GPVI levels in platelets: relationship to platelet function at high shear.
We have investigated the density of the collagen receptors glycoprotein VI (GPVI) and alpha 2 beta 1 on human platelets and their relationship to polymorphisms within the GPVI gene. GPVI levels varied 1.5-fold and showed a weak correlation (r = 0.35) with the levels of alpha 2 beta 1, which varied 3-fold. GPVI genotype had a significant effect on receptor levels with carriers of the proline 219 allele (approximately 22% of the population) having 10% lower GPVI levels than the more common serine homozygotes. GPVI and alpha 2 beta 1 levels were found to be significantly decreased on platelets from patients with myeloproliferative disorders (MPDs). In both the MPD and the control group, GPVI levels were found not to affect platelet function under high shear in whole blood. Similarly murine platelets that express up to 5-fold lower levels of GPVI showed no significant difference than controls in thrombus formation on a high-density collagen-coated surface. However platelets lacking the GPVI/Fc receptor gamma-chain (FcR gamma-chain) complex or a functional FcR gamma-chain (immunoreceptor tyrosine-based activation motif [ITAM] point mutant) exhibited severely abrogated thrombus formation at 800 s-1 and 1500 s-1. These results demonstrate that GPVI levels are tightly controlled and play a critical role in thrombus formation on collagen; nevertheless, a range of receptor densities can support platelet function under high shear.
Best
Denise
D
Department of Pharmacology, Oxford University, Mansfield Rd, Oxford, OX1 3QT, United Kingdom. denise.best@pharmacology.ox.ac.uk
Senis
Yotis A
YA
Jarvis
Gavin E
GE
Eagleton
Helen J
HJ
Roberts
David J
DJ
Saito
Takashi
T
Jung
Stephanie M
SM
Moroi
Masaaki
M
Harrison
Paul
P
Green
Fiona R
FR
Watson
Steve P
SP
D000483:Alleles; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion; D003094:Collagen / Q000378:metabolism; D003435:Crotalid Venoms / Q000378:metabolism; D005434:Flow Cytometry; D014644:Genetic Variation; D005838:Genotype; D006023:Glycoproteins / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009196:Myeloproliferative Disorders / Q000097:blood; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011392:Proline; D012694:Serine; D013314:Stress, Mechanical; D013927:Thrombosis / Q000378:metabolism; D014162:Transfection; D014841:von Willebrand Factor / Q000737:chemistry
D003435:Crotalid Venoms; D006023:Glycoproteins; D038982:Integrin alpha2beta1; D037181:Lectins, C-Type; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D014841:von Willebrand Factor; C028890:convulxin; D012694:Serine; D003094:Collagen; D011392:Proline