Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura
Severe deficiency in ADAMTS-13 (
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| Veröffentlicht in: | Journal of thrombosis and haemostasis 2023-06, Vol.21 (6), p.1544-1552 |
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| container_title | Journal of thrombosis and haemostasis |
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| creator | Underwood, Mary I. Alwan, Ferras Thomas, Mari R. Scully, Marie A. Crawley, James T.B. |
| description | Severe deficiency in ADAMTS-13 ( |
| doi_str_mv | 10.1016/j.jtha.2023.02.011 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2779342802</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1538783623001599</els_id><sourcerecordid>2779342802</sourcerecordid><originalsourceid>FETCH-LOGICAL-c400t-8216b9c0819b858b8f5a47146170ebc7adeedb945fa9f5eda90e814f13e9d49d3</originalsourceid><addsrcrecordid>eNp9kE9r3DAQxUVoSLbbfoEeio-92NFI_iNBL0uapoENOSQ5C1kas1rWlivJDfvt4-1mS0-BgRke7z2YHyFfgBZAob7aFtu00QWjjBeUFRTgjCyg4iJvBK8__Hdfko8xbikFWTF6QS55LYADiAXpVlPyekiu9dZhzHDY6MFgtvqxun96zIFnZoc6_NXckI06ORxSzF5c2mSu76cBs7QJvm99cuZ0mn3yIw6zME5hHv2JnHd6F_Hz216S5583T9e_8vXD7d31ap2bktKUCwZ1Kw0VIFtRiVZ0lS4bKGtoKLam0RbRtrKsOi27Cq2WFAWUHXCUtpSWL8m3Y-8Y_O8JY1K9iwZ3Oz2gn6JiTSN5ycSMbEnY0WqCjzFgp8bgeh32Cqg68FVbdeCrDnwVZWrmO4e-vvVPbY_2X-QEdDZ8Pxpw_vKPw6CimYkZtC6gScp6917_K6EpjXc</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2779342802</pqid></control><display><type>article</type><title>Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Underwood, Mary I. ; Alwan, Ferras ; Thomas, Mari R. ; Scully, Marie A. ; Crawley, James T.B.</creator><creatorcontrib>Underwood, Mary I. ; Alwan, Ferras ; Thomas, Mari R. ; Scully, Marie A. ; Crawley, James T.B.</creatorcontrib><description>Severe deficiency in ADAMTS-13 (<10%) and the loss of von Willebrand factor–cleaving function can precipitate microvascular thrombosis associated with thrombotic thrombocytopenic purpura (TTP). Patients with immune-mediated TTP (iTTP) have anti-ADAMTS-13 immunoglobulin G antibodies that inhibit ADAMTS-13 function and/or increase ADAMTS-13 clearance. Patients with iTTP are treated primarily by plasma exchange (PEX), often in combination with adjunct therapies that target either the von Willebrand factor-dependent microvascular thrombotic processes (caplacizumab) or the autoimmune components (steroids or rituximab) of the disease.
To investigate the contributions of autoantibody-mediated ADAMTS-13 clearance and inhibition in patients with iTTP at presentation and through the course of the PEX therapy.
Anti-ADAMTS-13 immunoglobulin G antibodies, ADAMTS-13 antigen, and activity were measured before and after each PEX in 17 patients with iTTP and 20 acute TTP episodes.
At presentation, 14 out of 15 patients with iTTP had ADAMTS-13 antigen levels of <10%, suggesting a major contribution of ADAMTS-13 clearance to the deficiency state. After the first PEX, both ADAMTS-13 antigen and activity levels increased similarly, and the anti-ADAMTS-13 autoantibody titer decreased in all patients, revealing ADAMTS-13 inhibition to be a modest modifier of the ADAMTS-13 function in iTTP. Analysis of ADAMTS-13 antigen levels between consecutive PEX treatments revealed that the rate of ADAMTS-13 clearance in 9 out of 14 patients analyzed was 4- to 10-fold faster than the estimated normal rate of clearance.
These data reveal, both at presentation and during PEX treatment, that antibody-mediated clearance of ADAMTS-13 is the major pathogenic mechanism that causes ADAMTS-13 deficiency in iTTP. Understanding the kinetics of ADAMTS-13 clearance in iTTP may now enable further optimization of treatment of patients with iTTP.
•At presentation, all patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) exhibited evidence of antibody-mediated ADAMTS-13 clearance.•Plasma exchange treatment in iTTP rapidly reduces anti–ADAMTS-13 autoantibody titer.•During the early plasma exchange treatments, antibody-mediated ADAMTS-13 clearance is the major pathogenic mechanism promoting ADAMTS-13 deficiency.•Autoantibodies in iTTP enhance ADAMTS-13 clearance by 4- to 10-fold.</description><identifier>ISSN: 1538-7836</identifier><identifier>EISSN: 1538-7836</identifier><identifier>DOI: 10.1016/j.jtha.2023.02.011</identifier><identifier>PMID: 36813118</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>ADAMTS-13 ; ADAMTS13 Protein ; Autoantibodies ; autoimmune disease ; Humans ; Immunoglobulin G ; purpura ; Purpura, Thrombocytopenic, Idiopathic ; Purpura, Thrombotic Thrombocytopenic ; Thrombosis ; thrombotic thrombocytopenic ; von Willebrand Factor</subject><ispartof>Journal of thrombosis and haemostasis, 2023-06, Vol.21 (6), p.1544-1552</ispartof><rights>2023 The Authors</rights><rights>Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-8216b9c0819b858b8f5a47146170ebc7adeedb945fa9f5eda90e814f13e9d49d3</citedby><cites>FETCH-LOGICAL-c400t-8216b9c0819b858b8f5a47146170ebc7adeedb945fa9f5eda90e814f13e9d49d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36813118$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Underwood, Mary I.</creatorcontrib><creatorcontrib>Alwan, Ferras</creatorcontrib><creatorcontrib>Thomas, Mari R.</creatorcontrib><creatorcontrib>Scully, Marie A.</creatorcontrib><creatorcontrib>Crawley, James T.B.</creatorcontrib><title>Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura</title><title>Journal of thrombosis and haemostasis</title><addtitle>J Thromb Haemost</addtitle><description>Severe deficiency in ADAMTS-13 (<10%) and the loss of von Willebrand factor–cleaving function can precipitate microvascular thrombosis associated with thrombotic thrombocytopenic purpura (TTP). Patients with immune-mediated TTP (iTTP) have anti-ADAMTS-13 immunoglobulin G antibodies that inhibit ADAMTS-13 function and/or increase ADAMTS-13 clearance. Patients with iTTP are treated primarily by plasma exchange (PEX), often in combination with adjunct therapies that target either the von Willebrand factor-dependent microvascular thrombotic processes (caplacizumab) or the autoimmune components (steroids or rituximab) of the disease.
To investigate the contributions of autoantibody-mediated ADAMTS-13 clearance and inhibition in patients with iTTP at presentation and through the course of the PEX therapy.
Anti-ADAMTS-13 immunoglobulin G antibodies, ADAMTS-13 antigen, and activity were measured before and after each PEX in 17 patients with iTTP and 20 acute TTP episodes.
At presentation, 14 out of 15 patients with iTTP had ADAMTS-13 antigen levels of <10%, suggesting a major contribution of ADAMTS-13 clearance to the deficiency state. After the first PEX, both ADAMTS-13 antigen and activity levels increased similarly, and the anti-ADAMTS-13 autoantibody titer decreased in all patients, revealing ADAMTS-13 inhibition to be a modest modifier of the ADAMTS-13 function in iTTP. Analysis of ADAMTS-13 antigen levels between consecutive PEX treatments revealed that the rate of ADAMTS-13 clearance in 9 out of 14 patients analyzed was 4- to 10-fold faster than the estimated normal rate of clearance.
These data reveal, both at presentation and during PEX treatment, that antibody-mediated clearance of ADAMTS-13 is the major pathogenic mechanism that causes ADAMTS-13 deficiency in iTTP. Understanding the kinetics of ADAMTS-13 clearance in iTTP may now enable further optimization of treatment of patients with iTTP.
•At presentation, all patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) exhibited evidence of antibody-mediated ADAMTS-13 clearance.•Plasma exchange treatment in iTTP rapidly reduces anti–ADAMTS-13 autoantibody titer.•During the early plasma exchange treatments, antibody-mediated ADAMTS-13 clearance is the major pathogenic mechanism promoting ADAMTS-13 deficiency.•Autoantibodies in iTTP enhance ADAMTS-13 clearance by 4- to 10-fold.</description><subject>ADAMTS-13</subject><subject>ADAMTS13 Protein</subject><subject>Autoantibodies</subject><subject>autoimmune disease</subject><subject>Humans</subject><subject>Immunoglobulin G</subject><subject>purpura</subject><subject>Purpura, Thrombocytopenic, Idiopathic</subject><subject>Purpura, Thrombotic Thrombocytopenic</subject><subject>Thrombosis</subject><subject>thrombotic thrombocytopenic</subject><subject>von Willebrand Factor</subject><issn>1538-7836</issn><issn>1538-7836</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9r3DAQxUVoSLbbfoEeio-92NFI_iNBL0uapoENOSQ5C1kas1rWlivJDfvt4-1mS0-BgRke7z2YHyFfgBZAob7aFtu00QWjjBeUFRTgjCyg4iJvBK8__Hdfko8xbikFWTF6QS55LYADiAXpVlPyekiu9dZhzHDY6MFgtvqxun96zIFnZoc6_NXckI06ORxSzF5c2mSu76cBs7QJvm99cuZ0mn3yIw6zME5hHv2JnHd6F_Hz216S5583T9e_8vXD7d31ap2bktKUCwZ1Kw0VIFtRiVZ0lS4bKGtoKLam0RbRtrKsOi27Cq2WFAWUHXCUtpSWL8m3Y-8Y_O8JY1K9iwZ3Oz2gn6JiTSN5ycSMbEnY0WqCjzFgp8bgeh32Cqg68FVbdeCrDnwVZWrmO4e-vvVPbY_2X-QEdDZ8Pxpw_vKPw6CimYkZtC6gScp6917_K6EpjXc</recordid><startdate>202306</startdate><enddate>202306</enddate><creator>Underwood, Mary I.</creator><creator>Alwan, Ferras</creator><creator>Thomas, Mari R.</creator><creator>Scully, Marie A.</creator><creator>Crawley, James T.B.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope></search><sort><creationdate>202306</creationdate><title>Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura</title><author>Underwood, Mary I. ; Alwan, Ferras ; Thomas, Mari R. ; Scully, Marie A. ; Crawley, James T.B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-8216b9c0819b858b8f5a47146170ebc7adeedb945fa9f5eda90e814f13e9d49d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>ADAMTS-13</topic><topic>ADAMTS13 Protein</topic><topic>Autoantibodies</topic><topic>autoimmune disease</topic><topic>Humans</topic><topic>Immunoglobulin G</topic><topic>purpura</topic><topic>Purpura, Thrombocytopenic, Idiopathic</topic><topic>Purpura, Thrombotic Thrombocytopenic</topic><topic>Thrombosis</topic><topic>thrombotic thrombocytopenic</topic><topic>von Willebrand Factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Underwood, Mary I.</creatorcontrib><creatorcontrib>Alwan, Ferras</creatorcontrib><creatorcontrib>Thomas, Mari R.</creatorcontrib><creatorcontrib>Scully, Marie A.</creatorcontrib><creatorcontrib>Crawley, James T.B.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of thrombosis and haemostasis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Underwood, Mary I.</au><au>Alwan, Ferras</au><au>Thomas, Mari R.</au><au>Scully, Marie A.</au><au>Crawley, James T.B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura</atitle><jtitle>Journal of thrombosis and haemostasis</jtitle><addtitle>J Thromb Haemost</addtitle><date>2023-06</date><risdate>2023</risdate><volume>21</volume><issue>6</issue><spage>1544</spage><epage>1552</epage><pages>1544-1552</pages><issn>1538-7836</issn><eissn>1538-7836</eissn><abstract>Severe deficiency in ADAMTS-13 (<10%) and the loss of von Willebrand factor–cleaving function can precipitate microvascular thrombosis associated with thrombotic thrombocytopenic purpura (TTP). Patients with immune-mediated TTP (iTTP) have anti-ADAMTS-13 immunoglobulin G antibodies that inhibit ADAMTS-13 function and/or increase ADAMTS-13 clearance. Patients with iTTP are treated primarily by plasma exchange (PEX), often in combination with adjunct therapies that target either the von Willebrand factor-dependent microvascular thrombotic processes (caplacizumab) or the autoimmune components (steroids or rituximab) of the disease.
To investigate the contributions of autoantibody-mediated ADAMTS-13 clearance and inhibition in patients with iTTP at presentation and through the course of the PEX therapy.
Anti-ADAMTS-13 immunoglobulin G antibodies, ADAMTS-13 antigen, and activity were measured before and after each PEX in 17 patients with iTTP and 20 acute TTP episodes.
At presentation, 14 out of 15 patients with iTTP had ADAMTS-13 antigen levels of <10%, suggesting a major contribution of ADAMTS-13 clearance to the deficiency state. After the first PEX, both ADAMTS-13 antigen and activity levels increased similarly, and the anti-ADAMTS-13 autoantibody titer decreased in all patients, revealing ADAMTS-13 inhibition to be a modest modifier of the ADAMTS-13 function in iTTP. Analysis of ADAMTS-13 antigen levels between consecutive PEX treatments revealed that the rate of ADAMTS-13 clearance in 9 out of 14 patients analyzed was 4- to 10-fold faster than the estimated normal rate of clearance.
These data reveal, both at presentation and during PEX treatment, that antibody-mediated clearance of ADAMTS-13 is the major pathogenic mechanism that causes ADAMTS-13 deficiency in iTTP. Understanding the kinetics of ADAMTS-13 clearance in iTTP may now enable further optimization of treatment of patients with iTTP.
•At presentation, all patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) exhibited evidence of antibody-mediated ADAMTS-13 clearance.•Plasma exchange treatment in iTTP rapidly reduces anti–ADAMTS-13 autoantibody titer.•During the early plasma exchange treatments, antibody-mediated ADAMTS-13 clearance is the major pathogenic mechanism promoting ADAMTS-13 deficiency.•Autoantibodies in iTTP enhance ADAMTS-13 clearance by 4- to 10-fold.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>36813118</pmid><doi>10.1016/j.jtha.2023.02.011</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | ADAMTS-13 ADAMTS13 Protein Autoantibodies autoimmune disease Humans Immunoglobulin G purpura Purpura, Thrombocytopenic, Idiopathic Purpura, Thrombotic Thrombocytopenic Thrombosis thrombotic thrombocytopenic von Willebrand Factor |
| title | Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura |
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