Effect of Various Antiplatelet Agents on Acute Arterial Thrombosis in the Rat

1993 ◽  
Vol 70 (05) ◽  
pp. 812-816 ◽  
Author(s):  
A Bernat ◽  
A M Mares ◽  
G Defreyn ◽  
J P Maffrand ◽  
J M Herbert
Keyword(s):  
Thrombus Formation ◽  
Platelet Activating Factor ◽  
Thromboxane A2 ◽  
Antiplatelet Agents ◽  
High Dose ◽  
Arterial Thrombus ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Thromboxane A2 Synthetase Inhibitor ◽  
Wall Injury

SummaryElectrical stimulation of the rat carotid artery causes a deep medial injury and the formation of a platelet-rich thrombus.Occlusive thrombosis at sites of vessel wall injury was significantly reduced after the oral administration of clopidogrel, a potent analogue of ticlopidine, which showed dose-dependent inhibition of the thrombus formation (ED50 = 1.0 ±0.2 mg/kg, p.o.). Accumulation of thrombotic material was also considerably reduced after the i. v. administration of SR 27417, a highly potent and selective platelet activating factor receptor antagonist (ED50 = μg/kg, i.v.), nafagrel, a thromboxane A2 synthetase inhibitor (ED50 = 1.3 mg/kg, i.v.) and hirudin (ED50 = 140 μg/ kg, i.v.). A high dose (20 mg/kg, i.v.) of the anti-adhesive tetrapeptide Arg-Gly-Asp-Ser (RGDS) showed only a slight effect on thrombus formation whereas aspirin was ineffective.These results confirm that ADP and thromboxane A2 play key roles in the initiation and progression of arterial thrombus formation and suggest that platelet activating factor may also modulate thrombosis in this experimental model.

scholarly journals Importance of platelets in experimental venous thrombosis in the rat

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2281-2286 ◽  
Author(s):  
JM Herbert ◽  
A Bernat ◽  
JP Maffrand
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Progressive Increase ◽  
High Dose ◽  
Experimental Conditions ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Tissue Thromboplastin ◽  
Dose Dependent

Abstract Venous thrombosis was induced by ligature of the inferior vena cava in rats whose blood was made hypercoagulable by intravenous (IV) administration of tissue thromboplastin. From a dose-response showing that the administration of increasing doses of tissue thromboplastin resulted in a subsequent progressive increase of thrombus weight, two concentrations of tissue thromboplastin were chosen: a high dose (550 microL/kg, IV) where thrombus formation was optimal and a concentration (7 microL/kg, IV) where tissue thromboplastin-hypercoagulability was intermediate. In both experimental conditions, leukopenia provoked by a myelotoxic drug did not influence the development of venous thrombosis. However, after thrombocytopenia induced by an antiplatelet antiserum, a dramatic decrease in thrombus formation was observed in animals that had been pre-challenged with the lower dose of tissue thromboplastin, whereas decrease in platelet count did not affect venous thrombosis under high thrombogenic challenge. When administered orally 2 hours before thrombosis induction, the ticlopidine analogue clopidogrel showed dose-dependent inhibition of thrombus formation in animals that were pre-challenged with a low dose of tissue thromboplastin (ED50 = 7.9 +/- 1.5 mg/kg, orally) but remained ineffective against high tissue thromboplastin-induced venous thrombosis. We further determined the effect of heparin and hirudin, and showed that both of these drugs exhibited a more potent antithrombotic activity after injection of the lower dose of tissue thromboplastin than after injection of a high dose of tissue thromboplastin. Therefore, using our model of stasis and hypercoagulability, platelet activation played a major role in the development of venous thrombosis when the thrombogenitic stimulus was mild.

scholarly journals Importance of platelets in experimental venous thrombosis in the rat

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2281-2286 ◽  
Author(s):  
JM Herbert ◽  
A Bernat ◽  
JP Maffrand
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Progressive Increase ◽  
High Dose ◽  
Experimental Conditions ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Tissue Thromboplastin ◽  
Dose Dependent

