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Clinical and Translational Science Dec 2022Low-dose aspirin is currently recommended for patients with polycythemia vera (PV), a myeloproliferative neoplasm with increased risk of arterial and venous thromboses....
Low-dose aspirin is currently recommended for patients with polycythemia vera (PV), a myeloproliferative neoplasm with increased risk of arterial and venous thromboses. Based on aspirin pharmacodynamics in essential thrombocythemia, a twice-daily regimen is recommended for patients with PV deemed at particularly high thrombotic risk. We investigated the effects of low-dose aspirin on platelet cyclooxygenase activity and in vivo platelet activation in 49 patients with PV, as assessed by serum thromboxane (TX) B and urinary TXA /TXB metabolite (TXM) measurements, respectively. A previously described pharmacokinetic-pharmacodynamic in silico model was used to simulate the degree of platelet TXA inhibition by once-daily (q.d.) and twice-daily (b.i.d.) aspirin, and to predict the effect of missing an aspirin dose during q.d. and b.i.d. regimens. Serum TXB averaged 8.2 (1.6-54.7) ng/ml and significantly correlated with the platelet count (γ = 0.39) and urinary TXM (γ = 0.52) in multivariable analysis. One-third of aspirin-treated patients with PV displayed less-than-maximal platelet TXB inhibition, and were characterized by significantly higher platelet counts and platelet-count corrected serum TXB than those with adequate inhibition. Eight patients with PV were sampled again after 12 ± 4 months, and had reproducible serum TXB and urinary TXM values. The in silico model predicted complete inhibition of platelet-derived TXB by b.i.d. aspirin, a prediction verified in a patient with PV with the highest TXB value while on aspirin q.d. and treated short-term with a b.i.d. regimen. In conclusion, one in three patients with PV on low-dose aspirin display less-than-maximal inhibition of platelet TXA production. Serum TXB measurement can be a valuable option to guide precision dosing of antiplatelet therapy in patients with PV.
Topics: Humans; Polycythemia Vera; Thromboxanes; Aspirin; Blood Platelets; Thromboxane B2; Thromboxane A2; Computer Simulation; Platelet Aggregation Inhibitors
PubMed: 36200184
DOI: 10.1111/cts.13415 -
Journal of Thrombosis and Haemostasis :... May 2010Thromboembolism is a relatively common complication of chronic heart failure (HF) and the place of antiplatelet therapy is uncertain.
SUMMARY BACKGROUND
Thromboembolism is a relatively common complication of chronic heart failure (HF) and the place of antiplatelet therapy is uncertain.
OBJECTIVES
We characterized the rate of thromboxane and prostacyclin biosynthesis in chronic HF of ischemic origin, with the aim of separating the influence of HF on platelet activation from that of the underlying ischemic heart disease (IHD).
PATIENTS AND METHODS
We compared urinary 11-dehydro-thromboxane (TX)B(2), 2,3 dinor 6-keto-PGF(1alpha,) 8-iso-prostaglandin (PG)F(2alpha), and plasma N-terminal pro-brain natriuretic peptide (NT-pro-BNP), asymmetric dimethylarginine (ADMA), and soluble CD40 ligand (sCD40L), in 84 patients with HF secondary to IHD, 61 patients with IHD without HF and 42 healthy subjects.
RESULTS
HF patients not on aspirin had significantly higher urinary 11-dehydro-TXB(2) as compared with healthy subjects (P < 0.0001) and IHD patients not on aspirin (P = 0.028). They also showed significantly higher 8-iso-PGF(2alpha) (P = 0.018), NT-pro-BNP (P = 0.021) and ADMA (P < 0.0001) than IHD patients not on aspirin. HF patients on low-dose aspirin had significantly lower 11-dehydro-TXB(2) (P < 0.0001), sCD40L (P = 0.007) and 2,3-dinor-6-keto-PGF(1alpha) (P = 0.005) than HF patients not treated with aspirin. HF patients in NYHA classes III and IV had significantly higher urinary 11-dehydro-TXB(2) than patients in classes I and II, independently of aspirin treatment (P < 0.05). On multiple linear regression analysis, higher NT-pro-BNP levels, lack of aspirin therapy and sCD40L, predicted 11-dehydro-TXB(2) excretion rate in HF patients (R(2) = 0.771).
CONCLUSIONS
Persistent platelet activation characterizes HF patients. This phenomenon is related to disease severity and is largely suppressable by low-dose aspirin. The homeostatic increase in prostacyclin biosynthesis is impaired, possibly contributing to enhanced thrombotic risk in this setting.
Topics: Aged; Aged, 80 and over; Aspirin; Epoprostenol; Female; Heart Failure; Humans; Male; Myocardial Ischemia; Severity of Illness Index; Thromboxanes
PubMed: 20180823
DOI: 10.1111/j.1538-7836.2010.03820.x -
Molecules (Basel, Switzerland) Sep 2022Some fruits and vegetables, rich in bioactive compounds such as polyphenols, flavonoids, and anthocyanins, may inhibit platelet activation pathways and therefore reduce... (Review)
Review
Some fruits and vegetables, rich in bioactive compounds such as polyphenols, flavonoids, and anthocyanins, may inhibit platelet activation pathways and therefore reduce the risk of suffering from CVD when consumed regularly. Stuntz (Maqui) is a shrub or tree native to Chile with outstanding antioxidant activity, associated with its high content in anthocyanins, polyphenols, and flavonoids. Previous studies reveal different pharmacological properties for this berry, but its cardioprotective potential has been little studied. Despite having an abundant composition, and being rich in bioactive products with an antiplatelet role, there are few studies linking this berry with antiplatelet activity. This review summarizes and discusses relevant information on the cardioprotective potential of Maqui, based on its composition of bioactive compounds, mainly as a nutraceutical antiplatelet agent. Articles published between 2000 and 2022 in the following bibliographic databases were selected: PubMed, ScienceDirect, and Google Scholar. Our search revealed that Maqui is a promising cardiovascular target since extracts from this berry have direct effects on the reduction in cardiovascular risk factors (glucose index, obesity, diabetes, among others). Although studies on antiplatelet activity in this fruit are recent, its rich chemical composition clearly shows that the presence of chemical compounds (anthocyanins, flavonoids, phenolic acids, among others) with high antiplatelet potential can provide this berry with antiplatelet properties. These bioactive compounds have antiplatelet effects with multiple targets in the platelet, particularly, they have been related to the inhibition of thromboxane, thrombin, ADP, and GPVI receptors, or through the pathways by which these receptors stimulate platelet aggregation. Detailed studies are needed to clarify this gap in the literature, as well as to specifically evaluate the mechanism of action of Maqui extracts, due to the presence of phenolic compounds.
Topics: Adenosine Diphosphate; Anthocyanins; Antioxidants; Elaeocarpaceae; Flavonoids; Fruit; Glucose; Plant Extracts; Platelet Aggregation Inhibitors; Polyphenols; Thrombin; Thromboxanes
PubMed: 36234679
DOI: 10.3390/molecules27196147 -
Polish Archives of Internal Medicine Jan 2018
Topics: Coronary Artery Disease; Humans; Leukotrienes; Myocardial Infarction; Thromboxanes
PubMed: 29385113
DOI: 10.20452/pamw.4196 -
Journal of the American College of... Jul 2022Persistent systemic thromboxane generation, predominantly from nonplatelet sources, in aspirin (ASA) users with cardiovascular disease (CVD) is a mortality risk factor.
BACKGROUND
Persistent systemic thromboxane generation, predominantly from nonplatelet sources, in aspirin (ASA) users with cardiovascular disease (CVD) is a mortality risk factor.
OBJECTIVES
This study sought to determine the mortality risk associated with systemic thromboxane generation in an unselected population irrespective of ASA use.
METHODS
Stable thromboxane B metabolites (TXB-M) were measured by enzyme-linked immunosorbent assay in banked urine from 3,044 participants (mean age 66 ± 9 years, 53.8% women) in the Framingham Heart Study. The association of TXB-M to survival over a median observation period of 11.9 years (IQR: 10.6-12.7 years) was determined by multivariable modeling.
