Download PDF
CC BY-NC-ND 4.0 · Semin Thromb Hemost 2025; 51(02): 145-154
DOI: 10.1055/s-0044-1792033
Review Article

Laboratory and Molecular Diagnosis of Factor XI Deficiency

Simon Davidson
1   Division of Medicine, Faculty of Medical Sciences, University College London, London, United Kingdom
,
Keith Gomez
2   Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, United Kingdom
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

The prevalence of factor XI (FXI) deficiency is 1 per 10 to 20,000 in the general population, much higher than that reported in most texts. The prevalence is higher in Ashkenazi Jews where it is about 1:20. Clinically, FXI deficiency presents as a mild bleeding disorder mostly associated with posttraumatic or postsurgical hemorrhages or unexplained minor bleeding. It is often discovered due to incidental finding of a prolonged activated partial thromboplastin time (aPTT) on routine laboratory screening. FXI deficiency is an autosomal recessive bleeding disorder with many causative F11 gene defects. Diagnosis is based on FXI activity, antigen levels, and molecular diagnostics. As FXI levels do not correlate with bleeding symptoms, identification of pathogenic genetic variants may be a more accurate predictor of bleeding risk and therefore aid in the clinical management of the patient. Two variants in the F11 gene account for most cases found in the Jewish and Arab populations. Patients with FXI deficiency can develop inhibitors to FXI although spontaneously acquired inhibitors are extremely rare. We will discuss laboratory and molecular assays used to diagnose FXI deficiency as well as interferences that can complicate diagnosis including new anticoagulants and acquired FXI inhibitors.

Keywords

factor XI deficiency - rare bleeding disorder - diagnosis - molecular - inhibitor


Publication History

Article published online:
04 November 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Lewandowska MD, Connors JM. Factor XI deficiency. Hematol Oncol Clin North Am 2021; 35 (06) 1157-1169
    CrossrefPubMedSearch in Google Scholar
  • 2 Asakai R, Chung DW, Davie EW, Seligsohn U. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med 1991; 325 (03) 153-158
    CrossrefPubMedSearch in Google Scholar
  • 3 Peretz H, Mulai A, Usher S. et al. The two common mutations causing factor XI deficiency in Jews stem from distinct founders: one of ancient Middle Eastern origin and another of more recent European origin. Blood 1997; 90 (07) 2654-2659
    CrossrefPubMedSearch in Google Scholar
  • 4 United Kingdom Haemophilia Centres' Doctors' Organization. Annual report 2023. 2023. Accessed October 15, 2024 at: https://www.ukhcdo.org/home-2/annual-reports/
    PubMed
  • 5 gnomAD. Genome Aggregation Database. Accessed October 15, 2024 at: https://gnomad.broadinstitute.org/
    PubMed
  • 6 Wiewel-Verschueren S, Arendz IJM, M Knol H, Meijer K. Gynaecological and obstetrical bleeding in women with factor XI deficiency - a systematic review. Haemophilia 2016; 22 (02) 188-195
    CrossrefPubMedSearch in Google Scholar
  • 7 Sharman Moser S, Chodick G, Ni YG. et al. The association between factor XI deficiency and the risk of bleeding, cardiovascular, and venous thromboembolic events. Thromb Haemost 2022; 122 (05) 808-817
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Bolton-Maggs PH, Patterson DA, Wensley RT, Tuddenham EG. Definition of the bleeding tendency in factor XI-deficient kindreds–a clinical and laboratory study. Thromb Haemost 1995; 73 (02) 194-202
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Santoro C, Di Mauro R, Baldacci E. et al. Bleeding phenotype and correlation with factor XI (FXI) activity in congenital FXI deficiency: results of a retrospective study from a single centre. Haemophilia 2015; 21 (04) 496-501
    CrossrefPubMedSearch in Google Scholar
  • 10 Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia 2008; 14 (06) 1183-1189
    CrossrefPubMedSearch in Google Scholar
  • 11 Hoffman M, Monroe III DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85 (06) 958-965
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Von dem Borne PA, Bajzar L, Meijers JC, Nesheim ME, Bouma BN. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest 1997; 99 (10) 2323-2327
    CrossrefPubMedSearch in Google Scholar
  • 13 Practical-Haemostasis.com. A practical guide to haemostasis. Accessed October 15, 2024 at: https://practical-haemostasis.com/
    PubMed
  • 14 Bolton-Maggs PH, Young Wan-Yin B, McCraw AH, Slack J, Kernoff PB. Inheritance and bleeding in factor XI deficiency. Br J Haematol 1988; 69 (04) 521-528
    CrossrefPubMedSearch in Google Scholar
  • 15 Halbmayer WM, Haushofer A, Schön R. et al. The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: evaluation of the incidence of FXII deficiency among 300 healthy blood donors. Thromb Haemost 1994; 71 (01) 68-72
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 1 (07) 1504-1514
    CrossrefPubMedSearch in Google Scholar
  • 17 Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood Rev 2003; 17 (Suppl. 01) S1-S5
    CrossrefPubMedSearch in Google Scholar
  • 18 Toulon P, Eloit Y, Smahi M. et al. In vitro sensitivity of different activated partial thromboplastin time reagents to mild clotting factor deficiencies. Int J Lab Hematol 2016; 38 (04) 389-396
    CrossrefPubMedSearch in Google Scholar
  • 19 Mornet C, Luque Paz D, Lippert E, Galinat H, Mingant F. Detection of intrinsic pathway factor deficiency associated with bleeding risk by kaolin-based aPTT. Int J Lab Hematol 2020; 42 (03) e107-e109
    CrossrefPubMedSearch in Google Scholar
  • 20 Lawrie AS, Kitchen S, Purdy G, Mackie IJ, Preston FE, Machin SJ. Assessment of Actin FS and Actin FSL sensitivity to specific clotting factor deficiencies. Clin Lab Haematol 1998; 20 (03) 179-186
    CrossrefPubMedSearch in Google Scholar
  • 21 Salloum-Asfar S, de la Morena-Barrio ME, Esteban J. et al. Assessment of two contact activation reagents for the diagnosis of congenital factor XI deficiency. Thromb Res 2018; 163: 64-70
    CrossrefPubMedSearch in Google Scholar
  • 22 Kasonga F, Feugray G, Chamouni P. et al. Evaluation of thrombin generation assay in factor XI deficiency. Clin Chim Acta 2021; 523: 348-354
    CrossrefPubMedSearch in Google Scholar
  • 23 Clinical and Laboratory Standards Institute (CLSI). One stage prothrombin time (PT) test and activated partial thromboplastin time (APTT) test. Approved guideline H47-A2.28(20). Wayne, PA: Clinical and Laboratory Standards Institute; 2008
    Search in Google Scholar
  • 24 Martinuzzo M, Barrera L, Rodriguez M, D'Adamo MA, López MS, Otaso JC. Do PT and APTT sensitivities to factors' deficiencies calculated by the H47-A2 2008 CLSI guideline reflect the deficiencies found in plasmas from patients?. Int J Lab Hematol 2015; 37 (06) 853-860
    CrossrefPubMedSearch in Google Scholar
  • 25 Lawrie AS, Kitchen S, Efthymiou M, Mackie IJ, Machin SJ. Determination of APTT factor sensitivity–the misguiding guideline. Int J Lab Hematol 2013; 35 (06) 652-657
    CrossrefPubMedSearch in Google Scholar
  • 26 Favaloro EJ, Kershaw G, Mohammed S, Lippi G. How to optimize activated partial thromboplastin time (APTT) testing: solutions to establishing and verifying normal reference intervals and assessing APTT reagents for sensitivity to heparin, lupus anticoagulant, and clotting factors. Semin Thromb Hemost 2019; 45 (01) 22-35
    Thieme ConnectPubMedSearch in Google Scholar
  • 27 Kershaw G. Performance of activated partial thromboplastin time (APTT): determining reagent sensitivity to factor deficiencies, heparin, and lupus anticoagulants. Methods Mol Biol 2017; 1646: 75-83
    CrossrefPubMedSearch in Google Scholar
  • 28 Adcock DM, Moore GW, Montalvão SL, Kershaw G, Gosselin RC. Activated partial thromboplastin time and prothrombin time mixing studies: current state of the art. Semin Thromb Hemost 2023; 49 (06) 571-579
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Franchini M, Lippi G, Favaloro EJ. Acquired inhibitors of coagulation factors: part II. Semin Thromb Hemost 2012; 38 (05) 447-453
    Thieme ConnectPubMedSearch in Google Scholar
  • 30 Bortoli R, Monticielo OA, Chakr RM. et al. Acquired factor XI inhibitor in systemic lupus erythematosus–case report and literature review. Semin Arthritis Rheum 2009; 39 (01) 61-65
    CrossrefPubMedSearch in Google Scholar
  • 31 Baker P, Platton S, Gibson C. et al; British Society for Haematology, Haemostasis and Thrombosis Task Force. Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis. Br J Haematol 2020; 191 (03) 347-362
    CrossrefPubMedSearch in Google Scholar
  • 32 Rodgers S, Duncan E. Chromogenic factor VIII assays for improved diagnosis of hemophilia A. Methods Mol Biol 2017; 1646: 265-276
    CrossrefPubMedSearch in Google Scholar
  • 33 Kitchen S, Adcock DM, Dauer R. et al. International Council for Standardization in Haematology (ICSH) recommendations for processing of blood samples for coagulation testing. Int J Lab Hematol 2021; 43 (06) 1272-1283
    CrossrefPubMedSearch in Google Scholar
  • 34 Lippi G, Blanckaert N, Bonini P. et al. Haemolysis: an overview of the leading cause of unsuitable specimens in clinical laboratories. Clin Chem Lab Med 2008; 46 (06) 764-772
    CrossrefPubMedSearch in Google Scholar
  • 35 Lippi G, Salvagno GL, Montagnana M, Lima-Oliveira G, Guidi GC, Favaloro EJ. Quality standards for sample collection in coagulation testing. Semin Thromb Hemost 2012; 38: 565-575
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Adcock-Funk D. Sample integrity and preanalytical variables. In: Kitchen S, Olson JD, Preston FE. eds. Quality in Laboratory Hemostasis and Thrombosis. 2nd ed.. Wiley-Blackwell; 2013: 45-56
    Search in Google Scholar
  • 37 Gosselin RC, Adcock DM, Bates SM. et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 2018; 118 (03) 437-450
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 He R, Chen D, He S. Factor XI: hemostasis, thrombosis, and antithrombosis. Thromb Res 2012; 129 (05) 541-550
    CrossrefPubMedSearch in Google Scholar
  • 39 Devreese KMJ, de Groot PG, de Laat B. et al. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis: Update of the guidelines for lupus anticoagulant detection and interpretation. J Thromb Haemost 2020; 18 (11) 2828-2839
    CrossrefPubMedSearch in Google Scholar
  • 40 Devreese KM, Verfaillie CJ, De Bisschop F, Delanghe JR. Interference of C-reactive protein with clotting times. Clin Chem Lab Med 2015; 53 (05) e141-e145
    CrossrefPubMedSearch in Google Scholar
  • 41 Salomon O, Zivelin A, Livnat T. et al. Prevalence, causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency. Blood 2003; 101 (12) 4783-4788
    CrossrefPubMedSearch in Google Scholar
  • 42 Reece EA, Clyne LP, Romero R, Hobbins JC. Spontaneous factor XI inhibitors. Seven additional cases and a review of the literature. Arch Intern Med 1984; 144 (03) 525-529
    CrossrefPubMedSearch in Google Scholar
  • 43 Uwingabiye J, Zahid H, El Amrani M. et al. Rare and unusual case of anti-factor XI antibodies in patient with plasma cell leukemia. BMC Hematol 2018; 18: 18
    CrossrefPubMedSearch in Google Scholar
  • 44 Goodrick MJ, Prentice AG, Copplestone JA, Pamphilon DH, Boon RJ. Acquired factor XI inhibitor in chronic lymphocytic leukaemia. J Clin Pathol 1992; 45 (04) 352-353
    CrossrefPubMedSearch in Google Scholar
  • 45 Murray NP, Ilabaca J, Guzman E, Orrega S. Management of mild congenital deficiency of Factor XI with a Factor XI inhibitor in pregnancy: a clinical case. Hematol Transfus Cell Ther 2022; 44 (03) 444-446
    CrossrefPubMedSearch in Google Scholar
  • 46 Andreani G, Uscello L, Montaruli B. et al. Acquired factor XI deficiency during SARS-CoV-2 infection: not only thrombosis. TH Open 2020; 4 (03) e233-e235
    Thieme ConnectPubMedSearch in Google Scholar
  • 47 Rochanda L, Del Zoppo GJ, Feinstein DI, Liebman HA. Approach to the treatment, characterization and diagnosis of an acquired auto-antibody directed against factors prothrombin, factor X and factor IX: a case report and review of the literature. Haemophilia 2012; 18 (01) 102-107
    CrossrefPubMedSearch in Google Scholar
  • 48 Hoffmann C, Amiral J, Rezig S. et al. A very potent factor V inhibitor interferes with the levels of all coagulation factors and causes a fatal hemorrhagic syndrome. Eur J Haematol 2019; 103 (02) 137-139
    CrossrefPubMedSearch in Google Scholar
  • 49 Meijer P, Peyvandi F, Young G, Pruthi R, de Lima Montalvão S, Kitchen S. International Council for Standardization in Haematology recommendations for laboratory measurement of factor VIII and FIX type I inhibitors. Int J Lab Hematol 2023; 45 (04) 413-424
    CrossrefPubMedSearch in Google Scholar
  • 50 Bertaggia Calderara D, Zermatten MG, Aliotta A. et al. Tissue factor-independent coagulation correlates with clinical phenotype in factor XI deficiency and replacement therapy. Thromb Haemost 2021; 121 (02) 150-163
    Thieme ConnectPubMedSearch in Google Scholar
  • 51 Pike GN, Cumming AM, Thachil J, Hay CR, Burthem J, Bolton-Maggs PH. Evaluation of the use of global haemostasis assays to monitor treatment in factor XI deficiency. Haemophilia 2017; 23 (02) 273-283
    CrossrefPubMedSearch in Google Scholar
  • 52 Désage S, Dargaud Y, Meunier S. et al. Report of surgeries, their outcome and the thrombin generation assay in patients with Factor XI deficiency: a retrospective single-centre study. Haemophilia 2022; 28 (02) 301-307
    CrossrefPubMedSearch in Google Scholar
  • 53 Riddell A, Abdul-Kadir R, Pollard D, Tuddenham E, Gomez K. Monitoring low dose recombinant factor VIIa therapy in patients with severe factor XI deficiency undergoing surgery. Thromb Haemost 2011; 106 (03) 521-527
    Thieme ConnectPubMedSearch in Google Scholar
  • 54 Dargaud Y, Wolberg AS, Gray E, Negrier C, Hemker HC. Subcommittee on Factor VIII, Factor IX, and Rare Coagulation Disorders. Proposal for standardized preanalytical and analytical conditions for measuring thrombin generation in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2017; 15 (08) 1704-1707
    CrossrefPubMedSearch in Google Scholar
  • 55 Saunders RE, Shiltagh N, Gomez K. et al. Structural analysis of eight novel and 112 previously reported missense mutations in the interactive FXI mutation database reveals new insight on FXI deficiency. Thromb Haemost 2009; 102 (02) 287-301
    Thieme ConnectPubMedSearch in Google Scholar
  • 56 Bolton-Maggs PH. Factor XI deficiency–resolving the enigma?. Hematology (Am Soc Hematol Educ Program) 2009; 2009 (01) 97-105
    CrossrefPubMedSearch in Google Scholar
  • 57 Berber E. Molecular characterization of FXI deficiency. Clin Appl Thromb Hemost 2011; 17 (01) 27-32
    CrossrefPubMedSearch in Google Scholar
  • 58 Kamel KS, Riddell A, Jradeh B, Jaslowska E, Gomez K. Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency-A large single-centre experience. Haemophilia 2024; (e-pub ahead of print)
    CrossrefPubMedSearch in Google Scholar
  • 59 Shpilberg O, Peretz H, Zivelin A. et al. One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews. Blood 1995; 85 (02) 429-432
    CrossrefPubMedSearch in Google Scholar
  • 60 Zivelin A, Bauduer F, Ducout L. et al. Factor XI deficiency in French Basques is caused predominantly by an ancestral Cys38Arg mutation in the factor XI gene. Blood 2002; 99 (07) 2448-2454
    CrossrefPubMedSearch in Google Scholar
  • 61 Bolton-Maggs PH, Peretz H, Butler R. et al. A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiency. J Thromb Haemost 2004; 2 (06) 918-924
    CrossrefPubMedSearch in Google Scholar
  • 62 EAHAD-CF DB. FXI: Coagulation factor variant databases. Accessed October 15, 2024 at: https://dbs.eahad.org/FXI
    PubMed
  • 63 O'Connell NM. Factor XI deficiency–from molecular genetics to clinical management. Blood Coagul Fibrinolysis 2003; 14 (Suppl. 01) S59-S64
    CrossrefPubMedSearch in Google Scholar
  • 64 Bauduer F, de Raucourt E, Boyer-Neumann C. et al; French Postmarketing Study Group. Factor XI replacement for inherited factor XI deficiency in routine clinical practice: results of the HEMOLEVEN prospective 3-year postmarketing study. Haemophilia 2015; 21 (04) 481-489
    CrossrefPubMedSearch in Google Scholar
  • 65 Ling G, Kagdi H, Subel B, Chowdary P, Gomez K. Safety and efficacy of factor XI (FXI) concentrate use in patients with FXI deficiency: a single-centre experience of 19 years. Haemophilia 2016; 22 (03) 411-418
    CrossrefPubMedSearch in Google Scholar
  • 66 Franchini M, Manzato F, Salvagno GL, Montagnana M, Lippi G. The use of desmopressin in congenital factor XI deficiency: a systematic review. Ann Hematol 2009; 88 (10) 931-935
    CrossrefPubMedSearch in Google Scholar
  • 67 Barg AA, Levy-Mendelovich S, Budnik I. et al. Pediatric severe factor XI deficiency: A multicenter study. Pediatr Blood Cancer 2022; 69 (03) e29545
    CrossrefPubMedSearch in Google Scholar
  • 68 Pilbrant A, Schannong M, Vessman J. Pharmacokinetics and bioavailability of tranexamic acid. Eur J Clin Pharmacol 1981; 20 (01) 65-72
    CrossrefPubMedSearch in Google Scholar
  • 69 Curry N, Bowles L, Clark TJ. et al. Gynaecological management of women with inherited bleeding disorders. A UK Haemophilia Centres Doctors' Organisation Guideline. Haemophilia 2022; 28 (06) 917-937
    CrossrefPubMedSearch in Google Scholar