Venous thrombosis was induced by ligature of the inferior vena cava in rats whose blood was made hypercoagulable by intravenous (IV) administration of tissue thromboplastin. From a dose-response showing that the administration of increasing doses of tissue thromboplastin resulted in a subsequent progressive increase of thrombus weight, two concentrations of tissue thromboplastin were chosen: a high dose (550 microL/kg, IV) where thrombus formation was optimal and a concentration (7 microL/kg, IV) where tissue thromboplastin-hypercoagulability was intermediate. In both experimental conditions, leukopenia provoked by a myelotoxic drug did not influence the development of venous thrombosis. However, after thrombocytopenia induced by an antiplatelet antiserum, a dramatic decrease in thrombus formation was observed in animals that had been pre-challenged with the lower dose of tissue thromboplastin, whereas decrease in platelet count did not affect venous thrombosis under high thrombogenic challenge. When administered orally 2 hours before thrombosis induction, the ticlopidine analogue clopidogrel showed dose-dependent inhibition of thrombus formation in animals that were pre-challenged with a low dose of tissue thromboplastin (ED50 = 7.9 +/- 1.5 mg/kg, orally) but remained ineffective against high tissue thromboplastin-induced venous thrombosis. We further determined the effect of heparin and hirudin, and showed that both of these drugs exhibited a more potent antithrombotic activity after injection of the lower dose of tissue thromboplastin than after injection of a high dose of tissue thromboplastin. Therefore, using our model of stasis and hypercoagulability, platelet activation played a major role in the development of venous thrombosis when the thrombogenitic stimulus was mild.

scholarly journals Hirudin interruption of heparin-resistant arterial thrombus formation in baboons

Blood ◽  
1991 ◽  
Vol 77 (5) ◽  
pp. 1006-1012 ◽  
Author(s):  
AB Kelly ◽  
UM Marzec ◽  
W Krupski ◽  
A Bass ◽  
Y Cadroy ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Fibrin Deposition ◽  
Recombinant Hirudin ◽  
Arterial Thrombus ◽  
Dependent Inhibition ◽  
Antithrombotic Effects ◽  
Dose Dependent

Abstract To determine the role of thrombin in high blood flow, platelet- dependent thrombotic and hemostatic processes we measured the relative antithrombotic and antihemostatic effects in baboons of hirudin, a highly potent and specific antithrombin, and compared the effects of heparin, an antithrombin III-dependent inhibitor of thrombin. Thrombus formation was determined in vivo using three relevant models (homologous endarterectomized aorta, collagen-coated tubing, and Dacron vascular graft) by measuring: (1) platelet deposition, using gamma camera imaging of 111In-platelets; (2) fibrin deposition, as assessed by the incorporation of circulating 125I-fibrinogen; and (3) occlusion. The continuous intravenous infusion of 1, 5, and 20 nmol/kg per minute of recombinant hirudin (desulfatohirudin) maintained constant plasma levels of 0.16 +/- 0.03, 0.79 +/- 0.44, and 3.3 +/- 0.77 mumol/mL, respectively. Hirudin interrupted platelet and fibrin deposition in a dose-dependent manner that was profound at the highest dose for all three thrombogenic surfaces and significant at the lowest dose for thrombus formation on endarterectomized aorta. Thrombotic occlusion was prevented by all doses studied. In contrast, heparin did not inhibit either platelet or fibrin deposition when administered at a dose that maximally prolonged clotting times (100 U/kg) (P greater than .1), and only intermediate effects were produced at 10-fold that dose (1,000 U/kg). Moreover, heparin did not prevent occlusion of the test segments. Hirudin inhibited platelet hemostatic function in concert with its antithrombotic effects (bleeding times were prolonged by the intermediate and higher doses). By comparison, intravenous heparin failed to affect the bleeding time at the 100 U/kg dose (P greater than .5), and only minimally prolonged the bleeding time at the 1,000 U/kg dose (P less than .05). We conclude that platelet-dependent thrombotic and hemostatic processes are thrombin-mediated and that the biologic antithrombin hirudin produces a potent, dose-dependent inhibition of arterial thrombus formation that greatly exceeds the minimal antithrombotic effects produced by heparin.

Prolonged Inhibition of PGI2 Production and Associated Increased Thrombogenic Effect in Arteries After Aspirin Administration

1979 ◽  
Author(s):  
M Buchanan ◽  
E Dejana ◽  
J Mustard ◽  
J Hirsh
Keyword(s):  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Inhibitory Effect ◽  
High Dose ◽  
Jugular Veins ◽  
Dose Aspirin ◽  
Prolonged Effect ◽  
Release Assay ◽  
Wall Injury ◽  
High Dose Aspirin

