Atherothrombotic risk factor clustering in healthy male relatives of male patients with intermittent claudication

Objective: Family history is an independent risk factor for premature acute myocardial infarction; in contrast, familial risk for peripheral arterial disease (PAD) has yet to be determined. Elevated levels of hemostatic proteins are consistently predictive for cardiovascular risk in "healthy" subjects, and may cluster with underlying insulin resistance. Atherothrombotic risk factor clustering occurs in first-degree relatives of subjects with coronary artery disease and type 2 diabetes. These may contribute to the enhanced cardiovascular risk in these subjects, and we hypothesised that familial clustering may occur in PAD. The objective of this study was to measure atherothrombotic risk factors in healthy male first-degree relatives of men with intermittent claudication, with emphasis on thrombotic risk. Methods. One hundred sixty-five healthy male first-degree relatives were compared with control subjects matched for age, sex, and race (n = 165), free from a personal or family history of premature cardiovascular disease. Primary outcome measures were fibrinogen, von Willebrand factor, factor VII clotting activity (FVII:C), and factor XIII levels. Atherosclerotic risk factors were measured, and subjects were genotyped for common functional polymorphisms (factor VII r353q and fibrinogen B beta-455). Results. Relatives had higher mean levels of fibrinogen (3.04 vs 2.89 g/L; P =.021), FVII:C (117% vs 104%; P = .000), factor XIII B subunit (1.11 vs 1.01 IU/mL; P = .000), and complex (A(2)B(2); 1.18 vs 1.11 IU/mL; P =.021). At multivariate analysis the association between relative status and fibrinogen, FVII:C, and factor XIII B subunit levels were independent of other variables. Conclusions. The healthy male relatives of men with PAD have elevated levels of fibrinogen, factor VII, and factor XIII. Our results support the existence of thrombotic risk factor clustering in this population at "high risk."