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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.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\u003EAssays for the activated form of thrombin activatable fibrinolysis Inhibitor(a) (TAFIa) can measure the extent of TAFI activation in patient populations. TAFI is a human plasma zymogen that is related to pancreatic carboxypeptidase B (CPB). The active form of TAFI (TAFIa), formed by thrombin cleavage of the zymogen, likely inhibits fibrinolysis by removal of the carboxyl-terminal lysine residues of partially degraded fibrin that stimulate plasminogen activation. TAFI is encoded by the CPB2 gene (chromosome 13) [Boffa MB et al. \u003Cem\u003EBiochemistry\u003C\/em\u003E 1999]. This article presents insights into the function and regulation of TAFI.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EThrombophilia\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\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EThrombophilia\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\u003Cli class=\u0022kwd\u0022\u003EHematology\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EAssays for the activated form of thrombin activatable fibrinolysis Inhibitor(a) (TAFIa) can measure the extent of TAFI activation in patient populations. TAFI is a human plasma zymogen that is related to pancreatic carboxypeptidase B (CPB). The active form of TAFI (TAFIa), formed by thrombin cleavage of the zymogen, likely inhibits fibrinolysis by removal of the carboxyl-terminal lysine residues of partially degraded fibrin that stimulate plasminogen activation. TAFI is encoded by the CPB2 gene (chromosome 13) [Boffa MB et al. \u003Cem\u003EBiochemistry\u003C\/em\u003E 1999]. Ann Gils, PhD, Katholieke Universiteit, Leuven, Leuven, Belgium, presented insights into the function and regulation of TAFI.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EDuring the cloning of TAFI cDNA from several human liver cDNA libraries, Zhao and colleagues \u003Cem\u003E[Thromb Haemost\u003C\/em\u003E 1998] identified a single nucleotide polymorphisms (SNP) at position 505A\/G in the coding region of the TAFI gene that resulted in a substitution of alanine for threonine at residue 147. Brouwers et al. \u003Cem\u003E[Blood\u003C\/em\u003E 2001] identified another SNP, 1040C\/T, in the coding region of the TAFI gene by comparing published sequences (GenBank no. \u003Ca class=\u0022external-ref external-ref-type-gen\u0022 href=\u0022\/lookup\/external-ref?link_type=GEN\u0026amp;access_num=NM_001872\u0026amp;atom=%2Fspmdc%2F13%2F13%2F28.atom\u0022\u003ENM_001872\u003C\/a\u003E and NM_016413). This SNP also resulted in an alanine substitution (Thr32511e) at residue 325.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EIt was previously shown that commercially available antigen assays underestimate the TAFI-Ile325 concentration (eg, 44\u00b18.9% and 100\u00b130% for the Ile\/Ile and Thr\/Thr isoforms, respectively) [Gils A et al. \u003Cem\u003EArterioscler Thromb Vase Biol\u003C\/em\u003E 2003]. On the other hand, studies using recombinant proteins have demonstrated a functional effect of the Thr325lle substitution on the stability of activated TAFI resulting in altered antifibrinolytic activity [Brouwers GI et al. \u003Cem\u003EBlood\u003C\/em\u003E 2001].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EQuantifying and detecting TAFI, TAFIa, and TAFIai can be accomplished via direct (ELISA or functional assay) or indirect measurement. The latter includes, among others, animal models and the Chandler Loop (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Vercauteren E et al. \u003Cem\u003EJ Thromb Haemost\u003C\/em\u003E 2013; Mutch NI et al. \u003Cem\u003EJ Thromb Haemost\u003C\/em\u003E 2003].\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\/28\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022The Chandler Loop System\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-2085279301\u0022 data-figure-caption=\u0022The Chandler Loop System\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\/28\/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\/28\/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\/28\/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\/13666\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-6\u0022 class=\u0022first-child\u0022\u003EThe Chandler Loop System\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from A Gils, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-7\u0022\u003EAccording to Prof. Gils, many pharmaceutical companies are attempting to inhibit TAFIa using TAFI-LMW, including 2-mercaptocyclopentanecarboxylic acid WO 10\/0330064 and aryl guanidinic TAFIa inhibitors WO 03\/080631.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EConclusions from mouse monoclonal antibodies in the pharmacologic inhibition of TAFI-Ab show that activation of TAFI as well as TAFIa can be targeted. T\/TM as well as plasmin-mediated TAFI activation seems important. \u003Cem\u003EIn vivo\u003C\/em\u003E studies are scarce due to lack of cross-reactivity with mouse or rat TAFI.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EPharmacologic inhibition of TAFI-Nb has shown that TAFI and the activation of TAFI and TAFIa can be targeted. Further, due to their size, VHH has better clot penetration. The short half-life and lack of cross-reactivity with mouse and rat TAFI hampers studies in mouse models. TAFI also plays a role in inflammation, with TAFIa inactivating C3a, C5a, thrombin cleaved osteopontin, and bradykinin.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EProf. Gils explained that in time the toolbox of TAFI(a) inhibitors allows to investigate the role of TAFI inhibition using animal models whilst the availability of assays to measure the extent of TAFI activation allows to explore the role of TAFI (activation) in different pathologies.\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\/28.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?nznpe2\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?nznpe2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}