Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[Classic Hemophilia, Factor VIII Deficiency]
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Authors:
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Cheryl L Brower, RN, MSPH
Arthur R Thompson, MD, PhD |
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Initial Posting:
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Last Update:
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Disease 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 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 year of life; without prophylactic treatment, they have an average of two to five spontaneous bleeding episodes each month. Individuals with moderately severe 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 from once a month to once a year. Individuals with mild hemophilia A do not have spontaneous bleeding; however, without preventive treatment, abnormal bleeding occurs with surgery, tooth extraction, 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. 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.
Diagnosis/testing. 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 disease-causing mutations in as many as 98% of individuals with hemophilia A. Such testing is available clinically.
Management. Treatment of manifestations: referral to one of the approximately 140 federally funded hemophilia treatment centers (HTCs) for assessment, education, and genetic counseling; for those with severe disease, intravenous infusion of plasma-derived or recombinant factor VIII concentrate within one hour of 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. Training and home treatment with parental followed by self-infusion are critical components of comprehensive care. Prevention of primary manifestations: For those with severe disease, prophylactic infusions of factor VIII concentrate three times a week or every other day usually maintain factor VIII clotting activity higher than 1% and prevent spontaneous bleeding. Prevention of secondary complications: reduction of chronic joint disease by prompt effective treatment of bleeding, including home therapy. Surveillance: For individuals with severe or moderately severe hemophilia A, annual assessments at an HTC are recommended; for individuals with mild hemophilia A, every two to three years; monitor carrier mothers for delayed bleeding post-partum unless it is known that their baseline factor VIII clotting activity is normal. 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. Testing of relatives at risk: to clarify genetic status of females at risk before pregnancy or early in pregnancy, to facilitate management. Therapies under investigation: ongoing clinical trials for a longer-acting factor VIII concentrate. 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.
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 mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation are carriers. Affected males transmit the mutation to all of their daughters and none of their sons. Carrier testing for family members at risk and prenatal testing for pregnancies at increased risk are possible if the F8 disease-causing mutation 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:
* Any severity, otherwise, especially in more severely affected persons
Coagulation screening tests. Evaluation of an individual with a suspected bleeding disorder includes: platelet count and platelet function analysis (PFA closure times) or bleeding time, activated partial thromboplastin time (APTT), and prothrombin time (PT). Thrombin time and/or plasma concentration of fibrinogen can be useful for rare disorders.
In individuals with hemophilia A, the above screening tests are normal, with the following exceptions:
Note: In many clinical laboratories, the APTT is not sensitive enough to diagnose mild hemophilia A.
Coagulation factor assays. Individuals with a history of a lifelong bleeding tendency should have specific coagulation factor assays performed even if all the coagulation screening tests are in the normal range:
The normal range for factor VIII clotting activity is 50%-150%.
Individuals with factor VIII clotting activity higher than 30% usually do not have bleeding [Kaufman et al 2006]. However, a mild bleeding tendency can occur with low to low-normal factor VIII clotting activity in hemophila A carrier females [Plug et al 2006] or in those with mild von Willebrand disease.
In hemophilia A, the factor VIII clotting activity is usually lower than 30%-35% with a normal, functional von Willebrand factor level.
Classification of hemophilia A based on in vitro clotting activity:
Severe hemophilia A: <1% factor VIII
Moderately severe hemophilia A: 1%-5% factor VIII
Mild hemophilia A: 6%-35% factor VIII
Note: Rarely, in individuals with mild hemophilia A, a standard "one-stage" factor VIII clotting activity assay shows near-normal or low-normal factor VIII clotting activity (40%-80%), whereas in a "two-stage" or chromogenic assay, factor VIII activity is low. Thus, low-normal in vitro clotting activity does not always exclude the presence of mild hemophilia A.
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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.
Gene. F8 is the only gene known to be associated with hemophilia A.
Clinical testing
An F8 intron 22-A gene inversion accounts for nearly half of families with severe hemophilia A [Kaufman et al 2006]. This inversion can be detected by Southern blotting or, more recently, by long-range [Bowen & Keeney 2003] or inverse [Rossetti et al 2005] PCR.
An F8 intron 1 gene inversion accounts for 2%-3% of severe hemophilia A. This inversion is typically detected by PCR [Bagnall et al 2002].
Mutation scanning or sequence analysis
The mutation detection rate in individuals with hemophilia A who do not have one of the two common inversions varies from 75% to 98%, depending on the screening method used.
