Uric acid enhances alteplase-mediated thrombolysis as an antioxidant

Abstract

Uric acid (UA) therapy may prevent early ischemic worsening after acute stroke in thrombolysis patients. The aim of this study was to examine the influence of UA on the thrombolytic efficacy of alteplase in human blood samples by measuring thrombolysis under flow conditions using a newly developed microchip-based flow-chamber assay. Human blood samples from healthy volunteers were exposed to UA, alteplase, or a combination of UA and alteplase. Whole blood and platelet-rich plasma were perfused over a collagen- and thromboplastin-coated microchip, and capillary occlusion was monitored with a video microscope and flow-pressure sensor. The area under the curve (extent of thrombogenesis or thrombolysis) at 30 minutes was 92% lower in the UA–alteplase-treated group compared with the alteplase-treated group. D-dimers were measured to evaluate these effects in human platelet-poor plasma samples. Although hydrogen peroxide significantly decreased the elevation of D-dimers by alteplase, UA significantly inhibited the effect of hydrogen peroxide. Meanwhile, rat models of thromboembolic cerebral ischemia were treated with either alteplase or UA–alteplase combination therapy. Compared with alteplase alone, the combination therapy reduced the infarct volume and inhibited haemorrhagic transformation. UA enhances alteplase-mediated thrombolysis, potentially by preventing oxidative stress, which inhibits fibrinolysis by alteplase in thrombi.

Effect of uric acid in animal models of ischemic stroke: A systematic review and meta-analysis

“…No additional record was identified in the reference lists of these articles and other relevant review articles. Subsequent reasoned exclusions rendered 16 studies included in the qualitative synthesis, 7 , 14 , 25–38 and 14 studies subjected to meta-analysis. 7 , 14 , 25–28 , 30–33 , 35–38 Analyses of the three outcomes were based on 19 comparisons reporting infarct size, 8 comparisons reporting BBB impairment or oedema and 14 comparisons reporting neurofunctional score.…”

“…Both structural and functional outcomes were measured, and relevant biomarker endpoints were also used in some cases, such as MRI assessment of brain injury, 32 , 35 , 36 as well as serum/plasma biomarkers of oxidative stress, 25 , 35 inflammatory response 35 and angiogenesis. 27 UA was tested in temporary models of ischaemia, mostly intraluminal filament MCAO, but also thromboembolism, 26 , 37 and the only study in permanent ischaemia was excluded because of imprecise sample sizes. 34 Evidence is also still lacking for outcome measurement beyond 14 days, and in species other than rodents.…”

“…34 Evidence is also still lacking for outcome measurement beyond 14 days, and in species other than rodents. Finally, although UA has been studied in animals co-treated with alteplase (rtPA), 26,37 no interaction studies with other medications commonly used by stroke patients such as statins, blood pressure-lowering medication and aspirin were identified. Median (Q1, Q3) quality score in the studies reporting infarct size was 7.5 (6, 10) of a possible 15.…”

Uric Acid as a Predictor for Early Allograft Dysfunction after Living Donor Liver Transplantation: A Prospective Observational Study

“…Interestingly, in healthy humans, the acute elevation of UA seems to prevent the increase in oxidative stress and arterial stiffness caused by hyperoxia [ 25 ]. UA treatment was also reported to prevent the worsening of early ischemic injury related to reperfusion after acute stroke in patients receiving thrombolysis [ 26 , 27 ]. Thus, a low UA level may imply the severity of initial liver injury and susceptibility to later reperfusion injury following liver transplantation.…”

Structural Biology and Protein Engineering of Thrombolytics

“…Neurological side-effects such as neuroinflammation and disruption of the blood-brain barrier by the interaction of various molecules with t-PA and plasmin negatively influence the outcome of the therapy. Unfavorable interactions and oxidative stress on thrombolytics in ischemic conditions are being tackled by using antibodies, protein antagonists of receptor binding, or small molecules [[342], [343], [344], [345], [346], [347], [348]]. Anti-inflammatory cytokines were recently tested as adjuvant therapy to alleviate inflammatory side-effects [348,349].…”