Bleeding is increased in amyloid precursor protein knockout mouse

• Main Authors: Nima Mazinani, Amy W. Strilchuk, James R. Baylis, Woosuk S. Hur, Wilfred A. Jefferies, Christian J. Kastrup
• Format: Article
• Language: English
• Published: Wiley 2020-07-01
• Series: Research and Practice in Thrombosis and Haemostasis
• Subjects: blood coagulation; cerebral amyloid angiopathy; fibrinolysis; hemorrhage; neurodegenerative diseases; thrombosis
• Online Access: https://doi.org/10.1002/rth2.12375

Abstract Background Amyloid precursor protein (APP) is highly expressed in platelets. APP is the precursor to amyloid beta (Aβ) peptides that accumulate in cerebral amyloid angiopathy and plaques in Alzheimer disease. APP and its metabolites interact with many components of the coagulation system, and have both anticoagulant and procoagulant properties, but it is unclear if APP contributes to hemostasis in vivo. Objectives To determine whether APP contributes to hemostasis in mice, including when inhibitors of coagulation are administered. Methods Blood loss in APP knockout (KO) mice was measured in liver laceration and tail transection models of hemorrhage. Blood loss was also measured following tail transection in mice given an inhibitor of coagulation factor Xa (apixaban), platelet inhibitors (aspirin + clopidogrel), tissue‐type plasminogen activator (t‐PA), or the antifibrinolytic tranexamic acid (TXA). Results and Discussion Blood loss from liver lacerations was similar between APP KO mice and wild‐type (WT) mice, but APP KO mice bled more from tail transections. When mice were challenged with aspirin + clopidogrel, the difference in bleeding between APP KO and WT mice was abrogated. In contrast, a difference in bleeding between the strains persisted when mice were treated with apixaban, t‐PA, or TXA. Blood collected from APP KO mice and analyzed with thromboelastography had longer clotting times, and the clots were less stiff and more susceptible to fibrinolysis compared to blood from WT mice. Conclusions The absence of APP measurably increases bleeding in mice, which is consistent with a role for platelet‐derived APP and Aβ peptides in hemostasis.