Hemophilia A is characterized by deficiency in factor VIII 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 VIII clotting activity.
- In severe hemophilia A, spontaneous joint or deep-muscle bleeding is the most frequent symptom. Individuals with severe hemophilia A 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 A 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, usually from once a month to once a year.
- Individuals with mild hemophilia A do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions; the frequency of bleeding episodes varies widely, typically from once a year to once every ten years. Individuals with mild hemophilia A are often not diagnosed until later in life.
In any individual with hemophilia A, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. Approximately 10% of carrier females are at risk for bleeding (even if the affected family member is mildly affected) and are thus symptomatic carriers, although symptoms are usually mild. After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity.
The diagnosis of hemophilia A is established in individuals with low factor VIII clotting activity in the presence of a normal von Willebrand factor (VWF) level. Molecular genetic testing of F8, the gene encoding factor VIII, identifies pathogenic variants in as many as 98% of individuals with hemophilia A.
Treatment of manifestations: Referral to one of the approximately 140 federally funded hemophilia treatment centers (HTCs) in the USA or worldwide for assessment, education, and genetic counseling and to facilitate management. Training and home infusions administered by parents followed by patient self-infusion are critical components of comprehensive care; especially for those with severe disease, intravenous infusion of factor VIII concentrate is most effective when infused within one hour of the onset of bleeding. For those with mild disease, including most symptomatic carriers, immediate treatment of bleeding or prophylaxis with intravenous or nasal desmopressin (DDAVP [1-deamino-8-D-arginine vasopressin]) or factor VIII concentrate.
Prevention of primary manifestations: For those with severe disease, prophylactic infusions of factor VIII concentrate three times a week or every other day to maintain factor VIII clotting activity higher than 1% nearly eliminates spontaneous bleeding and prevents chronic joint disease.
Prevention of secondary complications: Reduction of bleeding and chronic joint disease is achieved by prophylactic treatment and prompt effective treatment of bleeding, including home therapy.
Surveillance: For individuals with severe or moderate hemophilia A, assessments every six to 12 months at an HTC are recommended; for individuals with mild hemophilia A, at least every two to three years.
Agents/circumstances to avoid: Circumcision of at-risk males until hemophilia A is either excluded or treated with factor VIII 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 and to facilitate management.
Pregnancy management: Monitor carrier mothers for delayed bleeding postpartum unless it is known that their baseline factor VIII clotting activity is normal.
Therapies under investigation: Ongoing clinical trials of longer-acting factor VIII concentrates.
Other: Vitamin K does not prevent or control bleeding in hemophilia A; cryoprecipitate contains factor VIII but does not undergo viral inactivation so is no longer used to treat hemophilia A; no clinical trials for gene therapy in hemophilia A are currently in progress although several improved approaches are in pre-clinical testing.
Hemophilia A 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 F8 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 at-risk family members and prenatal testing for pregnancies at increased risk are possible if the F8 pathogenic variant has been identified in a family member or if informative intragenic linked markers have been identified.
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 or delayed bleeding or poor wound healing following surgery or trauma *
- Unexplained GI bleeding or hematuria *
- Menorrhagia, 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
Bleeding scores have been developed to assist in the diagnosis of individuals with suspected bleeding disorders. The International Society on Hemostasis and Thrombosis has developed a consensus Bleeding Assessment Tool (ISTH BAT; www.isth.org). The BAT is currently most helpful in excluding bleeding disorders in individuals with a negative score and in research applications [James & Coller 2012].
Coagulation screening tests. Evaluation of an individual with a suspected bleeding disorder includes: platelet count; activated partial thromboplastin time (aPTT); and prothrombin time (PT). Thrombin time and/or plasma concentration of fibrinogen can be useful in diagnosing rare disorders. Bleeding times and platelet function analysis (PFA closure times) have neither sufficient sensitivity nor specificity to be recommended for screening assays for platelet disorders [Hayward et al 2006], but may be useful in excluding von Willebrand disease in unselected populations [Castaman et al 2010].
In individuals with hemophilia A, the above screening tests are normal, with the following exceptions:
- The aPTT is prolonged in severe and moderate hemophilia A. Prolongations in aPTT that correct on mixing with an equal volume of normal plasma indicate an intrinsic system clotting factor deficiency, including factor VIII, without an inhibitor.
Note: It is important to confirm the diagnosis of hemophilia A and to exclude other deficiencies with a specific factor VIII clotting activity assay, which is available in most hospital laboratories or coagulation reference laboratories.
- The aPTT may be normal but is usually mildly prolonged in mild hemophilia A.
- The prothrombin time (PT) should be normal unless another hemostatic defect such as liver disease is present.
Note: In some 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 approximately 50% to 150%.
- Individuals with factor VIII clotting activity higher than 30% usually do not have bleeding [Kaufman et al 2013]. However, a mild bleeding tendency can occur with low to low-normal factor VIII clotting activity in hemophilia A carrier females [Plug et al 2006] or in those with mild von Willebrand disease. The risk of having a bleeding tendency appears to be higher in carriers of alleles associated with severe hemophilia A, regardless of the baseline factor VIII clotting activity [Miesbach et al 2011].
- 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
- Moderate hemophilia A. 1%-5% factor VIII
- Mild hemophilia A. 6%-40% 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.
