Imbalance between Fibrin Clot Formation and Fibrinolysis Predicts Cardiovascular Events in Patients with Stable Coronary Artery Disease

Abstract

Background Despite long-term antiplatelet therapy with aspirin, recurrent cardiovascular events remain common in patients with coronary artery disease (CAD). Objective We aimed to determine whether fibrin network characteristics are predictive of vascular events in patients with stable CAD treated with aspirin monotherapy. Methods We included 786 patients with angiographically documented CAD and either prior myocardial infarction, type 2 diabetes mellitus, or both. Median follow-up time was 3 years. At inclusion, fibrin clot properties were evaluated using a turbidimetric assay and the following clot parameters were studied: (1) maximum absorbance, a measure of clot density and fiber thickness; (2) lysis time, assessing fibrinolysis potential; and (3) area under the curve (AUC), a measure of clot formation and lysis. The primary endpoint was the composite of nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. Hazard ratios (HRs) were estimated using multivariable Cox proportional hazards regression. Results A total of 70 primary endpoints occurred. The primary endpoint occurred more frequently in CAD patients with increased clot AUC (crude HR for first vs. fourth quartile: 2.4 [95% confidence interval 1.2–4.6], p = 0.01). This finding remained significant after adjusting for potential confounders (adjusted HR: 2.4 [1.2–4.8], p = 0.01). Neither clot maximum absorbance nor lysis time showed significant association with future vascular events (adjusted HR for maximum absorbance 1.8 [0.9–3.7]; p = 0.09) and lysis time (1.6 [0.8–3.0]; p = 0.18). Conclusion We demonstrate that increased clot AUC predicts future cardiovascular events in stable CAD patients receiving aspirin monotherapy.

The ABO Locus is Associated with Increased Fibrin Network Formation in Patients with Stable Coronary Artery Disease

“…11 Furthermore, we recently demonstrated that increased fibrin clot formation predicts cardiovascular adverse events in stable CAD patients treated with low-dose aspirin. 12 Therefore, we hypothesized that the association between the ABO risk allele and MI risk in addition could be mediated through altered fibrin clot properties. Thus, we investigated the association between fibrin clot properties and the lead variant at the ABO locus.…”

Maturity onset diabetes of the young and fibrin-related thrombosis risk

“…Clot lysis area is a measure reflecting both clot formation and lysis, and has previously been used to predict the risk of vascular events. 13 The T1D group had the smallest lysis area (157 ± 14 AU) followed by the MODY group (238 ± 52 AU ( p = 0.16)). The largest lysis time was observed with T2DM (409 ± 56 AU), which was significantly elevated compared to T1DM ( p < 0.01) and MODY ( p = 0.04).…”

“…Clot structure was studied in all these samples using a validated turbidimetric assay as previously described. 12,13 Clot final turbidity, used as a measure of clot density, was recorded. We also investigated time from full clot formation to 50% lysis as a marker of lysis potential as well as clot lysis area, a complex measure of clot formation and lysis.…”

Fibrinolysis in Acute and Chronic Cardiovascular Disease

“…The study by Neergaard-Petersen and colleagues followed up 786 patients with stable CAD (90% had previous MI) over 3.1 years, and found that only area under the curve (AUC) of clot formation and lysis predicted composite cardiovascular outcomes, but not maximum turbidity or lysis time alone (►Table 2). 72 However, the study had relatively small sample size with only 70 (9%) events occurring during the 3.1 years of follow-up period. Thus, it was likely that the maximum turbidity or lysis time was underpowered to predict outcomes when analyzed separately, but the combined analysis (that essentially includes these two measures) had enough power to show an association.…”