The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion.
Platelet interaction with exposed adhesive ligands at sites of vascular injury is required to initiate a normal hemostatic response and may become a pathogenic factor in arterial diseases leading to thrombosis. We report a targeted disruption in a key receptor for collagen-induced platelet activation, glycoprotein (GP) VI. The breeding of mice with heterozygous GP VI alleles produced the expected frequency of wild-type, heterozygous, and homozygous genotypes, indicating that these animals had no reproductive problems and normal viability. GP VInull platelets failed to aggregate in response to type I fibrillar collagen or convulxin, a snake venom protein and known platelet agonist of GP VI. Nevertheless, tail bleeding time measurements revealed no severe bleeding tendency as a consequence of GP VI deficiency. Ex vivo platelet thrombus formation on type I collagen fibrils was abolished using blood from either GP VInull or FcR-gammanull animals. Reflection interference contrast microscopy revealed that the lack of thrombus formation by GP VInull platelets could be linked to a defective platelet activation following normal initial tethering to the surface, visualized as lack of spreading and less stable adhesion. These results illustrate the role of GP VI in postadhesion events leading to the development of platelet thrombi on collagen fibrils.
Kato
Kazunobu
K
Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Kanaji
Taisuke
T
Russell
Susan
S
Kunicki
Thomas J
TJ
Furihata
Kenichi
K
Kanaji
Sachiko
S
Marchese
Patrizia
P
Reininger
Armin
A
Ruggeri
Zaverio M
ZM
Ware
Jerry
J
D000818:Animals; D000911:Antibodies, Monoclonal; D001853:Bone Marrow; D018955:CD36 Antigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D016296:Mutagenesis; D010973:Platelet Adhesiveness / Q000502:physiology*; D038981:Receptors, Collagen / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D018955:CD36 Antigens; D038981:Receptors, Collagen; D017452:Receptors, IgG; D011994:Recombinant Proteins; D003094:Collagen