Anti-GPVI-associated ITP: an acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRgamma-chain complex from the human platelet surface.
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.
Boylan
Brian
B
Blood Research Institute, The Blood Center of Southeastern Wisconsin, PO Box 2178, 638 N 18th St, Milwaukee, WI 53201, USA.
Chen
Hong
H
Rathore
Vipul
V
Paddock
Cathy
C
Salacz
Michael
M
Friedman
Kenneth D
KD
Curtis
Brian R
BR
Stapleton
Michelle
M
Newman
Debra K
DK
Kahn
Mark L
ML
Newman
Peter J
PJ
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D002352:Carrier Proteins / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects / Q000276:immunology; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D002352:Carrier Proteins; D010455:Peptides; D010980:Platelet Membrane Glycoproteins; D017452:Receptors, IgG; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; D003094:Collagen