Hemophilia B (Factor IX Deficiency)

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com/article/779434-print
emedicine.medscape.com
Hemophilia B (Factor IX
Deficiency)
Updated: Jun 07, 2024
Author: Robert A Zaiden, MD; Chief Editor: Srikanth Nagalla, MD, MS, FACP
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.
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
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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]; fidanacogene elaparvovec [Beqvez])
See Treatment and Medication for more detail.
For related information, see Hemophilia A, Acquired Hemophilia, and Hemophilia C.
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 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.
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 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.
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 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.
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.
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.
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).
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.
Presentation
History
Hemophilia is suggested by a history of hemorrhage disproportionate to trauma or of spontaneous hemorrhage, or a family
history of bleeding problems. Concomitant illness may include chronic inflammatory disorders, autoimmune diseases,
hematologic malignancies (in acquired hemophilia), and allergic drug reactions.
For individuals with documented hemophilia, inquire regarding the type of deficiency (eg, VIII, IX, von Willebrand), percent factor
deficiency, known presence of inhibitors, and HIV/hepatitis status.
Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after
circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe
hematoma and prolonged bleeding from the cord or umbilical area or at sites of blood draws or immunizations.
After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-
tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and
tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures.
As physical activity increases in children, hemarthrosis and hematomas occur. Chronic arthropathy is a late complication of
recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires
urgent diagnosis and intervention.
With mild disease, hemorrhage is most likely to occur with trauma or surgery. A traumatic challenge relatively late in life may
have to occur before mild or moderate hemophilia is suspected.
Signs of hemorrhage include the following:
General - Weakness and orthostasis
Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)
CNS - Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes
GI - Hematemesis, melena, frank red blood per rectum, and abdominal pain
Genitourinary - Hematuria, renal colic, and postcircumcision bleeding
Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction),
compartment syndrome symptoms, and contusions
Joint and muscle hemorrhage are the most common manifestations of moderate and severe hemophilia. Petechiae usually do
not occur in patients with hemophilia because they are manifestations of capillary blood leaking, which is typically the result of
vasculitis or abnormalities in the number or function of platelets.
Chronic hepatitis, progressive cirrhosis, liver failure, and hepatocellular carcinoma are more common in older individuals with
hemophilia B who received the less pure earlier products. Before the introduction of hepatitis B vaccine, as many as 90% of
persons with hemophilia had antibodies to hepatitis B surface antigen, and as many as 15% became long-term carriers.
Hepatitis C virus (HCV) seropositivity is common in patients who started treatment before 1985.
The principal sites of bleeding in patients with hemophilia are as follows. Bleeds affect weight-bearing joints and other joints. The
muscles most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is
dangerous because of the large volumes of blood loss and because of compression of the femoral nerve.
In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate
common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia.
Physical Examination
Systemic signs of hemorrhage include the following:
Tachycardia
Tachypnea
Hypotension
Orthostasis
Organ system–specific signs of hemorrhage include the following:
Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, swelling, effusion, and warmth
Central nervous system - Abnormal neurologic exam findings, altered mental status, and meningismus
Gastrointestinal - Can be painless; hepatic/splenic tenderness and peritoneal signs
Genitourinary - Bladder spasm/distension/pain, costovertebral angle pain
Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)
Direct the examination to identify signs related to bleeding in the joints, muscles, and other soft tissues that has occurred
spontaneously or after minimal challenge. Observe the patient's stature. Examine the weight-bearing joints, especially the knees
and ankles, and, in general, the large joints for deformities or ankylosis.
Especially in older patients, look for manifestations of chronic infectious disease, such as the following: include the following:
Fatigue, poor appetite, and loss of energy with progression of chronic viral illnesses, including HIV and hepatitis C virus
infection
Jaundice, spider angiomas, hepatomegaly, abdominal tenderness, splenomegaly, and other signs related to chronic
hepatitis/cirrhosis
Weight loss, adenopathy, and opportunistic infections, particularly as a manifestation of AIDS
Clinical Classification
Hemophilia is classified according to the clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe
disease usually have less than 1% factor activity. It is characterized by spontaneous hemarthrosis and soft tissue bleeding in the
absence of precipitating trauma. Patients with moderate disease have 1-5% factor activity and bleed with minimal trauma.
Patients with mild hemophilia have more than 5% factor VIII (FVIII) activity and bleed only after significant trauma or surgery.
Table 1. Severity, Factor Activity, and Hemorrhage Type (Open Table in a new window)
Classification Factor Activity, % Cause of Hemorrhage
Mild >5-40 Major trauma or surgery
Moderate 1-5 Minor trauma or surgery; occasional spontaneous hemarthrosis
Severe <1 Lifelong spontaneous hemorrhages and hemarthroses starting in infancy
DDx
Diagnostic Considerations
Problems to be considered include vitamin K and other factor deficiencies, as well as acquired hemophilia. Other congenital
bleeding disorders must be excluded. These may include the following:
von Willebrand disease (autosomal dominant transmission)