Coagulation factor assays. Approximately 10% of hemophilia A carrier females have factor VIII clotting activity lower than 35% regardless of the severity of hemophilia A in the family. Bleeding may also be more severe in those with low-normal factor VIII activity [Plug et al 2006].
Factor VIII clotting activity is unreliable in the detection of hemophilia A carriers:
- Factor VIII clotting activity in plasma is increased with pregnancy, oral contraceptive use, aerobic exercise, and chronic inflammation.
- Factor VIII clotting activity in plasma is approximately 25% lower in individuals of blood group O than in individuals of blood groups A, B, or AB.
- The majority of obligate carriers, even of severe hemophilia A, have normal factor VIII clotting activities.
Molecular Genetic Testing
Gene. F8 is the only gene in which pathogenic variants are known to cause hemophilia A.
To confirm/establish 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 pathogenic variant in F8 in order to obtain information for genetic counseling of at-risk family members. If an affected individual is not available, an obligate carrier female can be tested.
In an individual who represents a simplex case, identification of the specific F8 pathogenic variant can help predict the clinical phenotype and assess the risk of developing a factor VIII inhibitor.
For (a) individuals with severe hemophilia A, (b) females with a family history of severe hemophilia A, or (c) females with a family history of hemophilia A of unknown severity in whom the family-specific pathogenic variant is not known, molecular genetic testing is generally performed in the following order:
- Targeted mutation analysis to identify the intron 22 or intron 1 inversion
- Sequence analysis of the 26 exons in F8
- Deletion/duplication analysis
- Linkage analysis
- Possibly appropriate if no mutation is detected by the above methods
- May be used to track an unidentified F8 disease-causing allele in a family and to identify the person in which the de novo mutation originated [Keeney et al 2010]
For (a) individuals with moderate or mild hemophilia A or (b) females with a family history of moderate or mild hemophilia A in whom the family-specific pathogenic variant is not known, molecular genetic testing is generally performed in the following order:
- Sequence analysis of the 26 exons, intron-exon boundaries and adjacent 5’ and 3’ areas of F8
- Deletion/duplication analysis
- Linkage analysis may be appropriate if no mutation is detected by the above methods. It may be used to track an unidentified F8 disease-causing allele in a family and to identify the person in which the de novo mutation originated [Keeney et al 2010]
Note: When carrier testing is performed without previous identification of the F8 pathogenic variant in the family, a negative result in an at-risk relative is not informative.
Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this GeneReview are associated with mutation of F8.
Hemophilia A 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 [Fogarty & Kessler 2013, Josephson 2013]. 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, or they may 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 in the neonatal period 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 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 prophylactically 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 severe hemophilia A have prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions.
Individuals with moderate hemophilia A 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 VIII concentrates varies from once a month to once a year. Signs and symptoms of bleeding are otherwise similar to those found in 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 and adults 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 factor VIII concentrates that initially were derived solely from donor plasma. Viral inactivation methods and donor screening of plasmas were introduced by the mid-1980s and recombinant factor VIII concentrates were introduced in the early 1990s, ending the risk of HIV transmission. Many individuals who received plasma-derived factor VIII concentrates from 1979 to 1985 contracted HIV. 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 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 eliminated this complication.
Approximately 30% of individuals with severe hemophilia A develop alloimmune inhibitors to factor VIII, usually within the first 20 exposures to infused factor VIII [Hay et al 2011] and, infrequently, in those who have received more than 50 exposures [Kempton 2010] (see Management, Treatment of Manifestations). Among individuals with hemophilia A, inhibitors are more prevalent in blacks and hispanics than whites. Reasons for these disparities are being actively investigated [Viel et al 2009, Miller et al 2012, Schwarz et al 2013].
- F8 intron 22 inversions are associated with severe hemophilia A and account for 45% of the severe cases [Kaufman et al 2013]. Of these, 20% to 30% develop alloimmune inhibitors. Occasionally, individuals considered to have moderate hemophilia A have been found to have F8 inversions. Often their assays 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 F8 [Bagnall et al 2002] is also associated with a severe phenotype, and some individuals have developed inhibitors.
- Single nucleotide variants 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 moderate hemophilia A [Nakaya et al 2001].)
- Splice site mutations often result in severe disease, but can result in mild or moderate disease, depending on the specific change and location.
- Missense mutations occur in fewer than 20% of individuals with severe hemophilia A but are found in nearly all of those with a diagnosis of mild or moderate disease.
- A single base change in the 5’ promoter region of F8 has been associated with mild hemophilia A [Riccardi et al 2009].
All males with a F8 pathogenic variant 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 to some extent.
Approximately 10% of females with one F8 pathogenic variant and one normal allele have a factor VIII clotting activity lower than 30% and a bleeding disorder; mild bleeding can occur in carriers with low-normal factor VIII activity [Plug et al 2006].
Anticipation is not observed.
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 in F8 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 [Fogarty & Kessler 2013]; however, reporting varies widely [Stonebraker et al 2010].
When an individual presents with bleeding or the history of being a "bleeder," the first task is to determine if he/she truly has abnormal bleeding. "Bleeding a lot" during or immediately after major trauma, after a tonsillectomy, or for a few hours following tooth extraction may not be significant. In contrast, prolonged or intermittent oozing that lasts several days following tooth extraction or mouth injury, renewed bleeding or increased pain and swelling several days after an injury, or developing a wound hematoma several days after surgery almost always indicates a coagulation problem. A detailed history of bleeding episodes can help determine if the individual has a lifelong, inherited bleeding disorder or an acquired (often transient) bleeding disorder.
