Hemophilia A

[Classic Hemophilia, Factor VIII Deficiency]

Clinical Diagnosis

A specific diagnosis of hemophilia A cannot be made on clinical findings. A coagulation disorder is suspected in individuals with any of the following:

• 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 bleeding or renewed bleeding following surgery or trauma *

• Unexplained GI bleeding or hematuria *

• Menorrhagia, especially at menarche *

• Prolonged nosebleeds, especially recurrent and bilateral *

• Excessive bruising, especially with firm, subcutaneous hematomas

* Any severity, otherwise, especially in more severely affected persons

Testing

Coagulation screening tests.   Evaluation of an individual with a suspected bleeding disorder includes: platelet count and platelet function analysis (PFA closure times) or bleeding time, activated partial thromboplastin time (APTT), and prothrombin time (PT). Thrombin time and/or plasma concentration of fibrinogen can be useful for rare disorders.

In individuals with hemophilia A, the above screening tests are normal, with the following exceptions:

• In severe and moderately severe hemophilia A, the APTT is prolonged.

• In mild hemophilia A, the APTT may be normal.

Note: In many clinical laboratories, the APTT is not sensitive enough to diagnose mild hemophilia A.

Coagulation factor assays.  Individuals with a history of a lifelong bleeding tendency should have specific coagulation factor assays performed even if all the coagulation screening tests are in the normal range:

• The normal range for factor VIII clotting activity is 50%-150%.

• Individuals with factor VIII clotting activity higher than 30% usually do not have bleeding [Kaufman et al 2006]. However, a mild bleeding tendency can occur with low to low-normal factor VIII clotting activity in hemophila A carrier females [Plug et al 2006] or in those with mild von Willebrand disease.

• In hemophilia A, the factor VIII clotting activity is usually lower than 30%-35% with a normal, functional von Willebrand factor level.

• Classification of hemophilia A based on in vitro clotting activity:

  • Severe hemophilia A: <1% factor VIII

  • Moderately severe hemophilia A: 1%-5% factor VIII

  • Mild hemophilia A: 6%-35% factor VIII

Note: Rarely, in individuals with mild hemophilia A, a standard "one-stage" factor VIII clotting activity assay shows near-normal or low-normal factor VIII clotting activity (40%-80%), whereas in a "two-stage" or chromogenic assay, factor VIII activity is low. Thus, low-normal in vitro clotting activity does not always exclude the presence of mild hemophilia A.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene.   F8 is the only gene known to be associated with hemophilia A.

Clinical testing

• Targeted mutation analysis

  • An F8 intron 22-A gene inversion accounts for nearly half of families with severe hemophilia A [Kaufman et al 2006]. This inversion can be detected by Southern blotting or, more recently, by long-range [Bowen & Keeney 2003] or inverse [Rossetti et al 2005] PCR.

  • An F8 intron 1 gene inversion accounts for 2%-3% of severe hemophilia A. This inversion is typically detected by PCR [Bagnall et al 2002].

• Mutation scanning or sequence analysis

  • The mutation detection rate in individuals with hemophilia A who do not have one of the two common inversions varies from 75% to 98%, depending on the screening method used.

  • In severe hemophilia A, gross gene alterations (including large deletions or insertions, frameshift and splice junction changes, and nonsense and missense mutations) of F8 account for approximately 50% of mutations detected [Kemball-Cook et al 1998, El-Maarri et al 2005, Kaufman et al 2006].

  • In mild to moderately severe hemophilia A, missense mutations within the exons coding for the three A domains or the two C domains account for most of the mutations detected [Kemball-Cook et al 1998, Kaufman et al 2006].

• Deletion analysis is available clinically to detect exonic, multi-exonic, or larger deletions in affected males. Deletion analysis is also available for direct diagnosis in potential carrier females.

Guidelines for laboratory practice for molecular analysis of F8 have been established in the UK [Keeney et al 2005].

Note: Mutation scanning and sequence analysis cannot detect gene deletions and rearrangements in females, except by quantitative methods available in limited research settings.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Hemophilia A

Test Method	Mutations Detected	Mutation Detection Frequency by Test Method		Test Availability
		Probands with Severe Hemophilia A	Probands with Mild to Moderately Severe Hemophilia A
Targeted mutation analysis	F8 intron 22-A gene inversion	48%	0%	Clinical
	F8 intron 1 gene inversion  1	3%	0%
Mutation scanning  2 or sequence analysis	F8 sequence variants	43%	98%
Deletion analysis	F8 exonic and large gene deletions  1	6%	<1%

1.  Intron 22 inversions can be accompanied by adjacent partial gene deletions or duplication/insertions [Andrikovics et al 2003].
2. A microarray approach identified 96% of known point mutations in a selected portion of the factor VIII coding sequence [Berber et al 2006]. However, because of the large number of distinct hemophilic mutations, it remains unclear whether such an approach would be economically feasible at present.

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Linkage analysis is used to track an unidentified F8 disease-causing allele in a family and to identify the origin of de novo mutations:

• Tracking an unidentified F8 mutation.   When a disease-causing mutation of the F8 gene is not identified in an affected family member by direct DNA testing, linkage analysis can be considered to obtain information for genetic counseling in families in which more than one family member has the unequivocal diagnosis of hemophilia A. Linkage studies are always based on accurate clinical diagnosis of hemophilia A in the affected family members and accurate understanding of the genetic relationships in the family. In addition, linkage analysis depends on the availability and willingness of family members to be tested and on the presence of informative heterozygous polymorphic markers. Use of up to five intragenic polymorphisms and one extragenic polymorphism is informative in approximately 80%-90% of families. Recombination events between F8 and the extragenic site occur in up to 5% of meioses, but have not been observed between hemophilic mutations and intragenic sites.

• Identifying the origin of a de novo mutation.  Among the nearly 50% of families with a simplex case of hemophilia A (i.e., occurrence in one family member only), the origin of a de novo mutation can often be identified by performing molecular genetic testing in conjunction with linkage analysis. The presence of the mutation on the affected individual's factor VIII haplotype is tracked back through the parents and, if necessary, through maternal grandparents to identify the individual in whom the mutation originated.

Testing Strategy

Establishing the diagnosis of hemophilia A in a proband requires measurement of factor VIII clotting activity.

Molecular genetic testing is performed on a proband to detect the family-specific mutation in F8 in order to obtain information for genetic counseling of at-risk family members.

For prognostication in individuals who represent a simplex case (i.e., who are the only affected member in a family), identification of the specific F8 mutation can help predict the clinical phenotype and assess the risk of developing a factor VIII inhibitor.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for an X-linked disorder and may develop clinical findings related to the disorder.

Prenatal diagnosis and preimplantation diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in F8.

Natural History

Hemophilia A in the untreated individual is characterized by delayed bleeding or prolonged oozing after injuries, tooth extractions, or surgery, or renewed bleeding after initial bleeding has stopped [Kessler & Mariani 2006]. Muscle hematomas or intracranial bleeding can occur four or 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 A of any severity may have prolonged oozing; but they can also heal normally without treatment. In severe hemophilia A, spontaneous joint bleeding is the most frequent symptom.

The age of diagnosis and frequency of bleeding episodes in the untreated individual are related to the factor VIII 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 A are usually diagnosed during the first year of life. On rare occasions, infants with severe hemophilia A have extra- or intracranial bleeding following birth. In untreated toddlers, bleeding from minor mouth injuries and large "goose eggs" from minor head bumps are common and are the most frequent presenting symptoms of severe hemophilia A. 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 adults with severe hemophilia A 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, but other sites include the kidneys, gastrointestinal tract, and brain. Without prophylactic treatment, individuals with hemophilia A have prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions.

Individuals with moderately severe hemophilia A seldom have spontaneous bleeding. However, without treatment they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years. Without treatment, the frequency of bleeding episodes varies from once a month to once a year. Signs and symptoms of bleeding are the same as for severe hemophilia A.

Individuals with mild hemophilia A 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 A are often not diagnosed until later in life when they undergo surgery or tooth extraction or experience major trauma.

Carrier females with a factor VIII clotting activity level lower than 35% 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 a baseline factor VIII clotting activity between 35% 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 with hemophilia A. Prior to the availability of such treatment, the median life expectancy for individuals with severe hemophilia A 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 is 63 years [Darby et al 2007].

Other.  Since the mid-1960s, the mainstay of treatment of bleeding episodes has been the use of plasma-derived factor VIII concentrate. Many individuals who received blood products from 1979 to 1985 contracted HIV. Approximately half of these individuals died of AIDS prior to the advent of effective HIV therapy.

Most individuals exposed to plasma-derived concentrates prior to the late 1980s became chronic carriers of the hepatitis C virus. Viral inactivation and detection methods developed in the 1980s have essentially eliminated this complication.

Approximately 30% of individuals with severe hemophilia A develop alloimmune inhibitors to factor VIII (see Management, Treatment of Manifestations).

Genotype-Phenotype Correlations

F8 gene inversions are associated with severe hemophilia A and account for 45% of the severe cases [Kaufman et al 2006]. Occasionally, individuals considered to have moderately severe hemophilia A have been found to have F8 gene inversions. Often their assays are found to have contained either some residual factor VIII clotting activity from a prior transfusion or the assay methods used were inaccurate at low levels.

An inversion between a 1-kb sequence in intron 1 and an inverted repeat 5' to the factor VIII gene [Bagnall et al 2002] is also associated with a severe phenotype, and some individuals have developed inhibitors.

Point mutations leading to new stop codons are essentially all associated with a severe phenotype, as are most frameshift mutations. (An exception is the insertion or deletion of adenosine bases resulting in a sequence of eight to ten adenosines, which may result in moderately severe hemophilia A [Nakaya et al 2001].)

Splice site mutations are often severe but may be mild, depending on the specific change and location.

Missense mutations occur in fewer than 20% of individuals with severe hemophilia A but nearly all of those with mild or moderately severe bleeding tendencies (see Locus-Specific Database) [Kaufman et al 2006].

Penetrance

All males with a F8 disease-causing mutation will be affected and will have approximately the same severity of disease as other affected males in the family. However, other genetic and environmental effects may modify the clinical severity somewhat.

Approximately 10% of females with one F8 disease-causing mutation and one normal allele have a mild bleeding disorder.

Anticipation

Anticipation is not observed.

Prevalence

The birth prevalence of hemophilia A is approximately 1:4,000 to 1:5,000 live male births worldwide.

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

Prevalence is approximately 1:10,000 in the US and other countries in which optimum treatment with clotting factor concentrates is available [Kessler & Mariani 2006].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with hemophilia A, the following evaluations are recommended:

• Identification of the specific disease-causing mutation in an individual to aid in determining: disease severity, the likelihood of inhibitor development, and the chance that immune tolerance will be successful if an inhibitor does develop

• A personal and family history of bleeding to help predict 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, particularly if blood products or plasma-derived clotting factor concentrates were administered prior to 1985

• Baseline CBC and platelet count, especially if there is a history of nose bleeds, GI bleeding, mouth bleeding, or, in women, menorrhagia

Treatment of Manifestations

Life expectancy for individuals with hemophilia A has greatly increased over the past four decades [Darby et al 2007]; disability has decreased with the intravenous infusion of factor VIII concentrate, home infusion programs, prophylactic treatment, and improved patient education.

Individuals with hemophilia A benefit from referral for assessment, education, and genetic counseling at one of the approximately 140 federally funded hemophilia treatment centers (HTCs) that can be located through the National Hemophilia Foundation. The treatment centers establish appropriate treatment plans and provide referrals or direct care for individuals with inherited bleeding disorders. They also are a resource for current information on new treatment modalities for hemophilia. An assessment at one of these centers usually includes extensive patient education, genetic counseling, and laboratory testing.

Intravenous infusion of factor VIII concentrate.  Recombinant factor VIII concentrates (including one that has no human- or animal-derived proteins) have been available for more than 15 years. Virucidal treatment of plasma-derived concentrates has eliminated the risk of HIV transmission since 1985, and of hepatitis B and C viruses since 1990.

Bleeding episodes are prevented or controlled quickly with intravenous infusions of either plasma-derived or recombinant factor VIII concentrate. Fast, effective treatment of bleeding episodes decreases pain, disability, and chronic joint disease. Ideally, the affected individual should receive clotting factor within an hour of noticing symptoms [Kessler & Mariani 2006]. Doses vary among individuals, but knowledge of a single in vivo recovery value is not particularly helpful in determining the appropriate dose [Bjorkman et al 2007]:

• Arranging efficient, effective treatment for infants and toddlers is especially challenging. Because frequent venipunctures may be necessary, it is important to identify staff members who are expert in performing venipunctures in small children.

• It is recommended that the parents of children age two to five years with severe hemophilia A be trained to administer the infusions as soon as it is feasible. Home treatment allows for prompt treatment after symptoms occur.

DDAVP (1-deamino-8-D-arginine vasopressin). For many individuals with mild hemophilia A, including most symptomatic carriers, immediate treatment of bleeding or prophylaxis can be achieved with desmopressin (DDAVP). A single intravenous dose often doubles or triples factor VIII clotting activity. Alternatively, a multi-use, nasal formulation of desmopressin (Stimate^®) is available.

Obstetrical issues [Lee et al 2006]. It is recommended that the carrier status of a woman at risk be established prior to pregnancy or as early in a pregnancy as possible.

At birth, or in the early neonatal period, intracranial hemorrhage in affected males is uncommon (1%-2%) even in those with severe hemophilia A who are delivered vaginally. Cesarean section is reserved for complicated deliveries.

If the mother is a symptomatic carrier (i.e., has baseline factor VIII clotting activity <35%), she will be somewhat protected by the natural rise of factor VIII clotting activity during pregnancy, which may even double by the end of the third trimester. However, postpartum factor VIII clotting activity can return to baseline within 48 hours, and delayed bleeding ensue.

Pediatric issues [Chalmers et al 2005]. Special considerations for care of infants and children with hemophilia A include the following:

• Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, is treated with factor VIII concentrate just prior to and subsequent to the procedure to prevent delayed oozing and poor wound healing.

• Intramuscular injections should be avoided; immunizations should be administered subcutaneously.

• Effective dosing of factor VIII requires an understanding of different pharmacokinetics in young children.

Inhibitors.  Inhibitors greatly compromise the ability to manage bleeding episodes [Hay et al 2006, Kessler & Mariani 2006]. The inhibitor can be eliminated by immune tolerance therapy in up to 70%-80% of cases. Individuals with large gene deletions are less likely to respond to immune tolerance than individuals with other types of mutations [Peyvandi et al 2006].

Prevention of Primary Manifestations

Children with severe hemophilia A are often given "primary" prophylactic infusions of factor VIII concentrate three times a week or every other day to maintain factor VIII clotting activity higher than 1%; these infusions prevent spontaneous bleeding and decrease the number of bleeding episodes. Prophylactic infusions almost completely eliminate joint bleeding and greatly decrease chronic joint disease.

Prevention of Secondary Complications

Prevention of chronic joint disease is a major concern. It is agreed that most individuals with severe hemophilia A benefit from primary prophylaxis but there is still controversy about when these regular infusions should begin. The age at which a child experiences the first joint bleed can vary greatly. Prophylactic infusions almost completely eliminate spontaneous joint bleeding, decreasing chronic joint disease, although complications of venous access ports in young children can occur [Feldman et al 2006, Manco-Johnson et al 2007].

"Secondary" prophylaxis is often used for several weeks if recurrent bleeding in a "target" joint or synovitis occurs.

Surveillance

Persons with hemophilia who are followed at hemophilia treatment centers (HTCs) (see Resources) have lower mortality than those who are not [Soucie et al 2000]. It is recommended that young children with severe or moderately severe hemophilia A have assessments at an HTC (accompanied by their parents) every six to 12 months to review their history of bleeding episodes and to 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 individuals with severe hemophilia A every three to six months after treatment with factor VIII concentrates has been initiated either for bleeding or prophylaxis; after 50 to 100 exposure days, annual screening is sufficient; in adults, it is usually performed only prior to any elective surgery. Testing for inhibitors should also be performed in any hemophilic individual whenever a sub-optimal clinical response to treatment is suspected, regardless of severity.

Older children and adults with severe or moderately severe hemophilia A benefit from regular contact with an HTC 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 A can benefit from maintaining a relationship with an HTC and having regular assessments every two to three years.

Agents/Circumstances to Avoid

Avoid the following:

• Activities that involve a high risk of trauma, particularly head injury

• Aspirin and all aspirin-containing products

Cautious use of other medications and herbal remedies that effect platelet function is indicated.

Testing 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 A).

Early determination of the genetic status of males at risk.  Either assay of factor VIII 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 F8 mutation identified in the family can establish or exclude the diagnosis of hemophilia A in newborn males at risk. Infants with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, factor VIII concentrate is administered just prior and subsequent to the procedure, to prevent delayed oozing and poor wound healing.

Note: The cord blood for factor VIII 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.

Determination of genetic status of females at risk.  Approximately 10% of carriers have factor VIII activity lower than 30%-35% and may have abnormal bleeding themselves. In a recent Dutch survey of hemophilia carriers, 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 VIII activity [Plug et al 2006]. Therefore, all daughters and mothers of an affected male and other at-risk females should have a baseline factor VIII 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.

It is recommended that the carrier status of a woman 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.

Therapies Under Investigation

A longer-acting factor VIII concentrate has recently been approved by the FDA for clinical trials. The hope is that one infusion a week rather than three to four infusions a week will provide prophylaxis against spontaneous bleeding [Spira et al 2006].

Attempts are being made to learn more about the immunology of inhibitors and ways to prevent them or improve the success rate of immune tolerance [Lollar 2006].

All clinical trials for gene therapy in hemophilia A have been discontinued because of complications and failure to achieve significant factor VIII expression in humans with hemophilia A. Although the hemophilia community remains hopeful, several obstacles must be overcome before new trials begin [Pierce et al 2007].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Vitamin K does not prevent or control bleeding in hemophilia A.

Cryoprecipitate is no longer used to treat hemophilia A because it is not treated with a virucidal agent.

Mode of Inheritance

Hemophilia A 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 a carrier of the mutation.

• Women who have an affected son and one other affected relative in the maternal line are obligate carriers.

• If a woman has more than one affected son and the disease-causing mutation cannot be detected in her DNA, she has germline mosaicism.

• One-third to one-half of affected males have no family history of hemophilia A. If an affected male represents a simplex case (an affected male with no known family history of hemophilia), 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 affected male has a de novo disease-causing mutation. Somatic mosaicism may occur in as many as 15% of probands with a point mutation and no known family history of hemophilia A [Leuer et al 2001]; germline mosaicism is rare.

  • The mother is a carrier of a de novo, disease-causing mutation that occurred:

    • As a germline mutation (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 DNA);

    • As a somatic mutation (i.e., a change that occurred very early in embryogenesis, resulting in somatic mosaicism in which the mutation is present in some but not all cells and may or may not be detectable in DNA); or

    • As germline mosaicism (in which some germ cells have the mutation and some do not, and in which the mutation is not detectable in DNA from her leukocytes).

  • The mother is a carrier and has inherited the disease-causing mutation either from her mother who has a de novo disease-causing mutation or from her asymptomatic father who is mosaic for the mutation.

  • The mother is a carrier of a mutation arising in a previous generation, which has been passed on through the family without manifesting symptoms in female carriers.

    Overall, the mother has an approximately 80% chance of being a carrier when her son is the first affected individual in the family; however, the mother of a severely affected male with an intron 22 inversion has a 98% chance of being a carrier.

• Molecular genetic testing combined with linkage analysis can often determine the point of origin of a de novo mutation. Determining the point of origin of a de novo mutation is important for determining which branches of the family are at risk for hemophilia A.

Sibs of a male proband

• The risk to the sibs depends on the mother's carrier status. If the proband's mother is a carrier, each male sib is at a 50% risk of having hemophilia A and each female sib is at a 50% risk of being a carrier.

• Germline mosaicism is possible, albeit uncommon. Thus, if an affected male represents a simplex case and if his mother has a normal factor VIII clotting activity and no evidence of her son's F8 disease-causing mutation in DNA from her leukocytes, she is still at a theoretically increased, but low, risk of having additional affected children.

• All sibs should have factor VIII clotting activity assayed unless mutation analysis confirms that they have not inherited the F8 mutation in their family.

Offspring of a male proband

• All daughters will be carriers for hemophilia A of the same severity as their father's hemophilia.

• No sons will inherit the mutant allele, have hemophilia A, or pass it on to their offspring.

Other family members of the proband.   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).

Carrier Detection

Carrier testing by molecular genetic testing is clinically available for most at-risk females if the mutation has been identified in the family.

• Large deletions are not detectable by sequence analysis in females.

• When carrier testing is performed without the previous identification of the F8 mutation in the family, a negative result in an at-risk relative is not informative.

• Factor VIII clotting activity, or its ratio to von Willebrand factor level, is not a reliable test for determining carrier status. It can only be suggestive, if low.

Related Genetic Counseling Issues

See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

See Ludlam et al 2005 for published guidelines for a UK framework for genetic services and Thomas et al 2007 for findings of a qualitative study in Australia on how cultural and religious issues influenced 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.

DNA banking.  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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing.  Prenatal testing is available for pregnancies of women who are carriers if the mutation has been identified in a family member or if linkage has been established in the family. The usual procedure is to determine fetal sex by performing chromosome analysis of fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15-18 weeks' gestation. If the karyotype is 46,XY, DNA extracted from fetal cells can be analyzed for the known F8 disease-causing mutation or for the informative markers.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Percutaneous umbilical blood sampling (PUBS).  If the disease-causing F8 mutation is not known and if linkage is not informative, prenatal diagnosis is possible using a fetal blood sample obtained by PUBS at approximately 18-21 weeks' gestation for assay of factor VIII clotting activity.

Requests for prenatal testing for conditions such as hemophilia A that do not affect intellect and have treatment available are not common. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Author History

Cheryl L Brower, RN, MSPH (2008-present)
Frank K Fujimura, PhD, FACMG; GMP Genetics, Inc, Waltham (2000-2003)
Maribel J Johnson, RN, MA; Puget Sound Blood Center, Seattle (2000-2008)
Arthur R Thompson, MD, PhD (2000-present)

Revision History

• 25 March 2008 (me) Comprehensive update posted to live Web site

• 17 August 2005 (me) Comprehensive update posted to live Web site

• 8 May 2003 (me) Comprehensive update posted to live Web site

• 21 September 2000 (me) Review posted to live Web site

• April 2000 (art) Original submission