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The precise mechanism for reduced thrombosis in prekallikrein null mice (Klkb1^−/−) is unknown. Klkb1^−/− mice have delayed carotid artery occlusion times on the rose bengal and ferric chloride thrombosis models. Klkb1^−/− plasmas have long-activated partial thromboplastin times and defective contact activation–induced thrombin generation that partially corrects upon prolonged incubation. However, in contact activation–induced pulmonary thromboembolism by collagen/epinephrine or long-chain polyphosphate, Klkb1^−/− mice, unlike F12^−/− mice, do not have survival advantage. Klkb1^−/− mice have reduced plasma BK levels and renal B2R mRNA. They also have increased expression of the renal receptor Mas and plasma prostacyclin. Increased prostacyclin is associated with elevated aortic vasculoprotective transcription factors Sirt1 and KLF4. Treatment of Klkb1^−/− mice with the Mas antagonist A-779 …