Genetics of hemophilia A and B

INTRODUCTION — Hemophilia A and B refer to factor VIII and factor IX deficiency, respectively. They are caused by pathogenic variants (eg, mutations) in the F8 or F9 gene. These are X-linked bleeding disorders that predominantly affect males. The genetics of hemophilia has implications for disease severity, inhibitor development, and preconception testing and counseling.

This topic reviews the genetics of hemophilia A and B.

Diagnosis and management of hemophilia and other bleeding disorders are discussed separately.

●Hemophilia A and B

•Diagnosis – (See "Clinical manifestations and diagnosis of hemophilia".)

•Treatment of bleeding and perioperative care (including inhibitor patients) – (See "Treatment of bleeding and perioperative management in hemophilia A and B".)

•Routine care, factor prophylaxis, and investigational approaches including gene therapy – (See "Hemophilia A and B: Routine management including prophylaxis".)

•Treatment of age-related conditions – (See "Chronic complications and age-related comorbidities in people with hemophilia".)

•Inhibitors and immune tolerance induction – (See "Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication".)

●Other bleeding disorders

•Overview – (See "Approach to the adult with a suspected bleeding disorder".)

•Factor XI deficiency (hemophilia C) – (See "Factor XI (eleven) deficiency".)

•Von Willebrand disease – (See "Clinical presentation and diagnosis of von Willebrand disease" and "von Willebrand disease (VWD): Treatment of major bleeding and major surgery".)

•Rare inherited clotting factor deficiencies – (See "Rare inherited coagulation disorders".)

•Acquired inhibitors including acquired hemophilia A – (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

●Genetics glossary – (See "Genetics: Glossary of terms".)

TERMINOLOGY — The following terminology is used herein:

●Hemophilia – Typically refers to factor VIII or factor IX deficiency (activity <40 percent of normal) due to a genetic cause.

•Hemophilia A – Factor VIII deficiency due to variation in the F8 gene.

•Hemophilia B – Factor IX deficiency due to variation in the F9 gene.

●Disease severity – When used for hemophilia A and B, disease severity is defined according to factor levels in the plasma.

•Severe disease – Factor activity <1 percent of normal

•Moderate disease – Factor activity 1 to 5 percent of normal

•Mild disease – Factor activity >5 percent (and <40 percent) of normal

●Inhibitor – When used in the context of hemophilia A or B, an inhibitor refers to an autoantibody that arises after administration of exogenous factor and typically interferes with the function of endogenous factor and administered factor concentrates.

●Hemophilia C – Sometimes used to refer to factor XI deficiency due to a genetic cause.

●Acquired hemophilia – Refers to hemophilia due to an acquired condition, most frequently an acquired autoantibody that acts as a factor inhibitor for one of the endogenous clotting factors. The most common is acquired factor VIII inhibitor, also called acquired hemophilia A.

ROLE OF FACTORS VIII AND IX IN HEMOSTASIS — The mechanisms of primary and secondary hemostasis are reviewed in a separate topic. (See "Overview of hemostasis".)

Factor VIII and IX both contribute to secondary hemostasis (formation of a fibrin clot) via their role in the intrinsic pathway X-ase (ten-ase) complex, which activates factor X. This is illustrated in the overview figure (figure 1) and the traditional depiction of the coagulation cascade (figure 2).

The X-ase complex consists of activated factor IX (factor IXa) as the protease; factor X as the substrate; and activated factor VIII (factor VIIIa), calcium, and phospholipids as cofactors in factor X cleavage, as discussed in more detail separately. (See "Biology and normal function of factor VIII and factor IX".)

PREVALENCE — The prevalence of hemophilia is as follows:

●Hemophilia A (factor VIII deficiency) – 1 in 5000 to 10,000 males. Approximately 60 percent have severe disease (factor VIII activity <1 percent of normal).

●Hemophilia B (factor IX deficiency) – 1 in 25,000 to 30,000 males. Approximately half have severe disease (factor IX activity <1 percent of normal).

Additional information and supporting studies are discussed separately. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Epidemiology'.)

TRANSMISSION — Hemophilia is usually inherited. However, sporadic cases are common. (See 'Sporadic cases' below.)

X-linked recessive inheritance — Hemophilia A and B are X-linked recessive disorders (figure 3). The factor VIII and factor IX genes (F8 and F9) are both located on the X chromosome, and males are hemizygous for most X-linked genes. Males with a variant (mutation such as a deletion or inversion) that interferes with factor activity are most likely to be affected.

●Males – Males are predominantly affected because they have a single X chromosome that contains the F8 or F9 gene with the hemophilia variant (ie, they are hemizygous for the variant).

Affected males can only transmit the disease-causing variant to their daughters, who are obligate carriers. This is because an affected male will transmit a Y chromosome to all of his sons and the affected X chromosome to all of his daughters.

●Females – Although female carriers typically have one normal factor allele, they may experience bleeding symptoms similar to those seen in a patient with mild factor deficiency (eg, due to partially skewed X-inactivation [skewed Lyonization]). Therefore, their care and symptoms should be carefully evaluated. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Bleeding in females/carriers'.)

Rarely, females may have more symptomatic hemophilia [1-3]. Possible explanations include coinheritance of pathogenic variants from both parents or more highly skewed X-inactivation [2,4].

Other causes of more symptomatic disease in females include the following:

•Loss of part of the normal X chromosome, as in Turner syndrome

•Skewed X-inactivation

•Coinheritance of hemophilia mutations from an affected father and a carrier mother

•Other rare genetic events such as chromosomal translocations or pathogenic variants in the XIST gene

Female carriers have a 50 percent chance to transmit the disease-causing variant to each of their children. Sons have a 50 percent chance to be affected, and daughters have a 50 percent chance to be carriers. The other half of sons and daughters will receive the unaffected X chromosome.

Sporadic cases — Sporadic cases of hemophilia, in which an affected male is born to a noncarrier female with a negative family history, are sometimes encountered.

The prevalence of sporadic hemophilia was previously estimated as approximately one-third of cases [5]. However, subsequent studies have shown that the frequency of sporadic disease varies depending on the population tested and the severity of disease [6].

●Hemophilia A – Sporadic cases account for approximately 55 percent of severe disease and approximately 30 percent of mild to moderate disease.

●Hemophilia B – Sporadic cases account for approximately 40 percent of severe disease and approximately 30 percent of mild to moderate disease.

Approximately 10 to 20 percent of de novo mutational events are likely to be explained by mosaicism, which is similar to the rates observed in other inherited diseases. This can occur when an individual has germline mosaicism, somatic mosaicism, or both. Studies have shown 13 percent of sporadic cases of hemophilia A were the result of somatic mosaicism and 11 percent of sporadic cases of hemophilia B were due to mosaicism [7-9].

The effect of mosaicism and the risk for transmission of the F8 or F9 variant that is mosaic in the individual's cells are dependent on the exact stage of embryonic development during which the mutational event occurred, and in turn, which tissues are involved. There have also been cases of men with sporadic mild hemophilia who went on to have a grandson with severe hemophilia due to the grandfather having somatic and germline mosaicism and the grandson having the variant in all of their cells [8-10].

When providing genetic counseling to families with sporadic hemophilia, the less likely modes of transmission should be considered. Mosaicism is not often detected by commonly available clinical testing that is provided to such families, although more detection is increasing with newer methodologies.

Mothers without a family history of hemophilia who have negative carrier testing have an approximately 5 percent risk of having a second child with hemophilia or a daughter who is a carrier due to maternal germline mosaicism [11].

OVERVIEW OF GENE VARIANTS

F8 gene (hemophilia A)

Gene structure — The F8 gene is large, comprising approximately 0.1 percent of the X chromosome. It is divided into 26 exons that span 186,000 base pairs and encode a mature protein of 2332 amino acids [12-16].

The factor VIII protein contains several areas of internal homology, consisting of a heavy chain with A1 and A2 domains; a connecting region with a B domain; and a light chain with A3, C1, and C2 domains [14,15]. Different epitopes on the C2 domain are responsible for binding to phosphatidylserine, the procoagulant phospholipid on activated platelets, as well as to endothelial cells, von Willebrand factor (which importantly slows the catabolism of factor VIII), factor Xa, and thrombin. The A2 domain and the A1/A3-C1-C2 dimer contribute to the binding of factor IXa. (See "Biology and normal function of factor VIII and factor IX", section on 'Factor VIII'.)

Spectrum of variants (F8) — Examination of F8 genetic variants in individuals with hemophilia A genes has demonstrated a wide range of alterations in multiple regions of the gene [17-21]. The large gene size and the presence of "hotspots" within the gene are thought to increase the likelihood of de novo mutations.

These include inversions, point mutations (missense and nonsense), small deletions and insertions, large deletions, and splice-site mutations [16]. The majority of variants are listed in searchable databases. (See 'Database resources' below.)

Information from genome sequencing has come from the My Life, Our Future (MLOF) project, which was established in 2012 to create a repository of hemophilia genetic information in the United States [22]. This builds on decades of previous work identifying F8 variants using other genetics tools and characterizing the clinical implications. An analysis from the project in 2018 involving nearly 10,000 individuals (affected males and carrier females) identified 700 previously unreported variants and reclassified nondeleterious variants that had previously been reported as causative [22].

Common F8 variants are illustrated in the figure (figure 4) and include the following:

●Intron 22 rearrangements – Intron 22 rearrangements (typically inversions, also referred to as IVS-22) are the most common type of hemophilia A variants. Approximately 40 to 45 percent of severe hemophilia A is caused by a major inversion of a section of the tip of the long arm of the X chromosome, one breakpoint of which is situated within intron 22 of the F8 gene. A consortium study involving 22 laboratories from 14 countries evaluated 2093 patients with severe hemophilia A and found that 740 (35 percent) had a distal F8 inversion and 140 (7 percent) had a proximal inversion [23].

●Intron 1 rearrangements – Intron 1 rearrangements (typically inversions, also referred to as IVS-1) also account for some hemophilia A variants. Approximately 1 to 5 percent of severe hemophilia A is caused by an inversion in intron 1 [16,24].

●Point mutations and small deletions/insertions – Other variations including point mutations (including nonsense mutations) and small deletions account for approximately 60 percent of hemophilia A, but no specific mutation or deletion predominates [16]. Mutational hotspots have been identified in the CpG sites (of which there are 70) and in one of two series of multiple adenines in exon 14. CpG island methylation and transcriptional slippage in strings of adenine are both well-characterized mechanisms for the introduction of new mutations. In an analysis of the first 3000 individuals entered in the MLOF repository, approximately 700 unique variants were identified, over 200 of which were new [21]. These were distributed throughout the F8 gene.

•Gene-disrupting variants are common in severe disease (factor activity <1 percent) [12,25].

•Point mutations that cause an amino acid change (ie, missense mutations) are common in mild to moderate disease.

In some cases, these amino acid changes interfere with factor activity but do not reduce protein levels. As a result, factor VIII antigen is normal (also referred to as cross-reacting material positive [CRM+]). This designation is less important since clinical assays measure factor VIII activity rather than factor VIII antigen. Many of these changes affect the A2 domain of the F8 gene and some were shown to interfere with factor VIII binding to factor IXa [26].

Mechanisms for the different types of variants and aspects of male and female germ cell development that facilitate them have been proposed [16,27-29].

Combined factor VIII and V deficiency (LMAN1 and MCFD2 genes) — An uncommon cause of factor VIII deficiency is a mutation in the LMAN1 gene, which causes a rare autosomal recessive condition of combined deficiency of factor VIII and factor V. (See "Rare inherited coagulation disorders", section on 'Factor V and VIII combined deficiency (F5F8D)'.)

The LMAN1 gene encodes a protein that may act as a molecular chaperone of factors VIII and V and other secreted proteins from the endoplasmic reticulum to the Golgi apparatus [30-32]. Combined deficiency of factors VIII and V is associated with a moderate bleeding tendency, with plasma levels of 5 to 30 percent of normal for both factors.

In other kindreds, combined factor VIII and V deficiency is associated with mutations in a gene on chromosome 2 called multiple coagulation factor deficiency 2 gene (MCFD2) [32]. MCFD2 encodes a protein that forms a Ca⁺⁺-dependent stoichiometric complex with the LMAN1 protein and acts as a cofactor in the intracellular trafficking of factors V and VIII [32].

Modifier genes — Variants in genes other than F8 have been reported to influence bleeding rates, although their contribution is substantially less than that of F8 genotype.

●Mediators of the inflammatory response may impact the extent of joint damage following joint bleeding [33].

●Thrombophilia mutations such as factor V Leiden and prothrombin G20210A may reduce bleeding [34].

We do not test for variants in modifier genes and we do not alter our management based on results outside of a research study.

F9 gene (hemophilia B) — The F9 gene is a 34 kb gene located near the terminus of the long arm of the X chromosome. It contains eight exons and seven introns. F9 is the largest gene in the family of vitamin K-dependent coagulation factors; it contains highly conserved features (exon number, splice junction types) that are highly conserved in homologous vitamin K-dependent proteins.

Spectrum of variants (F9) — Variants in F9 are highly heterogeneous [21,22,35]. They include deletions, duplications, insertions, splice-site variants, missense variants (which cause an amino acid substitution), and nonsense variants (which introduce a premature stop codon), as illustrated in the figure (figure 4). Most affected families show a unique variant, and next-generation sequencing continues to identify new variants.

The majority of variants are listed in searchable databases. (See 'Database resources' below.)

●Missense mutations are the most common type of variant, accounting for 47 percent of variants in one analysis from the MLOF database [21]. The first person diagnosed with factor IX deficiency, Mr. Christmas, had an F9 point mutation that resulted in a single amino acid change (C206S) and caused severe factor IX deficiency [36].

Similar to hemophilia A, some hemophilia B families have antigen-positive (cross-reacting material positive [CRM+]) variants, with clinical severity ranging from mild to severe. These patients have antigenic levels of factor IX that are near normal, but they have much lower factor IX activity levels. Approximately one-third of hemophilia B cases fall within this group. Mutations have been described that affect post-translational protein processing, gamma carboxylation and lipid binding, epidermal growth factor (EGF) domain function, zymogen activation, substrate recognition, and/or enzymatic activity.

•F9 Cambridge and F9 Oxford – Alterations in post-translational processing that prevent cleavage of the 18-amino-acid propeptide of factor IX [37,38].

•F9 Chapel Hill – Impaired activation of the zymogen due to interference with one of the factor IX cleavage sites [39].

•F9 Vancouver – Interference with factor IX catalytic activity toward factor X due to a point mutation changes an isoleucine to a threonine at amino acid position 397, which affects hydrogen bonding between threonine 397 and the carbonyl oxygen of tryptophan 385, which decreases factor IX binding to factor X in a configuration-favoring catalysis [40].

•Hemophilia Bm – A dysfunctional protein that causes prolongation of the prothrombin time (PT) only when the PT reagent is derived from ox brain as the source of thromboplastin. The Bm phenotype can be caused by mutations in F9 that affect amino acid residues 180, 181, or 182 near the amino terminus of the heavy chain or residues 311, 364, 368, 390, 396, or 397 near the beta cleavage site of factor IX [41,42]. Most affected individuals have clinically severe disease.

●Complete gene deletions have been described but are rare. In a study of 70 families in France, only two had complete gene deletions [43].

Leyden phenotype — Hemophilia B Leyden is a rare form of hemophilia B caused by a mutation in the F9 promoter rather than in the coding region [44-46]. A dozen different point mutations that cause hemophilia B Leyden have been described [17]. These promoter mutations disrupt the binding of transcription factors that increase factor IX expression after puberty. In individuals with the Leyden phenotype, factor IX levels increase following puberty, and these individuals often convert from a more severe to a milder clinical phenotype by adulthood [47].

Leyden phenotype mutations cluster in a region of the F9 promoter that spans from nucleotide c.-50 to c.-18, known as the Leyden-specific region (LSR) [48]. The normal LSR is regulated by transcription factors such as the liver-enriched hepatocyte nuclear factor 4 (HNF4/LF-A1) and Ets1 [48]. At puberty, growth hormone causes these transcription factors to increase. In one instructive case, a 29-year-old man with mild hemophilia B Leyden (baseline factor IX level of 1.2 international units/mL) developed a dramatic rise in factor IX levels (to 10.8 international units/mL) after using anabolic steroids for body building [49].

In contrast to patients with the Leyden phenotype, those with a point mutation at the -26 position of the F9 promoter that disrupts an androgen-responsive element (hemophilia B Brandenburg) do not show improved factor IX levels after puberty [50].

OVERVIEW OF AVAILABLE TOOLS

Database resources — Several searchable databases of hemophilia A and B mutations are available:

●EAHAD – The European Association for Haemophilia and Allied Disorders (EAHAD) hosts separate databases for F8 variants and F9 variants.

●MLOF repository The My Life, Our future (MLOF) project was established in 2012 to create a repository of hemophilia genetic information in the United States [22]. Data from this repository have identified numerous new mutations and have provided resources for research and clinical care.

●CDC – The Centers for Disease Control and Prevention (CDC) in the United States hosts the CDC Hemophilia Mutation Project (CHAMP for hemophilia A and CHBMP for hemophilia B) [51].

●HAMSTeRS – The Hemophilia A Mutation, Structure, Test, and Resources (HAMSTeRS) database was established in 1996 to facilitate identification of F8 gene variants [52]. It has been discontinued and is no longer available.

●Hemobase – A registry of F8 and F9 variants characterized in Spanish hemophilia patients [53].

Genotyping methods — There are several methods available for determining genotype in an individual with hemophilia; the choice among them may depend on whether the individual is a member of a known kindred or has an apparent new mutation.

●MLPA – Multiplex ligation-dependent probe amplification (MLPA) is a method for quantifying the copy number (dosage) of a genomic sequence and is especially useful for identifying gene deletions. MLPA has been used to identify F8 and F9 gene deletions, especially those that are missed by polymerase chain reaction (PCR), and in defining carrier status in females [54].

●PCR – Polymerase chain reaction (PCR) can be used to amplify specific regions of a gene and determine if specific changes (point mutations, intron 22 or intron 1 inversions) are present (ie, the PCR reaction only generates a product if the DNA variation is present) [55]. This method has been used in many clinical laboratories.

●Next-generation sequencing – More recent analyses have used next-generation sequencing (NGS) methods to perform whole genome or whole exome sequencing (WGS or WES), which can identify point mutations as well as more complex changes (deletions, inversions) and, from WGS, changes involving noncoding sequence (promoter regions, introns) [21,22]. In contrast to WGS, WES only analyzes coding regions and thus would not detect intron inversions. NGS methods are discussed in more detail separately. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Whole genome, exome, or gene panel'.)

●Sanger sequencing – Sanger sequencing was the method used to determine DNA sequence for many years before NGS methods became available, and it is considered the gold standard for determining sequence. Variants identified by NGS are confirmed by Sanger sequencing, and some laboratories may continue to use Sanger sequencing. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Terminology and evolution of technologies'.)

Predicting pathogenicity — Guidelines for characterizing pathogenicity are presented separately. (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)

WHEN, WHERE, AND HOW TO ORDER GENETIC TESTING — Genetic testing is appropriate in most patients with hemophilia and many of their female first-degree relatives, especially those who are expected to undergo a surgical procedure and/or may have children. Exceptions include individuals such as at-risk male relatives, who would have testing of their plasma factor activity level (factor VIII or factor IX, depending on the family) rather than genetic testing.

Ideally, testing is performed under the guidance of a local expert center such as a Comprehensive Care Centre (in Europe) or a Hemophilia Treatment Center (in the United States). These organizations can assist in determining the best methodologic approach for genetic testing and can provide comprehensive counseling and care for the entire family. Additional information about the diagnostic testing is presented separately. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Diagnostic evaluation'.)

Clinical genetic testing of the F8 and F9 genes will not identify the disease-causing variant in all individuals with hemophilia A or B, respectively. There are known to be cases of the bleeding disorder caused by variants not detected by the available methodology. Examples include deep intronic variants and large duplications [56-58]. Analysis of 3000 hemophilia patients through the My Life Our Future (MLOF) program detected a reportable variant in 99.3 percent of hemophilia A patients and 98.1 percent of hemophilia B patients [21,22].

CLINICAL IMPLICATIONS OF GENOTYPE

Overview of clinical implications — Information about the patient's genotype has the following uses:

●It can often be correlated with factor activity levels and disease severity. Some variants are associated with a wider range of factors levels, making it more challenging to predict disease severity. (See "Clinical manifestations and diagnosis of hemophilia" and 'Disease severity' below.)

●It may clarify diagnosis. As an example, identification of an F8 mutation in a patient with mild hemophilia A distinguishes the diagnosis of mild hemophilia from type 2N von Willebrand disease (VWD). (See "Clinical manifestations and diagnosis of hemophilia", section on 'Diagnostic evaluation'.)

●It helps predict the risk of inhibitor formation. (See "Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication", section on 'Pathogenesis' and 'Risk of inhibitor development' below.)

●It facilitates carrier identification in female family members. (See 'Testing at-risk relatives' below.)

●It may be useful for preconception or prenatal counseling and testing, especially if the information would result in a change in reproductive plans. (See 'Preconception and prenatal testing and counseling' below.)

Disease severity — The specific factor variant determines factor activity level, which is the major basis for disease severity. (See 'Terminology' above.)

Variants that substantially affect the production or levels of the clotting factor or prevent its major role in clotting are most likely to cause severe disease. Specific genotype-phenotype correlations are discussed above. (See 'Overview of gene variants' above.)

Clinical implications of disease severity are discussed in detail separately. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Clinical manifestations'.)

Risk of inhibitor development — Development of an inhibitor (antibody that blocks the function of infused [and endogenous] factor) is one of the most challenging complications of hemophilia. Individuals who develop an inhibitor typically can no longer use factor replacement to treat bleeding, prevent surgical bleeding, or prophylax against spontaneous bleeds. In hemophilia B, inhibitors are also associated with a risk of anaphylaxis or other severe allergic reactions to infused factor [59].

Genotype for the relevant factor gene (F8 or F9) plays an important role in inhibitor development.

●Hemophilia A – Inhibitors develop in approximately one-third of individuals with hemophilia A.

A risk score for the development of a factor VIII inhibitor weighted genotype as approximately one-third of the risk, with family history of an inhibitor and intensive treatment at first bleeding episode as the other two major contributors [60].

Factor VIII genotypes can be divided into high risk and low risk for inhibitor development.

•High-risk genotypes include large deletions, nonsense mutations (introduction of a premature stop codon), or gene inversions such as intron 22 inversions; in one early study, these all carried similar risks of inhibitor development (between 34 and 38 percent) [61].

•Low-risk genotypes include missense mutations and small deletions; the risk of inhibitor development in individuals with these variants in one study was 4 to 7 percent [61].

These differences are generally explained by whether the individual's immune system has been exposed to some endogenous factor VIII during early life and develops tolerance.

In nonsevere hemophilia A patients, it has been shown that mutations in the exons coding for the light chain of the protein are known to confer a higher risk for inhibitor development. A few specific sequence variants known to be associated with a particularly high risk of inhibitor development include the following [62-64]:

•p.Tyr2124Cys (Tyr2105Cys) – Inhibitor rate of 44 percent

•p.Arg2169His (Arg2150His) – Inhibitor rate of 24 percent

•p.Trp2248Cys (Trp2229Cys) – Inhibitor rate of 40 percent

•p.Asp2169His (Arg2150His) – Inhibitor rate of 16 to 24 percent

•p.Arg612Cys (Arg592Cys) – Inhibitor rate of 14 to 18 percent

●Hemophilia B – Inhibitors develop in approximately 3 to 5 percent of individuals with severe disease (factor IX activity <1 percent); some reports quote higher rates [22,65]. Complete deletion of the F9 gene is strongly associated with inhibitor development and anaphylaxis to infused factor [59].

The much lower rate of inhibitor development has been explained by the lower antigenicity of factor IX (perhaps because it is more antigenically similar to other vitamin K-dependent proteins) and because F9 variants are less likely to cause complete absence of the protein (causing infused factor to appear foreign to the recipient's immune system) [61].

Additional risk factors for inhibitor development including replacement product, age at which prophylaxis is initiated, and immunologic considerations, as well as a risk score for predicting inhibitor development, are discussed separately. (See "Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication".)

Genetic testing and counseling

Testing at-risk relatives — At-risk relatives and other family members of an individual with hemophilia may benefit from counseling and testing [66]. This is especially true for carrier detection in females who may have children or may undergo a surgical procedure. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Bleeding in females/carriers'.)

Preconception and prenatal testing and counseling — All individuals with a positive family history of hemophilia (known affected men, known carrier women, and those who are unsure of their status) should have access to preconception testing and counseling. This is an integral part of hemophilia treatment centers (HTCs) and can be provided by a certified genetic counselor or other clinician with expertise in hemophilia genetics. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Reproductive counseling and testing'.)

Pregnancy management of a hemophilia carrier is based on her factor activity level; delivery and immediate care of the neonate depend on the sex of the child, which should be assessed prenatally. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Obstetric considerations'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemophilia A and B".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Hemophilia (The Basics)")

SUMMARY

●Biology of FVIII and FIX – Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) are due to pathogenic variants (mutations) of the F8 and F9 genes, respectively. Factor VIII and IX both contribute to formation of a fibrin clot by activating factor X (figure 1). Activated factor IX (factor IXa) is a protease that cleaves factor X to Xa. Activated factor VIII (factor VIIIa) is a cofactor for this reaction, along with calcium and phospholipids. (See 'Terminology' above and "Overview of hemostasis" and "Biology and normal function of factor VIII and factor IX".)

●Inheritance – Hemophilia A and B are X-linked recessive disorders. They predominantly affect males; males have a single X chromosome that contains the F8 or F9 gene with the disease variant. Affected males transmit the gene variant to all of their daughters and none of their sons. Females are generally unaffected carriers, but they may have mild bleeding due to loss of part of the normal X chromosome (Turner syndrome, skewed X-inactivation, coinheritance of a pathogenic variant from an affected father and a carrier mother). Female carriers transmit the hemophilia gene to approximately half of their children. Hemophilia is mostly inherited, but sporadic cases are common and are responsible for up to half of individuals with hemophilia A and 40 percent with hemophilia B. (See 'Transmission' above.)

●Common variants – Common F8 and F9 variants are illustrated in the figure (figure 4), and searchable databases are listed above, along with information on genotyping methods and information on test ordering. Computer-based modeling (in silico analysis) may help predict which variants are likely to cause bleeding. (See 'Overview of available tools' above.)

●Genetic testing – Genetic testing is appropriate in most patients with hemophilia and many of their first-degree relatives. Ideally, testing is performed under the guidance of a local expert center such as a Comprehensive Care Centre in Europe or a Hemophilia Treatment Center (HTC) in the United States. These organizations can assist in determining the best approach for genetic testing and can provide comprehensive counseling and care for the entire family. (See 'When, where, and how to order genetic testing' above and "Clinical manifestations and diagnosis of hemophilia", section on 'Diagnostic evaluation'.)

●Clinical implications – The major clinical implications of hemophilia genotype for the patient are in correlating with disease severity and predicting the risk of inhibitor development. For first-degree relatives, genotype may facilitate carrier identification, which can be used for counseling predicting bleeding in females who require a surgical procedure. (See 'Clinical implications of genotype' above.)

●Diagnosis and management – The diagnosis and management of hemophilia A and B and related bleeding disorders are discussed in separate topic reviews listed above. (See 'Introduction' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD, and Lawrence LK Leung, MD, to earlier versions of this topic review.