Hemophilia B (Factor IX Deficiency)

Updated: Dec 22, 2022
  • Author: Robert A Zaiden, MD; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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Overview

Practice Essentials

Hemophilia B, or Christmas disease, is an inherited, recessive disorder that involves deficiency of functional coagulation factor IX (FIX) in plasma. Hemophilia B is caused by a variety of defects in the F9 gene. [1] As this gene is carried on the X chromosome, the disease usually manifests in males and is transmitted by females who carry the causative mutation on one of their X chromosomes. Spontaneous mutation and acquired immunologic processes can result in this disorder, as well. Hemophilia B constitutes about 20% of hemophilia cases.

Hemophilia B may be classified as severe, moderate, or mild, based on the plasma levels of FIX (< 1%, 1-5%, 6-40%, respectively). [2] About 50% of persons with hemophilia B have FIX levels greater than 1%.

The role of FIX in the hemostatic pathway is shown in the image below.

The hemostatic pathway: role of factor IX. The hemostatic pathway: role of factor IX.

Signs and symptoms

The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint (typically the ankles in children, and the ankles, knees, and elbows in adolescents and adults), resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths. Prolonged increase in intra-articular pressure may eventually lead to osteonecrosis, especially in the femoral head.

With mild hemophilia, hemorrhage is most likely to occur with trauma or surgery. Mild or moderate hemophilia may remain unsuspected until relatively late in life, when an inadequate response to a traumatic challenge suggests the diagnosis.

Signs and symptoms of moderate and severe hemophilia include the following:

  • Neonates: Prolonged bleeding and/or severe hematoma following procedures such as circumcision, phlebotomy, and/or immunizations; intracranial hemorrhage

  • Toddler: Trauma-related soft-tissue hemorrhage; oral bleeding during teething

  • Children: Hemarthrosis and hematomas with increasing physical activity; chronic arthropathy (late complication); traumatic intracranial hemorrhage (life threatening)

Older patients who received unpurified plasma‐derived clotting factor concentrates may have signs and symptoms of infectious disease (eg, hepatitis, HIV infection).

See Presentation for more detail.

Diagnosis

Examination in patients with hemophilia B may reveal the following signs of hemorrhage:

  • Systemic: Tachycardia, tachypnea, hypotension, and/or orthostasis
  • Musculoskeletal: Joint tenderness, pain with movement, decreased range of motion, swelling, effusion, warmth
  • Neurologic: Abnormal findings, altered mental status, meningismus
  • Gastrointestinal: Can be painless or present as hepatic/splenic tenderness and peritoneal signs
  • Genitourinary: Bladder spasm/distention/pain, costovertebral angle pain
  • Other: Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)

Laboratory tests

Laboratory studies for suspected hemophilia B include the following:

  • Complete blood cell count: Normal or low hemoglobin/hematocrit levels; normal platelet count

  • Coagulation studies: Do not delay coagulation correction pending test results; normal bleeding and prothrombin times; normal or prolonged activated partial thromboplastin time

  • FIX assay

  • von Willebrand factor (vWF) and factor VIII (FVIII) levels: To exclude vWF deficiency as primary diagnosis (low vWF and low FVIII)

  • Screening tests for HIV and hepatitis

  • Genetic carrier and fetal testing

Imaging studies

After initiating coagulation therapy, perform early and aggressive imaging, even when there is a low suspicion for hemorrhage. Imaging choices are guided by clinical suspicion and the anatomic location of involvement, such as the following:

  • Head computed tomography scanning (without contrast): To assess for spontaneous or traumatic intracranial hemorrhage

  • Magnetic resonance imaging: To further evaluate spontaneous/traumatic hemorrhage in the head or spinal column; also to assess cartilage, synovia, and joint spaces

  • Ultrasonography: To assess joints affected by acute or chronic effusions

  • Joint radiography: Of limited value in acute hemarthrosis; to evaluate untreated or inadequately treated disease; in those with recurrent joint hemorrhages, chronic degenerative joint disease may be evident

See Workup for more detail.

