Anti-GPVI-associated ITP: An acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRγ-chain complex from the human platelet surface
Medical College of Wisconsin, Milwaukee, Wisconsin, United States Blood
(Impact Factor: 10.45).
10/2004; 104(5):1350-5. DOI: 10.1182/blood-2004-03-0896
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.
Available from: Elizabeth Gardiner
- "Notably, other anti-GPVI autoantibodies result in depletion of platelet GPVI in vivo (Moroi et al., 1989; Boylan et al., 2004; Arthur et al., 2007b) although this could be owing to endocytosis rather than metalloproteolysis; similar effects of antibodies have been found in mice and monkeys. 2. In mice, glycocalicin (soluble GPIba ectodomain) is found in normal plasma at approximately 20 mg/ml (Bergmeier et al., 2000). "
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ABSTRACT: In the past 5 years, metalloproteinase-mediated ectodomain shedding of platelet receptors has emerged as a new mechanism for modulating platelet function. By regulating surface expression of the platelet-specific receptors, glycoprotein (GP)VI that binds collagen, and GPIbalpha (the major ligand-binding subunit of the GPIb-IX-V complex) that binds von Willebrand factor (VWF) and other procoagulant and proinflammatory ligands, shedding not only irreversibly downregulates GPVI/GPIbalpha function, but generates proteolytic fragments that might be unique biomarkers or modulators in plasma. This is potentially significant because GPVI and GPIbalpha are involved in initiating thrombotic diseases such as heart attack and stroke, as well as autoimmune diseases where anti-platelet antibodies result in thrombocytopenia. Altered expression levels of GPIbalpha/GPVI are associated with both thrombotic propensity and platelet aging, suggesting an additional role in platelet clearance. Although emerging data are elucidating molecular mechanisms underlying GPIbalpha/GPVI shedding, evidence for the functional consequences of shedding in vivo, either clinically or in animal models, is far more limited. Here we consider recent published evidence for GPVI or GPIbalpha shedding in humans, nonhuman primates and mice, and whether conservation of sheddase cleavage sites across species points to a functional role for metalloproteolytic shedding in vivo.
Available from: onlinelibrary.wiley.com
- "Mild bleeding disorders in patients with selective defects in platelet responses to collagen have been documented in secondary autoimmune thrombocytopenias (Sugiyama et al, 1987; Boylan et al, 2004; Kojima et al, 2006), systemic lupus erythematosis (Moroi et al, 1989; Takahashi & Moroi, 2001) and grey platelet syndrome (Nurden et al, 2004). Proposed mechanisms include antibody-mediated clearance of GPVI and sometimes the Fc gamma receptor from the platelet surface (Boylan et al, 2004; Kojima et al, 2006). Constitutive defects affecting GPVI expression (Moroi et al, 1989; Ryo et al, 1992; Arai et al, 1995) or GPVI signalling mechanisms (Dunkley et al, 2007) have been described. "
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ABSTRACT: Considerable progress has been made over the last two decades in delineating the key molecular events regulating the haemostatic function of platelets. Much of this new insight has been derived from the study of mouse models, in which the expression or structure of one or more platelet proteins has been genetically altered. Despite these advances on the research front, clinical progress in diagnosing patients with unexplained surgical bleeding or recurrent haemorrhage from mucocutaneous sites has been comparatively limited. There is a dearth of literature available to help physicians integrate and apply the burgeoning knowledge on platelet biology to diagnosing patients with atypical or unexplained platelet dysfunction. The purpose of this review is to summarise the major primary platelet disorders relevant to pathological bleeding in humans (excluding those primarily due to thrombocytopenia or acquired functional disorders), with a focus on lesions identified in mouse models that could represent candidate molecules for study in patients with impaired platelet function.
Available from: Elizabeth E Gardiner
- "The occurrence of anti-GPVI autoantibodies in ITP has been previously reported    ; however, the molecular mechanism linking occurrence of anti-GPVI autoantibodies with thrombocytopenia and accelerated clearance of platelets from the circulation remains to be defined. Boylan and colleagues (2004) demonstrated that the autoantibody bound to platelet GPVI, and hypothesized that this binding caused the observed depletion of GPVI from the platelet surface and associated mild thrombocytopenia . A similar effect has been reported in mice    or monkeys  treated with anti-GPVI antibodies, where a transient thrombocytopenia and removal of platelet surface GPVI was observed. "
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ABSTRACT: Receptors on platelets that contain immunoreceptor tyrosine-based activation motifs (ITAMs) include collagen receptor glycoprotein (GP) VI, and FcgammaRIIa, a low affinity receptor for immunoglobulin (Ig) G.
We examined the function of GPVI and FcgammaRIIa in a patient diagnosed with immune thrombocytopenic purpura (ITP) who had unexplained pathological bruising despite normalization of the platelet count with treatment.
Patient platelets aggregated normally in response to ADP, arachadonic acid and epinephrine, but not to GPVI agonists, collagen or collagen-related peptide, or to FcgammaRII-activating monoclonal antibody (mAb) 8.26, suggesting ITAM receptor dysfunction. Plasma contained an anti-GPVI antibody by MAIPA and aggregated normal platelets. Aggregating activity was partially (approximately 60%) blocked by FcgammaRIIa-blocking antibody, IV.3, and completely blocked by soluble GPVI ectodomain. Full-length GPVI on the patient platelet surface was reduced to approximately 10% of normal levels, and a approximately 10-kDa GPVI cytoplasmic tail remnant and cleaved FcgammaRIIa were detectable by western blot, indicating platelet receptor proteolysis. Plasma from the patient contained approximately 150 ng mL(-1) soluble GPVI by ELISA (normal plasma, approximately 15 ng mL(-1)) and IgG purified from patient plasma caused FcgammaRIIa-mediated, EDTA-sensitive cleavage of both GPVI and FcgammaRIIa on normal platelets.
In ITP patients, platelet autoantibodies can curtail platelet receptor function. Platelet ITAM receptor dysfunction may contribute to the increased bleeding phenotype observed in some patients with ITP.
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