Anti‐protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome
Summary Background Antiphospholipid antibodies may interfere with the anticoagulant activity of activated protein C (APC) to induce acquired APC resistance (APCr). Aims To investigate the frequency and characteristics of APCr by using recombinant human APC (rhAPC) and endogenous protein C activation...
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| Veröffentlicht in: | Journal of thrombosis and haemostasis 2014-11, Vol.12 (11), p.1801-1809 |
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| creator | Arachchillage, D. R. J. Efthymiou, M. Mackie, I. J. Lawrie, A. S. Machin, S. J. Cohen, H. |
| description | Summary
Background
Antiphospholipid antibodies may interfere with the anticoagulant activity of activated protein C (APC) to induce acquired APC resistance (APCr).
Aims
To investigate the frequency and characteristics of APCr by using recombinant human APC (rhAPC) and endogenous protein C activation in antiphospholipid syndrome (APS).
Methods
APCr was assessed in APS and non‐APS venous thromboembolism (VTE) patients on warfarin and normal controls with rhAPC or Protac by thrombin generation. IgG anti‐protein C and anti‐protein S antibodies and avidity were assessed by ELISA.
Results
APS patients showed greater resistance to both rhAPC and Protac than non‐APS patients and normal controls (median normalized endogenous thrombin potential inhibition): APS patients with rhAPC, 81.3% (95% confidence interval [CI] 75.2–88.3%; non‐APS patients with rhAPC, 97.7% (95% CI 93.6–101.8%; APS patients with Protac, 66.0% (95% CI 59.5–72.6%); and non‐APS patients with Protac, 80.7 (95% CI 74.2–87.2%). APS patients also had a higher frequency and higher levels of anti‐protein C antibodies, with 60% (15/25) high‐avidity antibodies. High‐avidity anti‐protein C antibodies were associated with greater APCr and with a severe thrombotic phenotype (defined as the development of recurrent VTE while patients were receiving therapeutic anticoagulation or both venous and arterial thrombosis). Twelve of 15 (80%) patients with high‐avidity anti‐protein C antibodies were classified as APS category I.
Conclusion
Thrombotic APS patients showed greater APCr to both rhAPC and activation of endogenous protein C by Protac. High‐avidity anti‐protein C antibodies, associated with greater APCr, may provide a marker for a severe thrombotic phenotype in APS. However, in patients with category I APS, it remains to be established whether anti‐protein C or anti‐β2‐glycoprotein I antibodies are responsible for APCr. |
| doi_str_mv | 10.1111/jth.12722 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_1622121503</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3490227091</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3882-1366a4be377e181db6cbb5b5acfce62630466b1fd99aa864a557f998c05811d63</originalsourceid><addsrcrecordid>eNp1kU1OGzEUxy1UVCh0wQWQpa5YBPwRezxLFEGhQmID65E_3jCOEntqO0TZ9Qg9QdWz9Cg9CS4B1A2Wnmw9_fx7sv8IHVFySus6m5fhlLKGsR20TwVXk0Zx-eH13HK-hz7lPCeEtoKRj2iPCdpKRdQ--nUeiv_74-eYYgEf_vyeYV07JjoPGesEWOccrdcFHF77MuAE2eeigwVcIobg4gOEuMr4f4Ut_lEXH0O1OaxxhkeorjKkuDSxeIvHod4qmxGwD88jxyHmWgs_eofzJriKwiHa7fUiw-eX_QDdX17cza4mN7dfr2fnNxPLlWITyqXUUwO8aYAq6oy0xggjtO0tSCY5mUppaO_aVmslp1qIpm9bZYlQlDrJD9CXrbc-4vsKcunmcZVCHdlRyRhlVBBeqZMtZVPMOUHfjckvddp0lHT_kuhqEt1zEpU9fjGuzBLcG_n69RU42wJrv4DN-6bu293VVvkE0CeZHQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1622121503</pqid></control><display><type>article</type><title>Anti‐protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Arachchillage, D. R. J. ; Efthymiou, M. ; Mackie, I. J. ; Lawrie, A. S. ; Machin, S. J. ; Cohen, H.</creator><creatorcontrib>Arachchillage, D. R. J. ; Efthymiou, M. ; Mackie, I. J. ; Lawrie, A. S. ; Machin, S. J. ; Cohen, H.</creatorcontrib><description>Summary
Background
Antiphospholipid antibodies may interfere with the anticoagulant activity of activated protein C (APC) to induce acquired APC resistance (APCr).