Management

FIX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage in patients with hemophilia B. Recombinant FIX is the preferred source for replacement therapy. Ideally, patients with hemophilia should be treated at a comprehensive hemophilia care center.

Management of hemophilia B includes the following:

  • Control of hemostasis
  • Treatment of bleeding episodes
  • Administration of factor replacement products and medications
  • Use of factor inhibitors
  • Rehabilitation of patients with hemophilia synovitis
  • Primary and/or secondary prophylaxis

Treatment may also vary with site-specific locations (eg, joints, mouth, gastrointestinal region, head).

Pharmacotherapy

The following medications are used in the management of hemophilia B:

  • Factor IX-containing products (eg, factor IX, recombinant factor IX, factor IX complex)
  • Recombinant coagulation factor VIIa
  • Recombinant coagulation factor IX
  • Antifibrinolytics (eg, epsilon aminocaproic acid, tranexamic acid)
  • Antihemophilic agents (eg, desmopressin, anti-inhibitor coagulant complex, human antihemophilic factor, recombinant human antihemophilic factor, plasma-derived prothrombin complex concentrates/factor IX complex concentrates, plasma-derived coagulation factor IX concentrate)
  • Monoclonal antibodies (eg, rituximab)
  • Analgesics (eg, narcotic agents, NSAIDS, acetaminophen with codeine or synthetic codeine analogs)
  • Gene therapy (ie, etranacogene dezaparvovec [Hemgenix]) 

See Treatment and Medication for more detail.

For related information, see Hemophilia AAcquired Hemophilia, and Hemophilia C.

 

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Background

Historical background

Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century.  The newspaper item below demonstrates what appears to be a late 18th-century record of hemophilia passed from mother to sons.

Obituary in the Salem Gazette (Massachusetts) of a Obituary in the Salem Gazette (Massachusetts) of a 19-year-old man, March 22, 1796.

The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937, when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilia factor (AHF).

Hemophilia B was differentiated from hemophilia A in 1952, when it was found that mixing plasma from patients with the two conditions corrected the clotting time. The hemophilia B patient in that study had the surname Christmas, and hence the disorder became known as Christmas disease. [3]

In the early 1960s, cryoprecipitate was the first concentrate available for the treatment of patients with hemophilia. In the 1970s, lyophilized intermediate-purity concentrates were obtained from a large pool of blood donors. The introduction of concentrated lyophilized products that are easy to store and transport has dramatically improved the quality of life of patients with hemophilia and facilitated their preparation for surgery and home care.

In the 1980s, the risk of transmitting viral contaminants in commercial FVIII concentrates became increasingly recognized. By the mid 1980s, most patients with severe hemophilia had been exposed to hepatitis A, hepatitis B, and hepatitis C viruses and human immunodeficiency virus (HIV). New viricidal techniques have been effective in eliminating new HIV transmissions and virtually eliminating hepatitis B and hepatitis C exposures. The present standard of using recombinant products, especially those without exposure to animal proteins, in the treatment of hemophilia virtually eliminates the risk of viral exposure.

Severity classification

The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or plasma procoagulant levels; the latter are the most widely used criteria. Persons with less than 1% normal factor (< 0.01 IU/mL) are considered to have severe hemophilia. Persons with 1-5% normal factor (0.01-0.05 IU/mL) are considered to have moderately severe hemophilia. Persons with more than 5% but less than 40% normal factor (> 0.05 to < 0.40 IU/mL) are considered to have mild hemophilia.

Clinical bleeding symptom criteria have been used because patients with factor IX levels of less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with symptoms of clinically severe disease. A minority of patients have coexisting thrombophilic states such as factor V Leiden mutation, protein C or protein S deficiency, or prothrombin G20210A mutations, which counterbalance bleeding tendencies and therefore lessen or delay symptoms.