Physical examination provides few specific diagnostic clues. An older individual with severe or moderate hemophilia A may have joint deformities and muscle contractures. Large bruises and subcutaneous hematomas for which no trauma can be identified may be present, but individuals with a mild bleeding disorder have no outward signs except during an acute bleeding episode. Petechial hemorrhages indicate severe thrombocytopenia and are not a feature of hemophilia A.
A family history with a pattern of autosomal dominant, autosomal recessive, or X-linked inheritance provides clues to the diagnosis of the bleeding disorder but is not definitive. Hemophilia A and hemophilia B are both inherited in an X-linked manner. F8 and F9 mutations occur de novo and the person in whom the de novo mutation occurred can be identified in up to half of the families with newly diagnosed, affected members. Some families with mild hemophilia A are mistakenly diagnosed as having von Willebrand disease [Lillicrap 2013] because both men and women have abnormal bleeding. With testing for von Willebrand disease, it is possible to determine that women in such families often do not have von Willebrand disease, but rather are symptomatic carriers of hemophilia A.
Hemophilia A is only one of several lifelong bleeding disorders, and coagulation factor assays are the main tools for determining the specific diagnosis. Other inherited bleeding disorders associated with a low factor VIII clotting activity include the following:
- Type 1 von Willebrand disease (VWD) accounts for approximately 70% of individuals with VWD and is characterized by a partial quantitative deficiency of von Willebrand factor (low VWF antigen, factor VIII clotting activity, and VWF activity). Mucous membrane bleeding and prolonged oozing after surgery or tooth extractions are the predominant symptoms; laboratory testing is needed to differentiate mild hemophilia from VWD. Essentially all individuals with hemophilia A have a normal VWF level. Inheritance of most VWD type 1 is autosomal dominant; penetrance varies.
- Type 2A or 2B VWD is characterized by a qualitative deficiency of VWF with a decrease of the high molecular weight multimers. Measures of VWF platelet or collagen binding activity are decreased, while VWF antigen and factor VIII clotting activity may be low-normal to mildly decreased. The inheritance of most cases of type 2A and 2B VWD is autosomal dominant. Type 2A VWD is caused by mutation resulting in abnormal multimer formation or stability. Type 2B VWD is caused by a gain of function in platelet binding and is often accompanied by thrombocytopenia. Molecular genetic testing can aid in diagnosis.
- Type 2M VWD is also characterized by a qualitative deficiency of VWF with a similar decrease in function as seen in type 2A; however, it is associated with a normal multimer pattern. Inheritance is autosomal dominant. Molecular genetic testing can aid in the diagnosis and distinction of subtypes of VWD type 2. Essentially all reported pathogenic variants resulting in VWD types 2B and 2M and approximately 80% of pathogenic variants resulting in type 2A are in exon 28 of VWF.
- Type 2N VWD is an uncommon variant resulting from one of several missense mutations in the amino terminus of the circulating VWF protein, resulting in defective binding of factor VIII to VWF. VWF platelet binding is completely normal. Clinically and biochemically, type 2N VWD is indistinguishable from mild hemophilia A; however, mild hemophilia A can be distinguished from type 2N VWD by molecular genetic testing of F8, molecular genetic testing of VWF, or measuring binding of factor VIII to VWF using ELISA or column chromatography. The low factor VIII clotting activity usually indicates autosomal recessive inheritance.
- Type 3 VWD is characterized by a complete or near-complete quantitative deficiency of VWF. Affected individuals experience frequent episodes of mucous membrane bleeding and joint and muscle bleeding similar to that seen in individuals with hemophilia A. The VWF level is often lower than 1% and the factor VIII clotting activity is most commonly 2%-8%. Inheritance is autosomal recessive. Heterozygous parents may have type 1 VWD but more often are asymptomatic.
- Mild combined factor V and factor VIII deficiencies are usually caused by rare autosomal recessive inheritance of a deficiency of one of two intracellular chaperone proteins encoded by LMAN1 or MCFD2 [Zhang et al 2008].
The following are other bleeding disorders with normal factor VIII clotting activity:
- Hemophilia B, caused by mutation of F9, is clinically indistinguishable from hemophilia A. Diagnosis is based on a factor IX clotting activity lower than 40%. Inheritance is X-linked.
- Factor XI deficiency is inherited in an autosomal recessive manner with heterozygotes showing a factor XI coagulant activity of 25% to 75% of normal, while homozygotes have activity of lower than 1% to 15%, depending on their genotype [Duga & Salomon 2013]. Two pathogenic variants are common among individuals of Ashkenazi Jewish descent. Both compound heterozygotes and homozygotes may exhibit bleeding similar to that seen in mild or moderate hemophilia A. A specific factor XI clotting assay establishes the diagnosis.
- Factor XII, prekallekrein, or high molecular weight kininogen deficiencies do not cause clinical bleeding but can cause a long activated partial thromboplastin time (aPTT).
