thromboxane-a2 and Hemorrhage

Patients surviving an acute coronary syndrome (ACS) remain at increased risk of ischemic events long term. This paper reviews current evidence and guidelines for oral antiplatelet therapy for secondary prevention following ACS, with respect to decreased risk of ischemic events versus bleeding risk according to individual patient characteristics and risk factors. Specifically, data are reviewed from clinical studies of clopidogrel, prasugrel, ticagrelor and vorapaxar, as well as the results of systematic reviews and meta-analyses looking at the benefits and risks of oral antiplatelet therapy, and the relative merits of shorter versus longer duration of dual antiplatelet therapy, in different patient groups.

Topics: Acute Coronary Syndrome; Adenosine Diphosphate; Administration, Oral; Aging; Blood Platelets; Cyclooxygenase 1; Diabetes Mellitus; Drug Administration Schedule; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Purinergic P2Y Receptor Antagonists; Receptor, PAR-1; Receptors, Purinergic P2Y12; Renal Insufficiency; Risk Factors; Secondary Prevention; Thrombin; Thromboxane A2; Time Factors; Vascular Diseases

Aspirin is an antiplatelet drug, inhibiting the cyclooxygenase activity of platelet prostaglandin H synthase-1 and almost complete suppressing platelet capacity to generate the prothrombotic and proatherogenic thromboxane A2. Antiplatelet therapy with aspirin reduces the risk of serious vascular events by about a quarter in patients who are at high risk because they already have occlusive vascular disease. However, the inhibition of thromboxane-dependent platelet function by aspirin is effective for the prevention of thrombosis, but is also associated with excess bleeding, although the absolute increase in major gastrointestinal or other major extracranial bleeds is an order of magnitude smaller. For secondary prevention of vascular events, the benefits of aspirin therapy substantially exceed the risks. Therefore, aspirin is a cornerstone of antithrombotic therapy in acute coronary syndromes, in chronic ischemic heart disease and in percutaneous coronary intervention. On the other hand, the role of aspirin in primary prevention remains uncertain and it is still debated, because the absolute risk of vascular complications is the major determinant of the absolute benefit of antiplatelet prophylaxis and the reduction in vascular events needs to be weighed against any increase in major bleeds. Future data from ongoing studies will help us to identify people at high vascular risk who take advantage from aspirin therapy for primary prevention or will indicate if specific category of high risk patients, like patients with diabetes, could be better protected from an increase in the frequency of aspirin administration.

Topics: Animals; Aspirin; Blood Platelets; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Hemorrhage; History, 20th Century; History, 21st Century; Humans; Myocardial Ischemia; Patient Selection; Platelet Aggregation Inhibitors; Primary Prevention; Risk Factors; Secondary Prevention; Thromboxane A2; Treatment Outcome

Topics: Adenosine Diphosphate; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atherosclerosis; Biomarkers; Biotransformation; Blood Coagulation Tests; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Hemorrhage; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Randomized Controlled Trials as Topic; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y12; Thrombosis; Thromboxane A2; Thromboxane B2; Ticlopidine; Treatment Failure

Topics: Anticoagulants; Coumarins; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudins; Humans; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Preoperative Care; Purinergic P2 Receptor Antagonists; Risk Factors; Thrombosis; Thromboxane A2

Aspirin has a well established role in the prevention of arterial thrombosis. Discussion on the efficacy and safety of aspirin in the treatment and prophylaxis of thrombosis in essential thrombocythemia (ET) has become an important issue. The rationale for its use in ET comes from the observation that arterial thrombosis and platelet-mediated microcirculatory disturbances are the major causes of morbidity and mortality in ET. Experimental data have shown persistently elevated levels of thromboxane A2 (TXA2) in ET patients probably reflecting an enhanced in vivo platelet activation. Increased TXA2 biosynthesis and platelet activation in vivo in ET are selectively suppressed by repeated low doses of aspirin. ET-related symptoms such as erythromelalgia, transient neurologic and ocular disturbances are sensitive to aspirin. However, the benefit of low-dose aspirin is still uncertain in the primary prevention of thrombosis in ET. Furthermore, aspirin may unmask a latent bleeding diathesis frequently present in ET which may result in severe hemorrhagic complications. Thus, aspirin is contraindicated in ET patients with a bleeding history or a very high platelet count (> 1500 x 10(9)/L) leading to the acquisition of von Willebrand factor deficiency. If indicated, aspirin is presently used in the widely accepted low-dose regimen of 100 mg daily. However, an optimal effective dose has not yet been established. To further evaluate the efficacy and safety of aspirin in ET, prospective clinical trials are needed.

