dinoprost and Thrombosis

The actions of prostanoids in various physiological and pathophysiological conditions have been being examined using mice lacking different prostanoid receptors. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic agent. PGF2alpha was found to be an essential inducer of labor. Several important actions of PGE2 are exerted via each of the four PGE2 receptor subtypes: EP1, EP2, EP3 and EP4. PGE2 participated in colon carcinogenesis via the EP1. PGE2 also participates in ovulation and fertilization and contributes to the control of blood pressure under high-salt intake via the EP2. PGE2 worked as a mediator of febrile responses to both endogenous and exogenous pyrogens and as a regulator of bicarbonate secretion induced by acid-stimulation in the duodenum via the EP3. It regulated the closure of ductus arteriosus and showed bone resorbing action via the EP4. PGD2 was found to be a mediator of allergic asthma. These studies have revealed important roles of prostanoids, some of which had not previously been known.

Topics: Animals; Asthma; Bicarbonates; Colonic Neoplasms; Dinoprost; Dinoprostone; Female; Fever; Hypertension; Inflammation; Labor, Obstetric; Mice; Mice, Knockout; Pregnancy; Prostaglandins; Receptors, Prostaglandin; Reproduction; Thrombosis; Thromboxane A2

Isoprostanes are emerging as a new class of biologically active products of arachidonic acid metabolism of potential relevance to human vascular disease. Their formation in vivo seems to reflect primarily, if not exclusively, a nonenzymatic process of lipid peroxidation. Enhanced urinary excretion of 8-iso-PGF2 alpha has been described in association with cardiac reperfusion injury and with cardiovascular risk factors, including cigarette smoking, diabetes mellitus, and hypercholesterolemia. Besides providing a likely noninvasive index of lipid peroxidation in these settings, measurements of specific F2 isoprostanes in urine may provide a sensitive biochemical end point for dose-finding studies of natural and synthetic inhibitors of lipid peroxidation. Although the biological effects of 8-iso-PGF2 alpha in vitro suggest that it and other isoeicosanoids may modulate the functional consequences of lipid peroxidation, evidence that this is likely in vivo remains inadequate at this time.

Topics: Antioxidants; Arteriosclerosis; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus; Dinoprost; F2-Isoprostanes; Free Radicals; Gas Chromatography-Mass Spectrometry; Humans; Hyperlipidemias; Immunoassay; Indicator Dilution Techniques; Lipid Peroxidation; Oxidative Stress; Platelet Aggregation; Prostaglandins F; Risk Factors; Thrombosis; Vasoconstrictor Agents

Hypoglycemia produces thrombosis activation, but little attention has been paid to the effects of hyperglycemia following recovery from hypoglycemia on thrombosis activation.. In both twenty-two healthy subjects and twenty-one matched persons with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normo-glycemia or hyperglycemia for another 2 h. After this, normal glycemia was maintained for the following 6 h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. In both controls and people with diabetes, the recovery with normo-glycemia was accompanied by a significant improvement of Von Willebrand factor (vWF), prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III-complexes (TAT), P-selectin, plasminogen activator inhibitor-1 (PAI-1), nitrotyrosine and 8-iso-prostaglandin F2α (8-iso-PGF2α) (p < 0.01 vs hypoglycemia for all the parameters), all directly affected by hypoglycemia itself (p < 0.01 vs baseline for all the parameters). On the contrary, the recovery with hyperglycemia after hypoglycemia worsens all these parameters (p < 0.01 vs normoglycemia for all the parameters), an effect persisting even after the additional 6 h of normo-glycemia. The effect of hyperglycemia following hypoglycemia was partially counterbalanced when vitamin C was infused (p < 0.01 vs hyperglycemia alone for all the parameters), suggesting that hyperglycemia following hypoglycemia may activate thrombosis through the oxidative stress production.. This study shows that, in type 1 diabetes as well as in controls, the way in which recovery from hypoglycemia takes place could play an important role in favoring the activation of thrombosis and oxidative stress, widely recognized cardiovascular risk factors.

