title: GPVI-deficient mice lack collagen responses and are protected against experimentally induced pulmonary thromboembolism.
abstract: Platelet glycoprotein VI (GPVI) is now considered to be a major player in platelet-collagen adhesive interactions leading to thrombus formation. GPVI blockade, or its depletion, has been shown in mice to result in complete protection against arterial thrombosis, without significant prolongation of bleeding time. GPVI may therefore represent a useful antithrombotic target. In order to reaffirm the role of GPVI in platelet-collagen interactions, we developed GPVI(null) mice by targeted disruption methodology. GPVI(null) mice platelets failed to respond to a high dose of fibrillar collagen, or convulxin, a GPVI agonist, but showed a normal response to other agonists such as ADP, PMA and arachidonic acid. We report, for the first time, that a proportion of GPVI(null) mice is protected against lethal thromboembolism, induced by the infusion of a mixture of collagen and epinephrine. Greater than 55% of GPVI(null) mice survived the challenge, whereas the maximal survival from the other genotypes was 17% (n=18 per genotype). Washed platelets obtained from GPVI(null) mice showed >90% reduction in adhesion to fibrillar collagen under static conditions. Platelet adhesion to collagen under dynamic conditions using a high shear rate (2600 s(-1)) was dramatically reduced using blood from GPVI(null) mice, while platelets from wild-type and heterozygous animals showed a similar amount of adhesion. Animals from each genotype had essentially similar tail bleeding time, suggesting that a complete deficiency of GPVI, at least in mice, does not result in an enhanced bleeding tendency. These observations clearly establish that blockade of GPVI may attenuate platelet-collagen interactions without adversely affecting the bleeding time.
authors.affiliation: Otsuka Maryland Medicinal Laboratories, 9900 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Lockyer
authors.forename: Keiji
authors.initials: K
authors.lastname: Okuyama
authors.forename: Shahinoor
authors.initials: S
authors.lastname: Begum
authors.forename: Sang
authors.initials: S
authors.lastname: Le
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Masuhiro
authors.initials: M
authors.lastname: Yoshitake
authors.forename: Junichi
authors.initials: J
authors.lastname: Kambayashi
authors.forename: Narendra N
authors.initials: NN
authors.lastname: Tandon
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D024022:Fibrillar Collagens; D051379:Mice; D018345:Mice, Knockout; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D011655:Pulmonary Embolism / Q000139:chemically induced* / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D024022:Fibrillar Collagens; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI