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Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency—A large single‐centre experience
Introduction Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in s...
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| Published in: | Haemophilia : the official journal of the World Federation of Hemophilia 2024-09, Vol.30 (5), p.1155-1163 |
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| container_issue | 5 |
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| container_title | Haemophilia : the official journal of the World Federation of Hemophilia |
| container_volume | 30 |
| creator | Kamel, Kirollos Salah Riddell, Anne Jradeh, Bilal Jaslowska, Ewa Gomez, Keith |
| description | Introduction
Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency ( |
| doi_str_mv | 10.1111/hae.15081 |
| format | article |
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Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency (<20 IU/dL) upon exposure to plasma‐based products. We report our experience of a large cohort of patients with severe FXI deficiency, including seven patients who developed FXI alloinhibitors, their presentation, natural history and subsequent perioperative management.
Methods
A single‐centre retrospective database review of patients with FXI deficiency, including those who have subsequently developed inhibitors, and extraction of clinical, laboratory and genotype data, including operative management records.
Results
A total of 682 patients were identified with FXI deficiency, of whom 113 had FXI < 20 IU/dL and 42 had FXI ≤ 1 IU/dL. Factor XI inhibitors were seen in seven patients, six of whom were homozygous for the type II variant (prevalence of inhibitor with this genotype of 30%, risk of inhibitor upon plasma exposure 50%). FXI inhibitors were not seen, despite similar exposures, in patients with other genotypes. No alteration in bleeding phenotype occurred after inhibitor development and subsequent surgery was managed on 13 occasions with recombinant factor VIIa (rFVIIa), including low doses (15–30 µg/kg), with good haemostasis. The inhibitor spontaneously disappeared in four of seven patients over 1–22 years.
Conclusion
FXI inhibitors were only observed in severe FXI deficient patients homozygous for p.Glu135* (null allele) upon plasma or FXI concentrate exposure, with a 30% prevalence. The bleeding phenotype was not altered and inhibitors may disappear with time. Adequate haemostasis in the perioperative setting is achievable with low doses of rFVIIa.</description><identifier>ISSN: 1351-8216</identifier><identifier>ISSN: 1365-2516</identifier><identifier>EISSN: 1365-2516</identifier><identifier>DOI: 10.1111/hae.15081</identifier><identifier>PMID: 39039722</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Adolescent ; Adult ; Aged ; Alleles ; bethesda assay ; Bleeding ; bleeding disorders ; Child ; Coagulation factor VIIa ; Coagulation factors ; factor XI ; Factor XI - genetics ; Factor XI - metabolism ; Factor XI deficiency ; Factor XI Deficiency - diagnosis ; Factor XI Deficiency - genetics ; Female ; Genotypes ; Humans ; inhibitors ; Male ; Middle Aged ; Patients ; Phenotypes ; Retrospective Studies ; thrombogenomics ; Young Adult</subject><ispartof>Haemophilia : the official journal of the World Federation of Hemophilia, 2024-09, Vol.30 (5), p.1155-1163</ispartof><rights>2024 John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2431-cad70f9eb4aa152beb21a1e20d8b4238d07b0a2fe3a1dfaff19e56bf0d896bed3</cites><orcidid>0000-0003-2794-4493 ; 0000-0001-6594-5353 ; 0000-0002-8934-0700</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/39039722$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kamel, Kirollos Salah</creatorcontrib><creatorcontrib>Riddell, Anne</creatorcontrib><creatorcontrib>Jradeh, Bilal</creatorcontrib><creatorcontrib>Jaslowska, Ewa</creatorcontrib><creatorcontrib>Gomez, Keith</creatorcontrib><title>Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency—A large single‐centre experience</title><title>Haemophilia : the official journal of the World Federation of Hemophilia</title><addtitle>Haemophilia</addtitle><description>Introduction
Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency (<20 IU/dL) upon exposure to plasma‐based products. We report our experience of a large cohort of patients with severe FXI deficiency, including seven patients who developed FXI alloinhibitors, their presentation, natural history and subsequent perioperative management.
Methods
A single‐centre retrospective database review of patients with FXI deficiency, including those who have subsequently developed inhibitors, and extraction of clinical, laboratory and genotype data, including operative management records.
Results
A total of 682 patients were identified with FXI deficiency, of whom 113 had FXI < 20 IU/dL and 42 had FXI ≤ 1 IU/dL. Factor XI inhibitors were seen in seven patients, six of whom were homozygous for the type II variant (prevalence of inhibitor with this genotype of 30%, risk of inhibitor upon plasma exposure 50%). FXI inhibitors were not seen, despite similar exposures, in patients with other genotypes. No alteration in bleeding phenotype occurred after inhibitor development and subsequent surgery was managed on 13 occasions with recombinant factor VIIa (rFVIIa), including low doses (15–30 µg/kg), with good haemostasis. The inhibitor spontaneously disappeared in four of seven patients over 1–22 years.
Conclusion
FXI inhibitors were only observed in severe FXI deficient patients homozygous for p.Glu135* (null allele) upon plasma or FXI concentrate exposure, with a 30% prevalence. The bleeding phenotype was not altered and inhibitors may disappear with time. Adequate haemostasis in the perioperative setting is achievable with low doses of rFVIIa.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Alleles</subject><subject>bethesda assay</subject><subject>Bleeding</subject><subject>bleeding disorders</subject><subject>Child</subject><subject>Coagulation factor VIIa</subject><subject>Coagulation factors</subject><subject>factor XI</subject><subject>Factor XI - genetics</subject><subject>Factor XI - metabolism</subject><subject>Factor XI deficiency</subject><subject>Factor XI Deficiency - diagnosis</subject><subject>Factor XI Deficiency - genetics</subject><subject>Female</subject><subject>Genotypes</subject><subject>Humans</subject><subject>inhibitors</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Retrospective Studies</subject><subject>thrombogenomics</subject><subject>Young Adult</subject><issn>1351-8216</issn><issn>1365-2516</issn><issn>1365-2516</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp10U1rFDEYB_Agiq1tD34BCXiph2nzsjM7c1z6YgsFLwrewpPMk9mUTLIms7R769mTh37CfhKzbhURzCUh-T1_An9C3nJ2wss6XQKe8Jq1_AXZ57KpK1Hz5uX2XPOqFbzZI29yvmWMS8Ga12RPdkx2cyH2yfdzB0OI2WUKoacjBBhwxDDRaKkFM8VEv15T8D66sHTalYtMXaArmFxhmd65aUlNDAMGN4H_a6hH60xBZvP08LigHtKANLsweHx6-GHKdEKK9ytMW4SH5JUFn_HoeT8gXy4vPp9dVTefPl6fLW4qI2aSVwb6ObMd6hkAr4VGLThwFKxv9UzItmdzzUBYlMB7C9byDutG2_LeNRp7eUCOd7mrFL-tMU9qdNmg9xAwrrOSrJVNy2ZMFvr-H3ob1ymU3ynJuZjXoqtZUR92yqSYc0KrVsmNkDaKM7UtSJWC1K-Cin33nLjWI_Z_5O9GCjjdgTvncfP_JHW1uNhF_gTiuJ5m</recordid><startdate>202409</startdate><enddate>202409</enddate><creator>Kamel, Kirollos Salah</creator><creator>Riddell, Anne</creator><creator>Jradeh, Bilal</creator><creator>Jaslowska, Ewa</creator><creator>Gomez, Keith</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/0000-0003-2794-4493</orcidid><orcidid>https://orcid.org/0000-0001-6594-5353</orcidid><orcidid>https://orcid.org/0000-0002-8934-0700</orcidid></search><sort><creationdate>202409</creationdate><title>Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency—A large single‐centre experience</title><author>Kamel, Kirollos Salah ; Riddell, Anne ; Jradeh, Bilal ; Jaslowska, Ewa ; Gomez, Keith</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2431-cad70f9eb4aa152beb21a1e20d8b4238d07b0a2fe3a1dfaff19e56bf0d896bed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Alleles</topic><topic>bethesda assay</topic><topic>Bleeding</topic><topic>bleeding disorders</topic><topic>Child</topic><topic>Coagulation factor VIIa</topic><topic>Coagulation factors</topic><topic>factor XI</topic><topic>Factor XI - genetics</topic><topic>Factor XI - metabolism</topic><topic>Factor XI deficiency</topic><topic>Factor XI Deficiency - diagnosis</topic><topic>Factor XI Deficiency - genetics</topic><topic>Female</topic><topic>Genotypes</topic><topic>Humans</topic><topic>inhibitors</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Patients</topic><topic>Phenotypes</topic><topic>Retrospective Studies</topic><topic>thrombogenomics</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kamel, Kirollos Salah</creatorcontrib><creatorcontrib>Riddell, Anne</creatorcontrib><creatorcontrib>Jradeh, Bilal</creatorcontrib><creatorcontrib>Jaslowska, Ewa</creatorcontrib><creatorcontrib>Gomez, Keith</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>Kamel, Kirollos Salah</au><au>Riddell, Anne</au><au>Jradeh, Bilal</au><au>Jaslowska, Ewa</au><au>Gomez, Keith</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency—A large single‐centre experience</atitle><jtitle>Haemophilia : the official journal of the World Federation of Hemophilia</jtitle><addtitle>Haemophilia</addtitle><date>2024-09</date><risdate>2024</risdate><volume>30</volume><issue>5</issue><spage>1155</spage><epage>1163</epage><pages>1155-1163</pages><issn>1351-8216</issn><issn>1365-2516</issn><eissn>1365-2516</eissn><abstract>Introduction
Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency (<20 IU/dL) upon exposure to plasma‐based products. We report our experience of a large cohort of patients with severe FXI deficiency, including seven patients who developed FXI alloinhibitors, their presentation, natural history and subsequent perioperative management.
Methods
A single‐centre retrospective database review of patients with FXI deficiency, including those who have subsequently developed inhibitors, and extraction of clinical, laboratory and genotype data, including operative management records.
Results
A total of 682 patients were identified with FXI deficiency, of whom 113 had FXI < 20 IU/dL and 42 had FXI ≤ 1 IU/dL. Factor XI inhibitors were seen in seven patients, six of whom were homozygous for the type II variant (prevalence of inhibitor with this genotype of 30%, risk of inhibitor upon plasma exposure 50%). FXI inhibitors were not seen, despite similar exposures, in patients with other genotypes. No alteration in bleeding phenotype occurred after inhibitor development and subsequent surgery was managed on 13 occasions with recombinant factor VIIa (rFVIIa), including low doses (15–30 µg/kg), with good haemostasis. The inhibitor spontaneously disappeared in four of seven patients over 1–22 years.
Conclusion
FXI inhibitors were only observed in severe FXI deficient patients homozygous for p.Glu135* (null allele) upon plasma or FXI concentrate exposure, with a 30% prevalence. The bleeding phenotype was not altered and inhibitors may disappear with time. Adequate haemostasis in the perioperative setting is achievable with low doses of rFVIIa.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>39039722</pmid><doi>10.1111/hae.15081</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-2794-4493</orcidid><orcidid>https://orcid.org/0000-0001-6594-5353</orcidid><orcidid>https://orcid.org/0000-0002-8934-0700</orcidid></addata></record> |
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| ispartof | Haemophilia : the official journal of the World Federation of Hemophilia, 2024-09, Vol.30 (5), p.1155-1163 |
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| subjects | Adolescent Adult Aged Alleles bethesda assay Bleeding bleeding disorders Child Coagulation factor VIIa Coagulation factors factor XI Factor XI - genetics Factor XI - metabolism Factor XI deficiency Factor XI Deficiency - diagnosis Factor XI Deficiency - genetics Female Genotypes Humans inhibitors Male Middle Aged Patients Phenotypes Retrospective Studies thrombogenomics Young Adult |
| title | Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency—A large single‐centre experience |
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