Page 22 - 2019_06-Haematologica-web

Editorials
Figure 1. GPV, a major target for autoantibodies in immune thrombocytopenia (ITP). (Left) Representation of a platelet showing the two principal receptor targets for platelet autoantibodies. Vollenberg et al.,4 while confirming the abundance of autoantibodies detected by direct MAIPA in a series of 343 positive samples from among 1140 tested ITP patients, also showed a significant presence of antibodies to GPV. (Middle) The GPIb-IX-V complex showing the presence of anti-GPV antibody and highlighting binding or cleavage sites for thrombin and metalloproteases ADAM10 and ADAM17. Vollenberg et al.4 raise questions as to the consequences of bound autoantibodies on GPV structure, the cleavage of released soluble forms, and a potential desialylation of the subunits on platelet survival in ITP. (Right) The detection of both high avidity autoantibodies to GPV by MAIPA and additional low avidity antibodies by surface plasmon resonance (SPR) technology is intriguing, as both of these appear to contribute to the diagnosis of ITP.
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to platelet clearance in the liver via aMb2 on Kupffer cells or Ashwell-Morell receptors (AMR) on hepatocytes.10 For GPV, loss of sialic acid occurs concomitantly to GPIba after cold stored platelets are rewarmed, a process also followed by metalloprotease-induced shedding of these receptors.11 It is now important to determine whether thrombocytopenia observed with anti-GPV antibodies results from a Fc-dependent clearance or from an Fc-inde- pendent mechanism implying liver receptors. Neuraminidases are present in platelet a-granules, but it is not known how they are translocated to the platelet surface or how they come into contact with sialic acid residues that are extended far from the surface. Is their action on the same platelet or after platelet-to-platelet contact? Not all anti-GPIb antibodies are capable of acti- vating the GPIb-IX complex; significantly, some directed against the ligand binding domain induce the juxtamem- brane mechanosensory domain (MSD) of GPIba to be unfolded and Fc-independent platelet clearance by a mechanosensory mechanism.12 It will be interesting to verify whether anti-GPV autoantibodies share some of these properties or will modify the sialic acid expression of GPIba, or indeed of GPV itself. Heterogeneity in the response may be predicted, as infusion of rat MoAbs to murine GPV had no effect in a mouse model, whereas MoAbs to GPIba resulted in thrombocytopenia and megakaryocyte abnormalities.13 Along with the target on GPV, it is difficult to speculate as to the relevance of high and low avidity anti-GPV antibodies.
The GPV ectodomain contains: i) a cleavage site for thrombin, leading to loss of the bulk of the extracellular domain of GPV from the platelet surface and the genera- tion of soluble GPV (sGPV); and ii) a second cleavage site
for endogeneous metalloproteinases and, in particular, ADAM17, which is the major sheddase for GPV on the platelet surface (Figure 1).14 Whether shedding of GPV is a contributor to or a consequence of immune clearance has still not been determined. The presence of elevated levels of sGPV in models of thrombosis suggests that it may be a marker of thrombotic activity.15 The role of sGPV in the circulation remains unknown, as does the possible role of natural antibodies in clearing the soluble form.
So far, the physiological role and function, if any, of GPV remains elusive. GPV-/- mouse platelets are morpho- logically indistinguishable from wild-type platelets, but two reports show an increased platelet sensitivity to low doses of thrombin in the absence of GPV, suggesting an anti-thrombotic role for GPV.9,16,17 In contrast, platelet GPV reportedly binds to collagen and participates in platelet adhesion and aggregation.18 Mice lacking GPV have mild- ly reduced tail bleeding times and, depending on the severity of the injury, display slightly accelerated throm- bus formation.19 So the fascinating questions as to the potential value of GPV as an anti-thrombotic target and the possible modulating roles of sGPV remain. Are these observations sufficient to predict a modification of platelet function when anti-GPV antibodies are present? Only future studies will be able to provide an answer.
In their report, Vollenberg et al.4 focus on the preva- lence of auto anti-GPV antibodies and their contribution to platelet clearance. They clearly establish the impor- tance of including this target in the diagnosis of ITP, and confirm the findings of previously published literature and of a recent short report by Porcelijn et al.20 GPV should certainly form part of antibody testing kits, but more studies are required to evaluate their clinical rele-
haematologica | 2019; 104(6)