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Hemophilia A and Hemophilia B
Epidemiology and Genetics
The hemophilias are the best known of the hereditary bleeding disorders. Hemophilia A or B arises as the result of a congenital deficiency of coagulation factor protein VIII or IX, respectively. Both are X-linked recessive disorders, almost exclusively affecting males, whereas daughters and mothers are carriers of the gene defect.
The incidence of hemophilia A and B is equal across all ethnic and racial groups. Hemophilia A occurs in 1 of every 5000 live male births and accounts for approximately 80% of hemophilia cases. Hemophilia B occurs less commonly (1 of every 30,000 live male births). Approximately 30% of hemophilia cases occur spontaneously, with no prior family history of hemophilia or maternal carriership of a defective factor VIII or factor IX gene.
The genes for factor VIII and factor IX are located on the X chromosome. The factor VIII gene comprises 186,000 base pairs and is considerably larger than the factor IX gene, which consists of 34,000 base pairs. Because of its large size, the factor VIII gene is more susceptible to mutations, which may account for the greater prevalence of hemophilia A than of hemophilia B (about 5 : 1).
Symptomatic hemophilia A or B rarely affects females but can do so by virtue of any of the following genetic mechanisms: (1) high degree of lyonization of factor VIII or IX alleles in carriers, leading to the symptomatic carrier state; (2) hemizygosity of the X chromosome (XO karyotype) in females with Turner syndrome; and (3) homozygosity in female progeny of maternal hemophilia carriers and paternal hemophilic males. Females in whom a low factor VIII level is detected should undergo diagnostic evaluation for exclusion of von Willebrand disease (VWD) variant type 2 Normandy (2N) or VWD type 3, or testicular feminization syndrome.
The most common mutation of the factor VIII gene, responsible for at least 45% of cases of severe hemophilia A, involves the inversion of intron 22 on the X chromosome. This results from the intrachromosomal translocation and unequal exchange of DNA between either of two telomere-located extragenic nonfunctional factor VIII–homologous DNA sequences with nested functional factor VIII genes within intron 22. A second inversion, involving intron 1, has been reported in up to 5% of cases. The mutations that lead to these recombinations appear to arise predominantly in the male germline and produce disjointed and inverted DNA sequences, which prevent the transcription of a normal full-length factor VIII molecule. The coded protein typically possesses no functional or immunologic factor VIII activity in severe hemophilia A. Less commonly, severe hemophilia A may be due to large gene deletions involving multiple or single domains, small point mutations resulting in the formation of stop codon sequences, or insertions and/or deletions within the gene. Types of hemophilia A of moderate and mild severity are mainly the result of missense mutations; many different point mutations and deletions have been identified in patients with mild or moderate hemophilia A.
The incidence of alloantibody inhibitors, which neutralize the coagulation function of exogenously administered native, normal factor VIII protein in individuals with severe hemophilia A, is highest in those with stop mutations in light-chain domains. This is significant in that alloantibodies (and autoantibody inhibitors) are directed against epitopes on the A 2 >C 2 >A 3 domains of the factor VIII coagulant protein. The A 2 and A 3 domains normally interact with factor IXa; C 2 interacts with phospholipid and von Willebrand factor (VWF) protein. Inhibitory antibodies that target and complex with these domains block these interactions and thus interfere with formation of the tenase complex of coagulation ( Fig. 3.1 ). Resources for cataloging the known mutations of factor VIII are the HAMSTeRS (Haemophilia A Mutation, Structure, Test, and Resource Site) website ( http://hadb.org.uk/WebPages/PublicFiles/Progress_2012.htm ) and the American Thrombosis and Hemostasis Network initiative My Life, Our Future Research Repository.
Numerous point mutations and deletions have been identified in individuals with hemophilia B. These frequently result in the production of a defective, nonfunctioning, but immunologically detectable factor IX protein in the plasma (cross-reacting material positive [CRM + ]). Individuals with large gene deletions and nonsense mutations are usually CRM − and are most susceptible to the development of factor IX alloantibodies. The Factor IX Mutation Database, which is an excellent resource for the factor IX gene, may be found on the Internet at http://www.kcl.ac.uk/ip/petergreen/haemBdatabase.html .
