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.

A HEP ARINE-LIKE ANTICOAGULANT IN A PATIENT WITH WEGENER’S GRANULOMATOSIS

1987 ◽  
Author(s):  
L Chrobák ◽  
V Rozsíval ◽  
V Herout
Keyword(s):  
Wegener’S Granulomatosis ◽  
Wegener's Granulomatosis ◽  
Thrombin Time ◽  
Protamine Sulphate ◽  
Normal Limits ◽  
Significant Prolongation ◽  
Lysis Time ◽  
Coagulation Tests

In a 23-year-old man with Wegener’s granulomatosis and mild bleeding coagulation studies revealed a significant prolongation of the coagulation time (CT) prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), failure of TT and aPTT to correct in a 1:1 mixture with pooled normal plasma (PNP), correction of the prolonged TT with toluidine blue and correction of TT and aPTT both in vitro and in vivo^protamine sulphate (P.S.).All other coagulation tests, i.e.,bleeding time, platelet count? fibrinogen level, euglobulme lysis time were within normal limits. The patient did not receive heparine. TT after administration of 5ml of protamine sulphate i.v. to the patient became normal - 18,2 s (19,7 s).In summary a patient with Wegener s granulomatosis associated with an endogenous heparine-like anticoagulant is reported. The anticoagulant could be corrected both in vitro and in vivo by protamine sulphate.

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.

Different mechanisms contribute to the biphasic pattern of carboxypeptidase U (TAFIa) generation during in vitro clot lysis in human plasma

2003 ◽  
Vol 89 (02) ◽  
pp. 264-271 ◽  
Author(s):  
Judith Leurs ◽  
Britt-Marie Wissing ◽  
Viveca Nerme ◽  
Katinka Schatteman ◽  
Petter Björquist ◽  
...  
Keyword(s):  
Human Plasma ◽  
Time Course ◽  
Thrombin Inhibitor ◽  
Clot Lysis ◽  
Time Period ◽  
Lysis Time ◽  
Two Peaks ◽  
Plasmin Inhibitor ◽  
Clot Lysis Time

SummaryCarboxypeptidase U (CPU, TAFIa) recently gained interest as a significant player in dampening the fibrinolytic rate. The aim of this study was to investigate the time course of the generation of CPU activity during coagulation and fibrinolysis using an in vitro clot lysis model in human plasma. A first peak of CPU activity appeared after initiation of the coagulation phase and a second rise in CPU activity was observed during the fibrinolysis. The decrease in the proCPU plasma concentration followed the same trend as the appearance of the CPU activity. The direct thrombin inhibitor inogatran eliminated the CPU generation during coagulation but not during fibrinolysis. Addition of the plasmin inhibitor aprotinin during fibrinolysis resulted in a decrease in CPU activation during the lysis phase. These results demonstrate that proCPU was activated during coagulation by thrombin and during fibrinolysis by plasmin. Addition of a CPU inhibitor before initiation of clotting decreased the clot lysis time as expected. However, addition in the time period between the two peaks of CPU activity had no apparent effect on the clot lysis time.

Influence of Moderate and Strenuous Daily Physical Activity on Fibrinolytic Activity of Blood: Possibility of Plasminogen Activator Stores Depletion

1979 ◽  
Vol 41 (04) ◽  
pp. 745-755 ◽  
Author(s):  
Dušan Keber ◽  
Mojca Stegnar ◽  
Irena Keber ◽  
Bojan Accetto
Keyword(s):  
Physical Activity ◽  
Plasminogen Activator ◽  
Fibrinolytic Activity ◽  
Regular Physical Activity ◽  
Clot Lysis ◽  
Moderate Activity ◽  
Lysis Time ◽  
Strenuous Activity ◽  
Activity Measurements ◽  
Clot Lysis Time

