INTRODUCTION — This monograph summarizes the implications of results from germline testing of the F11 gene, which encodes coagulation factor XI (FXI).
FXI circulates as an inactive form (zymogen) and becomes activated to FXIa, an enzyme that amplifies clotting and reduces clot breakdown (fibrinolysis), especially at sites of injury (figure 1).
Individuals with FXI deficiency can have a bleeding disorder of variable severity. They require a comprehensive management approach, best guided by consultation with a federally recognized hemophilia treatment center (HTC) or another center of excellence.
The general approach to evaluating bleeding disorders and detailed information about FXI deficiency and other specific coagulation factor deficiencies are discussed separately in UpToDate [1].
ASSESSMENT
How to read the report — Before acting on the results, confirm that the correct gene was tested and the test was performed in a clinical laboratory improvements amendment (CLIA)-certified laboratory. The table lists other caveats (table 1).
Coagulation factors are numbered using Roman numerals, and transposition of numerals can result in ordering or testing the incorrect factor, especially when testing factor activity levels (see 'Coagulation testing' below). Confirm that the correct/intended factor was tested and that the genetic test results match the intended gene.
It is important to assess the technology that was used to perform the testing. Some laboratories only test for known common variants in F11; however, laboratories are increasingly using next generation sequencing (NGS), which detects a wider range of variants. This may help identify whether further genetic testing is needed or warranted.
Not all variants that are identified cause a clinical disorder (table 2). Pathogenic and likely pathogenic variants (and some variants of uncertain significance [VUS]) in F11 will be associated with FXI deficiency. Correlation with clinical history and plasma factor XI activity is essential. (See 'Evaluation' below.)
F11 genetics — Over 200 distinct pathogenic variants have been reported in F11, distributed throughout the gene [2]. They may affect the catalytic region of the enzyme or a homodimerization domain required for secretion.
Two F11 variants are highly represented in individuals of Ashkenazi (Eastern or Central European) Jewish ancestry with factor XI deficiency (likely as founder mutations):
●Glu117Stop (E117X)
●Phe283Leu (F283L)
A less common variant in Ashkenazi Jewish individuals is c.1716+1G>A.
Additional F11 variants have been reported in certain groups [3]:
●Cys38Arg (C38R) in French Basque people
●Gln88Stop (Q88X) in French people from Nantes
●Cys128Stop (C128X) in people from the United Kingdom
●Ile436Lys (I436K) in people from Northeastern Italy
●Gln263Stop (Q263X) in people of Korean descent
Inheritance may be autosomal recessive or dominant, depending on whether the variant reduces expression of the FXI protein or acts as a dominant negative (creates an abnormal protein that interferes with function of normal FXI protein produced from the normal F11 allele). (See "Factor XI (eleven) deficiency", section on 'F11 gene variants'.)
●The majority of F11 variants that reduce protein expression show autosomal recessive inheritance. Homozygosity or compound heterozygosity is generally required for a clinical phenotype to manifest.
●A small number of variants have been identified that act dominantly and have an autosomal dominant inheritance pattern. Heterozygotes are affected.
Genotype-phenotype relationships are complex. Some individuals with the same genotype may have significant differences in FXI activity [4]. Certain genotypes, especially those associated with severe FXI deficiency, such as homozygosity for E117X, are more likely to be associated with formation of inhibitors (alloantibodies) after exposure to normal exogenous FXI [5,6]. This information may guide care (avoiding FXI exposure in some settings, monitoring FXI activity more closely after exposure, and inhibitor testing). (See 'Management' below.)
Factor XI deficiency
Epidemiology — Inherited FXI deficiency is rare, although the true prevalence is unknown. Some individuals with FXI deficiency may never come to medical attention. (See "Factor XI (eleven) deficiency", section on 'Epidemiology'.)
●The estimated prevalence ranges from 1 in 1 million for symptomatic presentations to 1 in 1000 for asymptomatic individuals, depending upon the populations evaluated.
●FXI deficiency is more prevalent in individuals of Ashkenazi (Eastern and Central European) Jewish and Iraqi Jewish ancestry, with a carrier frequency as high as 8 to 9 percent (1 in 11 individuals). Biallelic deficiency variants (homozygosity or compound heterozygosity) may be seen in 1 in 450.
●Unlike hemophilia A and B, which are X-linked and predominantly affect males, transmission is autosomal (both sexes are affected equally).
Bleeding risk — FXI deficiency generally does not cause spontaneous bleeding (such as seen in severe hemophilia A or B), even with severely reduced FXI activity (table 3). Bleeding in FXI deficiency is generally associated with injury, trauma, or an invasive procedure. Heavy menstrual bleeding may occur. (See "Factor XI (eleven) deficiency", section on 'Bleeding'.)
The correlation between FXI activity and bleeding phenotype is weak; not all individuals with FXI deficiency have serious surgical or traumatic bleeding, and FXI activity levels cannot be used to predict bleeding risk. Individuals who did not bleed with prior trauma or surgery may experience bleeding in the future. Factors that may modify the bleeding phenotype include other inherited hemostatic defects such as von Willebrand disease or medications that affect hemostasis such as aspirin.
Despite this variability, bleeding history remains important to assess clinical manifestations that may require intervention (eg, heavy menstrual bleeding), to plan for upcoming events and interventions, and to assure that patients and families have appropriate knowledge regarding optimal care. (See 'Bleeding history' below.)
Evaluation — Evaluation for FXI deficiency requires review of the family history, ethnic background, personal bleeding history, and coagulation testing including FXI activity [7].
Bleeding history — The bleeding history assesses any prior spontaneous bleeding or excessive bleeding with bleeding challenges. It typically consists of questions that can be scored using a bleeding assessment tool (BAT). A BAT from the International Society of Thrombosis and Haemostasis is available online (ISTH-SSC BAT) [8]. (See "Approach to the adult with a suspected bleeding disorder", section on 'Bleeding score'.)
Bleeding history is most useful for individuals who have had bleeding challenges (trauma, surgery, dental procedures, pregnancies). It may be less useful in young children, as they may not have experienced any events that could precipitate bleeding.
Coagulation testing — Any individual for whom there is concern about FXI deficiency (pathogenic variant in F11, positive family history, Ashkenazi Jewish ancestry) should undergo standard coagulation testing that includes a FXI activity level.
Initial testing (on a plasma sample) includes:
●Prothrombin time (PT) and activated thromboplastin time (aPTT).
●If the PT and/or aPTT is prolonged, one to one mixing with normal plasma. Correction to the normal range indicates a factor deficiency. (See "Clinical use of coagulation tests", section on 'Use of mixing studies'.)
●If a factor deficiency is suspected, appropriate specific clotting factor levels such as FXI activity.
Typically, FXI deficiency results in a prolonged aPTT that corrects in a mixing study, normal PT, normal FVIII and FIX activity, and decreased FXI activity.
However, it is important to evaluate a FXI activity level in individuals with a strong suspicion for FXI deficiency regardless of the PT and aPTT results, as some cases of partial deficiency and increased bleeding risk (FXI activity in the 20 to 60 percent range) may be associated with a normal aPTT, depending on the laboratory and/or reagents used.
Normal FXI activity excludes FXI deficiency. Individuals with a positive bleeding history (or positive family history) can undergo evaluation for other potential causes. (See "Approach to the adult with a suspected bleeding disorder".)
MANAGEMENT
General recommendations — The local hematologist provides coordinated care, supported by expert consultation with a hemophilia treatment center (HTC) or other center of excellence. The HTC or center of excellence will provide comprehensive evaluation and planning to assure optimal outcomes. Specific management considerations are summarized in the table (table 3).
Contact information is listed below. (See 'Resources' below.)
Attention to the following is especially important:
●Education
•Understanding of test results and implications (bleeding risk, inhibitor risk)
•Use of a medical alert bracelet and/or wallet card
•Contact information for the primary hematologist or center of excellence
•Avoidance of aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) for routine pain or fever
•Genetic counseling, including implications for first-degree relatives (See 'Considerations for family members' below.)
●Planning
•Therapies for heavy menstrual bleeding
•Planning for elective surgery and pregnancy
•Inhibitor screening for selected individuals
•Consultation regarding potential use of an antiplatelet agent or anticoagulant if needed (eg, in atrial fibrillation)
•Preconception testing and counseling
Surgery/invasive procedures — The HTC or center of excellence should be consulted with sufficient notice to review the procedure and develop a plan for management that may include:
●Use of antifibrinolytic therapy, plasma, a FXI concentrate, low dose recombinant activated factor VII (rFVIIa), or other hemostatic therapies [9]. These therapies may be given prophylactically, or they may be made available to be used if needed. Risks and benefits, including an increased risk of thrombosis, must be considered [10].
●Modifications to the procedure or anesthesia to reduce bleeding risk, or having the procedure performed at a different hospital with a dedicated HTC staff able to manage the patient should the need arise.
Inhibitors — Inhibitors are alloantibodies that develop in response to exogenous FXI exposure (from plasma transfusions or FXI concentrates). These are rare [11]. However, they can occur with certain genotypes, especially those associated with severely reduced FXI activity. In some individuals with a high risk of inhibitor development such as E117X homozygotes, plasma administration may be avoided so that it can be reserved for life-threatening bleeding. (See 'F11 genetics' above.)
Inhibitors are suspected when bleeding does not respond to treatment with FXI or may be identified by screening in an at-risk individual. Those who develop an inhibitor may require other interventions. (See "Factor XI (eleven) deficiency", section on 'rFVIIa'.)
Pregnancy and menstruation — Women with known FXI deficiency or Ashkenazi Jewish ancestry should have testing and/or genetic counseling prior to conception, including F11 genotype and FXI activity level. Paternal testing may be indicated.
Bleeding during pregnancy is variable in individuals with FXI deficiency; however, the risk of postpartum hemorrhage is increased; this risk may affect management of delivery and planning for neuraxial anesthesia (algorithm 1). Pregnancy and delivery should be managed in consultation with an HTC or center of excellence [12,13]. (See 'Resources' below.)
Women with heavy menstrual bleeding may benefit from taking an antifibrinolytic agent during the first few days of the menstrual cycle or using hormonal suppressive therapy. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)
CONSIDERATIONS FOR FAMILY MEMBERS — All first-degree relatives of an individual with FXI deficiency are candidates for an evaluation that includes bleeding history, coagulation testing with FXI activity, and genetic testing and counseling. The HTC or center of excellence can facilitate and coordinate this evaluation for appropriate family members. (See 'Resources' below.)
●First-degree relatives of individuals who are heterozygous for a pathogenic variant in F11 have a 1 in 2 chance of also being heterozygotes.
●Full siblings of individuals with biallelic pathogenic variants in F11 (homozygous or compound heterozygous) have a 1 in 4 chance of carrying biallelic variants and a 1 in 2 chance of carrying a variant on one F11 allele (being heterozygotes).
RESOURCES
●UpToDate topics
•FXI deficiency – (See "Factor XI (eleven) deficiency".)
•Bleeding disorder evaluation – (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder" and "Clinical use of coagulation tests".)
•Genetics concepts – (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)" and "Genetics: Glossary of terms" and "Genetic testing" and "Genetic counseling: Family history interpretation and risk assessment".)
●Genetics professionals
•Genetic counselors – National Society of Genetic Counselors (NSGC)
•Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Hemophilia resources
•World Federation of Hemophilia (WFH) – Global Treatment Centre Directory
•Centers for Disease Control and Prevention (CDC) in the United States – HTC Directory
•National Hemophilia Foundation (NHF) in the United States – Resources
