogs with hemophilia

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3622-3628 ◽  
Author(s):  
Jonathan H. Foley ◽  
Karl-Uwe Petersen ◽  
Catherine J. Rea ◽  
Lori Harpell ◽  
Sandra Powell ◽  
...  
Keyword(s):  
Protein C ◽  
Ex Vivo ◽  
Soluble Form ◽  
Clot Lysis ◽  
Lysis Time ◽  
Low Concentrations ◽  
Clot Lysis Time ◽  
Clot Stability

Solulin is a soluble form of thrombomodulin that is resistant to proteolysis and oxidation. It has been shown to increase the clot lysis time in factor VIII (fVIII)–deficient plasma by an activated thrombin-activatable fibrinolysis inhibitor (TAFIa)–dependent mechanism. In the present study, blood was drawn from humans and dogs with hemophilia, and thromboelastography was used to measure tissue factor–initiated fibrin formation and tissue-plasminogen activator–induced fibrinolysis. The kinetics of TAFI and protein C activation by the thrombin-Solulin complex were determined to describe the relative extent of anticoagulation and antifibrinolysis. In severe hemophilia A, clot stability increased by > 4-fold in the presence of Solulin while minimally affecting clot lysis time. Patients receiving fVIII/fIX prophylaxis showed a similar trend of increased clot stability in the presence of Solulin. The catalytic efficiencies of TAFI and protein C activation by the thrombin-Solulin complex were determined to be 1.53 and 0.02/μM/s, respectively, explaining its preference for antifibrinolysis over anticoagulation at low concentrations. Finally, hemophilic dogs given Solulin had improved clot strength in thromboelastography assays. In conclusion, the antifibrinolytic properties of Solulin are exhibited in hemophilic human (in vitro) and dog (in vivo/ex vivo) blood at low concentrations. Our findings suggest the therapeutic utility of Solulin at a range of very low doses.

Plasma Fibronectin Enhances Fibrinolytic System In Vitro

1985 ◽  
Vol 54 (03) ◽  
pp. 639-644 ◽  
Author(s):  
Nisan Gilboa ◽  
John E Kaplan
Keyword(s):  
Fibrinolytic System ◽  
Clot Lysis ◽  
Plasminogen Activation ◽  
Plasma Fibronectin ◽  
Amidolytic Activity ◽  
Lysis Time ◽  
Tissue Plasminogen ◽  
Clot Lysis Time

SummaryThe effects of plasma fibronectin on the fibrinolytic system were studied in vitro. Fibronectin caused a time and concentration-dependent increase (up to 99% with 330 ug/ml) in the amidolytic activity of tissue plasminogen activator (TPA) but not of urokinase. In the presence of fibronectin the Km of the amidolytic activity of TPA decreased without a change in Vmax. It also caused a concentration-dependent increase in lys-plas-minogen activation by TPA (up to 825% with 375 ug/ml) and by urokinase (up to 400% with 250 ug/ml), as well as in the amidolytic activity of plasmin (up to 55% with 300 ug/ml). Fibronectin did not enhance the activation of glu-plasminogen. In the presence of fibronectin the Km of lys-plasminogen activation decreased without a change in Vmax. In purified systems fibronectin significantly shortened the clot lysis time (CLT) by up to 28% and 30% in TPA- and plasmin-activated lysis, respectively. The presence of Ca2+ did not change fibronectin’s effect on CLT. Clots of non-fibronectin-depleted plasma were lysed up to about twice as fast as the clots of fibronectin-depleted plasma. In conclusion, physiologic concentrations of fibronectin enhanced the fibrinolytic system in vitro. Further studies will be required to elucidate the mechanisms involved and to document whether fibronectin has a similar effect in vivo.

