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Updated: Aug 23, 2025
Experimental and Imaging Techniques for Examining Fibrin Clot Structures in Normal and Diseased States
Published on: April 1, 2015
Homocysteine thiolactone contributes to the prognostic value of fibrin clot structure/function in coronary artery
Marta Sikora1, Paweł Skrzydlewski2, Joanna Perła-Kaján2
1European Center for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, Poznań, Poland.
Insights
Sulfur metabolites like homocysteine-thiolactone and cysteine impact fibrin clot lysis time, predicting adverse outcomes in coronary artery disease (CAD). B-vitamin therapy did not alter these clot properties or improve patient results.
Area of Science:
- Cardiovascular Medicine
- Biochemistry
- Clinical Trials
Background:
- Fibrin clot structure and function are implicated in cardiovascular disease pathogenesis.
- Sulfur-containing metabolites may influence fibrin clot properties and clinical outcomes.
- The efficacy of B-vitamin/folate therapy in coronary artery disease (CAD) remains incompletely understood.
Purpose of the Study:
- To investigate sulfur-containing metabolites as determinants of fibrin clot lysis time (CLT) and maximum absorbance (Absmax).
- To assess the relationship between CLT, Absmax, and clinical outcomes (acute myocardial infarction, mortality) in CAD patients.
- To evaluate the effect of B-vitamin/folate therapy on CLT and Absmax.
Main Methods:
- Plasma samples from 1,952 CAD patients in the Western Norway B-Vitamin Intervention Trial were analyzed.
- Patients were randomized to folic acid, vitamins B12, B6, or placebo.
- Clot lysis time (CLT) and maximum absorbance (Absmax) were measured using a turbidimetric assay; clinical outcomes were assessed over 7-year follow-up.
Main Results:
- Baseline urinary homocysteine-thiolactone (uHcy-thiolactone) and plasma cysteine (Cys) were associated with CLT.
- Plasma total homocysteine (tHcy) was associated with Absmax, independent of other risk factors.
- Increased baseline CLT and Absmax predicted higher rates of acute myocardial infarction and mortality.
- B-vitamin/folate therapy did not significantly affect CLT or Absmax.
Conclusions:
- Urinary homocysteine-thiolactone and plasma cysteine are novel determinants of CLT, a predictor of adverse CAD outcomes.
- CLT and Absmax are significant independent predictors of myocardial infarction and mortality in CAD patients.
- The lack of effect on CLT and Absmax may explain the inefficacy of B-vitamin/folate therapy in this CAD cohort.
Abstract:
Fibrin clot structure/function contributes to cardiovascular disease. We examined sulfur-containing metabolites as determinants of fibrin clot lysis time (CLT) and maximum absorbance (Absmax) in relation to outcomes in coronary artery disease (CAD) patients. Effects of B-vitamin/folate therapy on CLT and Absmax were studied. Plasma samples were collected from 1,952 CAD patients randomized in a 2 x 2 factorial design to (i) folic acid, vitamins B12, B6; (ii) folic acid, vitamin B12; (iii) vitamin B6; (iv) placebo for 3.8 years in the Western Norway B-Vitamin Intervention Trial. Clot lysis time (CLT) and maximum absorbance (Absmax) were determined using a validated turbidimetric assay. Acute myocardial infarction (AMI) and mortality were assessed during a 7-year follow-up. Data were analyzed using bivariate and multiple regression. Survival free of events was studied using Kaplan Mayer plots. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Baseline urinary homocysteine (uHcy)-thiolactone and plasma cysteine (Cys) were significantly associated with CLT while plasma total Hcy was significantly associated with Absmax, independently of fibrinogen, triglycerides, vitamin E, glomerular filtration rate, body mass index, age, sex plasma creatinine, CRP, HDL-C, ApoA1, and previous diseases. B-vitamins/folate did not affect CLT and Absmax. Kaplan-Meier analysis showed associations of increased baseline CLT and Absmax with worse outcomes. In Cox regression analysis, baseline CLT and Absmax (>cutoff) predicted AMI (CLT: HR 1.58, 95% CI 1.10-2.28; P = 0.013. Absmax: HR 3.22, CI 1.19-8.69; P = 0.021) and mortality (CLT: HR 2.54, 95% CI 1.40-4.63; P = 0.002. Absmax: 2.39, 95% CI 1.17-4.92; P = 0.017). After adjustments for other prognostic biomarkers these associations remained significant. Cys and uHcy-thiolactone, but not tHcy, were significant predictors of AMI in Cox regression models that included CLT. Conclusions uHcy-thiolactone and plasma Cys are novel determinants of CLT, an important predictor of adverse CAD outcomes. CLT and Absmax were not affected by B-vitamin/folate therapy, which could account for the lack of efficacy of such therapy in CAD. Trial registration: URL: http://clinicaltrials.gov. Identifier: NCT00354081.
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