- Prothrombin (factor II), factor V, factor X, and factor VII deficiencies are rare bleeding disorders inherited in an autosomal recessive manner [Thompson 2006, Peyvandi et al 2012]. Individuals may display easy bruising and hematoma formation, epistaxis, menorrhagia, and bleeding after trauma and surgery. Hemarthroses are uncommon. Spontaneous intracranial bleeding can occur. Factor VII deficiency should be suspected if the PT is prolonged and aPTT normal. Individuals with deficiency of factors II, V, or X usually have prolonged PT and aPTT, but specific coagulation factor assays establish the diagnosis. Combined (multiple) deficiencies are usually acquired disorders, although a few families have hereditary deficits of the vitamin K-dependent factors, often resulting from deficiency of gamma-carboxylase.
- Fibrinogen disorders can be severe, mild, or asymptomatic [Thompson 2006]:
- Congenital afibrinogenemia is a rare disorder inherited in an autosomal recessive manner with manifestations similar to hemophilia A except that bleeding from minor cuts is prolonged because of the lack of fibrinogen to support platelet aggregation.
- Hypofibrinogenemia can be inherited either in an autosomal dominant or autosomal recessive manner and is usually asymptomatic but may be combined with dysfibrinogenemia.
- Dysfibrinogenemia is inherited in an autosomal dominant manner. Individuals with hypofibrinogenemia or dysfibrinogenemia have mild-to-moderate bleeding symptoms or may be asymptomatic; some individuals with dysfibrinogenemia are at risk for thrombosis. Diagnosis is based on activity levels on kinetic coagulation assay that are lower than antigenic protein levels, although the thrombin time (a simple screening test) is usually prolonged.
- Factor XIII deficiency is a rare autosomal recessive disorder [Thompson 2006]. Umbilical stump bleeding occurs in more than 80% of individuals. Intracranial bleeding that occurs spontaneously or following minor trauma is seen in 30% of individuals. Subcutaneous hematomas, muscle hematomas, defective wound healing, and recurrent spontaneous abortion are also seen. Joint bleeding is rare. All kinetic coagulation screening tests are normal; a screening test for clot solubility or a specific assay for factor XIII (FXIII) activity must be performed.
- Platelet function disorders cause bleeding problems similar to those seen in individuals with thrombocytopenia. Individuals have skin and mucous membrane bleeding, recurring epistaxis, gastrointestinal bleeding, menorrhagia, and excessive bleeding during or immediately after trauma and surgery. Joint, muscle, and intracranial bleeding is rare. Diagnosis is made using platelet aggregation assays, flow cytometry, and platelet electron microscopy.
- Bernard-Soulier syndrome is inherited in an autosomal recessive manner and involves the VWF receptor, the platelet membrane GPIb-IX complex.
- Glanzmann thrombasthenia, also autosomal recessive, involves the GPIIb-IIIa receptor necessary for platelet aggregation. Abnormal platelet function is usually associated with a prolonged bleeding time or prolonged closure time on platelet function analysis.
- Storage pool and non-specific secretory defects are usually inherited in an autosomal dominant manner, and are more common than the platelet membrane receptor defects described above. Clinical bleeding symptoms are generally less severe than seen with membrane receptor defects.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with hemophilia A, the following evaluations are recommended:
- 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, 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 or postpartum hemorrhage
- Identification of the specific F8 pathogenic variant 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
- Medical genetics consultation, particularly if a new diagnosis in the family and for females of childbearing years.
Treatment of Manifestations
In developed countries, 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. The World Federation of Hæmophilia has published treatment guidelines for the diagnosis and management of individuals with hemophilia.
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) in the USA that can be located through the National Hemophilia Foundation. Worldwide, treatment centers can be found through the World Federation of Hæmophilia. 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 have been available for more than 20 years; some 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.
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 and disability and reduces the risk for chronic joint disease. Ideally, the affected individual should receive clotting factor within an hour of noticing symptoms [Fogarty & Kessler 2013]. Doses vary among individuals, but knowledge of a single in vivo recovery value does not always help 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 is feasible. Home treatment allows for prompt treatment after symptoms occur and facilitates prophylactic therapy.
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) [Castaman et al 2009]. A single intravenous dose often doubles or triples factor VIII clotting activity. Alternatively, a multi-use nasal formulation of desmopressin (Stimate®) is more convenient and available.
Pediatric issues. Special considerations for care of infants and children with hemophilia A include the following [Chalmers et al 2011]:
- 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 directly before and after 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. Alloimmune inhibitors to factor VIII greatly compromise the ability to manage bleeding episodes [Hay et al 2006, Fogarty & Kessler 2013]. High titer inhibitors can often be eliminated by immune tolerance therapy [Hay & DiMichele 2012]. Individuals with large gene deletions are less likely to respond to immune tolerance than individuals with other types of mutations [Coppola et al 2009].
Prevention of Primary Manifestations
Initiation of prophylactic infusions of factor VIII 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 [Nilsson et al 1992, Manco-Johnson et al 2007]. 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 infusions of factor VIII concentrate three times a week or every other day to maintain factor VIII clotting activity above 1%, although a less intense regimen may provide protection for some affected boys [Fischer et al 2002, Feldman et al 2006].
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. The greatest benefit is seen in affected individuals who start therapy before 2.5 – 3.0 years of age, though controversy still exists about what dosing regimens should be used.
"Secondary" prophylaxis, started after some joint damage has occurred, can be given on a long-term basis or around periods of increased activity or surgical procedures. Routine prophylaxis begun later in childhood or in adults significantly decreases bleeding episodes [Valentino et al 2012, Manco-Johnson et al 2013, Mondorf et al 2013]. Long-term effects on joint outcomes are under study.
It is recommended that young children with severe or moderate 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, and a discussion of any other problems related to the individual's hemophilia and family and community support.
Screening for alloimmune inhibitors is performed at least once during the first 10-20 treatment days in children with severe hemophilia and then 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 and screening prior to elective surgical procedures is sufficient. Testing for inhibitors should also be performed in any individual with hemophilia whenever a suboptimal clinical response to treatment is suspected, regardless of disease severity.
Older children and adults with severe or moderate hemophilia A benefit from at least yearly contact with 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 A can benefit from maintaining a relationship with an HTC and having regular assessments at least every two to three years. Affected individuals with comorbidities and other complications or treatment challenges may require more frequent visits.
Agents/Circumstances to Avoid
Avoid the following:
- Activities that involve a high risk of trauma, particularly head injury
- Aspirin and all aspirin-containing products
Note: Some adults with hemophilia and cardiovascular disease can tolerate low-dose aspirin, although this may require a low-dose prophylactic factor regimen, with treatment decisions made on a case-by-case basis [Konkle 2011].
Caution in the use of other medications and herbal remedies that affect platelet function is indicated.
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 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 family-specific F8 pathogenic variant 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 immediately before and after 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 20% of carriers have factor VIII activity lower than 40% and may have abnormal bleeding. In a survey of Dutch 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). Very occasionally, a woman will have particularly low factor VIII clotting activity that may result from heterozygosity for an F8 pathogenic variant associated with skewed X-chromosome inactivation or, on rare occasion, compound heterozygosity for two F8 pathogenic variants [Pavlova et al 2009].
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.
Obstetric issues. 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.
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 may ensue [Lee et al 2006].
Newborn males. Controversy remains as to indications for cesarean section versus vaginal delivery [James & Hoots 2010, Chalmers et al 2011]. For elective deliveries, the relative risks of cesarean section versus vaginal delivery should be considered, especially if a male has been diagnosed with hemophilia A prenatally.
At birth or in the early neonatal period, intracranial hemorrhage in affected males is uncommon (1%-2%), even in males with severe hemophilia A who are delivered vaginally.
Therapies Under Investigation
Longer-acting factor VIII (FVIII) concentrates are undergoing clinical trials. FVIII modified by pegylation or Fc fusion are in Phase III clinical trials and result in half-life extension by approximately 1.5 fold [Peyvandi et al 2013]. These may allow once- to twice-weekly infusions for prophylaxis. Other modifications of FVIII to further increase half-life are under study.
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 [Zakarija et al 2011, Hay & DiMichele 2012, Astermark et al 2013]. Several novel products that “bypass” the need for factor VIII or factor IX are in preclinical study [Kaufman & Powell 2013].
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 can begin with factor VIII [Chuah et al 2013].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Vitamin K does not prevent or control bleeding in hemophilia A.
Cryoprecipitate is no longer recommended to treat hemophilia A because it is not treated with a virucidal agent.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
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 F8 pathogenic variant.
- 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 pathogenic variant 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 pathogenic variant. Somatic mosaicism may occur in as many as 15% of probands with a single nucleotide variant 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 in one of the following ways:
- 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). Ninety-eight percent of mothers of a simplex case with an intron 22 inversion are carriers because most of these mutations occur in spermatogenesis.
- As a somatic mutation (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 or may not be detectable in DNA).
- As germline mosaicism (in which some germ cells have the pathogenic variant and some do not, and in which the pathogenic variant is not detectable in DNA from her leukocytes).
- The mother is a carrier and has inherited the pathogenic variant either from her mother who has a de novo disease-causing variant or from her asymptomatic father who is mosaic for the pathogenic variant.
- The mother is a carrier of a pathogenic variant that arose in a previous generation and 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 de novo mutation. Determining the point of origin of 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 pathogenic variant 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 pathogenic variant present in their family.
Offspring of a male proband
- All daughters will be carriers of the F8 pathogenic variant causing hemophilia A of the same severity as their father's hemophilia.
- No sons will inherit the mutant F8 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 testing by molecular genetic testing is possible for most at-risk females if the pathogenic variant has been identified in the family.
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 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)] for published guidelines for a UK framework for genetic services and Thomas et al  for findings of a qualitative study in Australia on how cultural and religious issues influence parental attitudes about genetic testing.
- 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 affected or 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.
Molecular genetic testing. If the pathogenic variant has been identified in an affected family member or linkage established in the family, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.
Percutaneous umbilical blood sampling (PUBS). If the F8 pathogenic variant is not known and linkage is not informative, prenatal diagnosis is possible using a fetal blood sample obtained by PUBS at approximately 18 to 21 weeks' gestation for assay of factor VIII clotting activity.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for conditions which (like hemophilia A) 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 an option for some families in which the pathogenic variant has been identified [Laurie et al 2010].
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- Canadian Hemophilia Society (CHS)400 - 1255 University StreetMontreal Quebec H3B 3B6CanadaPhone: 800-668-2686 (toll-free); 514-848-0503Fax: 514-848-9661Email: email@example.com
- Haemophilia SocietyPetersham House57a Hatton GardenFirst FloorLondon EC1N 8JGUnited KingdomPhone: 020 7831 1020; 0800 018 6068 (Toll-free Helpline)Fax: 020 7405 4824Email: firstname.lastname@example.org
- National Hemophilia Foundation (NHF)116 West 32nd Street11th FloorNew York NY 10001Phone: 212-328-3700Fax: 212-328-3777Email: email@example.com
- National Library of Medicine Genetics Home Reference
- NCBI Genes and Disease
- World Federation of Hemophilia1425 Rene Levesque Boulevard WestSuite 1010Montreal Quebec H3G 1T7CanadaPhone: 514-875-7944Fax: 514-875-8916Email: firstname.lastname@example.org
- Medline Plus
- American Thrombosis and Hemostasis Network (ATHN) RegistryChicago ILPhone: 800-360-2846Fax: 847-572-0967Email: email@example.com
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
|Gene Symbol||Chromosomal Locus||Protein Name||Locus Specific||HGMD|
|F8||Xq28||Coagulation factor VIII||Hemobase: Hemophilia A mutation registry|
F8 @ LOVD
Haemophilia A Mutation, Structure, Test & Resource Site (HAMSTeRS)
ISTH-SSC VWF Online Database - F8
CDC Hemophilia A Mutation Project - F8
Molecular Genetic Pathogenesis
Benign allelic variants. Benign variants are uncommon in the factor VIII transcript (Table 3).
Benign variants (and their dbSNP identifier) that are useful for linkage analysis include: a BclI restriction site in intron 18 (rs4898352), a single-base change in intron 7 (only informative if BclI is homozygous for the non-cleaved or less common allele, rs7058826), an XbaI site in intron 22, a BglI site in intron 25 (rs1509787), an A/G dimorphism at a MseI site in the 3' untranslated portion of exon 26 at base 8899 (rs1050705), and two series of CA repeat polymorphisms in introns 13 and 22. Only two coding sequence variants are frequently polymorphic in whites, c.3780C>G (rs1800291) and c.3864A>C (rs1800292), both in exon 14 (Table 3). In African Americans, the benign variant c.6771G in exon 25 is the most common allele, whereas essentially all individuals of northern European ancestry have the F8 variant c.6771A. These variants code for Val or Met, respectively, at amino acid 2257 [Viel et al 2007].
Pathogenic allelic variants. Gene inversions account for approximately 45% of the F8 pathogenic variants in severe hemophilia A [Kaufman et al 2013].
F8 inversions usually occur through recombination between a sequence located within intron 22 with one of two additional copies of homologous sequence that are located 400-500 kb 5’ from F8 (about half the distance to the telomere of the long arm of the X chromosome) [Bagnall et al 2006]. Of the two most frequent types, cross-over with the distal telomeric sequence (designated as int22h3) is more frequent than with the proximal sequence (designated as int22h2, which appears to require a separate inversion first in order to be in the opposite direction of the intron 22 sequence to align for mis-pairing). Infrequently, a third telomeric copy can be present and can lead to a variant intron 22 inversion pattern on Southern blotting; alternative patterns can also be seen when the inversion is accompanied by large partial-gene deletions or duplication-insertion events [Andrikovics et al 2003].
A different recurrent inversion occurs between a 1-kb sequence in intron 1 (designated int1h-1) that is repeated in the reverse orientation (designated int1h-2), approximately 140 kb 5' (telomeric) to F8 [Bagnall et al 2002]; intron 1 inversions occur in up to 3% of families with severe hemophilia A.
The remaining types of pathogenic variants span the entire spectrum including whole- or partial-gene deletions, large insertions, sequence duplications, small deletions or insertions (usually resulting in frameshifts), splice junction alterations, nonsense mutations, and missense mutations. These non-inversion mutations of F8 are cataloged (see Table A, Locus-Specific Databases).
Normal gene product. Factor VIII is expressed with a 19-amino acid signal peptide; the mature protein has 2332 residues [Thompson 2003, Kaufman et al 2013]. Its domain structure from the amino terminus is "A1-A2-B-A3-C1-C2" and is homologous to clotting factor V. The three A domains are homologous with ceruloplasmin and the two C domains with discoidins. The known crystal structure of ceruloplasmin has allowed models of the A domains and localization of hemophilic missense mutations (see Table A, Locus-Specific Databases). High-resolution crystal structure of a recombinant human C2 domain is known, and hemophilic missense mutations have been localized to it and to a model of the homologous C1 domain [Liu et al 2000]. Crystal structures of activated factor VIII have been solved at just under four angstrom resolutions [Ngo et al 2008, Shen et al 2008].
Factor VIII is synthesized primarily in the liver and circulates as an inactive clotting cofactor that has been variably cleaved towards the carboxy terminus of the B domain prior to secretion. Concentration in plasma is just under 1 nmol/L (0.1 µg/mL). In the circulation, factor VIII is stabilized by binding to von Willebrand factor (VWF). Once activated by trace amounts of thrombin, it is released from VWF and binds to phospholipid membrane surfaces such as those provided by activated platelets. There it interacts with factor IXa to become the "intrinsic system" factor X activator [Stoilova-McPhie et al 2002]. Intrinsic factor X activation is a critical step in the early stages of coagulation.
Abnormal gene product. Abnormal gene products vary from deficiency caused by absence of detectable protein (including the majority of individuals with severe hemophilia A) to those with normal levels of a dysfunctional protein. Some pathogenic variants are associated with comparably reduced levels of factor VIII clotting activity and antigen; where examined, these are caused by impaired secretion of factor VIII or instability of factor VIII in circulation. Certain premature termination codons, gene inversions, or gross gene alterations causing severe hemophilia A have an increased risk of being complicated by inhibitor development [Hay et al 2006, Salviato et al 2007, Coppola et al 2009, Gouw et al 2012, Astermark et al 2013, Eckhardt et al 2013].
Published Guidelines/Consensus Statements
Guidelines regarding genetic testing for this disorder have been published for the UK:
- Keeney S, Mitchell M, Goodeve A. Practice Guidelines for the Molecular Diagnosis of Haemophilia A. Available online. 2010. Accessed 5-30-14.
- 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 5-30-14. [PubMed: 15810917]
- Andrikovics H, Klein I, Bors A, Nemes L, Marosi A, Varadi A, Tordai A. Analysis of large structural changes of the factor VIII gene, involving intron 1 and 22, in severe hemophilia A. Haematologica. 2003;88:778–84. [PubMed: 12857556]
- Astermark J, Donfield SM, Gomperts ED, Schwarz J, Menius ED, Pavlova A, Oldenburg J, Kessing B, DiMichele DM, Shapiro AD, Winkler CA. The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Blood. 2013;121:1446–54. [PMC free article: PMC3578958] [PubMed: 23223434]
- Bagnall RD, Giannelli F, Green PM. Int22h-related inversions causing hemophilia A: a novel insight into their origin and a new more discriminant PCR test for their detection. J Thromb Haemost. 2006;4:591–8. [PubMed: 16460442]
- Bagnall RD, Waseem N, Green PM, Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood. 2002;99:168–74. [PubMed: 11756167]
- Bjorkman S, Folkesson A, Berntorp E. In vivo recovery of factor VIII and factor IX. Haemophilia. 2007;13:2–8. [PubMed: 17212717]
- Castaman G, Mancuso ME, Giacomelli SH, Tosetto A, Santagostino E, Mannucci PM, Rodeghiero F. Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A. J Thromb Haemost. 2009;7:1824–31. [PubMed: 19719828]
- Castaman G, Tosetto A, Goodeve A, Fererici AB, Lethagen S, Budde U, Batlle J, Meyer D, Mazurier C, Goudemand J, Eikenboom J, Schneppenheim R, Ingerslev J, Habart D, Hill F, Peake I. The impact of bleeding history, von Willebrand factor and PFA-100® on the diagnosis of type 1 von Willebrand disease: results from the European study MCMDM-1VWD. Br J Haematol. 2010;151:245–51. [PubMed: 20738304]
- 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]
- Chuah MK, Evens H, VandenDriessche T. Gene therapy for hemophilia. J Thromb Haemost. 2013;11 Suppl 1:99–110. [PubMed: 23809114]
- Coppola A, Margaglione M, Santagostino E, Rocino A, Grandone E, Mannucci PM, Di Minno G. AICE PROFIT Study Group; Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors. J Thromb Haemost. 2009;7:1809–15. [PubMed: 19740093]
- 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]
- Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost. 2013;39:621–31. [PubMed: 23929304]
- Eckhardt CL, van Velzen AS, Peters M, Astermark J, Brons PP, Castaman G, Cnossen MH, Dors N, Escuriola-Ettingshausen C, Hamulyak K, Hart DP, Hay CR, Haya S, van Heerde WL, Hermans C, Holmström M, Jimenez-Yuste V, Keenan RD, Klamroth R, Laros-van Gorkom BA, Leebeek FW, Liesner R, Mäkipernaa A, Male C, Mauser-Bunschoten E, Mazzucconi MG, McRae S, Meijer K, Mitchell M, Morfini M, Nijziel M, Oldenburg J, Peerlinck K, Petrini P, Platokouki H, Reitter-Pfoertner SE, Santagostino E, Schinco P, Smiers FJ, Siegmund B, Tagliaferri A, Yee TT, Kamphuisen PW, van der Bom JG, Fijnvandraat K. INSIGHT Study Group.; Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood. 2013;122:1954–62. [PubMed: 23926300]
- El-Maarri O, Herbiniaux U, Graw J, Schroder J, Terzic A, Watzka M, Brackmann HH, Schramm W, Hanfland P, Schwaab R, Muller CR, Oldenburg J. Analysis of mRNA in hemophilia A patients with undetectable mutations reveals normal splicing in the factor VIII gene. J Thromb Haemost. 2005;3:332–9. [PubMed: 15670040]
- Feldman BM, Pai M, Rivard GE, Israels S, Poon MC, Demers C, Robinson S, Luke KH, Wu JK, Gill K, Lillicrap D, Babyn P, McLimont M, Blanchette VS. Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study. J Thromb Haemost. 2006;4:1228–36. [PubMed: 16706965]
- 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]
- Fogarty PF, Kessler CM. Hemophilia A and B. In: Kitchens CS, Kessler CM, Konkle BA, eds. Consultative Hemostasis and Thrombosis. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2013:45-59.
