We examined the relationship between free protein S deficiency and cerebrovascular disease by reviewing the records of all patients with the diagnoses of cerebral thrombosis, cerebral embolism, and cerebral vascular occlusion who were referred for coagulation studies over a 12-month period. We assayed for free protein S antigen, protein C antigen, and antithrombin III and tested for lupus-like anticoagulant and anticardiolipin antibody. Twenty-two of 267 patients (8.2%) admitted with thrombotic strokes were referred for coagulation studies. Free protein S antigen was significantly lower in women than in men (62 +/- 25% versus 88 +/- 24%, p = 0.03; n = 11 in each group). Six women had free protein S antigen levels below the range recorded for a contemporary group of 24 age-matched normal women (17 to 59% versus 70 to 102%, p less than 0.001); four of these women had cerebral arterial thrombosis and two had venous dural sinus thrombosis. The six women were aged 29 to 55 at the time of their first strokes; two had family members with protein S deficiency, and one of these had died of a stroke at age 52. Other abnormalities in this population included a positive test for lupus-like anticoagulant or anticardiolipin in five patients, a modest decrease in protein S in two men, and one patient with an isolated deficiency of antithrombin III. We conclude that protein S deficiency may be an important risk factor for stroke in middle-aged women but this requires confirmation by prospective studies in unselected patients.

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