A diagnostic molecular algorithm, including the detection of inversions of introns 1 and 22, Next Generation Sequence (NGS) custom panel (the entire factor VIII, factor IX and VWF genes), and multiplex ligation-dependent probe amplification (MLPA) analysis, has been shown to reliably detect pathogenic variants of hemophilia A and hemophilia B.
Carrier Testing
The most common methods for identification of carrier status are direct gene sequencing and linkage analysis to identify DNA polymorphisms. For women with a family history of severe hemophilia A, first-line testing involves identification of the intron 22 inversion. In individuals in whom the inversion is not detected, or for whom no family members are available for testing, the more cumbersome and labor-intensive method of linkage analysis can be performed with restriction fragment length polymorphism in the search for DNA polymorphisms. Before any testing is suggested, patients should be referred to a genetic counselor, who can provide advice and recommendations for appropriate diagnostic testing. Mutations of the factor IX gene are more easily detected because it is one-third the size of the factor VIII gene. More than 300 mutations of the factor IX gene have been identified, the most common of which are single point mutations. Microarray analysis may provide rapid screening for factor IX gene mutations. (Information on genetic testing can be obtained from the GeneTests website of the National Center for Biotechnology Information [ http://www.genetests.org ] by searching on the term “hemophilia.”)
Prenatal Diagnosis
Techniques for detecting hemophilia in a fetus include chorionic villous sampling at 12 weeks gestation and amniocentesis at 16 weeks, with subsequent inversion analysis or DNA sequencing. The risk of miscarriage from these procedures ranges from 0.5% to 1.0% and potentially could be higher in cases of hemophilia, due to bleeding. Neither approach is required before delivery of a child who potentially could have hemophilia, given the availability of protocols for peripartum care that minimize the risk of neonatal bleeding (see later discussion). Fetal blood sampling through fetoscopy at 20 weeks to measure factor VIII activity is not recommended because of the significant risk of fetal demise (1% to 6%).
Noninvasive techniques like maternal plasma DNA analysis of hemophilia carriers to determine fetal mutational status are under study.
Postnatal Diagnosis
Postnatal recognition and diagnosis of hemophilia A or hemophilia B are facilitated when other family members are known to have hemophilia. The degree of severity of hemophilia is usually similar in all affected family members. The exception is Heckathorn disease, in which considerable variability of factor VIII levels is noted among family members with hemophilia A.
Frequently, family members and the details of their medical histories are unavailable at the time of patient presentation. Moreover, approximately 30% of all hemophilia is due to spontaneous mutations in families without a history of coagulation abnormalities. For instance, it is surmised that Queen Victoria of England sustained a spontaneous mutation in the factor IX gene, which led to hemophilia B in selected members of the European royal family. Measurement of factor VIII or factor IX activity in the affected individual is necessary to establish the diagnosis.
For hemophilia A, factor VIII coagulant activity can be assessed through a direct functional plasma clot-based assay or a chromogenic substrate-based assay. Factor IX activity levels primarily are measured with the use of a plasma clot-based assay. Hemophilia A must be differentiated from VWD by the measurement of VWF antigen and ristocetin cofactor activity, and by examination of the multimeric composition of the VWF protein with sodium dodecyl sulfate (SDS) gel chromatography, if clinically indicated. VWD type 3 may be phenotypically similar to severe hemophilia A, although the autosomally transmitted inheritance pattern of VWD should help distinguish it from hemophilia A, which has a sex-linked recessive genetic pattern (see Chapter 6 ). In addition, and in contrast to hemophilia A, replacement therapy with VWF-containing products produces an exaggerated recovery (higher than calculated incremental rise from baseline levels) and a sustained elevation and circulating half-life of factor VIII activity in individuals with VWD, particularly those with severe type 3 VWD.
