Approximately 60% of all ischemic strokes are believed to be due to emboli. It is well established that the risk of embolic stroke increases with age. Although certain underlying conditions have been associated with a higher risk of embolism, the majority of embolic strokes occur in patients for whom no definite cause can be identified. Thus, it is imperative that markers of stroke risk be developed for this particular mechanism of cerebral infarction. In order to identify markers of embolic stroke risk, it is logical to focus on the hemostatic system, which regulates clot formation. Fibrinogen and von Willebrand factor (vWF) levels have been associated with a higher risk of ischemic stroke, and are elevated in highrisk cardiac conditions, such as atrial fibrillation. Recently, polymorphisms in the genes encoding vWF, fibrinogen, and factor XIII have been identified and linked to thrombotic events. These polymorphisms increase circulating levels of vWF and fibrinogen, respectively, and contribute to the formation of unstable thrombus due to ineffective fibrinogen to factor XIII crosslinking. In addition, a polymorphism of factor XHI has been identified, which increases its enzymatic activity and appears to result in the formation of unstable clot. The proposed project is a 5year, casecontrol study at a single academic medical center collecting genetic material and factor levels on consecutive cases of embolic stroke, nonembolic stroke, nonstroke controls. The Specific Aims of this project are to: 1) test the hypothesis that the allele frequencies for polymorphisms in the genes encoding vWF, fibrinogen, and factor XIII are higher in patients with embolic stroke than in nonembolic stroke subtypes or nonstroke controls, 2) test the hypothesis that the levels of vWF and fibrinogen will increase with age and that there will be an interaction between age and allele status affecting the vWF and fibrinogen levels, 3) establish the effects of conventional stroke risk factors on the expression of polymorphisms in the vWF, fibrinogen, and factor XIII genes, and 4) determine whether there is an association between allele status in the vWF, fibrinogen, and factor XIII polymorphisms and short-term death or recurrent stroke.