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Hemophilia A

Synonym: Factor VIII Deficiency

, MD, , BS, and , BS.

Author Information

Initial Posting: ; Last Update: February 2, 2017.

Summary

Clinical characteristics.

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.

  • Individuals with severe hemophilia A are usually diagnosed during the first two years of life following bleeding from minor mouth injuries and large "goose eggs" from minor head bumps. Without prophylactic treatment, they may average up to two to five spontaneous bleeding episodes each month including spontaneous joint bleeds or deep-muscle hematomas, and prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions.
  • 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.

Approximately 30% of heterozygous females have clotting activity below 40% and are at risk for bleeding (even if the affected family member is mildly affected). After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity.

Diagnosis/testing.

The diagnosis of hemophilia A is established in an individual with low factor VIII clotting activity in the presence of a normal, functional von Willebrand factor level. Identification of a hemizygous F8 pathogenic variant on molecular genetic testing in a male proband confirms the diagnosis. Identification of a heterozygous F8 pathogenic variant on molecular genetic testing in a symptomatic female confirms the diagnosis.

Management.

Treatment of manifestations: Referral to a hemophilia treatment center (HTC) to facilitate treatment; intravenous infusion of factor VIII concentrate is most effective when infused within one hour of the onset of bleeding; training to facilitate home infusions administered by parents; immune tolerance therapy. For those with mild disease, including most symptomatic females, immediate treatment of bleeding with intravenous or nasal desmopressin acetate 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. Newer modified recombinant products with longer half-lives allow less frequent infusions.

Prevention of secondary complications. Reduction of bleeding and chronic joint disease is achieved by prophylactic treatment and prompt effective treatment of bleeding, including by use of home therapy.

Surveillance: For individuals with severe or moderate hemophilia A, assessments including inhibitor screen every six to 12 months at an HTC are recommended; for individuals with mild hemophilia A, assessment at an HTC every one to two years. Comorbidities may require more frequent visits.

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; cautious, if any, use of medications and herbal remedies that affect platelet function, including aspirin.

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 heterozygous females during pregnancy and for delayed bleeding post partum 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, bypassing agents, and gene therapy.

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.

Genetic counseling.

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 or if informative intragenic linked markers have been identified.

Diagnosis

Suggestive Findings

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

Clinical features

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

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

Laboratory features

  • Normal platelet count
  • Prolonged activated partial thromboplastin time (aPTT)
  • Normal prothrombin time (PT)

Establishing the Diagnosis

Male proband. The diagnosis of hemophilia A is established in a male proband by identification of deceased factor VIII clotting activity and a normal, functional von Willebrand factor level.

  • 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.

Identification of a hemizygous pathogenic variant in F8 by molecular genetic testing can help predict the clinical phenotype, assess the risk of developing a factor VIII inhibitor, and allow family studies (see Table 1).

Female proband. The diagnosis of hemophilia A is established by determination of low factor VIII clotting activity. Carrier status is determined by identification of a heterozygous pathogenic variant in F8 by molecular genetic testing (see Table 1). Factor VIII clotting activity is unreliable in the detection of heterozygous females; only approximately 30% of hemophilia A heterozygous females have factor VIII clotting activity lower than 40% [Plug et al 2006].

Molecular Testing

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing:

  • Single-gene testing. Targeted analysis for the intron 22 or intron 1 inversion is frequently performed first in (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.
    Sequence analysis of F8 followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found is performed if the common intron 22 or intron 1 inversion is not detected.
  • A multi-gene panel that includes F8 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests. (4) The ability of panels to detect structural variants in F8, a common cause of hemophilia A, should be confirmed.
    For more information on multi-gene panels click here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multi-gene panel that includes F8) fails to confirm a diagnosis in an individual with features of hemophilia A. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For more information on comprehensive genome sequencing click here.

Table 1.

Molecular Genetic Testing Used in Hemophilia A

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
Severe Hemophilia AModerate or Mild Hemophilia A
F8Targeted mutation analysis 3~48% 40% 4
Sequence analysis 5, 6~43% 776%-99% 7
Gene-targeted deletion/duplication analysis 81.3% 90.1% 9
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Intron 22 and intron 1 inversions can be detected by multiple techniques (e.g., long-range PCR [Bagnall et al 2006], inverse PCR [Rossetti et al 2008]), PCR-based “inverse shifting” procedure [Radic et al 2009]). Intron 22 inversions can be accompanied by adjacent deletions or duplications.

