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• W2142479940 abstract "Whilst the precipitating aetiology of immune thrombocytopenic purpura (ITP) remains unclear, the predominant cause of the thrombocytopenia is the presence of circulating anti-platelet autoantibodies that coat platelets, leading to platelet destruction and clearance, primarily in the spleen. Traditional clinical management of patients with ITP, including treatment with corticosteroids, intravenous immunoglobulins, splenectomy, rituximab, and cyclophosphamide, aims to curb platelet destruction (Nurden et al, 2009a). Newer reagents approved for trial to treat ITP patients, such as thrombopoietin mimetics, romiplostim (Kuter et al, 2008) and eltrombopag, act primarily in the bone marrow to stimulate thrombopoiesis. Whilst neither plasma thrombopoietin levels nor platelet production kinetics are markedly altered in ITP patients, ITP anti-platelet autoantibodies interfere with megakaryocyte proliferation and platelet production in vitro (Chang et al, 2003). Here we describe a significant improvement to the nature and function of platelet immunoreceptor tyrosine-based activation motif (ITAM) receptors in an ITP patient with an autoantibody to platelet glycoprotein (GP)VI receiving romiplostim. Previously, platelets in platelet rich plasma (PRP) isolated from the patient diagnosed with ITP did not aggregate in response to GPVI agonists, collagen and collagen-related peptide, or Fc receptor (FcγRIIa) engagement (Gardiner et al, 2008a). A normal response to collagen was achieved in PRP isolated from the ITP patient after 6 months of treatment with romiplostim (3 μg/kg romiplostim weekly for 6 months with normalisation of platelet count) (Fig. 1A). Responses to epinephrine (7 μmol/l), arachadonic acid (1 mmol/l) and ADP (4 μmol/l) were normal (data not shown). Circulating platelets isolated from an ITP patient respond to collagen and show no evidence of GPVI shedding and cleavage of FcγRIIa. (A) Aggregation of platelets in citrated PRP isolated from a healthy donor control or the patient diagnosed with ITP in response to 5 μg/ml collagen. (B) Equivalent amounts of washed platelets (3 × 108/ml) that had been isolated from either a control or the ITP patient and lysed in sodium dodecyl sulphate (SDS)-containing buffer were examined using 5–20% polyacrylamide/SDS gels and Western blot with antibodies directed against the cytoplasmic tail of GPVI or FcγRIIa that detect both full length and cleaved forms of each receptor. Bound antibody was detected using a horseradish peroxidase-conjugated anti-rabbit secondary antibody and enhanced chemiluminescence. All lanes within each figure came from the same experiment, and the same gel/Western blot. Data are representative of two identical experiments performed on separate days. The arrow indicates the position to where a 10-kDa GPVI cytoplasmic tail remnant would migrate. Previously, we demonstrated that a 55-kDa GPVI ectodomain fragment could be cleaved from platelets treated with GPVI agonists or FcγRIIa-activating antibodies, leaving an c.10-kDa remnant containing the cytoplasmic tail and transmembrane domains of GPVI associated with the platelet membrane (Gardiner et al, 2008b). Resting platelets isolated from healthy donors contain no detectable 10-kDa remnant fragment, although we previously demonstrated cleaved forms of GPVI and FcγRIIa receptors on circulating platelets from the ITP patient (Gardiner et al, 2008a). Washed platelets isolated from the ITP patient after 6 months of treatment with romiplostim or from a healthy donor (control) were lysed and levels of GPVI and FcγRIIa were examined by Western blot. Levels of intact GPVI and FcγRIIa in patient platelet lysates were equivalent to levels found in healthy donor platelets as determined by Western blotting with antibodies raised against the cytoplasmic tails of GPVI or FcγRIIa (Fig. 1B) consistent with the restored aggregation response to collagen (Fig. 1A) in the patient platelets. The remnant 10-kDa membrane-associated fragment of GPVI was no longer evident in lysed platelets from the ITP patient (Fig. 1B) implying that autoantibody-induced activation of platelet receptor shedding pathways was markedly