Topics: Adult; Antithrombin III; Ascorbic Acid; Blood Glucose; Diabetes Mellitus, Type 1; Dinoprost; Endothelium, Vascular; Female; Healthy Volunteers; Humans; Hyperglycemia; Hypoglycemia; Male; Oxidative Stress; P-Selectin; Peptide Fragments; Peptide Hydrolases; Plasminogen Activator Inhibitor 1; Protein Precursors; Prothrombin; Thrombosis; von Willebrand Factor; Young Adult

The goal of this study was to investigate whether omega-3 polyunsaturated fatty acids (n-3 PUFA) are able to alter plasma fibrin clot properties and reduce thrombin formation in stable coronary artery disease patients undergoing percutaneous coronary intervention (PCI).. In an investigator-initiated, prospective, double-blind, placebo-controlled, randomized study, patients undergoing PCI who received standard pharmacotherapy were assigned to the treatment with 1 g/day n-3 PUFA (n = 30) or placebo (n = 24) for 1 month. Plasma fibrin clot permeability (K(s)); lysis time (t(50%)); prothrombin fragment 1.2; and peak thrombin generation from automated thrombogram, 8-isoprostaglandin F(2α) (8-iso-PGF(2α), an oxidative stress marker), and C-reactive protein were determined at baseline, 3 to 5 days after randomization, and 30 days after randomization. At baseline, both treatment groups did not differ significantly. A 1-month treatment with n-3 PUFA compared with placebo was associated with 15.3% higher K(s), indicating larger pores in the fibrin network (P = 0.0005); 14.3% shorter t(50%), indicating increased susceptibility to fibrinolysis (P<0.0001); 33.8% lower prothrombin fragment 1.2 (P = 0.0013); 13.4% lower peak thrombin generation (P = 0.04); and 13.1% lower 8-iso-PGF(2α) (P = 0.009). Treatment with n-3 PUFA had no effect on fibrinogen and C-reactive protein. After 1 month of treatment, fibrinogen (r = -0.53, P<0.0001), treatment assignment (r = 0.29, P = 0.006) and 8-iso-PGF(2α) (r = -0.27, P = 0.015) were independently associated with clot permeability (P<0.0001, R(2) = 0.66).. Adding n-3 PUFA to standard therapy in stable patients undergoing PCI significantly decreases thrombin formation and oxidative stress and favorably alters fibrin clot properties. These findings indicate novel antithrombotic effects induced by n-3 PUFA in humans.

Topics: Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Aspirin; Biomarkers; Blood Coagulation; C-Reactive Protein; Chi-Square Distribution; Clopidogrel; Coronary Artery Disease; Dinoprost; Double-Blind Method; Down-Regulation; Drug Therapy, Combination; Fatty Acids, Omega-3; Female; Fibrin; Humans; Linear Models; Male; Middle Aged; Oxidative Stress; Peptide Fragments; Platelet Aggregation; Platelet Aggregation Inhibitors; Poland; Prospective Studies; Prothrombin; Thrombin; Thrombosis; Ticlopidine; Time Factors; Treatment Outcome

Enhanced oxidative stress occurs in atrial fibrillation (AF), however its impact on the efficacy and safety of anticoagulation is unknown. We sought to evaluate whether 8-isoprostaglandin F2 (8-isoprostane) levels are associated with clinical outcomes in anticoagulated AF patients.. In a study involving 243 AF patients (median age 69 years), we measured serum 8-isoprostane, along with prothrombotic markers, including plasma fibrin clot permeability, clot lysis time (CLT), endogenous thrombin potential (ETP), von Willebrand factor (VWF), and fibrinolytic proteins. Ischemic cerebrovascular events, major bleeding, and death were recorded during a median follow-up of 53 months while on anticoagulation, largely on non-vitamin K antagonist oral anticoagulants (NOACs).. Increased 8-isoprostane levels partly through altered fibrin clot structure are associated with thromboembolic events despite anticoagulant therapy in AF patients.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dinoprost; Female; Fibrin; Hemorrhage; Humans; Risk Factors; Stroke; Thromboembolism; Thrombosis; von Willebrand Factor

