Differential Impact of Serial Measurement of Nonplatelet Thromboxane Generation on Long‐Term Outcome After Cardiac Surgery

Kakouros, Nikolaos; Gluckman, Tyler J; Conte, John V.; Kickler, Thomas S.; Laws, Katherine; Barton, Bruce; Rade, Jeffrey J.

doi:10.1161/jaha.117.007486

Cited by 4 publications

(1 citation statement)

References 49 publications

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“…Poor agreement between test platforms has been reported previously in adult studies, including one where UTxB2‐based aspirin nonresponsiveness after ischemic stroke was more predictive for future major cardiovascular events than VN 3,16–18 . Early inflammatory‐induced (i.e., COX2‐associated) thromboxane production has been hypothesized as a major contributor to vascular complications after cardiac procedures due to its promotion of vasoconstriction and platelet aggregation, 18–20 though more studies have demonstrated its predictive value for long‐term major cardiovascular events 21–23 . The lack of thrombotic events in this pilot study did not allow determination of the relative predictive value of the two tests.…”

Section: Discussioncontrasting

confidence: 55%

Urinary 11‐dehydrothromboxane B2 aspirin efficacy testing is sensitive to perioperative inflammation in pediatric solid‐organ transplant patients

Boucher

Francisco

Pfeiffer

et al. 2021

Pediatric Blood & Cancer

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Background Evidence for aspirin efficacy testing in pediatrics is limited, especially outside of cardiology, yet thrombotic events have high morbidity in other areas such as pediatric transplant surgery. Debates about whether thromboembolic events while on aspirin represent “aspirin resistance” or “high on‐treatment platelet reactivity” persist, given the poor intertest agreement between testing platforms. Procedure This prospective observational study involved measuring aspirin efficacy using ex vivo testing of platelet aggregation (VerifyNow‐Aspirin, VN) and urine 11‐dehydrothromboxane B2 (AsprinWorks, UTxB2) contemporaneously at up to three time points after major noncardiac organ transplant surgery. The collection days (CD) were the second and seventh days after stable aspirin dosing and then a convalescent time point 2‐9 months later. Results Fifty‐five participants (age range, 0‐21 years) were enrolled, having undergone total pancreatectomy with islet autotransplantation (N = 36), orthotopic liver transplantation (N = 18), and combined liver‐kidney transplantation (N = 1). Platelet reactivity measured by VN remained unchanged, whereas UTxB2, which was elevated postoperatively, decreased significantly from CD1 to CD2 and CD3. Discordance in therapeutic efficacy was noted per manufacturer cutoffs, with therapeutic VN results in 86% of tests, whereas 12% of UTxB2 were therapeutic. Age‐based stratification of UTxB2 results using previously published pediatric median levels increased overall UTxB2 therapeutic rates (80%) and intertest concordance (67% vs 27% if using adult range). No thrombotic events were observed. Conclusions Our data suggest that urine thromboxane production may be an underappreciated reflection of postoperative inflammation. Validation of pediatric normal ranges for UTxB2 is a critical next step.

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Section: Discussioncontrasting

confidence: 55%

Urinary 11‐dehydrothromboxane B2 aspirin efficacy testing is sensitive to perioperative inflammation in pediatric solid‐organ transplant patients

Boucher

Francisco

Pfeiffer

et al. 2021

Pediatric Blood & Cancer

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Adjustment for Renal Function Improves the Prognostic Performance of Urinary Thromboxane Metabolites

