Anti-GPVI-associated ITP: an acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRgamma-chain complex from the human platelet surface. Blood 2004 Sep 01;104(5):1350-5
Date
05/20/2004Pubmed ID
15150079DOI
10.1182/blood-2004-03-0896Scopus ID
2-s2.0-4444244926 (requires institutional sign-in at Scopus site) 143 CitationsAbstract
Platelet glycoprotein (GP) VI is a 62-kDa membrane glycoprotein that exists on both human and murine platelets in a noncovalent complex with the Fc receptor (FcR) gamma chain. The GPVI/FcRgamma-chain complex serves as the major activating receptor for collagen, as evidenced by observations that platelets genetically deficient in GPVI or the FcRgamma chain are highly refractory to collagen-induced platelet activation. Recently, several different rat anti-murine GPVI monoclonal antibodies, termed JAQs 1, 2, and 3, were produced that had the unique property of "immunodepleting" GPVI from the murine platelet surface and rendering it unresponsive to collagen or GPVI-specific agonists like convulxin or collagen-related peptide (CRP). Herein, we describe a patient with a mild bleeding disorder and a moderately reduced platelet count whose platelets fail to become activated in response to collagen or CRP and inefficiently adhere to and form thrombi on immobilized collagen under conditions of arterial shear. Although the amount of GPVI platelet mRNA and the nucleotide sequence of the GPVI gene were found to be normal, both GPVI and the FcRgamma chain were nearly absent from the platelet surface and were markedly reduced in wholeplatelet detergent lysates. Patient plasma contained an autoantibody that bound specifically to GPVI-positive, normal platelets, and cleared soluble GPVI from the plasma, suggesting that the patient suffers from a rare form of idiopathic thrombocytopenic purpura caused by a GPVI-specific autoantibody that mediates clearance of the GPVI/FcRgamma-chain complex from the platelet surface. Since antibody-induced GPVI shedding now has been demonstrated in both humans and mice, these studies may provide a rationale for developing therapeutic reagents that induce temporary depletion of GPVI for the treatment of clinical thrombosis.
Author List
Boylan B, Chen H, Rathore V, Paddock C, Salacz M, Friedman KD, Curtis BR, Stapleton M, Newman DK, Kahn ML, Newman PJAuthors
Brian Curtis PhD Director in the Platelet & Neutrophil Immunology Laboratory department at BloodCenter of WisconsinKenneth D. Friedman MD Professor in the Medicine department at Medical College of Wisconsin
Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAnimals
Antibodies, Monoclonal
Autoantibodies
Carrier Proteins
Collagen
Female
Humans
Mice
Peptides
Platelet Activation
Platelet Membrane Glycoproteins
Purpura, Thrombocytopenic, Idiopathic
Receptors, IgG