In severe hemophilia A, gross gene alterations (including large deletions or insertions, frameshift and splice junction changes, and nonsense and missense mutations) of F8 account for approximately 50% of mutations detected [Kemball-Cook et al 1998 , El-Maarri et al 2005 , Kaufman et al 2006].
In mild to moderately severe hemophilia A, missense mutations within the exons coding for the three A domains or the two C domains account for most of the mutations detected [Kemball-Cook et al 1998 , Kaufman et al 2006].
Deletion analysis is available clinically to detect exonic, multi-exonic, or larger deletions in affected males. Deletion analysis is also available for direct diagnosis in potential carrier females.
Note: Mutation scanning and sequence analysis cannot detect gene deletions and rearrangements in females, except by quantitative methods available in limited research settings.
Table 1
summarizes molecular genetic testing for this disorder.
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1. Intron 22 inversions can be accompanied by adjacent partial gene deletions or duplication/insertions [Andrikovics et al 2003].
2. A microarray approach identified 96% of known point mutations in a selected portion of the factor VIII coding sequence [Berber et al 2006]. However, because of the large number of distinct hemophilic mutations, it remains unclear whether such an approach would be economically feasible at present. |
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Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Linkage analysis is used to track an unidentified F8 disease-causing allele in a family and to identify the origin of de novo mutations:
Tracking an unidentified F8 mutation. When a disease-causing mutation of the F8 gene is not identified in an affected family member by direct DNA testing, linkage analysis can be considered to obtain information for genetic counseling in families in which more than one family member has the unequivocal diagnosis of hemophilia A. Linkage studies are always based on accurate clinical diagnosis of hemophilia A in the affected family members and accurate understanding of the genetic relationships in the family. In addition, linkage analysis depends on the availability and willingness of family members to be tested and on the presence of informative heterozygous polymorphic markers. Use of up to five intragenic polymorphisms and one extragenic polymorphism is informative in approximately 80%-90% of families. Recombination events between F8 and the extragenic site occur in up to 5% of meioses, but have not been observed between hemophilic mutations and intragenic sites.
Identifying the origin of a de novo mutation. Among the nearly 50% of families with a simplex case of hemophilia A (i.e., occurrence in one family member only), the origin of a de novo mutation can often be identified by performing molecular genetic testing in conjunction with linkage analysis. The presence of the mutation on the affected individual's factor VIII haplotype is tracked back through the parents and, if necessary, through maternal grandparents to identify the individual in whom the mutation originated.
Establishing the diagnosis of hemophilia A in a proband requires measurement of factor VIII clotting activity.
Molecular genetic testing is performed on a proband to detect the family-specific mutation in F8 in order to obtain information for genetic counseling of at-risk family members.
For prognostication in individuals who represent a simplex case (i.e., who are the only affected member in a family), identification of the specific F8 mutation can help predict the clinical phenotype and assess the risk of developing a factor VIII inhibitor.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.
Note: Carriers are heterozygotes for an X-linked disorder and may develop clinical findings related to the disorder.
Prenatal diagnosis and preimplantation diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
No other phenotypes are associated with mutations in F8.
Hemophilia A in the untreated individual is characterized by delayed bleeding or prolonged oozing after injuries, tooth extractions, or surgery, or renewed bleeding after initial bleeding has stopped [Kessler & Mariani 2006]. Muscle hematomas or intracranial bleeding can occur four or five days after the original injury. Intermittent oozing may last for days or weeks after tooth extraction. Prolonged or delayed bleeding or wound hematoma formation after surgery is common. After circumcision, males with hemophilia A of any severity may have prolonged oozing; but they can also heal normally without treatment. In severe hemophilia A, spontaneous joint bleeding is the most frequent symptom.
The age of diagnosis and frequency of bleeding episodes in the untreated individual are related to the factor VIII clotting activity (see Table 2). In any affected individual, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. To some extent, this greater frequency is a function of both physical activity levels and vulnerability during more rapid growth.
Individuals with severe hemophilia A are usually diagnosed during the first year of life. On rare occasions, infants with severe hemophilia A have extra- or intracranial bleeding following birth. In untreated toddlers, bleeding from minor mouth injuries and large "goose eggs" from minor head bumps are common and are the most frequent presenting symptoms of severe hemophilia A. Intracranial bleeding may also result from head injuries. The untreated child almost always has subcutaneous hematomas; some have been referred for evaluation of possible non-accidental trauma.