Platelet disorders (eg, Glanzmann thrombasthenia)
Deficiency of other coagulation factors (ie, factor V [FV], FVII, FX, FXI, or fibrinogen)
Differentiating between severe hemophilia A and hemophilia B is almost clinically impossible, but specific laboratory factor
assays can help with the distinction. Conditions that can increase FVIII levels (eg, age, ABO blood type, stress, exercise) can
obscure the diagnosis of hemophilia A. The diagnosis of hemophilia B may be delayed by physiologically low levels of all vitamin
K–dependent coagulation factors. FIX Leyden, in which FIX levels progressively increase after puberty to nearly normal values,
must also be considered when hemophilia B is diagnosed.
Differential Diagnoses
Dermatofibrosis Lenticularis (Buschke-Ollendorf Syndrome)
Ehlers-Danlos Syndrome
Factor V Deficiency
Factor VII Deficiency
Factor XI Deficiency
Factor XIII Deficiency
Hemophilia A (Factor VIII Deficiency)
Hemophilia C
Physical Child Abuse
Platelet Disorders
von Willebrand Disease
Workup
Workup
Approach Considerations
Laboratory studies for suspected hemophilia B include a complete blood cell count, coagulation studies, and a factor IX (FIX)
assay. Never delay indicated coagulation correction pending diagnostic testing. The United Kingdom Haemophilia Centre
Doctors' Organization (UKHCDO) recommends that in the emergency setting, clinical assessment should be performed no more
than 15 minutes after the patient arrives, and if treatment is required it should be initiated no longer than 30 minutes after arrival.
[19]
On the hemoglobin/hematocrit, expect normal or low values. Expect a normal platelet count. On coagulation studies, the
bleeding time and prothrombin time (which assesses the extrinsic coagulation pathway) are typically normal.
Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, a normal aPTT does not exclude mild or even
moderate hemophilia because of the relative insensitivity of the test, especially with factor levels greater than 15%.[20] The
aPTT is significantly prolonged in severe hemophilia.
For FIX assays, levels are compared with a normal pooled-plasma standard, which is designated as having 100% activity or the
equivalent of FIX U/mL. Normal values are 50-150%. Values in hemophilia are as follows:
Mild - Greater than 5% to 40%

Moderate - 1-5%
Severe - Less than 1%
Spontaneous bleeding complications are severe in individuals with undetectable activity (< 0.01 U/mL), moderate in individuals
with activity (2-5% normal), and mild in individuals with factor levels greater than 5%.
Usually, von Willebrand factor (vWF) levels are also measured. The combination of low FVIII and low vWF may indicate vWF
deficiency as the primary diagnosis.
Because FIX is a large molecule that does not cross the placenta, the diagnosis can be made at birth with quantitative assay of
coagulation factors in the cord blood. However, early diagnosis of FIX deficiency is complicated by the physiologic reduction of
vitamin K–dependent factors in young infants. In term and healthy premature neonates, FIX values are low (20-50% of the
normal level), due to hepatic immaturity. Levels rise to normal after 6 months of age. FVIII levels are normal during that period of
life.
In patients with an established diagnosis of hemophilia B, laboratory evaluations include periodic screening for the presence of
FIX inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV. Screening for infectious
disease may be less important in patients who have received only recombinant product.
Imaging studies for acute bleeds

Early and aggressive imaging is indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated.
Imaging choices are guided by clinical suspicion and anatomic location of involvement.
Head computed tomography (CT) scans without contrast are used to assess for spontaneous or traumatic intracranial
hemorrhage. Perform magnetic resonance imaging on the head and spinal column for further assessment of spontaneous or
traumatic hemorrhage. Magnetic resonance imaging (MRI) is also useful in the evaluation of the cartilage, synovium, and joint
space.
Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for
evaluating the bone or cartilage. Special studies such as angiography and nucleotide bleeding scan may be clinically indicated.
Testing for Inhibitors

Laboratory confirmation of a FIX inhibitor is clinically important when infusion of adequate amounts of factor concentrate fails to
control a bleeding episode. For the assay, the aPTT measurement is repeated after incubating the patient's plasma with normal
plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, the inhibitor concentration is titrated using the Nijmegen
modification of the Bethesda inhibitor assay. Specific antibodies to FIX usually are IgG subclass 4 or a mixture of IgG
subclasses 1 and 4. An experienced laboratory must perform these tests.
By convention, more than 0.6 Bethesda units (BU) is considered a positive result for an inhibitor. Less than 5 BU is considered a
low titer of inhibitor, and more than 10 BU is a high titer. The distinction is clinically significant, as patients with low-titer inhibitors
may respond to higher doses of factor concentrate.
Carrier Testing and Fetal Testing