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Pathophysiology

Factor IX deficiency, dysfunctional factor IX, or factor IX inhibitors lead to disruption of the normal coagulation cascade, resulting in spontaneous hemorrhage and/or excessive hemorrhage in response to trauma. Hemorrhage sites include joints (eg, knee, elbow), muscles, central nervous system (CNS), GI system, genitourinary (GU) system, pulmonary system, and cardiovascular system. 

Factor IX structure, production, and half-life

FIX, a vitamin K–dependent single-chain glycoprotein, is synthesized first by the hepatocyte as a precursor protein. Before secretion from the hepatocyte, the FIX protein undergoes extensive posttranslational modifications, which include gamma-carboxylation, beta-hydroxylation, and removal of the signal peptide and propeptides, addition of carbohydrates, sulfation, and phosphorylation.

Gamma-carboxylation, as shown in the diagram below, is a vitamin K–dependent process in which the enzyme gamma-glutamylcarboxylase binds to specific sites on the propeptide region of the precursor protein in the liver. Gamma-carboxylation of the glutamic acid residues forms gamma-carboxyglutamyl (Gla) residues in the mature protein.

Vitamin K–dependent carboxylation of precursor fac Vitamin K–dependent carboxylation of precursor factor IX to procoagulant factor IX. Carboxylation of glutamate (Glu) to gamma-carboxyglutamate (Gla) residues in the precursor protein of the vitamin K–dependent factors occurs in the endoplasmic reticulum of the hepatocyte. Reduced vitamin K is oxidized in this process. Warfarin prevents the reduction and recycling of oxidized vitamin K.

These Gla regions are the high-affinity Ca2+ binding sites necessary for binding FIXa to lipid membranes so FIXa can express its full procoagulant activity. All of the vitamin K–dependent procoagulants and anticoagulants are biologically inactive unless the glutamic acid residues at the amino terminal end are carboxylated; the exact number of Gla regions varies with each protein.

Warfarin prevents the reduction and recycling of oxidized vitamin K (vitamin K epoxide) that is generated during this carboxylation reaction. As a result of the indirect inhibition of the carboxylation reaction due to a lack of available reduced vitamin K, hypocarboxylated and decarboxylated forms of the vitamin K–dependent factors are found in the circulation of patients taking warfarin. These abnormal forms have reduced or absent biological activity. Following these modifications, the carboxyterminal (C-terminal) region is recognized by the hepatic secretion process. Mutations that increase the charge of this region result in decreased hepatic secretion of all vitamin K–dependent proteins, including FIX, and lead to deficiencies of multiple vitamin K–dependent factors (procoagulants factor VII [FVII], factor X [FX], factor II [FII] and anticoagulant proteins C and S).

FIX is present in plasma in a concentration of 4-5 µg/mL with a half-life of approximately 18-24 hours. A 3-fold variation in the activity of FIX in plasma is normal. Since FIX is smaller than albumin, it distributes in both the extravascular and intravascular compartments.

Following intravenous (IV) administration, recovery of FIX concentrates varies significantly, which has been ascribed to the development of nonneutralizing antibodies. In vivo binding of FIX to collagen IV has been proposed as another reason for reduced recovery of FIX following infusion of FIX concentrates in hemophilia B patients. FIX concentrates generally are replaced every 18-24 hours under steady state conditions. Lower recoveries are seen with recombinant factor IX (rFIX) than with FIX concentrates. [4]

FIX shares extensive homology with the other vitamin K–dependent proteins, especially in the prepro sequence and the Gla regions. Despite numerous similarities, each vitamin K–dependent protein performs a different function in the hemostatic pathway, which is diagrammed in the following image.

The hemostatic pathway: role of factor IX. The hemostatic pathway: role of factor IX.

Activation

The gamma-carboxylated region of FIX is essential for calcium binding and is the site at which vitamin K–dependent coagulation proteins bind to cell surface phospholipids and efficient coagulation reactions take place. Ca2+ binding to the Gla region results in a conformational change leading to exposure of previously buried hydrophobic residues in the FIX molecule, which then can be inserted into the lipid bilayer.

