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

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 SH2B3 and KCNK5 loci may be implicated in regulation of platelet count, volume, and maturity.

INTRODUCTION: In recent genome-wide association studies, coronary artery disease (CAD) and myocardial infarction (MI) have been linked to a number of genetic variants, but their role in thrombopoiesis is largely unknown. AIM: We investigated the association between CAD and MI-associated genetic variants and five thrombopoiesis-related indices: platelet count (PC), mean platelet volume (MPV), immature platelet count (IPC), immature platelet fraction (IPF), and serum thrombopoietin (TPO). METHODS: We genotyped 45 genome-wide significant CAD/MI-markers in 879 stable CAD patients. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. Platelet indices were analysed using the Sysmex XE-2100 haematology analyser. TPO was measured by ELISA. RESULTS: Two variants were nominally associated with several indices; for rs10947789 (KCNK5), the adjusted geometric mean was 2% higher for MPV (95% confidence interval: 1-2%, p=0.002), 6% for IPC (0-12%, p=0.033), and 9% for IPF (3-16%, p=0.004) per CAD risk allele. Moreover, an 11% lower TPO (3-19%, p=0.010) was observed. Rs3184504 (SH2B3) was associated with a higher adjusted geometric mean of 3% (1-6%, p=0.003) per CAD risk allele for PC, and an 11% (5-17%, p<0.001) lower TPO. Furthermore, the adjusted IPC was 5% (0-9%, p=0.037) lower per CAD risk allele for PC, whereas IPF levels did not vary across genotypes. CONCLUSION: As a novel finding, our study suggests a role for KCNK5 in the regulation of platelet size and maturity. Furthermore, our findings confirm an association between the SH2B3-locus and platelet count.

A 45-SNP genetic risk score is increased in early-onset coronary artery disease but independent of familial disease clustering.

BACKGROUND AND AIMS: Common genetic risk variants may contribute to the heritability of early-onset coronary artery disease (CAD). We aimed to investigate the association of a genetic risk score (GRS) with age upon CAD-onset and to test the association between the GRS, familial clustering, and CAD severity in early-onset CAD. METHODS: 134 early-onset CAD patients (<40 years), 446 late-onset CAD patients (male >55 years/female >65 years), and 89 healthy controls were genotyped for 45 CAD-associated SNPs and a GRS was created. In early-onset CAD patients, family pedigrees with information on 1585 1st and 2nd degree relatives were used to calculate a stratified log-rank family score (SLFS) as a measure of familial clustering. RESULTS: Early-onset patients had a higher mean GRS than late-onset CAD patients (p = 0.02) and healthy controls (p < 0.0001). In the adjusted model, a GRS increase of one SD was associated with 1.2 years (95% CI 0.1-2.2) earlier onset. The GRS was not associated with the SLFS in the regression model (p = 0.41) and did not differ between SLFS tertiles (p = 0.98). The SLFS predicted the number of affected coronary vessels (OR [95% CI] per SD increase in SLFS: 2.0 [1.4-3.0]), whereas the association between the GRS and CAD severity was not statistically significant (OR [95% CI] per SD increase in GRS: 1.3 [0.9-1.9]). CONCLUSIONS: The GRS was increased in early-onset CAD patients, but not associated with the SLFS, suggesting that these common genetic variants are of minor importance in familial clustering of early-onset CAD. Furthermore, family pedigree analysis may predict CAD severity more precisely than common variants.