Plasma FIX levels are normal in approximately a third of FIX carriers. If the specific FIX gene mutation is known, direct genetic
testing provides accurate results. Linkage analysis by restriction fragment length polymorphism (RFLP) in multiple family
members can be used. Direct mutation analysis is available in several laboratories for unknown FIX mutations.
For fetal testing, if the mutation is known, then RFLP can be performed on chorionic villus or amniocentesis samples. If the
mutation is not known, gene sequencing can be performed.
Radiography
Radiography for joint assessment is of limited value in acute hemarthrosis. Evidence of chronic degenerative joint disease may
be visible on radiographs in patients who are untreated or inadequately treated or in those with recurrent joint hemorrhages. In
these patients, radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that
progresses with subchondral bone cyst formation.
Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage
and progressing to advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.[4]
See the image below. For discussion of the 5-stage Arnold-Hilgartner classification of hemophilic arthropathy, see Imaging in
Musculoskeletal Complications of Hemophilia
Knee radiographs in a patient with advanced hemophilic arthropathy demonstrate chronic severe arthritis, fusion, and loss of
cartilage and joint space.
Treatment
Approach Considerations
The treatment of hemophilia may involve management of hemostasis, management of bleeding episodes, use of factor
replacement products and medications, treatment of patients with factor inhibitors, and treatment and rehabilitation of patients
with hemophilic synovitis.
Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center. These
centers follow a multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery; nurses;
physiotherapists; social workers; and related allied health professionals. Patients treated at comprehensive care clinics have
been shown to have better access to care, less morbidity, and better overall outcome.
Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home
treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is
important to prevent long-term complications and disability.
Dose calculations are directed toward achieving a factor IX (FIX) activity level of 30% for most mild hemorrhages, of at least
50% for severe bleeds (eg, from trauma) or for prophylaxis of major dental surgery or major surgery, and 80-100% in life-
threatening hemorrhage. Hospitalization is reserved for severe or life-threatening bleeds, such as large soft tissue bleeds;
retroperitoneal hemorrhage; and hemorrhage related to head injury, surgery, or dental work.
Patients may be treated with prophylaxis or with intermittent, on-demand therapy for bleeding events. Prophylaxis has been
shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints.[21, 22] According
to a review of six randomized controlled trials, preventive therapy started early in childhood, as compared with on-demand
treatment, can reduce total bleeds and bleeding into joints, thus decreasing overall joint deterioration and improving patients'
quality of life.[23]
In most developed countries with access to recombinant product, prophylaxis is primary (ie, therapy is started in patients as
young as 1 y and continues into adolescence). A cost-benefit analysis indicates that this approach reduces overall factor use
and significantly reduces morbidity.[24] In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a
target joint has been established to prevent worsening of the joint) is instituted for a defined period.[25, 26]
Dosing is designed to maintain trough levels greater than 2%. With the development of FIX preparations that have extended
half-lives, dosing for routine prophylaxis may be as infrequent as every 10 days.
In the future, oral administration of FIX for prophylaxis may become possible, through the use of hydrogel carriers that protect
FIX from destruction in the stomach and release it in the intestines.[16] Gene therapy offers the potential for a definitive cure,
and has now entered clinical practice, with US Food and Drug Administration (FDA) approval of the first product in November
2022.[27]
Prehospital Care
Prehospital providers should address the emergency ABCs (airway, breathing, circulation) while rapidly transporting the patient
to a definitive care facility. In the prehospital setting, providers should do the following:
Apply aggressive hemostatic techniques

Assist patients capable of self-administered factor therapy
Gather focused historical data if the patient is unable to communicate
Emergency Department Care

Before a patient with hemophilia is treated, the following information should be obtained:
The type and severity of factor deficiency

