Temporal remodeling of the fibrin clot-bound proteome after myocardial infarction and its association with persistent prothrombotic phenotype
A Karcinska, A Stachowicz, K Nowak, J Nessler, A Undas, R Olszanecki, J ZalewskiAbstract
Background
Despite advances in the invasive treatment of acute myocardial infarction (MI) and the widespread use of guideline-based pharmacotherapy, long-term prognosis remains challenging. Many patients experience recurrent cardiovascular events and death within several years after acute coronary syndrome, reflecting a persistent residual risk, however the molecular determinants responsible for its maintenance remain insufficiently understood.
Purpose
We sought to identify fibrin clot-bound proteins and to assess their temporal changes between the acute phase of MI and six-month follow-up to better characterize the mechanisms contributing to the persistent prothrombotic risk.
Methods
Enrolled were 73 statin-naïve patients (median age 62 years, 55 males) with STEMI or high-risk NSTEMI undergoing primary PCI. On admission and at 6-month follow-up, peak thrombin generation and endogenous thrombin potential (ETP) were assessed ex vivo using calibrated automated thrombogram. Also ex-vivo fibrin clot structure and susceptibility to lysis were evaluated by clot permeability (Ks) reflecting fibrin pore size and clot lysis time, respectively. Qualitative and quantitative proteomic analysis of plasma fibrin clot-bound proteins was performed at both time points.
Results
A total of 231 clot-bound proteins were identified at both time points, clustering into distinct functional pathways. 43 proteins demonstrated significant changes over six months. 36 proteins, mainly involved in platelet and neutrophil degranulation, complement cascade, and positive regulation of immune response, decreased. 7 proteins, associated with plasma lipoprotein assembly, remodeling, and clearance, increased. Among 65 hemostasis-related proteins analyzed at follow-up, Ks negatively correlated with 9 proteins, with strongest associations observed for alpha-1-antitrypsin (r=-0.426, P<0.001), alpha-1-antichymotrypsin (r=-0.357, P=0.002), and plasminogen (P=-0.462, P<0.001). ETP positively correlated with 4 proteins, with the strongest association with apolipoprotein B-100 (r=0.321, P=0.006) and selenoprotein P (r=0.366, P=0.002). By multivariable analysis, after adjustment for fibrinogen, age and gender, Ks at follow-up was independently affected by clot-bound plasminogen (beta -0.359, confidence interval for beta -0.560 - -0.157, P<0.001)
Conclusions
The fibrin clot-bound proteome undergoes significant remodeling within six months after MI. Reduced inflammation- and degranulation-related proteins suggests attenuation of acute thrombo-inflammatory activity, whereas increased lipoprotein-associated proteins may reflect statin influence on lipid-driven prothrombotic characteristics. The associations between clot-bound proteins and hemostatic parameters indicate their potential role in modulating fibrin architecture and thrombin-generating capacity beyond the acute phase. These findings provide new mechanistic insight into the residual thrombotic risk after MI.