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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EInvestigation of patients with mild bleeding disorders might provide novel information on the regulation and role of platelet proteins. It might even identify new targets for prevention of thrombosis. However, gene mutations require phenotypic support to assign causation, according to findings from the observational study, Genotyping and Platelet Phenotyping [GAPP; \u003Ca href=\u0022\/external-ref?link_type=ISRCTN\u0026amp;access_num=ISRCTN77951167\u0022 class=\u0022external-ref external-ref-type-isrctn\u0022\u003EISRCTN77951167\u003C\/a\u003E; UKCRN ID 9858]. This article presents results to date from the study.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECoagulation Defects\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPurpurea\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EOther Hemorrhagic Conditions\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHematology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECoagulation Defects\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPurpurea\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EOther Hemorrhagic Conditions\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EInvestigation of patients with mild bleeding disorders might provide novel information on the regulation and role of platelet proteins. It might even identify new targets for prevention of thrombosis. However, gene mutations require phenotypic support to assign causation, according to findings from the observational study, Genotyping and Platelet Phenotyping [GAPP; \u003Ca href=\u0022\/external-ref?link_type=ISRCTN\u0026amp;access_num=ISRCTN77951167\u0022 class=\u0022external-ref external-ref-type-isrctn\u0022\u003EISRCTN77951167\u003C\/a\u003E; UKCRN ID 9858]. Steve P. Watson, PhD, University of Birmingham, Birmingham, United Kingdom, presented results to date from the study.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ESeveral factors have contributed to the fact that platelet function disorders are heavily underdiagnosed, including the absence of a \u201cgold standard\u201d point-of-care assay of platelet function and the variable penetrance of bleeding in families with inherited disorders of platelet function. The GAPP study is testing the hypothesis that a proportion of patients who present with excessive bleeding have a previously unrecognized impairment in platelet function that may explain their propensity to bleed in conditions that would not normally be associated with severe bleeding.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe study uses a combination of platelet phenotyping and a combination of targeted and whole exome gene sequencing to identify candidate mutations underlying platelet dysfunction. The effect of a small number of missense mutations discovered in the study on protein function is being investigated through expression studies in immortalized cell lines\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003ETo date more than 520 participants, including patients with excessive bleeding suggestive of inherited platelet dysfunction and healthy volunteers, have been recruited to this multicenter study. The main inclusion criteria for patients are patients of any age with excessive bleeding who are willing to participate and are able to provide informed consent. Exclusions include known platelet disorders, such as Glanzmann\u0027s thrombasthenia, Bernard Soulier syndrome, Hermansky Pudlak syndrome, and May Hegglin anomaly.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EToday, light transmission aggregometry (LTA) is used worldwide for the study of heritable platelet function disorders (PFDs), but interpretation of results is complicated by the feedback effects of adenosine diphosphate (ADP) and thromboxane A(2) [TxA(2)] and the overlap with the response of healthy volunteers [Dawood BB et al. \u003Cem\u003EBlood\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe GAPP study performed lumi-aggregometry on 9 platelet agonists in patients with suspected PFD and in healthy volunteers. Abnormal LTA or adenosine triphosphate (ATP) secretion test results were identified in 58% of patients in the GAPP study. In 84% of these, the patterns of response were consistent with defects in Gi receptor signaling, the TxA(2) pathway, and dense granule secretion. Targeted genotyping identified three participants with function-disrupting mutations in the p2Y (12), ADP, and TxA(2) receptors (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). Prof. Watson noted that the majority of defects were in platelet feedback pathways: ADP, thromboxane, and secretion.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/29\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Classification of Defects\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1321356267\u0022 data-figure-caption=\u0022Classification of Defects\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/29\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/29\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/29\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13667\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-8\u0022 class=\u0022first-child\u0022\u003EClassification of Defects\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EAdapted from Dawood BB et al. Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel. \u003Cem\u003EBlood\u003C\/em\u003E 2012;120:5041\u20135049.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-9\u0022\u003EResearch illustrates that detailed phenotypic analysis using a rationalized panel of LTA agonists and simultaneously measuring ATP secretion is a powerful tool for the diagnosis of PFDs and in guiding targeted genetic investigations [Watson SP et al. \u003Cem\u003EJ Throm Haemost\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/13\/13\/29.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nznpo1\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nznpo1\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}