Tissue factor (TF) is a glycosylated membrane protein present in cells surrounding blood vessels and in many organs. On the other hand, endothelial cells, tissue macrophages, and smooth muscle cells express TF only when stimulated by serine proteases, such as thrombin, and by inflammatory cytokines. In vivo, under physiologic conditions, only a trace amount of FVII is present in the activated form (activated factor VII [FVIIa] of approximately 1%). When TF becomes available, it complexes with FVII or FVIIa, and current concepts support the view that activation of FIX to FIXa is more rapid with the TF-FVII complex than with activated factor XI (FXIa). [5]  The activation peptide for FIX is detectable in the plasma of control subjects. [6]  The image below diagrams the activation of FIX.

Activation of factor IX and function of the intrin Activation of factor IX and function of the intrinsic tenase complex. Activation of factor IX is followed by formation of the intrinsic tenase complex, which activates factor X to activated factor X, leading to a second and larger burst of thrombin production during activation of hemostasis.

Following activation, the single-chain FIX becomes a 2-chain molecule, in which the 2 chains are linked by a disulfide bond attaching the enzyme to the Gla domain. Activated factor VIII (FVIIIa) is the specific cofactor for the full expression of FIXa activity. Platelets not only provide the lipid surface on which solid-phase reactions occur, but they also possess a binding site for FIXa that promotes complex formation with FVIIIa and Ca2+. The complex of FIXa, FVIIIa, Ca2+, and activated platelet (phospholipid surface) reaches its maximum potential to activate FX to activated factor X (FXa). This activator complex, which contains FIXa, is termed the intrinsic tenase complex in contradistinction to the FVIIa-TF (extrinsic tenase) or FXa, activated factor V (FVa), Ca2+, and phospholipid (prothrombinase) complexes; all ultimately lead to thrombin generation.

In vivo, the active FVIIa-TF complex is responsible for the initial activation of FX to FXa, leading first to the generation of small amounts of thrombin. When the FIXa generated by the FVIIa-TF complex is part of the intrinsic tenase complex, it activates additional FX to FXa and leads to the second and explosive burst of thrombin generation with subsequent clot formation.

Many feedback loops exist in the coagulation pathway, and some evidence suggests that FIXa can activate FVII and FVIII in addition to FX. Support for the important role of FIX in producing FVIIa, essential for normal hemostasis in vivo, was provided by a study using a sensitive, highly specific FVIIa assay, which showed that healthy individuals had basal FVIIa levels of 4.34 ng/mL. Patients with severe FIX deficiency were found to have markedly reduced FVIIa levels of 0.33 ng/mL, whereas individuals with severe FVIII deficiency had FVIIa levels of 2.69 ng/mL, values higher than those seen in patients with severe hemophilia B. [7]

Possible interactions between deficiencies of FIX and thrombin activatable fibrinolytic inhibitor

The demonstration that thrombi generated in plasmas obtained from patients with hemophilia A or B underwent premature lysis generated the hypothesis that bleeding in patients with hemophilia may be due not only to failure of adequate thrombin generation and clot formation, but also to a failure of adequate suppression of fibrinolysis leading to accelerated clot removal.

Proof of the concept of the latter has been provided for decades in patients with hemophilia, long before the role of thrombin activatable fibrinolytic inhibitor (TAFI) was even suspected, by the amply proven hemostatic adequacy of a single dose of replacement factor when combined with prolonged inhibition of fibrinolysis in patients with severe hemophilia undergoing dental or other mucocutaneous procedures. The demonstration in vitro of rapid clot lysis in hemophilic plasmas was followed by a demonstration of rapid clot lysis in plasmas deficient in FXI or factor XII (FXII), with prolongation of clot lysis by restitution of the missing factor.