When hemophilia is suspected in a male neonate of a known carrier, factor VIII or IX activity (or both) should be measured from a cord blood sample immediately after delivery. This avoids the need for venipuncture, which can produce clinically important bruising and/or hemorrhage in the severely affected neonate. The diagnosis of hemophilia B in the neonate may be confounded by the fact that factor IX levels (as well as those of other hepatically synthesized proteins) are significantly reduced at birth and may remain so for up to 6 months.
Normal plasma activity levels of coagulation factors VIII and factor IX in individuals after infancy range between 0.5 and 1.5 U/mL (50% and 150%). The severity of hemophilia is defined by the measured level of clotting factor activity: Severe hemophilia is defined as factor VIII or factor IX activities below 1% of normal (<0.01 U/mL); it occurs in approximately half of those with hemophilia. Moderately severe hemophilia occurs in about 10% of hemophilic patients, who have factor VIII or factor IX levels between 1% and 5% of normal (0.01 and 0.05 U/mL). Mild hemophilia occurs in 30% to 40% of hemophilic patients, who have factor VIII or factor IX activity levels above 5% of normal (>0.05 U/mL).
Between 2% and 8% of hemophilic infants develop intracranial hemorrhage and scalp hematoma during the perinatal period. These complications are associated with prolonged and difficult labor, the use of vacuum extraction and forceps to facilitate delivery, the presence of cephalopelvic disproportion, and precipitous delivery. Cesarean section does not eliminate bleeding risks. The Medical and Scientific Advisory Council of the National Hemophilia Foundation recommends that vacuum devices and instrumentation such as fetal scalp sampling and placement of internal fetal scalp monitors should not be used in potential hemophiliacs because of the risk of bleeding in the infant. Full recommendations may be found on the National Hemophilia Foundation website.
Intrauterine transfusion of clotting factor concentrate to the fetus immediately before delivery has been attempted, but because of rapid postnatal development of an alloantibody inhibitor the approach should be avoided.
Clinical Features of the Hemophilias
Manifestations Early in Life
In general, the most common initial bleeding event in children with severe hemophilia (factor VIII or factor IX activity level of <1% of normal) occurs in association with circumcision (which has led to at least initial avoidance of the procedure in all cases) and/or soft tissue trauma. Ecchymoses, especially deep soft tissue and intramuscular hematomas, may develop during the first few months of life, particularly as a result of trauma; however, truly spontaneous hemarthroses, the hallmark of the hemophilias, usually do not occur until approximately 1 year of age with the onset of walking. The development of hematomas at the site of routine intramuscular injections of vaccines or medications (including the postnatal administration of vitamin K) can be avoided by administering these injections subcutaneously or after pretreatment with clotting factor concentrates. Oral bleeding caused by loss of deciduous teeth, tongue biting, and frenulum injury is common in young children and may require clotting factor replacement and adjunctive use of antifibrinolytic agents such as tranexamic acid or ε-aminocaproic acid.
In contrast, mild hemophilia (factor VIII or factor IX activity level of >5% of normal) may not be recognized until much later in life, when bleeding related to trauma or surgery occurs or when routine preoperative screening of the coagulation mechanism incidentally reveals a prolonged partial thromboplastin time (PTT). Moderate hemophilia (factor VIII or factor IX activity level of 1% to 5%) may present as phenotypically mild or severe, depending on the baseline factor VIII or factor IX activity level, and other modulating factors.
Interestingly, there is evidence of phenotypic heterogeneity with respect to the severity of clinical bleeding in individuals with hemophilia associated with the same factor VIII or factor IX coagulant activity levels. For instance, 10% of patients with severe hemophilia A (≤1% factor VIII activity) manifest only a mild bleeding diathesis despite the biochemically undetectable levels of factor VIII. In one study, the bleeding tendency of carriers and male relatives with severe hemophilia A was greater in those with intron 22 inversions than in those with missense mutations. Furthermore, reduced bleeding tendencies have been reported in individuals with severe hemophilia who have coexisting thrombophilias, such as factor V Leiden (FVL) polymorphism or deficiency of either protein C (PC) or protein S (PS). These phenotypic differences may reflect the individual's innate capacity to generate thrombin, as determined by net compensatory effects of procoagulant forces in the context of a coagulation deficiency state.
Intraarticular Bleeding: Hemarthroses and Hemophilic Arthropathy
The most common sites of spontaneous bleeding in individuals with severe hemophilia A or B are the joints and muscles. The knees (>50% of all bleeding events), elbows, ankles, shoulders, and wrists are affected with decreasing incidence. It is the recurrent nature of the bleeds into these joints that results in degeneration of the cartilage and progressive destruction of the joint space. The pathophysiology of hemophilic arthropathy can be divided into three phases. After hemorrhage into the joint occurs, iron is deposited into the synovium and chondrocytes of the articular cartilage (the first phase). Subsequently, focal areas of villous hypertrophy develop on the synovial surface, which, because of their vascularity and friability, continues to rebleed with normal joint stresses as minimal as routine weight bearing. This may ultimately evolve into a “target joint” situation, characterized by recurrent, painful, and destructive bleeds repetitively rather than randomly into the same joint.
The Centers for Disease Control and Prevention define a target joint to be one into which recurrent bleeding has occurred on four or more occasions during the previous 6 months or in which 20 or more lifetime bleeding episodes have been documented.
Associated with iron deposition is the release of inflammatory cytokines that recruit macrophages and fibroblasts into the joint space and establish a favorable environment for progression of joint disease. This second phase of hemophilic arthropathy is characterized by the development of chronic synovitis, pain, fibrosis, and progressive joint stiffness with decreased range of motion. Within the joint space can be found hydrolytic and proteolytic enzymes, such as acid phosphatase and cathepsin D. In the final stage of hemophilic arthropathy (third phase), progressive and erosive destruction of the cartilage, narrowing of the joint space, subchondral cyst formation, and eventual collapse and sclerosis of the joint become apparent. Conventional radiographs traditionally have been used to monitor the progression of hemophilic arthropathy; however, until bone changes become apparent, the radiographs appear normal and may cause the clinician to underestimate the extent of joint disease. Magnetic resonance imaging (MRI) is more sensitive than conventional radiographic studies for early identification of hemarthrosis, synovial hypertrophy, hemosiderin deposition, and osteochondral changes (cartilage thinning and erosion). Ultrasound assessment of joints is an evolving point of care tool for the detection of early joint arthropathy and for discriminating between microbleed hemarthroses versus arthritic pain.
Joint scoring systems have been developed for use in evaluating the degree of joint destruction over time. The predominant clinical manifestations of recurrent joint hemorrhage are pain, swelling, and restricted range of motion. As a joint begins to bleed, and well before the onset of pain, patients may perceive “prickly sensations” and “burning” within the joint as the first manifestation of bleeding. If the bleeding is allowed to continue, pain and swelling lead to fixation of the joint in a flexed position until the swelling subsides; therefore aggressive factor replacement treatment should be initiated even before obvious swelling of the joint. Early recognition and prompt treatment of acute bleeding episodes are essential for preventing excessive hemorrhage into the joint space and minimizing subsequent joint destruction. The goal of administration of replacement clotting factor concentrate to treat the acute bleed (“on demand” therapy) is to increase factor VIII or factor IX activity levels to 30% to 50% of normal. Occasionally, repeat infusions of factor concentrate are necessary to terminate bleeding and reduce pain, especially in established target joints. If significant pain and swelling are protracted, a short course of corticosteroids (prednisone 1 mg/kg per day orally for 4 or 5 days) may be given. This has proved more beneficial in children than in adults and should probably be discouraged, if not avoided altogether in adults. Rarely, joint aspiration is performed in patients with intractable pain despite factor replacement therapy or in those with fever and in whom septic arthritis is suspected. Before joint aspiration, adequate factor replacement therapy should be administered. Aspiration should be avoided in patients with alloantibody inhibitors because of the increased risks of bleeding complications associated with the procedure.
Because use of nonsteroidal antiinflammatory drugs (NSAIDs) is generally contraindicated in hemophilic patients, narcotic analgesics frequently are a necessary therapeutic adjunct for pain control, and application of ice packs and avoidance of weight bearing with the use of crutches reduce the inflammation and pain that accompany the hemarthrosis. Initiation of physical therapy as soon as pain control is achieved reduces the development of muscle atrophy around the affected joint and prevents permanent flexion contractures. Plaster casting of target joints should not be performed.
Prophylactic administration of replacement therapy can be of immense benefit to patients with target joints. This consists of administering the appropriate clotting factor concentrate 2 or 3 times weekly to maintain trough clotting factor activity levels of at least 1% to 3%. When sustained for at least 3 months, this approach can effectively interrupt the cycle of recurrent bleeding. In patients who have developed chronic synovitis that is refractory to medical management, surgical débridement and synovectomy should be considered to reduce the bleeding and pain; however, joint destruction may progress, albeit at a much slower pace. This procedure is of greatest benefit in patients with minimal hemarthropathy.
Radiation and chemical nonsurgical synovectomies have been used to break the vicious cycle of hemarthrosis–chronic synovitis–hemarthrosis. Currently, these techniques are most commonly used in developing countries, where surgery and the required clotting factor replacement concentrates are not available. Nonsurgical synovectomies may also be beneficial for individuals with high-titer alloantibody inhibitors, in whom surgery is particularly risky and the ability to achieve adequate hemostasis is unpredictable even with administration of inhibitor-bypassing clotting factor replacement products. Most radionuclide synovectomies in patients with hemophilia have been performed using the beta-particle emitter isotopes yttrium 90 ( 89 Y) and phosphorus 32 ( 31 P); these are less likely than gamma emitters to be mutagenic and to produce localized inflammatory reactions within the synovium. A more than 50% reduction in frequency of bleeding events and pain occurs after radionuclide synovectomy, and the range of motion of the joints is stabilized or improved in more than 50% of patients. A long-term follow-up study indicated that despite decreased consumption of clotting factors and reduced incidence of clinical hemarthrosis in the short term, radioactive phosphorous synoviorthesis did not allow for the improvement of joint range of motion and did not prevent progression of radiological findings in hemophilic patients in the long term. Furthermore, concerns regarding the leukemogenicity of 32 P and the decreased availability of the isotope in recent years in the United States have reduced the inclination to perform this procedure.
Intramuscular Hemorrhage
Intramuscular hemorrhages, which comprise the second most common form of bleeding in individuals with hemophilia, account for 30% of bleeding events. The location of the intramuscular hemorrhage often determines the morbidity of the event. Hemorrhage into large muscles, although extensive, generally resolves without complications because it is not into a confined space. Bleeding into a closed fascial compartment may lead to significant compression of vital structures with resultant ischemia, gangrene, flexion contractures, and neuropathy (compartment syndrome). Intramuscular hematomas manifest with localized tenderness and pain and may be associated with low-grade fevers, large ecchymoses, and elevations of serum lactate dehydrogenase and creatine kinase levels. Bleeding into the psoas muscles and the retroperitoneal space can produce sudden onset of inguinal pain and decreased range of motion in the ipsilateral hip, which assumes a markedly flexed position, usually with lateral rotation. Hemorrhage may become life threatening if a large volume of blood is lost. In addition, femoral nerve compression can occur with permanent disability if a compartment syndrome develops. The diagnosis can be confirmed by pelvic ultrasonography or computed tomography (CT). Bleeding into this area must be controlled rapidly by raising and maintaining clotting factor activity at 80% to 100% of normal for at least 48 to 72 hours. Surgery is to be strictly avoided in this situation, although fascial release may be of benefit in compartment syndromes involving other anatomic locations.
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