Fibrin clot properties independently predict adverse clinical outcome following acute coronary syndrome: a PLATO substudy

Abstract

AimsTo determine whether fibrin clot properties are associated with clinical outcomes following acute coronary syndrome (ACS).Methods and resultsPlasma samples were collected at hospital discharge from 4354 ACS patients randomized to clopidogrel or ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. A validated turbidimetric assay was employed to study plasma clot lysis time and maximum turbidity (a measure of clot density). One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were estimated using Cox proportional hazards models. After adjusting for CV risk factors, each 50% increase in lysis time was associated with CV death/spontaneous MI [HR 1.17, 95% confidence interval (CI) 1.05–1.31; P < 0.01] and CV death alone (HR 1.36, 95% CI 1.17–1.59; P < 0.001). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death (HR 1.24, 95% CI 1.03–1.50; P = 0.024). After adjustment for other prognostic biomarkers (leukocyte count, high-sensitivity C-reactive protein, high-sensitivity troponin T, cystatin C, N-terminal pro B-type natriuretic peptide, and growth differentiation factor-15), the association with CV death remained significant for lysis time (HR 1.2, 95% CI 1.01–1.42; P = 0.042) but not for maximum turbidity. These associations were consistent regardless of randomized antiplatelet treatment (all interaction P > 0.05). Neither lysis time nor maximum turbidity was associated with major bleeding events. ConclusionFibrin clots that are resistant to lysis independently predict adverse outcome in ACS patients. Novel therapies targeting fibrin clot properties might be a new avenue for improving prognosis in patients with ACS.

Fibrinogen and fibrin: An illustrated review

“…Fibrin clot properƟes are clinically-relevant (reviewed in 44,[60][61][62][63][64][65] Examples: inflammatory bowel disease, anƟphospholipid syndrome, rheumatoid arthriƟs, chronic obstrucƟve pulmonary disease Clots with densely-packed fibers, increased sƟffness, and resistance to fibrinolysis are found in cardiovascular and other diseases.…”

Rationale and design of “Can Very Low Dose Rivaroxaban (VLDR) in addition to dual antiplatelet therapy improve thrombotic status in acute coronary syndrome (VaLiDate-R)” study

“…Unlike the enhanced platelet reactivity in these patients which reduced from admission to discharge, presumably reflecting the onset of effect of antiplatelet therapy, fibrinolysis in ACS patients appears unaffected by DAPT [15,16]. Our group has previously investigated the effects of P2Y 12 inhibitors on endogenous fibrinolysis and shown that these agents appear to have minimal impact on fibrinolysis [18].…”

“…In the last 2 years, two large prospective studies have confirmed that impaired fibrinolysis in patients with ACS is a novel independent marker of increased cardiovascular risk [15,16]. In a sub-study of > 4000 patients in the PLATO trial, assessment of fibrin clot lysis using a validated turbidimetric assay revealed that impaired fibrin clot lysis was an independent predictor of adverse outcome in ACS [15]. After adjusting for established cardiovascular risk factors, each 50% increase in lysis time was associated with cardiovascular death/spontaneous MI [Hazard ratio [HR] 1.17, 95% confidence interval (CI) 1.05-1.31; p < 0.01] and cardiovascular death alone [HR 1.36, 95% CI 1.17-1.59; p < 0.001].…”

“…Altered fibrin clot structure and increased resistance of the clot to lysis have been associate with myocardial infarction and stent thrombosis [11][12][13][14]. In the last 2 years, two large prospective studies have confirmed that impaired fibrinolysis in patients with ACS is a novel independent marker of increased cardiovascular risk [15,16]. In a sub-study of > 4000 patients in the PLATO trial, assessment of fibrin clot lysis using a validated turbidimetric assay revealed that impaired fibrin clot lysis was an independent predictor of adverse outcome in ACS [15].…”

Acute coronary syndromes: the tipping point of coronary artery disease

“…This has been addressed in the PLATO substudy 'Fibrin clot properties independently predict adverse clinical outcome following acute coronary syndrome' by Robert F. Storey and colleagues from the University of Sheffield in the UK in 4354 patients. 15 After adjusting for cardiovascular risk factors, each 50% increase in lysis time was associated with cardiovascular death or myocardial infarction, with hazard ratios of 1.17 and 1.36, respectively. Similarly, each 50% increase in maximum turbidity was associated with a 1.24-fold increased risk of cardiovascular death.…”