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Platelet receptor interplay regulates collagen-induced thrombus formation in flowing human blood.
- Source :
-
Blood [Blood] 2004 Feb 15; Vol. 103 (4), pp. 1333-41. Date of Electronic Publication: 2003 Oct 16. - Publication Year :
- 2004
-
Abstract
- The platelet glycoproteins (GPs) Ib, integrin alpha(2)beta(1), and GPVI are considered central to thrombus formation. Recently, their relative importance has been re-evaluated based on data from murine knockout models. To examine their relationship during human thrombus formation on collagen type I fibers at high shear (1000 s(-1)), we tested a novel antibody against GPVI, an immunoglobulin single-chain variable fragment, 10B12, together with specific antagonists for GPIb alpha (12G1 Fab(2)) and alpha(2)beta(1) (6F1 mAb or GFOGER-GPP peptide). GPVI was found to be crucial for aggregate formation, Ca(2+) signaling, and phosphatidylserine (PS) exposure, but not for primary adhesion, even with more than 97% receptor blockade. Inhibiting alpha(2)beta(1) revealed its involvement in regulating Ca(2+) signaling, PS exposure, and aggregate size. Both GPIb alpha and alpha(2)beta(1) contributed to primary adhesion, showing overlapping function. The coinhibition of receptors revealed synergism in thrombus formation: the coinhibition of adenosine diphosphate (ADP) receptors with collagen receptors further decreased adhesion and aggregation, and, crucially, the complete eradication of thrombus formation required the coinhibition of GPVI with either GPIb alpha or alpha(2)beta(1). In summary, human platelet deposition on collagen depends on the concerted interplay of several receptors: GPIb in synergy with alpha(2)beta(1) mediating primary adhesion, reinforced by activation through GPVI, which further regulates the thrombus formation.
- Subjects :
- Amino Acid Chloromethyl Ketones pharmacology
Antithrombins pharmacology
Calcium Signaling drug effects
Calcium Signaling physiology
Collagen Type I pharmacology
Humans
Integrin alpha2beta1 antagonists & inhibitors
Platelet Adhesiveness physiology
Platelet Glycoprotein GPIb-IX Complex antagonists & inhibitors
Platelet Glycoprotein GPIb-IX Complex metabolism
Platelet Membrane Glycoproteins antagonists & inhibitors
Pulsatile Flow
Purinergic P2 Receptor Antagonists
Receptors, Purinergic P2 metabolism
Blood Coagulation physiology
Integrin alpha2beta1 metabolism
Platelet Membrane Glycoproteins metabolism
Thrombosis metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 103
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 14563646
- Full Text :
- https://doi.org/10.1182/blood-2003-03-0889