Comparative Study on the Effect of Carbenicillin, Inhibitors of Platelet Function and Heparin on Experimental Thrombus Formation

Previous studies documented an impairment of haemostasis by synthetic penicillins (Thromb. Haem. 34: 115, 1976) and penicillin (Lancet II : 1039, 1976). Therefore the antithrombotic activity of synthetic penicillin. (carbenicillin)(C) was compared with that of aspirin (ASA), dipyridamole (DIPY) and heparin in 150 rabbits. Thrombus formation was induced by standardized endothelial lesions. The dose of C was adjusted to a 4.2 fold prolongation of bleeding time, similar to that seen in clinical patients. Analysis and composition of thrombi was done by measurement of incorporation of labeled blood elements (51cr labeled platelets, 125J-fibrinogen and 59Fe labeled red cells). The ‘specific thrombus/blood ratio’ with values of 19.1 and 50.9 (51cr) in venous and arterial thrombi evidenced the significance of platelets in this model. In the venous system C reduced formation of thrombi by 43%, ASA by 34%, ASA and DIPY by 55% and heparin by 90%. In the arterial system C inhibited thrombus formation by 89%, ASA by 15%, ASA and DIPY by 46% and heparin by 60%. It is concluded, that C effectively prevents thrombus formation in the arterial system and to lower extent in the venous system. The results prove the importance of platelets in arterial thrombogenesis and the efficacy of platelet aggregation inhibitors in preventing thrombi in the arterial system. In comparison with other known antiplatelet drugs it seems, that C is the most effective platelet aggregation inhibitor to date.

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Thrombosis Prevention by Coagulation and Platelet Aggregation Inhibitors, in Hyperlipemic Rats

Thrombosis and Haemostasis ◽

10.1055/s-0038-1654269 ◽

1970 ◽

Vol 24 (03/04) ◽

pp. 577-586 ◽

Cited By ~ 4

Author(s):

S Renaud ◽

F Lecompte

Keyword(s):

Platelet Aggregation ◽

Intravenous Injection ◽

Platelet Rich Plasma ◽

Anticoagulant Activity ◽

Platelet Aggregation Inhibitors ◽

Low Doses ◽

Antithrombotic Activity ◽

Inhibition Of Platelet Aggregation ◽

Aggregation Inhibitors

SummaryPhenylbutazone, oxyphenbutazone, and sulfinpyrazone were equally effective at the dosage of 100 mg/kg (per os) in inhibiting thrombin- and ADP-induced platelet aggregation in hyperlipemic rats, and in preventing the development of thrombosis initiated by the intravenous injection of an endotoxin. Despite a slight anticoagulant effect of these substances, their antithrombotic activity appears to be due mostly to inhibition of platelet aggregation.Thrombosis in hyperlipemic rats could also be prevented by a dicoumarol derivative, acenocoumarin, which only inhibits coagulation. Therefore, both platelet aggregation and fibrin formation appear to be essential for the occurrence of large thrombi under these conditions. Nevertheless, although acenocoumarin has no direct effect on platelet aggregation, it could indirectly affect this phenomenon by blocking the formation of thrombin, which is suspected of being the agent responsible for initiating thrombosis in hyperlipemic rats.Low doses of phenylbutazone and acenocoumarin, in condition, which when given alone were ineffective in inhibiting thrombosis, could decrease the severity of thrombosis by 33%. The substance GP45840, when added in vitro to platelet-rich plasma as well as given per os to hyperlipemic rats, was no more effective than sulfinpyrazone in inhibiting platelet aggregation. Nevertheless, this substance was significantly more efficient in reducing thrombosis than was sulfinpyrazone, apparently through some additional anticoagulant activity. The results of these experiments suggest that it could be beneficial to affect both coagulation and platelet aggregation in order to satisfactorily prevent thrombosis.