ASPIRIN ACETYLATES FIBRINOGEN AND ENHANCES FIBRINOLYSIS IN VIVO. FIBRINOLYTIC EFFECT IS INDEPENDENT OF CHANGES IN PLASMINOGEN ACTIVATOR LEVELS

1987 ◽  
Author(s):  
D Thorir ◽  
M D Bjornsson ◽  
Henry Berger
Keyword(s):  
Plasminogen Activator ◽  
Time Course ◽  
Clot Lysis ◽  
Thrombin Time ◽  
Lysis Time ◽  
Coagulation Tests ◽  
Clot Lysis Time ◽  
Increased Susceptibility

In addition to its antiplatelet effect, aspirin has been reported to have fibrinolytic and hypoprothrombinémie effects. The objective of this study was to investigate possible mechanisms underlying the enhanced fibrinolysis observed after aspirin. Five healthy subjects received 650 mg of aspirin ql2hr for five days. Blood samples were collected before aspirin (control) and immediately before (0 hr) and two hours after (2 hr) the last dose for determinations of clot lysis time, time course of thrombin-induced fibrin aggregation, tissue plasminogen activator (tPA), intrinsic pathway fibrinolytic activity (IPFA), plasminogen, fibrinogen, aspirin and salicylic acid, and the coagulation tests activated partial thromboplastin time, thrombin time and prothrombin time. Clot lysis time was shorter after aspirin, control: 9.1±12.4 min (mean±s.d.), 0 hr: 4.6±4.0 min, 2 hr: 5.7±6.2 min (p:0.04), and the fibrin aggregation curves showed increased turbidity (expressed as AUC over 10 min), control: 72.7±17.8 mnumin, 0 hr: 94.6±1.6 mnumin, 2 hr: 112.8±45.1 mnumin (p:0.02). Control values of tPA (0.11±0.04 IU/ml), IPFA (2.20±0.59 IU/ml), plasminogen (10.9±1.0 mg/dl), fibrinogen (288±37 mg/dl), and the coagulation tests were not differnet from those after aspirin. Plasma aspirin concentrations were below detection limits at 0 hr and averaged 1.63±0.97μg/ml at 2 hr. In vitro studies using fibrinogen-free plasma and added acetylated fibrinogen sfiowed an inverse relationship between the extent of acétylation and clot lysis time. Studies using 14C-acetyl-labeled aspirin and fibrinogen showed that fibrinogen is acetylated to form ε-N-acetyl-lysine on both D and E domains of the molecule (50.6±2.0 and 49.4±2.0%, respectively) and on α β and γchains of the molecule (34.4±1.6, 30.7±3.4 and 34.9±4.7%, respectively), with preferential acétylation on the E domain. On the average, 2.88±1.49 ε-N-acetyl-lysyl residues were formed on each fibrinogen molecule. These results suggest that N-acetylation of lysyl residues of fibrinogen is responsible for the increased susceptibility of fibrin clots to lysis after aspirin.

scholarly journals Comparison of in Vivo Biochemical Effects of Human Urokinase Prepared from Urinary and Tissue Culture Sources

1977 ◽  
Author(s):  
Victor J. Marder ◽  
Joseph F. Donahoe ◽  
William R. Bell ◽  
John J. Cranley ◽  
Hau C. Kwaan ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Pulmonary Embolism ◽  
Degradation Products ◽  
Human Kidney ◽  
Multicenter Trial ◽  
Clot Lysis ◽  
Clinical Aspects ◽  
Fibrin Plate ◽  
Euglobulin Lysis Time

In patients with pulmonary emboli, resolution has been shown to be more rapid in those receiving urinary urokinase than in those receiving heparin alone. A different source of urokinase has now been developed, namely human kidney cells grown in tissue culture. In a randomized, multicenter trial, two groups of 15 patients with pulmonary embolism received either the urinary or tissue culture urokinase. Blood samples prior to, during and after treatment were compared with regard to biochemical changes in the plasma fibrinolytic system. Both agents caused strikingly similar rates, degrees and durations of response, as reflected in the whole blood euglobulin lysis time, unheated fibrin plate lysis zones, 125-I tagged clot lysis, plasma plasminogen, plasma clottable protein and serum fibrin/fibrinogen degradation products. Bleeding occurred in about 50% of both groups of patients, primarily from cutdown sites. The results clearly indicate that the pharmacologic effect of tissue culture urokinase was the same as that of urinary urokinase, and it is reasonable to expect that both materials will be equally effective in the hemodynamic and clinical aspects of patients with pulmonary embolism.

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