4.

An intron 22 inversion is identified in approximately 43%-45% of individuals with severe hemophilia A [Kaufman et al 2013, www​.mylifeourfuture.org]. An intron 1 inversion is identified in 2%-5% of individuals with severe hemophilia A [Gouw et al 2012, www​.mylifeourfuture.org] and has not been described in families with moderate or mild hemophilia A.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Lack of amplification by PCR prior to sequence analysis or loss of coverage in next-generation sequencing can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

7.

Kemball-Cook et al [1998], El-Maarri et al [2005], Kaufman et al [2013, author communication]

8.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

9.

Deletions and duplications detected using MLPA in 2779 males with severe hemophilia A or 2312 males with moderate/mild hemophilia A in the MyLifeOurFuture project

Test characteristics. See Clinical Utility Gene Card [Keeney et al 2011] for information on test characteristics including sensitivity and specificity.

Clinical Characteristics

Clinical Description

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. While joints are the most common sites of spontaneous bleeding, 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.

Heterozygous females with a factor VIII clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, subtle abnormal bleeding may occur with a baseline factor VIII clotting activity between 35% and 60% or higher [Plug et al 2006, Paroskie et al 2015].

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 severely affected individuals in the UK receiving adequate treatment was reported in 2007 as 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, less frequently, in those who have received more than 50 exposures [Kempton 2010, Eckhardt et al 2013] (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].

Genotype-Phenotype Correlations

Evidence for an association between variant type and disease severity

  • F8 intron 22 inversions are associated with severe hemophilia A and account for 45% of individuals with severe hemophilia A [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 variants. (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 variants often result in severe disease, but can result in mild or moderate disease, depending on the specific change and location.
  • Missense variants 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].

Penetrance

All males with an 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 30% of females with one F8 pathogenic variant and one normal allele have a factor VIII clotting activity lower than 40% and a bleeding disorder; mild bleeding can occur in heterozygous females with low-normal factor VIII activity [Plug et al 2006]. Overall, carriers have more bleeding than unaffected females [Paroskie et al 2015].

Nomenclature

Hemophilia A has also been referred to as “classic hemophilia.”

Prevalence

The birth prevalence of hemophilia A in the United States is approximately 1:6,500 live male births. Worldwide the birth prevalence for hemophilia A and B has been estimated at 1:10,000, although reports vary widely between countries [Stonebraker et al 2010, Srivastava et al 2013].

The birth prevalence is thought to be approximately the same in all countries and all races, presumably because of the high spontaneous mutation rate of F8 and its presence on the X chromosome.

Differential Diagnosis

Increased bleeding with trauma, tonsillectomy, or for a few hours following tooth extraction may not be suggestive of a bleeding disorder. 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. 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.

Inherited Bleeding Disorders with a Low Factor VIII Clotting Activity

Type 1 von Willebrand disease (VWD) is characterized by a partial quantitative deficiency of von Willebrand factor (low VWF antigen, low factor VIII clotting activity, and low VWF activity). Mucous membrane bleeding and prolonged oozing after surgery or tooth extractions are the predominant symptoms. VWF levels can differentiate mild hemophilia A from VWD. Individuals with hemophilia A have a normal VWF antigen level. Inheritance is autosomal dominant; penetrance varies.

Type 2A and 2B VWD are 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. Type 2A VWD is caused by pathogenic variant 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 2A and 2B VWD are typically inherited in an autosomal dominant manner.

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. Molecular genetic testing can aid in the diagnosis. Inheritance is autosomal dominant.

Type 2N VWD is an uncommon variant resulting from one of several missense variants 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. Inheritance is autosomal recessive.

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 (OMIM) 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].

Bleeding Disorders with a 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 (OMIM) is caused by mutation of F11. Heterozygotes have a factor XI coagulant activity of 25% to 75% of normal while homozygotes have activity of lower than 1% to 15% [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 (OMIM), prekallikrein (OMIM), or high molecular-weight kininogen deficiencies (OMIM) do not cause clinical bleeding but can cause a long activated partial thromboplastin time (aPTT).

Prothrombin (factor II) (OMIM), factor V (OMIM), factor X (OMIM), and factor VII (OMIM) deficiencies are rare bleeding disorders inherited in an autosomal recessive manner. 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.

Inherited fibrinogen disorders include complete (afibrinogenemia) or partial (hypofibrinogenemia) fibrinogen deficiency. Afibrinogenemia (OMIM) 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 (OMIM) can be inherited in either an autosomal dominant or an autosomal recessive manner. In dysfibrinogenemia (OMIM) there is discordance between the functional and antigenic level, with the latter usually in the normal range. Dysfibrinogenemia is inherited in an autosomal dominant manner. Individuals with hypofibrinogenemia or dysfibrinogenemia have mild-to-moderate bleeding symptoms or may be asymptomatic; rarely individuals with dysfibrinogenemia are at risk for thrombosis. For all fibrinogen disorders the thrombin and reptilase times are almost always prolonged and functional measurements of fibrinogen decreased.

Factor XIII deficiency (OMIM, OMIM) is a rare autosomal recessive disorder. 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 coagulation screening tests are normal; a screening test for clot solubility or a specific assay for factor XIII (FXIII) activity can confirm the diagnosis.

Platelet function disorders include Bernard-Soulier syndrome (OMIM), Glanzmann thrombasthenia (OMIM), and storage pool and nonspecific secretory defects. Individuals with platelet function disorders 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.

Management

Evaluations Following Initial Diagnosis

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

  • A personal and family history of bleeding to help predict disease severity
  • A joint and muscle evaluation, particularly if the individual describes a history of hemarthrosis or deep-muscle hematomas
  • Screening for hepatitis A, B, and C as well as HIV if blood products or plasma-derived clotting factor concentrates were administered prior to 1990
  • Baseline CBC with a platelet count, especially if there is a history of nose bleeds, GI bleeding, mouth bleeding, or (in females) menorrhagia or postpartum hemorrhage
  • Referral to a hemophilia treatment center. For locations:
  • 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
  • Consultation with a clinical geneticist and/or genetic counselor, particularly for a new diagnosis in the family and for females of childbearing years

Treatment of Manifestations

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

Intravenous infusion of plasma-derived or recombinant factor VIII for bleeding episodes within an hour of noticing symptoms:

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

Pediatric issues. Special considerations for care of infants and children with hemophilia A include the following [Chalmers et al 2011, Srivastava et al 2013]:

  • 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.
  • Immunizations should be administered preferably subcutaneously; intramuscular injections should be avoided unless under factor coverage.
  • Effective dosing of factor VIII requires an understanding of different pharmacokinetics in young children.

DDAVP® (desmopressin acetate). For individuals with mild hemophilia A, including symptomatic females, immediate treatment of bleeding can be achieved with DDAVP®. A single intravenous dose often doubles or triples factor VIII clotting activity. Alternatively, a multi-use nasal formulation of DDAVP® Nasal may be more convenient.

Note: Hemophilia genotype influences DDAVP® response [Castaman et al 2009, Nance et al 2013].

Immune tolerance therapy. Alloimmune inhibitors to factor VIII greatly compromise the ability to manage bleeding episodes [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 variants [Coppola et al 2009].

Prevention of Primary Manifestations

Prophylactic treatment is recommended by the National Hemophilia Foundation and the World Federation of Hemophilia 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]. Newer modified recombinant products with longer half-lives allow less frequent infusions.

  • Factor VIII concentrate infusions given prophylactically in young boys before or just after their first few joint bleeds can nearly eliminate spontaneous bleeding and prevent chronic joint disease [Manco-Johnson et al 2007].
  • The greatest benefit is seen in affected individuals who start therapy before age 2.5 to three years. 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].
  • "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. An increasing number of adults with hemophilia are on long-term prophylaxis and clinical benefit is being documented in short- and long-term studies.

Prevention of Secondary Complications

Reduction of bleeding and chronic joint disease is achieved by prophylactic treatment and prompt effective treatment of bleeding, including by use of home therapy. Many recombinant products are now created without human- or animal-derived proteins in the process or final product. Virucidal treatment of plasma-derived concentrates has eliminated the risk of HIV transmission since 1985, and of hepatitis B and C viruses since 1990.

Surveillance

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

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

Screening for alloimmune inhibitors is indicated at least once during the first ten to 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 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 an assessment at an HTC every one to two years. Affected individuals with comorbidities and other complications or treatment challenges may require more frequent visits.

Agents/Circumstances to Avoid

Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is excluded; or, if present, the infant should be treated with factor VIII concentrate directly before and after the procedure.

Medications and herbal remedies that affect platelet function, including aspirin, should be avoided unless there is strong medical indication, such as in individuals with atherosclerotic cardiovascular disease. Individuals with severe hemophilia usually require clotting factor prophylaxis to allow aspirin and other platelet inhibitory drugs to be used safely [Angelini et al 2016].

Avoid the following:

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

Evaluation of Relatives at Risk

Identification of at-risk relatives. A thorough family history may identify other 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: Ideally, 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. If not available a standard blue top tube can be used.

Determination of genetic status of females at risk. Approximately 30% of heterozygous females have factor VIII activity lower than 40% and may have abnormal bleeding. In a survey of Dutch heterozygous females, bleeding symptoms correlated with baseline factor clotting activity; there was suggestion of a very mild increase in bleeding even in those with 40% to 60% factor 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 female 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 female at risk be established prior to pregnancy or as early in a pregnancy as possible.

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

Pregnancy Management

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

If the female is symptomatic (i.e., has baseline factor VIII clotting activity <40%), 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. The factor VIII level should be measured in the third trimester to confirm that the level is in the normal range, and if it is not, a plan for factor replacement therapy should be developed. Postpartum factor VIII clotting activity can return to baseline within 48 hours, and postpartum hemorrhage 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]. In retrospective data analysis of 580 males age 0-2 years with hemophilia, 17 suffered intracranial hemorrhages with delivery, and all but one were delivered vaginally [Kulkarni et al 2009]. This finding supports the recommendation of cesarean section for hemophilic infants, however, 12 of the 17 were born to women not known to be carriers, suggesting that a planned delivery may mitigate risks. In anticipation of delivery, the relative risks of cesarean section versus vaginal delivery should be considered and discussed with the family and obstetrician in anticipation of delivery so that a coordinated plan can be developed.

Therapies Under Investigation

Recombinant factor VIII molecules are being modified to extend their half-life and allow less frequent infusions [Young & Mahlangu 2016]. Two products are FDA approved, one modified by pegylation and one by Fc fusion; others are in clinical trials. These result in half-life extension by approximately 1.5 fold. Products with greater half-life extension are under development.

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 clinical or preclinical study [Kaufman & Powell 2013].

Clinical trials for gene therapy for hemophilia A have begun and others are in the preclinical phase [Spencer et al 2016].

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 recommended to treat hemophilia A because it is not treated with a virucidal agent.

Genetic Counseling

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 disorder nor will he be hemizygous for the F8 pathogenic variant; therefore, he does not require further evaluation/testing.
  • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a female has more than one affected son and no other affected relatives and the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
  • If the proband represents a simplex case, the mother of the affected male may or may not be a carrier. (A simplex case refers to an affected male with no family history of hemophilia; ~30% of affected males have no family history of hemophilia A.) Several possibilities regarding his mother's carrier status and the carrier risks of extended family members need to be considered:
    • The mother is not a carrier and the pathogenic variant occurred de novo in the affected male; as many as 15% of probands with a single nucleotide variant and no known family history of hemophilia A have somatic mosaicism for an F8 pathogenic variant [Leuer et al 2001].
    • The mother is a carrier of a de novo pathogenic variant that occurred in one of the following ways:
      • As a germline variant (i.e., in the egg or sperm at the time of her conception and thus present in every cell of her body and detectable in her leukocyte DNA). Ninety-eight percent of mothers of a simplex case with an intron 22 inversion are carriers because most of these pathogenic variants occur in spermatogenesis.
      • As a somatic variant (i.e., a change that occurred very early in embryogenesis, resulting in somatic mosaicism in which the pathogenic variant is present in some but not all cells and may or may not be detectable in her leukocyte 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 her leukocyte DNA)
    • The mother is a carrier of an inherited pathogenic variant. The mother may have inherited the pathogenic variant either from her mother who has a de novo pathogenic variant or from her asymptomatic father who is mosaic for the pathogenic variant. Alternatively, the mother may be a carrier of an inherited pathogenic variant that arose in a previous generation and has been passed on through the family without manifesting symptoms in female carriers.
      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 pathogenic variant. Determining the point of origin of a de novo pathogenic variant 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 genetic 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 an increased (but low) risk of having additional affected children.
  • All sibs should have factor VIII clotting activity assayed unless molecular genetic testing confirms that they have not inherited the F8 pathogenic variant present in the 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 F8 pathogenic variant, have hemophilia A, or pass it on to their offspring.

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

Heterozygote (Carrier) Detection

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

Factor 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 [2007] for findings of a qualitative study in Australia on how cultural and religious issues influence parental attitudes about genetic testing.

Family planning

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

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the F8 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for hemophilia A [Laurie et al 2010] are possible.

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

Resources

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 Street
    Montreal Quebec H3B 3B6
    Canada
    Phone: 800-668-2686 (toll-free); 514-848-0503
    Fax: 514-848-9661
    Email: chs@hemophilia.ca
  • Haemophilia Society
    Petersham House
    57a Hatton Garden
    First Floor
    London EC1N 8JG
    United Kingdom
    Phone: 020 7831 1020; 0800 018 6068 (Toll-free Helpline)
    Fax: 020 7405 4824
    Email: info@haemophilia.org.uk
  • My46 Trait Profile
  • National Hemophilia Foundation (NHF)
    116 West 32nd Street
    11th Floor
    New York NY 10001
    Phone: 212-328-3700
    Fax: 212-328-3777
    Email: handi@hemophilia.org
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • World Federation of Hemophilia
    1425 Rene Levesque Boulevard West
    Suite 1010
    Montreal Quebec H3G 1T7
    Canada
    Phone: 514-875-7944
    Fax: 514-875-8916
    Email: wfh@wfh.org
  • Medline Plus
  • American Thrombosis and Hemostasis Network (ATHN) Registry
    Chicago IL
    Phone: 800-360-2846
    Fax: 847-572-0967
    Email: info@athn.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Hemophilia A: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Hemophilia A (View All in OMIM)

300841COAGULATION FACTOR VIII; F8
306700HEMOPHILIA A; HEMA

Molecular Genetic Pathogenesis

Gene structure. F8 spans 186 kb and comprises 26 exons [Thompson 2003]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic 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 and 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). Infrequently, a third telomeric copy is present and may lead to an alternate intron 22 inversion; 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 variants, and missense variants. These non-inversion variants 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 variants (see Table A, Locus-Specific Databases). High-resolution crystal structure of a recombinant human C2 domain is known, and hemophilic missense variants have been localized to it and to a model of the homologous C1 domain [Liu et al 2000].

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. 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. Pathogenic variants may result in reduced levels of factor VIII clotting activity and antigen 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].

References

Published Guidelines Regarding Genetic Testing (for the UK)

  • Keeney S, Mitchell M, Goodeve A. Practice guidelines for the molecular diagnosis of haemophilia A. UK Haemophilia Centre, Doctors’ Organisation (UKHCDO), Haemophilia Genetics Laboratory Network, and Clinical Molecular Genetics Society. Available online. 2010. Accessed 1-26-17.
  • 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. UK Haemophilia Centre Doctors' Organisation. Available online. 2005. Accessed 1-26-17. [PubMed: 15810917]

Treatment Guidelines

  • Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A. Guidelines for the management of hemophilia. World Federation of Hemophilia. Available online. 2013. Accessed 1-26-17.
  • Pai M, Key NS, Skinner M, Curtis R, Feinstein M, Kessler C, Lane SJ, Makris M, Riker E, Santesso N, Soucie JM, Yeung CHT, Iorio A, Schünemann HJ. NHF-McMaster guideline on care models for haemophilia management. Available online. 2016. Accessed 1-26-17. [PubMed: 27348396]

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Suggested Reading

  • Carcao MD, van den Berg HM, Ljung R, Mancuso ME. Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A. Blood. 2013;121:3946–52. [PubMed: 23482934]
  • Goodeve A. Molecular genetic testing of hemophilia A. Semin Thromb Hemost. 2008;34:491–501. [PubMed: 19085648]
  • Marijke van den Berg H. Preventing bleeds by treatment: new era for haemophilia changing the paradigm. Haemophilia. 2016;22 Suppl 5:9–13. [PubMed: 27405669]
  • Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet. 2016;388:187–97. [PubMed: 26897598]
  • Peyvandi F, Kunicki T, Lillicrap D. Genetic sequence analysis of inherited bleeding diseases. Blood. 2013;122:3423–31. [PMC free article: PMC4260973] [PubMed: 24124085]
  • Winikoff R, Lee C. Hemophilia carrier status and counseling the symptomatic and asymptomatic adolescent. J Pediatr Adolesc Gynecol. 2010;23:S43–7. [PubMed: 21108512]

Chapter Notes

Author History

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

Revision History

  • 2 February 2017 (sw) Comprehensive update posted live
  • 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
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