RESULTS
In 1,363 (44.8%) participants taking ASA at the index examination, median TXB-M were lower than in ASA nonusers (1,147 pg/mg creatinine vs 4,179 pg/mg creatinine; P < 0.0001). TXB-M were significantly associated with all-cause and cardiovascular mortality irrespective of ASA use (HR: 1.96 and 2.41, respectively; P < 0.0001 for both) for TXB-M in the highest quartile based on ASA use compared with lower quartiles, and remained significant after adjustment for mortality risk factors for similarly aged individuals (HR: 1.49 and 1.82, respectively; P ≤ 0.005 for both). In 2,353 participants without CVD, TXB-M were associated with cardiovascular mortality in ASA nonusers (adjusted HR: 3.04; 95% CI: 1.29-7.16) but not in ASA users, while ASA use was associated with all-cause mortality in those with low (adjusted HR: 1.46; 95% CI: 1.14-1.87) but not elevated TXB-M.
CONCLUSIONS
Systemic thromboxane generation is an independent risk factor for all-cause and cardiovascular mortality irrespective of ASA use, and its measurement may be useful for therapy modification, particularly in those without CVD.
Topics: Aged; Aspirin; Cardiovascular Diseases; Creatinine; Female; Humans; Male; Middle Aged; Thromboxane B2; Thromboxanes
PubMed: 35660296
DOI: 10.1016/j.jacc.2022.04.034 -
The Journal of Clinical Investigation Mar 1983To assess the pharmacologic effects of aspirin on endogenous prostacyclin and thromboxane biosynthesis, 2,3-dinor-6-keto PGF1 alpha (PGI-M) and 2,3-dinor-thromboxane B2...
To assess the pharmacologic effects of aspirin on endogenous prostacyclin and thromboxane biosynthesis, 2,3-dinor-6-keto PGF1 alpha (PGI-M) and 2,3-dinor-thromboxane B2 (Tx-M) were measured in urine by mass spectrometry during continuing administration of aspirin. To define the relationship of aspirin intake to endogenous prostacyclin biosynthesis, sequential urines were initially collected in individuals prior to, during, and subsequent to administration of aspirin. Despite inter- and intra-individual variations, PGI-M excretion was significantly reduced by aspirin. However, full mass spectral identification confirmed continuing prostacyclin biosynthesis during aspirin therapy. Recovery of prostacyclin biosynthesis was incomplete 5 d after drug administration was discontinued. To relate aspirin intake to indices of thromboxane biosynthesis and platelet function, volunteers received 20 mg aspirin daily followed by 2,600 mg aspirin daily, each dose for 7 d in sequential weeks. Increasing aspirin dosage inhibited Tx-M excretion from 70 to 98% of pretreatment control values; platelet TxB2 formation from 4.9 to 0.5% and further inhibited platelet function. An extended study was performed to relate aspirin intake to both thromboxane and prostacyclin generation over a wide range of doses. Aspirin, in the range of 20 to 325 mg/d, resulted in a dose-dependent decline in both Tx-M and PGI-M excretion. At doses of 325-2,600 mg/d Tx-M excretion ranged from 5 to 3% of control values while PGI-M remained at 37-23% of control. 3 d after the last dose of aspirin (2,600 mg/d) mean Tx-M excretion had returned to 85% of control, whereas mean PGI-M remained at 40% of predosing values. Although the platelet aggregation response (Tmax) to ADP ex vivo was inhibited during administration of the lower doses of aspirin the aggregation response returned to control values during the final two weeks of aspirin administration (1,300 and 2,600 mg aspirin/d) despite continued inhibition of thromboxane biosynthesis. These results suggest that although chronic administration of aspirin results in inhibition of endogenous thromboxane and prostacyclin biosynthesis over a wide dose range, inhibition of thromboxane biosynthesis is more selective at 20 than at 2,600 mg aspirin/d. However, despite this, inhibition of platelet function is not maximal at the lower aspirin dosage. Doses of aspirin in excess of 80 mg/d resulted in substantial inhibition of endogenous prostacyclin biosynthesis. Thus, it is unlikely that any dose of aspirin can maximally inhibit thromboxane generation without also reducing endogenous prostacyclin biosynthesis. These results also indicate that recovery of endogenous prostacyclin biosynthesis is delayed following aspirin administration and that the usual effects of aspirin on platelet function ex vivo may be obscured during chronic aspirin administration in man.