The nature of the hemorrhage or the planned procedure
The patient's previous treatments with blood products
Whether inhibitors are present and if so, their probable titer
Use aggressive hemostatic techniques. Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage, but
never delay indicated coagulation correction pending diagnostic testing. If possible, draw blood for the coagulation studies (see
Workup), including 2 blue-top tubes to be spun and frozen for factor and inhibitor assays.
If admission is indicated, disposition (intensive care unit versus floor) should be based on severity of hemorrhage and potential
for morbidity and death. Choose the attending service based on hemorrhage site and etiology. Hematology/ blood
bank/pathology consultation is mandatory.
Further outpatient care for patients with minor hemorrhage (not life-threatening) consists of continued hemostatic measures (eg,
brief joint immobilization, bandaging). Hematologist or primary care physician follow-up care is indicated. The patient should
continue factor replacement and monitoring.
If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic, monitor the
patient's CD4 count, observe the patient for adverse effects of anti-HIV treatment, and monitor for and treat possible
opportunistic infections.
Factor IX Concentrates
Various FIX concentrates are available to treat hemophilia B. Fresh frozen plasma is no longer used in hemophilia because of
the lack of safe viral elimination and concerns regarding volume overload. Cryoprecipitate contains no FIX and is not appropriate
for hemophilia B therapy.
Various purification techniques are used in plasma-based FIX concentrates to reduce or eliminate the risk of viral transmission,
including heat treatment, cryoprecipitation, and chemical precipitation. These techniques inactivate viruses such as hepatitis B
virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and
poorly characterized agents (eg, prions) is still a potential problem.
Recombinant FIX products (eg, BeneFIX, Rixubis, Alprolix, Ixinity) are commercially available and have a lower risk of viral
contamination. All the products are approved by the FDA for control and prevention of bleeding episodes, and for perioperative
management in adults and children. Rixubis, Ixinity, and Alprolix are also approved for routine prophylaxis in adults and children.
Idelvion, a long-acting recombinant FIX albumin fusion protein (rIX-FP, albutrepenonacog alfa) was approved in 2016 for on-
demand control and prevention of bleeding episodes, management of postoperative bleeding, and as prophylaxis to reduce the
frequency of bleeding episodes. Approval was based on open-label trials in children and adults (n=90) with FIX activity < 2%.
Mean trough levels of FIX activity were 20 IU/dL on prophylaxis with rIX-FP 40 IU/kg weekly and 12 IU/dL FIX on prophylaxis
with 75 IU/kg every 2 weeks. The switch from on-demand treatment to prophylaxis with rIX-FP resulted in a 100% reduction in
the median annualized spontaneous bleeding rate and 100% resolution of target joints (P < 0.0001).[28]
Rixubis approval for adults was based on a study demonstrating that twice-weekly prophylactic treatment for 6 months achieved
a median annualized bleed rate of 2.0 with 43% of patients experiencing no bleeds.[29, 30]
Rebinyn (nonacog beta pegol) is a recombinant glycopegylated FIX with an extended half-life. Pegylation slows removal of FIX
from the blood circulation. Rebinyn was approved by the FDA in 2017 for control and prevention of bleeding episodes and for
perioperative management in adults and children.[31]
Doses of FIX concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in
Table 2 below. As a rule, FIX 1 U/kg increases FIX plasma levels by 1%. The reaction half-time is 16 hours.
Target levels by hemorrhage severity are as follows:
Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain a FIX level of 30%
Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with
negative findings on examination): Maintain a FIX level of 50%
Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain a FIX
level of 80-90%. Plasma levels are maintained above 40-50% for a minimum of 7-10 days
Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia B (Open Table in a new
window)
Factor level FIX Dose,

Indication or Site of Bleeding Comment
Desired, % IU/kg*
Severe epistaxis; mouth, lip, tongue, or

20-50 20-50 Consider aminocaproic acid (Amicar), 1-2 d
dental work
Joint (hip or groin) 40 40 Repeat transfusion in 24-48 h
No therapy if site small and not enlarging

Soft tissue or muscle 20-40 40
(transfuse if enlarging)
Muscle (calf and forearm) 30-40 40 None
Muscle deep (thigh, hip, iliopsoas) 40-60 40-60 Transfuse, repeat at 24 h, then as needed
Neck or throat 50-80 50-80 None
Hematuria 40 40 Transfuse to 40% then rest and hydration
Laceration 40 40 Transfuse until wound healed
GI or retroperitoneal bleeding 60-80 60-80 None
Head trauma (no evidence of CNS

50 50 None
bleeding)
Head trauma (probable or definite CNS Maintain peak and trough factor levels at
bleeding, eg, headache, vomiting, 100 100 100% and 50% for 14 d if CNS bleeding
neurologic signs) documented†
Trauma with bleeding, surgery 80-100 100 10-14 d
Variations in responses related to patient or product parameters make determinations of factor levels important. These
determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance
levels. Obtain factor assay levels daily before each infusion to establish a stable pattern of replacement regarding the dose and
frequency of administration.
Management of Bleeding Episodes by Site

