Bradykinin (BK) liberates nitric oxide, prostacyclin, and tissue plasminogen activator from endothelial cells. We hypothesized that BK B2 receptor knockout (KO) mice (BKB2R^-/-) have increased thrombosis risk. Paradoxically, the BKB2R^-/- mice have long bleeding times and delayed carotid artery thrombosis, 78 ± 6.7 minutes, versus 31 ± 2.7 minutes in controls. The mechanism(s) for thrombosis protection was sought. In BKB2R^-/- plasma coagulation, fibrinolysis and anticoagulant proteins are normal except for an increased prekallikrein and decreased factor XI. BKB2R^-/- mice have elevated BK 1-5 (160 ± 75 fmol/mL, vs 44 ± 29 fmol/mL in controls) and angiotensin II (182 ± 41 pg/mL, vs 49 ± 7 pg/mL in controls). Ramipril treatment shortens vessel occlusion time. BKB2R^-/- mice have elevated plasma 6-keto-PGF_1α (666 ± 232 ng/mL, vs 23 ± 5.3 ng/mL in controls) and serum nitrate (61 ± 5.3 μM, vs 24 ± 1.8 μMin controls). Treatment with L-NAME (N^G-mono-methyl-l-arginine ester) or nimesulide shortens the thrombosis time. BKB2R^-/- mice have increased angiotensin receptor 2 (AT₂R) mRNA and protein expression. Treatment with an AT₂R antagonist, PD123 319, normalizes the thrombosis time and nitrate and 6-keto-PGF_1α. The long bleeding times in BKB2R^-/- mice also correct with L-NAME and nimesulide therapy. In BKB2R^-/- mice, angiotensin II binding to an overexpressed AT₂R promotes thromboprotection by elevating nitric oxide and prostacyclin. These investigations indicate a pathway for thrombosis risk reduction via the plasma kallikrein/kinin and renin angiotensin systems. (Blood. 2006;108:192-199)