thromboxane-a2 and Coronary-Thrombosis

The crucial role of platelets in primary hemostasis and repair of injured endothelium is well established, as is their role in atherothrombosis. No other single cell type is responsible for as much morbidity and mortality, since death from ischemic heart disease or stroke is by far the leading cause of death worldwide. There is no doubt that our understanding of atherothrombosis has guided current antithrombotic strategies that have dramatically reduced ischemic complications and cardiovascular mortality within the last decades. Yet the rate of ischemic complications after optimal revascularization therapy remains disappointingly high. There is still a strong need for new and smart antiplatelet drugs. The ideal antithrombotic drug would spare physiological platelet function, hemostasis and vascular repair in order to avoid bleeding complications, but would exclusively target the pathological atherothrombotic process. As platelet activity might be determined early in the bone marrow, this review starts with insights into the birth of platelets, describes the essential and primary role of platelets in hemostasis with new evidence in signaling cascades, and closes with the deleterious role of platelets in atherosclerosis and atherothrombosis, with a focus on acute coronary syndromes.

Topics: Adenosine Diphosphate; Animals; Atherosclerosis; Blood Platelets; Coronary Artery Disease; Coronary Thrombosis; Fibrinolytic Agents; Hemostasis; Humans; Plaque, Atherosclerotic; Platelet Activation; Platelet Aggregation Inhibitors; Thrombin; Thrombosis; Thromboxane A2

Platelets are major players in arterial thrombosis, and antiplatelet therapy has a clear clinical benefit in the treatment and prevention of cardiovascular events. In particular, aspirin and clopidogrel have become cornerstones in the treatment of patients with atherothrombosis. However, despite the proven efficacy of antiplatelet drugs, cardiovascular events remain an important cause of morbidity and mortality in these patients. Furthermore, a considerable variability in platelet reactivity during treatment with established oral antiplatelet therapy has prompted the search for novel drugs against platelet-dependent thrombosis. Possible benefits of upcoming drugs include a more efficient platelet inhibition and a reversible effect on platelet function. Aspirin, clopidogrel, prasugrel, ticagrelor, terutroban, E5555, SCH 530348 and cilostazol are discussed. This review highlights the rationale for important oral antiplatelet drugs in development and provides clinical perspectives on their pharmacological advantages and challenges.

Topics: Adenosine; Administration, Oral; Cardiovascular Diseases; Cilostazol; Coronary Artery Disease; Coronary Thrombosis; Drug Resistance; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Tetrazoles; Thiophenes; Thromboxane A2; Ticagrelor

Multiple factors are involved in thrombus formation and require complex and highly therapeutic strategies. Platelet activation plays a critical role in the genesis of acute coronary syndromes involving not only platelets but also endothelial cells, leucocytes and erythrocytes. Angiotensin II (Ang II) is a vasoconstrictor that could participate in the thrombotic process. Platelets also express Ang II AT1 type receptors on their surface. Losartan is a non-peptidic inhibitor of AT1 receptors. It has been demonstrated that losartan reduced platelet aggregation induced by the thromboxane A2 (TXA2) analogue U46619. This effect was not observed with the losartan metabolite EXP 3174. The effect of losartan was assessed in binding studies in which losartan competitively inhibited the binding of [3H]U46619 to platelets in a dose-dependent manner. Irbesartan also inhibits the TXA2 receptor in platelets, an effect that was not obtained with the active form of candesartan, CV11974, and with valsartan. These results suggest that the structural requirements necessary to antagonize the TXA2/PGH2 platelet receptor may be different from those involved in AT1 receptor antagonism. The in vivo relevance of the in vitro findings has been confirmed by the fact that in vivo administration of losartan decreases P-selectin expression in platelets obtained from stroke-prone spontaneously hypertensive rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Coronary Disease; Coronary Thrombosis; Humans; Losartan; P-Selectin; Platelet Activation; Platelet Aggregation; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Thromboxane; Tetrazoles; Thrombosis; Thromboxane A2; Valine; Valsartan

Topics: Aspirin; Blood Coagulation Factors; Cholesterol, HDL; Cholesterol, LDL; Coronary Thrombosis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Thromboxane A2; Treatment Outcome

