PMID- 14563646
OWN - NLM
STAT- MEDLINE
DCOM- 20040318
LR  - 20210206
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 103
IP  - 4
DP  - 2004 Feb 15
TI  - Platelet receptor interplay regulates collagen-induced thrombus formation in 
      flowing human blood.
PG  - 1333-41
AB  - 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.
FAU - Siljander, Pia R-M
AU  - Siljander PR
AD  - Department of Biochemistry, University of Cambridge, Main Bldg, Downing Site, 
      Tennis Court Rd, CB2 1QW Cambridge, United Kingdom. prms2@mole.bio.cam.ac.uk
FAU - Munnix, Imke C A
AU  - Munnix IC
FAU - Smethurst, Peter A
AU  - Smethurst PA
FAU - Deckmyn, Hans
AU  - Deckmyn H
FAU - Lindhout, Theo
AU  - Lindhout T
FAU - Ouwehand, Willem H
AU  - Ouwehand WH
FAU - Farndale, Richard W
AU  - Farndale RW
FAU - Heemskerk, Johan W M
AU  - Heemskerk JW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20031016
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Antithrombins)
RN  - 0 (Collagen Type I)
RN  - 0 (Integrin alpha2beta1)
RN  - 0 (Platelet Glycoprotein GPIb-IX Complex)
RN  - 0 (Platelet Membrane Glycoproteins)
RN  - 0 (Purinergic P2 Receptor Antagonists)
RN  - 0 (Receptors, Purinergic P2)
RN  - 0 (glycoprotein receptor GPIb-IX)
RN  - 0 (platelet membrane glycoprotein VI)
RN  - N62UL02WW4 (phenylalanyl-prolyl-arginine-chloromethyl ketone)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - Antithrombins/pharmacology
MH  - Blood Coagulation/*physiology
MH  - Calcium Signaling/drug effects/physiology
MH  - Collagen Type I/pharmacology
MH  - Humans
MH  - Integrin alpha2beta1/antagonists & inhibitors/*metabolism
MH  - Platelet Adhesiveness/physiology
MH  - Platelet Glycoprotein GPIb-IX Complex/antagonists & inhibitors/metabolism
MH  - Platelet Membrane Glycoproteins/antagonists & inhibitors/*metabolism
MH  - Pulsatile Flow
MH  - Purinergic P2 Receptor Antagonists
MH  - Receptors, Purinergic P2/metabolism
MH  - Thrombosis/*metabolism
EDAT- 2003/10/18 05:00
MHDA- 2004/03/19 05:00
CRDT- 2003/10/18 05:00
PHST- 2003/10/18 05:00 [pubmed]
PHST- 2004/03/19 05:00 [medline]
PHST- 2003/10/18 05:00 [entrez]
AID - S0006-4971(20)50157-2 [pii]
AID - 10.1182/blood-2003-03-0889 [doi]
PST - ppublish
SO  - Blood. 2004 Feb 15;103(4):1333-41. doi: 10.1182/blood-2003-03-0889. Epub 2003 Oct 
      16.