Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia
Identifieur interne : 000B05 ( Pmc/Corpus ); précédent : 000B04; suivant : 000B06Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia
Auteurs : Christopher M. Ward ; Robert K. AndrewsSource :
- Research and Practice in Thrombosis and Haemostasis [ 2475-0379 ] ; 2019.
Abstract
The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6‐10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or ‘Capsules’ consisting of short text, three references and a figure, with topics including stroke, cancer‐associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure‐function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.
Url:
DOI: 10.1002/rth2.12225
PubMed: 31294333
PubMed Central: 6611378
Links to Exploration step
PMC:6611378Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Illustrated State‐of‐the‐Art Capsules of the <styled-content style="fixed-case" toggle="no">ISTH</styled-content>
2019 Congress in Melbourne, Australia</title>
<author><name sortKey="Ward, Christopher M" sort="Ward, Christopher M" uniqKey="Ward C" first="Christopher M." last="Ward">Christopher M. Ward</name>
<affiliation><nlm:aff id="rth212225-aff-0001"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="rth212225-aff-0002"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Andrews, Robert K" sort="Andrews, Robert K" uniqKey="Andrews R" first="Robert K." last="Andrews">Robert K. Andrews</name>
<affiliation><nlm:aff id="rth212225-aff-0003"></nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">31294333</idno>
<idno type="pmc">6611378</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611378</idno>
<idno type="RBID">PMC:6611378</idno>
<idno type="doi">10.1002/rth2.12225</idno>
<date when="2019">2019</date>
<idno type="wicri:Area/Pmc/Corpus">000B05</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B05</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Illustrated State‐of‐the‐Art Capsules of the <styled-content style="fixed-case" toggle="no">ISTH</styled-content>
2019 Congress in Melbourne, Australia</title>
<author><name sortKey="Ward, Christopher M" sort="Ward, Christopher M" uniqKey="Ward C" first="Christopher M." last="Ward">Christopher M. Ward</name>
<affiliation><nlm:aff id="rth212225-aff-0001"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="rth212225-aff-0002"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Andrews, Robert K" sort="Andrews, Robert K" uniqKey="Andrews R" first="Robert K." last="Andrews">Robert K. Andrews</name>
<affiliation><nlm:aff id="rth212225-aff-0003"></nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Research and Practice in Thrombosis and Haemostasis</title>
<idno type="eISSN">2475-0379</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>Abstract</title>
<p>The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6‐10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or ‘Capsules’ consisting of short text, three references and a figure, with topics including stroke, cancer‐associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure‐function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl></listBibl>
</div1>
</back>
</TEI>
<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Res Pract Thromb Haemost</journal-id>
<journal-id journal-id-type="iso-abbrev">Res Pract Thromb Haemost</journal-id>
<journal-id journal-id-type="doi">10.1002/(ISSN)2475-0379</journal-id>
<journal-id journal-id-type="publisher-id">RTH2</journal-id>
<journal-title-group><journal-title>Research and Practice in Thrombosis and Haemostasis</journal-title>
</journal-title-group>
<issn pub-type="epub">2475-0379</issn>
<publisher><publisher-name>John Wiley and Sons Inc.</publisher-name>
<publisher-loc>Hoboken</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31294333</article-id>
<article-id pub-id-type="pmc">6611378</article-id>
<article-id pub-id-type="doi">10.1002/rth2.12225</article-id>
<article-id pub-id-type="publisher-id">RTH212225</article-id>
<article-categories><subj-group subj-group-type="overline"><subject>Illustrated Review</subject>
</subj-group>
<subj-group subj-group-type="heading"><subject>Online‐only Articles</subject>
<subj-group subj-group-type="heading"><subject>Illustrated Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Illustrated State‐of‐the‐Art Capsules of the <styled-content style="fixed-case" toggle="no">ISTH</styled-content>
2019 Congress in Melbourne, Australia</article-title>
</title-group>
<contrib-group><contrib id="rth212225-cr-0001" contrib-type="author"><name><surname>Ward</surname>
<given-names>Christopher M.</given-names>
</name>
<degrees>MBChB, PhD</degrees>
<xref ref-type="aff" rid="rth212225-aff-0001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="rth212225-aff-0002"><sup>2</sup>
</xref>
</contrib>
<contrib id="rth212225-cr-0002" contrib-type="author" corresp="yes"><name><surname>Andrews</surname>
<given-names>Robert K.</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="rth212225-aff-0003"><sup>3</sup>
</xref>
<address><email>rob.andrews@monash.edu</email>
</address>
</contrib>
<contrib id="rth212225-cr-1120" contrib-type="author"><collab collab-type="authors">ISTH State of the Art Speakers<contrib-group><contrib id="rth212225-cr-1001" contrib-type="author"><name><surname>Barco</surname>
<given-names>Stefano</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1002" contrib-type="author"><name><surname>Battinelli</surname>
<given-names>E. M.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1003" contrib-type="author"><name><surname>Boilard</surname>
<given-names>Eric</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1004" contrib-type="author"><name><surname>Bos</surname>
<given-names>Mettine H. A.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1005" contrib-type="author"><name><surname>Chicanne</surname>
<given-names>G.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1006" contrib-type="author"><name><surname>Chuansumrit</surname>
<given-names>Ampaiwan</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1007" contrib-type="author"><name><surname>Conway</surname>
<given-names>Edward M.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1008" contrib-type="author"><name><surname>Curry</surname>
<given-names>N.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1009" contrib-type="author"><name><surname>Cutler</surname>
<given-names>Daniel</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1010" contrib-type="author"><name><surname>Danese</surname>
<given-names>Elisa</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1011" contrib-type="author"><name><surname>De Meyer</surname>
<given-names>Simon F.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1012" contrib-type="author"><name><surname>Del Rio</surname>
<given-names>Jose M.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1013" contrib-type="author"><name><surname>Despotovic</surname>
<given-names>Jenny</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1014" contrib-type="author"><name><surname>Di Paola</surname>
<given-names>Jorge</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1015" contrib-type="author"><name><surname>Eikelboom</surname>
<given-names>John</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1016" contrib-type="author"><name><surname>Emsley</surname>
<given-names>Jonas</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1017" contrib-type="author"><name><surname>Eto</surname>
<given-names>Koji</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1018" contrib-type="author"><name><surname>Fijnvandraat</surname>
<given-names>Karin</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1019" contrib-type="author"><name><surname>Flaumenhaft</surname>
<given-names>Robert</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1020" contrib-type="author"><name><surname>Flick</surname>
<given-names>Matthew</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1021" contrib-type="author"><name><surname>Fuchs</surname>
<given-names>Tobias A.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1022" contrib-type="author"><name><surname>Gomez</surname>
<given-names>Keith</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1023" contrib-type="author"><name><surname>Goto</surname>
<given-names>Shinya</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1024" contrib-type="author"><name><surname>Hamilton</surname>
<given-names>Justin R.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1025" contrib-type="author"><name><surname>Hitchcock</surname>
<given-names>Ian S.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1026" contrib-type="author"><name><surname>Jenne</surname>
<given-names>Craig N.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1027" contrib-type="author"><name><surname>Johnsen</surname>
<given-names>Jill M.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1028" contrib-type="author"><name><surname>Ju</surname>
<given-names>Lining A.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1029" contrib-type="author"><name><surname>Le Gal</surname>
<given-names>Grégoire</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1030" contrib-type="author"><name><surname>Levade</surname>
<given-names>M.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1031" contrib-type="author"><name><surname>Lip</surname>
<given-names>Gregory Y. H.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1032" contrib-type="author"><name><surname>Luyendyk</surname>
<given-names>Jim</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1033" contrib-type="author"><name><surname>Maas</surname>
<given-names>Coen</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1034" contrib-type="author"><name><surname>Magnusson</surname>
<given-names>Maria</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1035" contrib-type="author"><name><surname>Mangin</surname>
<given-names>Pierre</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1036" contrib-type="author"><name><surname>Mast</surname>
<given-names>Alan</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1037" contrib-type="author"><name><surname>McLintock</surname>
<given-names>Claire</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1038" contrib-type="author"><name><surname>Miranda</surname>
<given-names>Sébastien</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1039" contrib-type="author"><name><surname>Nathwani</surname>
<given-names>Amit</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1040" contrib-type="author"><name><surname>Ni</surname>
<given-names>Heyu</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1041" contrib-type="author"><name><surname>Áinle</surname>
<given-names>Fionnuala N.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1042" contrib-type="author"><name><surname>Nilsson</surname>
<given-names>Susie</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1043" contrib-type="author"><name><surname>Ny</surname>
<given-names>Tor</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1044" contrib-type="author"><name><surname>O’Brien</surname>
<given-names>Sarah H.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1045" contrib-type="author"><name><surname>O’Donnell</surname>
<given-names>James S.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1046" contrib-type="author"><name><surname>Payrastre</surname>
<given-names>B.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1047" contrib-type="author"><name><surname>Peter</surname>
<given-names>Karlheinz</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1048" contrib-type="author"><name><surname>Rak</surname>
<given-names>Janusz</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1049" contrib-type="author"><name><surname>Randi</surname>
<given-names>Anna M.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1050" contrib-type="author"><name><surname>Rauova</surname>
<given-names>Lubica</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1051" contrib-type="author"><name><surname>Reinhardt</surname>
<given-names>Christoph</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1052" contrib-type="author"><name><surname>Rodger</surname>
<given-names>Marc</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1053" contrib-type="author"><name><surname>Rondina</surname>
<given-names>Matthew</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1054" contrib-type="author"><name><surname>Schreiber</surname>
<given-names>Karen</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1055" contrib-type="author"><name><surname>Severin</surname>
<given-names>S.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1056" contrib-type="author"><name><surname>Shima</surname>
<given-names>Midori</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1057" contrib-type="author"><name><surname>Spyropoulos</surname>
<given-names>Alex</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1058" contrib-type="author"><name><surname>Stanworth</surname>
<given-names>S. J.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1059" contrib-type="author"><name><surname>Suzuki‐Inoue</surname>
<given-names>Katsue</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1060" contrib-type="author"><name><surname>Thomas</surname>
<given-names>Moumneh</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1061" contrib-type="author"><name><surname>Tsukiji</surname>
<given-names>Nagaharu</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1062" contrib-type="author"><name><surname>Urano</surname>
<given-names>Tetsumei</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1063" contrib-type="author"><name><surname>Valet</surname>
<given-names>C.</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1064" contrib-type="author"><name><surname>Vanhoorelbeke</surname>
<given-names>Karen</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1065" contrib-type="author"><name><surname>Verhamme</surname>
<given-names>Peter</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1066" contrib-type="author"><name><surname>Weitz</surname>
<given-names>Jeffrey</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1067" contrib-type="author"><name><surname>Wolberg</surname>
<given-names>Alisa</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1068" contrib-type="author"><name><surname>Zentner</surname>
<given-names>Dominica</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
<contrib id="rth212225-cr-1069" contrib-type="author"><name><surname>Zhu</surname>
<given-names>Cheng</given-names>
</name>
<xref ref-type="contrib" rid="rth212225-cr-1120"></xref>
</contrib>
</contrib-group>
</collab>
<xref ref-type="author-notes" rid="rth212225-note-0501"><sup>†</sup>
</xref>
</contrib>
</contrib-group>
<aff id="rth212225-aff-0001"><label><sup>1</sup>
</label>
<named-content content-type="organisation-division">Department of Haematology and Transfusion Medicine</named-content>
<institution>Royal North Shore Hospital</institution>
<city>Sydney</city>
<named-content content-type="country-part">NSW</named-content>
<country country="AU">Australia</country>
</aff>
<aff id="rth212225-aff-0002"><label><sup>2</sup>
</label>
<named-content content-type="organisation-division">Northern Blood Research Centre</named-content>
<institution>Kolling Institute of Medical Research University of Sydney</institution>
<city>Sydney</city>
<named-content content-type="country-part">NSW</named-content>
<country country="AU">Australia</country>
</aff>
<aff id="rth212225-aff-0003"><label><sup>3</sup>
</label>
<institution>Australian Centre for Blood Diseases</institution>
<institution>Monash University</institution>
<city>Melbourne</city>
<named-content content-type="country-part">VIC</named-content>
<country country="AU">Australia</country>
</aff>
<author-notes><fn id="rth212225-note-0501"><label>†</label>
<p>["Correction Statement added on December 11, 2019: ISTH State of the Art Speakers added in the author byline"]</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>05</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>7</month>
<year>2019</year>
</pub-date>
<volume>3</volume>
<issue>3</issue>
<issue-id pub-id-type="doi">10.1002/rth2.2019.3.issue-3</issue-id>
<fpage>431</fpage>
<lpage>497</lpage>
<permissions><pmc-comment> © 2019 International Society on Thrombosis and Haemostasis </pmc-comment>
<copyright-statement content-type="article-copyright">© 2019 The Authors. <italic>Research and Practice in Thrombosis and Haemostasis</italic>
published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.</copyright-statement>
<license license-type="creativeCommonsBy-nc-nd"><license-p>This is an open access article under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/">http://creativecommons.org/licenses/by-nc-nd/4.0/</ext-link>
License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="file:RTH2-3-431.pdf"></self-uri>
<abstract id="rth212225-abs-0001"><title>Abstract</title>
<p>The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6‐10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or ‘Capsules’ consisting of short text, three references and a figure, with topics including stroke, cancer‐associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure‐function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.</p>
</abstract>
<counts><fig-count count="0"></fig-count>
<table-count count="0"></table-count>
<page-count count="67"></page-count>
<word-count count="1069"></word-count>
</counts>
<custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name>
<meta-value>2.0</meta-value>
</custom-meta>
<custom-meta><meta-name>cover-date</meta-name>
<meta-value>July 2019</meta-value>
</custom-meta>
<custom-meta><meta-name>details-of-publishers-convertor</meta-name>
<meta-value>Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:04.02.2020</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body id="rth212225-body-1001"><p><table-wrap id="nlm-table-wrap-1" xml:lang="en" orientation="portrait" position="anchor"><caption><p>CONTENTS</p>
</caption>
<table frame="hsides" rules="groups"><col style="border-right:solid 1px #000000" span="1"></col>
<col style="border-right:solid 1px #000000" span="1"></col>
<col style="border-right:solid 1px #000000" span="1"></col>
<tbody><tr><td align="left" colspan="3" rowspan="1"><bold>ARTERIAL THROMBOSIS</bold>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Alisa Wolberg</td>
<td align="left" rowspan="1" colspan="1">Fibrin/ogen structure as a potential therapeutic target</td>
<td align="left" rowspan="8" colspan="1"><inline-graphic xlink:href="RTH2-3-431-g062.jpg" xlink:title="image"></inline-graphic>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Gregory Y. H. Lip</td>
<td align="left" rowspan="1" colspan="1">Triple therapy in patients with AF and ACS or PCI/Stenting</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">John Eikelboom</td>
<td align="left" rowspan="1" colspan="1">Combining antiplatelet and anticoagulant therapy</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Simon F. De Meyer</td>
<td align="left" rowspan="1" colspan="1">Novel therapeutic targets in stroke</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Alan Mast</td>
<td align="left" rowspan="1" colspan="1">TFPI: structure, function and therapeutic potential</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Matthew Flick</td>
<td align="left" rowspan="1" colspan="1">Plasminogen activation in inflammatory joint and bone disease</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Tetsumei Urano</td>
<td align="left" rowspan="1" colspan="1">Spatiotemporal regulation of plasminogen activation and its disruption</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Tor Ny</td>
