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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\u003EMolecular research over the past 25 years has yielded a wealth of data on the molecular and genetic features of von Willebrand disease. This article discusses the translation of this molecular knowledge into practical aspects of clinical diagnosis and treatment of this bleeding disorder. Also discussed is the future of coagulation factor replacement therapy for hemophilia.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHemorrhagic Disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHemorrhagic Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHematology\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ETRANSLATIONAL MEDICINE ADVANCES IN VON WILLEBRAND DISEASE\u003C\/h2\u003E\n         \u003Cp id=\u0022p-2\u0022\u003EMolecular research over the past 25 years has yielded a wealth of data on the molecular and genetic features of von Willebrand disease (VWD). David Lillicrap, MD, Queen\u0027s University Kingston, Ontario, Canada, discussed the translation of this molecular knowledge into practical aspects of clinical diagnosis and treatment of this bleeding disorder.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EThe gene for human von Willebrand factor (VWF) was cloned and characterized by four groups in 1985 [Verweij CL et al. \u003Cem\u003ENucleic Acids Res\u003C\/em\u003E 1985; Ginsburg D et al. \u003Cem\u003EScience\u003C\/em\u003E 1985; Sadler IE et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 1985; Lynch DC et al. \u003Cem\u003ECell\u003C\/em\u003E 1985]. Located on the short arm of chromosome 12, the VWF gene comprises 178 kilobases of DNA and 52 exons. Genetic analysis of this complex gene can be difficult due to the presence of a pseudogene sequence on chromosome 22 that differs in only 3% of the sequence analysis compared to the sequence in the middle of the VWF gene. Annotation of the VWF protein structure has recently been revised, with the D domains now referred to as D assemblies composed of smaller molecules, including von Willebrand D (VWD), 8-cysteine (C8), trypsin inhibitor-like (TIL), and E domains [Zhou YF et al. \u003Cem\u003EBlood\u003C\/em\u003E 2012]. The former B and C regions of the protein are now annotated as 6 tandem VWC and VWC-like domains [Zhou YF et al. \u003Cem\u003EBlood\u003C\/em\u003E 2012], which provide length and flexibility under conditions of shear.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EThe diagnosis of VWD involves three main components: a personal history of excessive mucocutaneous bleeding; laboratory hemostasis results compatible with quantitative or qualitative VWF pathology; and a family history of VWD. Mucocutaneous bleeding is evaluated using bleeding assessment tools such as the International Society on Thrombosis and Haemostasis (ISTH) -Bleeding Assessment Tool (BAT) [Rydz N, lames PD. \u003Cem\u003EJ Thromb Haemost\u003C\/em\u003E 2012]. According to Prof. Lillicrap, laboratory hemostasis testing has not changed much in the last 20 years. Hemostasis assays include those for VWF antigen (VWF:Ag); ristocetin cofactor (VWF:RCo); factor VIII binding (VWF:FVIIIB); collagen binding (VWF:CB); VWF propeptide (VWFpp) used as surrogate for clearance rate of VWF); multimeric analysis (VWF multimers); and ristocetin platelet agglutination (RIPA).\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EGenetic analysis is useful for family planning and management of VWD. The University of Sheffield, United Kingdom, is home to a VWD mutation database [\u003Ca href=\u0022http:\/\/www.vwf.group.shef.ac.uk\u0022\u003Ewww.vwf.group.shef.ac.uk\u003C\/a\u003E] that currently describes 399 unique VWF gene mutations. VWF mutation detection rates are \u221265% in type 1,90% in type 2 (2A, 2B, 2M, and 2N), and 85% in type 3 VWD. Currently, the number of known mutations is 127 in type 1, 75 in type 2A, 25 in type 2B, 29 in type 2M, 31 in type 2N, and 112 in type 3. The VWF genetic locus contains 181 polymorphisms, adding to the complexity of diagnosis and management.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EIn a study of VWD mutation patterns, Yadegari H et al. \u003Cem\u003E[Thromb Haemost\u003C\/em\u003E 2012] found mutations in 68%, 94%, and 94% of VWD type 1, 2, and 3, respectively. Of the mutations found in all VWD types, 54.4% were missense mutations, 14.7% were small deletions, 2.9% were small insertions, 10.3% were nonsense mutations, 7.4% were splice-site mutations, 8.8% were large deletions, and 1.5% were silent mutations. In patients with type 2 VWD, genetic testing can differentiate between identical phenotypes caused by mutations in different genes. For example, type 2B and platelet-type VWD have the same phenotypes but are due to mutations of the VWF and GP1ba genes, respectively. This distinction is important for selecting therapy (VWF and FVIII concentrate for VWF vs platelets for platelet-type).\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EThe CHARGE study identified 5 novel candidate genetic loci strongly associated with levels of VWF [Smith NL et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2010]. Syntax binding protein 5 (STXBP5) and syntaxin 2 (STX2) are associated with vesicular trafficking and exocytosis. Scavenger receptor class A member 5 (SCARA5), stabilin 2 (STAB2), and C-type lectin type 4 member M (CLEC4M) are receptor proteins that might be involved in clearing VWF.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EFew advances have been made in the treatment of VWD over the past 20 years. Desmopressin is effective but therapeutic trials including 1-, 2-, and 4-hour time points (to check for accelerated clearance) are required. Plasma derived (pd) concentrates are also available. The pd-VWF\/FVIII concentrates ranges from very high to intermediate purity and have variable RCo\/Ag and RCo\/FVIII levels (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E). Although these concentrates are safe and effective, their optimal use is not fully understood.\u003C\/p\u003E\n         \u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/13658\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/13658\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13658\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\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-9\u0022 class=\u0022first-child\u0022\u003EPlasma-Derived VWF\/FVIII Concentrates Licensed in Europe\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EA recent study of the safety, tolerability, and pharmacokinetics of a Chinese hamster ovary (CHO) cell-derived rVWF (VWF:RCo\/FVIII:C ratio 1.3:1) in 32 patients showed that it is safe and the pharmacokinetics of rVWF:RCo activity, VWF:Ag, and collagen binding activity (VWF:CB) were similar to those of pd-VWF\/FVIII [Mannucci PM et al. \u003Cem\u003EBlood\u003C\/em\u003E 2013].\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003ETranslational medicine progress has been much more rapid in hemophilia versus VWD. Cloning of the FVIII and FIX genes in the early 1980s led to rapid use of genetic diagnosis for hemophilia in the mid-1980s and recombinant protein therapy in the 1990s, and finally, to gene therapy for hemophilia B in 2012 (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\n         \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\/18\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Translational Medicine Advances in Hemophilia\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1474131022\u0022 data-figure-caption=\u0022Translational Medicine Advances in Hemophilia\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\/18\/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\/18\/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\/18\/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\/13653\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-12\u0022 class=\u0022first-child\u0022\u003ETranslational Medicine Advances in Hemophilia\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from D Lillicrap, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-13\u0022\u003ETranslational progress in VWD has been slower, with extensive basic science research ongoing since cloning of the gene in 1985. Genetic diagnosis was only introduced in the past decade, while research on recombinant protein therapy and gene therapy began just a few years ago (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\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\/18\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Translational Medicine Advances in von Willebrand Disease\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1474131022\u0022 data-figure-caption=\u0022Translational Medicine Advances in von Willebrand Disease\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/18\/F2.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\/18\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\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\/18\/F2.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\/13654\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 2.\u003C\/span\u003E \n               \u003Cp id=\u0022p-14\u0022 class=\u0022first-child\u0022\u003ETranslational Medicine Advances in von Willebrand Disease\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from D Lillicrap, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EThe relatively slow progress in translational advances in VWD is due to a number of factors. First, bleeding symptoms in type 1 VWD are mild compared with those in hemophilia. In the past, women\u0027s bleeding problems with VWD have not been addressed, although this is changing. Additionally, phenotypic testing for type 2 and 3 VWD is straightforward, resulting in less need for genetic testing. Although phenotypic diagnosis of type 1 VWD is difficult, genetic diagnosis also is difficult. Other reasons include the complexity of VWD genetics, the safety and efficacy of desmopressin and pd-concentrates, and the rarity of VWF immunogenicity. Prof. Lillicrap noted that although the translational clinical potential of research in VWD has not been achieved, the biologic potential is enormous, considering the many functions of VWF including its contributions to venous thrombosis, atherothrombosis, platelet adhesion and aggregation, inflammation, angiogenesis, cell proliferation, and apoptosis.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EFUTURE OF COAGULATION FACTOR REPLACEMENT THERAPY FOR HEMOPHILIA\u003C\/h2\u003E\n         \u003Cp id=\u0022p-16\u0022\u003ESubstantial improvements in hemophilia care have been achieved during the past 30 years. The current treatment standard is intravenous (IV) replacement therapy, given as needed during bleeding episodes or prophylactically on a routine schedule. Although safe and highly effective, hemophilia therapy involves frequent injections due to a short half-life and is immunogenic, costly, and unavailable to 70% of patients worldwide. These issues were addressed by Flora Peyvandi, MD, PhD, University of Milan, Milan, Italy, in her presentation on new generation therapies for hemophilia.\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EStrategies to extend the half-life, increase efficacy, and reduce immunogenicity of hemophilia therapies are under investigation, including the addition of polyethylene glycol (PEG) polymers and polysialic acids, drugs formulated with PEG-modified liposomes, and bioengineered fusion protein therapies. The covalent coupling of PEG to a protein product, known as pegylation, increases the drug\u0027s dynamic volume, resulting in reduced clearance by the kidneys and greater efficacy. Pegylation also masks the protein surface, which reduces immunogenicity and proteolytic degradation. This technology has been applied to FVIII, FIX, and FVIIa.\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003ETargeted pegylation is a technique in which PEG is attached to specific regions of coagulation factors. Glycopegylation of FVIII involves attaching PEG to the O-linked glycan in the truncated B-domain of rFVIII. Thrombin-mediated activation of the pegylated molecule releases the PEG B-domain, resulting in a fully functional activated molecule similar to endogenous FVIIIa [Stennicke HR et al. \u003Cem\u003EBlood\u003C\/em\u003E 2013]. In another technique, the Fc fragment of immunoglobulin or albumin is fused to the coagulation factor, increasing reuptake and half-life. Four long-acting rFVIII products are in clinical trials, including 3 ongoing studies and 1 completed study (\u003Ca id=\u0022xref-table-wrap-2-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T2\u0022\u003ETable 2\u003C\/a\u003E). The half-lives of these new products have been extended 1.5- to 1.8-times the half-life of rFVIII (\u003Ca id=\u0022xref-fig-3-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003EFigure 3\u003C\/a\u003E). Prophylactic treatment with long acting rFVIII will involve 1 to 2 infusions per week compared with 2 to 3 per week with standard rFVIII.\u003C\/p\u003E\n         \u003Cdiv id=\u0022T2\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/13659\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/13659\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13659\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\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 2.\u003C\/span\u003E \n               \u003Cp id=\u0022p-19\u0022 class=\u0022first-child\u0022\u003EClinical Studies of Long-Acting rFVIII\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cdiv id=\u0022F3\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\/18\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Half-Life Extension of Long Acting rFVIII Products\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1474131022\u0022 data-figure-caption=\u0022Half-Life Extension of Long Acting rFVIII Products\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 3.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/18\/F3.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\/18\/F3.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 3.\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\/18\/F3.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\/13655\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 3.\u003C\/span\u003E \n               \u003Cp id=\u0022p-20\u0022 class=\u0022first-child\u0022\u003EHalf-Life Extension of Long Acting rFVIII Products\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003EReproduced with permission from F Peyvandi, MD, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-21\u0022\u003EThree long acting rFIX products are being studied in Phase 2 and 3 trials (\u003Ca id=\u0022xref-table-wrap-3-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T3\u0022\u003ETable 3\u003C\/a\u003E). The half-lives of these products are extended 3- to 5-times the half-life of standard rFIX (\u003Ca id=\u0022xref-fig-4-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F4\u0022\u003EFigure 4\u003C\/a\u003E). Prophylaxis with long acting rFIX will require infusions every 1 or 2 weeks compared with 2 weekly infusions of standard rFIX.\u003C\/p\u003E\n         \u003Cdiv id=\u0022T3\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/13660\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/13660\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13660\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\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 3.\u003C\/span\u003E \n               \u003Cp id=\u0022p-22\u0022 class=\u0022first-child\u0022\u003EClinical Studies of Long Acting rFIX\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cdiv id=\u0022F4\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\/18\/F4.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Half-Life Extension With Long-Acting rFIX Products\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1474131022\u0022 data-figure-caption=\u0022Half-Life Extension With Long-Acting rFIX Products\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 4.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/18\/F4.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\/18\/F4.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 4.\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\/18\/F4.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\/13656\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 4.\u003C\/span\u003E \n               \u003Cp id=\u0022p-23\u0022 class=\u0022first-child\u0022\u003EHalf-Life Extension With Long-Acting rFIX Products\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-4\u0022\u003EReproduced with permission from F Peyvandi, MD, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-24\u0022\u003EThree long-acting rFVIIa products have been studied but two were discontinued due to unsatisfactory dose-response (N7-GP) and immunogenicity (BAY86-6150). A Phase 1 trial has been successfully completed for the remaining product, CSL689, an albumin fusion rFVIIa with a half-life 3- to 4-times longer than standard rFVIIa [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01542619\u0026amp;atom=%2Fspmdc%2F13%2F13%2F18.atom\u0022\u003ENCT01542619\u003C\/a\u003E].\u003C\/p\u003E\n         \u003Cp id=\u0022p-25\u0022\u003EPegylated proteins are well tolerated but vacuolization of renal tubules has been observed in animal models. It is possible that renally cleared pegylated proteins or their metabolites accumulate in the kidneys, causing formation of PEG hydrates that interfere with glomerular filtration. According to Prof. Peyvandi, long-term safety evaluations of these products are needed because data from prelicensing studies are insufficient to demonstrate their safety. Polypeptide chains are biologic alternatives to pegylation that are stable in plasma, fully biodegradable, do not accumulate in organs, and are not toxic or immunogenic in animals. Examples of these are half-life extension technology (XTEN), PASylation (PAS), elastin-like polypeptide (ELP) technology, and HESylation (HES).\u003C\/p\u003E\n         \u003Cp id=\u0022p-26\u0022\u003ESeveral alternative therapeutic strategies have been under investigation, including inhibition of tissue factor pathway inhibitor (TFPI; BAX499), inhibition of antithrombin(ALN-AT3), and bispecific antibody(ACE910). Studies of the TFPI inhibitor, BAX499 have stopped due to increased bleeding events.\u003C\/p\u003E\n         \u003Cp id=\u0022p-27\u0022\u003EThe antithrombin inhibitor, ALN-AT3, was developed using RNA interference (RNAi). RNAi involves gene silencing in a sequence-specific manner at the mRNA level. The mechanism involves breaking a double-stranded RNA (dsRNA) that matches a specific gene sequence into short pieces of RNA called small interfering RNAs (siRNAs) that can target a specific gene sequence. ALN-AT3 is an siRNA that targets antithrombin in the liver using a hepatocyte targeting ligand. Preclinical studies show that ALN-AT3 inhibits antithrombin in nonhuman primates. Antithrombin reduction was associated with increased thrombin generation and up to 4-fold increases in peak thrombin. ALN-AT3 has a long duration of action with the potential for once weekly or twice monthly subcutaneous dosing.\u003C\/p\u003E\n         \u003Cp id=\u0022p-28\u0022\u003EThe bispecific antibody, hBS23\/ACE910 has the same activity as FVIII, binding to both FIXa and FX and increasing thrombin generation [Kitazawa T et al. \u003Cem\u003ENat Med\u003C\/em\u003E 2012]. IV hBS23\/ACE910 has a half-life of 2 weeks, while bioavailability of subcutaneous hBS23\/ACE910 is 84%. A Phase I clinical study of this drug currently is recruiting in Japan [JapicCTI-121934].\u003C\/p\u003E\n         \u003Cp id=\u0022p-29\u0022\u003EConsiderable progress has been made in the treatment of hemophilia over the past 25 years but few options are available for patients with rare bleeding disorders. Fresh frozen plasma and cryoprecipitate are still used in most countries because specific products for specific deficiencies are not available everywhere. Novel drugs for the treatment of hemophilia and other bleeding disorders have the potential to change patients\u0027 lives but many issues remain. Among these are defining novel drugs for orphan drug status, the market impact of biosimilar drugs, and drug registration differences in different countries. Cost and reimbursement issues for novel drugs can present obstacles to global availability. Despite these issues, gene-and protein-based research is ongoing, with the goal of bringing a cure for bleeding disorders one step closer to reality, concluded Prof. Peyvandi.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F5\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\/18\/F5.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Current Status of Long Acting Coagulation Factor Products.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1474131022\u0022 data-figure-caption=\u0022Current Status of Long Acting Coagulation Factor Products.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 5.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/13\/18\/F5.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\/18\/F5.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 5.\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\/18\/F5.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\/13657\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 5.\u003C\/span\u003E \n               \u003Cp id=\u0022p-30\u0022 class=\u0022first-child\u0022\u003ECurrent Status of Long Acting Coagulation Factor Products.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-5\u0022\u003EReproduced with permission from F Peyvandi, MD, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\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\/18.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?nznp5p\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?nznp5p\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_tables.js?nznp5p\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}