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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\u003EThe trade-off between antithrombotic effect and bleeding hinders the efficacy of current anticoagulant therapy. An antibody in development has demonstrated dissociation of the antithrombotic effect from the bleeding effect in preclinical studies, showing promise as a revolutionary drug for the treatment of thrombosis.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHematology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EThrombophilia\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EThrombotic Disorders\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\u003EHematology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EThrombophilia\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EThrombotic Disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EThe trade-off between antithrombotic effect and bleeding hinders the efficacy of current anticoagulant therapy. An antibody in development has demonstrated dissociation of the antithrombotic effect from the bleeding effect in preclinical studies, showing promise as a revolutionary drug for the treatment of thrombosis, said Trevor Baglin, MB, ChB, PhD, Addenbrookes Hospital, Cambridge, United Kingdom.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EHe described a naturally occurring antibody discovered in a 54-year-old woman with a chronic subdural hematoma due to a head injury. The patient had a degree of anticoagulation consistent with hemophilia. \u003Cem\u003EIn vitro\u003C\/em\u003E coagulation assays showed a prothrombin time of 50 seconds, an activated partial thromboplastin time of 189 seconds, and a thrombin time \u0026gt;60 seconds, which normally would cause a life-threatening bleeding disorder. Yet, the patient recovered fully (no neurologic deficit) with conservative treatment without further intervention. Her only other relevant history was having undergone knee surgery 5 months prior with no bleeding episode; a preoperative clotting screen was not performed at that time.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe patient was found to have an acquired inhibitor of coagulation in the form of a monoclonal paraprotein immunoglobulin (Ig)A, present in her natural serum at a level of \u0026gt;5 g\/L\u003Csup\u003E\u22121\u003C\/sup\u003E. The antibody was purified by Jacalin agarose and when added back to plasma, was a potent inhibitor of thrombin, binding with a Kd of 1 nM, with a fast on-rate and slow off-rate. Exosite 1 binding was suggested by inhibition of fibrinogen cleavage but with retained cleavage of a small reporter molecule (a fluororphore). Competitive binding with fluorescently labeled hirugen confirmed exosite 1 as the binding site on thrombin. A Fab fragment was prepared from the antibody and cocrystallized with human PPACK-thrombin, and a 1.9\u00c5 structure was solved showing an interaction between the antibody and exosite 1 of thrombin, the main point of contact being CDRH3 of the antibody.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EThe purified antibody was tested in two animal models of arterial thrombosis. At a maximum concentration of 4 nM, which completely abolished thrombosis, tail bleeding times were not prolonged. At 40nM and higher concentrations of the antibody, fibrin deposition was reduced both early and late. In a murine carotid artery occlusion-model, with a 5% ferric chloride injury, the antibody prevented arterial occlusion and maintained blood flow in 4 of 7 animals. At the maximum concentration studied (400 nM), blood loss from a tail clip was not increased compared with saline controls.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EBy comparison, at 5% ferric chloride, a dose of heparin (200 U\/kg) that causes bleeding in all animals in this thrombosis\/bleeding model has no effect on arterial thrombosis, said Dr. Baglin. At 1000 U\/kg, heparin reduces occlusion but universally causes fatal bleeding.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EHe concluded that an antibody that appears to prevent thrombosis without causing bleeding has been identified. A therapeutic derivative of this IgA may potentially permit unlimited dose escalation of antithrombotic therapy without increasing bleeding, given the dissociation of the antithrombotic effect from the bleeding effect.\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\/12.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_openurl.js?nznoxe\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}