In this study, thrombotic risk was systematically assessed in two inbred strains of mice that have marked differences in susceptibility to diet-induced obesity, diet-induced atherosclerosis, and ligation-induced neointimal hyperplasia and vessel remodeling. Arterial occlusion time, tail bleeding and rebleeding time were evaluated as potential predictors of thrombotic response. Assessments of the two inbred strains were compared to values from gene targeted mice of the Plg network with altered fibrinolytic responses, as well as in leptin deficient mice with a reduced platelet function. Marked differences were found in the thrombotic response among the two inbred strains, B6 and A/J, and the observed differences were not correlated with change in coagulation or platelet function. Screening the CSS identified three chromosomes that harbored genes which contributed to the A/J phenotype of increased rebleeding time. Mice homosomic for these chromosomes or doubly heterosomic for two of the chromosomes, 5 and 17, were required to express the A/J phenotype, elevated rebleeding time. PAI-1 antigen and activity were decreased in both CSS-5 and CSS-17 and the heterosomic mice, CSS-5F1 and CSS-17F1, but not in the CSS-11 strain. Values were restored in the doubly heterosomic for two of chromosomes, 5 and 17. Arterial occlusion time was similar to B6 in the CSS-5 and CSS-17 homozygous strains, but increased in doubly heterosomic for two of chromosomes, 5 and 17.