Evidence for factor IX‐independent roles for factor XIa in blood coagulation

Summary Background Factor XIa is traditionally assigned a role in FIX activation during coagulation. However, recent evidence suggests this protease may have additional plasma substrates. Objective To determine whether FXIa promotes thrombin generation and coagulation in plasma in the absence of FIX...

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Veröffentlicht in:Journal of thrombosis and haemostasis 2013-12, Vol.11 (12), p.2118-2127
Hauptverfasser: Matafonov, A., Cheng, Q., Geng, Y., Verhamme, I. M., Umunakwe, O., Tucker, E. I., Sun, M.‐F., Serebrov, V., Gruber, A., Gailani, D.
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container_end_page 2127
container_issue 12
container_start_page 2118
container_title Journal of thrombosis and haemostasis
container_volume 11
creator Matafonov, A.
Cheng, Q.
Geng, Y.
Verhamme, I. M.
Umunakwe, O.
Tucker, E. I.
Sun, M.‐F.
Serebrov, V.
Gruber, A.
Gailani, D.
description Summary Background Factor XIa is traditionally assigned a role in FIX activation during coagulation. However, recent evidence suggests this protease may have additional plasma substrates. Objective To determine whether FXIa promotes thrombin generation and coagulation in plasma in the absence of FIX, and to determine whether FXI‐deficiency produces an antithrombotic effect in mice independently of FIX. Methods FXIa, FXIa variants and anti‐FXIa antibodies were tested for their effects on plasma coagulation and thrombin generation in the absence of FIX, and for their effects on the activation of purified coagulation factors. Mice with combined FIX and FXI deficiency were compared with mice lacking either FIX or FXI in an arterial thrombosis model. Results In FIX‐deficient plasma, FXIa induced thrombin generation, and anti‐FXIa antibodies prolonged clotting times. This process involved FXIa‐mediated conversion of FX and FV to their active forms. Activation of FV by FXIa required the A3 domain on the FXIa heavy chain, whereas activation of FX did not. FX activation by FXIa, unlike FIX activation, was not a calcium‐dependent process. Mice lacking both FIX and FXI were more resistant to ferric chloride‐induced carotid artery occlusion than FXI‐deficient or FIX‐deficient mice. Conclusion In addition to its predominant role as an activator of FIX, FXIa may contribute to coagulation by activating FX and FV. As the latter reactions do not require calcium, they may make important contributions to in vitro clotting triggered by contact activation. The reactions may be relevant to FXIa's roles in hemostasis and in promoting thrombosis.
doi_str_mv 10.1111/jth.12435
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M. ; Umunakwe, O. ; Tucker, E. I. ; Sun, M.‐F. ; Serebrov, V. ; Gruber, A. ; Gailani, D.</creator><creatorcontrib>Matafonov, A. ; Cheng, Q. ; Geng, Y. ; Verhamme, I. M. ; Umunakwe, O. ; Tucker, E. I. ; Sun, M.‐F. ; Serebrov, V. ; Gruber, A. ; Gailani, D.</creatorcontrib><description>Summary Background Factor XIa is traditionally assigned a role in FIX activation during coagulation. However, recent evidence suggests this protease may have additional plasma substrates. Objective To determine whether FXIa promotes thrombin generation and coagulation in plasma in the absence of FIX, and to determine whether FXI‐deficiency produces an antithrombotic effect in mice independently of FIX. Methods FXIa, FXIa variants and anti‐FXIa antibodies were tested for their effects on plasma coagulation and thrombin generation in the absence of FIX, and for their effects on the activation of purified coagulation factors. Mice with combined FIX and FXI deficiency were compared with mice lacking either FIX or FXI in an arterial thrombosis model. Results In FIX‐deficient plasma, FXIa induced thrombin generation, and anti‐FXIa antibodies prolonged clotting times. This process involved FXIa‐mediated conversion of FX and FV to their active forms. Activation of FV by FXIa required the A3 domain on the FXIa heavy chain, whereas activation of FX did not. FX activation by FXIa, unlike FIX activation, was not a calcium‐dependent process. Mice lacking both FIX and FXI were more resistant to ferric chloride‐induced carotid artery occlusion than FXI‐deficient or FIX‐deficient mice. Conclusion In addition to its predominant role as an activator of FIX, FXIa may contribute to coagulation by activating FX and FV. As the latter reactions do not require calcium, they may make important contributions to in vitro clotting triggered by contact activation. The reactions may be relevant to FXIa's roles in hemostasis and in promoting thrombosis.</description><identifier>ISSN: 1538-7933</identifier><identifier>ISSN: 1538-7836</identifier><identifier>EISSN: 1538-7836</identifier><identifier>DOI: 10.1111/jth.12435</identifier><identifier>PMID: 24152424</identifier><language>eng</language><publisher>England: Elsevier Limited</publisher><subject>Animals ; Blood Coagulation - physiology ; Electrophoresis, Polyacrylamide Gel ; Factor IX - immunology ; Factor IX - physiology ; Factor XIa - immunology ; Factor XIa - physiology ; factor IX ; factor V ; factor X ; factor XI ; factor XIa ; Humans ; Mice ; Mice, Inbred C57BL ; Proteolysis</subject><ispartof>Journal of thrombosis and haemostasis, 2013-12, Vol.11 (12), p.2118-2127</ispartof><rights>2013 International Society on Thrombosis and Haemostasis</rights><rights>2013 International Society on Thrombosis and Haemostasis.</rights><rights>Copyright © 2013 International Society on Thrombosis and Haemostasis</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4435-dc5c56b43a1a2b6c47b008d74b1d6f5ade31cab81d00f1c104a2d16926ab25103</citedby><cites>FETCH-LOGICAL-c4435-dc5c56b43a1a2b6c47b008d74b1d6f5ade31cab81d00f1c104a2d16926ab25103</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24152424$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matafonov, A.</creatorcontrib><creatorcontrib>Cheng, Q.</creatorcontrib><creatorcontrib>Geng, Y.</creatorcontrib><creatorcontrib>Verhamme, I. M.</creatorcontrib><creatorcontrib>Umunakwe, O.</creatorcontrib><creatorcontrib>Tucker, E. I.</creatorcontrib><creatorcontrib>Sun, M.‐F.</creatorcontrib><creatorcontrib>Serebrov, V.</creatorcontrib><creatorcontrib>Gruber, A.</creatorcontrib><creatorcontrib>Gailani, D.</creatorcontrib><title>Evidence for factor IX‐independent roles for factor XIa in blood coagulation</title><title>Journal of thrombosis and haemostasis</title><addtitle>J Thromb Haemost</addtitle><description>Summary Background Factor XIa is traditionally assigned a role in FIX activation during coagulation. However, recent evidence suggests this protease may have additional plasma substrates. Objective To determine whether FXIa promotes thrombin generation and coagulation in plasma in the absence of FIX, and to determine whether FXI‐deficiency produces an antithrombotic effect in mice independently of FIX. Methods FXIa, FXIa variants and anti‐FXIa antibodies were tested for their effects on plasma coagulation and thrombin generation in the absence of FIX, and for their effects on the activation of purified coagulation factors. Mice with combined FIX and FXI deficiency were compared with mice lacking either FIX or FXI in an arterial thrombosis model. Results In FIX‐deficient plasma, FXIa induced thrombin generation, and anti‐FXIa antibodies prolonged clotting times. This process involved FXIa‐mediated conversion of FX and FV to their active forms. Activation of FV by FXIa required the A3 domain on the FXIa heavy chain, whereas activation of FX did not. FX activation by FXIa, unlike FIX activation, was not a calcium‐dependent process. Mice lacking both FIX and FXI were more resistant to ferric chloride‐induced carotid artery occlusion than FXI‐deficient or FIX‐deficient mice. Conclusion In addition to its predominant role as an activator of FIX, FXIa may contribute to coagulation by activating FX and FV. As the latter reactions do not require calcium, they may make important contributions to in vitro clotting triggered by contact activation. The reactions may be relevant to FXIa's roles in hemostasis and in promoting thrombosis.</description><subject>Animals</subject><subject>Blood Coagulation - physiology</subject><subject>Electrophoresis, Polyacrylamide Gel</subject><subject>Factor IX - immunology</subject><subject>Factor IX - physiology</subject><subject>Factor XIa - immunology</subject><subject>Factor XIa - physiology</subject><subject>factor IX</subject><subject>factor V</subject><subject>factor X</subject><subject>factor XI</subject><subject>factor XIa</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Proteolysis</subject><issn>1538-7933</issn><issn>1538-7836</issn><issn>1538-7836</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUtKBDEURYMo_gduQAqc6KDtvHzqMxFE_LQIOlDoWUglqTZNdaVNqhRnLsEluBaX4kqMdisqmMFLIIfDfVyEtgDvQzz9cXu7D4RRvoBWgdO8l-U0Xfx6F5SuoLUQxhhDwQleRiuEASeMsFV0dXxvtWmUSSrnk0qq1vnXl8Hw7enZNtpMTRxNm3hXm_ALGQ5kYpukrJ3TiXJy1NWyta7ZQEuVrIPZnN_r6Obk-ProrHdxeTo4OrzoKRaD9rTiiqcloxIkKVPFshLjXGesBJ1WXGpDQckyB41xBQowk0RDWpBUloQDpuvoYOadduXEaBVTelmLqbcT6R-Fk1b8_mnsrRi5e0ELljFKo2B3LvDurjOhFRMblKlr2RjXBQEcM8YLirOI7vxBx67zTVxPAMsIJpDmH4n2ZpTyLgRvqu8wgMVHTyL2JD57iuz2z_Tf5FcxEejPgAdbm8f_TeL8-mymfAcq3p87</recordid><startdate>201312</startdate><enddate>201312</enddate><creator>Matafonov, A.</creator><creator>Cheng, Q.</creator><creator>Geng, Y.</creator><creator>Verhamme, I. M.</creator><creator>Umunakwe, O.</creator><creator>Tucker, E. I.</creator><creator>Sun, M.‐F.</creator><creator>Serebrov, V.</creator><creator>Gruber, A.</creator><creator>Gailani, D.</creator><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201312</creationdate><title>Evidence for factor IX‐independent roles for factor XIa in blood coagulation</title><author>Matafonov, A. ; Cheng, Q. ; Geng, Y. ; Verhamme, I. M. ; Umunakwe, O. ; Tucker, E. I. ; Sun, M.‐F. ; Serebrov, V. ; Gruber, A. ; Gailani, D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4435-dc5c56b43a1a2b6c47b008d74b1d6f5ade31cab81d00f1c104a2d16926ab25103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Blood Coagulation - physiology</topic><topic>Electrophoresis, Polyacrylamide Gel</topic><topic>Factor IX - immunology</topic><topic>Factor IX - physiology</topic><topic>Factor XIa - immunology</topic><topic>Factor XIa - physiology</topic><topic>factor IX</topic><topic>factor V</topic><topic>factor X</topic><topic>factor XI</topic><topic>factor XIa</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Proteolysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Matafonov, A.</creatorcontrib><creatorcontrib>Cheng, Q.</creatorcontrib><creatorcontrib>Geng, Y.</creatorcontrib><creatorcontrib>Verhamme, I. M.</creatorcontrib><creatorcontrib>Umunakwe, O.</creatorcontrib><creatorcontrib>Tucker, E. I.</creatorcontrib><creatorcontrib>Sun, M.‐F.</creatorcontrib><creatorcontrib>Serebrov, V.</creatorcontrib><creatorcontrib>Gruber, A.</creatorcontrib><creatorcontrib>Gailani, D.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of thrombosis and haemostasis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Matafonov, A.</au><au>Cheng, Q.</au><au>Geng, Y.</au><au>Verhamme, I. M.</au><au>Umunakwe, O.</au><au>Tucker, E. I.</au><au>Sun, M.‐F.</au><au>Serebrov, V.</au><au>Gruber, A.</au><au>Gailani, D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evidence for factor IX‐independent roles for factor XIa in blood coagulation</atitle><jtitle>Journal of thrombosis and haemostasis</jtitle><addtitle>J Thromb Haemost</addtitle><date>2013-12</date><risdate>2013</risdate><volume>11</volume><issue>12</issue><spage>2118</spage><epage>2127</epage><pages>2118-2127</pages><issn>1538-7933</issn><issn>1538-7836</issn><eissn>1538-7836</eissn><abstract>Summary Background Factor XIa is traditionally assigned a role in FIX activation during coagulation. However, recent evidence suggests this protease may have additional plasma substrates. Objective To determine whether FXIa promotes thrombin generation and coagulation in plasma in the absence of FIX, and to determine whether FXI‐deficiency produces an antithrombotic effect in mice independently of FIX. Methods FXIa, FXIa variants and anti‐FXIa antibodies were tested for their effects on plasma coagulation and thrombin generation in the absence of FIX, and for their effects on the activation of purified coagulation factors. Mice with combined FIX and FXI deficiency were compared with mice lacking either FIX or FXI in an arterial thrombosis model. Results In FIX‐deficient plasma, FXIa induced thrombin generation, and anti‐FXIa antibodies prolonged clotting times. This process involved FXIa‐mediated conversion of FX and FV to their active forms. Activation of FV by FXIa required the A3 domain on the FXIa heavy chain, whereas activation of FX did not. FX activation by FXIa, unlike FIX activation, was not a calcium‐dependent process. Mice lacking both FIX and FXI were more resistant to ferric chloride‐induced carotid artery occlusion than FXI‐deficient or FIX‐deficient mice. Conclusion In addition to its predominant role as an activator of FIX, FXIa may contribute to coagulation by activating FX and FV. As the latter reactions do not require calcium, they may make important contributions to in vitro clotting triggered by contact activation. The reactions may be relevant to FXIa's roles in hemostasis and in promoting thrombosis.</abstract><cop>England</cop><pub>Elsevier Limited</pub><pmid>24152424</pmid><doi>10.1111/jth.12435</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection
subjects Animals
Blood Coagulation - physiology
Electrophoresis, Polyacrylamide Gel
Factor IX - immunology
Factor IX - physiology
Factor XIa - immunology
Factor XIa - physiology
factor IX
factor V
factor X
factor XI
factor XIa
Humans
Mice
Mice, Inbred C57BL
Proteolysis
title Evidence for factor IX‐independent roles for factor XIa in blood coagulation
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