Impaired thrombolysis: a novel cardiovascular risk factor in end-stage renal disease

Sharma, Sumeet; Farrington, Ken; Kozarski, Robert; Christopoulos, C.; Niespialowska-Steuden, Maria; Moffat, Daniel; Gorog, Diana A.

doi:10.1093/eurheartj/ehs300

Cited by 40 publications

(28 citation statements)

References 63 publications

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“…[16][17][18] We have confirmed and extended these initial observations by demonstrating a strong reciprocal correlation between serum TAFI and plasmin activity with loss of renal function in clinical specimens. We wanted to understand the potential significance of this in an experimental setting and selected the rat 5/6 SNx model on the basis of similar observations of impaired plasmin and elevated TAFI activity with the development of renal function decline in this model.…”

Section: Discussionsupporting

confidence: 71%

“…14,15 While PAI-1 and plasmin are most often associated with the regulation of fibrinolytic system, recent studies have indicated an additional contribution to renal impairment and mortality. [16][17][18] Furthermore, increasing evidence also suggests that members of the fibrinolytic system, such as fibrinogen, 19,20 plasmin, 15 tissue plasmin activator (tPA), 21 urokinase plasmin activator (uPA) 22 and thrombin-activated fibrinolysis inhibitor activity (TAFI) [23][24][25] are important players in the fibrotic response to cellular injury.…”

mentioning

confidence: 99%

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Inhibition of Thrombin-Activated Fibrinolysis Inhibitor Increases Survival in Experimental Kidney Fibrosis

Atkinson

Pullen

Silva-Lodge

et al. 2015

Journal of the American Society of Nephrology

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Uncontrolled diabetes, inflammation, and hypertension are key contributors to progressive renal fibrosis and subsequent loss of renal function. Reduced fibrinolysis appears to be a feature of ESRD, but its contribution to the fibrotic program has not been extensively studied. Here, we show that in patients with CKD, the activity levels of serum thrombin-activated fibrinolysis inhibitor and plasmin strongly correlated with the degree of renal function impairment. We made similar observations in rats after subtotal nephrectomy and tested whether pharmacologic inhibition of thrombin-activated fibrinolysis inhibitor with UK-396082 could reduce renal fibrosis and improve renal function. Compared with untreated animals, UK-396082-treated animals had reduced glomerular and tubulointerstitial fibrosis after subtotal nephrectomy. Renal function, as measured by an increase in creatinine clearance, was maintained and the rate of increase in proteinuria was reduced in UK-396082-treated animals. Furthermore, cumulative survival improved from 16% to 80% with inhibition of thrombin-activated fibrinolysis inhibitor. Taken together, these data support the importance of the fibrinolytic axis in regulating renal fibrosis and point to a potentially important therapeutic role for suppression of thrombin-activated fibrinolysis inhibitor activity.

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Section: Discussionsupporting

confidence: 71%

mentioning

confidence: 99%

Inhibition of Thrombin-Activated Fibrinolysis Inhibitor Increases Survival in Experimental Kidney Fibrosis

Atkinson

Pullen

Silva-Lodge

et al. 2015

Journal of the American Society of Nephrology

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“…Besides, renal dysfunction was reported to be independently associated with reduction of efficacy in stroke reperfusion therapy [10]. The underlying mechanism may be the greater cerebrovascular disease burden and poorer collateral circulation [23], altered fibrin clot properties and structures [24,25], and decreased endogenous thrombolysis [26] in patients with renal dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Is Renal Dysfunction Associated with Adverse Stroke Outcome after Thrombolytic Therapy?

et al. 2013

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Background: Renal dysfunction is a prevalent comorbidity in acute stroke patients requiring thrombolytic therapy. Reports studying the relationship between renal dysfunction and risk of postthrombolytic symptomatic intracerebral hemorrhage (SICH) are contradictory. We aimed to compare the safety and effectiveness of thrombolytic therapy in acute stroke patients with and without renal dysfunction. Methods: Based on the prospective stroke registries of 4 hospitals in Taiwan from 2007-2012, we identified acute stroke patients who received thrombolytic therapy. Clinically significant renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m². Renal dysfunction was further defined as stage 3 (30 ≤ eGFR < 60 ml/min/ 1.73 m²), stage 4 (15 ≤ eGFR < 30 ml/min/1.73 m²) and stage 5 (<15 ml/min/1.73 m²). The rates of SICH and poor outcome (defined as modified Rankin scale score ≥4) at 3 months after thrombolytic therapy were compared in patients with and without renal dysfunction. SICH was determined according to the definition of the National Institute of Neurological Disorders and Stroke. Multivariable logistic regression was used to determine the effect of renal dysfunction on outcome. Patients with different stages of renal dysfunction were further analyzed to determine the effect of disease severity on outcome. Results: Of the 657 stroke patients with thrombolysis, 239 (36%) had renal dysfunction, including 212 patients in stage 3, 17 patients in stage 4 and 10 patients in stage 5 of renal dysfunction. Patients with renal dysfunction were older and more likely to have hypertension, ischemic heart disease, congestive heart failure and prior antiplatelet use than those without. There were no differences in SICH (8 vs. 7%, p = 0.580) and poor outcome (41 vs. 39%, p = 0.758) between patients with and without renal dysfunction. After multivariable analysis, renal dysfunction was not associated with SICH (odds ratio: 1.03, 95% confidence interval: 0.55-1.92) and poor outcome. Pretreatment stroke severity was the only factor significantly associated with both SICH and poor outcome at 3 months. When stratifying renal dysfunction into stage 3 and stage ≥4, there was no significant increase in SICH as the severity of renal dysfunction increased after multivariable adjustment. Conclusions: Renal dysfunction did not increase the risk of SICH and poor outcome at 3 months after stroke thrombolysis. Further study comparing directly the risk and benefit of thrombolytic therapy versus no therapy in stroke patients with renal dysfunction is warranted.

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“…The plasmin inhibitor tranexamic acid prevented plasminogen activator–induced thrombolysis, whereas inhibition of clot retraction by cytochalasin B did not affect the lysis time . The potential clinical relevance of assessing lysis time has been shown in patients with recent acute coronary syndromes and with renal failure in whom impaired endogenous thrombolysis, as demonstrated by prolonged lysis time, was associated with an increased risk of myocardial infarction and cardiovascular death. In a small cohort of patients presenting with ST‐elevation myocardial infarction, those with spontaneous ST resolution and normal coronary flow before intervention had very short lysis times (efficient endogenous lysis), and those with markedly impaired (prolonged) lysis times had higher incidence of no‐flow and future adverse events …”

Section: Assessment Of Endogenous Thrombolytic Statusmentioning

confidence: 99%

Platelet Function Tests: Why They Fail to Guide Personalized Antithrombotic Medication

Gorog

Jeong

2015

JAHA

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Impaired thrombolysis: a novel cardiovascular risk factor in end-stage renal disease

Abstract: Impaired endogenous thrombolysis is a novel risk factor in ESRD, strongly associated with cardiovascular events.

Cited by 40 publications

References 63 publications

Inhibition of Thrombin-Activated Fibrinolysis Inhibitor Increases Survival in Experimental Kidney Fibrosis

Inhibition of Thrombin-Activated Fibrinolysis Inhibitor Increases Survival in Experimental Kidney Fibrosis

Is Renal Dysfunction Associated with Adverse Stroke Outcome after Thrombolytic Therapy?

Platelet Function Tests: Why They Fail to Guide Personalized Antithrombotic Medication

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