Barton,

Kronsberg,

Hariri

et al. 2024

Clinical Chemistry

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Background Systemic thromboxane A2 generation, assessed by quantifying the concentration of stable thromboxane B2 metabolites (TXB2-M) in the urine adjusted for urinary creatinine, is strongly associated with mortality risk. We sought to define optimal TXB2-M cutpoints for aspirin users and nonusers and determine if adjusting TXB2-M for estimated glomerular filtration rate (eGFR) in addition to urinary creatinine improved mortality risk assessment. Methods Urinary TXB2-M were measured by competitive ELISA in 1363 aspirin users and 1681 nonusers participating in the Framingham Heart Study. Cutpoints were determined for TXB2-M and TXB2-M/eGFR using log-rank statistics and used to assess mortality risk by Cox proportional hazard modeling and restricted mean survival time. Multivariable models were compared using the Akaike Information Criterion (AIC). A cohort of 105 aspirin users with heart failure was used for external validation. Results Optimized cutpoints of TXB2-M were 1291 and 5609 pg/mg creatinine and of TXB2-M/eGFR were 16.6 and 62.1 filtered prostanoid units (defined as pg·min/creatinine·mL·1.73 m2), for aspirin users and nonusers, respectively. TXB2-M/eGFR cutpoints provided more robust all-cause mortality risk discrimination than TXB2-M cutpoints, with a larger unadjusted hazard ratio (2.88 vs 2.16, AIC P < 0.0001) and greater differences in restricted mean survival time between exposure groups (1.46 vs 1.10 years), findings that were confirmed in the external validation cohort of aspirin users. TXB2-M/eGFR cutpoints also provided better cardiovascular/stroke mortality risk discrimination than TXB2-M cutpoints (unadjusted hazard ratio 3.31 vs 2.13, AIC P < 0.0001). Conclusion Adjustment for eGFR strengthens the association of urinary TXB2-M with long-term mortality risk irrespective of aspirin use.

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Nonplatelet thromboxane generation is associated with impaired cardiovascular performance and mortality in heart failure

Hariri

Kakouros

Bunsick

et al. 2022

American Journal of Physiology-Heart and Circulatory Physiology

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Background: Non-platelet thromboxane generation, stimulated largely by oxidative stress, is a novel mortality risk factor in individuals with coronary artery disease. Though inversely associated with left ventricular ejection fraction (LVEF), a potential role in the pathobiology of heart failure (HF) remains poorly defined. Methods: Non-platelet thromboxane generation and oxidative stress were assessed by measuring urine thromboxane B2 metabolites (TXB2-M) and 8-isoPGF2α by ELISA in 105 subjects taking aspirin undergoing right heart catheterization for evaluation of HF, valve disease or after transplantation. Multivariable logistic regression and survival analyses were used to define associations of TXB2-M to invasive measures of cardiovascular performance and 4-year clinical outcome. Results: TXB2-M was elevated (>1500 pg/mg creatinine) in 46% of subjects and correlated with HF severity by NYHA functional class and brain natriuretic peptide level, modestly with LVEF, but not with HF etiology. There was no association of oxidative stress to HF type or etiology but a trend with NYHA functional class. Multiple invasive hemodynamic parameters independently associated with TXB2-M after adjustment for oxidative stress, age, sex and race with pulmonary effective arterial elastance (Ea (pulmonary)), reflective of right ventricular afterload, being the most robust on hierarchical analysis. Similar to Ea (pulmonary), elevated urinary TXB2-M associated with increased risk of death (adjusted HR 2.15, P=0.037) and combination of death, transplant, or mechanical support initiation (adjusted HR 2.0, P=0.042). Conclusions: Non-platelet TXA2 thromboxane generation independently associated with HF severity reflected by invasive measures of cardiovascular performance, particularly right ventricular afterload, and independently predicted long-term mortal

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Differential Impact of Serial Measurement of Nonplatelet Thromboxane Generation on Long‐Term Outcome After Cardiac Surgery

Cited by 4 publications

References 49 publications

Urinary 11‐dehydrothromboxane B2 aspirin efficacy testing is sensitive to perioperative inflammation in pediatric solid‐organ transplant patients

Urinary 11‐dehydrothromboxane B2 aspirin efficacy testing is sensitive to perioperative inflammation in pediatric solid‐organ transplant patients

Adjustment for Renal Function Improves the Prognostic Performance of Urinary Thromboxane Metabolites

Nonplatelet thromboxane generation is associated with impaired cardiovascular performance and mortality in heart failure

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