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Formation and Embolization of Thrombi after Electrical Stimulation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649085 ◽

1973 ◽

Vol 30 (02) ◽

pp. 352-362

Author(s):

B. A Spilker ◽

H van Balken

Keyword(s):

Electrical Stimulation ◽

Platelet Aggregation ◽

Thrombus Formation ◽

Drug Effects ◽

Platelet Aggregation Inhibitors ◽

Inhibit Platelet Aggregation ◽

Brain Vessels ◽

Rat Mesentery ◽

Aggregation Inhibitors ◽

Stimulation Of

SummaryCharacteristics of thrombi produced upon electrical stimulation of mesentery and brain vessels were studied in five species. Parameters for measuring drug effects were also evaluated to determine which were sensitive to platelet aggregation inhibitors. The current required to cause vasoconstriction in 50% of the rat mesentery arteries stimulated was increased by vasodilators, but not by inhibitors of platelet aggregation. The threshold of current necessary to cause thrombus formation was increased by Imipramine in both acute and chronic experiments and by aspirin and papaverine in chronic experiments. Since these were the only agents tested which inhibit platelet aggregation there appears to be a relationship between this property and the threshold of current necessary to cause thrombus formation. This parameter may possibly be used to differentiate between platelet aggregation inhibitors and streptokinase-like or heparin-like agents. Changes in mean embolization time under present conditions were not related to activity in inhibiting platelet aggregation.

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ADP Plays a Key Role in Thrombogenesis in Rats

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642759 ◽

1988 ◽

Vol 59 (02) ◽

pp. 225-230 ◽

Cited By ~ 63

Author(s):

J P Maffrand ◽

A Bernat ◽

D Delebassée ◽

G Defreyn ◽

J P Cazenave ◽

...

Keyword(s):

Platelet Aggregation ◽

Bleeding Time ◽

Thrombus Formation ◽

Vascular Wall ◽

Cyclooxygenase Inhibitors ◽

High Dose ◽

Silk Thread ◽

Dense Granules ◽

Prolonged Bleeding Time ◽

Venous Shunt

SummaryThe relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency. Taken together, the results obtained with the drugs and with the fawn-hooded rats support the concept that ADP plays a key role in thrombogenesis in rats.

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Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/llla Inhibitors in Animal Models of Platelet-Mediated Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642390 ◽

1994 ◽

Vol 71 (01) ◽

pp. 095-102 ◽

Cited By ~ 43

Author(s):

Désiré Collen ◽

Hua Rong Lu ◽

Jean-Marie Stassen ◽

Ingrid Vreys ◽

Tsunehiro Yasuda ◽

...

Keyword(s):

Platelet Aggregation ◽

Bleeding Time ◽

Bolus Injection ◽

Cell Injury ◽

Ex Vivo ◽

Thrombus Formation ◽

Femoral Vein ◽

Thrombotic Occlusion ◽

Antithrombotic Effects

SummaryCyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-a-aspartyl-cyclic (1→5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-arginyl-glycyl-L-α-aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1→9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor.The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 μg/kg, ex vivo ADP-induccd platelet aggregation with ID50 of 10 μg/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 ± 9 to 1,100 ± 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 μg/kg, ex vivo platelet aggregation with an ID50 of 50 μg/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 μg/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induccd ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 ± 0.4 to 12 ± 2 min. Infusion of 300 μg/kg of TP9201 over 60 min completely prevented thrombotic occlusion, inhibited ex vivo platelet aggregation, but was not associated with prolongation of the template bleeding time.TP9201, unlike G4120, inhibits in vivo platelet-mediated thrombus formation without associated prolongation of the template bleeding time.

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Platelet Anti-Aggregating Activity and Tolerance of Clopidogrel in Atherosclerotic Patients

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650689 ◽

1996 ◽

Vol 76 (06) ◽

pp. 0939-0943 ◽

Cited By ~ 74

Author(s):

B Boneu ◽

G Destelle ◽

Keyword(s):