In recent studies in rabbits, high dose aspirin (ASA) which inhibited prostacyclin(PGI2) synthesis by veins augmented thrombus formation in jugular veins. This thrombogenic effect was short-lived and lasted only 1-2 hrs. We have shown that the inhibitory effect of ASA on PGI2 synthesis in arteries lasts much longer than in veins. We therefore examined the effects of high dose ASA on arterial thrombosis in rabbits by measuring PGI2 production, 51Cr platelet adhesion and 125I-fibrin accretion onto a mechanically-induced injury site in carotid arteries. PGI2 production, quantitated by a thrombin-induced 14C-5HT release assay, was 0.13 ± 0.01 ng/10 mm2vessel. 51Cr platelet adhesion and 125I-fibrin accretion onto these vessels 1 hr after injury was 1.00 ± 0.13 × 106 platelets and 57 ± 5 μg fibrin/10 mm2 respectively (mean = SE, n = 22). After ASA treatment (100 mg/kg, IV), PGI2 production was inhibited by at least 84% for 6 hrs and returned to 56% of control by 20 hrs. This PGI2 inhibition was associated with a marked increase in platelet adhesion (>100%) which lasted for at least 20 hrs. There was no significant increase in fibrin accretion. These results show that the more prolonged effect of ASA on PGI2 production in arteries than in veins is paralleled by a more prolonged thrombogenic effect on arterial vessel wall injury.

scholarly journals Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2285-2292 ◽  
Author(s):  
Anetta Undas ◽  
Kathleen E. Brummel-Ziedins ◽  
Kenneth G. Mann
Keyword(s):  
Factor Xiii ◽  
Thrombus Formation ◽  
Thromboxane A2 ◽  
Fibrin Clot ◽  
Aspirin Resistance ◽  
Clot Lysis ◽  
High Dose ◽  
Laboratory Findings ◽  
Antithrombotic Effects ◽  
Platelet Thromboxane

Abstract Aspirin is effective in the prevention of cardiovascular events in high-risk patients. The primary established effect of aspirin on hemostasis is to impair platelet aggregation via inhibition of platelet thromboxane A2 synthesis, thus reducing thrombus formation on the surface of the damaged arterial wall. Growing evidence also indicates that aspirin exerts additional antithrombotic effects, which appear to some extent unrelated to platelet thromboxane A2 production. Aspirin can reduce thrombin generation with the subsequent attenuation of thrombin-mediated coagulant reactions such as factor XIII activation. Aspirin also acetylates lysine residues in fibrinogen resulting in increased fibrin clot permeability and enhanced clot lysis as well as directly promoting fibrinolysis with high-dose aspirin. The variable effectiveness of aspirin in terms of clinical outcomes and laboratory findings, which has been termed aspirin resistance, may be related to these additional antithrombotic effects that are altered when associated with common genetic polymorphisms such as the Leu33Pro β3-integrin or Val34Leu factor XIII mutations. However, the clinical relevance of these observations is still unclear. Elucidation of the actual impacts of aspirin other than antiaggregation effects could be important in view of the widespread use of this drug in the prevention of thrombotic manifestations of atherosclerosis.

Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients

2007 ◽  
Vol 97 (03) ◽  
pp. 487-492 ◽  
Author(s):  
Urooj Zafar ◽  
Julio Osende ◽  
Daichi Shimbo ◽  
Stella Palencia ◽  
Julia Crook ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Thrombus Formation ◽  
Factor Xa ◽  
High Dose ◽  
Factor X ◽  
Direct Factor ◽  
Percent Reduction ◽  
Arterial Thrombus ◽  
Factor Xa Inhibition ◽  
Coronary Patients

SummaryIt was the objective of this study to evaluate the anti-thrombotic potency of direct factor-Xa inhibition with ZK-807834 in stable coronary patients, using an ex-vivo model of arterial thrombus formation. Tissue factor pathway is important in atherothrom-bosis. Direct factor-Xa blockade may more potently reduce thrombosis and prevent coronary events. Badimon Perfusion Chamber 5-minute quantitative studies have shown 40-55% arterial thrombus reduction with abciximab, 23% with Clopidogrel, but none with heparin. Coronary patients (n= 18, 59 ± 9 years, 55% males) were blindly randomized to four groups receiving 24-hour infusion of a low, medium or high dose of direct factor-Xa inhibitor ZK-807834, or placebo. Arterial thrombus formation was measured in Badimon Chamber at baseline, end-of-infusion [Eol], and four hours and eight hours after Eol, and factor-X activity, prothrombin time [PT] ratio and plasma drug levels were measured simultaneously. For the low-, medium- and high-dose ZK-807834 groups, mean percent-reduction in thrombus size from baseline to Eol were 29%, 34% and 68%, respectively (p<0.00l), and at 8-h post Eol were 11%, 19% and 27%, respectively (p<0.01). Mean PT-ratio prolongation showed a strong linear relationship (Pearson’s r=0.93) with ZK-807834 plasma concentration. Mean percent-reduction in factor-X activity from baseline was 13%, 42% and 58%, respectively. Placebo had no effect on thrombus size or factor-X activity. In conclusion, direct factor-Xa inhibition with ZK-807834 markedly reduces ex-vivo arterial thrombus formation and factor-X activity in a dose-dependent manner. Plasma levels of ZK-807834 show a strong linear correlation with PT ratio. This direct factor-Xa inhibitor may reduce the need for additional potent glycoprotein llbllla inhibition.