SummaryFibrinolysis was studied in 10 alpinists during regular physical activity of different intensity. Blood was sampled at rest and after exposure to submaximal workload on the treadmill on three occasions: before and after 6 months physical conditioning (moderate physical activity), and after 6 weeks of an alpinistic expedition (strenuous physical activity). Measurements included submaximal working capacity, fibrinogen, euglobulin clot lysis time (ELT), whole plasma clot lysis time, and estimations derived from ELT - percent increase in fibrinolytic activity after exercise (RFS), and absolute increase in fibrinolytic activity after exercise (PAR).Regular moderate activity increased the resting level of ELT, but strenuous activity decreased is. After each treadmill testing, a marked increase in fibrinolytic activity was observed. RFS was unaltered at all three testings. PAR increased after moderate activity, but decreased after strenuous activity.The results indicate that regular physical activity can lead from enhanced to decreased resting activity of plasminogen activator in blood. It is presumed that increased release of activator during prolonged stress causes partial depletion of endothelial stores with the consequence of decreased activator activity in the blood.

The Roles of α2-Antiplasmin and Plasminogen Activator Inhibitor 1 (PAI-1) in the Inhibition of Clot Lysis

1993 ◽  
Vol 70 (02) ◽  
pp. 301-306 ◽  
Author(s):  
Linda A Robbie ◽  
Nuala A Booth ◽  
Alison M Croll ◽  
Bruce Bennett
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Dependent Inhibition ◽  
Activator Inhibitor ◽  
Pai 1

SummaryThe relative importance of the two major inhibitors of fibrinolysis, α2-antiplasmin (α2-AP) and plasminogen activator inhibitor (PAI-1), were investigated using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen and tissue plasminogen activator (t-PA) at concentrations close to physiological. Purified α2-AP and PAI-1 caused dose-dependent inhibition. All the inhibition due to normal plasma, either platelet-rich or poor, was neutralised only by antibodies to α2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 × 108/ml, markedly inhibited clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of plasma to platelets, α2-AP was the dominant inhibitor. When the platelet:plasma ratio was raised some 20-fold, platelet PAI-1 provided a significant contribution. High local concentrations of PAI-1 do occur in thrombi in vivo, indicating a role for PAI-1, complementary to that of α2-AP, in such situations.

Anticoagulant Properties of Three Mucopolysaccharides Used in Rheumatology

1983 ◽  
Vol 50 (03) ◽  
pp. 652-655 ◽  
Author(s):  
F Bauer ◽  
P Schulz ◽  
G Reber ◽  
C A Bouvier
Keyword(s):  
Factor Xa ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Thrombin Time ◽  
Coagulation Tests ◽  
Amplification System ◽  
Relative Potencies ◽  
In Vivo Administration

SummaryThree mucopolysaccharides (MPS) used in the treatment of degenerative joint disease were compared to heparin to establish their relative potencies on 3 coagulation tests, the aPTT, the antifactor X a activity and the dilute thrombin time. One of the compounds, Arteparon®, was one fourth as potent as heparin on the aPTT, but had little or no influence on the 2 other tests. Further in vitro studies suggested that Arteparon® acted at a higher level than factor Xa generation in the intrinsic amplification system and that its effect was independent of antithrombin III. In vivo administration of Arteparon® confirmed its anticoagulant properties, which raises the question of the clinical use of this MPS.

Identification and characterisation of monoclonal antibodies that impair the activation of human thrombin activatable fibrinolysis inhibitor through different mechanisms

2011 ◽  
Vol 106 (07) ◽  
pp. 90-101 ◽  
Author(s):  
Niraj Mishra ◽  
Ellen Vercauteren ◽  
Jan Develter ◽  
Riet Bammens ◽  
Paul J. Declerck ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Lysis Time ◽  
Human Thrombin ◽  
Fibrinolysis Inhibitor ◽  
Dose Dependent ◽  
Clot Lysis Time

SummaryThrombin activatable fibrinolysis inhibitor (TAFI) forms a molecular link between coagulation and fibrinolysis and is a putative target to develop profibrinolytic drugs. Out of a panel of monoclonal antibodies (MA) raised against TAFI-ACIIYQ, we selected MA-TCK11A9, MA-TCK22G2 and MA-TCK27A4, which revealed high affinity towards human TAFITI- wt. MA-TCK11A9 was able to inhibit mainly plasmin-mediated TAFI activation, MA-TCK22G2 inhibited plasmin- and thrombin-mediated TAFI activation and MA-TCK27A4 inhibited TAFI activation by plasmin, thrombin and thrombin/thrombomodulin (T/TM) in a dose-dependent manner. These MA did not interfere with TAFIa activity. Using an eightfold molar excess of MA over TAFI, all three MA were able to reduce clot lysis time significantly, i.e. in the presence of exogenous TM, MATCK11A9, MA-TCK22G2 and MA-TCK27A4 reduced clot lysis time by 47 ± 9.1%, 80 ± 8.6% and 92 ± 14%, respectively, compared to PTCI. This effect was even more pronounced in the absence of TM i.e. MATCK11A9, MA-TCK22G2 and MA-TCK27A4 reduced clot lysis time by 90 ± 14%, 140 ± 12% and 147 ± 29%, respectively, compared to PTCI. Mutagenesis analysis revealed that residues at position 268, 272 and 276 are involved in the binding of MA-TCK11A9, residues 147 and 148 in the binding of MA-TCK22G2 and residue 113 in the binding of MATCK27A4. The present study identified three MA, with distinct epitopes, that impair the activation of human TAFI and demonstrated that MATCK11A9 which mainly impairs plasmin-mediated TAFI activation can also reduce significantly clot lysis time in vitro.

P-selectin-targeting of the fibrin selective thrombolytic Desmodus rotundus salivary plasminogen activator α1

2004 ◽  
Vol 92 (11) ◽  
pp. 956-965 ◽  
Author(s):  
Ningzheng Dong ◽  
Valdeci Da Cunha ◽  
Andrej Citkowicz ◽  
Faye Wu ◽  
Jon Vincelette ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Fusion Protein ◽  
Plasminogen Activator ◽  
Therapeutic Potential ◽  
Bleeding Risk ◽  
Clot Lysis ◽  
Desmodus Rotundus ◽  
Dog Model

SummaryDuring thrombosis, P-selectin is expressed on the surface of activated endothelial cells and platelets. We hypothesized that targeting a plasminogen activator (PA) to P-selectin would enhance local thrombolysis and reduce bleeding risk. Previously, a urokinase (uPA)/anti-P-selectin antibody (HuSZ51) fusion protein was shown to increase fibrinolysis in a hamster pulmonary embolism model. To explore the therapeutic potential of this targeting strategy, we fused the fibrin-selective Desmodus rotundus salivary PA α1 (dsPAα1) to HuSZ51 and compared the fibrinolytic activity of P-selectin-targeted dsPAα1 (HuSZ51-dsPAα1) to unmodified dsPAα1 in vitro and in vivo. HuSZ51-dsPAα1 and dsPAα1 were expressed in CHO cells and purified to homogeneity by affinity chromatography. HuSZ51dsPAα1 bound to thrombin-activated human and dog platelets with comparable affinities to that of parental antibody SZ51. The fusion protein retained the catalytic activities of dsPAα1 in chromogenic and clot lysis assays, indicating that dsPAα1 is fully functional when fused to HuSZ51. Compared to dsPAα1, HuSZ51-dsPAα1 had similar thrombolytic efficacy in a rat pulmonary embolism model and anti-thrombotic potency in a dog model of femoral artery thrombosis. However, HuSZ51dsPAα1 was less effective in lysis of preexisting arterial thrombi in the dog model. The reduced arterial thrombolysis was not due to the pharmacokinetic properties of HuSZ51-dsPAα1 because antigen level and amidolytic activity were higher in plasma from HuSZ51-dsPAα1-treated groups than corresponding dsPAα1-treated groups. These data indicate that the thrombolytic efficacy of HuSZ51-dsPAα1 varied dependent on the physical composition of thrombi. The lack of stimulation by fibrin in arterial thrombi may contribute to the attenuated thrombolytic efficacy of HuSZ51-dsPAα1 in the dog model.

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.

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