Platelet Aggregation ◽

Large Scale ◽

Bleeding Time ◽

Antithrombotic Activity ◽

Ambulatory Patients ◽

Patients At Risk ◽

Set Up ◽

Ischemic Events ◽

Large Scale Clinical Trial ◽

Selection Of

SummaryThe anti-aggregating activity of five rising doses of clopidogrel has been compared to that of ticlopidine in atherosclerotic patients. The aim of this study was to determine the dose of clopidogrel which should be tested in a large scale clinical trial of secondary prevention of ischemic events in patients suffering from vascular manifestations of atherosclerosis [CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) trial]. A multicenter study involving 9 haematological laboratories and 29 clinical centers was set up. One hundred and fifty ambulatory patients were randomized into one of the seven following groups: clopidogrel at doses of 10, 25, 50,75 or 100 mg OD, ticlopidine 250 mg BID or placebo. ADP and collagen-induced platelet aggregation tests were performed before starting treatment and after 7 and 28 days. Bleeding time was performed on days 0 and 28. Patients were seen on days 0, 7 and 28 to check the clinical and biological tolerability of the treatment. Clopidogrel exerted a dose-related inhibition of ADP-induced platelet aggregation and bleeding time prolongation. In the presence of ADP (5 \lM) this inhibition ranged between 29% and 44% in comparison to pretreatment values. The bleeding times were prolonged by 1.5 to 1.7 times. These effects were non significantly different from those produced by ticlopidine. The clinical tolerability was good or fair in 97.5% of the patients. No haematological adverse events were recorded. These results allowed the selection of 75 mg once a day to evaluate and compare the antithrombotic activity of clopidogrel to that of aspirin in the CAPRIE trial.

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New Platelet Aggregation Inhibitors

Hämostaseologie ◽

10.1055/s-0038-1660012 ◽

1997 ◽

Vol 17 (01) ◽

pp. 43-48 ◽

Cited By ~ 1

Author(s):

R. Verhaeghe ◽

J. Vermylen

Keyword(s):

Platelet Aggregation ◽

Platelet Aggregation Inhibitors ◽

Aggregation Inhibitors

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Antiplatelet Effect of FK633, a Platelet Glycoprotein Ilb/IIIa Antagonist, on Thrombus Formation and Vascular Patency after Thrombolysis in the Injured Hamster Carotid Artery

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656006 ◽

1997 ◽

Vol 77 (03) ◽

pp. 562-567 ◽

Cited By ~ 14

Author(s):

Takehiro Kaida ◽

Hiroyuki Matsuno ◽

Masayuki Niwa ◽

Osamu Kozawa ◽

Hideo Miyata ◽

...

Keyword(s):

Platelet Aggregation ◽

Carotid Artery ◽

Vascular Injury ◽

Bleeding Time ◽

Thrombus Formation ◽

Separate Experiment ◽

Platelet Glycoprotein ◽

Neointima Formation ◽

Vascular Patency ◽

Injured Artery

SummaryThe antithrombotic and restenosis-preventing effects of FK633, an inhibitor of platelet aggregation via binding to the glycoprotein (GP) Ilb/IIIa receptor, were studied. IC50 value of FK633 against platelet aggregation ex vivo induced by 2.5 |iM adenosine diphosphate (ADP) was 5.4 X 10"7 M as determined using hamster platelet rich plasma. The inhibitory effect was also investigated in vivo on thrombus formation at the carotid arterial wall injured by a modified catheter. As a control, the left carotid artery was injured and the time required to develop a thrombotic occlusion (3.9 ±1.1 min, mean ± S.E.M., n = 18) was determined. Then, the right carotid artery of the same animal was injured while a continuous intravenous (i.v.) infusion of FK633 was administered at doses of 0 (saline), 0.1,0.3 or 1.0 mg/kg/h. The time to occlusion was dose-dependently prolonged. In a separate experiment, 10% of the total tPA dose (0.52 mg/kg) was injected into the injured artery as a bolus and the remaining was infused i.v. at a constant rate for 30 min. When FK633 (0.3 or 1.0 mg/kg/h) was infused together with tPA, late patency of the reperfused artery was much improved as compared with that of treatment with tPA alone. Bleeding time, measured at the end of the tPA infusion, was markedly prolonged when the higher dose of FK633 (1.0 mg/kg/h) was coadministered, however coadministration of the lower dose of FK633 (0.3 mg/kg/h) was almost without prolongation on the bleeding time, despite a significant effect on the vascular patency after thrombolysis. Next, neointima formation was evaluated 2 weeks after the vascular injury. When FK633 (0.3 mg/kg/h) was continuously infused i. v. by an implanted osmotic pump for 3,7 or 14 days after the vascular injury, the neointimal area formation was significantly suppressed in the treatment groups for 7 or 14 days. These findings suggest that FK633 inhibits platelet activation in the injured artery and improves vascular patency after thrombolysis with tPA with a concomitant suppression of neointima formation.

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