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

Wael Sumaya, Lars Wallentin, Stefan K James, Agneta Siegbahn, Katja Gabrysch, Maria Bertilsson, Anders Himmelmann, Ramzi A Ajjan, Robert F Storey, Wael Sumaya, Lars Wallentin, Stefan K James, Agneta Siegbahn, Katja Gabrysch, Maria Bertilsson, Anders Himmelmann, Ramzi A Ajjan, Robert F Storey

Abstract

Aims: To determine whether fibrin clot properties are associated with clinical outcomes following acute coronary syndrome (ACS).

Methods and results: Plasma 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.

Conclusion: Fibrin 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.

Figures

Figure 1
Figure 1
Relationship between fibrin clot parameters and 1-year cumulative event rate of cardiovascular death or spontaneous myocardial infarction. The Kaplan–Meier curves for cumulative event rate of the combined outcome of cardiovascular death or spontaneous myocardial infarction per quartile group of lysis time (A) and maximum turbidity (B).
Figure 2
Figure 2
Relationship between fibrin clot parameters and 1-year cumulative event rate of cardiovascular death. The Kaplan–Meier curves for 1-year cumulative event rate of cardiovascular death per quartile group of lysis time (A) and maximum turbidity (B).
Figure 3
Figure 3
Relationship between fibrin clot parameters and 1-year rates of cardiovascular death or major bleeding according to randomized treatment group. One-year rates of cardiovascular death (A and B) or major bleeding (C and D) in relation to maximum turbidity (A and C) or lysis time (B and D), transformed using restricted cubic splines, according to randomized treatment with clopidogrel (C, pink lines) or ticagrelor (T, blue lines). Shaded areas represent 95% confidence intervals. Vertical lines indicate quartiles.
Take home Figure
Take home Figure
High-risk conditions are associated with increased thrombotic potential through a variety of mechanisms. Dual antiplatelet therapy successfully targets platelet reactivity. However, hypofibrinolysis remains unaffected and constitutes a potential therapeutic target. LDL-C, low-density lipoprotein cholesterol; PAI-1, plasminogen activation inhibitor-1; TAFI, thrombin activatable fibrinolysis inhibitor.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6019045/bin/ehy013f4.jpg

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