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Abnormal coagulation and enhanced fibrinolysis due to lysinuric protein intolerance associates with bleeds and renal impairment
Introduction Lysinuric protein intolerance (LPI), a rare autosomal recessive transport disorder of cationic amino acids lysine, arginine and ornithine, affects intestines, lungs, liver and kidneys. LPI patients may display potentially life‐threatening bleeding events, which are poorly understood. Ai...
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Published in: | Haemophilia : the official journal of the World Federation of Hemophilia 2018-09, Vol.24 (5), p.e312-e321 |
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creator | Pitkänen, H. H. Kärki, M. Niinikoski, H. Tanner, L. Näntö‐Salonen, K. Pikta, M. Kopatz, W. F. Zuurveld, M. Meijers, J. C. M. Brinkman, H. J. M. Lassila, R. |
description | Introduction
Lysinuric protein intolerance (LPI), a rare autosomal recessive transport disorder of cationic amino acids lysine, arginine and ornithine, affects intestines, lungs, liver and kidneys. LPI patients may display potentially life‐threatening bleeding events, which are poorly understood.
Aims
To characterize alterations in haemostatic and fibrinolytic variables associated with LPI.
Methods
We enrolled 15 adult patients (8 female) and assessed the clinical ISTH/SSC‐BAT bleeding score (BS). A variety of metabolic and coagulation assays, including fibrin generation test derivatives, clotting time (CT) and clot lysis time (CLT), thromboelastometry (ROTEM), and PFA‐100 and Calibrated Automated Thrombogram (CAT), were used.
Results
All patients had mild‐to‐moderate renal insufficiency, and moderate bleeding tendency (BS 4) without spontaneous bleeds. Mild anaemia and thrombocytopenia occurred. Traditional clotting times were normal, but in contrast, CT in fibrin generation test, and especially ROTEM FIBTEM was abnormal. The patients showed impaired primary haemostasis in PFA, irrespective of normal von Willebrand factor activity, but together with lowered fibrinogen and FXIII. Thrombin generation (TG) was reduced in vitro, according to CAT‐derived endogenous thrombin potential, but in vivo TG was enhanced in the form of circulating prothrombin fragment 1 and 2 values. Very high D‐dimer and plasmin‐α2‐antiplasmin (PAP) complex levels coincided with shortened CLT in vitro.
Conclusions
Defective primary haemostasis, coagulopathy, fibrin abnormality (FIBTEM, CT and CLT), low TG in vitro and clearly augmented fibrinolysis (PAP and D‐dimer) in vivo were all detected in LPI. Altered fibrin generation and hyperfibrinolysis were associated with the metabolic and renal defect, suggesting a pathogenetic link in LPI. |
doi_str_mv | 10.1111/hae.13543 |
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Lysinuric protein intolerance (LPI), a rare autosomal recessive transport disorder of cationic amino acids lysine, arginine and ornithine, affects intestines, lungs, liver and kidneys. LPI patients may display potentially life‐threatening bleeding events, which are poorly understood.
Aims
To characterize alterations in haemostatic and fibrinolytic variables associated with LPI.
Methods
We enrolled 15 adult patients (8 female) and assessed the clinical ISTH/SSC‐BAT bleeding score (BS). A variety of metabolic and coagulation assays, including fibrin generation test derivatives, clotting time (CT) and clot lysis time (CLT), thromboelastometry (ROTEM), and PFA‐100 and Calibrated Automated Thrombogram (CAT), were used.
Results
All patients had mild‐to‐moderate renal insufficiency, and moderate bleeding tendency (BS 4) without spontaneous bleeds. Mild anaemia and thrombocytopenia occurred. Traditional clotting times were normal, but in contrast, CT in fibrin generation test, and especially ROTEM FIBTEM was abnormal. The patients showed impaired primary haemostasis in PFA, irrespective of normal von Willebrand factor activity, but together with lowered fibrinogen and FXIII. Thrombin generation (TG) was reduced in vitro, according to CAT‐derived endogenous thrombin potential, but in vivo TG was enhanced in the form of circulating prothrombin fragment 1 and 2 values. Very high D‐dimer and plasmin‐α2‐antiplasmin (PAP) complex levels coincided with shortened CLT in vitro.