Mepacrine Blockade of Arachidonate-lnduced Washed Platelet Aggregation: Relationship to Mepacrine Inhibition of Platelet Cyclooxygenase

1983 ◽  
Vol 50 (04) ◽  
pp. 784-786 ◽  
Author(s):  
Amiram Raz
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Thromboxane A2 ◽  
Inhibitory Effect ◽  
Thromboxane B2 ◽  
Concomitant Increase ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Arachidonate Release ◽  
Dose Dependent

SummaryMepacrine, in addition to its established antilipolytic activity, was also found to inhibit the conversion of 14C-arachidonic acid to 14C-thromboxane B2 in human washed platelets. In the concentration range of 3.33-33 μM, mepacrine exerted a dose dependent inhibition of arachidonate conversion to thromboxane B2 in parallel to inhibition of arachidonate-induced platelet aggregation. Mepacrine inhibition of thromboxane formation was not accompanied by a concomitant increase in other cyclooxygenase products. Furthermore, mepacrine did not affect platelet transformation of added prostaglandin H2 to thromboxane A2 and other products. These results indicate that mepacrine inhibits the cyclooxygenase enzyme and not thromboxane synthase. In washed platelets, mepacrine inhibition of arachidonic acid conversion to thromboxane A2 appears to be a major factor in the overall inhibitory effect of the compound on the combined process of arachidonate release from cellular phospholipids and its conversion to proaggregatory products.

scholarly journals Dose-Dependent Inhibition of Experimental Arterial Thrombosis by Carbenicillin and Ticarcillin

1977 ◽  
Author(s):  
B.T. Lyman ◽  
G.J. Johnson ◽  
J.G. White
Keyword(s):  
Arterial Thrombosis ◽  
Low Dose ◽  
Thrombosis Prophylaxis ◽  
High Dose ◽  
Antithrombotic Agents ◽  
Total Occlusion ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
High Doses ◽  
Dose Dependent

Drugs that inhibit platelet (PL) function may be useful in the prophylaxis of arterial thrombosis. We have shown that carbenicillin (CARB) and ticarcillin (TIC) cause dose-dependent inhibition of PL aggregation (AGG) in dogs, and that high doses of either of these penicillins significantly decrease the frequency of thrombosis in pronase (PN) injected arteries of dogs. Using this model we have compared the thrombosis prophylaxis effectiveness of these penicillins administered in low dose (250mg/Kg/24 hr, s.c.) (LD-P) versus high dose (750mg/Kg/24 hr, s.c.) (HD-P). Treatment for 3 to 7 days with LD-P resulted in marked inhibition of ADP-induced AGG, but had little or no effect on collagen-induced AGG, while HD-P routinely inhibited collagen as well as ADP-induced AGG. Control dogs were untreated, and their PL function remained normal. Thrombosis with total occlusion occurred in 13 of 15 arteries in control dogs, while only 3 of 29 segments totally occluded in HD-P treated dogs (χ2 = 21.7; p<0.001). However, total occlusion developed in 13 of 20 arteries in dogs receiving LD-P (χ2 = 1.1; p<0.3). The frequency of occlusion was significantly lower (p<0.001) following treatment with HD-P than LD-P. Aspirin (ASA) administration in low dose (650mg/24 hr p.o.) (LD-A) or high dose (2600mg/24 hr p.o.) (HD-A) uniformly inhibited collagen-induced PL AGG, but total occlusion developed in 11 of 16 PN injected arteries in dogs given LD-A, and in 10 of 12 arteries in dogs given HD-A. We conclude that CARB and TIC are effective experimental antithrombotic agents. Their effect is dose-dependent and closely correlated with inhibition of collagen-induced PL AGG. In high doses CARB and TIC are more effective than ASA in preventing PN induced arterial thrombosis. CARB and TIC warrant further study as potentially useful antithrombotic agents in humans.

