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Platelet amyloid precursor protein is a modulator of venous thromboembolism in mice

Ilaria Canobbio, Caterina Visconte, Stefania Momi, Gianni Francesco Guidetti, Marta Zarà, Jessica Canino, Emanuela Falcinelli, Paolo Gresele and Mauro Torti

Key points

  • APP is dispensable for platelet activation and arterial thrombosis.

  • APP is an important novel regulator of vein thrombosis and controls coagulation and NETs formation.

Abstract

The amyloid precursor protein (APP), primarily known as the precursor of amyloid peptides that accumulate in the brain of Alzheimer's disease patients, is abundant in platelets but its physiological function remains unknown. In this study, we investigated the role of APP in hemostasis and thrombosis using APP knockout (KO) mice. Ex vivo aggregation, secretion, and integrin αIIbβ3 inside-out activation induced by several agonists were normal in APP-deficient platelets, but the number of circulating platelets was reduced by about 20%, and their size was slightly increased. Tail bleeding time was normal and, in vivo, the absence of APP did not alter thrombus formation in the femoral artery. By contrast, in a model of vein thrombosis induced by flow restriction in the inferior vena cava, APP-KO mice, as well as chimeric mice with selective deficiency of APP in blood cells, developed much larger thrombi than control animals, and were more sensitive to embolization. Consistent with this, in a pulmonary thromboembolism model, larger vessels were occluded. APP-KO mice displayed a shorter APTT, but not PT, when measured in the presence of platelets. Moreover, the activity of FXIa, but not FXIIa was higher in APP-KO mice compared to controls. APP-KO mice presented a higher number of circulating platelet-leukocyte aggregates and neutrophils displayed a greater tendency to protrude extracellular traps, that were more strongly incorporated into venous thrombi. These results indicate that platelet APP limits venous thromboembolism, through a negative regulation of both fibrin formation and neutrophil function.

  • Submitted January 26, 2017.
  • Accepted June 8, 2017.