<td align="left" rowspan="1" colspan="1">Plasminogen in wound healing</td>
</tr>
<tr><td align="left" colspan="3" rowspan="1"><bold>BLEEDING</bold>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Daniel Cutler</td>
<td align="left" rowspan="1" colspan="1">VWF storage, secretion and function</td>
<td align="left" rowspan="8" colspan="1"><inline-graphic xlink:href="RTH2-3-431-g063.jpg" xlink:title="image"></inline-graphic>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Cheng Zhu</td>
<td align="left" rowspan="1" colspan="1">VWF and force</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Anna M. Randi</td>
<td align="left" rowspan="1" colspan="1">VWF and angiogenesis</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">James S. O'Donnell</td>
<td align="left" rowspan="1" colspan="1">VWD diagnostic thresholds</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Sarah H. O'Brien</td>
<td align="left" rowspan="1" colspan="1">VWD in children and young women</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Karin Fijnvandraat</td>
<td align="left" rowspan="1" colspan="1">Inhibitor development in non‐severe hemophilia A</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Midori Shima</td>
<td align="left" rowspan="1" colspan="1">Bispecific antibodies and advances in non‐gene therapy options in hemophilia</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Amit Nathwani</td>
<td align="left" rowspan="1" colspan="1">Gene therapy</td>
</tr>
<tr><td align="left" colspan="3" rowspan="1"><bold>COAGULATION CONSULTS</bold>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Jim Luyendyk</td>
<td align="left" rowspan="1" colspan="1">Coagulation proteins and liver disease</td>
<td align="left" rowspan="7" colspan="1"><inline-graphic xlink:href="RTH2-3-431-g064.jpg" xlink:title="image"></inline-graphic>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Karen Vanhoorelbeke</td>
<td align="left" rowspan="1" colspan="1">ADAMTS13 and VWF in TTP</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Stefano Barco</td>
<td align="left" rowspan="1" colspan="1">Risk stratification of patients with acute PE: Implications for home treatment and reperfusion strategies</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Ampaiwan Chuansumrit</td>
<td align="left" rowspan="1" colspan="1">Management strategies for hematological derangement in dengue hemorrhagic fever</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Simon J. Stanworth</td>
<td align="left" rowspan="1" colspan="1">Massive transfusion: algorithm‐based or empiric therapy?</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Jose M. Del Rio</td>
<td align="left" rowspan="1" colspan="1">Mechanical circulatory support coagulopathy: monitoring and management</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Elisabeth M. Battinelli</td>
<td align="left" rowspan="1" colspan="1">Platelets, angiogenesis, and malignancy</td>
</tr>
<tr><td align="left" colspan="3" rowspan="1"><bold>NEW TECHNOLOGIES</bold>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Mettine H. A. Bos</td>
<td align="left" rowspan="1" colspan="1">Factor X variants: from outback to bedside</td>
<td align="left" rowspan="8" colspan="1"><inline-graphic xlink:href="RTH2-3-431-g065.jpg" xlink:title="image"></inline-graphic>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Christoph Reinhardt</td>
<td align="left" rowspan="1" colspan="1">Microbiota and cardiovascular risk</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Karlheinz Peter</td>
<td align="left" rowspan="1" colspan="1">Innovative molecular imaging and drug delivery techniques</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Keith Gomez</td>
<td align="left" rowspan="1" colspan="1">ThromboGenomics</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Elisa Danese</td>
<td align="left" rowspan="1" colspan="1">Epigenetics in hemostasis</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Janusz Rak</td>
<td align="left" rowspan="1" colspan="1">Coagulome, oncogenes, and oncomirs in cancer</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Robert Flaumenhaft</td>
<td align="left" rowspan="1" colspan="1">Thiol isomerases: novel regulation of thrombosis</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Jorge Di Paola</td>
<td align="left" rowspan="1" colspan="1">Genomic discovery approaches for inherited bleeding disorders</td>
</tr>
<tr><td align="left" colspan="3" rowspan="1"><bold>PLATELETS</bold>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Susie Nilsson</td>
<td align="left" rowspan="1" colspan="1">Interplay between HSCs and megakaryocytes</td>
<td align="left" rowspan="11" colspan="1"><inline-graphic xlink:href="RTH2-3-431-g066.jpg" xlink:title="image"></inline-graphic>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Sonia Severin</td>
<td align="left" rowspan="1" colspan="1">PI3K function in platelet production</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Koji Eto</td>
<td align="left" rowspan="1" colspan="1">Beyond platelet production in vitro</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Ian S. Hitchcock</td>
<td align="left" rowspan="1" colspan="1">Activation and regulation of the thrombopoietin receptor</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Heyu Ni</td>
<td align="left" rowspan="1" colspan="1">Mechanisms of Fc‐independent thrombocytopenia</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Jenny Despotovic</td>
<td align="left" rowspan="1" colspan="1">Immune thrombocytopenia in children</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Eric Boilard</td>
<td align="left" rowspan="1" colspan="1">Platelet microparticles and inflammatory diseases</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Matthew Rondina</td>
<td align="left" rowspan="1" colspan="1">Influence of platelets on other cells: mechanisms and consequences</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Pierre Mangin</td>
<td align="left" rowspan="1" colspan="1">Platelet adhesion reception in hemostatic and non‐hemostatic function</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Justin R. Hamilton</td>
<td align="left" rowspan="1" colspan="1">Platelet protease‐activated receptors (PARs): function and targeting</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Katsue Suzuki‐Inoue</td>
<td align="left" rowspan="1" colspan="1">Platelet CLEC‐2 and lung development</td>
</tr>
<tr><td align="left" colspan="3" rowspan="1"><bold>VASCULAR BIOLOGY</bold>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Edward M. Conway</td>
<td align="left" rowspan="1" colspan="1">Molecular links between coagulation and innate immunity</td>
<td align="left" rowspan="8" colspan="1"><inline-graphic xlink:href="RTH2-3-431-g067.jpg" xlink:title="image"></inline-graphic>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Coen Maas</td>
<td align="left" rowspan="1" colspan="1">Contact pathway activation: an unfolding story</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Jonas Emsley</td>
<td align="left" rowspan="1" colspan="1">Structure and function of FXI/FXII</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Craig N. Jenne Thrombin, NETs and platelets in vivo</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Tobias A. Fuchs</td>
<td align="left" rowspan="1" colspan="1">Neutrophil extracellular traps and therapeutic options</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Jeffrey Weitz</td>
<td align="left" rowspan="1" colspan="1">Clinical trials with FXI inhibitors</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Jill M. Johnsen</td>
<td align="left" rowspan="1" colspan="1">Modifiers and genetics of VWF</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Lubica Rauova</td>
<td align="left" rowspan="1" colspan="1">Endothelial cell contribution to the pathology in HIT</td>
</tr>
<tr><td align="left" colspan="3" rowspan="1"><bold>VENOUS THROMBOSIS</bold>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Alex Spyropoulos</td>
<td align="left" rowspan="1" colspan="1">Venous thromboembolic risk assessment in hospitalized medical patients</td>
<td align="left" rowspan="4" colspan="1"><inline-graphic xlink:href="RTH2-3-431-g068.jpg" xlink:title="image"></inline-graphic>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Shinya Goto</td>
<td align="left" rowspan="1" colspan="1">Is there an ethnic difference in the risk of bleeding complications with the use of antithrombotic agents?</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Peter Verhamme</td>
<td align="left" rowspan="1" colspan="1">Which patients should receive long‐term anticoagulation? What dose?</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Marc Rodger</td>
<td align="left" rowspan="1" colspan="1">Recurrent VTE on anticoagulant therapy: what next?</td>
</tr>
<tr><td align="left" colspan="3" rowspan="1"><bold>WOMEN'S & CHILDREN'S COAGULATION</bold>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Fionnuala Ní Áinle</td>
<td align="left" rowspan="1" colspan="1">Risk assessment in pregnancy</td>
<td align="left" rowspan="5" colspan="1"><inline-graphic xlink:href="RTH2-3-431-g069.jpg" xlink:title="image"></inline-graphic>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Karen Schreiber</td>
<td align="left" rowspan="1" colspan="1">Obstetric antiphospholipid syndrome</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Gregoire Le Gal</td>
<td align="left" rowspan="1" colspan="1">Diagnosis of PE in pregnancy</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Dominica Zentner</td>
<td align="left" rowspan="1" colspan="1">VKA are the AC of choice for mechanical valves in pregnancy (debate)</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Maria Magnusson</td>
<td align="left" rowspan="1" colspan="1">Hemostasis in liver disease</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
<sec id="rth212225-sec-0001"><title>Fibrin/ogen structure as a potential therapeutic target</title>
<p><bold>Alisa Wolberg PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
UNC Blood Research Center, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC</p>
<p>Email: <email>alisa_wolberg@med.unc.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0001" orientation="portrait"><graphic xlink:href="RTH2-3-431-g001.jpg" position="anchor" id="nlm-graphic-1" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>For references, see1‐3.</p>
</sec>
<sec id="rth212225-sec-0002"><title>Triple therapy in patients with atrial fibrillation and acute coronary syndrome or PCI/stenting</title>
<p><bold>Gregory Y. H. Lip MD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom; and Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark</p>
<p>Email: <email>gregory.lip@liverpool.ac.uk</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0002" orientation="portrait"><graphic xlink:href="RTH2-3-431-g002.jpg" position="anchor" id="nlm-graphic-3" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Several considerations are necessary when managing patients with atrial fibrillation and acute coronary syndrome or percutaneous cardiovascular intervention/stenting:•Stroke prevention, which requires oral anticoagulation (OAC) with well‐managed vitamin K antagonists (VKAs) or optimal doses of direct OACs.<sup>4</sup>
•Prevention of recurrent cardiac events or ischemia with antiplatelet drugs.<sup>5</sup>
•Reducing stent thrombosis with antiplatelet drugs.<sup>5</sup>
•Managing risk of serious bleeding related to combinations of OACs and antiplatelets.</p>
<p>Mitigating bleeding in this setting requires attention to modifiable bleeding risk factors (eg. uncontrolled hypertension, excess alcohol, concomitant nonsteroidal anti‐inflammatory drugs, labile international normalized ratios if on a vitamin K antagonist, etc), then flagging up the “high‐risk” patients (eg. HAS‐BLED score ≥ 3) for early review and follow‐up.<sup>6</sup>
Percutaneous cardiovascular intervention with radial access reduces periprocedural bleeding, and proton pump inhibitors may be considered. In combination with a P2Y12 inhibitor (not aspirin), bleeding is lower with direct OACs than VKAs, without compromising thrombotic outcomes.<sup>6</sup>
</p>
</sec>
<sec id="rth212225-sec-0003"><title>Combining antiplatelet and anticoagulant therapy</title>
<p><bold>John Eikelboom MBBS, Msc<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Division of Hematology & Thromboembolism, Department of Medicine, McMaster University, Hamilton, Canada</p>
<p>Email: <email>MSceikelbj@mcmaster.ca</email>
; <email>hilllynd@HHSC.CA</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0003" orientation="portrait"><graphic xlink:href="RTH2-3-431-g003.jpg" position="anchor" id="nlm-graphic-5" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>In the arterial circulation, thrombus formation is most commonly triggered by atherosclerotic plaque disruption, which leads to activation of the tissue factor pathway to generate thrombin, and activation of platelets. Thrombin in turn cleaves fibrinogen to form fibrin and is also a potent platelet activator. Less commonly, thrombus formation is triggered by exposure of blood to artificial surfaces (eg, mechanical heart valves), which leads to activation of the contact pathway to generate thrombin. Activated platelets provide a phospholipid surface for thrombin generation and release inorganic polyphosphates that trigger activation of the contact pathway.</p>
<p>When used in combination, antiplatelet and anticoagulant therapy can work synergistically to reduce fibrin formation and platelet activation and thereby prevent thrombus formation. Emerging clinical evidence demonstrates that dual pathway inhibition is beneficial if safe drug combinations are used.</p>
</sec>
<sec id="rth212225-sec-0004"><title>Novel therapeutic targets in stroke</title>
<p><bold>Simon F. De Meyer PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Katholieke Universiteit, Leuven, Kulak, Belgium</p>
<p>Email: <email>simon.demeyer@kuleuven-kortrijk.be</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0004" orientation="portrait"><graphic xlink:href="RTH2-3-431-g004.jpg" position="anchor" id="nlm-graphic-7" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Structural analysis of occluding thrombi retrieved from ischemic stroke patients reveals histologic indications for therapy resistance. This picture shows a Martius Scarlet Blue staining, showing the typical RBC‐rich areas stained yellow and platelet‐rich areas stained pink/red) in a stroke thrombus. RBC‐rich areas have limited complexity as they consist of red blood cells that are densely packed in a meshwork of thin fibrin. In contrast, platelet‐rich areas are characterized by dense fibrin structures aligned with von Willebrand factor (VWF) and abundant white blood cells and extracellular DNA, possibly part of neutrophil extracellular traps (NETs). Hence, in addition to targeting fibrin via tissue‐type plasminogen activator (t‐PA), targeting DNA with DNAse1<sup>9</sup>
and targeting VWF with ADAMTS‐13<sup>10</sup>
are new approaches to improve thrombolysis. Such novel targets could become particularly relevant for treatment of t‐PA‐resistant (platelet‐rich) occlusions in stroke patients.<sup>11</sup>
</p>
</sec>
<sec id="rth212225-sec-0005"><title>TFPI: structure, function, and therapeutic potential</title>
<p><bold>Alan Mast MD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Versiti Blood Center of Wisconsin, Versiti Blood Research Institute, Milwaukee, Wisconsin</p>
<p>Email: <email>alan.mast@bcw.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0005" orientation="portrait"><graphic xlink:href="RTH2-3-431-g005.jpg" position="anchor" id="nlm-graphic-9" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>For references, see12‐14.</p>
</sec>
<sec id="rth212225-sec-0006"><title>Plasminogen activation in inflammatory joint and bone disease</title>
<p><bold>Matthew Flick PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Cincinnati Children's Hospital, Cincinnati, Ohio</p>
<p>Email: <email>matthew.flick@cchmc.org</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0006" orientation="portrait"><graphic xlink:href="RTH2-3-431-g006.jpg" position="anchor" id="nlm-graphic-11" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Rheumatoid arthritis (RA) is a common, yet heterogeneous, chronic inflammatory disease that affects approximately 1% of the population worldwide, with considerable variation among patients in disease progression and severity. A contribution for hemostatic system components is implied by the fact that (1) fibrin deposits along cartilage surfaces and within the inflamed synovium of affected joints is a commonly observed feature of RA patients and experimental animals with inflammatory arthritis, and (2) fibrin degradation products (eg, D‐dimer) accumulate in the synovial fluid of RA patients. Studies of mice with plasminogen activation (PA) system deficiencies have yielded mixed results, suggesting that the contribution of PA is context dependent. Nevertheless, multiple studies suggest 2 potent contributions of PA to inflammatory joint disease pathogenesis. Findings indicate a fundamental role for urokinase plasminogen activator (uPA) and uPA receptor–expressing hematopoietic cells in driving arthritis incidence and progression in autoimmune‐driven arthritis (left panel).<sup>15,16</sup>
Additionally, plasminogen appears to be a key molecular determinant of tumor necrosis factor α–driven inflammatory joint disease capable of driving or ameliorating arthritis pathogenesis in distinct anatomic locations in the same subject (right panel).<sup>17</sup>
</p>
</sec>
<sec id="rth212225-sec-0007"><title>Spatiotemporal regulation of plasminogen activation and its disruption</title>
<p><bold>Tetsumei Urano MD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Hamamatsu University School of Medicine, Hamamatsu, Japan</p>
<p>Email: <email>uranot@hama-med.ac.jp</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0007" orientation="portrait"><graphic xlink:href="RTH2-3-431-g007.jpg" position="anchor" id="nlm-graphic-13" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>C‐terminal lysine in partially digested fibrin is a key factor in spatiotemporal regulation of fibrinolysis. A quick dissolution of generated thrombi is achieved by (1) “native machinery of plasminogen activation and fibrinolysis,” in which plasminogen binding to fibrin surface through its lysine‐binding sites together with tissue‐type plasminogen activator (t‐PA) is a key event. Activated platelet surfaces on which t‐PA and plasminogen assembled appeared to initiate fibrinolysis after forming fibrin (A). In (2) “stabilization of hemostatic thrombi,” a removal of C‐terminal lysine by thrombin‐activatable fibrinolysis inhibitor (TAFI) after activation by thrombin/thrombomodulin is a key event. Soluble thrombomodulin attenuated both plasminogen accumulation and fibrinolysis through TAFI activation (B). (3) “Potential to express PA activity on fibrin” is determined by the balance between t‐PA and plasminogen activator inhibitor‐1. These spatiotemporal regulatory mechanisms of fibrinolysis were revealed by recently advanced real‐time imaging techniques.<sup>18,19</sup>
</p>
</sec>
<sec id="rth212225-sec-0008"><title>Plasminogen in wound healing</title>
<p><bold>Tor Ny PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden</p>
<p>Email: <email>tor.ny@umu.se</email>