Post-pulmonary embolism (PE) syndrome occurs in up to 50% of PE patients. The pathophysiology of this syndrome is obscure.. We investigated whether enhanced oxidative stress and prothrombotic state may be involved in post-PE syndrome.. We studied 101 normotensive noncancer PE patients (aged 56.5 ± 13.9 years) on admission, after 5-7 days and after a 3-month anticoagulation, mostly with rivaroxaban. A marker of oxidative stress, 8-isoprostane, endogenous thrombin potential, fibrinolysis proteins, clot lysis time (CLT) and fibrin clot permeability (K. Enhanced oxidative stress and prothrombotic fibrin clot properties could be involved in the pathogenesis of the post-PE syndrome. Elevated growth differentiation factor 15 assessed at 3 months might be a new biomarker of this syndrome.

Topics: Adult; Aged; Biomarkers; Dinoprost; Female; Growth Differentiation Factor 15; Humans; Male; Middle Aged; Oxidative Stress; Pulmonary Embolism; Syndrome; Thrombosis

Blood stasis syndrome is the pre-state of thrombotic disease. The model of blood stasis syndrome in rats was induced by sleep deprivation to study on effects of blood stasis syndrome on platelet activation. The weight, the color of tongue and hemorheology for the blood stasis syndrome of Chinese medicine were measured after modeling. The release of platelet granules and platelet activation factors in plasma were detected by ELISA kit related indicators to provide experimental basis for platelet function evaluation and related drug effects in syndrome research. The results showed that the weight of the model group rats was significantly lower than that of the normal group (

Topics: Animals; Dinoprost; Disease Models, Animal; Hemorheology; Medicine, Chinese Traditional; Platelet Activating Factor; Platelet Activation; Rats; Sleep Deprivation; T-Box Domain Proteins; Thrombosis

Platelets generate oxidized LDL (ox-LDL) via NOX2-derived oxidative stress. We investigated if once generated by activated platelets ox-LDL can propagate platelet activation.. Experiments were performed in platelets from healthy subjects (HS), hyper-cholesterolemic patients and patients with NOX2 hereditary deficiency.. Agonist-stimulated platelets from HS added with LDL were associated with a dose-dependent increase of reactive oxidant species and ox-LDL. Agonist-stimulated platelets from HS added with a fixed dose of LDL (57.14 μmol/L) or added with homogenized human atherosclerotic plaque showed enhanced ox-LDL formation (approximately +50% and +30% respectively), which was lowered by a NOX2 inhibitor (approximately -35% and -25% respectively). Compared to HS, ox-LDL production was more pronounced in agonist-stimulated platelet rich plasma (PRP) from hyper-cholesterolemic patients but was almost absent in PRP from NOX2-deficient patients. Platelet aggregation and 8-iso-PGF2α-ΙΙΙ formation increased in LDL-treated washed platelets (+42% and +53% respectively) and PRP (+31% and +53% respectively). Also, LDL enhanced platelet-dependent thrombosis at arterial shear rate (+33%) but did not affect platelet activation in NOX2-deficient patients. Platelet activation by LDL was significantly inhibited by CD36 or LOX1 blocking peptides, two ox-LDL receptor antagonists, or by a NOX2 inhibitor. LDL-added platelets showed increased p38MAPK (+59%) and PKC (+51%) phosphorylation, p47(phox) translocation to platelet membrane (+34%) and NOX2 activation (+30%), which were inhibited by ox-LDL receptor antagonists.. Platelets oxidize LDL, which in turn amplify platelet activation via specific ox-LDL receptors; both effects are mediated by NOX2 activation.

