title: Activation of human platelets by misfolded proteins.
abstract: OBJECTIVE
  Protein misfolding diseases result from the deposition of insoluble protein aggregates that often contain fibrils called amyloid. Amyloids are found in Alzheimer disease, atherosclerosis, diabetes mellitus, and systemic amyloidosis, which are diseases where platelet activation might be implicated.
  
  
  RESULTS
  We induced amyloid properties in 6 unrelated proteins and found that all induced platelet aggregation in contrast to fresh controls. Amyloid-induced platelet aggregation was independent of thromboxane A2 formation and ADP secretion but enhanced by feedback stimulation through these pathways. Treatments that raised cAMP (iloprost), sequestered Ca2+ (BAPTA-AM) or prevented amyloid-platelet interaction (sRAGE, tissue-type plasminogen activator [tPA]) induced almost complete inhibition. Modulation of the function of CD36 (CD36-/- mice), p38(MAPK) (SB203580), COX-1 (indomethacin), and glycoprotein Ib alpha (Nk-protease, 6D1 antibody) induced approximately 50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of alphaIIb beta3-independent aggregation (agglutination).
  
  
  CONCLUSIONS
  Protein misfolding resulting in the appearance of amyloid induces platelet aggregation. Amyloid activates platelets through 2 pathways: one is through CD36, p38(MAPK), thromboxane A2-mediated induction of aggregation; the other is through glycoprotein Ib alpha-mediated aggregation and agglutination. The platelet stimulating properties of amyloid might explain the enhanced platelet activation observed in many diseases accompanied by the appearance of misfolded proteins with amyloid.
authors.affiliation: Laboratory of Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Eszter
authors.initials: E
authors.lastname: Herczenik
authors.forename: Barend
authors.initials: B
authors.lastname: Bouma
authors.forename: Suzanne J A
authors.initials: SJ
authors.lastname: Korporaal
authors.forename: Remo
authors.initials: R
authors.lastname: Strangi
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Zeng
authors.forename: Piet
authors.initials: P
authors.lastname: Gros
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Martijn F B G
authors.initials: MF
authors.lastname: Gebbink
authors.forename: Jan-Willem N
authors.initials: JW
authors.lastname: Akkerman
mesh_terms: D000682:Amyloid / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D012016:Reference Values; D012680:Sensitivity and Specificity; D013928:Thromboxane A2 / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism
chemical_list: D000682:Amyloid; D018955:CD36 Antigens; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D013928:Thromboxane A2; D010959:Tissue Plasminogen Activator