As the child grows and becomes more active, spontaneous joint bleeds occur with increasing frequency unless the child is on a prophylactic treatment program. Spontaneous joint bleeds or deep-muscle hematomas initially cause pain or limping before swelling appears. Children and adults with severe hemophilia A who are not treated have an average of two to five spontaneous bleeding episodes each month. Joints are the most common sites of spontaneous bleeding, but other sites include the kidneys, gastrointestinal tract, and brain. Without prophylactic treatment, individuals with hemophilia A have prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions.
Individuals with moderately severe hemophilia A seldom have spontaneous bleeding. However, without treatment they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years. Without treatment, the frequency of bleeding episodes varies from once a month to once a year. Signs and symptoms of bleeding are the same as for severe hemophilia A.
Individuals with mild hemophilia A do not have spontaneous bleeding. However, without treatment abnormal bleeding occurs with surgery, tooth extractions, and major injuries. The frequency of bleeding may vary from once a year to once every ten years. Individuals with mild hemophilia A are often not diagnosed until later in life when they undergo surgery or tooth extraction or experience major trauma.
Carrier females with a factor VIII clotting activity level lower than 35% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with a baseline factor VIII clotting activity between 35% and 60% [Plug et al 2006].
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1. Clinical severity does not always correlate with the in vitro assay result.
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Complications of untreated bleeding. The leading cause of death related to bleeding is intracranial hemorrhage. The major cause of disability from bleeding is chronic joint disease [Luck et al 2004]. Currently available treatment with clotting factor concentrates is normalizing life expectancy and reducing chronic joint disease for children with hemophilia A. Prior to the availability of such treatment, the median life expectancy for individuals with severe hemophilia A was 11 years — the current life expectancy for affected individuals in several developing countries. Excluding death from HIV, life expectancy for those severely affected individuals receiving adequate treatment is 63 years [Darby et al 2007].
Other. Since the mid-1960s, the mainstay of treatment of bleeding episodes has been the use of plasma-derived factor VIII concentrate. Many individuals who received blood products from 1979 to 1985 contracted HIV. Approximately half of these individuals died of AIDS prior to the advent of effective HIV therapy.
Most individuals exposed to plasma-derived concentrates prior to the late 1980s became chronic carriers of the hepatitis C virus. Viral inactivation and detection methods developed in the 1980s have essentially eliminated this complication.
Approximately 30% of individuals with severe hemophilia A develop alloimmune inhibitors to factor VIII (see Management, Treatment of Manifestations).
F8 gene inversions are associated with severe hemophilia A and account for 45% of the severe cases [Kaufman et al 2006]. Occasionally, individuals considered to have moderately severe hemophilia A have been found to have F8 gene inversions. Often their assays are found to have contained either some residual factor VIII clotting activity from a prior transfusion or the assay methods used were inaccurate at low levels.
An inversion between a 1-kb sequence in intron 1 and an inverted repeat 5' to the factor VIII gene [Bagnall et al 2002] is also associated with a severe phenotype, and some individuals have developed inhibitors.
Point mutations leading to new stop codons are essentially all associated with a severe phenotype, as are most frameshift mutations. (An exception is the insertion or deletion of adenosine bases resulting in a sequence of eight to ten adenosines, which may result in moderately severe hemophilia A [Nakaya et al 2001].)
Splice site mutations are often severe but may be mild, depending on the specific change and location.
Missense mutations occur in fewer than 20% of individuals with severe hemophilia A but nearly all of those with mild or moderately severe bleeding tendencies (see Locus-Specific Database) [Kaufman et al 2006].
All males with a F8 disease-causing mutation will be affected and will have approximately the same severity of disease as other affected males in the family. However, other genetic and environmental effects may modify the clinical severity somewhat.
Approximately 10% of females with one F8 disease-causing mutation and one normal allele have a mild bleeding disorder.
Anticipation 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 and its presence on the X chromosome.
Prevalence is approximately 1:10,000 in the US and other countries in which optimum treatment with clotting factor concentrates is available [Kessler & Mariani 2006].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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, or after a tonsillectomy, or for a few hours following tooth extraction may not be significant. On the other hand, 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 careful 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 moderately severe 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. Some families with mild hemophilia A are mistakenly diagnosed as having von Willebrand disease because both men and women have abnormal bleeding. With improved testing for von Willebrand disease, it is now 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:
Mild (type 1) von Willebrand disease (VWD) accounts for 80% of individuals with VWD and is characterized by a quantitative deficiency of von Willebrand factor (low VWF antigen, factor VIII clotting activity, and ristocetin cofactor activity). Mucous membrane bleeding and prolonged oozing after surgery or tooth extractions are the predominant symptoms but laboratory testing is needed to differentiate mild hemophilia from VWD. Essentially all individuals with hemophilia A have a normal VWF level. Inheritance of VWD is autosomal dominant; penetrance varies.
Type 2A or 2B von Willebrand disease (type 2 VWD) is characterized by a qualitative deficiency of VWF with a decrease of the high molecular weight multimers. VWF antigen and factor VIII clotting activity may be low-normal to mildly decreased. Functional VWF level is low in a ristocetin cofactor assay. Inheritance is autosomal dominant.
Type 2N von Willebrand disease (type 2N VWD) is an uncommon variant caused by several missense mutations in the amino terminus of the VWF protein, resulting in defective binding of factor VIII to VWF. Platelet function 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 the F8 gene, molecular genetic testing of the VWF gene, or measuring binding of factor VIII to VWF using ELISA or column chromatography. The low factor VIII clotting activity usually shows autosomal recessive inheritance.
Severe (type 3) von Willebrand disease (type 3 VWD) is characterized by frequent episodes of mucous membrane bleeding, and joint and muscle bleeding similar to that seen in individuals with hemophilia A. The VWF level is lower than 1% and the factor VIII clotting activity is 2%-8%. Inheritance is autosomal recessive. 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 genes (LMAN1 or MCFD2) encoding intracellular chaperone proteins [Zhang & Ginsburg 2006].
The following are other bleeding disorders with normal factor VIII clotting activity:
Hemophilia B is clinically indistinguishable from hemophilia A. Diagnosis is based on a factor IX clotting activity lower than 30%. Inheritance is X-linked.
Factor XI deficiency [Thompson 2006] is inherited in an autosomal recessive manner with heterozygotes showing a factor XI coagulant activity of 25%-75% of normal, while homozygotes have activity of lower than 1% to 15%. Two mutations are common among individuals of Ashkenazi Jewish descent. Both compound heterozygotes and homozygotes may exhibit bleeding similar to that seen in mild or moderately severe 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 APTT.
Prothrombin (factor II), factor V, factor X, and factor VII deficiencies [Thompson 2006] 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.
Fibrinogen disorders [Thompson 2006] can be severe, mild, or asymptomatic:
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 venous thrombosis. Diagnosis is based on kinetic being lower than antigenic protein levels, although the thrombin time is usually prolonged and is a simple screening test.
Factor XIII deficiency [Thompson 2006] 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 kinetic coagulation screening tests are normal; a specific test for clot solubility 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.
Bernard-Soulier syndrome is inherited in an autosomal recessive manner and involves the VWF receptor and platelet GPIb.
Glanzmann's 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.
To establish the extent of disease in an individual diagnosed with hemophilia A, the following evaluations are recommended:
Identification of the specific disease-causing mutation in an individual to aid in determining: disease severity, the likelihood of inhibitor development, and the chance that immune tolerance will be successful if an inhibitor does develop
A personal and family history of bleeding to help predict severity
A joint and muscle evaluation, particularly if the individual describes a history of hemarthrosis or deep muscle hematomas
Screening for hepatitis A, B, and C, as well as HIV, particularly if blood products or plasma-derived clotting factor concentrates were administered prior to 1985
Baseline CBC and platelet count, especially if there is a history of nose bleeds, GI bleeding, mouth bleeding, or, in women, menorrhagia
Life expectancy for individuals with hemophilia A has greatly increased over the past four decades [Darby et al 2007]; disability has decreased with the intravenous infusion of factor VIII concentrate, home infusion programs, prophylactic treatment, and improved patient education.
Individuals with hemophilia A benefit from referral for assessment, education, and genetic counseling at one of the approximately 140 federally funded hemophilia treatment centers (HTCs) that can be located through the National Hemophilia Foundation . The treatment centers establish appropriate treatment plans and provide referrals or direct care for individuals with inherited bleeding disorders. They also are a resource for current information on new treatment modalities for hemophilia. An assessment at one of these centers usually includes extensive patient education, genetic counseling, and laboratory testing.
Intravenous infusion of factor VIII concentrate. Recombinant factor VIII concentrates (including one that has no human- or animal-derived proteins) have been available for more than 15 years. Virucidal treatment of plasma-derived concentrates has eliminated the risk of HIV transmission since 1985, and of hepatitis B and C viruses since 1990.
Bleeding episodes are prevented or controlled quickly with intravenous infusions of either plasma-derived or recombinant factor VIII concentrate. Fast, effective treatment of bleeding episodes decreases pain, disability, and chronic joint disease. Ideally, the affected individual should receive clotting factor within an hour of noticing symptoms [Kessler & Mariani 2006]. Doses vary among individuals, but knowledge of a single in vivo recovery value is not particularly helpful in determining the appropriate dose [Bjorkman et al 2007]:
Arranging efficient, effective treatment for infants and toddlers is especially challenging. Because frequent venipunctures may be necessary, it is important to identify staff members who are expert in performing venipunctures in small children.
It is recommended that the parents of children age two to five years with severe hemophilia A be trained to administer the infusions as soon as it is feasible. Home treatment allows for prompt treatment after symptoms occur.
DDAVP (1-deamino-8-D-arginine vasopressin). For many individuals with mild hemophilia A, including most symptomatic carriers, immediate treatment of bleeding or prophylaxis can be achieved with desmopressin (DDAVP). A single intravenous dose often doubles or triples factor VIII clotting activity. Alternatively, a multi-use, nasal formulation of desmopressin (Stimate®) is available.
Obstetrical issues [Lee et al 2006]. It is recommended that the carrier status of a woman at risk be established prior to pregnancy or as early in a pregnancy as possible.
At birth, or in the early neonatal period, intracranial hemorrhage in affected males is uncommon (1%-2%) even in those with severe hemophilia A who are delivered vaginally. Cesarean section is reserved for complicated deliveries.
If the mother is a symptomatic carrier (i.e., has baseline factor VIII clotting activity <35%), she will be somewhat protected by the natural rise of factor VIII clotting activity during pregnancy, which may even double by the end of the third trimester. However, postpartum factor VIII clotting activity can return to baseline within 48 hours, and delayed bleeding ensue.
Pediatric issues [Chalmers et al 2005]. Special considerations for care of infants and children with hemophilia A include the following:
Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, is treated with factor VIII concentrate just prior to and subsequent to the procedure to prevent delayed oozing and poor wound healing.
Intramuscular injections should be avoided; immunizations should be administered subcutaneously.
Effective dosing of factor VIII requires an understanding of different pharmacokinetics in young children.
Inhibitors. Inhibitors greatly compromise the ability to manage bleeding episodes [Hay et al 2006 , Kessler & Mariani 2006]. The inhibitor can be eliminated by immune tolerance therapy in up to 70%-80% of cases. Individuals with large gene deletions are less likely to respond to immune tolerance than individuals with other types of mutations [Peyvandi et al 2006].
Children with severe hemophilia A are often given "primary" prophylactic infusions of factor VIII concentrate three times a week or every other day to maintain factor VIII clotting activity higher than 1%; these infusions prevent spontaneous bleeding and decrease the number of bleeding episodes. Prophylactic infusions almost completely eliminate joint bleeding and greatly decrease chronic joint disease.
Prevention of chronic joint disease is a major concern. It is agreed that most individuals with severe hemophilia A benefit from primary prophylaxis but there is still controversy about when these regular infusions should begin. The age at which a child experiences the first joint bleed can vary greatly. Prophylactic infusions almost completely eliminate spontaneous joint bleeding, decreasing chronic joint disease, although complications of venous access ports in young children can occur [Feldman et al 2006 , Manco-Johnson et al 2007].
"Secondary" prophylaxis is often used for several weeks if recurrent bleeding in a "target" joint or synovitis occurs.
Persons with hemophilia who are followed at hemophilia treatment centers (HTCs) (see Resources) have lower mortality than those who are not [Soucie et al 2000]. It is recommended that young children with severe or moderately severe hemophilia A have assessments at an HTC (accompanied by their parents) every six to 12 months to review their history of bleeding episodes and to adjust treatment plans as needed. Early signs and symptoms of possible bleeding episodes are reviewed. The assessment should also include a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, and a discussion of any other problems related to the individual's hemophilia and family and community support.
Screening for alloimmune inhibitors is usually done in individuals with severe hemophilia A every three to six months after treatment with factor VIII concentrates has been initiated either for bleeding or prophylaxis; after 50 to 100 exposure days, annual screening is sufficient; in adults, it is usually performed only prior to any elective surgery. Testing for inhibitors should also be perf