; <email>weslou54@gmail.com</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0008" orientation="portrait"><graphic xlink:href="RTH2-3-431-g008.jpg" position="anchor" id="nlm-graphic-15" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Wound healing consists of partially overlapping inflammatory, proliferation, and tissue‐remodeling phases. A successful wound healing depends on a proper activation and subsequent termination of the inflammatory phase. Plasminogen is a critical regulator of the wound healing processes that mediate its effects by activating both immune and nonimmune cells.<sup>20</sup>
Early after wound formation, plasminogen is transported to acute wounds by inflammatory cells, where it leads to intracellular signaling events that result in induction of cytokines that potentiate the early inflammatory response and increased levels of growth factors. Plasminogen also plays an important role in later phases of wound healing, where it indirectly or directly through plasmin activates wound debridement and resolution of inflammation. The multiple and vital functions of plasminogen during wound healing makes plasminogen a very attractive novel drug candidate to treat various wounds, including acute wounds, burns, and various chronic wounds. IL‐6, interlekuin‐6; IL‐10, interleukin‐10; NGF, nerve growth factor; uPA; urokinase‐type plasminogen activator.</p>
</sec>
<sec id="rth212225-sec-0009"><title>VWF storage, secretion and function</title>
<p><bold>Daniel Cutler PhD</bold>
</p>
<p><sup>1</sup>
University College London, MRC Lab for Molecular Cell Biology, Cell Biology Unit, London, England</p>
<p>Email: <email>d.cutler@ucl.ac.uk</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0009" orientation="portrait"><graphic xlink:href="RTH2-3-431-g009.jpg" position="anchor" id="nlm-graphic-17" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Many cellular controls can affect the Weibel‐Palade body population available for release and ultimately the hemostatic response initiated. The left side of the figure shows factors reducing VWF functioning (hemostatic response). The right side shows those producing increased haemostatic response (extremes illustrated).<sup>21‐23</sup>
</p>
</sec>
<sec id="rth212225-sec-0010"><title>VWF and force</title>
<p><bold>Lining A. Ju PhD<sup>1</sup>
, Cheng Zhu PhD<sup>2</sup>
</bold>
</p>
<p><sup>1</sup>
Heart Research Institute, Charles Perkins Centre, School of Aerospace, Mechanical and Mechatronic Engineering, The University of Sydney, Camperdown, NSW, Australia; <sup>2</sup>
Coulter Department of Biomedical Engineering, Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA</p>
<p>Email: <email>cheng.zhu@bme.gatech.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0010" orientation="portrait"><graphic xlink:href="RTH2-3-431-g010.jpg" position="anchor" id="nlm-graphic-19" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Platelets often aggregate near vessel stenosis caused by atherosclerotic plaques or medical device implants, attesting to their extreme mechanosensitivity to blood flow disturbance. Such platelet aggregation is driven by biomechanical rather than biochemical mechanisms, as such prothrombotic effect cannot be eliminated by aspirin and clopidogrel.<sup>24</sup>
Using a stenosed microfluidic model, we demonstrated that the biomechanical platelet aggregation is mainly supported by integrin αIIbβ3 with an extended‐closed (EC) conformation (A).<sup>25</sup>
We also developed a dual biomembrane force probe to visualize integrin biomechanical activation on a living platelet.<sup>26</sup>
We found that, upon mechano‐signaling of GPIb, αIIbβ3 adopts the EC conformation and possesses affinity and bond lifetime that are intermediate between the well‐characterized active and resting states. This inside‐out mechano‐signaling is distinct from the biochemical signaling by agonists and potentiates the outside‐in mechano‐signaling of αIIbβ3 for affinity maturation (B).<sup>24</sup>
Our work highlighted the existence, genesis, and regulation of a semistable intermediate state of αIIbβ3 that is fundamental in mechanically driven thrombosis.<sup>26</sup>
</p>
</sec>
<sec id="rth212225-sec-0011"><title>VWF and angiogenesis</title>
<p><bold>Anna M. RandiMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Imperial College, National Heart and Lung Institute, London, England</p>
<p>Email: <email>a.randi@imperial.ac.uk</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0011" orientation="portrait"><graphic xlink:href="RTH2-3-431-g011.jpg" position="anchor" id="nlm-graphic-21" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The discovery that the hemostatic protein von Willebrand factor (VWF), best known for mediating platelet adhesion, controls blood vessel formation has provided a novel hypothesis to explain the pathogenesis of vascular malformations (angiodysplasia) and gastrointestinal (GI) bleeding in patients with congenital von Willebrand disease (VWD) or acquired von Willebrand syndrome (AWVS).<sup>27</sup>
VWF is found predominantly in 3 pools: cellular, plasmatic, and subendothelial; VWF binds to many proteins, some of which regulate angiogenesis. Loss of VWF in endothelial cells (ECs) in vitro and in vivo results in abnormal angiogenesis.<sup>28</sup>
The mechanism is not completely understood, but is likely to involve angiopoietin‐2 (Ang‐2), a coregulator of angiogenesis, and possibly other components of the endothelial organelles Weibel‐Palade bodies (WPBs). Clinical evidence indicates that high‐molecular‐weight multimers of VWF are also likely to be involved.<sup>29</sup>
Understanding the contribution of these pathways will be key to developing new therapeutic approaches and improve patients’ treatment.</p>
</sec>
<sec id="rth212225-sec-0012"><title>VWD diagnostic thresholds</title>
<p><bold>James S. O'DonnellMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Royal College of Surgeons in Ireland, Irish Centre for Vascular Biology, Department of Molecular and Cellular Therapeutics Dublin</p>
<p>Email: <email>jamesodonnell@rcsi.ie</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0012" orientation="portrait"><graphic xlink:href="RTH2-3-431-g012.jpg" position="anchor" id="nlm-graphic-23" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Since the pathophysiology and heritability of low von Willebrand factor (VWF) levels remain poorly understood, diagnosis and management of these patients continues to pose significant clinical challenges. Data from the Low VWF Ireland Cohort (LoVIC) study have demonstrated that blood group O females are overrepresented in those registered with low VWF.<sup>30</sup>
Despite having modest reductions in plasma VWF:Ag levels, Low VWF patients can have significant bleeding, particularly heavy menstrual bleeding (HMB) and postpartum hemorrhage (PPH).<sup>31</sup>
In the majority of patients, low VWF levels are due to reductions in VWF synthesis that appear to be largely independent of any <italic>VWF</italic>
gene mutations.<sup>30</sup>
Enhanced VWF clearance may also contribute to pathophysiology in some individuals with low VWF, with abnormal VWF glycosylation involved in the etiology of this increased VWF clearance.<sup>32</sup>
Importantly however, any reduction in VWF plasma half‐life is usually mild and does not significantly impair duration of DDAVP‐induced VWF responses.</p>
</sec>
<sec id="rth212225-sec-0013"><title>VWD in children and young women</title>
<p><bold>Sarah H. O'BrienMD, MSc<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Nationwide Children's Hospital, Pediatric Hematology/Oncology, Columbus</p>
<p>Email: <email>sarah.obrien@nationwidechildrens.org</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0013" orientation="portrait"><graphic xlink:href="RTH2-3-431-g013.jpg" position="anchor" id="nlm-graphic-25" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>This review focuses on 4 management issues commonly faced by clinical providers in the care of children and adolescents with von Willebrand disease (VWD): epistaxis, heavy menstrual bleeding, and preparation for tooth extraction and tonsillectomy. A variety of management strategies are available, including desmopressin, antifibrinolytics, plasma‐derived and recombinant factor replacement, hormonal contraception for heavy menses, and local measures for epistaxis.<sup>33</sup>
While many aspects of management are similar to hematologic care for adults with VWD, there are pediatric‐specific considerations. For example, desmopressin is typically avoided in patients under 4 years of age due to the increased risk of hyponatremia‐related seizures. For heavy menstrual bleeding in adolescents, monophasic formulations of oral contraceptives with low‐dose estrogen (30–35 micrograms) are preferred over triphasic or ultra‐low‐estrogen formulations.<sup>34</sup>
Finally, when planning for tonsillectomy, the risk of delayed bleeding (days 5–12) must be considered.<sup>35</sup>
</p>
</sec>
<sec id="rth212225-sec-0014"><title>Inhibitor development in nonsevere hemophilia A</title>
<p><bold>Karin FijnvandraatMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Emma's Children's Hospital AMC, Pediatric Hematology, Amsterdam</p>
<p>Email: <email>c.j.fijnvandraat@amc.nl</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0014" orientation="portrait"><graphic xlink:href="RTH2-3-431-g014.jpg" position="anchor" id="nlm-graphic-27" orientation="portrait"></graphic>
</boxed-text>
<boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0015" orientation="portrait"><graphic xlink:href="RTH2-3-431-g015.jpg" position="anchor" id="nlm-graphic-29" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The development of neutralizing factor VIII (FVIII) antibodies (inhibitors) is a major challenge in patients with nonsevere hemophilia A (NSHA).<sup>36</sup>
In contrast to severe hemophilia, NSHA patients have a lifelong risk of inhibitor development. In the studies of the INSIGHT consortium, we demonstrated that inhibitors are associated with a deterioration of bleeding phenotype and increased mortality rate.<sup>37</sup>
</p>
<p><italic>F8</italic>
genotype is an important risk factor for inhibitor development. Inhibitor development in NSHA is provoked by exposure to a peptide sequence of wild‐type FVIII that overlaps with the mutated sequence in endogenous FVIII. The patient's immune system is tolerant to the endogenous peptide (A), but naïve to the wild‐type sequence of this specific peptide (B). When this peptide is presented to the T‐cell receptor, an immune response will be elicited. Thus, T‐cell epitopes in NSHA patients are likely to be associated with the location of the missense mutation. This concept is supported by studies that demonstrate that T‐cell epitopes in NSHA inhibitor patients generally include the wild‐type sequence overlapping the mutated sequence in endogenous FVIII, indicating that a relatively small sequence mismatch can provoke a T‐cell response, subsequently resulting in inhibitor development.<sup>38</sup>
</p>
</sec>
<sec id="rth212225-sec-0015"><title>Bispecific antibodies and advances in non–gene therapy options in hemophilia</title>
<p><bold>Midori ShimaMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Pediatrics, Nara Medical University, Nara, Japan</p>
<p>Email: <email>mshima@naramed-u.ac.jp</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0016" orientation="portrait"><graphic xlink:href="RTH2-3-431-g016.jpg" position="anchor" id="nlm-graphic-31" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Emicizumab is a bispecific antibody recognizing factor IXa (FIXa) and factor X (FX). It promotes activation of FX in the absence of factor VIII (FVIII).<sup>39</sup>
Emicizumab initially reacts with FIXa mediated by the factor FVIIa (FVIIa)/tissue factor (TF) complex (A). Under physiologic circumstances, FVIIa/TF activity is limited by tissue factor pathway inhibitor (TFPI), but emicizumab‐driven FXa and thrombin generation is enhanced in the presence of FIXa derived from FXIa‐dependent reactions. Hence, FIXa is supplied through a FXI activation‐loop, and emicizumab‐driven FXa and thrombin generation is maintained. The products of emicizumab activity are regulated by natural anticoagulants including activated protein C (APC), antithrombin (AT), and TFPI (A). Emicizumab provides a novel therapeutic strategy for hemophilia A with several clinical advantages, including subcutaneous availability, longer half‐life, and effectiveness in the presence of an FVIII inhibitor.<sup>40</sup>
The use of emicizumab for early prophylaxis offers the prevention of bleeding and long‐term maintenance of intact joints. Several options should be considered on an individual basis, however (B).</p>
</sec>
<sec id="rth212225-sec-0016"><title>Gene therapy</title>
<p><bold>Amit Nathwani MBChB, FRCP, FRCPath, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
University College of London Cancer Institute, Haematology, London, England</p>
<p>Email: <email>amit.nathwani@ucl.ac.uk</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0017" orientation="portrait"><graphic xlink:href="RTH2-3-431-g017.jpg" position="anchor" id="nlm-graphic-33" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Gene therapy offer the potential for a cure for the hemophilias. Recombinant adeno‐associated virus (AAV) vectors are particularly attractive for gene therapy because of their excellent safety profile and ability to mediate efficient transduction of the liver following systemic administration of vector (A). The liver is an attractive site for gene transfer, as it is the site of synthesis of many clotting factors and its ability to induce tolerance to transgenic protein. The first trial to provide clear evidence of efficacy after a single peripheral vein infusion of AAV vector encoding the human factor IX gene in patients with hemophilia B was reported by our group.<sup>41,42</sup>
Longer follow‐up of these patients has not unveiled any toxicities, while plasma factor IX levels have remained stable in all 3 dose cohorts over a period extending 8 years (B), resulting in persistent reduction in annualized bleed rates and factor concentrate usage (C). Similar efficacy with AAV vectors has also been reported in haemophilia A.<sup>43</sup>
</p>
</sec>
<sec id="rth212225-sec-0017"><title>Coagulation proteins and liver disease</title>
<p><bold>Jim Luyendyk PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Michigan State University, Center for Integrative Toxicology, Department of Pathobiology & Diagnostic Investigation, East Lansing, MI</p>
<p>Email: <email>luyendyk@cvm.msu.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0061" orientation="portrait"><graphic xlink:href="RTH2-3-431-g061.jpg" position="anchor" id="nlm-graphic-35" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The liver synthesizes a majority of pro‐ and anticoagulant factors. Thus, hepatic dysfunction in acute and chronic liver diseases results in substantial changes in function of the hemostatic system. Importantly, hepatic dysfunction produces a fragile rebalancing of hemostasis, leaving patients with liver disease often prone to both bleeding and thrombosis. Experimental evidence has linked coagulation proteases and their targets (eg, Protease‐activated receptors (PARs), fibrinogen) to the development of diseases of high concern including alcoholic and nonalcoholic fatty liver disease, and to end‐stage pathologies of liver diseases such as fibrosis/cirrhosis. This connection is under investigation in patients with liver fibrosis. Finally, the role of coagulation factors in liver injury is clearly context dependent, as emerging experimental and clinical evidence links fibrinogen‐driven mechanisms to pro‐repair and pro‐regenerative responses after acute liver injury and partial liver resection.<sup>44‐46</sup>
</p>
</sec>
<sec id="rth212225-sec-0018"><title>ADAMTS13 and VWF in TTP</title>
<p><bold>Karen Vanhoorelbeke PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Katholieke Universiteit, Leuven, Kulak, Belgium</p>
<p>Email: <email>karen.vanhoorelbeke@kuleuven-kulak.be</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0018" orientation="portrait"><graphic xlink:href="RTH2-3-431-g018.jpg" position="anchor" id="nlm-graphic-37" orientation="portrait"></graphic>
</boxed-text>
</p>
</sec>
<sec id="rth212225-sec-0019"><title>Risk stratification of patients with acute pulmonary embolism (PE): implications for home treatment and reperfusion strategies</title>
<p><bold>Stefano Barco MD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany</p>
<p>Email: <email>stefano.barco@unimedizin-mainz.de</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0019" orientation="portrait"><graphic xlink:href="RTH2-3-431-g019.jpg" position="anchor" id="nlm-graphic-39" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The severity of acute pulmonary embolism (PE) can be estimated based on (1) the presence and degree of right ventricular (RV) dysfunction as assessed by imaging tests, (2) the levels of cardiac biomarkers in the circulation, and (3) demographic and clinical factors.<sup>50</sup>
</p>
<p>Patients with hemodynamic instability and cardiogenic shock (high‐risk PE) are candidates for systemic thrombolysis or other reperfusion therapy.<sup>50</sup>
On the other hand, primary reperfusion has an unfavorable risk‐benefit ratio in patients with intermediate‐risk PE; in future clinical trials, safer regimens and techniques (eg, low‐dose systemic thrombolysis or catheter‐directed reperfusion) will need to be tested as a therapeutic option for selected normotensive patients.<sup>51</sup>
Direct oral anticoagulant agents are an effective and safe treatment option for the vast majority of patients with PE.<sup>50</sup>
Potential candidates for early discharge and home anticoagulant treatment can be identified based on the severity of PE, the presence and burden of comorbidities, and a supportive social/family environment.<sup>52</sup>
</p>
</sec>
<sec id="rth212225-sec-0020"><title>Management strategies for hematological derangement in dengue hemorrhagic fever</title>
<p><bold>Ampaiwan Chuansumrit MD <sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand</p>
<p>Email: <email>ampaiwan.jua@mahidol.ac.th</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0020" orientation="portrait"><graphic xlink:href="RTH2-3-431-g020.jpg" position="anchor" id="nlm-graphic-41" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Dengue hemorrhagic fever (DHF) is a clinical diagnosis with 3 stages: febrile, toxic, and defervescence. The febrile stage lasts 2–7 days, followed by the toxic stage of 24–48 hours, and clinical recovery in the defervescence stage. Vasculopathy with positive tourniquet test indicating the increased vascular permeability starts from the early febrile stage. The plasma leakage from the intravascular compartment is most prominent during the toxic stage, resulting in hemoconcentration, hypoproteinemia/hypoalbuminemia, pleural effusion, ascites, threatened shock, and profound shock. The bleeding diathesis is caused by vasculopathy, thrombocytopenia, platelet dysfunction, and coagulopathy. Variable reductions in the activities of several coagulation factors have been reported.<sup>53</sup>
Low levels of protein C and S and antithrombin III were found to be associated with increased severity of dengue manifestation.<sup>54</sup>
Optimal fluid therapy to maintain the functions of the vital organs during the critical period and effective bleeding control will lead to favorable outcomes.<sup>55</sup>
</p>
</sec>
<sec id="rth212225-sec-0021"><title>Massive transfusion: algorithm‐based or empiric therapy?</title>
<p><bold>Simon J. StanworthMA, PhD<sup>1</sup>
, Nicola Curry MRCP, FRCPath, MD<sup>2</sup>
</bold>
</p>
<p><sup>1</sup>
NHS Blood and Transplant/ Oxford University Hospitals NHS Foundation Trust, Level 2, John Radcliffe Hospital, Oxford, England; <sup>2</sup>
Haematology and Transfusion Medicine, University of Oxford, Oxford, England</p>
<p>Email: <email>simon.stanworth@nhsbt.nhs.uk</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0021" orientation="portrait"><graphic xlink:href="RTH2-3-431-g021.jpg" position="anchor" id="nlm-graphic-43" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Worldwide, trauma remains a leading cause of death in the younger populations. There has been a paradigm change in our approach to supportive care and transfusion practice for trauma hemorrhage resuscitation, with increased emphasis on timely delivery of “balanced” blood components,<sup>56</sup>
less crystalloids, and use of tranexamic acid. Measures to target trauma‐induced coagulopathy are integral to current management approaches, but our understanding of the pathophysiology is incomplete, including the role of endothelial activation and the interactions between hemostatic and inflammatory pathways.<sup>57</sup>
Randomized trials are increasingly informing optimal practice (eg, tranexamic acid, plasma), but the size and methodological quality of all the studies varies very considerably.<sup>58</sup>
Areas of current uncertainty relate to use of platelets, concentrated sources of fibrinogen, and whole blood, in addition to the treatment approaches for older patients taking anticoagulants or antiplatelet agents. It is unclear whether protocols in trauma should be generalized to other hospital clinical settings of major bleeding. SLT, standard laboratory tests; VHA, viscoelastic hemostatic assays.</p>
</sec>
<sec id="rth212225-sec-0022"><title>Mechanical circulatory support coagulopathy: monitoring and management</title>
<p><bold>Jose M. Del Rio PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Divisions of Cardiothoracic Anesthesiology & Critical Care, Department of Anesthesiology, Duke University Medical Center, Durham, NC</p>
<p>Email: <email>jm.delrio@duke.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0022" orientation="portrait"><graphic xlink:href="RTH2-3-431-g022.jpg" position="anchor" id="nlm-graphic-45" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Exposure to extracorporeal circulation circuits and consequent blood‐circuit surface interaction triggers a cascade of events that promote both bleeding and thrombosis. Platelet activation is a central event that contributes to both. Platelet activation generates microthromboses and local ischemia, which can have a significant role in organ dysfunction in this setting. Importantly, hemolysis also promotes both a prothrombotic and a vasoconstrictive state due to nitric oxide consumption via free hemoglobin.</p>
<p>In addition to the consumption coagulopathy that can result from platelet activation and loss (similar to the coagulopathic stage of disseminated intravascular coagulation), it is well described that exposure of glycoprotein ADAMTS‐13 lytic site and proteolysis of high‐molecular‐weight von Willebrand multimers results in acquired von Willebrand syndrome. This syndrome, along with angiodysplasia, is more comprehensively described with long‐term support with left ventricular assist devices (LVADs). Both mechanisms lead to increased risk of bleeding; therefore, bleeding and thrombosis can coexist and complicate the use of anticoagulation in this population. Our understanding of the role of platelets and immunothromboses as important factors in occurrence of short‐ and long‐term organ dysfunction in this unique patient population is still evolving.<sup>59‐61</sup>
</p>
</sec>
<sec id="rth212225-sec-0023"><title>Platelets, angiogenesis, and malignancy</title>
<p><bold>Elisabeth M. Battinelli MD, PhD<sup>1,2</sup>
</bold>
</p>
<p><sup>1</sup>
Division of Hematology, Department of Medicine; Brigham and Women's Hospital; Boston, MA; <sup>2</sup>
Harvard Medical School, Boston, MA</p>
<p>Email: <email>ebattinelli@partners.org</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0023" orientation="portrait"><graphic xlink:href="RTH2-3-431-g023.jpg" position="anchor" id="nlm-graphic-47" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Functional versatility of platelets beyond hemostasis is best exemplified in their resourcefulness in malignancy. Platelets promote metastasis and support tumor growth. Platelet activation and increased production are associated with a poor cancer‐related prognosis. It is unknown whether these platelet responses are epiphenomenal or due to malignancy. We have made significant discoveries in understanding platelets regulation of tumor growth. Platelets are activated by tumor cells.<sup>62</sup>
Activated platelets release biologically active protein cargo including cytokines and growth factors that support neovascularization and metastasis. Platelet secretion of these factors can be blocked by platelet‐targeted therapies like aspirin.<sup>63</sup>
One cytokine released upon activation is chemokine ligand 5 (CCL5), which interacts with the chemokine receptor type 5 (CCR5) receptor on tumor cells stimulating the pAKT pathway, leading to tumor cell secretion of interleukin‐8.<sup>64</sup>
CCL5 also drives megakaryocytopoiesis. By understanding how tumor cells hijack platelets, we will elucidate the platelet's role in malignancy and determine key regulators of megakaryocytopoeisis.</p>
</sec>
<sec id="rth212225-sec-0024"><title>Factor X variants: from outback to bedside</title>
<p><bold>Mettine H. A. Bos PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands</p>
<p>Email: <email>M.H.A.Bos@lumc.nl</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0024" orientation="portrait"><graphic xlink:href="RTH2-3-431-g024.jpg" position="anchor" id="nlm-graphic-49" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The venom of several Australian Elapid snakes, including the common or eastern brown snake (<italic>Pseudonaja textilis</italic>
), contains procoagulant factor (F)Xa‐Va‐like enzymes that, once injected into the bloodstream of the prey, convert prey prothrombin into thrombin.<sup>65</sup>
Both venom proteins comprise exceptional structural and functional features,<sup>66</sup>
with venom FXa carrying specific modifications of the substrate‐binding aromatic S4 subpocket within its active site that disrupt high‐affinity engagement of the direct FXa‐inhibiting oral anticoagulants.<sup>67</sup>
Human FX variants comprising a similarly modified S4 subsite resulting either from a single point mutation at position Phe174 (chymotrypsinogen numbering) or insertion of a unique snake venom FXa 99‐loop demonstrated a 10‐ to 100‐fold loss of FXa inhibitor‐sensitivity.<sup>67</sup>
As these FX variants are able to restore hemostasis in plasma inhibited by the FXa inhibitors, they have the potential to bypass the direct factor Xa inhibitor–mediated anticoagulation in patients that require restoration of blood coagulation.</p>
</sec>
<sec id="rth212225-sec-0025"><title>Microbiota and cardiovascular risk</title>
<p><bold>Christoph Reinhardt PhD<sup>1,2</sup>
</bold>
</p>
<p><sup>1</sup>
Center for Thrombosis and Hemostasis, University Medical Center Mainz, Johannes Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; <sup>2</sup>
German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Mainz, Germany</p>
<p>Email: <email>christoph.reinhardt@unimedizin-mainz.de</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0025" orientation="portrait"><graphic xlink:href="RTH2-3-431-g025.jpg" position="anchor" id="nlm-graphic-51" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The gut microbiota is an environmental factor that impacts vascular physiology, locally in the intestine,<sup>68</sup>
but also through remote signalling.<sup>69</sup>
Dependent on diet, numerous mouse studies demonstrated that this gut‐resident microbial ecosystem affects atherogenesis.<sup>70</sup>
Atherosclerotic lesion formation can be driven by gut microbial metabolites, such as the choline‐metabolite trimethylamine, but also by microbiota‐derived microbial‐associated molecular patterns that reach the circulation and affect endothelial cell activation and organ‐specific immunity.<sup>69,70</sup>
We and others could show a reduced thrombus growth in germ‐free mice in various carotid artery injury models, implicating the gut microbiota in arterial thrombosis.<sup>66,67</sup>
The deposition of platelets to the vascular injury site of germ‐free mice was diminished due to reduced von Willebrand factor plasma levels and impaired platelet integrin function.<sup>66</sup>
This recent evidence broadens our perception of colonizing gut microbes beyond their established role in bloodstream infections.</p>
</sec>
<sec id="rth212225-sec-0026"><title>Innovative molecular imaging and drug delivery techniques</title>
<p><bold>Karlheinz PeterMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Baker IDI Heart and Diabetes Institute, Atherothrombosis & Vascular Biology, Melbourne, Victoria, Australia</p>
<p>Email: <email>karlheinz.peter@baker.edu.au</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0026" orientation="portrait"><graphic xlink:href="RTH2-3-431-g026.jpg" position="anchor" id="nlm-graphic-53" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Recently, platelets have attracted major interest in regards to their various roles beyond thrombosis and hemostasis. To study the role of platelets in 2 common diseases, myocardial infarction and cancer, which are major causes of mortality/morbidity, we generated a single‐chain antibody (scFv, consisting only of the variable region of the heavy [VH] and light chain [VL]) that specifically binds to activated glycoprotein (GP)IIb/IIIa and thus allows molecular targeting toward activated platelets.</p>
<p>We showed that platelets are highly abundant in areas of cardiac ischemia/reperfusion (I/R). The coupling of the anti‐inflammatory, activated platelet‐targeted scFv‐CD39 construct could indeed fully prevent I/R injury and thus maintain cardiac function.<sup>71</sup>
</p>
<p>Furthermore, we could show that platelets are highly abundant in tumors and indeed can be used as a target to diagnose cancer, including metastases, either by using ultrasound, fluorescence, or positron emission tomography (PET) imaging (see example in figure).<sup>72</sup>
Most interestingly, targeting platelets with chemotherapeutic drugs or radioactive drugs demonstrates an effective anticancer approach.<sup>73</sup>
</p>
<p>In summary, activated platelets present a highly promising target for diagnostic and therapeutic, or the combination of both, theranostic approaches in I/R and cancer.</p>
</sec>
<sec id="rth212225-sec-0027"><title>ThromboGenomics</title>
<p><bold>Keith Gomez MD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Royal Free Hospital, Katharine Dormandy Haemophilia and Thrombosis Centre; University College London, Haematology, London, England</p>
<p>Email: <email>k.gomez@ucl.ac.uk</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0027" orientation="portrait"><graphic xlink:href="RTH2-3-431-g027.jpg" position="anchor" id="nlm-graphic-55" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>ThromboGenomics was the first high‐throughput sequencing (HTS) test covering known genes responsible for monogenic bleeding and thrombotic and platelet disorders. It was introduced in 2015 and has issued reports on 2390 index cases from around the world. The rate of a genetic diagnosis depends on the type of disorder (A). For established monogenic coagulation factor deficiencies, the diagnostic rate was nearly 70%. For heritable thrombotic or platelet disorders, the diagnosis rate was lower. Unexplained bleeding disorders with normal laboratory evaluation and no established molecular mechanism have a low genetic diagnosis rate, perhaps because these have a polygenic or nongenetic etiology.</p>
<p>Of 756 unique variants identified, half are novel. Establishing pathogenicity with novel variants is difficult, leading to classification as variants of uncertain significance (VUS; B). VUS can be reclassified as benign or pathogenic through sharing information in online databases. Clinicians need to be aware of this possibility when explaining results to patients.</p>
</sec>
<sec id="rth212225-sec-0028"><title>Epigenetics in hemostasis</title>
<p><bold>Elisa Danese PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
University of Verona, Life and Reproduction, Verona, Italy</p>
<p>Email:<email>elisa.danese@univr.it</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0028" orientation="portrait"><graphic xlink:href="RTH2-3-431-g028.jpg" position="anchor" id="nlm-graphic-57" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Epigenetics is one of the fastest growing research domains in biomedicine. Recent studies suggested that microRNAs (miRNAs) and DNA methylation may have a clear‐cut impact on regulation of the hemostatic balance and, in particular, in development of the prothrombotic state associated with coronary artery disease.<sup>74</sup>
Reliable evidence has been provided that some modifications play a crucial role in triggering endothelial dysfunction, platelet activation, impaired fibrinolysis, and increased values of procoagulant factors, thus opening exciting perspectives for understanding the molecular mechanisms involved in the pathophysiology of hemostasis and also for designing new diagnostic and prognostic disease biomarkers.<sup>74,75</sup>
Epigenetics may also provide complementary, and often more informative, value than that gained from pharmacogenetic and pharmacodynamic studies for predicting response to anticoagulant and antiplatelet therapies.<sup>76</sup>
However, before such promising epigenetic biomarkers will enter clinical practice, multiple challenges need to be addressed, such as the lack of analytical standardization and poor standardization of preanalytical phase.</p>
</sec>
<sec id="rth212225-sec-0029"><title>Coagulome, oncogenes, and oncomirs in cancer</title>
<p><bold>Janusz Rak MD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
McGill University, Montreal, Quebec, Canada</p>
<p>Email: <email>janusz.rak@mcgill.ca</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0029" orientation="portrait"><graphic xlink:href="RTH2-3-431-g029.jpg" position="anchor" id="nlm-graphic-59" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>While cancer‐associated thrombosis (CAT) represents a complex nexus of cellular, stromal, and microenvironmental influences, it is not an “unspecific” condition. Rather, CAT is a consequence of oncogenic driver events that alter the phenotype of cancer cells and their communication with stroma and the hemostatic system. In glioblastoma mutiforme (GBM), this is exemplified by the profile of coagulation‐related genes (coagulome), which is a function of molecular subtypes of the disease. Indeed, morphologically similar GBMs (eg, proneural, mesenchymal, or classical) and other brain tumors exhibit different profiles of oncogenes (IDH1, EGFR, oncomirs), as well as coagulomes and risks of thrombosis<sup>77,78</sup>
(A, B). Moreover, each GBM subtype represents a combinatorial mixture of cells with distinct coagulation profiles with enrichment of different effectors, including podoplanin (PDPN), tissue factor (TF), and other regulators.<sup>79</sup>
This coagulant heterogeneity predicts the existence of genetically/epigenetically combinatorial CAT subtypes with different targetable mechanisms and different thrombotic severities.</p>
</sec>
<sec id="rth212225-sec-0030"><title>Thiol isomerases: novel regulators of thrombosis</title>
<p><bold>Robert Flaumenhaft MD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Beth Israel Deaconess Medical Center, New York, NY</p>
<p>Email: <email>rflaumen@bidmc.harvard.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0030" orientation="portrait"><graphic xlink:href="RTH2-3-431-g030.jpg" position="anchor" id="nlm-graphic-61" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Protein disulfide isomerase (PDI) is an essential component of in vivo clot formation. Using a high‐throughput screen, we identified rutin and isoquercetin as inhibitors of PDI. These compounds also inhibited in vivo thrombus formation.<sup>80</sup>
Following oral ingestion in humans, isoquercetin inhibited platelet‐dependent thrombin generation in a PDI‐dependent manner.<sup>81</sup>
Isoquercetin was subsequently evaluated in a phase II study of patients with advanced cancer to assess its effect on hypercoaguability.<sup>82</sup>
Isoquercetin ingestion resulted in PDI inhibitory activity in plasma, reduced D‐dimer levels, reduced soluble P‐selectin levels, and inhibited platelet‐dependent thrombin generation ex vivo. While approximately 20% of patients experienced a thrombotic event in a similarly designed study,<sup>83</sup>
none of the patients receiving isoquercetin demonstrated deep vein thrombosis (DVT) or pulmonary embolism (PE) during this study. Five incidental catheter‐associated DVT or superficial clots that did not meet the prespecified venous thromboembolism (VTE) endpoint criteria were detected. There were no severe adverse events attributable to isoquercetin. No major hemorrhages were observed.</p>
</sec>
<sec id="rth212225-sec-0031"><title>Genomic discovery approaches for inherited bleeding disorders</title>
<p><bold>Jorge Di Paola MD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Genomic Discovery Approaches for Inherited Bleeding Disorders, University of Colorado Denver Pediatrics/Genetics, Denver, Colorado</p>
<p>Email: <email>jorge.dipaola@ucdenver.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0031" orientation="portrait"><graphic xlink:href="RTH2-3-431-g031.jpg" position="anchor" id="nlm-graphic-63" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The use of high‐throughput sequencing has significantly improved scientists and physicians’ ability to characterize the genetic mechanisms of bleeding disorders. Over the past decade, there has been a surge of reports identifying candidate sequence variants not only for single‐gene Mendelian diseases but also for complex inherited coagulation and platelet disorders and traits. Large‐scale worldwide whole‐genome sequencing projects that link genotypes with health records have become invaluable tools in understanding the link between gene mutations and disease. These discoveries have been coupled with genome‐wide RNA and chromatin immunoprecipitation sequencing databases, allowing investigators to understand the effect of genetic variants on transcription and chromatin regulation. The recent introduction of efficient genome editing by CRISPR, the generation of relevant animal models and induced pluripotent stem cells from patients have significantly advanced our understanding of the functional consequence of these mutations and their effect on the complex biology of hemostasis.<sup>84‐86</sup>
</p>
</sec>
<sec id="rth212225-sec-0032"><title>Interplay between HSCs and megakaryocytes</title>
<p><bold>Susie Nilsson PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Biomedical Manufacturing, CSIRO, ARMI, Monash University, Melbourne, Victoria, Australia</p>
<p>Email: <email>susie.nilsson@csiro.au</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0032" orientation="portrait"><graphic xlink:href="RTH2-3-431-g032.jpg" position="anchor" id="nlm-graphic-65" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Interactions between hematopoietic stem cells (HSCs) and the cellular and extracellular constituents of the endosteal bone marrow niche are crucial for HSC regulation. However, the precise interactions regulating HSC function remain unclear. Interestingly, we showed that following HSC transplant into nonablated recipients, 68% of transplanted cells lodge within 2 cells of mature megakaryocytes (MKs); large multiploidal cells responsible for platelet production that account for approximately 0.1% to 0.2% of marrow cells. MKs have now been identified as key components of the bone marrow (BM) stem cell niche, directly regulating HSC through the maintenance of cell quiescence; which we identified to occur via multiple mechanisms, including thrombin cleaved osteopontin (tcOPN), insulin‐like growth factor‐1 (IGF‐1) and insulin‐like growth factor binding protein 3 (IGFBP‐3). Furthermore, the absence of mature MKs, coincides with dysregulation of the HSC pool, which in our hands results in a significant increase in marrow HSC and endogenous mobilization.<sup>87‐89</sup>
</p>
</sec>
<sec id="rth212225-sec-0033"><title>PI3K function in platelet production</title>
<p><bold>Sonia SeverinPhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Inserm U1048 and Paul Sabatier University, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0033" orientation="portrait"><graphic xlink:href="RTH2-3-431-g033.jpg" position="anchor" id="nlm-graphic-67" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The class II PI3K PI3KC2α and the class III PI3K Vps34 regulate specific pools of their common lipid product, phosphatidylinositol 3 monophosphate (PI3P), and have different implications in platelet production and activation. On one hand, the class II PI3K PI3KC2α, by regulating a basal pool of PI3P and organizing the spectrin‐rich membrane skeleton, is important for maintaining normal platelet membrane morphology/remodeling that is important for platelet thrombotic capacities.<sup>90</sup>
On the other hand, the class III PI3K Vps34 regulates a stimulation‐dependent pool of PI3P involved in control of platelet secretion and arterial thrombus growth. Also, Vps34, by regulating a specific pool of PI3P that controls endocytic/endosomal trafficking, granule biogenesis, and directional migration in megakaryocytes, maintains normal platelet production (platelet granule content and circulating platelet count and size).<sup>91</sup>
In summary, PI3KC2α and Vps34 could be promising targets for antiplatelet therapy as their inhibition may decrease thrombosis without increasing bleeding risk.</p>
</sec>
<sec id="rth212225-sec-0034"><title>Beyond platelet production in vitro</title>
<p><bold>Koji EtoMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan</p>
<p>Email: <email>kojieto@cira.kyoto-u.ac.jp</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0034" orientation="portrait"><graphic xlink:href="RTH2-3-431-g034.jpg" position="anchor" id="nlm-graphic-69" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>To overcome the limitations in supply and safety of current platelet transfusion products, the ex vivo production of human platelets using pluripotent stem cells has been developed.<sup>92</sup>
One of strategies is to establish expandable megakaryocyte lines as a source of cyclic guanosine monophosphate (cGMP)‐manufacturing platelets.<sup>93</sup>
Additionally, industrial scaling up of manufacture needs a new concept on the development of bioreactor. Recently, we found by in vivo observation in mice that (1) turbulent flow is present at the active bone marrow megakaryocyte sites, and (2) optimal ranges of turbulent energy and shear stress under turbulent flow conditions are required for ex vivo intact platelet manufacturing at levels of 100 billion order.<sup>94</sup>
We further elucidated the new mechanism whereby turbulent flow released 6 factors from megakaryocytes, where insulin‐like growth factor–binding protein 2 (IGFBP2), macrophage migration inhibitory factor (MIF), and nardilysin mostly contributed to platelet shedding. Figure shows development of bioreactor system (left), and hypothesized illustration of platelet biogenesis (right).</p>
</sec>
<sec id="rth212225-sec-0035"><title>Activation and regulation of the thrombopoietin receptor</title>
<p><bold>Ian S. Hitchcock PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
York Biomedical Research Institute, Department of Biology, University of York, UK</p>
<p>Email: <email>ian.hitchcock@york.ac.uk</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0035" orientation="portrait"><graphic xlink:href="RTH2-3-431-g035.jpg" position="anchor" id="nlm-graphic-71" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Thrombopoietin (TPO) and its receptor, MPL, are critical for hematopoietic stem cell maintenance and megakaryocyte differentiation. Similar to other homodimeric type I cytokine receptors, MPL lacks intrinsic kinase activity, instead associating with the nonreceptor tyrosine kinase Janus kinase 2 (JAK2) via Box1/2 motifs in the intracellular domain of MPL and the FERM domain of JAK2 (A).<sup>95</sup>
Residues at the N‐terminus of the extracellular domain are essential for TPO‐binding and receptor glycosylation (B).<sup>96</sup>
The current dogma suggests that MPL exists at the plasma membrane as a preformed dimer.<sup>97</sup>
However, using single imaging, we now have conclusive data that MPL is present predominantly in monomeric form and dimerize following association with TPO (C). Furthermore, we have found that intermolecular interactions between the JAK2 pseudokinase (PK) domains stabilise dimerization (D), which is further potentiated by oncogenic mutations at the PK‐PK interface.</p>
</sec>
<sec id="rth212225-sec-0036"><title>Mechanisms of Fc‐independent thrombocytopenia</title>
<p><bold>Heyu NiMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Laboratory Medicine and Pathobiology, University of Toronto</p>
<p>Email: <email>nih@smh.ca</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0036" orientation="portrait"><graphic xlink:href="RTH2-3-431-g036.jpg" position="anchor" id="nlm-graphic-73" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized primarily by antibody‐mediated platelet destruction. The major platelet autoantigens targeted in ITP are localized on glycoprotein (GP)IIbIIIa (αIIbβ3 integrin) and the GPIbα complex. Platelet destruction is thought to be mediated by an Fc‐dependent pathway, where the Fc‐portion of platelet‐associated antibodies and Fc receptors on macrophages (eg, in spleen) interact, initiating phagocytosis and opsonized platelet destruction. Interestingly, Dr Nieswandt and our group found that anti‐GPIbα antibodies can cause Fc‐independent thrombocytopenia, which is more resistant to intravenous immunoglobulin (IVIG) and steroid therapies.<sup>98,99</sup>
We further found that anti‐GPIbα and some anti‐GPIIbIIIa antibodies can induce platelet activation, sialidase neuraminidase‐1(NEU 1) translocation and desialylation, leading to platelet clearance in the liver via Ashwell‐Morell receptors. This platelet clearance can be inhibited by sialidase inhibitors.<sup>100</sup>
These findings shed light on Fc‐independent thrombocytopenia, designating desialylation as a potential diagnostic/prognostic biomarker and therapeutic target for refractory ITP treatment.</p>
</sec>
<sec id="rth212225-sec-0037"><title>Immune thrombocytopenia in children</title>
<p><bold>Jenny Despotovic DO, MS<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Pediatrics, Section of Hematology‐Oncology, Baylor College of Medicine, Houston, TX</p>
<p>Email: <email>jmdespot@txch.org</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0037" orientation="portrait"><graphic xlink:href="RTH2-3-431-g037.jpg" position="anchor" id="nlm-graphic-75" orientation="portrait"></graphic>
</boxed-text>
<boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0038" orientation="portrait"><graphic xlink:href="RTH2-3-431-g038.jpg" position="anchor" id="nlm-graphic-77" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The pathophysiology of ITP is complex and incompletely understood. There are many mechanisms, which can vary among patients (Top Panel):1. Autoantibodies target platelet glycoproteins. Opsonized platelets bind Fcγ receptors on antigen presenting cells (APCs), resulting in phagocytosis. APCs express platelet glycoproteins, which are recognized by CD4<sup>+</sup>
T cells. T‐cell clones interact with B cells and propagate antibody production.<sup>101</sup>
2. Antibodies can target megakaryocytes, reducing mature megakaryocytes and causing abnormal maturation.<sup>101</sup>
3. Cytotoxic T cells can target platelets.<sup>102</sup>
4. T‐regulatory cells are decreased in number and function.<sup>102</sup>
5. B‐regulatory cells are decreased and less responsive to cytokines.<sup>102</sup>
6T‐cell balance is shifted toward CD4+ Th0/Th1 and Th17 activation and decreased Th2 responses.<sup>101,102</sup>
</p>
<p>Hepatic platelet clearance may be an Fc‐independent mechanism of platelet clearance (Bottom Panel).<sup>103</sup>
GP1b antibodies can induce Fc‐independent platelet clearance through desialylation. Desialylated platelets bind hepatic Ashwell‐Morell receptors, then undergo phagocytosis and subsequent removal from circulation.</p>
<p>Figure design by Taylor Kim MD</p>
</sec>
<sec id="rth212225-sec-0038"><title>Platelet microparticles and inflammatory diseases</title>
<p><bold>Eric Boilard PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
CHU de Québec‐Université Laval Research Center, Quebec City, Canada</p>
<p>Email: <email>eric.boilard@crchudequebec.ulaval.ca</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0039" orientation="portrait"><graphic xlink:href="RTH2-3-431-g039.jpg" position="anchor" id="nlm-graphic-79" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Platelet extracellular vesicles (EVs), also known as microparticles, harbor platelet receptors, and a subpopulation of them express surface phosphatidylserine. Platelet EVs contain a vast repertoire of molecules, such as cytokines, growth factor, lipid mediators, transcription factors, enzymes, and nucleic acids (eg, messenger RNA and microRNA).<sup>104</sup>
Moreover, some platelet EVs contain mitochondria and recent investigations highlight the presence of functional 20S proteasome. During inflammation, the blood vasculature (in red in the schematic) is more leaky and favors the egress of the platelet EVs outside the blood vessels through gaps formed between endothelial cells.<sup>105</sup>
However, exactly how EVs escape the blood circulation and the exact location of the egress is not completely understood. While platelets are absent in lymph, platelet EVs are very abundant in lymphatic circulation (in green in the schematic) during inflammation.<sup>106</sup>
As platelet EVs contain organelles and molecules from platelets, platelet EVs can disseminate platelet components in tissue locations normally unreached by platelets through lymph.</p>
</sec>
<sec id="rth212225-sec-0039"><title>Influence of platelets on other cells: mechanisms and consequences</title>
<p><bold>Matthew Rondina MD<sup>1,2,3</sup>
</bold>
</p>
<p><sup>1</sup>
Departments of Internal Medicine and Pathology, University of Utah Health Sciences Center, Salt Lake City, UT; <sup>2</sup>
Molecular Medicine Program, University of Utah, Salt Lake City, UT; <sup>3</sup>
Department of Internal Medicine and GRECC, George E. Wahlen VAMC, Salt Lake City, UT</p>
<p>Email: <email>matt.rondina@u2m2.utah.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0040" orientation="portrait"><graphic xlink:href="RTH2-3-431-g040.jpg" position="anchor" id="nlm-graphic-81" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Activated platelets interact with and signal to leukocytes. (Top panel) Platelet interactions with monocytes, through P‐selectin and PSGL1, triggering proinflammatory cytokine synthesis by monocytes. In some settings, this may contribute to thromboinflammation and injurious host responses. (Bottom panel) During sepsis, platelets may signal to T cells, leading to suppression of T‐cell number and function, and contributing to the risk of secondary infections and adverse host outcomes. (Illustration by Diana Lim)<sup>104‐106</sup>
</p>
</sec>
<sec id="rth212225-sec-0040"><title>Platelet adhesion reception in hemostatic and non‐hemostatic function</title>
<p><bold>Pierre Mangin PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Université de Strasbour, INSERM, Strasbourg, France</p>
<p>Email: <email>pierre.mangin@efs.sante.fr</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0041" orientation="portrait"><graphic xlink:href="RTH2-3-431-g041.jpg" position="anchor" id="nlm-graphic-83" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Platelet adhesion at site of injury is challenged by the rheological conditions and the complex composition of the vessel wall. Under elevated blood flow (>1000/s), the glycoprotein (GP)Ib‐IX‐V complex is the only receptor that supports platelet recruitment to immobilized von Willebrand factor (VWF). Under low shear, this receptor teams up with integrins to sustain their adhesion and initiate activation sufficient to dimerize GPVI, which in turn binds collagen and initiates strong activation, directly through its signaling cascade and indirectly through released ADP and thromboxane A2 (TxA2). The GPIb‐IX‐V complex and integrin αIIbβ3 are also instrumental in thrombus growth, allowing platelet recruitment through VWF and fibrinogen bound to activated platelets, respectively.<sup>110</sup>
GPVI plays a central role in thrombus buildup through its ability to promote and sustain platelet activation.<sup>111</sup>
The ability of platelets to interact with their adhesion receptors to counter receptors on pathogens, immune cells, or tumor cells also contributes to their nonhemostatic functions. FN, fibronectin; FGN, fibrinogen; LM, laminins.</p>
</sec>
<sec id="rth212225-sec-0041"><title>Platelet protease‐activated receptors (PARs): function and targeting</title>
<p><bold>Justin R. Hamilton PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia</p>
<p>Email: <email>justin.hamilton@monash.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0042" orientation="portrait"><graphic xlink:href="RTH2-3-431-g042.jpg" position="anchor" id="nlm-graphic-85" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Thrombin‐induced platelet activation is mediated via the two protease‐activated receptors, PAR1 and PAR4, and is central to arterial thrombosis. Both PARs are targets of antiplatelet drugs: a PAR1 antagonist (vorapaxar) is approved for prevention of myocardial infarction and peripheral arterial disease,<sup>112</sup>
while PAR4 antagonists are in clinical trial.<sup>113</sup>
PAR1 is a higher‐affinity thrombin receptor but blockade of this receptor with vorapaxar increases bleeding when administered in addition to standard‐of‐care therapy. In contrast to all other current antiplatelet approaches, including PAR1, PAR4 blockade prevents thrombosis by inhibiting the late‐stage platelet activation events of phosphatidylserine exposure and platelet procoagulant function.<sup>114</sup>
Early platelet responses to low thrombin concentrations are triggered by PAR1 and are more important for hemostasis, while later platelet responses to higher thrombin concentrations are triggered by PAR4 and are more important for thrombosis, suggesting that PAR4 is a target for safe and effective antiplatelet therapy with a unique mechanism of action.</p>
</sec>
<sec id="rth212225-sec-0042"><title>Platelet CLEC‐2 and lung development</title>
<p><bold>Katsue Suzuki‐InoueMD, PhD<sup>1</sup>
, Nagaharu Tsukiji PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan</p>
<p>Email: <email>katsuei@yamanashi.ac.jp</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0043" orientation="portrait"><graphic xlink:href="RTH2-3-431-g043.jpg" position="anchor" id="nlm-graphic-87" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>We have shown that platelets facilitate lung development through the interaction between the platelet activation receptor C‐type lectin‐like receptor‐2 (CLEC‐2), and its ligand membrane protein, podoplanin.<sup>115‐117</sup>
CLEC‐2 deletion in mouse platelets led to neonatal lethality due to lung malformation and respiratory failure. In the primary alveolar septa of these embryos, α‐smooth muscle actin‐positive alveolar duct myofibroblasts (adMYFs) were almost absent, which was caused by abnormal differentiation of lung mesothelial cells (luMCs) into adMYFs. In the developing lung, podoplanin expression was detected in alveolar epithelial cells, luMCs, and lymphatic endothelial cells (LECs), but only specific deletion of podoplanin from LECs resulted in neonatal lethality and lung malformation. These lung abnormalities were also observed after thrombocytopenia or transforming growth factor‐β (TGF‐β) depletion in fetuses. We propose that the interaction between platelet CLEC‐2 and LEC podoplanin stimulates differentiation of luMCs into adMYFs through TGF‐β released from activated platelets.</p>
</sec>
<sec id="rth212225-sec-0043"><title>Molecular links between coagulation and innate immunity</title>
<p><bold>Edward M. ConwayMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
University of British Columbia, Centre for Blood Research, Vancouver, Canada</p>
<p>Email: <email>ed.conway@ubc.ca</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0044" orientation="portrait"><graphic xlink:href="RTH2-3-431-g044.jpg" position="anchor" id="nlm-graphic-89" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Inflammatory, infectious, malignant, metabolic, and thrombotic diseases often feature simultaneous excess activation of complement and coagulation.<sup>118</sup>
Mechanisms by which a positive feedback loop escalates to generate damaging amounts of thrombin (IIa), are exemplified in atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH), caused by gain‐of‐function (GOF) and loss‐of‐function (LOF) mutations in complement proteins.<sup>119,120</sup>
Following an ill‐defined trigger, complement activations leads to excess formation of biologically active C5a and C5b‐9. These induce prothrombotic and proinflammatory effects including exposure of tissue factor (TF), leukocyte adhesion molecules (CAM) and P‐selectin, release of reactive oxygen species (ROS) and polyphosphate (PolyP), reduced thrombomodulin (THBD) expression, erythrocyte release of hemoglobin (Hb), and reduced bioavailability of nitric oxide (NO). These disturbances converge to cause a sustained increase in thrombin generation, with widespread microvascular thrombosis and further activation of complement. Without rapid and appropriate intervention, this positive feedback loop persists and escalates to cause multiorgan damage.</p>
</sec>
<sec id="rth212225-sec-0044"><title>Contact pathway activation: an unfolding story</title>
<p><bold>Coen Maas PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands</p>
<p>Email: <email>cmaas4@umcutrecht.nl</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0045" orientation="portrait"><graphic xlink:href="RTH2-3-431-g045.jpg" position="anchor" id="nlm-graphic-91" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The contact pathway depends on factor XII (FXII) activation. FXII changes conformation during surface binding and becomes susceptible to activating cleavage.<sup>121</sup>
This suggests that the activation loop of FXII is usually shielded in solution, protecting it from misdirected activation. Human mutations can disturb this mechanism and cause disease. These are mostly located in or around the proline‐rich region of FXII. At least 3 separate mutations make FXII vulnerable to enzymatic truncation, which exposes the activation loop.<sup>122,123</sup>