Rupture of the lipid-rich atheromatous plaque, intraplaque hemorrhage, and intraluminal thrombus are three pathological hallmarks most commonly recognized in the infarct-related coronary artery at the site of acute myocardial infarction. Rupture of the atheromatous plaque is closely related to but does not fully explain the genesis of occlusive intracoronary thrombus formation and thus the development of acute myocardial infarction. Besides a variety of hematologic disorders, one should emphasize the role of the platelet-derived mediators that promote an environment where thrombosis and vasoconstriction occur, including TXA2, serotonin, ADP, platelet-derived growth factor, tissue factor, and the diminished availability of those natural endogenous substances that inhibit platelet aggregation, such as EDRF, tissue plasminogen activator, and PGI2. PGI2 released from vascular endothelial cells is extremely unstable. Our group provided the first evidence that HDL stabilizes PGI2 through the newly discovered function of Apo A-I, which is associated with the surface of HDL particles and identified as PGI2 stabilizing factor. Decrease in HDL-associated Apo A-I in patients with unstable angina and during the acute phase of myocardial infarction indicates that HDL plays an important role in preventing coronary atherosclerosis and intracoronary thrombus formation by stabilizing PGI2 in addition to the generally accepted biochemical property of HDL to prevent the accumulation of cholesterol by mobilizing free cholesterol from tissues or macrophages. There is also a PGI2 synthesis-stimulating factor in serum that has not yet been identified chemically. EDRF or nitric oxide provides another important regulating system in the vessel wall. Lipoproteins are inhibitors of endothelium-dependent relaxation of rabbit aorta.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Apolipoprotein A-I; Apolipoprotein A-II; Coronary Artery Disease; Coronary Thrombosis; Coronary Vessels; Endothelium, Vascular; Epoprostenol; Humans; Myocardial Infarction; Nitric Oxide; Thromboxane A2

Topics: Angina, Unstable; Aspirin; Coronary Thrombosis; Humans; Myocardial Ischemia; Platelet Activation; Prostaglandins; Thrombolytic Therapy; Thromboxane A2

The stimulation of platelets, activation of the coagulation cascade, release of platelet-derived vasoconstrictors, and endothelial dysfunction all contribute to the thrombotic vascular occlusion that results in myocardial infarction. Despite the importance of platelets in the initiation of this process, they are activated by multiple endogenous mediators. Thus, one might anticipate that redundancy in the system would confound the efficacy of antiplatelet drugs that were mediator-specific. The success of aspirin in clinical trials is likely to reflect the role of thromboxane A2 (TxA2) as an amplification signal for other platelet agonists. Activated platelets provide a substrate for assembly of the prothrombinase complex and both heparin and warfarin also reduce the mortality due to thrombotic vascular disease. The relative efficacy of these compounds versus aspirin and the safety of their combination, particularly in the setting of therapeutic thrombolysis, are under investigation. Novel antiplatelet agents, particularly those directed against the glycoprotein 11b/111a complex, are more potent than aspirin in animal models. Similarly, direct thrombin inhibitors seem superior to heparin. Whether such compounds can be administered safely in effective doses to humans is under study. It is hoped that the success of aspirin does not impede the clinical evaluation of theoretically more attractive antithrombotic drugs.

Topics: Animals; Anticoagulants; Aspirin; Blood Platelets; Coronary Thrombosis; Humans; Platelet Aggregation Inhibitors; Thromboxane A2

Platelets and their interaction with the vessel wall play a role in atherogenesis and in the formation of the coronary thrombus. Supplementation of the diet with n-3 PUFA shifts the platelet-vessel wall interaction in anti-thrombotic direction in healthy persons and in patients with IHD. This is in part caused by an inhibition of Tx synthesis and also by an increased synthesis of PGI2 and PGI3 in the vessel wall. However, the clinical significance of these findings needs to be elucidated in clinical trials. Large, dense platelets are more reactive than small ones. Platelet size and density are determined at thrombopoiesis. Large, reactive platelets have in states with an increased platelet demand been shown to be produced from large, high-ploidy megakaryocytes. In patients with thrombopoiesis in steady-state an inverse relation between the bleeding time and both the DNA content and the size of the bone marrow megakaryocytes has been demonstrated. The bone marrow megakaryocytes in these patients were larger in men than in women, which may explain the sex difference in bleeding time observed by others. In experimental atherosclerosis changes in megakaryocyte size have been demonstrated. The significance of these changes are still unclear. In a single study stimulation of the platelet-megakaryocyte axis was associated with an acceleration of experimental atherosclerosis. This study suggests that large, high ploidy megakaryocytes may produce a large amount of atherogenic platelets that may be responsible for the increased formation of atheroma in this model. However, due to the complexity of the study design this hypothesis needs verification in other experimental and clinical studies. In patients suffering from an AMI the mean platelet volume is increased. The bleeding time is shortened at the time of infarction in these patients probably due to increased synthesis of TxA2, but an increased production of adrenaline may also be of importance. These large, reactive platelets present in AMI may be a reflection of an altered thrombopoiesis in these patients. It remains to be established whether these changes in platelet reactivity are present before the time of coronary thrombus formation.

Topics: Animals; Arteriosclerosis; Blood Platelets; Coronary Disease; Coronary Thrombosis; Endothelium, Vascular; Epoprostenol; Fatty Acids, Unsaturated; Humans; Megakaryocytes; Platelet Aggregation; Thromboxane A2

Topics: Coronary Thrombosis; Coronary Vessels; Endothelium, Vascular; Humans; Myocardial Infarction; Platelet Adhesiveness; Platelet Aggregation; Thromboxane A2

A number of reports indicate the TX receptor antagonists may be useful in preventing coronary artery reocclusion following fibrinolytic therapy, reducing myocardial ischemia/reperfusion injury and consequent neutrophil accumulation, preventing thrombocardiac sudden death, and attenuating the sequelae of endotoxic shock. Limited clinical studies have been initiated, and no adverse clinical effects can be associated with specific TX receptor blockade. Further clinical studies will be required to confirm the provocative animal studies, as well as defining the role of TX as a mediator of coronary vasospasm, respiratory disorders, and renal failure and rejection episodes.

Topics: Animals; Cardiovascular Diseases; Coronary Thrombosis; Humans; Myocardial Infarction; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Septic; Thromboxane A2

Considerable attention is being given to the interactions that occur among blood platelets, neutrophils, and the vascular endothelium. There is an increasing awareness that the various blood elements interact in the process of thrombus formation and vascular occlusion. In addition, interactions among these cells can lead to the formation and release of vasoactive substances that have the potential to modulate regional blood flow. This review focuses on the coronary vascular bed and an assessment of how cell-cell interactions, under normal physiological conditions as well as in the presence of myocardial injury, may lead to alterations in coronary vascular resistance and myocardial function. Should related events be operative in human clinical states of disease, the circulating elements of the blood may serve as targets in the development of therapeutic interventions to regulate myocardial blood flow.

Topics: Animals; Blood Cells; Coronary Disease; Coronary Thrombosis; Coronary Vessels; Dogs; Endothelium; Free Radicals; Leukocytes; Oxygen; Platelet Activating Factor; Platelet Aggregation; Rabbits; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction; Vasodilation; Xanthine Oxidase

Topics: Coronary Disease; Coronary Thrombosis; Epoprostenol; Humans; Myocardial Infarction; Platelet Aggregation; Thromboxane A2; Urokinase-Type Plasminogen Activator

The antiplatelet and antithrombotic effects of ent-16β,17-dihydroxy-kauran-19-oic acid (DDKA) isolated from Siegesbeckia pubescens were investigated with different methods both in vitro and in vivo. We tested the antithrombotic activity of DDKA in arterio-venous shunt model. The effects of DDKA on adenosine diphosphate (ADP)-, Thrombin-, Arachidonic acid-induced rat platelets aggregation were tested in vitro. We also assessed its bleeding side effect by measuring coagulation parameters after intravenous administration for 5 days and investigated the potential mechanisms underlying such activities. In vivo, DDKA significantly reduced thrombus weight in the model of arterio-venous shunt. Meanwhile, DDKA increased plasma cAMP level determined by radioimmunoassay in the same model. Notably, DDKA prolonged PT and APTT in rats after intravenous administration DDKA for successive 5 days. In vitro, pretreatment with DDKA on washed rat platelets significantly inhibited various agonists stimulated platelet aggregation and caused an increase in cAMP level in platelets activated by ADP. These findings support our hypothesis that DDKA possesses antiplatelet and antithrombotic activities. The mechanisms underlying such activities may involve the anticoagulatory effect and cAMP induction.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Animals; Asteraceae; Coronary Thrombosis; Cyclic AMP; Diterpenes, Kaurane; Epoprostenol; Female; Fibrinolytic Agents; Hemorrhage; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Thrombin; Thromboxane A2; Thyroglobulin

Vapiprost (GR32191, a TxA2 antagonist), r-hirudin, aspirin, ticlopidine and aspirin plus ticlopidine were examined for their ability to prevent electrically-induced thrombosis in an artificially stenosed coronary artery in the anaesthetised dog. Drugs or vehicle were administered prior to a 2 h period of electrical damage which was followed by a further 2 h observation period. In all vehicle-treated animals, blood flow markedly declined with onset of the damaging current; 80% completely occluded. All treatments reduced the incidence of complete occlusion to a similar extent. Vapiprost and r-hirudin also largely prevented the decline in blood flow both during and following the damage period whilst aspirin and ticlopidine, either alone or in combination were much less effective. With r-hirudin treatment, marked cyclic changes in flow occurred throughout the experiment; these were abolished by administration of vapiprost. In this dog model, TxA2 and thrombin appear to work in concert to produce coronary thrombosis, ADP being of minor importance. The superior effect of vapiprost over aspirin suggests a beneficial role for endogenous prostacyclin.

Topics: Anesthesia; Animals; Aspirin; Biphenyl Compounds; Blood Coagulation Tests; Coronary Circulation; Coronary Thrombosis; Dogs; Drug Synergism; Drug Therapy, Combination; Electric Stimulation; Female; Fibrinolytic Agents; Heptanoic Acids; Hirudin Therapy; Hirudins; Male; Platelet Aggregation; Recombinant Proteins; Thrombin; Thromboxane A2; Ticlopidine

The coronary artery produces large amounts of prostacyclin (PGI2) and a small amount of thromboxane A2 (TXA2); this high PGI2/TXA2 ratio contributes to the antithrombotic properties of the coronary artery. This study was designed to determine whether this ratio changes after coronary artery thrombosis and thrombolysis and accounts for coronary artery reocclusion. Anesthetized dogs (N = 12) were subjected to electrically induced coronary artery thrombosis and tissue plasminogen activator-induced thrombolysis. Thrombolysis was achieved in 11 dogs, and the coronary artery reoccluded in five of these dogs after the initial reperfusion. Spontaneous and ionophore A23,187-stimulated PGI2 and TXA2 synthesis in normal circumflex and ischemic-reperfused left anterior descending coronary artery segments was measured by radioimmunoassay of thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively. Production of TXA2 was 413% to 656% greater in left anterior descending segments (from the region of thrombosis and sites proximal and distal to the thrombus) compared with normal circumflex segments (p < 0.001). Production of PGI2 was also increased but only by 46% to 80% in the left anterior descending segments compared with normal circumflex segments (p < 0.05). TXA2 production was greater in coronary artery segments that reocculded compared with segments that stayed open (p < 0.02). Scanning electron microscopy revealed platelet deposition in thrombosed left anterior descending segments but not in segments proximal or distal to the thrombus site, indicating that the vascular wall per se may be a source of increased production of TXA2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcimycin; Coronary Thrombosis; Coronary Vessels; Dogs; Epoprostenol; Female; Indomethacin; Male; Microscopy, Electron, Scanning; Recurrence; Thrombolytic Therapy; Thromboxane A2; Tissue Plasminogen Activator

During i.v. infusion of rose bengal (48 mg/kg/h), the proximal portion of the rat left coronary artery was illuminated from the outside of the myocardium by green light (540 nm) to produce a transluminal thrombus subsequent to endothelial damages. The primary endothelial damages within the illuminated vascular portion, which resulted from the photochemical reaction between the dye and green light, and the subsequent formation of transluminal platelet-rich thrombus, were easily revealed by both light and electron microscopy. The establishment of the thrombus was accompanied in all cases by the occurrence of ventricular arrhythmias due to myocardial ischaemia. The times required to initiate ventricular premature beats (VPBs) and ventricular tachycardia (VT) were 381 +/- 96 s and 444 +/- 114 s (mean +/- SEM, n = 10), respectively. Pretreatment of the rat with acetylsalicylic acid (3 and 10 mg/kg, i.v.) before the initiation of illumination had no effect on the times required to exhibit the first VPBs and VT, the incidences of both types of arrhythmias were not reduced, and the thrombus was finally formed. On the other hand, pretreatment with Y-20811, a novel thromboxane A2 synthetase inhibitor (0.3, 1 and 3 mg/kg, i.v.), delayed the onset of both VPB and VT in a dose-dependent manner. The incidences of VPBs and VT were significantly reduced at 1 and 3 mg/kg, and the thrombus formation was prevented. The formation of a transluminal thrombus in the left coronary artery by the present technique was highly reproducible and could be functionally evaluated by the occurrence of ventricular arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Aspirin; Coronary Thrombosis; Histocytochemistry; Imidazoles; Male; Myocardium; Photochemistry; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Thromboxane A2; Thromboxane-A Synthase; Ventricular Function

Inhibition of thromboxane (TX) A2 with aspirin enhances the response to coronary thrombolysis. However, experimental evidence suggests that platelet activation during coronary thrombolysis is mediated by a number of agonists, in addition to TXA2. As a consequence, greater benefit would be expected with antiplatelet agents that have a broader spectrum of activity. However, a recent clinical trial, combining tissue plasminogen activator (t-PA) with the prostacyclin analog, iloprost, did not detect such a benefit. To address the mechanism of this response, we compared the effect of iloprost, a stable analog of prostacyclin, with GR32191, a TXA2/prostaglandin endoperoxide receptor antagonist, on the response to i.v. t-PA in a closed chest, canine model of coronary thrombosis. GR32191 reduced the time to reperfusion by 47% (n = 6, P less than .05), consistent with a role for TXA2-mediated platelet activation in impairing thrombolysis. In contrast, iloprost increased the time to reperfusion by 50% (n = 5, P = NS) and in four of nine animals reperfusion failed to occur despite inhibition of platelet aggregation. In a separate series of experiments, steady-state plasma t-PA clearance increased by 38% (407 +/- 49 vs. 294 +/- 42 ml/min; n = 8, P less than .02) during infusion of iloprost and recovered after its withdrawal. This appeared to be a specific effect, as infusion of nitroglycerin at a dose which induced a similar fall in blood pressure altered neither the time to reperfusion nor plasma t-PA. Iloprost impairs the thrombolytic response to t-PA via an increase in the clearance of this agent.

Topics: Alprostadil; Animals; Biphenyl Compounds; Coronary Thrombosis; Dogs; Drug Interactions; Heptanoic Acids; Iloprost; Male; Platelet Aggregation; Reperfusion; Thrombolytic Therapy; Thromboxane A2; Tissue Plasminogen Activator

Topics: Aspirin; Coronary Thrombosis; Cross-Sectional Studies; Humans; Intracranial Embolism and Thrombosis; Platelet Activation; Risk Factors; Thromboxane A2; Thromboxane B2

In open-chest dogs, cyclic flow reductions (CFRs, 5.1-6.6/hr in controls; n = 24) caused by platelet deposition/dislodgment at sites of endothelial cell injury in critically stenosed left anterior descending coronary arteries (59% flow reduction) were attenuated to the same extent either by single thromboxane A2 (TXA2) synthase inhibition (0.31 mg/kg i.v. ridogrel; CFR, 0.16 +/- 0.16/hr; n = 6; p less than 0.05) or by a comparatively modest degree of TXA2/prostaglandin endoperoxide receptor antagonism on top of TXA2 synthase inhibition (5 mg/kg i.v. ridogrel; CFR, 0.22 +/- 0.1/hr; n = 10; p less than 0.05). By contrast, occlusive thrombosis on deep vascular damage elicited by intraluminal stimulation (150-microA anodal constant current) in nonpreconstricted canine coronary arteries (time to occlusion, 237.1 +/- 13.9 minutes; n = 7; incidence of occlusion within 300 minutes, six of seven experiments) was not affected by platelet cyclooxygenase inhibition (5 mg/kg i.v. acetylsalicylic acid; n = 7), single TXA2 synthase inhibition (1.25 mg/kg i.v. ridogrel; n = 7), or single TXA2/prostaglandin endoperoxide receptor antagonism (10 mg/kg + 10 mg/kg/hr i.v. sulotroban for 300 minutes; n = 5). However, such an occlusive thrombus formation was significantly reduced by combined TXA2 synthase/prostaglandin endoperoxide receptor inhibition (5 mg/kg i.v. ridogrel; time to occlusion greater than 300 minutes, n = 7; incidence of occlusion within 300 minutes, one of seven experiments; p less than 0.05). This study reveals 1) a differential efficacy of TXA2 synthase inhibition, singly or combined with TXA2/prostaglandin endoperoxide receptor antagonism, depending on the extent of the vessel wall lesion triggering thrombosis and the size of the thrombus required to obstruct the vascular lumen and 2) a significant synergism in preventing occlusive thrombosis of extensively damaged coronary arteries between strong TXA2 synthase inhibition and comparatively modest TXA2/prostaglandin endoperoxide receptor antagonism with ridogrel.

Topics: Animals; Coronary Thrombosis; Coronary Vessels; Dogs; Endothelium, Vascular; Female; Hemodynamics; In Vitro Techniques; Male; Pentanoic Acids; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

To assess the platelet inhibitory effect of high doses of fish oils and relate it to alterations in eicosanoid synthesis, we used a canine model in which coronary thrombosis, the time to reperfusion induced by recombinant tissue-type plasminogen activator (rt-PA), and the rate of spontaneous reocclusion are sensitive to platelet inhibition. In the animals fed fish oil, the time to rt-PA induced thrombolysis was accelerated (mean, 63 vs. 27 minutes; p less than 0.003). The time to thrombotic occlusion and the rate of reocclusion were unaltered. The ratio of eicosapentaenoic acid (EPA) to arachidonic acid rose in platelet and endothelial cell membranes, whereas serum thromboxane (Tx) B levels fell a mean 86%, and basal excretion of 2,3-dinor-TxB2 (TxA2-M) declined. Basal prostaglandin (PG) I2 formation was unaltered, whereas biosynthesis of EPA-derived TxA3 and PGI3 increased. In control animals, TxA2 formation increased during thrombosis; there was a further, more marked rise during reperfusion. PGI2 formation also increased, probably as a response to platelet-vascular interactions. Stimulated production of both eicosanoids was strikingly suppressed in the animals fed fish oil. Fish oils significantly enhance the efficacy of rt-PA in vivo, albeit to a modest extent. Because the time to reperfusion is highly sensitive to Tx-dependent platelet activation, this effect is likely to reflect the demonstrated suppression of TxA2 biosynthesis by fish oils.

Topics: Animals; Blood Platelets; Coronary Disease; Coronary Thrombosis; Dietary Fats, Unsaturated; Dogs; Epoprostenol; Fish Oils; Male; Membrane Lipids; Phospholipids; Platelet Aggregation Inhibitors; Thromboxane A2; Tissue Plasminogen Activator

We tested the hypothesis that simultaneous inhibition of TxA2 synthase and blockade of TxA2/PHG2 receptors is more effective in enhancing thrombolysis and preventing reocclusion after discontinuation of tissue plasminogen activator (t-PA) than either intervention alone. Coronary thrombosis was induced in 35 dogs by placing a copper coil into the left anterior descending coronary artery. Coronary flow was measured with a Doppler flow probe. 30 min after thrombus formation, the animals received saline (controls, n = 10); SQ 29548 (0.4 mg/kg bolus + 0.4 mg/kg per h infusion), a TxA2/PGH2 receptor antagonist (n = 8); dazoxiben (5 mg/kg bolus + 5 mg/kg per h infusion), a TxA2 synthase inhibitor (n = 9); or R 68070 (5 mg/kg bolus + 5 mg/kg per h infusion), a drug that blocks TxA2/PGH2 receptors and inhibits TxA2 synthase (n = 8). Then, all dogs received heparin (200 U/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg per min) for up to 90 min or until reperfusion was achieved. The time to thrombolysis did not change significantly in SQ 29548-treated dogs as compared with controls (42 +/- 5 vs. 56 +/- 7 min, respectively, P = NS), but it was significantly shortened by R 68070 and dazoxiben (11 +/- 2 and 25 +/- 6 min, respectively, P less than 0.001 vs. controls and SQ 29548-treated dogs). R 68070 administration resulted in a lysis time significantly shorter than that observed in the dazoxiben-treated group (P less than 0.01). Reocclusion was observed in eight of eight control dogs, five of seven SQ 29548-treated dogs, seven of nine dazoxiben-treated dogs, and zero of eight R 68070-treated animals (P less than 0.001). TxB2 and 6-keto-PGF1 alpha, measured in blood samples obtained from the coronary artery distal to the thrombus, were significantly increased at reperfusion and at reocclusion in control animals and in dogs receiving SQ 29548. R 68070 and dazoxiben prevented the increase in plasma TxB2 levels, whereas 6-keto-PGF1 alpha levels were significantly increased with respect to control and SQ 29548-treated dogs. Thus, simultaneous inhibition of TxA2 synthase and blockade of TxA2/PGH2 receptors is more effective than either intervention alone in this experimental model in enhancing thrombolysis and preventing reocclusion after t-PA administration.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Coronary Thrombosis; Cricetinae; Dogs; Fatty Acids, Unsaturated; Fibrinolysis; Hydrazines; Imidazoles; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandins; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Thromboxane-A Synthase; Tissue Plasminogen Activator

Topics: Aspirin; Coronary Artery Disease; Coronary Disease; Coronary Thrombosis; Humans; Thromboxane A2

Dynamic changes of the thrombus after its formation due to platelet activation may affect the speed of thrombolysis. In the present study, we wanted to evaluate the role played by thromboxane A2 (TXA2) and serotonin (5HT) in mediating platelet activation during lysis of intracoronary thrombi with human recombinant tissue-type plasminogen activator (t-PA). Coronary thrombi were induced in 26 anesthetized, open-chest dogs by inserting a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Presence of the thrombus was documented for 30 minutes. The dogs were then assigned to one of four groups as follows: group 1 dogs (n = 8), serving as controls, received a bolus of heparin (200 units/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg/min) for up to 90 minutes or until reperfusion was achieved; group 2 dogs (n = 10) received, immediately before heparin and t-PA, an intravenous bolus of SQ29548 (SQ) (0.4 mg/kg, a selective TXA2-receptor antagonist) and LY53857 (LY) (0.2 mg/kg, a selective serotonin S2-receptor antagonist); group 3 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of SQ alone (0.4 mg/kg); and group 4 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of LY alone (0.2 mg/kg). After thrombolysis, all dogs were monitored for 90 minutes or until a persistent reocclusion occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Coronary Disease; Coronary Thrombosis; Dogs; Drug Therapy, Combination; Ergolines; Fatty Acids, Unsaturated; Hydrazines; Myocardial Reperfusion; Platelet Aggregation; Recombinant Proteins; Recurrence; Serotonin; Serotonin Antagonists; Thromboxane A2; Time Factors; Tissue Plasminogen Activator

Platelet activation is markedly increased during coronary thrombolysis and limits the response to thrombolytic therapy. A possible mediator of platelet activation in this setting is thromboxane (TX) A2, a potent platelet agonist formed in greatly increased amounts during coronary thrombolysis in man. To address this hypothesis, we examined the role of TXA2 in modulating the response to intravenous tissue-type plasminogen activator (t-PA) in a chronic canine model of coronary thrombosis. Reperfusion occurred in 60 +/- 5 minutes and was complicated by spontaneous reocclusion. The times to reperfusion and reocclusion were platelet-dependent. Consistent with a role for TXA2 in this process, TXA2 biosynthesis, determined a excretion of its enzymatic metabolite, 2,3-dinor-TXB2, was markedly increased during coronary thrombolysis. Furthermore, inhibition of TXA2 by aspirin, given alone or in combination with a TXA2/prostaglandin endoperoxide receptor antagonist, accelerated reperfusion and partly inhibited cyclic flow variations during reperfusion. The delay in reperfusion and reocclusion induced by TXA2 appeared to be mediated by platelet aggregation since the F(ab')2 fragment of 7E3, a monoclonal antibody to the platelet GPIIb/IIIa, also accelerated reperfusion and prevented reocclusion without altering TXA2 biosynthesis. These finding suggest that platelet aggregation limits the response to coronary thrombolysis and that platelet activation in this setting is partly TXA2-dependent.

Topics: Angiography; Animals; Antibodies, Monoclonal; Blood Coagulation; Blood Platelets; Coronary Disease; Coronary Thrombosis; Dogs; Epoprostenol; Fibrinolytic Agents; Immunoglobulin Fab Fragments; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Tissue Plasminogen Activator

The effects of thromboxane (Tx)A2 antagonism were examined in a canine model of platelet-dependent coronary occlusion. The novel TxA2 antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazo lepropanoic acid (Bay u 3405) was studied to ensure that antithrombotic effects seen in vivo were platelet-mediated and did not reflect unspecific compound effects. Bay u 3405 (1, 3, 10 and 30 mg/kg i.v.) inhibited in vivo platelet aggregation and increased the time to thrombotic vascular occlusion by 2.8 h (p less than 0.05) after 30 mg/kg were given. A dose-dependent reduction of intravascular occlusive thrombus growth occurred: thrombus wet weight decreased from 66 +/- 6 mg in vehicle controls to 42 +/- 6 mg, 25 +/- 5 mg, 18 +/- 3 mg and 6 +/- 2 mg after administration of 1, 3, 10 and 30 mg Bay u 3405 i.v., respectively. Electrocardiographic signs for developing myocardial ischemia were largely prevented by the compound. Collagen-induced platelet aggregation ex vivo was inhibited by over 60% in drug-treated animals. The observed delay of thrombotic coronary occlusion reflected an inhibition of platelet aggregation and protection from coronary vasoconstriction at the site of thrombus formation, most likely mediated through blockade of TxA2 receptors.

Topics: Animals; Blood Pressure; Carbazoles; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Dogs; Electric Stimulation; Female; Fibrinolytic Agents; Heart Rate; Humans; In Vitro Techniques; Male; Myocardial Infarction; Sulfonamides; Thromboxane A2

Human recombinant tissue-type plasminogen activator (rt-PA) has been shown to be an effective and safe agent for coronary thrombolysis in patients with acute myocardial infarction. However, thrombolysis is associated with a high rate of acute reocclusion after discontinuation of rt-PA. The goals of the present study were to assess whether reocclusion after thrombolysis is caused by intracoronary platelet aggregation and to determine the role of thromboxane A2 (TxA2) and serotonin (5HT) in mediating this phenomenon. Accordingly, coronary thrombosis was induced in anesthetized, open-chest dogs by insertion of a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Thrombolysis was achieved with rt-PA (0.05 mg/kg bolus + micrograms/kg/min infusion) in 23 +/- 3 min. rt-PA was then discontinued and each animal received a bolus of heparin (150 U/kg) every hour. Reperfusion was followed by repeated cycles of gradual occlusions followed by spontaneous restorations of blood flow (cyclic flow variations, CFVs) before a persistent occlusion recurred. In control dogs (n = 6), heparin alone did not prevent CFVs and reocclusion time was 25 +/- 4 min. Administration of an intravenous bolus of 0.2 +/- 0.06 mg/kg SQ29548, a TxA2/prostaglandin H2-receptor antagonist, and an intravenous bolus of 0.2 +/- 0.04 mg/kg ketanserin, a 5HT2-receptor antagonist, completely abolished CFVs in six of six dogs and reocclusion time was greater than 158 +/- 14 min (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Dogs; Fatty Acids, Unsaturated; Hydrazines; Ketanserin; Platelet Aggregation; Recombinant Proteins; Recurrence; Serotonin; Thromboxane A2; Tissue Plasminogen Activator

The purpose of this investigation was to examine the potential beneficial effect of the selective endoperoxide/thromboxane A2 (TxA2) receptor antagonist, sulotroban (BM 13.177), on tissue type plasminogen activator (tPA)-induced coronary thrombolysis in the dog. A stenosis that eliminated reactive hyperemic capacity was placed on the circumflex coronary artery and an occlusive thrombus was produced by electrical injury to the intimal surface of the artery. Upon occlusion, sodium heparin was administered (300 U/kg i.v.) followed by 100 U/kg i.v. every hour thereafter. All dogs received i.v. tPA 60 min after the formation of the occlusive thrombus at a dose of 10 micrograms/kg/min for up to 90 min, if necessary, to elicit reperfusion. Thrombolysis was demonstrated in all dogs by restoration of coronary blood flow. Dogs were randomized to one of three groups. Group I consisted of 24 animals that received vehicle infusion along with tPA. Group II consisted of 10 animals that received sulotroban at a bolus dose of 1 mg/kg i.v. followed by 1 mg/kg/hr i.v. administered simultaneously with tPA. Group III consisted of 11 animals that received sulotroban at a bolus of 10 mg/kg i.v. followed by 10 mg/kg/hr i.v. administered simultaneously with tPA. Infusions of either vehicle or sulotroban were continued for 2 hr, post-thrombolysis. tPA was infused for at least 30 min, after which infusion of tPA was terminated upon achieving a reperfusion level of coronary blood flow equivalent to 50% or greater than control blood flow. All animals occluded spontaneously to electrolytic stimulation between 32 and 62 min. tPA-induced thrombolysis occurred in Group I vehicle-infused animals at 32 +/- 5 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Dogs; Drug Therapy, Combination; Female; Fibrinolytic Agents; Male; Platelet Aggregation Inhibitors; Sulfonamides; Thromboxane A2; Tissue Plasminogen Activator

Topics: Animals; Coronary Disease; Coronary Thrombosis; Endothelium, Vascular; Epoprostenol; Fibrinolytic Agents; Humans; Myocardial Infarction; Platelet Aggregation; Rabbits; Thromboxane A2; Thromboxane-A Synthase; Vasodilation

An experimental model of acute myocardial infarction is presented. Intracoronary thrombus was precipitated by a mock ruptured atheromatous plaque, which is a cholesterol-collagen mixture, protruding into the stenosed left anterior descending coronary artery. Twenty-five dogs, divided into two groups, were studied: a control group of 15 dogs and a treated group of 10 dogs. Intracoronary thrombus was precipitated by the mock atheromatous plaque in 13 of 15 control animals. Myocardial infarction was induced in 10 and sudden death in two. Coronary blood flow decreased gradually or cyclically to end in myocardial infarction. The model was utilized to investigate the effects of a thromboxane synthetase inhibitor, OKY-046, on 10 additional animals. OKY-046 could significantly decrease the incidence of occlusive thrombus formation and myocardial infarction when administered intravenously during coronary blood flow reduction (3 of 10 in the treated group vs 12 of 15 in the control group, p less than 0.02). Thromboxane B2 was significantly elevated in the coronary venous blood during reduction of the coronary blood flow, while thromboxane B2 was reduced and 6-ketoprostaglandin F1 alpha increased during OKY-046 administration. The reduction in thromboxane A2 production associated with increased prostacyclin appeared to be the major mechanism of the interruption of the thrombus formation by OKY-046.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Coronary Thrombosis; Dogs; Epoprostenol; Female; Male; Methacrylates; Myocardial Infarction; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase