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Dependence of platelet thrombus stability on sustained glycoprotein IIb/IIIa activation through adenosine 5'-diphosphate receptor stimulation and cyclic calcium signaling.

Abstract：

OBJECTIVES:We sought to evaluate the mechanisms that support the stability of platelet aggregates on a thrombogenic surface exposed to flowing blood. BACKGROUND:Activation of the membrane glycoprotein (GP) IIb/IIIa--mediated in part through the P2Y1 and P2Y12 adenosine 5'-diphosphate (ADP) receptors--is necessary for platelet aggregation. Platelets in growing thrombi exhibit cyclic calcium signal, suggesting that sustained activation may be required for thrombus stability. METHODS:Blood was perfused over type I collagen fibrils at the wall shear rate of 1,500 s(-1). Three-dimensional visualization of platelet thrombi was obtained in real time with confocal microscopy. The intracytoplasmic Ca2+ concentration ([Ca2+]i) was measured in fluo-3AM-loaded platelets. RESULTS:The height of platelet thrombi in control blood was 13.5 +/- 3.3 microm after 6 min, and increased to 16.3 +/- 4.5 microm (n = 8) after an additional 6 min. In contrast, the height was reduced to 5.4 +/- 2.2 and 3.3 +/- 1.3 microm, respectively (p < 0.01, n = 8), when the blood used in the second 6-min perfusion contained a P2Y1 (MRS2179) or P2Y12 (AR-C69931MX) inhibitor. The [Ca2+]i of platelets within forming thrombi oscillated between 212 +/- 38 nmol/l and 924 +/- 458 nmol/l, with cycles lasting 4.2 +/- 2.8 s that were inhibited completely by AR-C69931MX and partially by MRS2179. Accordingly, thrombi became unstable upon perfusion of blood containing the Ca2+ channel blocker, lanthanum chloride. Flow cytometric studies demonstrated that AR-C69931MX, MRS2179, and lanthanum chloride reduced monoclonal antibody PAC-1 binding to platelets, indicating a decrease of membrane-expressed activated GP IIb/IIIa. CONCLUSIONS:Continuous P2Y1 and P2Y12 stimulation resulting in cyclic [Ca2+]i oscillations is required for maintaining the activation of GP IIb/IIIa needed for thrombus stability in flowing blood.

journal_name

J Am Coll Cardiol

journal_title

Journal of the American College of Cardiology

authors

Goto S,Tamura N,Ishida H,Ruggeri ZM

doi

10.1016/j.jacc.2005.08.055

subject

Has Abstract

pub_date

2006-01-03 00:00:00

pages

155-62

issue

eissn

0735-1097

issn

1558-3597

pii

S0735-1097(05)02428-9

journal_volume

pub_type

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Dependence of platelet thrombus stability on sustained glycoprotein IIb/IIIa activation through adenosine 5'-diphosphate receptor stimulation and cyclic calcium signaling.