Subsequent accelerated FXII activation causes hereditary angioedema, an acute inflammatory disorder caused by excessive production of bradykinin. We have now identified a new, chronic inflammatory disorder that is caused by a FXII mutation. The mutation influences the conformation of FXII, leading to continuous exposure of the activation loop and constitutive low‐grade systemic contact activation. In conclusion, the conformation of FXII is of critical importance for control over the contact pathway.</p>
<p>Scissors indicate activating cleavage events, which can for example be executed by plasma kallikrein, activated FXII or plasmin. The unfolding of FXII has (so far) been demonstrated to expose its activation loop on dextran sulfate polymers (indicated by “Surface”). EGF‐1, EGF‐like domain 1; EGF‐2, EGF‐like domain 2; FnI, fibronectin type 1 domain; FnII, fibronectin type II domain; KR, Kringle domain; PR, proline‐rich region; Protease, protease domain.</p>
</sec>
<sec id="rth212225-sec-0045"><title>Structure and function of FXI/FXII</title>
<p><bold>Jonas Emsley PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
University of Nottingham, Pharmacy, Centre for Biomolecular Sciences, NottinghamEmail: <email>jonas.emsley@nottingham.ac.uk</email>
</p>
<p>Email: <email>jonas.emsley@nottingham.ac.uk</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0046" orientation="portrait"><graphic xlink:href="RTH2-3-431-g046.jpg" position="anchor" id="nlm-graphic-93" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The contact activation system (CAS) is central to the crosstalk between coagulation and inflammation and contributes to diverse disorders affecting the cardiovascular system.<sup>124</sup>
CAS initiation contributes to thrombosis but is not required for hemostasis and can trigger plasma coagulation via the intrinsic pathway (factor XI [FXI]). Activation of contact factor FXII can initiate proteolytic cleavages of FXI and prekallikrein (PK). PK is a plasma protease that performs a double cleavage of substrate kininogen to release the nonapeptide bradykinin (BK). The crystal structure of the activated full length PKa reveals a remarkable conformational change of apple domain disc rotation when compared to the homologous zymogen structure of coagulation FXI.<sup>125</sup>
Apple domain disc rotation may underlie key processes of auto‐activation, FXII reciprocal activation and substrate recruitment. The in‐depth knowledge of the 3‐dimensional structure of the contact factors provides a platform to understand the molecular basis of contact activation and develop novel therapeutics.</p>
</sec>
<sec id="rth212225-sec-0046"><title>Thrombin, NETs and platelets in vivo</title>
<p><bold>Craig N. Jenne PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary AB, Canada</p>
<p>Email: <email>cnjenne@ucalgary.ca</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0047" orientation="portrait"><graphic xlink:href="RTH2-3-431-g047.jpg" position="anchor" id="nlm-graphic-95" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>In response to a wide variety of infections and inflammatory injury, both platelets and neutrophils are activated and recruited to the site of insult. This cellular activation can be the result of direct interaction with the pathogen (or pathogen‐associated molecular patterns [PAMPs]) or secondarily via cytokines and damage‐associated molecular patterns (DAMPs) released from immune sentinels (ie, Kupffer cells) or damaged host tissues.<sup>126</sup>
These activated neutrophils adhere to the vasculature and interact with circulating platelets via integrins. Platelets aggregate on the surface of the neutrophil, providing further activating signals that trigger the release of neutrophil extracellular traps (NETs).<sup>127</sup>
Nets are interwoven structures of extracellular DNA decorated in both nuclear (histone) and granular proteins (neutrophil elastase, myeloperoxidase, etc). Although NETs capture, sequester, and kill pathogens, this potent mix of cytotoxic proteins can damage host tissues and can directly activate thrombin.<sup>128</sup>
This NET‐induced thrombin leads to the generation of thrombi within the microvasculature, obstructing blood flow and resulting in ischemic tissue damage leading to organ dysfunction and adverse patient outcomes.</p>
</sec>
<sec id="rth212225-sec-0047"><title>Neutrophil extracellular traps and therapeutic options</title>
<p><bold>Tobias A. Fuchs PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Pediatrics, Harvard Medical School, Immune Disease Institute, Hamburg, Germany</p>
<p>Email: <email>t.fuchs@uke.de</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0048" orientation="portrait"><graphic xlink:href="RTH2-3-431-g048.jpg" position="anchor" id="nlm-graphic-97" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Host factors limit inflammation to prevent tissue injury and mortality. Neutrophils are the first leukocytes recruited to sites of infection and sterile inflammation. At infected sites, neutrophils generate extracellular traps (NETs) to immobilize and neutralize pathogens.<sup>129</sup>
NETs are lattices of high‐molecular‐weight DNA (HMW‐DNA) that carry biologically active molecules. In addition to their antimicrobial function, NETs can harm host cells. Indeed, excessive NET formation (NETosis) is associated with numerous inflammatory and autoimmune diseases.<sup>130</sup>
To prevent disease, blood contains 2 DNA degrading enzymes, DNASE1 and DNASE1‐LIKE 3 (DNASE1L3), which cleave HMW‐DNA of NETs into low‐molecular‐weight DNA (LMW‐DNA).<sup>131</sup>
In the absence of circulatory DNases, intravascular NETs accumulate and aggregate during neutrophilic inflammation. Clots of NETs are sufficient to occlude blood vessels and cause ischemic organ injury in models of sterile neutrophilia and septicemia. Therapeutic targeting of NET clots may limit vascular occlusion and host injury in inflammatory diseases.</p>
</sec>
<sec id="rth212225-sec-0048"><title>Clinical trials with factor XI inhibitors</title>
<p><bold>Jeffrey Weitz MD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Medicine and the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada</p>
<p>Email: <email>weitzj@mcmaster.ca</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0049" orientation="portrait"><graphic xlink:href="RTH2-3-431-g049.jpg" position="anchor" id="nlm-graphic-99" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>The contact pathway can be activated by polyphosphate (polyP) and neutrophil extracellular traps (NETs) released from activated platelets and neutrophils, respectively. In the presence of polyanions, factor (F) XI also is activated by thrombin generated via the extrinsic pathway when tissue factor (TF) is exposed. Thus, FXI bridges the contact and common pathways and allows feedback activation from the extrinsic pathway. FXI inhibitors currently undergoing phase 2 evaluation include the antisense oligonucleotide IONIS‐416858 that inhibits FXI biosynthesis, MAA‐868, a monoclonal antibody that binds FXI and prevents its activation, BAY‐1213790, a monoclonal antibody that inhibits FXIa and BMS‐986177, a small molecule that targets the active site of FXIa. (Figure adapted from Weitz JI and Fredenburgh JC. Front. Med. 4:19. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fmed.2017.00019">https://doi.org/10.3389/fmed.2017.00019</ext-link>
).</p>
<p><table-wrap id="nlm-table-wrap-2" xml:lang="en" orientation="portrait" position="anchor"><table frame="hsides" rules="groups"><col style="border-right:solid 1px #000000" span="1"></col>
<col style="border-right:solid 1px #000000" span="1"></col>
<col style="border-right:solid 1px #000000" span="1"></col>
<col style="border-right:solid 1px #000000" span="1"></col>
<col style="border-right:solid 1px #000000" span="1"></col>
<thead valign="top"><tr style="border-bottom:solid 1px #000000"><th align="left" valign="top" rowspan="1" colspan="1">Class</th>
<th align="left" valign="top" rowspan="1" colspan="1">Compounds</th>
<th align="left" valign="top" rowspan="1" colspan="1">Mechanisms of action</th>
<th align="left" valign="top" rowspan="1" colspan="1">Administration</th>
<th align="left" valign="top" rowspan="1" colspan="1">Onset/Offset</th>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">Antisense oligonucleotide</td>
<td align="left" rowspan="1" colspan="1">IONIS‐416858</td>
<td align="left" rowspan="1" colspan="1">Reduces hepatic synthesis of FXI by inducing catalytic degradation of FXI mRNA</td>
<td align="left" rowspan="1" colspan="1">Parenteral</td>
<td align="left" rowspan="1" colspan="1">Slow onset and offset</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Monoclonal antibodies</td>
<td align="left" rowspan="1" colspan="1">BAY1213790, MAA868</td>
<td align="left" rowspan="1" colspan="1">Suppress FXIa generation and/or inhibit FXIa activity</td>
<td align="left" rowspan="1" colspan="1">Parenteral</td>
<td align="left" rowspan="1" colspan="1">Rapid onset and slow offset</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">Small molecule</td>
<td align="left" rowspan="1" colspan="1">BMS‐986177</td>
<td align="left" rowspan="1" colspan="1">Binds to the catalytic domain of FXIa</td>
<td align="left" rowspan="1" colspan="1">Oral</td>
<td align="left" rowspan="1" colspan="1">Rapid onset and offset</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="rth212225-sec-0049"><title>Modifiers and genetics of VWF</title>
<p><bold>Jill M. Johnsen MD<sup>1,2,3</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Medicine, University of Washington, Seattle, WA; <sup>2</sup>
Bloodworks Northwest Research Institute, Seattle, WA; <sup>3</sup>
Washington Center for Bleeding Disorders, Seattle, WA</p>
<p>Email: <email>jjohnsen@uw.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0050" orientation="portrait"><graphic xlink:href="RTH2-3-431-g050.jpg" position="anchor" id="nlm-graphic-101" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>(A) Plasma von Willebrand factor (VWF) antigen levels vary widely in the normal population (50–200 IU/dL). (B<bold>)</bold>
About one‐third of this variation is due to environmental/acquired conditions. Some are dramatic, such as in pregnancy, when VWF increases by > 200% late in gestation. Other variation can be more subtle (eg, with aging). The other two‐thirds of VWF variation is attributable to genetic causes. (C) In von Willebrand disease (VWD), deleterious <italic>VWF</italic>
gene variants (indicated by a lightning bolt) are commonly identified, particularly in patients with severe disease. Non–disease‐causing DNA variants (indicated by stars) can also influence VWF. <italic>VWF</italic>
gene variation accounts for approximately 5% of VWF variation the population. ABO blood group accounts for approximately 25% to 30% of VWF variation. Numerous other non‐<italic>VWF</italic>
and non‐<italic>ABO</italic>
genes have been implicated to influence VWF through multiple mechanisms including secretion, glycosylation, and clearance. However, a proportion of VWF variation remains unexplained.<sup>135‐137</sup>
</p>
</sec>
<sec id="rth212225-sec-0050"><title>Endothelial cell contribution to the pathology in HIT</title>
<p><bold>Lubica RauovaMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
The Children's Hospital of Philadelphia, Pediatrics/Hematology, Philadelphia, PA</p>
<p><email>lubica@email.chop.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0051" orientation="portrait"><graphic xlink:href="RTH2-3-431-g051.jpg" position="anchor" id="nlm-graphic-103" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Heparin‐induced thrombocytopenia (HIT) is a prothrombotic disorder caused by immune complexes that activate platelets, monocytes, neutrophils and vascular endothelium. The glycocalyx expressed on healthy endothelial cells<sup>138</sup>
offers a vast antithrombotic surface that is disrupted by inflammation and vascular disease. Platelet factor 4 (PF4) released from platelets activated on inflamed/injured endothelium binds to endothelial glycosaminoglycans (GAGs), generating targets for HIT antibodies.<sup>139</sup>
This in turn leads to expression of tissue factor and adhesion of platelets. Activated endothelium also releases von Willebrand factor, which binds PF4 and HIT antibodies, promotes platelet adhesion and additional PF4 release, creating a feed‐forward prothrombotic pathway.<sup>140</sup>
HIT immune complexes assembling on PF4 bound to GAGs expressed on monocytes signal through Fcγ receptors to stimulate production of thrombin that transactivates platelets in concert with their direct activation by HIT antibodies. Neutrophils activated by HIT antibodies adhere to venous endothelium, accumulate downstream of the evolving thrombus, and contribute to venous thrombosis at least partially through a peptidyl arginine deiminase 4 (PAD4)‐dependent pathway.</p>
</sec>
<sec id="rth212225-sec-0051"><title>Venous thromboembolic risk assessment in hospitalized medical patients</title>
<p><bold>Alex Spyropoulos MD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Hofstra/Northwell University, New York</p>
<p>Email: <email>aspyropoul@northwell.edu</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0052" orientation="portrait"><graphic xlink:href="RTH2-3-431-g052.jpg" position="anchor" id="nlm-graphic-105" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Acutely‐ill hospitalized medical patients are at risk of venous thromboembolism (VTE), both in‐hospital and in the immediate postdischarge period. Although inpatient thromboprophylaxis reduces VTE risk by 50% to 60%, “universal” thromboprophylaxis as recommended by some guidelines, is challenging because of perceived higher risk of bleeding and lower risk of VTE in practice than seen in clinical trials.<sup>141</sup>
Population‐based studies reveal that “universal” hospital‐only thromboprophylaxis does not reduce the burden of VTE in this population.<sup>141</sup>
Five large randomized placebo‐controlled trials of extended postdischarge thromboprophylaxis have had mixed results in demonstrating net clinical benefit in hospitalized medical patients, but analyses in key subgroups did reveal net clinical benefit.<sup>142</sup>
Recent VTE and bleeding risk assessment models, some of which incorporate D‐dimer, have shown good model discrimination and calibration.<sup>141</sup>
Using these models to provide individualized, risk‐adapted thromboprophylaxis has promise to reduce VTE, bleeding, and perhaps other vascular events in this population.<sup>141</sup>
</p>
</sec>
<sec id="rth212225-sec-0052"><title>Is there an ethnic difference in the risk of bleeding complications with the use of antithrombotic agents?</title>
<p><bold>Shinya GotoMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Medicine (Cardiology), Tokai University School of Medicine, Metabolic Disease Research Center, Tokai University Graduate School of Medicine, Isehara, Japan</p>
<p>Email: <email>shinichi@is.icc.u-tokai.ac.jp</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0053" orientation="portrait"><graphic xlink:href="RTH2-3-431-g053.jpg" position="anchor" id="nlm-graphic-107" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>There is a strong perception that the efficacy and safety of antithrombotic therapy is not homogenous across the globe. Recent clinical research indicates that this perception is at least partly right, especially for East Asian patients. Indeed, intracranial hemorrhage occurred more frequently with the use of vitamin K antagonists (VKAs) in East Asians.<sup>144</sup>
Thus, a lower prothrombin timr (PT)–international normalized ratio (INR) target is recommended for warfarin use among the elderly in East Asia. Lower‐dose rivaroxaban is also recommend in Japan. For antiplatelet agents, lower doses were used for the majority of P2Y12 inhibitors in Japan. Accumulating clinical evidence strongly suggests the presence of ethnic or regional difference in the risk of atherosclerosis,<sup>145</sup>
thrombosis, and serious bleeding events with the use of antithrombotic agents. Extensive future research is necessary to clarify the major contributors to the higher bleeding rates with these treatments in East Asians.</p>
</sec>
<sec id="rth212225-sec-0053"><title>Which patients should receive long‐term anticoagulation? What dose?</title>
<p><bold>Peter VerhammeMD, PhD<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Vascular Medicine and Haemostasis, University of Leuven, Leuven, Belgium</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0054" orientation="portrait"><graphic xlink:href="RTH2-3-431-g054.jpg" position="anchor" id="nlm-graphic-109" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Patients with venous thromboembolism (VTE) that is unprovoked or related to persistent risk factors such as cancer or major thrombophilia are at high risk for recurrent VTE. These patients benefit from extended anticoagulant treatment. Patients with VTE that is provoked by a transient risk factor, with distal deep vein thrombosis or subsegmental pulmonary embolism, or patients at increased bleeding risk, should not continue anticoagulant treatment beyond 3 months.<sup>146,147</sup>
</p>
<p>Direct oral anticoagulants are preferred over vitamin K antagonists for most patients because of the lower risk of major bleeding and their convenience. For long‐term anticoagulation, the reduced dose of apixaban and rivaroxaban was as effective as the treatment dose to prevent recurrences.<sup>148</sup>
This reduced dose harmonizes dosing regimens for primary and secondary prevention of VTE. However, patients with the highest risk of recurrent VTE, such as patients with active cancer or antiphospholipid syndrome, were not included in these trials.<sup>148</sup>
</p>
</sec>
<sec id="rth212225-sec-0054"><title>Recurrent VTE on anticoagulant therapy: what next?</title>
<p><bold>Sébastien Miranda MD<sup>1,2</sup>
Marc Rodger MD<sup>3,4,5</sup>
</bold>
</p>
<p><sup>1</sup>
Rouen University Hospital, Department of Internal Medicine, Rouen France; <sup>2</sup>
Normandie Univ, UNIROUEN, INSERM U1096 EnVI, Rouen, France; <sup>3</sup>
Ottawa Blood Disease Centre, Ottawa Hospital, Ottawa, Ontario, Canada; <sup>4</sup>
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; <sup>5</sup>
Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada</p>
<p>Email: <email>M.rodger@toh.ca</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0055" orientation="portrait"><graphic xlink:href="RTH2-3-431-g055.jpg" position="anchor" id="nlm-graphic-111" orientation="portrait"></graphic>
</boxed-text>
</p>
</sec>
<sec id="rth212225-sec-0055"><title>Risk assessment in pregnancy</title>
<p><bold>Fionnuala Ní ÁinlePhD, MB<sup>1</sup>
></bold>
</p>
<p><sup>1</sup>
Rotunda Hospital, Haematology; Mater Misericordiae University Hospital, Dublin</p>
<p>Email: <email>fniainle@mater.ie</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0056" orientation="portrait"><graphic xlink:href="RTH2-3-431-g056.jpg" position="anchor" id="nlm-graphic-113" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Venous thromboembolism (VTE) is a leading cause of maternal death in developed countries: In the United Kingdom and Ireland, thrombosis/thromboembolism resulted in 1.39 (0.95–1.96) mortalities per 100 000 maternities during 2014–2016.<sup>152</sup>
VTE risk increases during pregnancy and reaches a peak during the postpartum period.<sup>153</sup>
