Hemophilia A

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 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, 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.

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].

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.

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 variants 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 613625) 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 612416) 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 234000), prekallikrein (OMIM 612423), or high molecular weight kininogen deficiencies (OMIM 228960) do not cause clinical bleeding but can cause a long activated partial thromboplastin time (aPTT).

Prothrombin (factor II) (OMIM 613679), factor V (OMIM 227400), factor X (OMIM 227600), and factor VII (OMIM 227500) 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 202400) 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 616004) can be inherited in either an autosomal dominant or an autosomal recessive manner. In dysfibrinogenemia (OMIM 616004) 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 613225, 613235) 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 231200), Glanzmann thrombasthenia (OMIM 273800), 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.

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:
  • Worldwide, see World Federation of Hæmophilia;
  • US only, see National Hemophilia Foundation.
• 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 US 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 multiuse 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