Topics: Adenosine Diphosphate; Adult; Aspirin; Blood Platelets; Epoprostenol; Humans; Male; Platelet Aggregation; Prostaglandins; Radioimmunoassay; Thromboxanes
PubMed: 6338043
DOI: 10.1172/jci110814 -
Acta Physiologica (Oxford, England) Aug 2022Cyclooxygenase-2 (COX-2) activity protects against oxidative stress and apoptosis early in experimental kidney injury. The present study was designed to test the...
AIM
Cyclooxygenase-2 (COX-2) activity protects against oxidative stress and apoptosis early in experimental kidney injury. The present study was designed to test the hypothesis that COX-2 activity attenuates fibrosis and preserves microvasculature in injured kidney. The murine unilateral ureteral-obstruction (UUO) model of kidney fibrosis was employed and compared with human nephrectomy tissue with and without chronic hydronephrosis.
METHODS
Fibrosis and angiogenic markers were quantified in kidney tissue from wild-type and COX-2 mice subjected to UUO for 7 days and in human kidney tissue. COX-enzymes, prostaglandin (PG) synthases, PG receptors, PGE , and thromboxane were determined in human tissue.
RESULTS
COX-2 immunosignal was observed in interstitial fibroblasts at baseline and after UUO. Fibronectin, collagen I, III, alpha-smooth muscle actin, and fibroblast specific protein-1 mRNAs increased significantly more after UUO in COX-2 vs wild-type mice. In vitro, fibroblasts from COX-2 kidneys showed higher matrix synthesis. Compared to control, human hydronephrotic kidneys showed (i) fibrosis, (ii) no significant changes in COX-2, COX-1, PGE -, and prostacyclin synthases, and prostacyclin and thromboxane receptor mRNAs, (iii) increased mRNA and protein of PGE -EP receptor level but unchanged PGE tissue concentration, and (iv) two- to threefold increased thromboxane synthase mRNA and protein levels, and increased thromboxane B tissue concentration in cortex and outer medulla.
CONCLUSION
COX-2 protects in the early phase against obstruction-induced fibrosis and maintains angiogenic factors. Increased PGE -EP receptor in obstructed human and murine kidneys could contribute to protection.
Topics: Animals; Cyclooxygenase 2; Dinoprostone; Fibrosis; Humans; Kidney; Mice; Prostaglandins E; Prostaglandins I; RNA, Messenger; Receptors, Prostaglandin E, EP2 Subtype; Thromboxanes; Up-Regulation; Ureter; Ureteral Obstruction
PubMed: 35543087
DOI: 10.1111/apha.13828 -
Journal of the American College of... Oct 1984Small doses of aspirin have been shown to inhibit platelet thromboxane A2 while sparing vascular prostacyclin synthesis. Because leukocytes generate prostacyclin and...
Small doses of aspirin have been shown to inhibit platelet thromboxane A2 while sparing vascular prostacyclin synthesis. Because leukocytes generate prostacyclin and participate in thrombosis along with platelets, the effects of three different doses of aspirin (40, 325 and 650 mg) on platelet function as well as on endogenous biosynthesis of thromboxane A2 and prostacyclin in whole blood were examined. In normal volunteers given a single 40 mg dose of aspirin, platelet aggregation and adenosine triphosphate release were inhibited for 24 hours. In contrast, platelet function was inhibited for 4 to 7 days in volunteers given 325 or 650 mg of aspirin. Platelet and whole blood generation of thromboxane A2 was inhibited less than 60% by the 40 mg dose, but almost completely by both the 325 and 650 mg doses. Likewise, whole blood generation of prostacyclin was inhibited 70% by the 40 mg dose and over 90% by the larger doses. Inhibition of thromboxane A2 as well as of prostacyclin was evident for 4 days with the 40 mg dose and for 7 days with the larger doses. Decreases in whole blood thromboxane A2 and prostacyclin with any dose of aspirin were of similar magnitude. These data indicate that aspirin in doses of 40 to 650 mg inhibits platelet function and biosynthesis of thromboxane A2 and prostacyclin in whole blood in human beings in a dose-dependent fashion.
Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Triphosphate; Adult; Aspirin; Blood Platelets; Epoprostenol; Female; Humans; Male; Platelet Aggregation; Thromboxane A2; Thromboxanes
PubMed: 6384329
DOI: 10.1016/s0735-1097(84)80410-6 -
The Biochemical Journal May 1984The inter-relationships between receptor occupancy, inositol phospholipid metabolism and elevation of cytosolic free Ca2+ in thromboxane A2-induced human platelet...
The inter-relationships between receptor occupancy, inositol phospholipid metabolism and elevation of cytosolic free Ca2+ in thromboxane A2-induced human platelet activation were investigated by using the stable thromboxane A2 mimetic, 9,11-epoxymethanoprostaglandin H2, and the thromboxane A2 receptor antagonist, EPO45. 9,11-Epoxymethanoprostaglandin H2 stimulated platelet phosphatidylinositol metabolism as indicated by the rapid accumulation of [32P]phosphatidate and later accumulation of [32P]phosphatidylinositol in platelets pre-labelled with [32P]Pi. These effects of 9,11-epoxymethanoprostaglandin H2 were concentration-dependent and half-maximal [32P]phosphatidate formation occurred at an agonist concentration of 54 +/- 8 nM. With platelets labelled with the fluorescent Ca2+ indicator quin 2, resting cytosolic free Ca2+ was 86 +/- 12 nM. 9,11-Epoxymethanoprostaglandin H2 induced a rapid, concentration-dependent elevation of cytosolic free Ca2+ to a maximum of 300-700 nM. Half-maximal stimulation was observed at an agonist concentration of 80 +/- 23 nM. The thromboxane A2 receptor antagonist EPO45 selectively inhibited 9,11-epoxymethanoprostaglandin H2-induced [32P]phosphatidate formation and elevation of cytosolic free Ca2+, indicating that both events are sequelae of receptor occupancy. Human platelets contain a single class of stereospecific, saturable, high affinity (KD = 70 +/- 13 nM) binding sites for 9,11-epoxymethano[3H]prostaglandin H2. The concentration-response curve for receptor occupancy (9,11-epoxymethano-[3H]prostaglandin H2 binding) is similar to that for 9,11-epoxymethanoprostaglandin H2-induced [32P]phosphatidate formation and for elevation of cytosolic free Ca2+. These observations indicate that human platelet thromboxane A2 receptor occupation is closely linked to inositol phospholipid metabolism and to elevation of cytosolic free Ca2+. Both such events may be necessary for thromboxane A2-induced human platelet activation.
Topics: Blood Platelets; Calcium; Cytosol; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Phosphatidic Acids; Phospholipids; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Prostaglandins, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxanes
PubMed: 6234886
DOI: 10.1042/bj2190833 -
Archives of Disease in Childhood Aug 1986To study whether prostacyclin and thromboxane A2 might play a role in neonatal adaption pieces of the umbilical arteries of infants born vaginally (n = 18) or by...
To study whether prostacyclin and thromboxane A2 might play a role in neonatal adaption pieces of the umbilical arteries of infants born vaginally (n = 18) or by elective caesarean section (n = 11) were superfused in vitro and the release of 6-keto-PGF1a (hydration product of prostacyclin) and thromboxane B2 (metabolite of thromboxane A2) measured by radioimmunoassay. In addition, the capacity of fetal platelets to produce thromboxane A2 and the neonatal urinary concentrations of 6-keto-PGF1a were measured. Infants born by caesarean section had lower diastolic blood pressure, higher heart rate, and smaller differences between rectal and skin temperature compared with infants born vaginally during the first two hours of life. The only difference encountered in the prostanoids between the groups was reduced urinary excretion of 6-keto-PGF1a in infants born by caesarean section, whose release of 6-keto-PGF1a by the umbilical artery was positively correlated with heart rate, respiration frequency, and dermal temperature. Thus prostacyclin may be a regulatory determinant, particularly in infants born by caesarean section.
Topics: 6-Ketoprostaglandin F1 alpha; Blood Pressure; Body Temperature; Cesarean Section; Delivery, Obstetric; Epoprostenol; Female; Fetus; Heart Rate; Humans; Infant, Newborn; Pregnancy; Radioimmunoassay; Thromboxane A2; Thromboxane B2
PubMed: 3527082
DOI: 10.1136/adc.61.8.766