attenuated in the ITP patient after romiplostim treatment. In our previous report, levels of intact GPVI on the ITP patient platelets were estimated to be 10–20% of levels on control platelets as detected by flow cytometry using any of 1A12, 4B8 or 1G5 monoclonal anti-GPVI antibodies (Gardiner et al, 2008a) (Table I). After romiplostim treatment, levels of GPVI as well as GPIbα and αIIbβ3 (data not shown) were similar to those observed on healthy donor platelets by flow cytometry (Table I). This is in agreement with the observed normal aggregatory response to GPVI agonists and immunoblots detecting a single band corresponding to intact GPVI (Fig. 1). Romiplostim treatment may directly influence expression of GPVI. Kanaji et al (2005) reported that thrombopoietin initiated the receptor-mediated demethylation of a cytosine-phosphate-guanosine-rich island within the promotor region of the GP6 gene in megakaryocytes, upregulating expression of GPVI. Analysis of surface levels of GPVI in a cohort of patients before and after treatment with romiplostim may confirm this. We recently established a sandwich enzyme-linked immunosorbent assay (ELISA) to measure levels of the shed GPVI ectodomain in human citrated-plasma samples (Al-Tamimi et al, 2009). Using our assay, the level of soluble GPVI in plasma from healthy donors was c.15 ng/ml. Previously, plasma from the ITP patient contained c.150 ng/ml soluble GPVI and in this study, levels of soluble GPVI were shown to be c.127 ng/ml after romiplostim treatment. Using an ELISA similar to that used to measure anti-GPVI autoantibody in a patient with lupus nephritis (Nurden et al, 2009b), we noted that levels of circulating anti-GPVI autoantibody were still detectable after romiplostim treatment (Table I). The explanation for the elevated level of soluble GPVI remains unclear, but may reflect the increased platelet count, an underlying low level of GPVI shedding and a potential prolonged clearance time for soluble plasma GPVI due to its O-linked carbohydrate mucin core. Currently, there is no information regarding the stability of soluble GPVI in plasma; however, other members of the immunoglobulin family of adhesion receptors, including vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 are shed from both leucocytes and endothelial cells by metalloproteinases. Soluble ICAM-1 displays resistance to proteolysis by plasmin and proteases present in inflamed synovium in plasma and plasma-soluble VCAM-1 and soluble ICAM-1 display prolonged elevation in inflammatory and myocardial diseases (reviewed in Garton et al, 2006). It is possible that soluble GPVI also exhibits an extended lifetime in plasma. The relatively high level of soluble GPVI in plasma may also reflect platelet ITAM receptor engagement by the patient’s anti-GPVI antibody in bone marrow. It is unclear what impact the platelet autoantibody has on shedding activity in the bone marrow of the patient under romiplostim treatment and whether such treatment leads to increased shedding activity under conditions of accelerated platelet production. Nishikii et al (2008) observed metalloproteinase-dependent cleavage of platelet receptors GPIbα, GPV and GPVI in murine embryonic stem cells grown in thrombopoietin-containing culture medium, however our data indicates improved platelet GPVI function and no evidence of increased shedding of GPVI on circulating platelets (that is, no detectable 10-kDa remnant fragment). Acquired tolerance of anti-platelet autoantibodies may be an important additional consequence of romiplostim treatment in patients with ITP. We thank Dr Frank Cordingley, Fremantle Hospital for referring the patient and the National Health and Medical Research Council of Australia for financial support." @default.
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• W2142479940 date "2010-04-25" @default.
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• W2142479940 title "Restored platelet function after romiplostim treatment in a patient with immune thrombocytopenic purpura" @default.
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• W2142479940 doi "https://doi.org/10.1111/j.1365-2141.2010.08092.x" @default.
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