A large amount of information has accrued regarding the pathophysiologic role of TAFI in thrombohemorrhagic disorders. TAFI, a single-chain carboxypeptidase B–like zymogen, is activated by thrombin to generate activated TAFI (TAFIa). Thrombin, plasmin, and trypsin all can activate TAFI, but thrombin bound to thrombomodulin has an approximate 1250-fold greater catalytic rate than thrombin alone; however, thrombin alone is sufficient to achieve significant TAFI activation.

The importance of TAFIa in influencing fibrinolysis is emphasized by the fact that conversion of only 1% of the zymogen to TAFIa is sufficient to suppress normal fibrinolysis by approximately 60%. TAFIa suppresses fibrinolysis by removing C-terminal lysine and arginine residues in a fibrin clot that has been partially degraded by plasmin. Removal of C-terminal lysine residues reduces the rate of plasminogen activation by a number of mechanisms, attenuating fibrinolysis. This effect is counterbalanced in normal plasma by the activation of protein C, which has profibrinolytic properties due to its ability to suppress thrombin generation by its major effect in degrading FVa and, to a lesser extent, FVIIIa.

In normal plasma, a balance exists between the effects of activated protein C on the one hand (profibrinolytic) and TAFIa on the other (antifibrinolytic). Thrombin secures survival of the thrombus created by its action on fibrinogen by activating TAFI, thereby inhibiting fibrinolysis. In this context, note that cross-linking of fibrin induced by activated factor XIII (FXIIIa, activated by thrombin) also renders the clot insoluble (for more information, see Factor XIII). Thus, thrombin uses multiple prongs to assure survival of its creation, fibrin, and affects the normal delicate balance between thrombus formation and thrombus resolution.

A reduction in the level of FIX via reduction of thrombin generation reduces TAFI activation and increases fibrinolysis, whereas persistence of FVa (as is the case with co-inheritance of factor V [FV] Leiden) leads to increased (persistent) thrombin production and TAFI activation, thereby inhibiting fibrinolysis.

Cell surface–directed hemostasis

The concept of coagulation as a waterfall or cascade, with a series of reactions each impacting the subsequent reaction, dates back to the 1960s. [8]  The fact that fluid-phase reactions are inefficient and that platelets and other cell surfaces provide the anionic phospholipids needed for complex formation so that reactions can proceed efficiently also has been recognized. This model allowed  conceptual visualization of the activated partial thromboplastin time (aPTT) and prothrombin time (PT) tests as the intrinsic and extrinsic pathways. One review proposed that coagulation is essentially a cell surface–based event in overlapping phases, suggesting the need for a paradigm shift from the old concept in which coagulation reactions were controlled by coagulation proteins to a new concept in which the process is controlled by cellular elements.

In this model, diagrammed below, 3 phases are proposed including (1) initiation of coagulation on the surface of a TF-bearing cell, with formation of FXa, FIXa, and thrombin, (2) amplification of this reaction next on the platelet surface as platelets are activated, adhere, and accumulate factors/cofactors on their surfaces, and (3) the propagation phase, in which the large second burst of thrombin occurs on the platelet surface resulting from the interaction of proteases with their cofactors, resulting in fibrin polymerization. Platelets are an early and essential feature of hemostasis, making them an ideal cell to regulate this process, and these authors provide a series of cogent reasons for switching to this concept of hemostasis. [9, 10]

Clinical manifestations

The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint (typically the ankles in children and the ankles, knees, and elbows in adults and adolescents), resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths. Prolonged increase in intra-articular pressure may eventually lead to osteonecrosis, especially in the femoral head.

Human synovial cells synthesize high levels of TF pathway inhibitor, resulting in a higher degree of factor Xa inhibition, which predisposes hemophilic joints to bleed. Joint bleeds result in progressive synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage, with eventual subchondral bone-cyst formation.

Inhibitors

Approximately 3-5% of patients with severe hemophilia B develop alloantibody inhibitors that can neutralize FIX. These inhibitors are usually immunoglobulin G antibodies and appear after the first infusions of FIX concentrate.

