Glycoprotein V is a relevant immune target in patients with immune thrombocytopenia

Abstract

Platelet autoantibody-induced platelet clearance represents a major pathomechanism in immune thrombocytopenia (ITP). There is growing evidence for clinical differences between anti-glycoprotein IIb/IIIa and anti-glycoprotein Ib/IX mediated ITP. Glycoprotein V is a well characterized target antigen in Varicella-associated and drug-induced thrombocytopenia. We conducted a systematic study assessing the prevalence and functional capacity of autoantibodies against glycoprotein V. A total of 1140 patients were included. In one-third of patients, platelet-bound autoantibodies against glycoproteins Ib/IX, IIb/IIIa, or V were detected in a monoclonal antibody immobilization of platelet antigen assay; platelet-bound autoantiglycoprotein V was present in the majority of samples (222 out of 343, 64.7%). Investigation of patient sera revealed the presence of free autoantibodies against glycoprotein V in 13.5% of these patients by an indirect monoclonal antibody immobilization of platelet antigen assay, but in 39.6% by surface plasmon resonance technology. These antibodies showed significantly lower avidity (association/dissociation ratio 0.32±0.13 vs . 0.73±0.14; P <0.001). High- and low-avidity antibodies induced comparable amounts of platelet uptake in a phagocytosis assay using CD14 + positively-selected human macrophages [mean phagocytic index, 6.81 (range, 4.75-9.86) vs . 6.01 (range, 5.00-6.98); P =0.954]. In a NOD/SCID mouse model, IgG prepared from both types of anti-glycoprotein V autoantibodies eliminated human platelets with no detectable difference between the groups from the murine circulation [mean platelet survival at 300 minutes, 40% (range, 27-55) vs . 35% (16-46); P =0.025]. Our data establish glycoprotein V as a relevant immune target in immune thrombocytopenia. We would suggest that further studies including glycoprotein V will be required before ITP treatment can be tailored according to platelet autoantibody specificity.

Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments

“… 8 Anti-GPV antibodies have recently been detected in ITP patients: they were associated with anti-GPIb/IX in most of the cases, and were the unique antiplatelet antibody detected in only 2.9% of the patients. 9 Despite their lower avidity to platelets, their involvement in platelet destruction has been confirmed in a murine model. 9 …”

FcγRI and FcγRIII on splenic macrophages mediate phagocytosis of anti-glycoprotein IIb/IIIa autoantibody-opsonized platelets in immune thrombocytopenia

“… 1 IgG autoantibodies are detected in up to 81% of patients with ITP by the direct monoclonal antibody immobilization of platelet antigens (MAIPA) assay, 2 and target several platelet glycoproteins (GP) including GPIIb/IIIa, GPIb/IX, and GPV. 2 , 3 While anti-GPIb antibodies can mediate FcγR-independent modes of platelet clearance, 4 anti-GPIIb/IIIa autoantibodies are presumed to drive FcγR-dependent platelet clearance through mononuclear phagocytes in the spleen (splenic macrophages). However, the role of specific types of FcγR in the phagocytosis of autoantibodyopsonized platelets is unknown.…”

Integrative Genomic Analysis and Functional Studies Reveal GP5, GRN, MPO and MCAM as Causal Protein Biomarkers for Platelet Traits

“…Mutations in GP5 are not known to cause Bernard-Soulier syndrome (enlarged platelets associated with bleeding and thrombocytopenia) unlike other gene members of the GPIb-V-IX complex. However, prior and recent work has suggested that alloantibodies targeting GP5 40 , as well as pediatric varicella 41 , gold-triggered autoimmune responses in rheumatoid arthritis 42 , and quinidine-related platelet directed antibodies 43 may trigger immune thrombocytopenia via GP5. These studies suggest that GP5 alterations may trigger platelet clearance, and that maintenance of normal GP5 function or high levels on platelets could preserve platelet numbers in circulation.…”