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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1657.)
© 2007 American Heart Association, Inc.

Thrombosis

Activation of Human Platelets by Misfolded Proteins

Eszter Herczenik; Barend Bouma; Suzanne J.A. Korporaal; Remo Strangi; Qinghong Zeng; Piet Gros; Miranda Van Eck; Theo J.C. Van Berkel; Martijn F.B.G. Gebbink; Jan-Willem N. Akkerman

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.

Correspondence to Prof Dr Jan-Willem N. Akkerman, Laboratory of Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology - G03.550, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. 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), p38^MAPK (SB203580), COX-1 (indomethacin), and glycoprotein Ib (Nk-protease, 6D1 antibody) induced 50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of _IIbß₃-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–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.

Protein misfolding is a common feature in Alzheimer disease, atherosclerosis, diabetes mellitus, and systemic amyloidosis. These diseases are associated with platelet hyperactivity. This study demonstrates that amyloid properties in proteins represent a novel platelet activating property. These properties explain the increased platelet activation in many diseases with appearance of misfolded proteins.

Key Words: amyloid • platelet activation • sRAGE • tissue plasminogen activator • CD36 • glycoprotein Ib

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