Anti-GPVI–associated ITP: an acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRγ-chain complex from the human platelet surface

Abstract

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) ␥ chain. The GPVI/FcR␥-chain complex serves as the major activating receptor for collagen, as evidenced by observations that platelets genetically deficient in GPVI or the FcR␥ 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 FcR␥ 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 GPVIspecific autoantibody that mediates clearance of the GPVI/FcR␥-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.

Antigen Modulation Confers Protection to Red Blood Cells from Antibody through Fcγ Receptor Ligation

“…In particular, target tissues appear to possess the ability to alter the autoantigen(s) or alloantigen(s) being recognized such that Ab binding is substantially decreased or eliminated. Such pathways have been observed for nicotinic cholinergic receptors in myasthenia gravis (19,20), Ags on platelets during idiopathic thrombocytopenic purpura (21), and Ags on RBCs during autoimmune hemolytic anemia (22). Similar pathways have been observed in response to alloantibodies as well, which may play a role in transplanted organs "accommodating" over time to alloantibodies (23,24).…”

“…Ag modulation has been difficult to study in vivo, because the target cells typically have ongoing synthesis of the target Ag, resulting in steady state equilibria that complicate analysis of the fate of particular Ag molecules (21,25). Moreover, as target cells have ongoing division, tracking their numerical destruction over time (or lack thereof) after Ab binding is likewise challenging (21,25).…”

“…Moreover, as target cells have ongoing division, tracking their numerical destruction over time (or lack thereof) after Ab binding is likewise challenging (21,25). To circumvent both of these limitations, we have made specific use of a model of Ag modulation using RBCs as cellular targets.…”

Anti–protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis

“…16,17 Human platelets supplemented with heparin (0.6 IU/mL), protamine (6 mg/mL), heparin (0.6 IU/mL) and protamine (6 mg/mL), or buffer were injected into NOD/SCID mice (The Jackson Laboratory, Bar Harbor, Maine). After 30 minutes (baseline), the IgG fraction of anti-protamineheparin antibody-positive sera (or controls) was intraperitoneally injected.…”

Braking platelet activation: deactivating the receptors

“…This predicts blunted collagen-induced platelet activation in HIT patients, a finding of considerable interest and in need of further supporting evidence. Also relevant in this context are the previous observations that GPVI antibody depletes platelet GPVI in vivo and decreases collagen responses in immune thrombocytopenic purpura (ITP) patients 2,3 and in mouse models, 4,5 and that GPVI antibody has an antithrombotic effect. 5 Proteolytic cleavage of GPVI is the mechanism in at least some of these studies.…”