This baseline risk increases further with additional VTE risk factors, many of which are common and dynamic (A).<sup>154</sup>
One of the strongest risk factors, prior unprovoked VTE (or VTE provoked by a hormonal risk factor), is rare but because of the very high associated VTE risk, thromboprophylaxis is indicated both antenatally and during the postpartum period. The optimal thromboprophylaxis regimen is being evaluated in a randomized trial (www.highlowstudy.org; NCT01828697) (B). Risk assessment and detection of VTE risk factors in pregnant and postpartum women is essential: (1) It can save lives and (2) is feasible even in busy maternity units, through multidisciplinary collaboration.</p>
</sec>
<sec id="rth212225-sec-0056"><title>Obstetric antiphospholipid syndrome</title>
<p><bold>Karen SchreiberMD, MRCP<sup>1</sup>
</bold>
</p>
<p><sup>1</sup>
Guy's and Saint Thomas’ Hospitals NHS Trust, Thrombosis and Haemostasis, London, England</p>
<p>Email: <email>karen.schreiber@gstt.nhs.uk</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0057" orientation="portrait"><graphic xlink:href="RTH2-3-431-g057.jpg" position="anchor" id="nlm-graphic-115" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the persistent presence of antiphospholipid (aPL) antibodies, including lupus anticoagulant, anticardiolipin antibodies IgG/IgM and anti‐β2‐glycoprotein1 antibodies IgG/IgM.<sup>155</sup>
APS can present with a variety of clinical phenotypes, such as venous or arterial thrombosis and thrombosis in the microvasculature (thrombotic APS) as well as obstetric complications (obstetric APS). The pathophysiologic hallmark is thrombosis, but other factors such as complement activation might be important.</p>
<p>Pregnancy morbidity includes unexplained recurrent early pregnancy loss, fetal death, and late obstetric manifestations such as preeclampsia, premature birth, or fetal growth restriction associated with placental insufficiency. Current treatment to prevent obstetric morbidity is based on low‐dose aspirin and/or low‐molecular‐weight heparin and has improved pregnancy outcomes to achieve successful live birth in >70% of pregnancies. Although hydroxychloroquine and pravastatin might further improve pregnancy outcomes, prospective clinical trials are required to confirm these findings.<sup>156</sup>
</p>
</sec>
<sec id="rth212225-sec-0057"><title>Diagnosis of PE in pregnancy</title>
<p><bold>Moumneh ThomasMD<sup>1,2</sup>
Grégoire Le GalMD, PhD<sup>2</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Emergency Medicine, University Hospital of Angers, University of Angers, MITOVASC Institute, Angers, France; <sup>2</sup>
Division of Hematology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada</p>
<p>Email: <email>glegal@toh.ca</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0058" orientation="portrait"><graphic xlink:href="RTH2-3-431-g058.jpg" position="anchor" id="nlm-graphic-117" orientation="portrait"></graphic>
</boxed-text>
</p>
<p><bold>Acknowledgments</bold>
</p>
<p>Caleb MacGillivray</p>
</sec>
<sec id="rth212225-sec-0058"><title>VKA are the AC of choice for mechanical valves in pregnancy (debate)</title>
<p><bold>Dominica ZentnerMBBSHons, FRACP, PhD<sup>1,2</sup>
, Claire McLintockMB, ChB, FRACP, FRCPA<sup>3</sup>
</bold>
</p>
<p><sup>1</sup>
Department of Cardiology, Royal Melbourne Hospital, Parkville, Victoria, Australia<sup>2</sup>
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia<sup>3</sup>
National Women's Health, Auckland City Hospital, Auckland, New Zealand</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0059" orientation="portrait"><graphic xlink:href="RTH2-3-431-g059.jpg" position="anchor" id="nlm-graphic-119" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>Management of pregnant women with mechanical heart valves is extremely challenging. Options include vitamin K antagonists (VKAs) throughout pregnancy, therapeutic‐dose low‐molecular‐weight heparin (LMWH) during the first trimester, then warfarin in the second and third trimesters, with transition to LMWH and then unfractionated heparin in preparation for birth, or LMWH throughout pregnancy.<sup>160</sup>
VKAs are the most effective anticoagulants in minimizing the risk of complications from valve thrombosis but cross the placenta with adverse fetal effects. Adverse fetal outcomes are minimized with LMWH, but valve thrombosis can occur. Anticoagulant‐related maternal bleeding can also occur.<sup>161</sup>
No option is without risk, and women with mechanical heart valves must be involved in the decision making.<sup>162</sup>
Local health service capacity (eg, ability to monitor anti‐Xa levels) should also be considered, and involvement of an experienced multidisciplinary team is essential.</p>
</sec>
<sec id="rth212225-sec-0059"><title>Hemostasis in liver disease</title>
<p><bold>Maria MagnussonMD, PhD<sup>1,2</sup>
</bold>
</p>
<p><sup>1</sup>
Karolinska University Hospital, Stockholm, Sweden; <sup>2</sup>
Clinical Chemistry and Blood Coagulation Research, MMK, Department of Pediatrics, CLINTEC, Karolinska Institutet, Solna, Sweden</p>
<p>Email: <email>maria.magnusson@ki.se</email>
</p>
<p><boxed-text position="anchor" content-type="graphic" id="rth212225-blkfxd-0060" orientation="portrait"><graphic xlink:href="RTH2-3-431-g060.jpg" position="anchor" id="nlm-graphic-121" orientation="portrait"></graphic>
</boxed-text>
</p>
<p>© 2018 Maria Magnusson, BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health. All rights reserved. Magnusson M. et al. Arch Dis Child. 2016;101(9):854‐9.</p>
<p>A concomitant loss of reserve in the pro‐ and anticoagulant systems is often seen in liver failure secondary to a reduced synthetic capacity of the hepatocytes. This leads to a fragile balance between bleeding and thrombosis (narrows the distance between these 2 endpoints in the figure). However, additional risk factors are very important for the actual development of bleeding or thrombosis, including disturbed vascular flow and endothelial dysfunction. Low vascular flow increases the risk for portal vein thrombosis, and rupture of varicose veins in portal hypertension causes gastrointestinal bleeding. The specific type of liver disease is also of importance; for example, coagulopathy is more commonly reported in metabolic liver disease, vitamin K–deficiency bleeding is often due to cholestasis, and thrombosis occurs more frequently in liver abscess. Consequently, several aspects need to be considered when evaluating the risk of bleeding and thrombosis in children with liver disease.<sup>163‐165</sup>
</p>
</sec>
<sec id="rth212225-sec-1059"><title>ISTH STATE OF THE ART SPEAKERS</title>
<p>Christopher M. Ward, Robert K. Andrews, Stefano Barco, Elisabeth M. Battinelli, Eric Boilard, Mettine H. A. Bos, Ampaiwan Chuansumrit, Edward M. Conway, Nicola Curry, Daniel Cutler, Elisa Danese, Simon F. De Meyer, J. Mauricio Del Rio, Jenny Despotovic, Jorge Di Paola, John Eikelboom, Jonas Emsley, Koji Eto, Karin Fijnvandraat, Robert Flaumenhaft, Matthew Flick, Tobias A. Fuchs, Keith Gomez, Shinya Goto, Justin R. Hamilton, Ian S. Hitchcock, Craig N. Jenne, Jill M. Johnsen, Lining A. Ju, Grégoire Le Gal, Gregory Y. H. Lip, Jim Luyendyk, Coen Maas, Maria Magnusson, Pierre Mangin, Alan Mast, Claire McLintock, Sébastien Miranda, Amit Nathwani, Heyu Ni, Fionnuala Ní Áinle, Susie Nilsson, Tor Ny, Sarah H. O'Brien, James S. O'Donnell, Karlheinz Peter, Janusz Rak, Anna M. Randi, Lubica Rauova, Christoph Reinhardt, Marc Rodger, Matthew Rondina, Karen Schreiber, S. Severin, Midori Shima, Alex Spyropoulos, Simon J. Stanworth, Katsue Suzuki‐Inoue, Moumneh Thomas, Nagaharu Tsukiji, Tetsumei Urano, Karen Vanhoorelbeke, Peter Verhamme, Jeffrey Weitz, Alisa Wolberg, Dominica Zentner, Cheng Zhu.</p>
</sec>
</body>
<back><ref-list content-type="uncited-references" id="rth212225-bibl-0001"><title>REFERENCES</title>
<p>1. Wolberg AS, Aleman MM, Leiderman K, Machlus KR. Procoagulant activity in hemostasis and thrombosis: Virchow's triad revisited. Anesth Analg. 2012;114(2):275‐85.</p>
<p>2. Wolberg AS. Determinants of fibrin formation, structure, and function. Curr Opin Hematol. 2012;19(5):349‐56.</p>
<p>3. Kattula S, Byrnes JR, Martin SM, Holle LA, Cooley BC, Flick MJ, Wolberg AS. Factor XIII in plasma, but not in platelets, mediates red blood cell retention in clots and venous thrombus size in mice. Blood Adv. 2018;2(1):25‐35.</p>
<p>4. Lip G, Freedman B, De Caterina R, Potpara TS. Stroke prevention in atrial fibrillation: past, present and future. Comparing the guidelines and practical decision‐making. Thromb Haemost. 2017;117:1230–9.</p>
<p>5. Sibbing D, Angiolillo DJ, Huber K. Antithrombotic therapy for acute coronary syndrome: past, present and future. Thromb Haemost. 2017;117:1240–8.</p>
<p>6. Lip GYH, Banerjee A, Boriani G, Chiang CE, Fargo R, Freedman B, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest. 2018;154:1121–201.</p>
<p>7. Coppens M, Weitz JI, Eikelboom JWA. Synergy of dual pathway inhibition in chronic cardiovascular disease. Circ Res. 2019;124:416–25.</p>
<p>8. Chan NC, Weitz JI. Antithrombotic agents. Circ Res. 2019;124:426–36.</p>
<p>9. Laridan E, Denorme F, Desender L, François O, Andersson T, Deckmyn H, et al. Neutrophil extracellular traps in ischemic stroke thrombi. Ann Neurol. 2017;82:223–32.</p>
<p>10. Denorme F, Langhauser F, Desender L, Vandenbulcke A, Rottensteiner H, Plaimauer B, et al. ADAMTS13‐mediated thrombolysis of t‐PA–resistant occlusions in ischemic stroke in mice. Blood. 2016;127:2337–45.</p>
<p>11. Staessens S, Denorme F, François O, Desender L, Dewaele T, Vanacker P,et al. Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance. Haematologica 2019; in press.</p>
<p>12. Wood JP, Bunce MW, Maroney SA, Tracy PB, Camire RM, Mast AE. TFPIα inhibits blood coagulation during the initiation of blood coagulation. Proc Natl Acad Sci U S A. 2013;110:17838–43.</p>
<p>13. Wood JP, Baumann Kreuziger LM, Ellery PER, Maroney SA, Mast AE. Reduced prothrombinase inhibition by TFPI contributes to the FVL hypercoagulable state. Blood Adv. 2017;1:386–95.</p>
<p>14. Eitzman DT, Westrick RJ, Bi X, Manning SL, Wilkinson JE, Broze GJ, Ginsburg D. Lethal perinatal thrombosis in mice resulting from the interaction of TFPI and FVL. Circulation. 2002;105:2139–42.</p>
<p>15. De Nardo CM, Lenzo JC, Pobjoy J, Hamilton JA, Cook AD. Urokinase‐type plasminogen activator and arthritis progression: contrasting roles in systemic and monoarticular arthritis models. Arthritis Res Ther. 2010;12:R199.</p>
<p>16. Thornton S, Raghu H, Cruz C, Frederick MD, Palumbo JS, Mullins ES, et al. Urokinase plasminogen activator and receptor promote collagen‐induced arthritis through expression in hematopoietic cells. Blood Adv. 2017;1:545–56.</p>
<p>17. Raghu H, Jone A, Cruz C, Rewerts CL, Frederick MD, Thornton S, et al. Plasminogen is a joint‐specific positive or negative determinant of arthritis pathogenesis in mice. Arthritis Rheumatol. 2014;66:1504–16.</p>
<p>18. Urano T, Castellino FJ, Suzuki Y. Regulation of plasminogen activation on cell surfaces and fibrin. J Thromb Haemost. 2018;16:1487–97.</p>
<p>19. Brzoska T, Suzuki Y, Sano H, Suzuki A, Tanaka H, Urano T. Imaging analyses of coagulation‐dependent initiation of fibrinolysis on activated platelets and its modification by thrombin‐activatable fibrinolysis inhibitor. Thromb Haemost. 2017;7:682–90.</p>
<p>20. Sulniute R, Shen Y, Guo YZ, Fallah M, Ahlskog N, Ny L, et al. Plasminogen is a critical regulator of cutaneous wound healing. Thromb Haemost. 2016;115:1001–9.</p>
<p>21. MacCormack JJ, Lopes da Silva M, Ferraro F, Patella F, Cutler DF. Weibel‐Palade bodies. J Cell Science. 2017;130: 3611–7.</p>
<p>22. Ferraro F, Kriston‐Vizi J, Metcalf DJ, Martin‐Martin B, Freeman J, Burden JJ, et al. A two‐tier Golgi‐based control of organelle size underpins the functional plasticity of endothelial cells. Dev Cell. 2014;29:292–304.</p>
<p>23. Nightingale TD, McCormack JJ, Grimes W, Robinson C, Lopes da Silva M, White IJ, et al. Tuning the endothelial response: differential release of exocytic cargos from Weibel‐Palade bodies. J Thromb Haemost. 2018;16:1873–86.</p>
<p>24. Nesbitt W, Westein E, Tovar‐Lopez F, Tolouei E, Mitchell A, Fu J, et al. A shear gradient–dependent platelet aggregation mechanism drives thrombus formation. Nat Med. 2009;15:665–73.</p>
<p>25. Chen Y, Ju LA, Zhou F, Liao J, Xue L, Su QP, et al. An integrin alphaIIbbeta3 intermediate affinity state mediates biomechanical platelet aggregation. Nat Mater. 2019; in press.</p>
<p>26. Ju L, Chen Y, Li K, Yuan Z, Liu B, Jackson SP, et al. Dual biomembrane force probe enables single‐cell mechanical analysis of signal crosstalk between multiple molecular species. Sci Rep. 2017;7:14185.</p>
<p>27. Randi AM, Smith KE, Castaman G. von Willebrand factor regulation of blood vessel formation. Blood. 2018;132:132–40.</p>
<p>28. Starke RD, Ferraro F, Paschalaki KE, Dryden NH, McKinnon TA, Sutton RE, et al. Endothelial von Willebrand factor regulates angiogenesis. Blood. 2011;117:1071–80.</p>
<p>29. Castaman G, Federici AB, Tosetto A, La MS, Stufano F, Mannucci PM, Rodeghiero F. Different bleeding risk in type 2A and 2M von Willebrand disease: a 2‐year prospective study in 107 patients. J Thromb Haemost. 2012;10:632–8.</p>
<p>30. Lavin M, Aguila S, Schneppenheim S, Dalton N, O'Sullivan JM, O’ Connell N, et al. Novel insights into the clinical phenotype and pathophysiology underlying Low VWF levels. The Low von Willebrand factor Ireland Cohort (LoVIC) study. Blood. 2017;130:2344–53.</p>
<p>31. Lavin M, Aguila S, Dalton N, Nolan M, Byrne M, Ryan K, et al. Significant gynaecological bleeding in women with low von Willebrand factor levels. Blood Adv. 2018;2:1784–91.</p>
<p>32. Aguila S, Lavin M, Dalton N, Patmore S, Chion A, Trahan G, et al. Reduced α2‐6 linked sialylation and enhanced clearance in patients with low von Willebrand factor. Blood. 2019;133:1585–96.</p>
<p>33. National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). The diagnosis, evaluation, and management of von Willebrand Disease. Bethesda (MD): National Institute of Health: Department of Health and Human Services; NIH Pub. No. 08–5832. 2007:112.</p>
<p>34. O'Brien SH. Evaluation and management of heavy menstrual bleeding in adolescents: the role of the hematologist. Hematology Am Soc Hematol Educ Program. 2018;2018:390–8.</p>
<p>35. Dunn AL, Cox Gill J. Adenotonsillectomy in patients with desmopressin responsive mild bleeding disorders: a review of the literature. Haemophilia. 2010;16:711–6.</p>
<p>36. Castaman G, Fijnvandraat K. Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A. Blood. 2014;124:2333–6.</p>
<p>37. Eckhardt CL, van Velzen AS, Peters M, Astermark J, Brons PB, Castaman G, et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood. 2013;122:1954–62.</p>
<p>38. Hartholt RB, Peyron I, Voorberg J. Hunting down factor VIII in the immunopeptidome. Cell Immunol. 2016;301:59–64.</p>
<p>39. Kitazawa T, Igawa T, Sampei Z, Muto A, Kojima T, Soeda T, et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med. 2012;18:1570–4.</p>
<p>40. Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, et al. Factor VIII–mimetic function of humanized bispecific antibody in hemophilia A. New Engl J Med. 2016;374:2044–53.</p>
<p>41. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus‐associated virus vector‐mediated gene transfer in hemophilia B. N Engl J Med. 2011;365:2357–65.</p>
<p>42. Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, et al. Long‐term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994–2004.</p>
<p>43. Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, et al. AAV5‐factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017;377:2519–30.</p>
<p>44. Groeneveld D, Pereyra D, Veldhuis Z, Adelmeijer J, Ottens P, Kopec AK, et al. Intrahepatic fibrin(ogen) deposition drives liver regeneration after partial hepatectomy in mice and humans. Blood. 2019;14:1245–56.</p>
<p>45. Pant A, Kopec AK, Luyendyk JP. Role of the blood coagulation cascade in hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol. 2018;315:G171–6.</p>
<p>46. Lisman T, Porte RJ. Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases. Res Pract Thromb Haemost. 2017;1:150–61.</p>
<p>47. Muia J, Zhu J, Gupta G, Haberichter SL, Friedman KD, Feys HB, et al. Allosteric activation of ADAMTS13 by von Willebrand factor. Proc Natl Acad Sci U S A. 2014;111:18584–9.</p>
<p>48. South K, Luken BM, Crawley JTB, Phillips R, Thomas M, Collins RF, et al. Conformational activation of ADAMTS13. Proc Natl Acad Sci U S A. 2014;111:18578–83.</p>
<p>49. Roose E, Schelpe AS, Joly BS, Peetermans M, Verhamme P, Voorberg J, et al. An open conformation of ADAMTS‐13 is a hallmark of acute acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. 2018;16:378–88.</p>
<p>50. Konstantinides SV, Barco S, Lankeit M, Meyer G. Management of pulmonary embolism: an update. J Am Coll Cardiol. 2016;67:976–90.</p>
<p>51. Barco S, Vicaut E, Klok FA, Lankeit M, Meyer G, Konstantinides SV; PEITHO Investigators. Improved identification of thrombolysis candidates amongst intermediate‐risk pulmonary embolism patients: implications for future trials. Eur Respir J. 2018;51:pii: 1701775.</p>
<p>52. Peacock F, Singer A. Reducing the hospital burden associated with the treatment of pulmonary embolism. J Thromb Haemost. 2019. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1111/jth.14423">https://doi.org/10.1111/jth.14423</ext-link>
. Epub.</p>
<p>53. Sosothikul D, Seksarn P, Pongsewalak S, Thisyakorn U, Lusher J. Activation of endothelial cells, coagulation and fibrinolysis in children with dengue virus infection. Thromb Haemost. 2007;97:627–34.</p>
<p>54. Wills BA, Oragui EE, Stephens AC, Daramola OA, Dung NM, Loan HT, et al. Coagulation abnormalities in dengue hemorrhagic fever: serial investigations in 167 Vietnamese children with dengue shock syndrome. Clin Infect Dis. 2002;35:277–85.</p>
<p>55. Chuansumrit A, Tangnararatchakit K. Pathophysiology and management of dengue hemorrhagic fever. TATM. 2006;8(Suppl 1):3–11.</p>
<p>56. Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313:471–82.</p>
<p>57. Cap A, Hunt B. Acute traumatic coagulopathy. Curr Opin Crit Care. 2014;20:638–45.</p>
<p>58. Fabes J, Brunskill SJ, Curry N, Doree C, Stanworth SJ. Pro‐coagulant haemostatic factors for the prevention and treatment of bleeding in people without haemophilia. Cochrane Database Syst Rev. 2018;12:CD010649.</p>
<p>59. Flierl U, Tongers J, Berliner D, Sieweke J‐ T, Zauner F, Wingert C, et al. Acquired von Willebrand syndrome in cardiogenic shock patients on mechanical circulatory microaxial pump support. PLoS One. 2017;12:e0183193.</p>
<p>60. Shah P, Tantry US, Bliden KP, Gurbel PA. Bleeding and thrombosis associated with ventricular assist device therapy. J Heart Lung Transplant. 2017;36:1164–73.</p>
<p>61. Jilma‐Stohlawetz P, Quehenberger P, Schima H, Stoiber M, Knöbl P, Steinlechner B, et al. Acquired von Willebrand factor deficiency caused by LVAD is ADAMTS‐13 and platelet dependent. Thromb Res. 2016;137:196–201.</p>
<p>62. Battinelli EM, Markens BA, Kulenthirarajan RA, Machlus KR, Flaumenhaft R, Italiano JE Jr. Anticoagulation inhibits tumor cell‐mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response. Blood. 2014;123:101–12.</p>
<p>63. Johnson KE, Ceglowski JR, Roweth HG, Forward JA, Tippy MD, El‐Husayni S, et al. Aspirin inhibits platelets from reprogramming breast tumor cells and promoting metastasis. Blood Adv. 2019;3:198–211.</p>
<p>64. Machlus KR, Johnson KE, Kulenthirarajan R, Forward JA, Tippy MD, Soussou TS, et al. CCL5 derived from platelets increases megakaryocyte proplatelet formation. Blood. 2016;127:921–6.</p>
<p>65. Bos MHA, Camire RM. Procoagulant adaptation of a blood coagulation prothrombinase‐like enzyme complex in Australian Elapid venom. Toxins. 2010;2:1554–67.</p>
<p>66. Bos MHA, Boltz M, St. Pierre L, Masci PP, de Jersey J, Lavin MF, Camire RM. Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations. Blood. 2009;114:686–92.</p>
<p>67. Verhoef D, Visscher KM, Vosmeer CR, Cheung KL, Reitsma PH, Geerke DP, Bos MHA. Engineered factor Xa variants retain procoagulant activity independent of direct factor Xa inhibitors. Nat Commun. 2017;8:528–38.</p>
<p>68. Reinhardt C, Bergentall M, Greiner TU, Schaffner F, Östergren‐Lundén G, Petersen LC, et al. Tissue factor and PAR1 promote microbiota‐induced intestinal vascular remodelling. Nature. 2012;483:627–31.</p>
<p>69. Jäckel S, Kiouptsi K, Lillich M, Hendrikx T, Khandagale A, Kollar B, et al. Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll‐like receptor‐2. Blood. 2017;130:541–53.</p>
<p>70. Kiouptsi K, Reinhardt C. Contribution of the commensal microbiota to atherosclerosis and arterial thrombosis. Br J Pharmacol. 2018;175:4439–49.</p>
<p>71. Ziegler M, Hohmann JD, Searle AK, Abraham MK, Nandurkhar HH, Wang X, Peter K. A single‐chain antibody‐CD39 fusion protein targeting activated platelets protects from cardiac ischaemia/reperfusion injury. Eur Heart J. 2018;39:111–16.</p>
<p>72. Yap ML, McFadyen JD, Wang X, Zia NA, Hohmann JD, Ziegler M, et al. Targeting activated platelets: a unique and potentially universal approach for cancer imaging. Theranostics. 2017;7:2565–74.</p>
<p>73. Yap ML, McFadyen JD, Wang X, Ziegler M, Chen YC, Willcox A, et al. Activated platelets in the tumor microenvironment for targeting of antibody‐drug conjugates to tumors and metastases. Theranostics. 2019;9:1154–69.</p>
<p>74. Gao J, Ma X, Zhang Y, Guo M, Shi D. The role of microRNAs in prethrombotic status associated with coronary artery disease. Thromb Haemost. 2017;117:429–36.</p>
<p>75. Ward‐Caviness CK, Huffman JE, Evertt K, Germain M, Van Dongen, Hill WD, et al. DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta‐analysis. Blood. 2018;132:1842–50.</p>
<p>76. Arroyo AB, de Los Reyes‐García AM, Teruel‐Montoya R. microRNAs in the haemostatic system: More than witnesses of thromboembolic diseases? Thromb Res. 2018;166:1–9.</p>
<p>77. Magnus N, Gerges N, Jabado N, Rak J. Coagulation‐related gene expression profile in glioblastoma is defined by molecular disease subtype. J Thromb Haemost. 2013;11:1197–200.</p>
<p>78. D'Asti E, Huang A, Kool M, Meehan B, Chan JA, Jabado N, et al. Tissue factor regulation by miR‐520 g in primitive neuronal brain tumor cells: a possiblelink between oncomirs and the vascular tumor microenvironment. Am J Pathol. 2016;186:446–59.</p>
<p>79. Tawil N, Chennakrishnaiah S, Bassawon R, Johnson R, D'Asti E, Rak J. Single cell coagulomes as constituents of the oncogene‐driven coagulant phenotype in brain tumours. Thromb Res. 2018;164(Suppl 1):S136–42.</p>
<p>80. Jasuja R, Passam FH, Kennedy DR, Kim SH, van Hessem L, Lin L, et al. Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents.J Clin Invest. 2012;122:2104–13. </p>
<p>81. Stopa JD, Neuberg D, Puligandla M, Furie B, Flaumenhaft R, Zwicker JI.Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation.JCI Insight. 2017;2:e89373.</p>
<p>82. Zwicker JI, Schlechter BL, Stopa JD, Liebman HA, Aggarwal A, Puligandla M,et al; CATIQ Investigators. Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer.JCI Insight. 2019;4:e125851.</p>
<p>83. Zwicker JI, Liebman HA, Bauer KA, Caughey T, Campigotto F, Rosovsky R, et al. Prediction and prevention of thromboembolic events with enoaxaparin in cancer patient with elevated tissue factor‐bearing microparticles: a randomized‐controlled phase II trial (the Microtec study). Br J Haematol. 2013;160:530–7.</p>
<p>84. Lentaigne C, Freson K, Laffan MA, et al. Inherited platelet disorders: toward DNA‐based diagnosis. Blood. 2016;127:2814–23.</p>
<p>85. Fisher MH, Di Paola J. Genomics and transcriptomics of megakaryocytes and platelets: Implications for health and disease. Res Pract Thromb Haemost. 2018;2:630–9.</p>
<p>86. Johnsen JM, Fletcher SN, Huston H, et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017;1:824–34.</p>
<p>87. Storan MJ, Heazlewood SY, Heazlewood CK, Haylock DN, Alexander WS, Neaves RJ, et al. Factors released by megakaryocytes thrombin cleave osteopontin to negatively regulate hematopoietic stem cells. Stem Cells. 2015;33:2351–7.</p>
<p>88. Heazlewood SY, Neaves RJ, Williams B, Haylock DN, Adams TE, Nilsson SK. Megakaryocytes co‐localise with hemopoietic stem cells and release cytokines that up‐regulate stem cell proliferation. Stem Cell Res. 2013;11:782–92.</p>
<p>89. Bruns I, Lucas D, Pinho S, Ahmed J, Lambert MP, Kunisaki Y, et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat. Med. 2014;20:1315–20.</p>
<p>90. Valet C, Chicanne G, Severac C, Chaussade C, Whitehead M, Cabou C, et al. Essential role of class II PI3K‐C2α in platelet membrane morphology. Blood. 2015;126:1128–37.</p>
<p>91. Valet C, Levade M, Chicanne G, Bilanges B, Cabou C, Viaud J, et al. A dual role for the class III PI3K, Vps34, in platelet production and thrombus growth. Blood. 2017;130:2032–42.</p>
<p>92. Sugimoto N., Eto K. Platelet production from induced pluripotent stem cells. J Thromb Haemost. 2017;15:1717–27.</p>
<p>93. Nakamura S, Takayama N, Hirata S, Seo H, Endo H, Ochi K, et al. Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from induced pluripotent stem cells. Cell Stem Cell. 2014;14:535–48.</p>
<p>94. Ito Y, Nakamura S, Sugimoto N, Shigemori T, Kato Y, Ohno M, et al. Turbulence activates platelet biogenesis to enable clinical scale ex vivo production. Cell. 2018;174:636–48.</p>
<p>95. Robb L. Cytokine receptors and hematopoietic differentiation. Oncogene. 2007;26:6715–23.</p>
<p>96. Chen WM, Yu B, Zhang Q, and Xue P. Identification of the residues in the extracellular domain of thrombopoietin receptor involved in the binding of thrombopoietin and a nuclear distribution protein. J Biol Chem. 2010;285:26697–709.</p>
<p>97. Staerk J, Defour JP, Pecquet C, Leroy E, Antoine‐Poirel H, Brett I, et al. Orientation‐specific signalling by thrombopoietin receptor dimers. EMBO J. 2011;30:4398–413.</p>
<p>98. Webster ML, Sayeh E, Crow M, Chen P, Nieswandt B, Freedman J, et al. Relative efficacy of intravenous immunoglobulin G in ameliorating thrombocytopenia induced by antiplatelet GPIIbIIIa versus GPIbα antibodies. Blood. 2006;108:943–6.</p>
<p>99. Zeng Q, Zhu L, Tao L, Bao J, Yang M, Simpson EK, et al. Relative efficacy of steroid therapy in immune thrombocytopenia mediated by anti‐platelet GPIIbIIIa versus GPIbα antibodies. Am J Hematol. 2012;87:206–8.</p>
<p>100. Li J, van der Wal DE, Zhu G, Xu M, Yougbare I, Ma L, et al. Desialylation is a mechanism of Fc‐independent platelet clearance and a therapeutic target in immune thrombocytopenia. Nat Commun. 2015;6:7737.</p>
<p>101. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: pathogenic and clinical diversity. Blood. 2009; 113:6511–21.</p>
<p>102. Zufferey A, Kapur R, Semple JW.Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP). J Clin Med. 2017;9:e16.</p>
<p>103. Li J, van der Wal DE, Zhu G, Xu M, Youbare I, Ma L, et al. Desialylation is a mechanism of Fc‐independent platelet clearance and a therapeutic target in immune thrombocytopenia. Nat Commun. 2015; 6:7737.</p>
<p>104. Boilard E, Duchez AC, Brisson A. The diversity of platelet microparticles. Curr Opin Hematol. 2015;22:437–44.</p>
<p>105. Cloutier N, Pare A, Farndale RW, Schumacher HR, Nigrovic PA, Lacroix S, Boilard E. Platelets can enhance vascular permeability. Blood. 2012;120:1334–43.</p>
<p>106. Milasan A, Tessandier N, Tan S, Brisson A, Boilard E, Martel C. Extracellular vesicles are present in mouse lymph and their level differs in atherosclerosis. J Extracell Vesicles. 2016;5:31427.</p>
<p>107. Campbell RA, Franks Z, Bhatnagar A, Rowley JW, Manne BK, Supiano MA, et al. Granzyme A in human platelets regulates the synthesis of proinflammatory cytokines by monocytes in aging. J Immunol. 2018;200(1):295–304.</p>
<p>108. Semple JW, Italiano JE Jr, Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11(4):264–74.</p>
<p>109. Rossaint J, Margraf A, Zarbock A. Role of platelets in leukocyte recruitment and resolution of inflammation. Front Immunol. 2018;9:2712.</p>
<p>110. Kulkarni S, Dopheide SM, Yap CL, Ravanat R, Freund M, Mangin P, et al. A revised model of platelet aggregation. J Clin Invest. 2000;105:783–91.</p>
<p>111. Mangin PH, Onselaer MB, Receveur N, Le Lay N, Hardy AT, Wilson C, et al. Immobilized fibrinogen activates human platelets through glycoprotein VI. Haematologica. 2018;103(5):898–907.</p>
<p>112. French SL, Arthur JF, Tran HA, Hamilton JR. Approval of the first protease‐activated receptor antagonist: rationale, development, significance, and considerations of a novel anti‐platelet agent. Blood Rev. 2015;29:179–89.</p>
<p>113. Wong PC, Seiffert D, Bird JE, Watson CA, Bostwick JS, Giancarli M, et al. Blockade of protease‐activated receptor‐4 (PAR4) provides robust antithrombotic activity with low bleeding. Sci Trans Med. 2017;9:5294.</p>
<p>114. French SL, Arthur JF, Lee H, Nesbitt WS, Andrews RK, Gardiner EE, Hamilton JR. Inhibition of protease‐activated receptor 4 impairs platelet procoagulant activity during thrombus formation in human blood. J Thromb Haemost. 2016;14:1642–54.</p>
<p>115. Suzuki‐Inoue K, Kato Y, Inoue O, Kaneko MK, Mishima K, Yatomi Y, et al. Involvement of the snake toxin receptor CLEC‐2, in podoplanin‐mediated platelet activation, by cancer cells. J Biol Chem. 2007;282:25993–6001.</p>
<p>116. Suzuki‐Inoue K, Osada M, Ozaki Y. Physiologic and pathophysiologic roles of interaction between C‐type lectin‐like receptor 2 and podoplanin: partners from in utero to adulthood. J Thromb Haemost. 2017;15:219–29.</p>
<p>117. Tsukiji N, Inoue O, Morimoto M, Tatsumi N, Nagatomo H, Ueta K, et al. Platelets play an essential role in murine lung development through Clec‐2/podoplanin interaction. Blood. 2018;132:1167–79.</p>
<p>118. Wong EDS, Kavanagh D. Diseases of complement dysregulation—an overview. Semin Immunopathol. 2018;40:49–64.</p>
<p>119. Keragala CB, Draxler DF, McQuilten ZK, Medcalf RL. Haemostasis and innate immunity—a complementary relationship: a review of the intricate relationship between coagulation and complement pathways. Br J Haematol. 2018;180:782–98.</p>
<p>120. Baines AC, Brodsky RA. Complementopathies. Blood Rev. 2017;31:213–23.</p>
<p>121. de Maat S, Maas C. Factor XII: form determines function. J Thromb Haemost. 2016;14:1498–506.</p>
<p>122. de Maat S, Björkqvist J, Suffritti C, Wiesenekker CP, Nagtegaal W, Koekman A, et al. Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations. J Allergy Clin Immunol [Internet]. 2016 Nov [cited 2017 Jul 27];138:1414–1423.e9. Available from: <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/pubmed/27130860">http://www.ncbi.nlm.nih.gov/pubmed/27130860</ext-link>
</p>
<p>123. de Maat S, Clark CC, Boertien M, Parr N, Sanrattana W, Hofman ZLM, et al. Factor XII truncation accelerates activation in solution. J Thromb Haemost. 2019; 17:183–94.</p>
<p>124. Pathak M, Kaira BG, Slater A, Emsley J. Cell receptor and cofactor interactions of the contact activation system and factor XI. Front Med (Lausanne). 2018;5:66.</p>
<p>125. Li C, Voos KM, Pathak M, Hall G, McCrae KR, Dreveny I, Li R, Emsley J. Plasma kallikrein structure reveals apple domain disc rotated conformation compared to cactor XI. J Thromb Haemost. 2019. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1111/jth.14418">https://doi.org/10.1111/jth.14418</ext-link>
. Epub.</p>
<p>126. Jenne CN, Wong CHY, Zemp FJ, McDonald B, Rahman MM, Forsyth PA, et al. Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe. 2013;13:169–80.</p>
<p>127. Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13:463–69.</p>
<p>128. McDonald B, Davis RP, Kim S‐J, Tse M, Esmon CT, Kolaczkowska E, Jenne CN. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood. 2017;129:1357–67.</p>
<p>129. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science 2004;303:1532–5.</p>
<p>130. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18:134–47.</p>
<p>131. Jimenez‐Alcazar M, Rangaswamy C, Panda R, Bitterling J, Simsek YJ, Long AT, et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science 2017;358:1202–6.</p>
<p>132. Weitz JI, Fredenburgh JC. 2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis: factor XI as a target for new anticoagulants. Arterioscler Thromb Vasc Biol. 2018;38:304–10.</p>
<p>133. Buller HR, Bethune C, Bhanot S, Gailani D, Monia BP, Raskob GE, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372:232–40.</p>
<p>134. Koch AW, Schiering N, Melkko S, Ewert S, Salter J, Zhang Y, et al. MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulants in humans. Blood. 2019; E‐pub ahead of print.</p>
<p>135. Swystun LL, Lillicrap D. Genetic regulation of plasma von Willebrand factor levels in health and disease. J Thromb Haemost. 2018;16:2375‐90.</p>
<p>136. Johnsen JM, Ginsburg D. von Willebrand Disease. In: Kaushansky K, Levi MM, editors. Williams hematology hemostasis and thrombosis. 1st edition. New York: McGraw‐Hill Education/Medical; 2018. Chapter 16; pp. 349–68.</p>
<p>137. Drury‐Stewart DN, Lannert KW, Chung DW, Teramura GT, Zimring JC, Konkle BA, et al. Complex changes in von Willebrand factor–associated parameters are acquired during uncomplicated pregnancy. PLoS One. 2014;9:e112935.</p>
<p>138. Hayes V, Johnston I, Arepally GM, McKenzie SE, Cines DB, <underline underline-style="single">Rauova L</underline>
, Poncz M. Endothelial antigen assembly leads to thrombotic complications in heparin‐induced thrombocytopenia. J Clin Invest. 2017:1090–8.</p>
<p>139. Tutwiler V, Madeeva D, Ahn HS, Andrianova I, Hayes V, Zheng XL, et al. Platelet transactivation by monocytes promotes the prothrombotic state in heparin‐induced thrombocytopenia. Blood. 2016;127:464–72.</p>
<p>140. Gollomp K, Kim M, Johnston I, Hayes V, Welsh J, Arepally GM, et al. Neutrophil accumulation and NET release contribute to thrombosis in HIT. JCI Insight. 2018;3(18): pii: 99445.</p>
<p>141. Spyropoulos AC<italic>,</italic>
Raskob CE. New paradigms in venous thromboprophylaxis of medically ill patients. Thromb Haemost. 2017;117:1162–70.</p>
<p>142. Liew AY, Piran S, Eikelboom JW, Douketis JD. Extended‐duration versus short‐duration pharmacological thromboprophylaxis in acutely Ill hospitalized medical patients: a systematic review and meta‐analysis of randomized controlled trials. J Thromb Thrombolysis. 2017;43:291–301.</p>
<p>143. Gibson CM, Korjian S, Chi G, Daaboul Y, Jain P, Arbetter D, et al; APEX Investigators. Comparison of fatal or irreversible events with extended‐duration betrixaban versus standard dose enoxaparin in acutely ill medical patients: an APEX trial substudy. J Am Heart Assoc. 2017;6:pii: e006015.</p>
<p>144. Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Col Cardiol. 2007;50:309–15.</p>
<p>145. Resch JA, Okabe N, Loewenson RB, Kimoto K, Katsuki S, Baker AB. Pattern of vessel involvement in cerebral atherosclerosis. A comparative study between a Japanese and Minnesota population. J Atheroscler Res. 1969;9:239–50.</p>
<p>146. Mazzolai L, Aboyans V, Ageno W, Agnelli G, Alatri A, Bauersachs R, et al. Diagnosis and management of acute deep vein thrombosis: a joint consensus document from the European Society of Cardiology working groups of aorta and peripheral vascular diseases and pulmonary circulation and right ventricular function. Eur Heart J. 2018;39:4208–18.</p>
<p>147. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315–52.</p>
<p>148. Castellucci LA, de Wit K, Garcia D, Ortel TL, Le Gal G. Extended anticoagulation for unprovoked venous thromboembolism. Res Pract Thromb Haemost. 2018;2:529–34.</p>
<p>149. Le Gal G, Kovacs MJ, Carrier M, Do K, Kahn SR, Wells PS, et al. Validation of a diagnostic approach to exclude recurrent venous thromboembolism. J Thromb Haemost. 2009;7(5):752–9.</p>
<p>150. Delluc A, Antic D, Lecumberri R, Ay C, Meyer G, Carrier M. Occult cancer screening in patients with venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2017;15(10):2076–9.</p>
<p>151. Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost. 2009;7(5):760–5.</p>
<p>152. Knight M et al on behalf of MBRRACE‐UK. Saving Lives, Improving Mothers’ Care: lessons learned to inform maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2014–16. National Perinatal Epidemiology Unit, University of Oxford; 2018.</p>
<p>153. O'Shaughnessy F, Donnelly JC, Cooley SM, Deering M, Raman A, Gannon G, et al. Thrombocalc: implementation and uptake of personalized postpartum venous thromboembolism risk assessment in a high‐throughput obstetric environment. Acta obstetricia et gynecologica Scandinavica. 2017;96:1382–90.</p>
<p>154. O'Shaughnessy F, Donnelly J, Cooley S, Bennett K, Ní Áinle F, Cleary B. VTE risk factors in an Irish urban obstetric population (OC 73.1). Res Pract Thromb Haemost. 2017;1(S1):196–7.</p>
<p>155. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295‐306.</p>
<p>156. Schreiber K, Sciascia S, de Groot PG, et al. Antiphospholipid syndrome. Nat Rev Dis Primers. 2018;4:18005.</p>
<p>157. Righini M, Robert‐Ebadi H, Elias A, Sanchez O, Le Moigne E, Schmidt J, et al. Diagnosis of pulmonary embolism during pregnancy: a multicenter prospective management outcome study. Ann Intern Med. 2018;169:766–73.</p>
<p>158. van der Pol LM, Tromeur C, Bistervels IM, Ni Ainle F, van Bemmel T, Bertoletti L, et al. Pregnancy‐adapted YEARS algorithm for diagnosis of suspected pulmonary embolism. N Engl J Med. 2019; 380:1139–49.</p>
<p>159. Le Gal G, Righini M, Sanchez O, Roy P‐M, Baba‐Ahmed M, Perrier A, et al. A positive compression ultrasonography of the lower limb veins is highly predictive of pulmonary embolism on computed tomography in suspected patients. Thromb Haemost. 2006; 95:963–6.</p>
<p>160. Regitz‐Zagrosek V, Roos‐Hesselink JW, Bauersachs J, Blomstrom‐Lundqvist C, Cifkova R, De Bonis M, et al. 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018;39:3165–241.</p>
<p>161. D'Souza R, Ostro J, Shah PS, Silversides CK, Malinowski A, Murphy KE, et al. Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta‐analysis. Eur Heart J. 2017;38:1509–16.</p>
<p>162. McLintock C. Anticoagulant therapy in pregnant women with mechanical prosthetic heart valves: no easy option. Thromb Res. 2011;127(Suppl 3):S56‐60.</p>
<p>163. Magnusson M, Ignjatovic V, Hardikar W, Monagle P. A conceptual and practical approach to haemostasis in paediatric liver disease. Arch Dis Child. 2016;101(9):854–9.</p>
<p>164. Beattie W, Magnusson M, Hardikar W, Monagle P, Ignjatovic V. Characterisation of the coagulation profile in children with liver disease. Pediatr Hematol Oncol. 2017;34:107–19.</p>
<p>165. Magnusson M, Berndtsson M, Fischler B, Petrini P, Schulman S, Renné T, et al. Thrombin generation test in children and adolescents with liver disease. Thromb Res. 2015;135:382–7.</p>
</ref-list>
</back>
</pmc>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000B05 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000B05 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= ChloroquineV1 |flux= Pmc |étape= Corpus |type= RBID |clé= PMC:6611378 |texte= Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:31294333" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \ | NlmPubMed2Wicri -a ChloroquineV1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |