Clinical characteristics.

Hemophilia B is characterized by deficiency in factor IX clotting activity that results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the level of factor IX clotting activity.

• In individuals with severe hemophilia B, spontaneous joint or deep-muscle bleeding is the most frequent sign. Individuals with severe hemophilia B are usually diagnosed during the first two years of life; without prophylactic treatment, they may average up to two to five spontaneous bleeding episodes each month.
• Individuals with moderate hemophilia B seldom have spontaneous bleeding; however, they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years; the frequency of bleeding episodes varies from once a month to once a year.
• Individuals with mild hemophilia B do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions; the frequency of bleeding may vary from once a year to once every ten years. Individuals with mild hemophilia B are often not diagnosed until later in life.

In any individual with hemophilia B, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. Approximately 30% of heterozygous females have factor IX clotting activity lower than 40% and are at risk for bleeding (even if the affected family member has mild hemophilia B), although symptoms are usually mild. After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity.

Diagnosis/testing.

The diagnosis of hemophilia B is established in individuals with low factor IX clotting activity. Identification of a hemizygous F9 pathogenic variant on molecular genetic testing in a male proband confirms the diagnosis. Identification of a heterozygous F9 pathogenic variant on molecular genetic testing in a symptomatic female confirms the diagnosis.

Management.

Treatment of manifestations: Referral to a hemophilia treatment center (HTC) for assessment, education, genetic counseling, and treatment. Intravenous infusion of plasma-derived or recombinant factor IX for bleeding episodes within an hour of noticing symptoms. Training and home infusions for those with severe hemophilia B.

Prevention of primary manifestations: For those with severe disease, prophylactic infusions of factor IX concentrate twice weekly to maintain factor IX clotting activity higher than 1% nearly eliminates spontaneous bleeding and prevents chronic joint disease. Some individuals require higher trough levels for this effect. Longer-acting products that allow weekly or biweekly dosing are now available.

Prevention of secondary complications: Recombinant factor IX produced without human- or animal-derived proteins and virucidal treatment of plasma-derived concentrates has eliminated the risk of HIV and hepatitis B and C viruses.

Surveillance: For individuals with severe or moderate hemophilia B, assessments every six to 12 months at an HTC; for individuals with mild hemophilia B, assessments at least every two to three years.

Agents/circumstances to avoid: Circumcision of at-risk males until hemophilia B is either excluded or treated with factor IX concentrate regardless of severity; intramuscular injections; activities with a high risk of trauma, particularly head injury; aspirin and all aspirin-containing products. Cautious use of other medications and herbal remedies that affect platelet function.

Evaluation of relatives at risk: To clarify genetic status of females at risk before pregnancy or early in pregnancy in order to facilitate management.

Pregnancy management: Maternal factor IX levels do not increase during pregnancy and heterozygous females are more likely to need factor infusion support for delivery or to treat or prevent postpartum hemorrhage; monitor heterozygous mothers for delayed bleeding post partum.

Therapies under investigation: Clinical trials of additional longer-acting recombinant factor IX concentrates and gene therapy using intravenous infusion of an adeno-associated viral vector expressing factor IX are underway.

Other: Vitamin K does not prevent or control bleeding in hemophilia B.

Genetic counseling.

Hemophilia B is inherited in an X-linked manner. The risk to sibs of a proband depends on the carrier status of the mother. Carrier females have a 50% chance of transmitting the F9 pathogenic variant in each pregnancy. Sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant are carriers. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Carrier testing for family members at risk and prenatal testing for pregnancies at increased risk are possible if the F9 pathogenic variant has been identified in a family member or if informative intragenic linked markers have been identified.

Suggestive Findings

Hemophilia B should be suspected in an individual with any of the following clinical features and/or laboratory features.

Clinical features

• Hemarthrosis, especially with mild or no antecedent trauma
• Deep-muscle hematomas
• Intracranial bleeding in the absence of major trauma
• Neonatal cephalohematoma or intracranial bleeding
• Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
• Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
• Unexplained GI bleeding or hematuria *
• Heavy menstrual bleeding, especially with onset at menarche (in symptomatic carriers) *
• Prolonged nosebleeds, especially recurrent and bilateral *
• Excessive bruising, especially with firm, subcutaneous hematomas

* Of any severity, or especially in more severely affected persons

Laboratory features

• Normal platelet count
• Prolonged activated partial thromboplastin time (aPTT) in severe and moderate hemophilia B. Normal or mildly prolonged aPTT in mild hemophilia B.
• Normal prothrombin time (PT)

Establishing the Diagnosis

The diagnosis of hemophilia B is established in a male proband by identification of deceased factor IX clotting activity.

• Severe hemophilia B. <1% factor IX
• Moderate hemophilia B. 1%-5% factor IX
• Mild hemophilia B. >5%-40% factor IX

Note: (1) The normal range for factor IX clotting activity is approximately 50%-150% [Khachidze et al 2006]. Individuals with factor IX clotting activity higher than 40% usually have normal coagulation in vivo. However, some increased bleeding can occur with low to low-normal factor IX clotting activity in hemophilia B carrier females [Plug et al 2006]. (2) Somatic mosaicism in males with hemophilia B has been described [Ketterling et al 1999].

Identification of a hemizygous pathogenic variant in F9 by molecular genetic testing can help predict the clinical phenotype and allow family studies (see Table 1).

Heterozygous females. The diagnosis of hemophilia B is established by determination of low factor IX clotting activity. Approximately 30% of heterozygous females have a factor IX clotting activity below 40%, regardless of the severity of hemophilia B in their family. Bleeding symptoms may be present in those with factor IX activity in the low-normal range [Plug et al 2006].

Carrier status is determined by identification of a heterozygous pathogenic variant in F9 by molecular genetic testing (see Table 1). Factor IX clotting activity is unreliable in the detection of heterozygous females; the majority of obligate carriers, even of severe hemophilia B, have normal factor IX clotting activities.

Clinical Description

Hemophilia B in the untreated individual is characterized by immediate or delayed bleeding or prolonged oozing after injuries, tooth extractions, or surgery or renewed bleeding after initial bleeding has stopped [Josephson 2013, Peyvandi et al 2016]. Muscle hematomas or intracranial bleeding can occur immediately or up to four to five days after the original injury. Intermittent oozing may last for days or weeks after tooth extraction. Prolonged or delayed bleeding or wound hematoma formation after surgery is common. After circumcision, males with hemophilia B of any severity may have prolonged oozing, or they may heal normally. In severe hemophilia B, spontaneous joint bleeding is the most frequent sign.

The age of diagnosis and frequency of bleeding episodes are generally related to the factor IX clotting activity (see Table 2). In any affected individual, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. To some extent, this greater frequency is a function of both physical activity levels and vulnerability during more rapid growth.

Individuals with severe hemophilia B are usually diagnosed as newborns due to birth- or neonatal-related procedures or during the first year of life [Kulkarni et al 2009]. In untreated toddlers, bleeding from minor mouth injuries and large "goose eggs" from minor head bumps are common; these are the most frequent presenting symptoms of severe hemophilia B. Intracranial bleeding may also result from head injuries. The untreated child almost always has subcutaneous hematomas; some have been referred for evaluation of possible non-accidental trauma.

As the child grows and becomes more active, spontaneous joint bleeds occur with increasing frequency unless the child is on a prophylactic treatment program. Spontaneous joint bleeds or deep-muscle hematomas initially cause pain or limping before swelling appears. Children and young adults with severe hemophilia B who are not treated have an average of two to five spontaneous bleeding episodes each month. Joints are the most common sites of spontaneous bleeding; other sites include the muscles, kidneys, gastrointestinal tract, brain, and nose. Without prophylactic treatment, individuals with hemophilia B have prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions.

Individuals with moderate hemophilia B seldom have spontaneous bleeding but bleeding episodes may be precipitated by relatively minor trauma. Without pretreatment (as for elective invasive procedures) they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years. The frequency of bleeding episodes requiring treatment with factor IX concentrates varies from once a month to once a year. Signs and symptoms of bleeding are otherwise similar to those found in severe hemophilia B.

Individuals with mild hemophilia B do not have spontaneous bleeding. However, without treatment, abnormal bleeding occurs with surgery, tooth extractions, and major injuries. The frequency of bleeding may vary from once a year to once every ten years. Individuals with mild hemophilia B are often not diagnosed until later in life when they undergo surgery or tooth extraction or experience major trauma.

Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [Plug et al 2006].

Complications of untreated bleeding. The leading cause of death related to bleeding is intracranial hemorrhage. The major cause of disability from bleeding is chronic joint disease [Luck et al 2004]. Currently available treatment with clotting factor concentrates is normalizing life expectancy and reducing chronic joint disease for children and adults with hemophilia B. Prior to the availability of such treatment, the median life expectancy for individuals with severe hemophilia B was 11 years (the current life expectancy for affected individuals in several developing countries). Excluding death from HIV, life expectancy for those severely affected individuals receiving adequate treatment was 63 years in 2000 [Darby et al 2007], having been greatly improved with factor replacement therapy [Tagliaferri et al 2010].

Other. Since the late1960s, the mainstay of treatment of bleeding episodes has been factor IX concentrates that initially were derived solely from donor plasma. By the late 1970s, more purified preparations became available, reducing the risk for thrombogenicity. Viral inactivation methods and donor screening of plasmas were introduced by 1990 and a recombinant factor IX concentrate became available shortly thereafter [Monahan & Di Paola 2010]. A second recombinant factor IX concentrate was FDA licensed in 2013. Two long-acting modified recombinant factor IX concentrates are now FDA approved, extending the factor IX half-life three- to fivefold compared to unmodified products [Powell et al 2013, Santagostino et al 2016] . HIV transmission from concentrates occurred between 1979 and 1985. Approximately half of these individuals died of AIDS prior to the advent of effective HIV therapy.

Hepatitis B transmission from earlier plasma-derived concentrates was eliminated with donor screening and then vaccination introduced in the 1970s. Most individuals exposed to plasma-derived concentrates prior to the late 1980s became chronic carriers of the hepatitis C virus. Viral inactivation methods implemented in concentrate preparation and donor screening assays developed by 1990 have essentially eliminated hepatitis C transmission from plasma-derived concentrates.

Alloimmune inhibitors occur much less frequently than in hemophilia A. Approximately 2% of individuals with severe hemophilia B develop alloimmune inhibitors to factor IX [Puetz et al 2014]. These individuals usually have partial- or whole-gene deletions or certain nonsense variants (see Genotype-Phenotype Correlations and Table A, Locus-Specific Databases). At times, the onset of an alloimmune response has been associated with anaphylaxis to transfused factor IX or development of nephrotic syndrome [DiMichele 2007, Chitlur et al 2009].

Genotype-Phenotype Correlations

Disease severity

• Large deletions, nonsense variants, and most frameshift variants cause severe disease.
• Missense variants can cause severe, moderate, or mild disease depending on their location and the specific substitutions involved.

Alloimmune inhibitors

• Alloimmune inhibitors occur with the greatest frequency (40%-60%) in individuals with large partial (>50-bp) deletions, whole-gene deletions or early termination (<100 predicted amino acids) variants [Goodeve 2015, Saini et al 2015].
• Missense variants are rarely associated with inhibitors.

Unlike hemophilia A, severe hemophilia B is often caused by a missense variant and several of these are associated with normal cross-reacting material (factor IX antigen) levels (see Table A, Locus-Specific Databases).

Uncommon variants within the carboxylase-binding domain of the propeptide cause increased sensitivity to warfarin anticoagulation in individuals without any baseline bleeding tendency [Oldenburg et al 2001] (see Management).

In hemophilia B Leyden, more than 20 different causative variants in the proximal F9 promoter region have been described [Funnell & Crossley 2014]; the severity of disease decreases after puberty; mild disease disappears and severe disease becomes mild, depending on the specific pathogenic variant.

Penetrance

All males with an F9 pathogenic variant are affected and will have hemophilia B of approximately the same severity as all other affected males in the family; however, other genetic and environmental effects may modify the clinical severity to some extent.

Approximately 30% of females with one F9 pathogenic variant and one normal allele have a factor IX clotting activity lower than 40% and a bleeding disorder; mild bleeding can occur in carriers with low-normal factor IX activities [Plug et al 2006].

Prevalence

The birth prevalence of hemophilia B is approximately one in 30,000 live male births worldwide. Hemophilia B is about one fifth as prevalent as hemophilia A.

The birth prevalence is the same in all countries and all races, presumably because of the high spontaneous mutation rate of F9 and its presence on the X chromosome.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hemophilia B, the following evaluations are recommended if they have not already been completed:

• A personal and family history of bleeding to help predict disease severity
• A joint and muscle evaluation, particularly if the individual describes a history of hemarthrosis or deep-muscle hematomas
• Screening for hepatitis A, B, and C as well as HIV if blood products or plasma-derived clotting factor concentrates were administered prior to 1990
• Baseline CBC including platelet count and ferritin, especially if there is a history of nose bleeds, GI bleeding, mouth bleeding, or in females, heavy menstrual bleeding or postpartum hemorrhage
• Referral to a hemophilia treatment center. For locations:
  • Worldwide, see World Federation of Hæmophilia;
  • US only, see National Hemophilia Foundation.
• Identification of the specific F9 pathogenic variant in an individual to aid in determining disease severity, the likelihood of inhibitor development, and the risk of anaphylaxis if an inhibitor does develop
• Consultation with a clinical geneticist and/or genetic counselor, particularly if a new diagnosis in the family and for females of childbearing years

Treatment of Manifestations

The World Federation of Hæmophilia has published treatment guidelines for the management of individuals with hemophilia. Treatment should be coordinated through a hemophilia treatment center (for locations in the USA: see National Hemophilia Foundation; elsewhere worldwide: see World Federation of Hæmophilia).

Intravenous infusion of plasma-derived or recombinant factor IX for bleeding episodes should be initiated within an hour of noticing symptoms.

• Dosing is weight based and target levels and duration of treatment vary by the severity of bleeding and/or the risk associated with the surgery or procedure.
• Identify staff members who are expert in performing venipunctures in infants and toddlers because frequent venipunctures may be necessary.
• Parents of children age two to five years with severe hemophilia B should be trained to administer the infusions as soon as is feasible. Home treatment allows for prompt treatment and facilitates prophylactic therapy.

Pediatric issues. Special considerations for care of infants and children with hemophilia B include the following [Chalmers et al 2011]:

• Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
• Immunizations should be administered subcutaneously; intramuscular injections should be avoided unless under factor coverage.
• Effective dosing of factor IX requires an understanding of different pharmacokinetics in young children.

Inhibitors. Alloimmune inhibitors to factor IX, seen in 1%-3% of persons with severe hemophilia B, greatly compromise the ability to manage bleeding episodes [Hay et al 2006]. Their onset can be associated with anaphylactic reactions to factor IX infusion and nephrotic syndrome [DiMichele 2007, Chitlur et al 2009]. Immune tolerance can be challenging and long-term bypassing therapy may be needed for treatment.

Prevention of Primary Manifestations

Prophylactic treatment is recommended by the National Hemophilia Foundation and the World Federation of Hæmophilia for children with severe hemophilia and is usually administered as infusion of factor IX concentrate twice weekly or every other day to maintain factor IX clotting activity above 1%, although a less intense regimen may provide protection for some affected boys [Fischer et al 2002]. Also, some individuals will require troughs higher than 1% to prevent bleeding. Longer-acting factor IX concentrates that extend the half-life three- to fivefold are now available. Choice of product should be individualized based on clinical factors and activity levels. Initiation of prophylactic infusions of factor IX concentrate in young boys before or just after their first few joint bleeds has been shown to nearly eliminate spontaneous bleeding and prevent chronic joint disease [Manco-Johnson et al 2007]. Prophylaxis in adults is standard of care in many countries and has been shown to decrease bleeding and improve joint function and quality of life [Josephson 2013, Manco-Johnson et al 2013]

Prevention of Secondary Complications

Many recombinant products are now produced without human- or animal-derived proteins in the process or final product. Virucidal treatment of plasma-derived concentrates has eliminated the risk of HIV transmission since 1985, and of hepatitis B and C viruses since 1990.

Surveillance

Persons with hemophilia followed at hemophilia treatment centers (HTCs) (see Resources) have lower mortality than those who are not [Soucie et al 2000, Pai et al 2016].

Young children with severe or moderate hemophilia B should be evaluated at an HTC (accompanied by the parents) every six to 12 months to review their history of bleeding episodes and adjust treatment plans as needed. Early signs and symptoms of possible bleeding episodes are reviewed. The assessment should also include a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, and a discussion of any other problems related to the individual's hemophilia and family and community support.

Screening for alloimmune inhibitors is usually done in those with severe hemophilia B after treatment with factor IX concentrates has been initiated for either bleeding or prophylaxis. Affected individuals at increased risk for inhibitor formation should be closely monitored during initial infusions and additional screening is usually performed up to a few years of age when the genotype is a large partial deletion, complete F9 deletion, or early termination variant (<100 predicted amino acids) (see Genotype-Phenotype Correlations and Molecular Genetics, Pathogenic variants). Testing for inhibitors should also be performed in any individual with hemophilia B whenever a suboptimal clinical response to treatment is suspected, regardless of disease severity; with hemophilia B, the onset may be heralded by an allergic reaction to infused factor IX concentrate.

Older children and adults with severe or moderate hemophilia B benefit from at least yearly assessments at an HTC (see Resources) and periodic assessments to review bleeding episodes and treatment plans, evaluate joints and muscles, screen for an inhibitor, perform viral testing if indicated, provide education, and discuss other issues relevant to the individual's hemophilia.

Individuals with mild hemophilia B can benefit from an assessment at an HTC every one to two years.

Agents/Circumstances to Avoid

The following should be avoided:

• Circumcision of infant males with a family history of hemophilia B unless hemophilia B is excluded; OR if circumcision is performed on an infant with hemophilia B, the infant should be treated with factor IX concentrate directly before and after the procedure.
• Intramuscular injections
• Activities that involve a high risk of trauma, particularly of head injury
• Medications and herbal remedies that affect platelet function, including aspirin unless there is strong medical indication (e.g., in individuals with atherosclerotic cardiovascular disease). Individuals with severe hemophilia usually require clotting factor prophylaxis to allow aspirin and other platelet inhibitory drugs to be used safely [Angelini et al 2016].

Older, intermediate purity plasma-derived “prothrombin complex” concentrates should be used cautiously (if at all) in hemophilia B because of their thrombogenic potential.

Evaluation of Relatives at Risk

Identification of at-risk relatives. A thorough family history may identify other male relatives who are at risk but have not been tested (particularly in families with mild hemophilia B).

Early determination of the genetic status of males at risk. Either assay of factor IX clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue) or molecular genetic testing for the family-specific F9 pathogenic variant can establish or exclude the diagnosis of hemophilia B in newborn males at risk. Infants with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, factor IX concentrate is administered immediately before and after the procedure to prevent delayed oozing and poor wound healing.

Note: (1) The cord blood for factor IX clotting activity assay should be drawn into a syringe containing one-tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. (2) Factor IX clotting activity in cord blood in a normal-term newborn is lower than in adults (mean: ~30%; range: 15%-50%); thus, the diagnosis of hemophilia B can be established in an infant with activity lower than 1%, but is equivocal in an infant with moderately low (15%-20%) activity.

Determination of genetic status of females at risk. Approximately 30% of heterozygous females have factor IX clotting activity lower than 40% and may have abnormal bleeding. In a recent Dutch survey of heterozygous females, bleeding symptoms correlated with baseline factor clotting activity; there was suggestion of a very mild increase in bleeding even in those with 40% to 60% factor IX clotting activity [Plug et al 2006]. Joint range of motion in female carriers with factor VIII or factor IX activity lower than 40% was found to be significantly different from that measured in normal controls and inversely related to factor level [Sidonio et al 2014]. All daughters and mothers of an affected male and other at-risk females should have a baseline factor IX clotting activity assay to determine if they are at increased risk for bleeding (unless they are known to be non-carriers based on molecular genetic testing). Very occasionally, a female will have particularly low factor IX clotting activity that may result from heterozygosity for an F9 pathogenic variant associated with skewed X-chromosome inactivation or, on rare occasion, compound heterozygosity for two F9 pathogenic variants.

It is recommended that the carrier status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Obstetric issues. It is recommended that the carrier status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible.

Unlike for factor VIII (FVIII), maternal factor IX levels do not increase during pregnancy and carriers are more likely to need factor infusion support for delivery or to treat or prevent postpartum hemorrhage. In carriers, postpartum hemorrhage has been a prominent feature, despite the absence of heavy menstrual bleeding [Yang & Ragni 2004].

If the female has a baseline factor IX clotting activity below approximately 40%, she by definition has hemophilia and is at risk for excessive bleeding, particularly post partum, and may require therapy with factor IX concentrate [Yang & Ragni 2004].

Newborn males. Controversy remains as to indications for cesarean section versus vaginal delivery [James & Hoots 2010, Ljung 2010]. For elective deliveries, the relative risks of cesarean section versus vaginal delivery should be considered, especially if a male has been diagnosed with severe hemophilia B prenatally.

At birth or in the early neonatal period, intracranial hemorrhage is uncommon (<1%-2%), even in males with severe hemophilia B who are delivered vaginally.

Therapies Under Investigation

Recombinant factor IX (FIX) proteins with prolonged survival. Two products with modifications to prolong half-life (Fc or albumin fusion proteins) are now FDA approved and others, including with site-specific PEGylation, have completed Phase III clinical trials [Powell et al 2013, Peyvandi et al 2016, Santagostino et al 2016]. Clinical trial data show a three- to five fold prolongation of FIX half-life with the fusion proteins.

Gene therapy for hemophilia B. Several clinical trials of gene therapy using intravenous infusion of an adeno-associated viral vector expressing factor IX are underway; some have shown sustained factor levels [Lheriteau et al 2015]. These vectors use liver-restricted promoters to target synthesis to the natural site of FIX synthesis.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

Vitamin K does not prevent or control bleeding caused by hemophilia B.

Fresh frozen plasma is no longer recommended to treat hemophilia B because it is not treated with a virucidal agent.

Mode of Inheritance

Hemophilia B is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disease nor will he be hemizygous for the F9 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a female has more than one affected son and no other affected relatives and the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If the proband represents a simplex case, the mother of the affected male may or may not be a carrier. (A simplex case refers to an affected male with no family history of hemophilia; ~50% of affected males have no family history of hemophilia B.) Several possibilities regarding his mother's carrier status and the carrier risks of extended family members need to be considered:
  • The mother is not a carrier and the pathogenic variant occurred de novo in the affected male.
  • The mother is a carrier of a de novo pathogenic variant that occurred in one of the following ways:
    • As a germline variant (i.e., in the egg or sperm at the time of her conception, and thus present in every cell of her body and detectable in her leukocyte DNA)
    • As a somatic variant (i.e., a change that occurred very early in embryogenesis, resulting in somatic mosaicism, in which the pathogenic variant is present in some but not all cells and may be detectable in her leukocyte DNA); reported in ≤11% of families [Ketterling et al 1999]
    • As germline mosaicism (in which some germ cells have the pathogenic variant and some do not, and the pathogenic variant is not detectable in her leukocyte DNA)
  • The mother is a carrier of an inherited pathogenic variant. The mother may have inherited the pathogenic variant either from her mother who has a de novo pathogenic variant or from her asymptomatic father who is mosaic for the pathogenic variant. Alternatively, the mother is a carrier of an inherited pathogenic variant that arose in a previous generation and has been passed on through the family without manifesting symptoms in female carriers.
• Molecular genetic testing – combined, if needed, with linkage analysis – can determine the point of origin of a de novo pathogenic variant in up to half of the families with newly diagnosed, affected members [Sommer et al 2001]. Determining the point of origin of a de novo variant is important for determining which branches of the family are at risk for hemophilia B.

Sibs of a male proband

• The risk to the sibs depends on the mother's genetic status: if the proband's mother is a carrier, each male sib has a 50% chance of having hemophilia B and each female sib is at a 50% risk of being a carrier.
• Germline mosaicism, while rare, has been reported. Thus, if an affected male represents a simplex case and if his mother has normal factor IX clotting activity and no evidence of her son's F9 pathogenic variant in DNA from her leukocytes, she is still at an increased (but low) risk of having additional affected children.
• All sibs should have factor IX clotting activity assayed unless molecular genetic testing confirms that they have not inherited the F9 pathogenic variant present in the family.

Offspring of a male proband

• All daughters will be carriers of the F9 pathogenic variant causing hemophilia B of the same severity as their father's hemophilia.
• No sons will inherit the F9 pathogenic variant, have hemophilia B, or pass it on to their offspring.

Other family members. The proband's maternal aunts and their offspring may be at risk of being carriers or being affected (depending on their gender, family relationship, and the carrier status of the proband's mother).

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Factor IX clotting activity is not a reliable test for determining carrier status: it can only be suggestive if low.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

See Ludlam et al [2005] (full text), published guidelines for a UK framework for genetic services, and Thomas et al [2007], findings of a qualitative study in Australia on how cultural and religious issues influence parental attitudes about genetic testing.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the F9 pathogenic variant has been identified in an affected family member or linkage established in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis [Laurie et al 2010] are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Published Guidelines/Consensus Statements

Guidelines regarding genetic testing for this disorder have been published for the UK:

• Ludlam CA, Pasi KJ, Bolton-Maggs P, Collins PW, Cumming AM, Dolan G, Fryer A, Harrington C, Hill FG, Peake IR, Perry DJ, Skirton H, Smith M; UK Haemophilia Centre Doctors' Organisation. A framework for genetic service provision for haemophilia and other inherited bleeding disorders. Available online. 2005. Accessed 7-3-18. [PubMed: 15810917]
• Mitchell M, Keeney S, Goodeve A. Practical guidelines for the molecular diagnosis of haemophilia B. UK Haemophilia Centre Doctors’ Organisation, the Haemophilia Genetics Laboratory Network and the Clinical Molecular Genetics Society. Available online. 2010. Accessed 7-3-18.

Literature Cited

• Angelini D, Konkle BA, Sood SL. Aging among persons with hemophilia: contemporary concerns. Semin Hematol. 2016;53:35–9. [PubMed: 26805905]
• Bajaj SP, Thompson AR. Molecular and structural biology of factor IX. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5 ed. Philadelphia, PA: Lippincott-Raven; 2006:131-50.
• Chalmers E, Williams M, Brennand J, Liesner R, Collins P, Richards M., Paediatric Working Party of the United Kingdom Haemophilia Doctors’ Organization. Guideline on the management of haemophilia in the fetus and neonate. Br J Haematol. 2011;154:208–15. [PubMed: 21554256]
• Chitlur M, Warrier I, Rajpurkar M, Lusher JM. Inhibitors in factor IX deficiency a report of O the ISTH-SSC international FIX inhibitor registry (1997-2006). Haemophilia. 2009;15:1027–31. [PubMed: 19515028]
• Darby SC, Kan SW, Spooner RJ, Giangrande PL, Hill FG, Hay CR, Lee CA, Ludlam CA, Williams M. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood. 2007;110:815–25. [PubMed: 17446349]
• DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol. 2007;138:305–15. [PubMed: 17614818]
• Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost. 2013;39:621–31. [PubMed: 23929304]
• Fischer K, Astermark J, van der Bom JG, Ljung R, Berntorp E, Grobbee DE, van den Berg HM. Prophylactic treatment for severe haemophilia: comparison of an intermediate-dose to a high-dose regimen. Haemophilia. 2002;8:753–60. [PubMed: 12410643]
• Funnell APW, Crossley M. Hemophilia B Leyden and once mysterious cis-regulatory mutations. Trends Genet. 2014;30:18–23. [PubMed: 24138812]
• Goodeve AC. Hemophilia B: molecular pathogenesis and mutation analysis. J Thromb Haemost. 2015;13:1184–95. [PMC free article: PMC4496316] [PubMed: 25851415]
• Hay CR, Brown S, Collins PW, Keeling DM, Liesner R. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation. Br J Haematol. 2006;133:591–605. [PubMed: 16704433]
• James AH, Hoots K. The optimal mode of delivery for the haemophilia carrier expecting an affected infant is caesarean delivery. Haemophilia. 2010;16:420–4. [PubMed: 20028425]
• Josephson N. The hemophilias and their clinical management. Hematology Am Soc Hematol Educ Program. 2013;2013:261–7. [PubMed: 24319189]
• Kanagasabai V, Schmidt AE, Marder VJ, Krishnaswamy S, Bajaj SP. Structure and function of vitamin K-dependent coagulant and anticoagulant proteins. In: Marder VJ, Aird WC, Bennett JS, Schulman S, White GC II, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 6 ed. Philadelphia, PA: Lippincott-Williams & Wilkins; 2013:208-32.
• Ketterling RP, Vielhaber E, Li X, Drost J, Schaid DJ, Kasper CK, Phillips JA 3rd, Koerper MA, Kim H, Sexauer C, Gruppo R, Ambriz R, Paredes R, Sommer SS. Germline origins in the human F9 gene: frequent G:C-->A:T mosaicism and increased mutations with advanced maternal age. Hum Genet. 1999;105:629–40. [PubMed: 10647899]
• Khachidze M, Buil A, Viel KR, Porter S, Warren D, Machiah DK, Soria JM, Souto JC, Ameri A, Lathrop M, Blangero J, Fontcuberta J, Warren ST, Almasy L, Howard TE. Genetic determinants of normal variation in coagulation factor (F) IX levels: genome-wide scan and examination of the FIX structural gene. J Thromb Haemost. 2006;4:1537–45. [PubMed: 16839351]
• Kristensen LH, Olsen OH, Blouse GE, Brandstetter H. Releasing the brakes in coagulation Factor IXa by co-operative maturation of the substrate-binding site. Biochem J. 2016;473:2395–2411. [PubMed: 27208168]
• Kulkarni R, Soucie JM, Lusher J, Presley R, Shapiro A, Gill J, Manco-Johnson M, Koerper M, Mathew P, Abshire T, Dimichele D, Hoots K, Janco R, Nugent D, Geraghty S, Evatt B., Haemophilia Treatment Center Network Investigators. Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from the Centers for Disease Control and Prevention's (CDC) Universal Data Collection (UDC) project. Haemophilia. 2009;15:1281–90. [PubMed: 19637999]
• Laurie AD, Hill AM, Harraway JR, Fellowes AP, Phillipson GT, Benny PS, Smith MP, George PM. Preimplantation genetic diagnosis for hemophilia A using indirect linkage analysis and direct genotyping approaches. J Thromb Haemost. 2010;8:783–9. [PubMed: 20102489]
• Lheriteau E, Davidoff AM, Nathwani AC. Haemophilia gene therapy: progress and challenges. Blood Rev. 2015;29:321–8. [PubMed: 26049173]
• Ljung R. The optimal mode of delivery for the haemophilia carrier expecting an affected infant is vaginal delivery. Haemophilia. 2010;16:415–9. [PubMed: 19925629]
• Luck JV Jr, Silva M, Rodriguez-Merchan EC, Ghalambor N, Zahiri CA, Finn RS. Hemophilic arthropathy. J Am Acad Orthop Surg. 2004;12:234–45. [PubMed: 15473675]
• Ludlam CA, Pasi KJ, Bolton-Maggs P, Collins PW, Cumming AM, Dolan G, Fryer A, Harrington C, Hill FG, Peake IR, Perry DJ, Skirton H, Smith M. A framework for genetic service provision for haemophilia and other inherited bleeding disorders. Haemophilia. 2005;11:145–63. [PubMed: 15810917]
• Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, Mathew P, Matsunaga A, Medeiros D, Nugent D, Thomas GA, Thompson AA, McRedmond K, Soucie JM, Austin H, Evatt BL. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357:535–44. [PubMed: 17687129]
• Manco-Johnson MJ, Kempton CL, Reding MT, Lissitchkov T, Goranov S, Gercheva L, Rusen L, Ghinea M, Uscatescu V, Rescia V, Hong W. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost. 2013;11:1119–27. [PubMed: 23528101]
• Mitchell M, Keeney S, Goodeve A. Practical guidelines for the molecular diagnosis of haemophilia B. UK Haemophilia Centre Doctors’ Organisation, the Haemophilia Genetics Laboratory Network and the Clinical Molecular Genetics Society. Available online. 2010. Accessed 3-1-18.
• Monahan PE, Di Paola J. Recombinant factor IX for clinical and research use. Semin Thromb Hemost. 2010;36:498–509. [PubMed: 20632248]
• Oldenburg J, Kriz K, Wuillemin WA, Maly FE, von Welten A, Siegemun A, Keeling DM, Baker P, Chu K, Konkle BA, Lammie B, Albert T, et al. Genetic predisposition to bleeding during oral anticoagulant therapy: evidence for common founder mutations (FIXVal-10 and FIXThr-10) and an independent CpG hotspot mutation. Thromb Haemost. 2001;85:454–7. [PubMed: 11307814]
• Pai M, Key NS, Skinner M, Curtis R, Feinstein M, Kessler C, Lane SJ, Makris M, Riker E, Santesso N, Soucie JM, Yeung CHT, Iorio A, Schunemann HJ. NHF-McMaster guideline on care models for haemophilia management. Haemophilia. 2016;22:6–16. [PubMed: 27348396]
• Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet. 2016;388:187–97. [PubMed: 26897598]
• Plug I, Mauser-Bunschoten EP, Brocker-Vriends AH, van Amstel HK, van der Bom JG, van Diemen-Homan JE, Willemse J, Rosendaal FR. Bleeding in carriers of hemophilia. Blood. 2006;108:52–6. [PubMed: 16551972]
• Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, Josephson NC, Perry D, Manco-Johnson MJ, Apte S, Baker RI, Chan GC, Novitzky N, Wong RS, Krassova S, Allen G, Jiang H, Innes A, Li S, Cristiano LM, Goyal J, Sommer JM, Dumont JA, Nugent K, Vigliani G, Brennan A, Luk A, Pierce GF. B-LONG Investigators. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med. 2013;369:2313–23. [PubMed: 24304002]
• Puetz J, Soucie JM, Kempton CL, Monahan PE., Hemophilia Treatment Center Network (HTCN) Investigators. Prevalent inhibitors in haemophilia B subjects enrolled in the Universal Data Collection database. Haemophilia. 2014;20:25–31. [PMC free article: PMC4520536] [PubMed: 23855900]
• Rallapalli PM, Kemball-Cook G, Tuddenham EG, Gomez K, Perkins SJ. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. J Thromb Haemost. 2013;11:1329–40. [PubMed: 23617593]
• Saini S, Hamasaki-Katagiri N, Pandey GS, Yanover C, Guelcher C, Simhadri VL, Dandekar S, Guerrera MF, Kimchi-Sarfaty C, Sauna ZE. Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia B. Haemophilia. 2015;21:210–8. [PubMed: 25470321]
• Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, Boggio L, Negrier C, Pabinger I, von Depka Prondzinski M, Altisent C, Castaman G, Yamamoto K, Alvarez-Roman MT, Voigt C, Blackman N, Jacobs I., PROLONG-9FP Investigators Study Group. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016;127:1761–9. [PMC free article: PMC4825413] [PubMed: 26755710]
• Sidonio RF, Mili FD, Li T, Miller CH, Hooper WC, DeBaun MR, Soucie M., Hemophilia Treatment Center Network. Females with FVIII and FIX deficiency have reduced joint range of motion. Am J Hematol. 2014;89:831–6. [PMC free article: PMC4477796] [PubMed: 24838518]
• Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med. 2009;361:1671. [PubMed: 19846852]
• Sommer SS, Scaringe WA, Hill KA. Human germline mutation in the factor IX gene. Mutat Res. 2001;487:1–17. [PubMed: 11595404]
• Soucie JM, Nuss R, Evatt B, Abdelhak A, Cowan L, Hill H, Kolakoski M, Wilber N. Mortality among males with hemophilia: relations with source of medical care. The Hemophilia Surveillance System Project Investigators. Blood. 2000;96:437–42. [PubMed: 10887103]
• Tagliaferri A, Rivolta GF, Iorio A, Oliovecchio E, Mancuso ME, Morfini M, Rocino A, Mazzucconi MG, Franchini M, Ciavarella N, Scaraggi A, Valdrè L, Tagariello G, Radossi P, Muleo G, Iannaccaro PG, Biasoli C, Vincenzi D, Serino ML, Linari S, Molinari C, Boeri E, La Pecorella M, Carloni MT, Santagostino E, Di Minno G, Coppola A, Rocino A, Zanon E, Spiezia L, Di Perna C, Marchesini M, Marcucci M, Dragani A, Macchi S, Albertini P, D'Incà M, Santoro C, Biondo F, Piseddu G, Rossetti G, Barillari G, Gandini G, Giuffrida AC, Castaman G, et al. Mortality and causes of death in Italian persons with haemophilia, 1990-2007. Haemophilia. 2010;16:437–46. [PubMed: 20148978]
• Thomas S, Herbert D, Street A, Barnes C, Boal J, Komesaroff P. Attitudes towards and beliefs about genetic testing in the haemophilia community: a qualitative study. Haemophilia. 2007;13:633–41. [PubMed: 17880455]
• Yang MY, Ragni MV. Clinical manifestations and management of labor and delivery in women with factor IX deficiency. Haemophilia. 2004;10:483–90. [PubMed: 15357775]

Suggested Reading

• Rogaev EI, Grigorenko AP, Faskhutdinova G, Kittler EL, Moliaka YK. Genotype analysis identifies the cause of the "royal disease". Science. 2009;326:817. [PubMed: 19815722]
• Winikoff R, Lee C. Hemophilia carrier status and counseling the symptomatic and asymptomatic adolescent. J Pediatr Adolesc Gynecol. 2010;23:S43–7. [PubMed: 21108512]

Author History

Cheryl L Brower, RN, MSPH; Puget Sound Blood Center (2008-2011)
Frank K Fujimura, PhD, FACMG; GMP Genetics, Inc (2000-2003)
Haley Huston, BS (2017-present)
Maribel J Johnson, RN, MA; Puget Sound Blood Center (2000-2008)
Neil C Josephson, MD; Seattle Genetics (2011-2017)
Barbara A Konkle, MD (2011-present)
Shelley Nakaya Fletcher, BS (2011-present)
Arthur R Thompson, MD, PhD; University of Washington (2000-2014)

Revision History

• 15 June 2017 (sw) Comprehensive update posted live
• 5 June 2014 (me) Comprehensive update posted live
• 22 September 2011 (me) Comprehensive update posted live
• 8 April 2008 (me) Comprehensive update posted to live Web site
• 17 August 2005 (me) Comprehensive update posted to live Web site
• 11 May 2004 (cd) Revision: molecular genetic testing table
• 8 May 2003 (me) Comprehensive update posted to live Web site
• 2 October 2000 (me) Review posted to live Web site
• August 2000 (at) Original submission