- Gouw SC, van den Berg HM, Oldenburg J, Astermark J, de Groot PG, Margaglione M, Thrompson AR, van Heerde W, Boekhorst J, Miller CH, le Cessie S, van der Bom JG. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systemic review and meta-analysis. Blood. 2012;119:2922–34. [PubMed: 22282501]
- 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]
- Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012;119:1335–44. [PubMed: 22101900]
- Hay CR, Palmer B, Chalmers E, Liesner R, Maclean R, Rangarajan S, Williams M, Collins PW. Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood. 2011;117:6367–70. [PubMed: 21471523]
- Hayward CP, Harrison P, Cattaneo M, Ortel TL. Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost. 2006;4:312–9. [PubMed: 16420557]
- James AH, Hoots WK. The optimal mode of delivery for the haemophilia carrier expecting an affected infant is caesarean delivery. Haemophilia. 2010;16:420–4. [PubMed: 20028425]
- James P, Coller BS. Phenotyping bleeding. Curr Opin Hematol. 2012;19:406–12. [PMC free article: PMC3673282] [PubMed: 22759628]
- Josephson N. The hemophilias and their clinical management. Hematology Am Soc Hematol Educ Program. 2013;2013:261-7. [PubMed: 24319189]
- Kaufman RJ, Fay PJ, Popolo L, Ortel TL. Factor V and factor VIII. In: Marder VJ, Aird WC, Bennett JS, Schulman S, White GC, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 6 ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2013:179-96.
- Kaufman RJ, Powell JS. Molecular approaches for improved clotting factors for hemophilia. Hematology Am Soc Hematol Educ Program. 2013;2013:30-6. [PubMed: 24319159]
- Keeney S, Cumming T, Jenkins PV, O'Donnell JS, Nash MJ. Clinical utility gene card for: haemophilia A. Eur J Hum Genet. 2011;19(11) [PMC free article: PMC3198139] [PubMed: 21654722]
- Keeney S, Mitchell M, Goodeve A. Practice Guidelines for the Molecular Diagnosis of Haemophilia A. Available online. 2010. Accessed 5-30-14.
- Kemball-Cook G, Tuddenham EGD, Wacey AI. The factor VIII structure and mutation resource site: HAMSTeRS v4. Nucleic Acids Res. 1998;26:216–9. [PMC free article: PMC147260] [PubMed: 9399839]
- Kempton CL. Inhibitors in previously treated patients: a review of the literature. Haemophilia. 2010;16:61–5. [PMC free article: PMC4277611] [PubMed: 20536987]
- Konkle BA. Clinical challenges within the aging hemophilia population. Thromb Res. 2011;127 Suppl 1:S10–3. [PubMed: 21056901]
- 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]
- Lee CA, Chi C, Pavord SR, Bolton-Maggs PH, Pollard D, Hinchcliffe-Wood A, Kadir RA. The obstetric and gynaecological management of women with inherited bleeding disorders--review with guidelines produced by a taskforce of UK Haemophilia Centre Doctors' Organization. Haemophilia. 2006;12:301–36. [PubMed: 16834731]
- Leuer M, Oldenburg J, Lavergne JM, Ludwig M, Fregin A, Eigel A, Ljung R, Goodeve A, Peake I, Olek K. Somatic mosaicism in hemophilia A: a fairly common event. Am J Hum Genet. 2001;69:75–87. [PMC free article: PMC1226050] [PubMed: 11410838]
- Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis and therapy. Blood. 2013;122:3735–40. [PMC free article: PMC3952678] [PubMed: 24065240]
- Liu ML, Shen BW, Nakaya S, Pratt KP, Fujikawa K, Davie EW, Stoddard BL, Thompson AR. Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure. Blood. 2000;96:979–87. [PubMed: 10910913]
- 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]
- Miesbach W, Alesci S, Geisen C, Oldenburg J. Association between phenotype and genotype in carriers of haemophilia A. Haemophilia. 2011;17:246–51. [PubMed: 21118332]
- Miller CH, Benson J, Ellingsen D, Driggers J, Payne A, Kelly FM, Soucie JM, Hooper W. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012;18:375–82. [PubMed: 22103590]
- Mondorf W, Kalnins W, Klamroth R. Patient-reported outcomes of 182 adults with severe haemophilia in Germany comparing prophylactic vs. on-demand replacement therapy. Haemophilia. 2013;19:558–63. [PubMed: 23560639]
- Nakaya S, Liu ML, Thompson AR. Some factor VIII exon 14 frameshift mutations cause moderately severe haemophilia A. Br J Haematol. 2001;115:977–82. [PubMed: 11843836]
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Cheryl L Brower, RN, MSPH; Puget Sound Blood Center (2008-2011)
Frank K Fujimura, PhD, FACMG; GMP Genetics, Inc (2000-2003)
Maribel J Johnson, RN, MA; Puget Sound Blood Center (2000-2008)
Neil C Josephson, MD (2011-present)
Barbara A Konkle, MD (2011-present)
Shelley Nakaya Fletcher, BS (2011-present)
Arthur R Thompson, MD, PhD; University of Washington (2000-2014)
- 5 June 2014 (me) Comprehensive update posted live
- 22 September 2011 (me) Comprehensive update posted live
- 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
Puget Sound Blood Center
Puget Sound Blood Center
Initial Posting: September 21, 2000; Last Update: June 5, 2014.
University of Washington, Seattle, Seattle (WA)
Konkle BA, Josephson NC, Nakaya Fletcher S. Hemophilia A. 2000 Sep 21 [Updated 2014 Jun 5]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.