Conclusions
Defective primary haemostasis, coagulopathy, fibrin abnormality (FIBTEM, CT and CLT), low TG in vitro and clearly augmented fibrinolysis (PAP and D‐dimer) in vivo were all detected in LPI. Altered fibrin generation and hyperfibrinolysis were associated with the metabolic and renal defect, suggesting a pathogenetic link in LPI.</description><identifier>ISSN: 1351-8216</identifier><identifier>EISSN: 1365-2516</identifier><identifier>DOI: 10.1111/hae.13543</identifier><identifier>PMID: 30070418</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Adult ; Amino Acid Metabolism, Inborn Errors - complications ; Amino Acid Metabolism, Inborn Errors - pathology ; Arginine ; Bleeding ; Blood Coagulation - genetics ; Clotting ; Coagulation ; coagulation disorder ; Female ; Fibrin ; Fibrinogen ; Fibrinolysis ; Fibrinolysis - genetics ; Hemorrhage - etiology ; Hemorrhage - pathology ; Hereditary diseases ; Humans ; Intolerance ; Kidneys ; Liver ; Lysine ; lysinuric protein intolerance ; Lysis ; Male ; Metabolism ; Middle Aged ; Ornithine ; Plasmin ; Prothrombin ; Renal insufficiency ; Renal Insufficiency - etiology ; Renal Insufficiency - pathology ; Thrombin ; thrombin generation ; Thrombocytopenia ; Von Willebrand factor ; Young Adult</subject><ispartof>Haemophilia : the official journal of the World Federation of Hemophilia, 2018-09, Vol.24 (5), p.e312-e321</ispartof><rights>2018 John Wiley & Sons Ltd</rights><rights>2018 John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3883-df6009c127ac72565767d44c26f7dd010a58e2507c33aa4d45c26faff6e3b22a3</citedby><cites>FETCH-LOGICAL-c3883-df6009c127ac72565767d44c26f7dd010a58e2507c33aa4d45c26faff6e3b22a3</cites><orcidid>0000-0002-2259-3244</orcidid></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/30070418$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pitkänen, H. H.</creatorcontrib><creatorcontrib>Kärki, M.</creatorcontrib><creatorcontrib>Niinikoski, H.</creatorcontrib><creatorcontrib>Tanner, L.</creatorcontrib><creatorcontrib>Näntö‐Salonen, K.</creatorcontrib><creatorcontrib>Pikta, M.</creatorcontrib><creatorcontrib>Kopatz, W. F.</creatorcontrib><creatorcontrib>Zuurveld, M.</creatorcontrib><creatorcontrib>Meijers, J. C. M.</creatorcontrib><creatorcontrib>Brinkman, H. J. M.</creatorcontrib><creatorcontrib>Lassila, R.</creatorcontrib><title>Abnormal coagulation and enhanced fibrinolysis due to lysinuric protein intolerance associates with bleeds and renal impairment</title><title>Haemophilia : the official journal of the World Federation of Hemophilia</title><addtitle>Haemophilia</addtitle><description>Introduction
Lysinuric protein intolerance (LPI), a rare autosomal recessive transport disorder of cationic amino acids lysine, arginine and ornithine, affects intestines, lungs, liver and kidneys. LPI patients may display potentially life‐threatening bleeding events, which are poorly understood.
Aims
To characterize alterations in haemostatic and fibrinolytic variables associated with LPI.
Methods
We enrolled 15 adult patients (8 female) and assessed the clinical ISTH/SSC‐BAT bleeding score (BS). A variety of metabolic and coagulation assays, including fibrin generation test derivatives, clotting time (CT) and clot lysis time (CLT), thromboelastometry (ROTEM), and PFA‐100 and Calibrated Automated Thrombogram (CAT), were used.
Results
All patients had mild‐to‐moderate renal insufficiency, and moderate bleeding tendency (BS 4) without spontaneous bleeds. Mild anaemia and thrombocytopenia occurred. Traditional clotting times were normal, but in contrast, CT in fibrin generation test, and especially ROTEM FIBTEM was abnormal. The patients showed impaired primary haemostasis in PFA, irrespective of normal von Willebrand factor activity, but together with lowered fibrinogen and FXIII. Thrombin generation (TG) was reduced in vitro, according to CAT‐derived endogenous thrombin potential, but in vivo TG was enhanced in the form of circulating prothrombin fragment 1 and 2 values. Very high D‐dimer and plasmin‐α2‐antiplasmin (PAP) complex levels coincided with shortened CLT in vitro.
