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Experimental and Imaging Techniques for Examining Fibrin Clot Structures in Normal and Diseased States
Published on: April 1, 2015
Altered fibrin clot structure and function in the healthy first-degree relatives of subjects with intermittent
Neeraj Bhasin1, Robert A S Ariëns, Robert M West
1Division of Cardiovascular and Diabetes Research, University of Leeds, Leeds Vascular Institute, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, West Yorkshire, United Kingdom.
Insights
Healthy relatives of individuals with intermittent claudication (IC) exhibit abnormal fibrin clot structures, including thicker fibers and increased resistance to breakdown. These findings suggest a potential genetic link to peripheral arterial disease and elevated cardiovascular risk in these individuals.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Hematology
Background:
- First-degree relatives (FDR) of individuals with intermittent claudication (IC) show increased cardiovascular risk factors and events.
- The role of genetic factors in peripheral arterial disease (PAD) is not well-defined.
- Fibrin clot structure is influenced by genetics and is central to the atherothrombotic process.
Purpose of the Study:
- To investigate whether healthy male FDR of subjects with IC have abnormalities in their fibrin clot structure.
- To explore potential genetic underpinnings of PAD by examining clot characteristics in at-risk family members.
Main Methods:
- A case-control family study involving 106 healthy male FDR of male IC subjects and 107 age-matched male controls.
- Ex vivo assays were performed on plasma to assess fibrin clot permeation, fiber thickness, factor XIII (FXIII) cross-linking activity, and fibrinolysis.
- Linear regression analysis was used to identify factors associated with observed clot parameters.
Main Results:
- FDR exhibited significantly thicker fibrin fibers (405.1 nm vs 315.8 nm) and increased FXIII cross-linking activity (133% vs 105%) compared to controls.
- Fibrin clots from FDR showed reduced fibrinolysis, with a slower lysis front velocity (4.83 µm/min vs 12.66 µm/min).
- Cholesterol levels were associated with alterations in specific fibrin clot parameters.
Conclusions:
- Healthy FDR of IC subjects produce fibrin clots with thicker fibers, enhanced cross-linking, and impaired fibrinolysis, suggesting a potential genetic basis for PAD.
- These structural clot abnormalities in apparently healthy FDR indicate an elevated cardiovascular risk.
- Cholesterol may play a role in the development of these abnormal clot structures, contributing to increased cardiovascular risk in this population.
Objective:
Studies report clustering of cardiovascular risk factors and increased cardiovascular events in healthy first-degree relatives (FDR) of subjects with intermittent claudication (IC). Family history is an independent risk factor in coronary artery disease but the role of genetic factors is undefined in peripheral arterial disease. The fibrin clot is the final product of the atherothrombotic process and is subject to genetic influence. We proposed that healthy male FDR of subjects with IC possess abnormalities in their fibrin clots.
Methods:
This was a case-control family study. The FDR were recruited from claudicants attending vascular surgery out-patient clinics with the control subjects being recruited from the local primary care register. A total of 106 white European male FDR of male subjects with IC were age matched with 107 white European male control subjects from an identical geographic area. The control subjects had no FDR with a history of symptomatic cardiovascular disease, and subjects from both groups were free from a personal history of symptomatic cardiovascular disease or diabetes mellitus. Ex vivo assays for fibrin clot permeation, fiber thickness, factor XIII cross-linking activity, and fibrinolysis were performed on the plasma of the above subjects. In addition, linear regression analysis was undertaken to determine factors associated with clot parameters.
Results:
For controls and FDR, respectively, fiber thickness by turbidity was 0.75 (0.67-0.93) vs 0.86 (0.75-0.98) (P < .001), and FXIII cross-linking activity was 105% (87-141) vs 133% (103-155) (P < .001). On confocal microscopy, fibers measured 315.8 (307.0-324.6) vs 405.1 (397.6-412.6) nm (P < .001), and lysis front velocity was 12.66 (6.38-18.94) vs 4.83 (2.50-7.17), mum/min (P = .018). Linear regression analysis revealed cholesterol was associated with changes in certain clot parameters.
Conclusion:
The healthy FDR of subjects with IC produce clots which have thicker fibers, increased cross-linking, and resistance to fibrinolysis when compared to controls. This supports the potential genetic basis of peripheral arterial disease and highlights that cholesterol may contribute to this abnormal structure. This suggests that the FDR of subjects with IC, an apparently healthy sub-group of the population, have an elevated cardiovascular risk associated with abnormalities in their clot structure.
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