Musculoskeletal bleeding
The most common sites of clinically significant bleeding are joint spaces. Weight-bearing joints in the lower extremities are often
target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is
followed by progressive swelling in the involved joint.
Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain.
Early infusion upon the recognition of pain may often eliminate the need for a second infusion by preventing the inflammatory
reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications. Cases in which
treatment begins late or causes no response may require repeated infusions for 2-3 days.
Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may
pose particular problems because they interfere with the blood supply.
Hip joint hemorrhages can be complicated by aseptic necrosis of the femoral head. Administer adequate replacement therapy
for at least 3 days.
Deep intramuscular hematomas are difficult to detect and may result in serious muscular contractions. Appropriate and timely
replacement therapy is important to prevent such disabilities.
Iliopsoas muscle bleeding may be difficult to differentiate from hemarthrosis of the hip joint. Physical examination usually reveals
normal hip rotation but significant limitation of extension.
Ultrasonography in the involved region may reveal a hematoma in the iliopsoas muscle. This condition requires adequate
replacement therapy for 10-14 days and a physical therapy regimen that strengthens the supporting musculature.
Closed-compartment hemorrhages pose a significant risk of damaging the neurovascular bundle. These occur in the upper arm,
forearm, wrist, and palm of the hand. They cause swelling, pain, tingling, numbness, and loss of distal arterial pulses. Infusion
must be aimed at maintaining a normal level of FIX.
Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.
Oral bleeding
Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the
increased fibrinolytic activity of the saliva.
Combine adequate replacement therapy with an antifibrinolytic agent (e-aminocaproic acid [EACA]) to neutralize the fibrinolytic
activity in the oral cavity.
Topical agents such as fibrin sealant, bovine thrombin, and human recombinant thrombin can also be used.[32]
Hematoma in the pharynx or epiglottic regions frequently results in partial or complete airway obstruction; therefore, it should be
treated with aggressive infusion therapy. Such bleeding may be precipitated by local infection or surgery.
Administer prophylactic factor infusion therapy before an oral surgical procedure to prevent the need for further treatment.
Gastrointestinal bleeding
GI bleeds are unusual compared with those associated with von Willebrand disease and, therefore, require an evaluation for an
underlying cause. Depending on their location, they may be confused with acute abdomen or appendicitis. Manage GI
hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FIX.
Intracranial bleeding
Intracranial hemorrhage is often trauma induced; in the pediatric population, spontaneous intracranial hemorrhages are more
common than those related to trauma. If CNS hemorrhage is suspected, immediately begin an infusion prior to radiologic
confirmation. Maintain the factor level in the normal range for 7-10 days until a permanent clot is established. Late-onset
bleeding has been reported at up to 4 weeks.
All head injuries must be managed with close observation and investigated by imaging such as CT scanning or MRI. If the
patient is not hospitalized, instruct the patient and family regarding the neurologic signs and symptoms of CNS bleeding so that
the patient can know when to return for reinfusion.
Treatment of Patients with Inhibitors