Aims
To investigate the frequency and characteristics of APCr by using recombinant human APC (rhAPC) and endogenous protein C activation in antiphospholipid syndrome (APS).
Methods
APCr was assessed in APS and non‐APS venous thromboembolism (VTE) patients on warfarin and normal controls with rhAPC or Protac by thrombin generation. IgG anti‐protein C and anti‐protein S antibodies and avidity were assessed by ELISA.
Results
APS patients showed greater resistance to both rhAPC and Protac than non‐APS patients and normal controls (median normalized endogenous thrombin potential inhibition): APS patients with rhAPC, 81.3% (95% confidence interval [CI] 75.2–88.3%; non‐APS patients with rhAPC, 97.7% (95% CI 93.6–101.8%; APS patients with Protac, 66.0% (95% CI 59.5–72.6%); and non‐APS patients with Protac, 80.7 (95% CI 74.2–87.2%). APS patients also had a higher frequency and higher levels of anti‐protein C antibodies, with 60% (15/25) high‐avidity antibodies. High‐avidity anti‐protein C antibodies were associated with greater APCr and with a severe thrombotic phenotype (defined as the development of recurrent VTE while patients were receiving therapeutic anticoagulation or both venous and arterial thrombosis). Twelve of 15 (80%) patients with high‐avidity anti‐protein C antibodies were classified as APS category I.
Conclusion
Thrombotic APS patients showed greater APCr to both rhAPC and activation of endogenous protein C by Protac. High‐avidity anti‐protein C antibodies, associated with greater APCr, may provide a marker for a severe thrombotic phenotype in APS. However, in patients with category I APS, it remains to be established whether anti‐protein C or anti‐β2‐glycoprotein I antibodies are responsible for APCr.</description><identifier>ISSN: 1538-7933</identifier><identifier>ISSN: 1538-7836</identifier><identifier>EISSN: 1538-7836</identifier><identifier>DOI: 10.1111/jth.12722</identifier><identifier>PMID: 25196808</identifier><language>eng</language><publisher>England: Elsevier Limited</publisher><subject>Activated Protein C Resistance - blood ; Activated Protein C Resistance - diagnosis ; Activated Protein C Resistance - drug therapy ; Activated Protein C Resistance - immunology ; activated protein C resistance ; Adult ; Aged ; antibodies ; Antibodies, Antiphospholipid - blood ; Anticoagulants - therapeutic use ; antiphospholipid syndrome ; Antiphospholipid Syndrome - blood ; Antiphospholipid Syndrome - complications ; Antiphospholipid Syndrome - diagnosis ; Antiphospholipid Syndrome - drug therapy ; Antiphospholipid Syndrome - immunology ; Biomarkers - blood ; Blood Coagulation Tests ; Case-Control Studies ; Cross-Sectional Studies ; Enzyme-Linked Immunosorbent Assay ; Female ; Fibrinolytic Agents - therapeutic use ; Humans ; Intercellular Signaling Peptides and Proteins ; Male ; Middle Aged ; Peptides - therapeutic use ; Phenotype ; Protac ; Protein C - immunology ; Protein C - therapeutic use ; protein C ; Recombinant Proteins - therapeutic use ; Severity of Illness Index ; venous thromboembolism ; Venous Thromboembolism - blood ; Venous Thromboembolism - diagnosis ; Venous Thromboembolism - immunology ; Venous Thromboembolism - prevention & control ; Warfarin - therapeutic use</subject><ispartof>Journal of thrombosis and haemostasis, 2014-11, Vol.12 (11), p.1801-1809</ispartof><rights>2014 International Society on Thrombosis and Haemostasis</rights><rights>2014 International Society on Thrombosis and Haemostasis.</rights><rights>Copyright © 2014 International Society on Thrombosis and Haemostasis</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3882-1366a4be377e181db6cbb5b5acfce62630466b1fd99aa864a557f998c05811d63</citedby><cites>FETCH-LOGICAL-c3882-1366a4be377e181db6cbb5b5acfce62630466b1fd99aa864a557f998c05811d63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25196808$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Arachchillage, D. R. J.</creatorcontrib><creatorcontrib>Efthymiou, M.</creatorcontrib><creatorcontrib>Mackie, I. J.</creatorcontrib><creatorcontrib>Lawrie, A. S.</creatorcontrib><creatorcontrib>Machin, S. J.</creatorcontrib><creatorcontrib>Cohen, H.</creatorcontrib><title>Anti‐protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome</title><title>Journal of thrombosis and haemostasis</title><addtitle>J Thromb Haemost</addtitle><description>Summary
Background
Antiphospholipid antibodies may interfere with the anticoagulant activity of activated protein C (APC) to induce acquired APC resistance (APCr).
