thromboxane-a2 and Thromboembolism

Aspirin is integral to the secondary prevention of cardiovascular disease and acts to impair the development of platelet-mediated atherothromboembolic events by irreversible inhibition of platelet cyclooxygenase-1 (COX-1). Inhibition of this enzyme prevents the synthesis of the potent pro-aggregatory prostanoid thromboxane A2. A large number of patients continue to experience atherothromboembolic events despite aspirin therapy, so-called 'aspirin treatment failure', and this is multifactorial in aetiology. Approximately 10% however do not respond appropriately to aspirin in a phenomenon known as 'aspirin resistance', which is defined by various laboratory techniques. In this review we discuss the reasons for aspirin resistance in a systematic manner, starting from prescription of the drug and ending at the level of the platelet. Poor medication adherence has been shown to be a cause of apparent aspirin resistance, and may in fact be the largest contributory factor. Also important is high platelet turnover due to underlying inflammatory processes, such as atherosclerosis and its complications, leading to faster regeneration of platelets, and hence of COX-1, at a rate that diminishes the efficacy of once daily dosing. Recent developments include the identification of platelet glycoprotein IIIa as a potential biomarker (as well as possible underlying mechanism) for aspirin resistance and the discovery of an anion efflux pump that expels intracellular aspirin from platelets. The absolute as well as relative contributions of such factors to the phenomenon of aspirin resistance are the subject of continuing research.

Topics: Aspirin; Blood Platelets; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Humans; Integrin beta3; Medication Adherence; Tachyphylaxis; Thromboembolism; Thromboxane A2; Treatment Failure

The exact etiology of the conflicting hemostatic disorder in the advanced stage of chronic renal disease, i.e. prothrombotic versus bleeding tendency, is not completely understood. Abnormal platelet function in patients with renal failure is not caused by high concentrations of urea, although the presence of fibrinogen fragments may prevent binding of normal fibrinogen and formation of platelet aggregates. Hemostatic abnormalities in end-stage kidney disease may be affected, to some extent, by the choice of renal replacement therapy. Patients on hemodialysis have an increased risk of thrombotic events, primarily due to the release of thromboxane A2 and adenosine diphosphate into the circulation, as well as platelet degranulation. Some activation of platelets occurs due to the exposure of blood to the roller pump segment, but microbubbles may also play a role. Renal transplantation is the treatment of choice for patients with end-stage renal disease. Immunosuppressive therapy is associated with an increased risk of thromboembolic complications. Additional research is required to identify the potential benefits of different immunosuppressive therapies in relation to platelet aggregation, keeping in mind the long- term need for immunosuppression in renal transplant patients.

Topics: Adenosine Diphosphate; Blood Platelet Disorders; Humans; Kidney Failure, Chronic; Kidney Transplantation; Platelet Aggregation; Renal Dialysis; Renal Replacement Therapy; Risk Factors; Thromboembolism; Thrombosis; Thromboxane A2

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Blood Platelets; Cardiovascular Diseases; Celecoxib; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Depression, Chemical; Dinoprostone; Epoprostenol; Gastric Mucosa; Gastrointestinal Hemorrhage; Humans; Incidence; Intestinal Mucosa; Isoenzymes; Lactones; Membrane Proteins; Peptic Ulcer; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; Randomized Controlled Trials as Topic; Substrate Specificity; Sulfonamides; Sulfones; Thromboembolism; Thromboxane A2; Treatment Outcome

Thromboxanes are cyclooxygenase products of C-20 polyenoic fatty acids. The arachidonic acid derivate, thromboxane A2 (TXA2), is the only biologically relevant product and is mainly generated in blood platelets. Hyperreactivity of blood platelets appears to be an important risk factor for thromboembolic vessel occlusion in the presence of preexisting vascular pathology. Starting with acetylsalicylic acid, which is still the reference standard, several attempts have been made over the past few years to develop more specific drugs which selectively modify platelet TXA2 formation, a most important feedback-stimulator of platelet function. Thromboxane synthase inhibitors were the first compounds which were tested clinically. Some data suggest beneficial effects in several types of cardiovascular disease. However, the overall impression is that the compounds available so far may not be superior to acetylsalicylic acid. Thromboxane receptor antagonists and mixed type synthase inhibitor/receptor blocking compounds would appear to be more promising from a theoretical point of view. These compounds exhibit a number of beneficial effects in animal studies. However, clinical experience so far is very limited. It is concluded that fresh insight into the regulation and types of thromboxane receptors, the development of long-lasting synthase inhibitors, non-competitive thromboxane receptor antagonists and combined mode-active drugs, as well as a better understanding of interactions between several classes of platelet-active mediators (prostacyclin, nitric oxide, PAF) will probably result in improved drug treatment of ischaemic cardiovascular disease in the near future.

Topics: Blood Platelets; Humans; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboembolism; Thromboxane A2; Thromboxane-A Synthase

Topics: Aspirin; Blood Platelets; Blood Vessels; Chemistry, Pharmaceutical; Clinical Trials as Topic; Cyclooxygenase Inhibitors; Epoprostenol; Female; Humans; Male; Myocardial Infarction; Platelet Aggregation; Pregnancy; Thromboembolism; Thromboxane A2

Nephrotic syndrome characterized by hypoalbuminemia and hyperlipidemia is associated with an increased incidence of thromboembolism and increased platelet hyperaggregability. Although plasma coagulation proteins are also abnormal, changes are too inconsistent to attribute thromboembolic complications to the coagulation cascade alone. Antithrombin III (ATIII) has been shown to be deficient in nephrotic syndrome. There is, however, an increase in alpha 2 macroglobulin. It is clear that platelet to platelet interactions require exposure of platelet fibrinogen receptors, the binding of fibrinogen to these receptors, platelet crossbridging, and subsequent platelet aggregation. Fibrinogen is consistently elevated in nephrotic syndrome. Hyperlipidemia and hypoalbuminemia in nephrotic syndrome increases the availability of thromboxane A2 (TxA2) by increasing the availability of TxA2 precursors and the removal of TxA2 inhibitors. Thromboxane A2 is a known inducer of platelet aggregation probably through the exposure of platelet fibrinogen receptors. Recently, fibronectins a group of adhesive proteins, were implicated in platelet to platelet interactions. Since thrombin increases the expression of platelet surface fibronectin, fibronectin may be involved in thrombus formation in nephrotic syndrome. Thromboembolic formation in nephrotic syndrome is a composite mechanism involving the coagulation cascade, platelet-platelet interactions, and platelet-surface interactions.

Topics: beta-Thromboglobulin; Blood Platelets; Epoprostenol; Fibrinogen; Fibronectins; Humans; Nephrotic Syndrome; Platelet Aggregation; Platelet Factor 4; Thromboembolism; Thromboxane A2

Topics: Animals; Arachidonic Acids; Aspirin; Dipyridamole; Dogs; Epoprostenol; Hemostasis; Humans; Platelet Adhesiveness; Platelet Aggregation; Pulmonary Embolism; Thromboembolism; Thrombophlebitis; Thromboxane A2

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Blood Pressure; Cardiovascular Physiological Phenomena; Coronary Circulation; Epoprostenol; Humans; Hypertension; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandins; Thromboembolism; Thromboxane A2; Thromboxanes; Vascular Resistance

Metabolism of arachidonic acid (AA) in blood platelets and in vascular endothelium does not lead to prostaglandins, but thromboxane A2 and prostacyclin are generated. These labile metabolites of AA antagonize each other: thromboxane A2 is a vasoconstrictor and proaggregatory agent, whereas prostacyclin dilates arteries, prevents platelets from aggregation, and dissipates the preformed platelet clumps. Prostacyclin is a powerful stimulator of adenylate cyclase in platelets and therefore its antiplatelet action is potentiated by phosphodiesterase inhibitors such as theophylline or dipyridamole. Cyclo-oxygenase of AA is inhibited by aspirin, thromboxane synthetase by analogues of prostaglandin endoperoxides, and prostacyclin synthetase by linear lipid peroxides. A hypothesis is put forward that atherosclerosis develops because of pathological, nonenzymic lipid peroxides. A hypothesis is put forward that atherosclerosis develops because of pathological, nonenzymic lipid peroxydation in the body and the subsequent molecular damage to prostacyclin synthetase in the rheologically determined areas of arterial walls. Endothelium deprived of prostacyclin is the basis for microthrombi formation, and follows a sequence of events described by Rokitansky and later by Ross. Prostacyclin is also a circulating hormone which is generated by the lungs. Thereby a damage of this "endocrine gland" by respiratory disorders, air pollution, or tobacco smoking are likely to contribute to pathogenesis of atherosclerosis, myocardial infarction, and arterial thromboembolism. Pharmacological treatment and prevention of these diseases should logically include antioxydants, prostacyclin and its analogues, thromboxane synthetase inhibitors and perhaps cyclooxygenase inhibitors (aspirin ?). Prostacyclin was already infused intravenously to men and its powerful antiaggregatory and deaggregatory actions were demonstrated. These properties of prostacyclin along with its vasodilator and positive inotropic actions destine this hormone to be a new type of antithrombotic drug in acute myocardial infarction.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Aspirin; Blood Circulation; Blood Vessels; Carotid Artery Thrombosis; Cyclooxygenase Inhibitors; Dogs; Epoprostenol; Female; Humans; Infusions, Parenteral; Male; Mice; Myocardial Infarction; Platelet Aggregation; Prostaglandins; Rabbits; Rats; Structure-Activity Relationship; Thromboembolism; Thromboxane A2; Thromboxanes

Topics: Animals; Aspirin; Clinical Trials as Topic; Depression, Chemical; Epoprostenol; Humans; Platelet Aggregation; Rats; Thromboembolism; Thromboxane A2

Topics: Aspirin; Blood Platelets; Blood Vessels; Chemistry, Pharmaceutical; Clinical Trials as Topic; Cyclooxygenase Inhibitors; Epoprostenol; Female; Humans; Male; Myocardial Infarction; Platelet Aggregation; Pregnancy; Thromboembolism; Thromboxane A2

Topics: Animals; Aspirin; Clinical Trials as Topic; Depression, Chemical; Epoprostenol; Humans; Platelet Aggregation; Rats; Thromboembolism; Thromboxane A2

The vine stem of Spatholobus suberectus is a widely used blood-activating and stasis-dispelling medicine for the treatment of diseases related to blood stasis syndrome in traditional medicine in Korea, Japan, and China.. To demonstrate the clinical effects of Spatholobus suberectus against blood stasis syndromes using in vitro and in vivo platelet aggregation studies and to investigate its exact mechanisms.. We extracted vine stems of Spatholobus suberectus, using 95% EtOH (SSE) and investigated its antiplatelet activity on platelet aggregation induced by collagen and ADP in human platelet-rich plasma (PRP). For the mechanism study, a glycoprotein IIb/IIIa (GP IIb/IIIa) assay using flow cytometric analysis and a thromboxane A(2) (TXA(2)) assay were performed. In addition, we investigated the effects of SSE in a thromboembolic mouse model.. SSE significantly inhibited ADP- and collagen-induced platelet aggregation in human PRP concentration-dependently without affecting plasma clotting time. It also significantly inhibited fibrinogen binding to the GP IIb/IIIa receptor and partly inhibited the formation of TXA(2). In the in vivo study, oral administration of SSE dose-dependently suppressed the death of thromboembolism model mice induced by intravenous injection of collagen plus epinephrine.. SSE showed antiplatelet activity without anticoagulant effects mainly through the inhibition of fibrinogen binding to the GP IIb/IIIa receptor. Our current results support the clinical usage of SSE in the East Asian region treating atherothrombotic diseases and may represent a new natural source to develop antiplatelet agents.

Topics: Adenosine Diphosphate; Animals; Asia, Eastern; Collagen; Dose-Response Relationship, Drug; Epinephrine; Fabaceae; Female; Fibrinogen; Humans; Mice; Mice, Inbred ICR; Phytotherapy; Plant Extracts; Plant Stems; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet-Rich Plasma; Thromboembolism; Thromboxane A2

Platelets stably interact with collagen via glycoprotein (GP)VI and alpha2beta1integrin. With alpha2-null mice, we investigated the role of alpha2beta1 in thrombus formation and stability in vivo and in vitro. Using a FeCl(3)-induced thrombosis model, in arteries from alpha2-null mice smaller thrombi were formed with more embolization compared to vessels from wild-type mice. Aspirin treatment of wild-type mice causes similar effects, while the thromboxane A(2) analogue U46619 was borderline effective in suppressing the embolisation in alpha2-null mice. In vitro, perfusion of alpha2-null blood over collagen resulted in formation of thrombi that were smaller and looser in appearance, regardless of the presence or absence of coagulation. Aspirin treatment or blockage of thromboxane receptors provoked embolus formation in wildtype blood, while U46619 normalized thrombus formation in blood from alpha2-null mice. We conclude that integrin alpha2beta1 plays a role in stabilizing murine thrombi, likely by enhancing GPVI activation and thromboxane A(2) release. The increased embolization in alpha2-null mice may argue against the use of alpha2beta1 integrin inhibitors for antithrombotic therapy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aspirin; Chlorides; Collagen; Ferric Compounds; Integrin alpha2beta1; Mice; Mice, Knockout; Thromboembolism; Thrombosis; Thromboxane A2

We have used the EaHy926 endothelial cell line, able to secrete both pro and anti-aggregant platelet agents, as a model for thrombo-embolic diseases. We experimentally established, by comparing these two secretions with or without a Faraday cage, that the environmental electromagnetic field significantly increases the thrombo-embolic risks in this endothelial cell line.

Topics: 6-Ketoprostaglandin F1 alpha; Cell Line; Electromagnetic Fields; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Humans; Risk Factors; Thromboembolism; Thromboxane A2; Thromboxane B2

Topics: Animals; Aspirin; Cause of Death; Cyclooxygenase Inhibitors; Disease Models, Animal; Humans; Platelet Aggregation Inhibitors; Pulmonary Embolism; Risk Factors; Thromboembolism; Thromboxane A2; Vasoconstrictor Agents

The involvement of prostaglandins in thromboembolic processes, as induced by wall puncture, was studied in rabbit mesenteric arterioles and venules using intravital videomicroscopy. Inhibition of prostaglandin formation with aspirin (100 mg/kg, i.v.) significantly increased in arterioles duration of embolization (from 91 to 200 s) and number of emboli produced (from 4 to 8.5 per vessel), while rate of embolus production was not influenced. In venules, aspirin only influenced embolization rate (a significant decrease from one embolus/14 s to one/23 s). Specific blockade of TXA2-receptors by sulotroban (30 mg/kg, i.v.) only influenced the arteriolar reaction: it significantly decreased embolization duration (from 560 to 218 s) and number of emboli produced (from 23 to 10 emboli per vessel), without affecting embolization rate. These findings indicate that both platelet activating and inhibiting prostaglandins play a more important role in thromboembolism in arterioles than in venules; this suggests a difference in prostaglandin synthetic capacity between arteriolar and venular endothelium.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arterioles; Aspirin; Epoprostenol; Female; Hydroxyeicosatetraenoic Acids; Leukocytes; Male; Mesentery; Platelet Activation; Prostaglandins; Rabbits; Receptors, Thromboxane; Regional Blood Flow; Sulfonamides; Thromboembolism; Thromboxane A2; Venules; Videotape Recording

The model of AA-induced sudden death employed in these investigations seems to be appropriate for studying the efficacy of TXA2-antagonists. The actions of TXA2 on platelets, respiratory and vascular tissue are considered as key events resulting in the death of the animals. The results obtained in this study, using BAY U 3405 as a selective TXA2 receptor antagonist, clearly show that TXA2 mediated processes are effectively abolished by this type of drug. Since TXA2 is implicated in the pathophysiology of many diseases, potent TXA2 antagonists appear to be useful for treatment of these disorders. BAY U 3405 seems to fulfil these requirements. The threshold dose is 1 to 3 mg/kg p.o. In addition, there is a rapid onset and long duration of action at 10 mg/kg p.o. under the experimental conditions used.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Bronchoconstriction; Carbazoles; Death, Sudden; Dose-Response Relationship, Drug; Male; Platelet Aggregation; Rabbits; Sulfonamides; Survival Rate; Thromboembolism; Thromboxane A2; Thromboxanes

Topics: Aspirin; Dose-Response Relationship, Drug; Epoprostenol; Humans; Platelet Aggregation; Thromboembolism; Thromboxane A2

The effects of 1,2-bis(nicotinamido)propane (AVS) on platelet function and vascular endothelium were investigated using various experimental thrombosis and vascular endothelial injury models. Neither in vitro platelet aggregation induced by ADP, collagen or arachidonate nor ex vivo platelet aggregation by ADP or collagen could be antagonized by AVS. On the other hand, AVS prevented mice, rats and rabbits from death induced by acute cerebral or pulmonary thromboembolism following the injection of arachidonate or collagen. These activities were as potent as those of acetylsalicylic acid. The disrupting actions of citrate and/or lipidperoxide (13-hydroperoxy linoleic acid) on endothelium were well inhibited by the pretreatment of AVS. AVS did not inhibit cyclooxygenase, increased prostacyclin (PGI2)/thromboxane A2 (TXA2) ratio in the coupled system of platelets and aortic microsomes. In conclusion, AVS inhibited thrombus formation in vivo while it was ineffective in vitro platelet alone system, which may result from the actions of this agent on both platelets and vascular endothelium. The above-mentioned results clearly show that AVS may be a new potent anti-vascular damaging agent with both endothelium stabilizing and PGI2 enhancing activities.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Blood Vessels; Cerebrovascular Disorders; Collagen; Dinoprostone; Endothelium; In Vitro Techniques; Mice; Microscopy, Electron, Scanning; Niacinamide; Platelet Aggregation; Prostaglandins E; Rabbits; Rats; Rats, Inbred Strains; Thromboembolism; Thrombosis; Thromboxane A2