Topics: Abortion, Habitual; Aspirin; Cerebrovascular Disorders; Cohort Studies; Contraindications; Erythromelalgia; Female; Fibrinolytic Agents; Forecasting; Hemorrhage; Humans; Incidence; Middle Aged; Myeloproliferative Disorders; Pilot Projects; Platelet Activation; Platelet Aggregation Inhibitors; Pregnancy; Pregnancy Complications, Hematologic; Retrospective Studies; Safety; Thrombocythemia, Essential; Thrombophilia; Thrombosis; Thromboxane A2; Vision Disorders; von Willebrand Diseases

The major benefits of the perioperative administration of nonsteroidal anti-inflammatory drugs (NSAIDs) are related to the ability of these agents to provide analgesia without cardiovascular or respiratory depression. However, there are several possible adverse effects of NSAIDs. All NSAIDs reduce the synthesis of prostaglandins by the kidneys, but their administration in the perioperative period appears to have little potential for renal toxicity when adequate hydration is maintained and renal function is not dependent on renal prostaglandins. However, NSAIDs may cause impairment of renal function in patients with conditions such as hypovolaemia, congestive cardiac failure, or hepatic cirrhosis, since renal function in these patients may be dependent on the vascular effects of prostaglandins. Platelet aggregation is inhibited by the administration of NSAIDs, and most studies of their haematological effects report that NSAIDs are associated with an increase in bleeding times. In patients with normal haemostatic function before NSAID administration, almost all indices of coagulation remain within the normal range after NSAID treatment. Most studies of perioperative blood loss have reported no significant difference between the effects of NSAIDs and placebo in this regard. The incidence of major allergic reactions in the general population appears to be small with NSAIDs. Overall, NSAIDs appear to be safe and well tolerated drugs with a valuable role to play in the treatment of postoperative pain.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Drug Hypersensitivity; Hemorrhage; Humans; Kidney; Pain, Postoperative; Platelet Aggregation; Postoperative Complications; Prostaglandins; Thromboxane A2

Topics: Anemia; Aspirin; Bleeding Time; Blood Platelets; Blood Transfusion; Cryoprotective Agents; Deamino Arginine Vasopressin; Erythrocyte Transfusion; Erythropoietin; Estrogens; Hemorrhage; Humans; Parathyroid Hormone; Platelet Adhesiveness; Platelet Aggregation; Thromboxane A2; Uremia; von Willebrand Factor

Topics: Animals; Cytochrome P-450 Enzyme System; Diet; Epoprostenol; Hemorrhage; Humans; Intramolecular Oxidoreductases; Platelet Aggregation; Prostaglandin Endoperoxides; Thrombosis; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes

Topics: Aspirin; Dipyridamole; Epoprostenol; Hemorrhage; Humans; Platelet Aggregation; Prostaglandins; Thrombosis; Thromboxane A2; Thromboxanes

Platelet aggregation is widely used in clinical laboratories to evaluate patients with bleeding disorders of suspected platelet aetiology. Simultaneous monitoring of ATP release as a measure of dense granule secretion provides additional information to aid diagnosis. There is, however, no standard way of performing or interpreting these tests. The present study has evaluated aggregation and ATP secretion to eight platelet agonists in healthy donors and has evaluated the reproducibility of response for a number of variables, including platelet number and time after donation. The effect of inhibition of the two major platelet feedback mediators, ADP and thromboxane A(2) (TxA(2)), was investigated using the P2Y(1) and P2Y(12) receptor antagonists, MRS2179 and AR-C67085, and the cyclooxygenase inhibitor, indomethacin. The results demonstrate that, if used within certain boundaries, the investigation of platelet aggregation and secretion is a powerful way to discriminate between differing pathways of platelet activation. The present data-set are an invaluable resource to the clinical laboratory to aid evaluation of patients with suspected platelet-based bleeding disorders.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Blood Platelets; Cyclooxygenase Inhibitors; Diagnosis, Differential; Female; Hemorrhage; Humans; Indomethacin; Male; Platelet Aggregation; Platelet Function Tests; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y12; Reference Standards; Secretory Vesicles; Thromboxane A2

The arachidonic acid (AA) cascade plays a significant role in platelet aggregation. AA released from membrane phospholipids is metabolized by cyclooxygenase (COX) pathway to thromboxane A

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Arachidonate 12-Lipoxygenase; Arachidonic Acid; Blood Coagulation Disorders, Inherited; Blood Platelets; Calcium; Disease Susceptibility; Genetic Predisposition to Disease; GTP Phosphohydrolases; Hemorrhage; High-Throughput Nucleotide Sequencing; Humans; Inositol 1,4,5-Trisphosphate; Mutation; Pedigree; Phospholipase C beta; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Signal Transduction; Thromboxane A2

Uncontrollable bleeding is still a worldwide killer. In this study, we aimed to investigate a novel approach to exhibit effective haemostatic properties, which could possibly save lives in various bleeding emergencies. According to the structure-based enzymatic design, we have engineered a novel single-chain hybrid enzyme complex (SCHEC), COX-1-10aa-TXAS. We linked the C-terminus of cyclooxygenase-1 (COX-1) to the N-terminus of the thromboxane A

Topics: Amino Acids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 1; Dinoprostone; Epoprostenol; HEK293 Cells; Hemorrhage; Hemostatics; Humans; Mice, Transgenic; Platelet Aggregation; Prostaglandin H2; Recombinant Fusion Proteins; Thromboxane A2; Thromboxane-A Synthase

Aberrant activation of platelets has a critical role in thrombotic vascular events, including atherosclerosis, arterial thrombosis and myocardial infarction. The process of platelet activation is associated with multiple intracellular signaling pathways, including the phosphoinositide 3‑kinase/AKT serine/threonine kinase (Akt) pathway. The well‑known medicinal herb Rhizoma Ligusticum Wallichii (RLW) has long been used in China to clinically treat various cardiovascular disorders. As the most pharmacologically active component of RLW, ligustrazine has been demonstrated to possess a potent antiplatelet activity. However, the precise mechanisms mediating the bioactivities of ligustrazine have not been thoroughly elucidated. The present study evaluated the effects of ligustrazine hydrochloride (LH; the clinical‑grade form of ligustrazine) on platelet activation and investigated the underlying molecular mechanisms. In vitro and ex vivo platelet activation models were used, established by stimulating rat platelet‑rich plasma either with the platelet activator adenosine diphosphate (ADP) or with the specific Akt pathway activator insulin‑like growth factor‑1 (IGF‑1). The results demonstrated that treatment with LH significantly and dose‑dependently inhibited ADP‑induced platelet aggregation, in addition to thromboxane A2 (TXA2) secretion and intracellular Ca2+ mobilization in platelets, in vitro and ex vivo. In addition, LH markedly suppressed ADP‑induced Akt phosphorylation in vitro and ex vivo. Furthermore, LH markedly inhibited IGF‑1‑induced Akt phosphorylation, platelet aggregation, TXA2 formation and Ca2+ mobilization in vitro. Finally, LH was able to reverse adrenaline‑induced shortening of bleeding time. Taken together, these results suggested that ligustrazine possesses a broad range of antiplatelet activities without apparent hemorrhagic side-effects, and suppression of Akt signaling may be one of the mechanisms by which ligustrazine exerts its antiplatelet activities.

Topics: Animals; Calcium; Hemorrhage; Insulin-Like Growth Factor I; Male; Phosphorylation; Platelet Activation; Platelet Aggregation; Proto-Oncogene Proteins c-akt; Pyrazines; Rats, Sprague-Dawley; Signal Transduction; Thromboxane A2

Platelets contract forcefully after their activation, contributing to the strength and stability of platelet aggregates and fibrin clots during blood coagulation. Viscoelastic approaches can be used to assess platelet-induced clot strengthening, but they require thrombin and fibrin generation and are unable to measure platelet forces directly. Here, we report a rapid, microfluidic approach for measuring the contractile force of platelet aggregates for the detection of platelet dysfunction. We find that platelet forces are significantly reduced when blood samples are treated with inhibitors of myosin, GPIb-IX-V, integrin α

Topics: Adult; Aspirin; Blood Coagulation; Blood Platelets; Computer Simulation; Cross-Sectional Studies; Drug Monitoring; Female; Hemorrhage; Humans; Male; Microfluidics; Middle Aged; Myosins; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIb-IX Complex; Platelet Glycoprotein GPIIb-IIIa Complex; Prognosis; Thromboxane A2; Wounds and Injuries

Apelin peptide and its receptor APJ are directly implicated in various physiological processes ranging from cardiovascular homeostasis to immune signaling. Here, we show that apelin is a key player in hemostasis with an ability to inhibit thrombin- and collagen-mediated platelet activation. Mice lacking apelin displayed a shorter bleeding time and a prothrombotic profile. Their platelets exhibited increased adhesion and a reduced occlusion time in venules, and displayed a higher aggregation rate after their activation by thrombin compared with wild-type platelets. Consequently, human and mouse platelets express apelin and its receptor APJ. Apelin directly interferes with thrombin-mediated signaling pathways and platelet activation, secretion, and aggregation, but not with ADP and thromboxane A2-mediated pathways. IV apelin administration induced excessive bleeding and prevented thrombosis in mice. Taken together, these findings suggest that apelin and/or APJ agonists could potentially be useful adducts in antiplatelet therapies and may provide a promising perspective for patients who continue to display adverse thrombotic events with current antiplatelet therapies.

Topics: Adipokines; Animals; Apelin; Apelin Receptors; Blood Platelets; Hemorrhage; Humans; Intercellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Platelet Adhesiveness; Receptors, G-Protein-Coupled; Signal Transduction; Thrombin; Thrombosis; Thromboxane A2

Current antithrombotic drugs have an adverse effect on bleeding, highlighting the need for new molecular targets for developing antithrombotic drugs that minimally affect hemostasis. Here we show that LIMK1(-/-) mice have defective arterial thrombosis in vivo but do not differ from wild-type mice with respect to bleeding time. LIMK1(-/-) mice show a selective defect in platelet activation induced through the von Willebrand Factor (VWF) receptor, the glycoprotein Ib-IX-V complex (GPIb-IX), but not by GPIb-IX-independent platelet agonists. In fact, LIMK1(-/-) platelets show an enhanced reaction to certain GPIb-IX-independent agonists. The defect of LIMK1(-/-) platelets in GPIb-IX-mediated platelet activation is attributed to a selective inhibition in VWF/GPIb-IX-induced phosphorylation of cytosolic phospholipase A2 (cPLA2) and consequent thromboxane A2 (TXA2) production. Supplementing a TXA2 analog, U46619, corrected the defect of LIMK1(-/-) platelets in VWF-induced stable platelet adhesion. Although LIMK1(-/-) platelets also showed reduced actin polymerization after GPIb-IX-mediated platelet aggregation, actin polymerization inhibitors did not reduce TXA2 generation, but rather accelerated platelet aggregation, suggesting that the role of LIMK1 in GPIb-mediated platelet activation is independent of actin polymerization. Thus, LIMK1 plays a novel role in selectively mediating GPIb-IX-dependent TXA2 synthesis and thrombosis and represents a potential target for developing antithrombotic drugs with minimal bleeding side effect.

Topics: Actin Depolymerizing Factors; Actins; Animals; Blood Platelets; Cell Adhesion; Drug Design; Fibrinolytic Agents; Hemorrhage; Humans; Lim Kinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Stress, Mechanical; Thrombosis; Thromboxane A2; von Willebrand Factor

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

We investigated the role of low-amplitude magnetic pulse with low repetition frequency superimposed on the environmental electromagnetic field (EMF) on the secretion of anti-aggregant (Prostacyclin or PGI(2)) and pro-aggregant (Thromboxane A(2)) agents in endothelial cells of the human umbilical cord vein (HUVEC). We established that magnetic pulse exposure modulates both PGI(2) and TXA(2). These modulations depend on the frequency, width of the pulse, and intensity of the magnetic field. Moreover, we corroborated previous results obtained with an endothelial cell line (EaHy-926), concerning the increased thrombo-embolic risk for the 1 Hz frequency.

Topics: Animals; Cell Line; Electromagnetic Fields; Endothelial Cells; Epoprostenol; Hemorrhage; Humans; Platelet Activating Factor; Platelet Aggregation Inhibitors; Thrombosis; Thromboxane A2; Time Factors

In the present study, we investigated the role of the central cholinergic system in mediating the pressor effect of intracerebroventricularly administrated U-46619, a thromboxane A2 (TxA2) analog, in hemorrhaged hypotensive rats. Hemorrhage was performed by withdrawing a total volume of 2.1 ml of blood per 100 g body weight over a period of 10 min. Intracerebroventricular (i.c.v.) injection of U-46619 (0.5, 1, 2 micro g) produced a dose- and time-dependent increase in arterial pressure and reversed the hypotension of this condition. Hemorrhage caused small increases in extracellular hypothalamic acetylcholine and choline levels. Intracerebroventricular administration of U-46619 (1 micro g) further increased the levels of extracellular acetylcholine and choline by 57% and 41%, respectively. Pretreatment with SQ-29548 (8 mug; i.c.v.), a selective TxA2 receptor antagonist, completely abrogated the effects of subsequent injection of U-46619 (1 mug; i.c.v.) on arterial pressure and extracellular acetylcholine and choline levels. Pretreatment with mecamylamine (50 micro g; i.c.v.), a cholinergic nonselective nicotinic receptor antagonist, attenuated the pressor effect of U-46619 (1 micro g, i.c.v.) in hemorrhaged rats whereas pretreatment with atropine (10 micro g; i.c.v.), a cholinergic nonselective muscarinic receptor antagonist, had no effect. Interestingly, pretreatment of rats with methyllycaconitine (10 micro g; i.c.v.) or alpha-bungarotoxin (10 micro g; i.c.v.), selective antagonists of alpha-7 subtype nicotinic acetylcholine receptors (alpha7nAChRs), partially abolished the pressor effect of U-46619 (1 micro g; i.c.v.) in the hypotensive condition. Pretreatment with a combination of mecamylamine plus methyllycaconitine or mecamylamine plus alpha-bungarotoxin attenuated the reversal effect of U-46619, but only to the same extent as pretreatment with either antagonist alone. In conclusion, i.c.v. administration of U-46619 restores arterial pressure and increases posterior hypothalamic acetylcholine and choline levels by activating central TxA2 receptors in hemorrhaged hypotensive rats. The activation of central nicotinic cholinergic receptors, predominantly alpha7nAChRs, partially acts as a mediator in the pressor responses to i.c.v. injection of U-46619 under these conditions.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Cholinergic Fibers; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Fluid; Fatty Acids, Unsaturated; Hemorrhage; Hydrazines; Hypotension; Hypothalamus, Posterior; Injections, Intraventricular; Male; Neural Pathways; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Time Factors; Vasoconstrictor Agents

1. In the present study, we aimed to determine the involvement of brain thromboxane A2 (TXA2) in blood pressure decreases evoked by acute and/or graded haemorrhage in rats. 2. Sprague-Dawley rats were used throughout the study. Acute haemorrhage was achieved by withdrawing a total volume of 2.1 and 2.5 mL blood/100 g bodyweight over a period of 10 min. A microdialysis study was performed in a hypothalamic area to measure extracellular TXA2 levels. Graded haemorrhage was conducted successively by withdrawing carotid arterial blood (0.55 mL/100 g bodyweight) over a 10 s period four times (S1-S4) at 5 min intervals. Furegrelate (125, 250 and 500 microg), a TXA2 synthase inhibitor, was injected intracerebroventricularly (i.c.v.) 60 min before acute or graded haemorrhage was initiated. U-46619 (0.5, 1 and 2 microg, i.c.v.), a synthetic TXA2 analogue, was administered 5 min before acute haemorrhage (2.1 mL/100 g bodyweight). 3. Acute haemorrhage produced a severe and long-lasting decrease in blood pressure and had a tendency to increase heart rate. Both haemorrhage protocols (2.1 or 2.5 mL/100 g) generated similar approximate twofold increases in extracellular hypothalamic TXA2 levels. Intracerebroventricular furegrelate (250 microg) pretreatment completely blocked the TXA2 increases induced by acute haemorrhage. Furegrelate administration (100, 250 and 500 microg, i.c.v.) attenuated the fall in arterial pressure evoked by acute haemorrhage and caused significant increases in heart rate at all doses injected. 4. Graded haemorrhage progressively lowered arterial pressure and increased plasma vasopressin and adrenaline levels in the last period. Furegrelate-injected rats were greatly resistant to the hypotensive effect of haemorrhage for all degrees of blood removed. Plasma adrenaline and vasopressin levels were significantly elevated in furegrelate-pretreated rats compared with the saline-treated group during S2-S3 and S4, respectively. U-46619 administration caused small but statistically significant decreases in arterial pressure induced by haemorrhage. 4. The results show that acute hypotensive haemorrhage increases extracellular hypothalamic TXA2 levels. The increase in brain endogenous TXA2 levels involves a decrease in blood pressure evoked by haemorrhage because the blockade of TXA2 synthesis by furegrelate pretreatment attenuated the haemorrhagic hypotension. Increases in plasma adrenaline and vasopressin levels may mediate this effect.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzofurans; Blood Pressure; Disease Models, Animal; Epinephrine; Heart Rate; Hemorrhage; Hypotension; Hypothalamus; Injections, Intraventricular; Male; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane-A Synthase; Time Factors; Vasoconstrictor Agents; Vasopressins

In the present study, we investigated the cardiovascular effects of centrally injected U-46619, a thromboxane A(2) (TXA(2)) analog, and the central and peripheral mechanisms of these effects in hemorrhagic shock conditions. Hemorrhage was performed by withdrawing a total volume of 2.1 ml of blood/100 g body weight over a period of 10 min. Injections were made into the lateral cerebral ventricle (LCV), nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM) and paraventricular nucleus of hypothalamus (PVN). U-46619 (0.1, 1 and 2 microg) increased blood pressure and reversed hypotension in hemorrhagic shock. The pressor effect was dose- and time-dependent in all investigated brain areas. Heart rate changes were not significantly different in all groups. Pretreatment of rats with an injection of SQ-29548 (4 or 8 microg), a TXA(2) receptor antagonist, into the LCV, NTS, RVLM and PVN completely blocked the pressor effect of U-46619 (1 microg) injected into respective brain areas. Hemorrhage itself increased plasma adrenaline, noradrenaline, vasopressIN levels and renin activity. U-46619 (1 microg) injected into the LCV, PVN, RVLM and NTS produced additional increases in these hormone levels and in renin activity. Intravenous pretreatments of rats with prazosin (0.5 mg/kg), an alpha(1)-adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl(1), O-Me-Tyr(2),Arg(8)]- vasopressin (10 microg/kg), a vasopressin V(1)-receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, in hemorrhaged rats partially blocked the pressor response to U-46619 (1 microg) injected into the LCV, PVN, RVLM and NTS. Results show that centrally administered U-46619, a TXA(2) analog, increases blood pressure and reverses hypotension in hemorrhagic shock. Activation of central TXA(2) receptors mediates the pressor effect of the drug. Furthermore, the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity are involved in these effects.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenergic alpha-1 Receptor Antagonists; Angiotensin II Type 1 Receptor Blockers; Animals; Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Brain; Bridged Bicyclo Compounds, Heterocyclic; Catecholamines; Fatty Acids, Unsaturated; Heart Rate; Hemodynamics; Hemorrhage; Hydrazines; Hypotension; Injections; Injections, Intraventricular; Male; Medulla Oblongata; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Renin; Shock, Hemorrhagic; Solitary Nucleus; Thromboxane A2; Vasoconstrictor Agents; Vasopressins

Thromboxane A2 (TXA2) and endothelin-1 (ET-1) have been proposed as the important vasoconstrictors that increase portal venous resistance in paracrine or autocrine fashion. We hypothesized that the hepatic damage following trauma-hemorrhage (T-H) is induced by the impaired hepatic circulation due to the increased production of vasoconstrictors such as ET-1 and TXA2 by the liver. To test this, male Sprague-Dawley rats (n = 6/group) were subjected to trauma (i.e., midline laparotomy) and hemorrhage (35-40 mmHg for 90 min followed by fluid resuscitation) or sham operation. At 2 or 5 h after the end of resuscitation, the liver was isolated and perfused and portal inflow pressure, bile flow, and release of ET-1 and thromboxane B2 (TXB2; a stable metabolite of TXA2) into the perfusate were measured. The level of portal pressure was higher at 5 h following T-H compared with 2 h after T-H and sham. The portal pressure was inversely correlated to the amount of bile production. Furthermore, the bile flow was significantly correlated to the hepatic damage as evidenced by release of lactate dehydrogenase into the perfusate. The level of ET-1 at 5 h following T-H in the perfusate after 30 min of recirculation did not show any difference from sham. However, the levels of TXB2 in the T-H group were significantly higher than those in sham at that interval. These results indicate that the increased release of TXA2 but not ET-1 following T-H might be responsible for producing the increased portal resistance, decreased bile production, and hepatic damage.

Topics: Abdominal Injuries; Alanine Transaminase; Animals; Bile; Endothelin-1; Hemorrhage; Hypertension, Portal; In Vitro Techniques; L-Lactate Dehydrogenase; Liver; Male; Perfusion; Portal Vein; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane B2; Venous Pressure; Wounds, Penetrating

Three subgroups have been distinguished in essential thrombocythaemia (ET) patients, on the basis of clinical and laboratory findings. ET patients with bleeding incidents had smaller platelet volume, lower concentrations of beta-thromboglobulin and platelet factor 4 in their plasma, 10%, 26%, and 26% lower compared to patients without complications, respectively. ATP secretion from platelets of bleeders, clotters, and "no-complications" ET patients was found to be 75%, 36%, and 45%, respectively, lower than in healthy people. Spontaneous platelet aggregation appeared to be normal in about 90% of ET patients with no complications and in all bleeders but only in 35% patients with clotting incidents. All bleeders had abnormal agonist-evoked aggregation assays. Among remaining ET patients 30%-60% displayed normal values of different evoked aggregation tests. Thus, clinically distinguished group of bleeding ET patients may be differentiated from other subgroups on the basis of laboratory findings.

Topics: Adenosine Triphosphate; Adult; Aged; Blood Platelets; Female; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation; Reference Values; Thrombocytosis; Thrombosis; Thromboxane A2

We studied the effects of a thromboxane A2 synthetase inhibitor (RS-5186), a thromboxane A2 antagonist (ONO-3708), a 5-lipoxygenase inhibitor (AA-861) and a peptidoleukotriene antagonist (ONO-1078) on infarct size, polymorphonuclear leukocyte infiltration, gross myocardial hemorrhage and arrhythmias in the canine coronary occlusion (2 hour)-reperfusion model (5 hour). The infarct size and risk area were determined by a double staining technique. Thirty minutes prior to occluding the coronary arteries, dogs were randomly assigned to one of the following five groups: the thromboxane A2 synthetase inhibitor group (n = 11) receiving RS-5186 10 mg/kg i.v., the thromboxane A2 antagonist group (n = 12) receiving continuous intravenous infusion of ONO-3708 1 microgram/kg/min, the lipoxygenase inhibitor group (n = 11) receiving AA-861 3 mg/kg i.v., the peptidoleukotriene antagonist group (n = 11) receiving continuous intravenous infusion of ONO-1078 1 microgram/kg/min and the vehicle control group (n = 15). Except for ONO-3708, all the other drugs reduced the infarct size (RS-5186: 26.3 +/- 2.4% of risk area (mean +/- SEM), AA-861: 21.8 +/- 1.3%, ONO-1078: 22.5 +/- 4.4% vs control: 54.0 +/- 6.4%, p less than 0.01 respectively) as well as reducing the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of infarct size, AA-861: 5.1 +/- 2.4%, ONO-1078: 5.2 +/- 2.5% vs control: 22.3 +/- 3.9%, p less than 0.01 respectively). RS-5186 and AA-861 reduced the intensity of polymorphonuclear leukocyte infiltration into the infarcted area, however, neither ONO-3708 nor ONO-1078 had any significant influence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Benzoquinones; Cardiomyopathies; Chromones; Coronary Disease; Dogs; Hemorrhage; Lipoxygenase Inhibitors; Male; Myocardial Infarction; Myocardium; Neutrophils; Quinones; SRS-A; Thiophenes; Thromboxane A2; Thromboxane-A Synthase

Subnormal platelet responses to thromboxane A2 (TXA2) were found in a patient with polycythemia vera, and the mechanism of this dysfunction was analyzed. The patient's platelets showed defective aggregation and release reaction to arachidonic acid, enzymatically generated TXA2 and synthetic TXA2 mimetics (STA2, U-46619). In contrast, they showed normal responses to thrombin. When the platelet TXA2 receptor was examined with both a 125I-labelled derivative of a TXA2 receptor antagonist ([125I]-PTA-OH) and a 3H-labelled TXA2 agonist ([3H]U-46619), the equilibrium dissociation rate constants (Kd) and the maximal concentrations of binding sites (Bmax) of the patient's platelets to both ligands were within normal ranges, suggesting that the binding capacity of their TXA2 receptor was normal. STA2 failed to induce normal elevation in the cytoplasmic free calcium ion concentration, phosphatidic acid formation and 40 kD protein phosphorylation in the patient's platelets, whereas these responses to thrombin were within normal ranges. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) also evoked normal response in the 40 kD protein phosphorylation in the patient's platelets. These results suggested that the patient's platelets had TXA2 receptor abnormalities which were characterized by defective transduction of the binding signal to postreceptor reactions after normal TXA2 binding.

Topics: Adenine Nucleotides; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Blood Proteins; Calcium; Cell Communication; Hematologic Diseases; Hemorrhage; Humans; Male; Middle Aged; Phosphatidic Acids; Phosphorylation; Platelet Aggregation; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

Tissue plasminogen activator and urokinase were evaluated in a model of prosthetic graft thrombosis. In addition, the effects of thrombus age on lysability and the effect of thrombolytic agents on endothelium were examined. Polytef (polytetrafluoroethylene [PTFE]) grafts (3 mm X 3.5 cm) were placed in femoral arteries of dogs and graft thrombosis was induced. Grafts were treated with a local infusion of either urokinase or tissue plasminogen activator (4000 units/min) and the times for initial flow, complete thrombolysis, and anastomotic bleeding were noted. The luminal surfaces of the grafts and the proximal arterial segments were assayed for the production of thromboxane A2 and prostacyclin and examined with scanning electron microscopy. No difference in the ease of graft lysis was observed, but 50% of tissue plasminogen activator-treated vs 0% of urokinase treated grafts had extravasation of blood through the wall. Grafts treated with tissue plasminogen activator produced less thromboxane A2 and had less thrombus than those treated with urokinase. No differences between arteries exposed to either agent and control arteries were seen. Grafts treated 1,3,5, and 7 days after thrombosis were progressively more difficult to lyse. We conclude that tissue plasminogen activator is an effective thrombolytic agent, but has a potential for local bleeding complications. Grafts of PTFE are thrombogenic after lysis, but may be less so with tissue plasminogen activator than with urokinase. No effect on arterial endothelium was seen, and our studies confirm the clinical impression that older thrombi are more difficult to lyse.

Topics: Animals; Arteries; Blood Vessel Prosthesis; Disease Models, Animal; Dogs; Epoprostenol; Graft Occlusion, Vascular; Hemorrhage; Microscopy, Electron, Scanning; Polytetrafluoroethylene; Thrombosis; Thromboxane A2; Time Factors; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

The 'Simplate' technique for measuring skin bleeding time was adapted to quantify thromboxane A2 in the emerging blood as the stable degradation product thromboxane B2 in twelve Swedish and ten English volunteers. During the bleeding time thromboxane B2 concentrations increased, but as the rate of blood loss fell the rate of production of thromboxane A2 was constant. The English subjects had shorter bleeding times and produced more thromboxane A2 than the Swedish subjects. When the Swedish subjects were grouped according to bleeding times those with the shortest had more thromboxane A2 than those with longer bleeding times. Clotting venous blood in vitro produced much more thromboxane A2 than bleeding-time blood and there was no correlation with bleeding time. Determination of the capacity of clotting blood to form thromboxane A2 is therefore irrelevant to in-vivo haemostasis. Acetylsalicylic acid greatly diminished the appearance of thromboxane A2 in the bleeding time and prevented the increase of thromboxane A2 concentration with time.

Topics: Adenosine Diphosphate; Adult; Aspirin; Bleeding Time; England; Hemorrhage; Hemostasis; Humans; Male; Platelet Aggregation; Platelet Function Tests; Skin; Sweden; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: Animals; Arachidonic Acids; Chemical Phenomena; Chemistry; Epoprostenol; Hemorrhage; Hemostasis; Humans; Prostaglandins; Rats; Thrombosis; Thromboxane A2

Animal work suggests that with certain doses of aspirin the antithrombotic effect exerted via the inhibition of the proaggregatory platelet thromboxane A2 (TXA2) may be neutralised by the concomitant vascular reduction of the antiaggregatory prostacyclin (PGI2). Such a situation might result not only in therapeutic ineffectiveness but also in a thrombotic tendency. A patient with a bleeding disorder characterised by a mildly prolonged bleeding time and defective platelet-release reaction due to a congenital deficiency of cyclo-oxygenase provided an opportunity for studying this problem. Her platelets did not aggregate with arachidonic acid, but they did so with a synthetic endoperoxide analogue. Thrombin added to her platelet-rich plasma and whole blood did not generate thromboxane B2 (TXB2). Washed platelets, when incubated with 14C-arachidonic acid, did not produce the cyclo-oxygenase metabolites. A biopsy specimen of her vein did not generate PGI2, as measured both by platelet-aggregation inhibition and radioimmunoassay of 6-keto-PGF1 alpha. Clinically, the patient had a mild bleeding tendency but no thrombotic problems. The findings suggest that in man aspirin therapy, even at doses which inhibit PGI2 formation, would only impair haemostasis mildly without producing a thrombotic tendency.

Topics: Adenosine Diphosphate; Adult; Arachidonic Acids; Aspirin; Blood Coagulation Tests; Blood Platelet Disorders; Cells, Cultured; Chromatography, Thin Layer; Epoprostenol; Hemorrhage; Humans; Male; Oxygenases; Plasma; Platelet Aggregation; Prostaglandins; Thromboxane A2; Thromboxanes

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