Aims
To investigate the frequency and characteristics of APCr by using recombinant human APC (rhAPC) and endogenous protein C activation in antiphospholipid syndrome (APS).
Methods
APCr was assessed in APS and non‐APS venous thromboembolism (VTE) patients on warfarin and normal controls with rhAPC or Protac by thrombin generation. IgG anti‐protein C and anti‐protein S antibodies and avidity were assessed by ELISA.
Results
APS patients showed greater resistance to both rhAPC and Protac than non‐APS patients and normal controls (median normalized endogenous thrombin potential inhibition): APS patients with rhAPC, 81.3% (95% confidence interval [CI] 75.2–88.3%; non‐APS patients with rhAPC, 97.7% (95% CI 93.6–101.8%; APS patients with Protac, 66.0% (95% CI 59.5–72.6%); and non‐APS patients with Protac, 80.7 (95% CI 74.2–87.2%). APS patients also had a higher frequency and higher levels of anti‐protein C antibodies, with 60% (15/25) high‐avidity antibodies. High‐avidity anti‐protein C antibodies were associated with greater APCr and with a severe thrombotic phenotype (defined as the development of recurrent VTE while patients were receiving therapeutic anticoagulation or both venous and arterial thrombosis). Twelve of 15 (80%) patients with high‐avidity anti‐protein C antibodies were classified as APS category I.
Conclusion
Thrombotic APS patients showed greater APCr to both rhAPC and activation of endogenous protein C by Protac. High‐avidity anti‐protein C antibodies, associated with greater APCr, may provide a marker for a severe thrombotic phenotype in APS. However, in patients with category I APS, it remains to be established whether anti‐protein C or anti‐β2‐glycoprotein I antibodies are responsible for APCr.</description><subject>Activated Protein C Resistance - blood</subject><subject>Activated Protein C Resistance - diagnosis</subject><subject>Activated Protein C Resistance - drug therapy</subject><subject>Activated Protein C Resistance - immunology</subject><subject>activated protein C resistance</subject><subject>Adult</subject><subject>Aged</subject><subject>antibodies</subject><subject>Antibodies, Antiphospholipid - blood</subject><subject>Anticoagulants - therapeutic use</subject><subject>antiphospholipid syndrome</subject><subject>Antiphospholipid Syndrome - blood</subject><subject>Antiphospholipid Syndrome - complications</subject><subject>Antiphospholipid Syndrome - diagnosis</subject><subject>Antiphospholipid Syndrome - drug therapy</subject><subject>Antiphospholipid Syndrome - immunology</subject><subject>Biomarkers - blood</subject><subject>Blood Coagulation Tests</subject><subject>Case-Control Studies</subject><subject>Cross-Sectional Studies</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Female</subject><subject>Fibrinolytic Agents - therapeutic use</subject><subject>Humans</subject><subject>Intercellular Signaling Peptides and Proteins</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Peptides - therapeutic use</subject><subject>Phenotype</subject><subject>Protac</subject><subject>Protein C - immunology</subject><subject>Protein C - therapeutic use</subject><subject>protein C</subject><subject>Recombinant Proteins - therapeutic use</subject><subject>Severity of Illness Index</subject><subject>venous thromboembolism</subject><subject>Venous Thromboembolism - blood</subject><subject>Venous Thromboembolism - diagnosis</subject><subject>Venous Thromboembolism - immunology</subject><subject>Venous Thromboembolism - prevention & control</subject><subject>Warfarin - therapeutic use</subject><issn>1538-7933</issn><issn>1538-7836</issn><issn>1538-7836</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU1OGzEUxy1UVCh0wQWQpa5YBPwRezxLFEGhQmID65E_3jCOEntqO0TZ9Qg9QdWz9Cg9CS4B1A2Wnmw9_fx7sv8IHVFySus6m5fhlLKGsR20TwVXk0Zx-eH13HK-hz7lPCeEtoKRj2iPCdpKRdQ--nUeiv_74-eYYgEf_vyeYV07JjoPGesEWOccrdcFHF77MuAE2eeigwVcIobg4gOEuMr4f4Ut_lEXH0O1OaxxhkeorjKkuDSxeIvHod4qmxGwD88jxyHmWgs_eofzJriKwiHa7fUiw-eX_QDdX17cza4mN7dfr2fnNxPLlWITyqXUUwO8aYAq6oy0xggjtO0tSCY5mUppaO_aVmslp1qIpm9bZYlQlDrJD9CXrbc-4vsKcunmcZVCHdlRyRhlVBBeqZMtZVPMOUHfjckvddp0lHT_kuhqEt1zEpU9fjGuzBLcG_n69RU42wJrv4DN-6bu293VVvkE0CeZHQ</recordid><startdate>201411</startdate><enddate>201411</enddate><creator>Arachchillage, D. R. J.</creator><creator>Efthymiou, M.</creator><creator>Mackie, I. J.</creator><creator>Lawrie, A. S.</creator><creator>Machin, S. J.</creator><creator>Cohen, H.</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></search><sort><creationdate>201411</creationdate><title>Anti‐protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome</title><author>Arachchillage, D. R. J. ; Efthymiou, M. ; Mackie, I. J. ; Lawrie, A. S. ; Machin, S. J. ; Cohen, H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3882-1366a4be377e181db6cbb5b5acfce62630466b1fd99aa864a557f998c05811d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Activated Protein C Resistance - blood</topic><topic>Activated Protein C Resistance - diagnosis</topic><topic>Activated Protein C Resistance - drug therapy</topic><topic>Activated Protein C Resistance - immunology</topic><topic>activated protein C resistance</topic><topic>Adult</topic><topic>Aged</topic><topic>antibodies</topic><topic>Antibodies, Antiphospholipid - blood</topic><topic>Anticoagulants - therapeutic use</topic><topic>antiphospholipid syndrome</topic><topic>Antiphospholipid Syndrome - blood</topic><topic>Antiphospholipid Syndrome - complications</topic><topic>Antiphospholipid Syndrome - diagnosis</topic><topic>Antiphospholipid Syndrome - drug therapy</topic><topic>Antiphospholipid Syndrome - immunology</topic><topic>Biomarkers - blood</topic><topic>Blood Coagulation Tests</topic><topic>Case-Control Studies</topic><topic>Cross-Sectional Studies</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Female</topic><topic>Fibrinolytic Agents - therapeutic use</topic><topic>Humans</topic><topic>Intercellular Signaling Peptides and Proteins</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Peptides - therapeutic use</topic><topic>Phenotype</topic><topic>Protac</topic><topic>Protein C - immunology</topic><topic>Protein C - therapeutic use</topic><topic>protein C</topic><topic>Recombinant Proteins - therapeutic use</topic><topic>Severity of Illness Index</topic><topic>venous thromboembolism</topic><topic>Venous Thromboembolism - blood</topic><topic>Venous Thromboembolism - diagnosis</topic><topic>Venous Thromboembolism - immunology</topic><topic>Venous Thromboembolism - prevention & control</topic><topic>Warfarin - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Arachchillage, D. R. J.</creatorcontrib><creatorcontrib>Efthymiou, M.</creatorcontrib><creatorcontrib>Mackie, I. J.</creatorcontrib><creatorcontrib>Lawrie, A. S.</creatorcontrib><creatorcontrib>Machin, S. J.</creatorcontrib><creatorcontrib>Cohen, H.</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 & Medical Complete (Alumni)</collection><jtitle>Journal of thrombosis and haemostasis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Arachchillage, D. R. J.</au><au>Efthymiou, M.</au><au>Mackie, I. J.</au><au>Lawrie, A. S.</au><au>Machin, S. J.</au><au>Cohen, H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anti‐protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome</atitle><jtitle>Journal of thrombosis and haemostasis</jtitle><addtitle>J Thromb Haemost</addtitle><date>2014-11</date><risdate>2014</risdate><volume>12</volume><issue>11</issue><spage>1801</spage><epage>1809</epage><pages>1801-1809</pages><issn>1538-7933</issn><issn>1538-7836</issn><eissn>1538-7836</eissn><abstract>Summary
Background
Antiphospholipid antibodies may interfere with the anticoagulant activity of activated protein C (APC) to induce acquired APC resistance (APCr).
Aims
To investigate the frequency and characteristics of APCr by using recombinant human APC (rhAPC) and endogenous protein C activation in antiphospholipid syndrome (APS).
Methods
APCr was assessed in APS and non‐APS venous thromboembolism (VTE) patients on warfarin and normal controls with rhAPC or Protac by thrombin generation. IgG anti‐protein C and anti‐protein S antibodies and avidity were assessed by ELISA.
Results
APS patients showed greater resistance to both rhAPC and Protac than non‐APS patients and normal controls (median normalized endogenous thrombin potential inhibition): APS patients with rhAPC, 81.3% (95% confidence interval [CI] 75.2–88.3%; non‐APS patients with rhAPC, 97.7% (95% CI 93.6–101.8%; APS patients with Protac, 66.0% (95% CI 59.5–72.6%); and non‐APS patients with Protac, 80.7 (95% CI 74.2–87.2%). APS patients also had a higher frequency and higher levels of anti‐protein C antibodies, with 60% (15/25) high‐avidity antibodies. High‐avidity anti‐protein C antibodies were associated with greater APCr and with a severe thrombotic phenotype (defined as the development of recurrent VTE while patients were receiving therapeutic anticoagulation or both venous and arterial thrombosis). Twelve of 15 (80%) patients with high‐avidity anti‐protein C antibodies were classified as APS category I.
Conclusion
Thrombotic APS patients showed greater APCr to both rhAPC and activation of endogenous protein C by Protac. High‐avidity anti‐protein C antibodies, associated with greater APCr, may provide a marker for a severe thrombotic phenotype in APS. However, in patients with category I APS, it remains to be established whether anti‐protein C or anti‐β2‐glycoprotein I antibodies are responsible for APCr.</abstract><cop>England</cop><pub>Elsevier Limited</pub><pmid>25196808</pmid><doi>10.1111/jth.12722</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of thrombosis and haemostasis, 2014-11, Vol.12 (11), p.1801-1809 |
| issn | 1538-7933 1538-7836 1538-7836 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Activated Protein C Resistance - blood Activated Protein C Resistance - diagnosis Activated Protein C Resistance - drug therapy Activated Protein C Resistance - immunology activated protein C resistance Adult Aged antibodies Antibodies, Antiphospholipid - blood Anticoagulants - therapeutic use antiphospholipid syndrome Antiphospholipid Syndrome - blood Antiphospholipid Syndrome - complications Antiphospholipid Syndrome - diagnosis Antiphospholipid Syndrome - drug therapy Antiphospholipid Syndrome - immunology Biomarkers - blood Blood Coagulation Tests Case-Control Studies Cross-Sectional Studies Enzyme-Linked Immunosorbent Assay Female Fibrinolytic Agents - therapeutic use Humans Intercellular Signaling Peptides and Proteins Male Middle Aged Peptides - therapeutic use Phenotype Protac Protein C - immunology Protein C - therapeutic use protein C Recombinant Proteins - therapeutic use Severity of Illness Index venous thromboembolism Venous Thromboembolism - blood Venous Thromboembolism - diagnosis Venous Thromboembolism - immunology Venous Thromboembolism - prevention & control Warfarin - therapeutic use |
| title | Anti‐protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome |
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