Increased Severity of Hemorrhage in Transgenic Mice Expressing Cerebral Protease Nexin-2/Amyloid -Protein Precursor

Background and Purpose—Secreted isoforms of amyloid -protein precursor (A PP) that contain the Kunitz proteinase inhibitor domain, also known as protease nexin-2 (PN2), are enriched in brain. Although little is known of its physiological function, the potent inhibition of certain prothrombotic proteinases by PN2/A PP suggests that it may function to regulate cerebral thrombosis during vascular injury events. Methods—To examine the antithrombotic function of cerebral PN2/A PP in vivo, we performed measurements of carotid artery thrombosis and experimental intracerebral hemorrhage in transgenic mice with specific and modest overexpression of PN2/A PP in brain. Comparisons were made with wild-type mice and Tg-rPF4/APP mice, a model that possesses specific and modest overexpression of PN2/A PP in platelets and exhibits reduced thrombosis in vivo. Results—Modest overexpression of PN2/A PP in transgenic mouse brain had no effect on intraluminal carotid arterial thrombosis but resulted in larger hematoma volumes and hemoglobin levels (23.1 2.7 mm [n 6; P 0.01] and 1411 202 g/hemisphere [n 12; P 0.01], respectively), compared with wild-type mice (15.9 2.2 mm [n 6] and 935 418 g/hemisphere [n 12], respectively). Conclusions—These findings indicate that cerebral PN2/A PP plays a significant role in regulating thrombosis in brain and that modest age-related increases in the cerebral levels of this protein could markedly enhance the extent of cerebral hemorrhage. (Stroke. 2007;38:2598-2601.)