Both genetic and environmental factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions, stop codon mutations, frameshift mutations) and an absence or paucity of endogenous factor IX (severe disease) are associated with a higher incidence of inhibitor development. Inhibitors are more likely to develop in Black children. In addition, purified products (some no longer marketed) have been associated with increased inhibitor development.

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Etiology

Hemophilia B is an X-linked recessive disease caused by a mutation in the factor IX gene or by an acquired factor IX inhibitor. Similar to hemophilia A, approximately 30% of cases represent a de novo mutation. The gene for factor IX, ​F9, is located on the long arm of the X chromosome in band q27. Factor IX contains 415 amino acids and has a molecular weight of 57,000 d. The gene that encodes this protein is 33 kb and contains 8 exons and 7 introns.

More than 1000 mutations with different amino acid substitutes have been described in hemophilia B. [1] These mutations include partial and total deletions, missense mutations, and others that result in the decreased or absent production of factor IX or the production of an abnormal protein. Most patients deficient in FIX have point mutations.

Variability in clinical bleeding manifestations is due to heterogeneity of the molecular defects found in this disorder, with each mutation resulting in a specific pattern of alteration of FIX activity. Baseline levels of FIX and the severity of bleeding tend to be similar in members of a family, who have inherited the same specific defect.

Three groups of mutations are particularly instructive and have important clinical consequences. The first group consists of gross F9 gene deletions and gene rearrangements causing severe deficiency of FIX, which results in a severe bleeding diathesis. These patients are prone to developing severe anaphylactic reactions when factor replacement therapy is started. Allergic/anaphylactic reactions are associated with development of a specific FIX inhibitor.

New patients with severe FIX deficiency should be screened for such large gene defects, which can alert the clinician prior to development of life-threatening anaphylaxis. Patients with large gene defects should be selected to receive initial FIX product infusions under well-supervised conditions that will allow prompt attention to serious complications.

The second group consists of the FIX Leyden phenotype, which is caused by several different point mutations in the FIX promoter region. [1]  In the Leyden phenotype, baseline FIX levels are in the 1-13% range, and FIX levels can rise to approximately 30% in childhood (age 4-5 y) and to approximately 70% with the onset of puberty and testosterone production. [11]  Patients may become clotting factor independent by early adulthood. [12] Anabolic steroids also can raise the level of FIX in these patients.

The third group involves missense mutations in the propeptide sequence of FIX, resulting in a markedly decreased affinity of abnormal FIX for vitamin K–dependent carboxylase. Patients have normal baseline levels of FIX, but because of increased sensitivity to vitamin K antagonists, they develop unexpected and severe reductions in FIX following administration of oral anticoagulants, which then predisposes them to an increased risk of bleeding.

Identification of mutations in families is feasible because of the small size of the gene, and it is useful for carrier detection. The different types of intragenic polymorphisms vary with the ethnic group. These are useful in counseling families with unknown mutations. Evaluation and knowledge of the specific gene defect in families with severe hemophilia enables accurate gene tracking, carrier analysis, and prenatal diagnosis.

Factor IX inhibitors

FIX gene deletions are present in 50% of patients with FIX inhibitors. In contrast, the risk of inhibitor development is 20% in patients with mutations resulting in loss of coding information.

A study of eight alloantibodies to FIX that developed after repeated infusions of FIX in patients with hemophilia B showed that the antibodies were immunoglobulin G (IgG), predominantly IgG subclass 1 and IgG subclass 4. They were directed against the Gla and protease domains and inhibited binding of FIX to phospholipids and binding of the light chain of FVIIIa to FIXa. They also inhibited the FVIIIa-dependent activation of FX. [13]

Combined disorders

Combined congenital deficiencies of vitamin K–dependent factors include reductions in FIX. A mutation in the carboxylase enzyme can lead to a reduction in all Gla-containing proteins, including FIX. Bleeding manifestations depend on the basal level of factors. Patients have a heterogeneous response to oral/parenteral vitamin K administration, varying between a slight response to no response.