Prolonged Inhibition of PGI2 Production and Associatedincreased Thrombogenic Effect in Arteries After Aspirin Administration

1979 ◽  
Author(s):  
M.R. Buchanan ◽  
E. Dejana ◽  
J.F. Mustard ◽  
J. Hirsh
Keyword(s):  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Inhibitory Effect ◽  
High Dose ◽  
Jugular Veins ◽  
Dose Aspirin ◽  
Prolonged Effect ◽  
Release Assay ◽  
Wall Injury ◽  
High Dose Aspirin

In recent studies in rabbits, high dose aspirin (ASA) which inhibited prostacyclin(PG I2) synthesis by veins augmented thrombus formation in jugular veins. This thrombogenic effect was short-lived and lasted only 1-2 hrs. we have shown that the inhibitory effect of ASA on PG I2 synthesis in arteries lasts much longer than in veins. We therefore examined the effects of high dose ASA on arterial thrombosis in rabbits by measuring PG I2 production, 51cr platelet adhesion and 125I-fibrin accretion onto a mechanically-induced injury site in carotid arteries. PG I2 production, quantitated by a thrombin-induced 14C-5HT release assay, was 0.13 ± 0.01 ng/10 mm2 vessel. 51Cr platelet adhesion and 125 I -fibrin accretion onto these vessels 1 nr after injury was 1.00 ± 0.13 × 106 platelets and 57 ± 5 μg fibrin/10 mm2 respectively (mean = SE, n = 22). After ASA treatment (100 mg/kg, IV), PG I2 production was inhibited by at least 84% for 6 hrs and returned to 56% of control by 20 hrs. This PG I2 inhibition was associated with a marked increase in platelet adhesion (>100%) which lasted for at least 20 hrs. There was no significant increase in fibrin accretion. These results show that the more prolonged effect of ASA on PG I2 production in arteries than in veins is paralleled by a more prolonged thrombogenic effect on arterial vessel wall injury.

Recombinant Full-length Tissue Factor Pathway Inhibitor (TFPI) Prevents Thrombus Formation and Rethrombosis after Lysis in a Rabbit Model of Jugular Vein Thrombosis

1996 ◽  
Vol 76 (04) ◽  
pp. 615-620 ◽  
Author(s):  
Brigitte Kaiser ◽  
Jawed Fareed
Keyword(s):  
Blood Flow ◽  
Vessel Wall ◽  
Tissue Factor Pathway Inhibitor ◽  
Jugular Vein ◽  
Thrombus Formation ◽  
Thrombotic Occlusion ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Tissue Factor Pathway ◽  
Dose Dependent

SummaryIn the jugular vein of rabbits thrombus formation was induced by vessel wall damage using a balloon catheter and following reduction of blood flow by 80-90% for 60 min (partial stasis). The blood flow in the vein was measured continuously and the incidence of primary thrombus formation, the time until lysis with recombinant tissue-type plasminogen activator (rt-PA) as well as the incidence of rethrombosis after lysis were determined. At the end of the experiment the wet weight of the thrombus formed inside the vessel was measured. For the determination of haemostaseological parameters blood was drawn from the cannulated femoral artery.Recombinant full-length tissue factor pathway inhibitor (TFPI) was studied with regard to its effect both on primary thrombus formation and on rethrombosis after lysis. In control animals damage of the vessel wall combined with partial stasis led to the formation of occlusive venous thrombi. In vitro bolus injection of TFPI (5,10,20 Μg/kg) at the time of thrombus induction prevented the formation of venous thrombi during the 1 h period of partial stasis. In the subsequent observation period a dose-dependent inhibition of later occurring partial or complete thrombotic occlusion was found. At the dose of 20 Μg/kg i.v. in all animals TFPI prevented a complete thrombotic occlusion of the vein up to 3 h after stasis. To study the effectiveness of TFPI on rethrombosis after lysis TFPI was injected i.v. after lysis of the thrombus with rt-PA (600 Μg/kg i.v. bolus + 600 Μg/kg i.v. infusion over 60 min). In saline treated control rabbits a reocclusion of the vessel was seen in 8 of 10 animals. TFPI (10, 20, 40 Μg/kg i.v.) injected at the end of rt-PA administration caused a dose-dependent inhibition of thrombotic reocclusion after lysis. At 40 Μg/kg i.v. the formation of occlusive thrombi was prevented up to 3 h after lysis. TFPI at the doses used caused modest anticoagulant effects in global clotting assays; activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) were only slightly prolonged. A clear and dose-dependent prolongation of clotting times was only seen in the Heptest® assay.The results show that the physiologic coagulation inhibitor TFPI acts as a strong antithrombotic agent in an experimental model of venous thrombus formation and thrombotic reocclusion after lysis in rabbits.

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