on May 17, 2007
Published online before print May 17, 2007, doi: 10.1161/ATVBAHA.107.143479
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Submitted on November 30, 2006
Accepted on May 3, 2007
Activation of Human Platelets by Misfolded Proteins
Eszter Herczenik ;
From the Thrombosis and Haemostasis Laboratory, Department of Clinical Chemistry and Haematology (E.H., B.B., S.J.A.K., M.F.B.G.G., J.-W.N.A.), University Medical Center Utrecht, Crossbeta Biosciences B.V. (B.B., R.S., M.F.B.G.G.), Crystal and Structural Chemistry (Q.Z., P.G.), Bijvoet Center of Biomolecular Research, Utrecht University, Utrecht, and the Division of Biopharmaceutics (M.V.E., T.J.C.VB.), Leiden Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, The Netherlands.
* To whom correspondence should be addressed. E-mail: j.w.n.akkerman{at}umcutrecht.nl.
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.
Methods and 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), p38MAPK (SB203580), COX-1 (indomethacin), and glycoprotein Ib
(Nk-protease, 6D1 antibody) induced 
50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of IIb
3-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, p38MAPK, thromboxane A2-mediated induction of aggregation; the other is through glycoprotein Ib-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.
Key words: amyloid • platelet activation • sRAGE • tissue plasminogen activator • CD36 • glycoprotein Ib
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