Hemophilia B may be associated with other hemostatic defects due to co-inheritance of von Willebrand disease, platelet defects, or other defects, which then compromise hemostasis at multiple sites, thus further accentuating bleeding manifestations.

Co-inheritance of thrombophilic mutations can ameliorate bleeding in patients with FIX deficiency and can predispose patients to thrombosis when FIX levels are normal and patients are subject to a thrombogenic stimulus.

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Epidemiology

Hemophilia has a worldwide distribution. The incidence of hemophilia B is estimated to be approximately 1 case per 25,000-30,000 male births. The prevalence of hemophilia B is 5.3 cases per 100,000 male individuals, with 44% of those having severe disease.

Hemophilia B is much less common than hemophilia A. Of all hemophilia cases, 80-85% are hemophilia A, 14% are hemophilia B, and the remainder are various other clotting abnormalities.

Racial, sexual, and age-related differences in incidence

Hemophilia B occurs in all races and ethnic groups. In general, the demographics of hemophilia follow the racial distribution in a given population; for example, rates of hemophilia among whites, Blacks, and Hispanic males in the United States are similar.

Because hemophilia is an X-linked, recessive condition, it occurs predominantly in males. Females usually are asymptomatic carriers. However, carriers may have mild hemophilia. In one study, 5 of 55 patients with mild hemophilia (factor IX levels 5-50%) were girls. [14]  Females may have clinical bleeding due to hemophilia if one of the following conditions is present:

  • Extreme lyonization (ie, inactivation of the normal factor IX allele in one of the X chromosomes
  • Homozygosity for the hemophilia gene (ie, father with hemophilia and mother who is a carrier, two independent mutations, or some combination of inheritance and new mutations)
  • Turner syndrome (XO) associated with the affected hemophilia gene.

Significant deficiency in factor IX may become evident in the neonatal period and continue through the life of the affected individual. The absence of hemorrhagic manifestations at birth does not exclude hemophilia. Excessive bleeding after normal trauma encountered during ambulation at the toddler stage may be the first indication of hemophilia. Mild hemophilia may remain undetected until relatively late in life, when a traumatic challenge reveals impaired hemostasis.

Mortality/Morbidity

The consequences of the repeated bleeding experienced by individuals with hemophilia are serious and result from the repeated need for FIX replacement to control bleeding. Availability of replacement products has changed the lives of patients with FIX deficiency, although serious problems were incurred by the use of the less pure earlier products. Currently available concentrates and recombinant products have a better safety profile. [15]

Persons with severe hemophilia have recurrent joint and muscle bleeds, which are spontaneous or follow minor trauma and cause severe acute pain and limitation of movement. The presence of blood in the joint leads to synovial hypertrophy, with a tendency to rebleed, which results in chronic synovitis, with destruction of synovium, cartilage, and bone leading to chronic pain, stiffness of the joints, and limitation of movement because of progressive severe joint damage.

Intramuscular hemorrhage, the second most common bleeding event, also produces acute pain, swelling, and limitation of movement. Other sites of bleeding and many other complications contribute to morbidity and mortality. These include diffuse alveolar hemorrhage, which is rare but potentially life-threatening. [16]

Current treatment methods have succeeded in reducing not only the morbidity but also the death rate, and for the first time, persons with hemophilia have been able to pursue economically viable careers. However, several problems remain.

Spontaneous or trauma-related hemarthroses and bleeding are controlled better using home care programs, which allow on-demand and prompt treatment of bleeds by the use of prophylactic and/or therapeutic infusions of FIX concentrates. This has led to a marked improvement in the quality of life for persons with hemophilia and allows them to participate in activities previously denied to them. With currently available products, some individuals with hemophilia B can achieve a normal lifespan.

Death results from central nervous system (CNS) bleeding, anaphylaxis in children, development of inhibitors with severe bleeding. In patients who received replacement therapy before the advent of highly purified and recombinant FIX concentrates, causes of death also included hepatitis-induced liver failure and AIDS.