Inhibitors are antibodies that neutralize FIX and can render replacement therapy ineffective. FIX inhibitors are less common than
FVIII inhibitors; they occur found in only 1-3% of patients with severe hemophilia B. These inhibitors typically appear after the
first infusions of FIX concentrate. Patients with FIX inhibitors can have anaphylactic reactions to FIX infusions, and may develop
steroid-resistant nephrotic syndrome due to immune complex formation; this typically occurs in individuals with complete gene
deletions.
The relatively low frequency of FIX inhibitors has lead to a dearth of experience in its treatment. Early hematology consultation
for these patients is essential.
Low-titer inhibitors and, occasionally, high-titer inhibitors can be overcome with high doses of FIX concentrate. Recombinant
human coagulation factor VIIa (rFVIIa) is indicated for the treatment of patients with bleeding episodes and for the prevention of
bleeding in surgical interventions or invasive procedures in patients with inhibitors to FIX.[33]
Activated prothrombin complex concentrate (PCC) has shown promise, although it may trigger disseminated intravascular
coagulopathy (DIC) at doses greater than 200 IU/kg/d. Desensitization and immune-tolerance strategies in those with identified
inhibitors have been successful as well.
Recombinant activated FVIIa
Recombinant activated FVIIa (rFVIIa) is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived
FVIIa.[34] It is manufactured by using DNA biotechnology. Intravenous recombinant FVIIa has also been studied for treating
bleeding episodes and for providing hemostasis during surgery in patients with particular bleeding diathesis.
Recombinant FVIIa is also effective and well tolerated in patients with acquired hemophilia and in those with Glanzmann
thrombasthenia.
To date, recombinant activated FVIIa has proven to be relatively free of the risk of antigenicity, thrombogenicity, and viral
transmission. However, the cost of this product has precluded its use as prophylaxis in patients with FIX inhibitors. In addition,
when recombinant activated FVIIa has been used for this indication, select patients have had severe complications related to
bleeding.
In pediatric patients, off-label treatment with recombinant FVIIa significantly reduced blood product administration, with 82% of
patients subjectively classified as responders. Clinical context and pH values before administration were independently
associated with response and 28-day mortality. Thromboembolic adverse events were reported in 5.4% of patients.[35]
Desensitization
Desensitization in nonemergency situations also may be feasible. This therapy includes large doses of FIX along with steroids or
intravenous immunoglobulin (IVIG) and cyclophosphamide. Success rates of 50-80% have been reported. In life-threatening
bleeding, methods to quickly remove the inhibiting antibody have been tried, such as vigorous plasmapheresis in conjunction
with immunosuppression and infusion of FIX with or without antifibrinolytic therapy.
Immune tolerance induction
In immune tolerance induction (ITI), patients are rendered tolerant to FIX by means of daily exposure to FIX over several months
to years.[36] The overall likelihood of success with ITI is 70% ± 10%. In patients with high-titer FIX inhibitors, ITI is less
successful than it is in patients with FVIII inhibitors.
First described by Backmann in 1977, ITI has been used with variations in the dosing schedule for FIX and with or without
immunosuppressive therapy. This technique is well established in acquired hemophilia but not in congenital hemophilia.
Rituximab, a chimeric human-mouse monoclonal antibody against CD20, has been used with success in patients with
hemophilia B and high titer inhibitors.[37] Reports describe durable complete responses with brief courses of rituximab and
prednisone with or without cyclophosphamide in patients with autoimmune hemophilia and inhibitor titers of 5 to more than 200
BU.[38] Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary hemophilia.[39,
40]
In several small trials, a 4-week course of weekly rituximab has resulted in durable and complete responses. The addition of
prednisone with or without cyclophosphamide has increased response rates.
An international immune tolerance study was started in 2002 to compare the efficiency, morbidity, and cost-effectiveness of low-
versus high-dose ITI. For information, please see the study Web site Immune Tolerance Induction Study.
Concizumab
Concizumab is a subcutaneously administered monoclonal IgG4 antibody that promotes thrombin generation by binding to
tissue factor pathway inhibitor (TFPI); TFPI is the primary inhibitor of the initiation of coagulation. In phase II trials, concizumab
has demonstrated benefit for prophylaxis in patients with hemophilia B with inhibitors.[41, 42] Phase III trials of concizumab were
paused after the occurrence of thromboembolic events in 3 patients, but the trials have since been restarted with risk mitigation
in place.[42] The European Commission has granted orphan drug designation to concizumab for the treatment of hemophilia B.
[43] The US Food and Drug Administration granted concizumab Breakthrough Therapy designation for treatment of patients with
hemophilia B with inhibitors.[44]
Prophylactic Factor Infusions