Topics: Adult; Atherosclerosis; Blood Platelets; Case-Control Studies; Collagen; Dinoprost; Female; Humans; Hypercholesterolemia; Lipoproteins, LDL; Male; Membrane Glycoproteins; Middle Aged; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Perfusion; Platelet Activation; Thrombosis

Methionine ingestion (100mg/kg) identifies subjects in whom fasting total homocysteine (tHcy) may be normal but the post-methionine load (PML) tHcy is abnormally high.. In 96 subjects [54 M/42 F, 40.4 ± 12.3 yrs old; 28 with the 68 bp844 ins of the cystathionine-β-synthase gene (CBSins+); 20 homozygotes for the C677T mutation of the methylene-tetrahydrofolate reductase gene (MTHFR++); 13 with the combination of the two, and 35 without any of them], we have evaluated in vivo oxidative stress and platelet activation, as reflected by urinary excretions of 8-iso-PGF(2α) and of 11-dehydro-TXB(2) respectively, before and after a methionine load test (PML). A history of early-onset thrombosis (18 arterial, 32 venous, 2 both) was present in 52/96 of them.. Baseline; tHcy was highest in MTHFR++ carriers (p < 0,05); 8-iso-PGF(2α) and 11-dehydro-TXB(2) levels were independent of sex, MTHFR++ and/or CBSins + (p > 0.05). PML; The ~3-fold increase (p < 0.01 vs baseline) in tHcy reached a plateau within 6-8 hrs. Mean PML tHcy was maximal in MTHFR++ carriers (p = 0.000). 8-iso-PGF(2α) and 11-dehydro-TXB(2) increase reached a maximum within 4 hrs. 11-dehydro-TXB(2) increase was highest (p = 0.023 vs baseline) in subjects with a history of thrombosis. Baseline 11-dehydro-TXB(2) and a history of thrombosis independently predicted PML 11-dehydro-TXB(2) (β = 0.287, p = 0.000 and β = 0.308, p = 0.026, respectively).The PML increase in 8-iso-PGF(2α) or in 11-dehydro-TXB(2) were comparable in the different genotypes (p > 0.05).. Regardless genotypes associated with moderate hyperhomocysteinemia, following a methionine loading test, in vivo oxidative stress and platelet activation occur, being the latter maximal in subjects with a history of early-onset thrombosis.

Topics: Adult; Age of Onset; Analysis of Variance; Biomarkers; Case-Control Studies; Chi-Square Distribution; Cystathionine beta-Synthase; Dinoprost; Female; Homocysteine; Homozygote; Humans; Hyperhomocysteinemia; Italy; Linear Models; Male; Methionine; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Mutation; Oxidative Stress; Phenotype; Platelet Activation; Platelet Function Tests; Thrombosis; Thromboxane B2; Time Factors

The protective role of folate in vascular disease has been related to antioxidant effects. In 45 patients with previous early-onset (at age <50 years) thrombotic episodes and the 677TT methylenetetrahydrofolate reductase genotype, we evaluated the effects of a 28 d-course (15 mg/d) of 5-methyltetrahydrofolate (MTHF) on homocysteine metabolism and on in vivo generation of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a reliable marker of oxidative stress. At baseline, patients' fasting total homocysteine (tHcy) was 11.5 micromol/l (geometric mean) and urinary excretion of 8-iso-PGF2alpha was 304 pg/mg creatinine, with the highest metabolite levels in the lowest quartile of plasma folate distribution (P < 0.05). After 5-MTHF supplementation, plasma folate levels increased approximately 13-fold (P < 0.0001 versus baseline); tHcy levels (6.7 micromol/l, P < 0.0001) and urinary 8-iso-PGF2alpha (254 pg/mg creatinine, P < 0.001) were both significantly lowered, their reduction being proportional to baseline values (r = 0.98 and r = 0.77, respectively) and maximal in patients with the lowest pre-supplementation folate levels (P < 0.05). The effects on folate (P < 0.0001) and tHcy (P = 0.0004) persisted for at least up to 2 months after withdrawing 5-MTHF. In parallel with long-lasting tHcy-lowering effects, a short-course 5-MTHF supplementation reduces in vivo formation of 8-iso-PGF2alpha in this population, supporting the antioxidant protective effects of folate in vascular disease.

Topics: Adult; Age of Onset; Case-Control Studies; Dietary Supplements; Dinoprost; Female; Homocysteine; Humans; Linear Models; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Mutation; Oxidative Stress; Tetrahydrofolates; Thrombosis; Thromboxane B2

Diabetes mellitus (DM) is associated with enhanced lipid oxidation and persistent platelet activation. We investigated whether oxidant stress (OS) also affects circulating proteins and is associated with an abnormal coagulative pattern. In 72 type 2 DM (T2DM) patients, urinary 8-iso-prostaglandin (PG) F2alpha and 11-dehydro-thromboxane B2 (TXM) were measured as markers of lipid peroxidation and platelet activation, respectively. The carbonyl content of plasma proteins (PCARB) was measured as global index of protein oxidation. 8-Iso-PGF2alpha and PCARB levels were higher in DM patients than in controls (P < 0.05). Likewise, both TXM and prothrombin F1+2 levels were higher in diabetics (P < 0.05). By contrast, anticoagulant markers, such as activated protein C, protein C activation peptide, and soluble thrombomodulin (TM) were depressed in T2DM (P < 0.05). In conclusion, OS in T2DM involves circulating proteins and is associated with an unbalanced promotion of procoagulant reactions. These effects in concert with platelet activation may contribute to atherothrombotic complications in T2DM.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Proteins; Case-Control Studies; Diabetes Mellitus, Type 2; Dinoprost; F2-Isoprostanes; Female; Hemostasis; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Platelet Activation; Thrombosis; Thromboxane B2

Homocysteine is a risk factor for the development of atherosclerosis and its thrombotic complications. We have employed an animal model to explore the hypothesis that an increase in reactive oxygen species and a subsequent loss of nitric oxide bioactivity contribute to endothelial dysfunction in mild hyperhomocysteinemia. We examined endothelial function and in vivo oxidant burden in mice heterozygous for a deletion in the cystathionine beta-synthase (CBS) gene, by studying isolated, precontracted aortic rings and mesenteric arterioles in situ. CBS(-/+) mice demonstrated impaired acetylcholine-induced aortic relaxation and a paradoxical vasoconstriction of mesenteric microvessels in response to superfusion of methacholine and bradykinin. Cyclic GMP accumulation following acetylcholine treatment was also impaired in isolated aortic segments from CBS(-/+) mice, but aortic relaxation and mesenteric arteriolar dilation in response to sodium nitroprusside were similar to wild-type. Plasma levels of 8-epi-PGF(2alpha) (8-IP) were somewhat increased in CBS(-/+) mice, but liver levels of 8-IP and phospholipid hydroperoxides, another marker of oxidative stress, were normal. Aortic tissue from CBS(-/+) mice also demonstrated greater superoxide production and greater immunostaining for 3-nitrotyrosine, particularly on the endothelial surface. Importantly, endothelial dysfunction appears early in CBS(-/+) mice in the absence of structural arterial abnormalities. Hence, mild hyperhomocysteinemia due to reduced CBS expression impairs endothelium-dependent vasodilation, likely due to impaired nitric oxide bioactivity, and increased oxidative stress apparently contributes to inactivating nitric oxide in chronic, mild hyperhomocysteinemia.

Topics: Acetylcholine; Animals; Aorta; Arteriosclerosis; Cystathionine beta-Synthase; Dinoprost; Disease Models, Animal; Endothelium, Vascular; F2-Isoprostanes; Heterozygote; Humans; Hyperhomocysteinemia; In Vitro Techniques; Lipid Peroxides; Mice; Mice, Mutant Strains; Nitroprusside; Reactive Oxygen Species; Risk Factors; Thrombosis; Tyrosine; Vasodilation

This animal study was designed to compare a collagen coated heparin bonded vascular graft (CHG) versus a collagen coated vascular graft (CG) regarding intraoperative blood loss and healing process. 24 polyester vascular grafts (12 CHG and 12 CG) of 6 mm in diameter and 5 mm in length were implanted between the common iliac and external iliac artery in 12 adult dogs. The grafts were explanted between the first and the sixth months which followed the implantations. The healing process was observed by gross examination, microscopic and scanning electron microscopic examination. Prostaglandin PGE2, TXB2, 6 keto PGF1 alpha and PGF2 alpha were measured by radioimmunologic assay from samples retrieved from the medium part of the graft. During implantation, there was no notable difference in blood loss through the graft. At the time of explantation, 20 grafts were patent (10 CHG, 10 CG). In both grafts, the healing process developed progressively between 2 and 6 months and 90% of the internal surface of the grafts were covered with endothelial like cells. At 6 months, the internal layer was thinner in heparinized graft. PGI2 secretion was found with the two types of grafts. In conclusion, the present study showed no difference in the blood loss or healing characteristic of CHG and CG except for a potentially thinner internal layer with CHG. Comparative studies in humans are necessary to evaluate the potential benefit of heparin bonded graft in clinical practice.

Topics: 6-Ketoprostaglandin F1 alpha; Anastomosis, Surgical; Animals; Blood Loss, Surgical; Blood Vessel Prosthesis; Collagen; Dinoprost; Dinoprostone; Dogs; Epoprostenol; Graft Occlusion, Vascular; Heparin; Iliac Artery; Microscopy, Electron, Scanning; Polyesters; Radioimmunoassay; Thrombosis; Thromboxane B2; Vascular Patency

Topics: Arrhythmias, Cardiac; Blood Viscosity; Coronary Disease; Dinoprost; Heart Conduction System; Humans; Nucleotides, Cyclic; Platelet Aggregation; Prognosis; Thrombosis; Thromboxane B2

Thrombus appearance during luteolysis with and without exogenous prostaglandin (PGF2 alpha) was studied in immature golden hamsters between days 4 and 7 after stimulation with pregnant mares' serum gonadotrophin (PMSG) followed by human chorionic gonadotrophin. Both ovaries were weighed and cut in series for light-microscopic evaluation. The fibrinolytic activity was determined by the fibrin slide method after treatment with PGF2 alpha on day 4 after PMSG stimulation and compared with controls of days 3 and 4 after PMSG stimulation. There was a marked decrease in ovarian weights in the experimental and the control group between days 4 and 7 after PMSG. Few necrotic cells were seen in corpora lutea on day 5, but many on day 6. All of them had disappeared on day 7. The number of ovaries with thrombi was 80-100% in both groups on day 4 and declined to approximately zero levels on day 7. The amount of thrombus formation appeared to be higher in the PGF2 alpha-treated groups than in controls. Fibrinolytic activity was high in controls on day 3 and low in controls and in PGF2 alpha-treated animals on day 4 after PMSG. It is concluded that thrombus formation occurs in superstimulated ovaries during luteolysis; and thrombus formation is related to a decrease in fibrinolytic activity.

Topics: Animals; Chorionic Gonadotropin; Corpus Luteum; Cricetinae; Dinoprost; Female; Fibrinolysis; Gonadotropins, Equine; Mesocricetus; Ovary; Prostaglandins F; Thrombosis

The internal surface of the rat mesentery venule was exposed to laser. Microthrombogenesis was studied from the time of maximal thrombus formation, time of the first embolism occurrence, thrombus area, and rate of embolism formation. Intravenous infusion of PGE1 and prostacyclin led to the reduction of microhemostasis as shown by all the characteristics. PGF2 alpha, on the contrary, exhibited prothrombogenous activity; PGE2 was little effective. Comparison of the active concentrations of the substances administered has demonstrated prostacyclin to have the most powerful action.

Topics: Alprostadil; Animals; Dinoprost; Dinoprostone; Lasers; Male; Mesentery; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Thrombosis; Veins; Venules