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), μm/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.Clinical Relevance:
This study furthers our understanding of the pathophysiology of peripheral arterial disease, and is supported by our previous work on abnormalities in fibrin clot structure in the formation and progression of coronary artery disease. The study highlights the possible contribution of familial factors through transmission of an abnormal clot structure to the development of symptomatic cardiovascular disease. Most importantly, this work identifies the apparently healthy FDR group of the population as potentially at high cardiovascular risk and raises the question regarding the need for primary prevention in this group.