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Prognosis

With appropriate education and treatment, patients with hemophilia can live full and productive lives. Prophylaxis and early treatment with factor concentrate that is safe from viral contamination have dramatically improved the prognosis of patients regarding morbidity and mortality due to severe hemophilia. Nevertheless, approximately one quarter of patients with severe hemophilia age 6-18 years have below-normal motor skills and academic performance and have more emotional and behavioral problems than others. [17]

Factor concentrates have made home-replacement therapy possible, improving patients' quality of life. In addition, dramatic gains in life expectancy occurred during the era of replacement therapy. Currently, the mortality rate in people with hemophilia is approaching that of the general population. [18]  

However, viral infection from contaminated factor concentrate became a problem during the replacement era. Most patients with hemophilia who received plasma-derived products that were not treated to eliminate potential contaminating viruses became infected with HIV or hepatitis A, B, or C viruses.

The most serious of these was HIV infection. The first deaths of people with hemophilia due to AIDS were observed in the early 1980s. Rates of HIV seroconversion were more than 75% for those with severe disease, 46% for those with moderate disease, and 25% for those with mild disease.

In the United States, death rates of patients with hemophilia increased from 0.4 deaths per million population in 1979-1981 to 1.2 deaths per million population in 1987-1989; AIDS accounted for 55% of all hemophilia deaths. Causes of death shifted from intracranial and other bleeding to AIDS and cirrhosis from hepatitis. After the year 2000, however, the percentage of deaths attributable to HIV in persons with hemophilia dropped to 13.9%. The proportion of deaths due to hemorrhage remained unchanged, at 26% [18]

With improved screening of donors, new methods of factor concentrate purification, and recombinant concentrates, infectious complications are now mostly of historical importance. However, even with these methods, some viruses (eg, parvovirus B19) cannot be removed and may be transmitted through plasma-derived products. Other potential infectious agents include those that cause Creutzfeldt-Jakob disease. With the development of animal protein–free products, the risk of contamination with these agents may be decreased.

Intracranial hemorrhage and hemorrhages into the soft tissue around vital areas, such as the airway or internal organs, remain the most important life-threatening complications. The lifetime risk of intracranial bleeding is 2-8% and accounts for one third of deaths due to hemorrhage, even in the era of factor replacement. Intracranial hemorrhage is the second most common cause of death and the most common cause of death related to hemorrhage. Of patients with severe hemophilia, 10% have intracranial bleeding, with a mortality rate of 30%.

Chronic debilitating joint disease results from repeated hemarthrosis; synovial membrane inflammation; hypertrophy; and, eventually, destructive arthritis. Early replacement of coagulation factors by means of infusion is essential to prevent functional disability. Thus, prophylactic therapy administered 2-3 times weekly, starting when patients are young, is considered the standard of care in most developed countries.

Before the widespread use of replacement therapy, patients with severe hemophilia had a shortened lifespan and diminished quality of life that was greatly affected by hemophilic arthropathy. Home therapy for hemarthroses became possible with factor concentrates. Prophylactic therapies with lyophilized concentrates that eliminate bleeding episodes help prevent joint deterioration, especially when instituted early in life (ie, at age 1-2 y).

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Patient Education

Starting in infancy, regular dental evaluation is recommended, along with instruction regarding proper oral hygiene, dental care, and adequate fluoridation.

Encourage the patient to engage in appropriate exercise. Advise the patient against participating in contact and collision sports.

Patient and family education about early recognition of hemorrhage signs and symptoms is important for instituting or increasing the intensity of replacement therapy. This treatment helps prevent the acute and chronic complications of the disease that may vary from life-threatening events to quality-of-life–impairing events.

In addition, educating patients or family members about factor replacement administration at home has greatly enhanced the quality of life of patients with severe hemophilia.

For patient education information, see Hemophilia.

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