Conclusions
Defective primary haemostasis, coagulopathy, fibrin abnormality (FIBTEM, CT and CLT), low TG in vitro and clearly augmented fibrinolysis (PAP and D‐dimer) in vivo were all detected in LPI. Altered fibrin generation and hyperfibrinolysis were associated with the metabolic and renal defect, suggesting a pathogenetic link in LPI.</description><subject>Adult</subject><subject>Amino Acid Metabolism, Inborn Errors - complications</subject><subject>Amino Acid Metabolism, Inborn Errors - pathology</subject><subject>Arginine</subject><subject>Bleeding</subject><subject>Blood Coagulation - genetics</subject><subject>Clotting</subject><subject>Coagulation</subject><subject>coagulation disorder</subject><subject>Female</subject><subject>Fibrin</subject><subject>Fibrinogen</subject><subject>Fibrinolysis</subject><subject>Fibrinolysis - genetics</subject><subject>Hemorrhage - etiology</subject><subject>Hemorrhage - pathology</subject><subject>Hereditary diseases</subject><subject>Humans</subject><subject>Intolerance</subject><subject>Kidneys</subject><subject>Liver</subject><subject>Lysine</subject><subject>lysinuric protein intolerance</subject><subject>Lysis</subject><subject>Male</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Ornithine</subject><subject>Plasmin</subject><subject>Prothrombin</subject><subject>Renal insufficiency</subject><subject>Renal Insufficiency - etiology</subject><subject>Renal Insufficiency - pathology</subject><subject>Thrombin</subject><subject>thrombin generation</subject><subject>Thrombocytopenia</subject><subject>Von Willebrand factor</subject><subject>Young Adult</subject><issn>1351-8216</issn><issn>1365-2516</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kU1v1DAQhi1ERUvhwB9AlriUQ1p_xI73uKpailSpFzhHE3vCunLsxU5U7Ym_jtMtHJDwZWzN48cjv4R84OyS13W1A7zkUrXyFTnjUqtGKK5fr3vFGyO4PiVvS3lkjEvB9BtyKhnrWMvNGfm1HWLKEwRqE_xYAsw-RQrRUYw7iBYdHf2QfUzhUHyhbkE6J7oe4pK9pfucZvSR-jingHm9QqGUZD3MWOiTn3d0CIiuPFszxvqWn_bg84RxfkdORggF37_Uc_L99ubb9V1z__Dl6_X2vrHSGNm4UTO2sVx0YDuhtOp059rWCj12zjHOQBkUinVWSoDWtWptwThqlIMQIM_JxdFb5_25YJn7yReLIUDEtJReMCPYhhuhK_rpH_QxLbmOXan1u43aaFOpz0fK5lRKxrHfZz9BPvSc9SvW11T651Qq-_HFuAwTur_knxgqcHUEnnzAw_9N_d325qj8DbE3l9Y</recordid><startdate>201809</startdate><enddate>201809</enddate><creator>Pitkänen, H. H.</creator><creator>Kärki, M.</creator><creator>Niinikoski, H.</creator><creator>Tanner, L.</creator><creator>Näntö‐Salonen, K.</creator><creator>Pikta, M.</creator><creator>Kopatz, W. F.</creator><creator>Zuurveld, M.</creator><creator>Meijers, J. C. M.</creator><creator>Brinkman, H. J. M.</creator><creator>Lassila, R.</creator><general>Wiley Subscription Services, Inc</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>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-2259-3244</orcidid></search><sort><creationdate>201809</creationdate><title>Abnormal coagulation and enhanced fibrinolysis due to lysinuric protein intolerance associates with bleeds and renal impairment</title><author>Pitkänen, H. H. ; Kärki, M. ; Niinikoski, H. ; Tanner, L. ; Näntö‐Salonen, K. ; Pikta, M. ; Kopatz, W. F. ; Zuurveld, M. ; Meijers, J. C. M. ; Brinkman, H. J. M. ; Lassila, R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3883-df6009c127ac72565767d44c26f7dd010a58e2507c33aa4d45c26faff6e3b22a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Amino Acid Metabolism, Inborn Errors - complications</topic><topic>Amino Acid Metabolism, Inborn Errors - pathology</topic><topic>Arginine</topic><topic>Bleeding</topic><topic>Blood Coagulation - genetics</topic><topic>Clotting</topic><topic>Coagulation</topic><topic>coagulation disorder</topic><topic>Female</topic><topic>Fibrin</topic><topic>Fibrinogen</topic><topic>Fibrinolysis</topic><topic>Fibrinolysis - genetics</topic><topic>Hemorrhage - etiology</topic><topic>Hemorrhage - pathology</topic><topic>Hereditary diseases</topic><topic>Humans</topic><topic>Intolerance</topic><topic>Kidneys</topic><topic>Liver</topic><topic>Lysine</topic><topic>lysinuric protein intolerance</topic><topic>Lysis</topic><topic>Male</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Ornithine</topic><topic>Plasmin</topic><topic>Prothrombin</topic><topic>Renal insufficiency</topic><topic>Renal Insufficiency - etiology</topic><topic>Renal Insufficiency - pathology</topic><topic>Thrombin</topic><topic>thrombin generation</topic><topic>Thrombocytopenia</topic><topic>Von Willebrand factor</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pitkänen, H. H.</creatorcontrib><creatorcontrib>Kärki, M.</creatorcontrib><creatorcontrib>Niinikoski, H.</creatorcontrib><creatorcontrib>Tanner, L.</creatorcontrib><creatorcontrib>Näntö‐Salonen, K.</creatorcontrib><creatorcontrib>Pikta, M.</creatorcontrib><creatorcontrib>Kopatz, W. F.</creatorcontrib><creatorcontrib>Zuurveld, M.</creatorcontrib><creatorcontrib>Meijers, J. C. M.</creatorcontrib><creatorcontrib>Brinkman, H. J. M.</creatorcontrib><creatorcontrib>Lassila, R.</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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Haemophilia : the official journal of the World Federation of Hemophilia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pitkänen, H. H.</au><au>Kärki, M.</au><au>Niinikoski, H.</au><au>Tanner, L.</au><au>Näntö‐Salonen, K.</au><au>Pikta, M.</au><au>Kopatz, W. F.</au><au>Zuurveld, M.</au><au>Meijers, J. C. M.</au><au>Brinkman, H. J. M.</au><au>Lassila, R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Abnormal coagulation and enhanced fibrinolysis due to lysinuric protein intolerance associates with bleeds and renal impairment</atitle><jtitle>Haemophilia : the official journal of the World Federation of Hemophilia</jtitle><addtitle>Haemophilia</addtitle><date>2018-09</date><risdate>2018</risdate><volume>24</volume><issue>5</issue><spage>e312</spage><epage>e321</epage><pages>e312-e321</pages><issn>1351-8216</issn><eissn>1365-2516</eissn><abstract>Introduction
Lysinuric protein intolerance (LPI), a rare autosomal recessive transport disorder of cationic amino acids lysine, arginine and ornithine, affects intestines, lungs, liver and kidneys. LPI patients may display potentially life‐threatening bleeding events, which are poorly understood.
Aims
To characterize alterations in haemostatic and fibrinolytic variables associated with LPI.
Methods
We enrolled 15 adult patients (8 female) and assessed the clinical ISTH/SSC‐BAT bleeding score (BS). A variety of metabolic and coagulation assays, including fibrin generation test derivatives, clotting time (CT) and clot lysis time (CLT), thromboelastometry (ROTEM), and PFA‐100 and Calibrated Automated Thrombogram (CAT), were used.
Results
All patients had mild‐to‐moderate renal insufficiency, and moderate bleeding tendency (BS 4) without spontaneous bleeds. Mild anaemia and thrombocytopenia occurred. Traditional clotting times were normal, but in contrast, CT in fibrin generation test, and especially ROTEM FIBTEM was abnormal. The patients showed impaired primary haemostasis in PFA, irrespective of normal von Willebrand factor activity, but together with lowered fibrinogen and FXIII. Thrombin generation (TG) was reduced in vitro, according to CAT‐derived endogenous thrombin potential, but in vivo TG was enhanced in the form of circulating prothrombin fragment 1 and 2 values. Very high D‐dimer and plasmin‐α2‐antiplasmin (PAP) complex levels coincided with shortened CLT in vitro.
Conclusions
Defective primary haemostasis, coagulopathy, fibrin abnormality (FIBTEM, CT and CLT), low TG in vitro and clearly augmented fibrinolysis (PAP and D‐dimer) in vivo were all detected in LPI. Altered fibrin generation and hyperfibrinolysis were associated with the metabolic and renal defect, suggesting a pathogenetic link in LPI.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30070418</pmid><doi>10.1111/hae.13543</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-2259-3244</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Adult Amino Acid Metabolism, Inborn Errors - complications Amino Acid Metabolism, Inborn Errors - pathology Arginine Bleeding Blood Coagulation - genetics Clotting Coagulation coagulation disorder Female Fibrin Fibrinogen Fibrinolysis Fibrinolysis - genetics Hemorrhage - etiology Hemorrhage - pathology Hereditary diseases Humans Intolerance Kidneys Liver Lysine lysinuric protein intolerance Lysis Male Metabolism Middle Aged Ornithine Plasmin Prothrombin Renal insufficiency Renal Insufficiency - etiology Renal Insufficiency - pathology Thrombin thrombin generation Thrombocytopenia Von Willebrand factor Young Adult |
title | Abnormal coagulation and enhanced fibrinolysis due to lysinuric protein intolerance associates with bleeds and renal impairment |
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