Most of the care for children with severe forms of hemophilia now takes place at home, in the community, and at school, allowing
children with hemophilia to participate in normal activities that are otherwise impossible. This resulted from the development of
prophylactic regimens of factor concentrate infusions that are administered at home, usually by a parent.
The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to joints. Hemophilic
arthropathy that results from recurrent or target joint bleeding can be prevented by this method.
Prophylaxis is not universally accepted, with only about one third of children with hemophilia B receiving this treatment modality
in the United States. Reasons cited for the lack of acceptance of this modality include need for venous access, factor availability,
repeated venipunctures, cost, and others.
Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule. Tools have
now been developed to assess long-treatment effects.
The long-acting recombinant FIX albumin fusion protein (Idelvion) was approved in 2016 for prophylaxis to reduce the frequency
of bleeding episodes. Adults who respond to once-weekly prophylaxis may be switched to a slightly higher dose administered
every 2 weeks. Clinical trial results demonstrated a 100% reduction in the median annualized spontaneous bleeding rate (AsBR)
and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P < 0.0001).
[28]
In 2013, the FDA approved the first recombinant coagulation factor IX (Rixubis) specifically indicated for the routine prevention of
bleeding in patients with hemophilia B in children and adults.[45, 46] In addition to routine prophylaxis (prevention or reduction in
frequency of bleeding episodes), Rixubis is indicated for the control of bleeding episodes and perioperative management in
these patients. This purified protein is supplied in single-use vials of freeze-dried powder, and it is injected intravenously after
reconstitution with sterile water. For routine prophylaxis, Rixubis is administered twice a week.[45, 46]
Approval of Rixubis was based on a multicenter study of 73 males (age range, 12-65 years) who received the drug for routine
prophylaxis or as needed for hemostasis. Patients taking this agent prophylactically had a 75% lower annual rate of bleeding
relative to those who had received on-demand therapy.[45, 46] The most common side effects associated with Rixubis in clinical
studies included distorted taste, pain in an extremity, and atypical blood test results. Life-threatening anaphylaxis occurred less
commonly.[45, 46]
In 2014, Rixubis was approved for routine prophylactic treatment, control and prevention of bleeding episodes, and perioperative
management in children with hemophilia B. Approval was based on the results of a clinical trial in 23 previously-treated male
patients aged < 12 years with severe or moderately severe hemophilia B. The tiral used a twice-weekly prophylaxis regimen
(mean dose 56 IU/kg; mean treatment duration 6 months, mean of 54 exposure days). The median annualized bleeding rate
was 2.0 (0.0 for spontaneous bleeds and joint bleeds). Nine patients in the study (39.1%) experienced no bleeds and 23
bleeding episodes (88.5%) were treated with 1-2 infusions. There were no reports of inhibitor development, no severe allergic
reactions, and no thrombotic or treatment-related adverse events among the study participants.[30]
The long-acting recombinant Fc fusion factor IX (rFIXFc), Alprolix, was approved by the FDA in 2014 for patients with hemophilia
B. It is the first treatment designed to require less frequent injections for routine prophylaxis. The safety and efficacy were
evaluated in a multicenter clinical trial that compared each of 2 prophylactic treatment regimens with on-demand treatment. A
total of 123 individuals with severe hemophilia B, aged 12-71 years, were followed for up to 18 months. The studies
demonstrated effectiveness in preventing and treating bleeding episodes and during perioperative management of patients
undergoing surgical procedures.[47, 48]
Another long-acting recombinant, Ixinity, gained approval for routine prophylaxis for patients aged 12 years and older in 2020, in
addition to its previous indications for on-demand usage and perioperative management.
In 2013, the FDA expanded the indication for anti-inhibitor coagulant complex (Feiba NF) to include routine prophylaxis to
prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors. The
approval was based on data from a pivotal Phase III study in which treatment with a prophylactic regimen showed a 72%
reduction in median annual bleed rate (ABR) compared to treatment with an on-demand regimen.[49] An earlier study showed a
62% reduction in all bleeding episodes with anti-inhibitor coagulant complex prophylaxis compared with an on-demand regimen.
[50]
Assessing adherence to prophylaxis
The Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) prophylaxis is a patient/parent
questionnaire that uses 6 subscales (time, dose, plan, remember, skip, communicate), each containing 4 items, to assess
patient adherence to prophylactic hemophilia treatment. In a study of 67 patients with hemophilia, including 53 with severe FVIII
deficiency, Duncan et al found a strong correlation between VERITAS-Pro scores and adherence assessments (eg, infusion log
entries).[51]
Pain Management
Pain management can be challenging in patients with severe hemophilia. Acute bleeding in joints and soft tissues can be
extremely painful. This requires immediate analgesic relief.
Hemophilic chronic arthropathy is associated with pain. Narcotic agents have been used, but frequent use of these drugs may
result in addiction. Nonsteroidal anti-inflammatory drugs may be used instead because their effects on platelet function are
reversible and because these drugs can be effective in managing acute and chronic arthritic pain. Avoid aspirin because of its
irreversible effect on platelet function.
Other analgesics may include acetaminophen in combination with small amounts of codeine or synthetic codeine analogs.
Surgical Care
Appropriate preoperative evaluation includes an activated partial thromboplastin time (aPTT) mixing test after incubation for 1-2
hours at 37°C with pooled normal plasma to exclude an inhibitor, followed by administration of an appropriate preoperative dose
of concentrate, followed by appropriate postoperative treatment.
A review by Hazendonk et al of perioperative management in hemophilia B recommends the following perioperative target
ranges for FIX[52] :
Day 1 (0-24 hours) - 0.80-1.00 IU/mL −1

Days 2-5 (24-120 hours) - 0.50-0.80 IU/mL −1
Days ≥6 (> 120 hours) - 0.30-0.50 IU/mL −1
These authors note that targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of
therapy. In their review of 255 surgical procedures in 118 patients with hemophilia B, 60% of FIX levels within 24 hours of
surgery were below target, while > 6 days after surgery, 59% of FIX levels were above target. However, clinically relevant
bleeding complications occurred in only 7 procedures (2.7%). During the first 24 hours postoperatively, only bolus infusion was
predictive of lower FIX levels, compared with continuous infusion.[52]
Long-acting FIX products have proved effective for surgical hemostasis, with nearly all patients requiring only a single
preoperative dose and infrequent postoperative doses.[53, 54] In patients with FIX inhibitors, recombinant FVIIa has consistently
demonstrated effectiveness, and with only rare thrombotic events.[55]
The use of fibrin sealants (ie, fibrin glue, fibrin adhesive), which consist of fibrinogen and thrombin with variable incorporation of
factor XIII (FXIII) and fibrinolytic inhibitors, has helped improve surgical hemostasis markedly, thereby permitting necessary high-
risk surgery (eg, pseudocyst removal, surgery in patients with hemophilia with inhibitors). This technology reduces or eliminates
the need for prolonged replacement using expensive clotting factor concentrates and may eliminate or reduce the need for
hospitalization.
Complications
HIV-associated immune thrombocytopenia is an exceedingly serious complication in patients with hemophilia because it may
result in lethal intracranial bleeding. Correct platelet counts to more than 50,000/mL. Steroids are of limited effectiveness, and
intravenous immunoglobulin or anti-Rh(D) generally induces transient remissions. Anti-HIV medications and splenectomies may
result in long-term improvement of thrombocytopenia.
Allergic reactions are occasionally reported with the use of factor concentrates. Premedication or adjustment of the rate of
infusion may resolve the problem.
Deterrence/Prevention
Do not circumcise male infants born to mothers who are known or thought to be carriers of hemophilia until disease in the infant
has been excluded with appropriate laboratory testing. Perform blood assays of FIX with cord blood. When a cord blood sample
is not available, obtain a sample from a superficial limb vein; avoid femoral and jugular sites.
Routine immunizations that require injection (eg, diphtheria, tetanus toxoids, and pertussis [DPT] or measles-mumps-rubella
[MMR] vaccines) may be given by means of a deep subcutaneous route (rather than deep intramuscular route) with a fine-gauge
needle.
Administer the hepatitis B vaccine (now routinely administered to all children) soon after birth to all infants with hemophilia.
Administer the hepatitis A vaccine to those individuals with hemophilia and no hepatitis A virus antibody in their serum.
In severe hemophilia, consider prophylactic or scheduled FIX infusions. Prophylactic replacement is used to maintain a
measurable FIX level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and
inflammation that results in destructive arthritis.[56] This goal is achieved by administering factor 2-3 times a week. The National
Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at age 1-2 years.
Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in
childbearing who have a family history of hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not
desired because a cesarean delivery may be planned or replacement therapy can be scheduled for the perinatal period.
Phenotypic and genotypic (ie, restriction fragment–length polymorphism) methods have advantages and disadvantages.
Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro
fertilization to help patients avoid having children with hemophilia or other serious inherited diseases.[57, 58, 59] The genetic
diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ
hybridization is used. This technique circumvents pregnancy termination.
Gene Therapy
With the cloning of FIX and advances in molecular technologies, the possibility of a cure for hemophilia with gene therapy was
conceived. Preclinical studies in mice and dogs with hemophilia resulted in long-term correction of the bleeding disorders, and in
some cases a permanent cure. However, the induction of neutralizing antibodies often precluded stable phenotypic correction.
In addition, the relatively high prevalence of antibodies against adeno-associated virus serotype 8 (AAV8), which has been used
as a vector for the normal FIX gene, has limited enrollment of clinical trial subjects.[60] Nevertheless, Nathwani and colleagues
reported sustained long-term expression of therapeutic levels of FIX in 10 men with severe hemophilia B after a single
intravenous infusion of an AAV8 vector expressing a codon-optimized FIX transgene.[61]
Etranacogene dezaparvovec
Other AAV serotypes have also proved effective as vectors. In 2022, the FDA approved etranacogene dezaparvovec
(Hemgenix), an AAV5-based gene therapy, for the treatment of adults with hemophilia B who currently use FIX prophylaxis
therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.[27]
The approval was supported by the single-arm, open-label HOPE-B trial in 54 men who relied on FIX replacement therapy. Over
the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = 0.0002), and FIX-
treated bleeds fell 77% (P < 0.0001). Additionally, 98% of subjects treated with a full dose of etranacogene dezaparvovec
discontinued FIX prophylaxis. Durability remains uncertain, but mean FIX activity was 39 IU/dL at 6 months (39% of normal) and
36.9 IU/dL at 18 months (approximately 37% of normal). To date, no patient has developed inhibitors against the infusion.[62]
Fidanacogene elaparvovec
Fidanacogene elaparvovec (Beqvez) is an AAV vector–based one-time gene therapy indicated for treatment of adult males with
moderate-to-severe congenital hemophilia B. It is indicated in patients who:
Currently use factor IX prophylaxis therapy, or

Have current or historical life-threatening hemorrhage, or
Have repeated, serious spontaneous bleeding episodes, and
Do not have neutralizing antibodies to AAV serotype Rh74var (AAVRh74var) capsid, as detected by an FDA-approved
test
Results from the ongoing, prospective, open-label, single-arm, global phase 3 BENEGENE-2 study (n = 45) supported the
approval. In the study, a single dose of fidanacogene elaparvovec resulted in a 71% reduction in annualized bleed rate (ABR);
the mean ABR decreased from 4.5 during the lead-in pre-treatment period to 2.5 in the efficacy evaluation period, defined as
between week 12 and data cutoff (median 1.8 years of follow-up). Bleeds were eliminated in 60% of patients.[63]
Investigational gene therapies
In a phase 1-2 trial of AAVS3 gene therapy with FLT180a (verbrinacogene setparvovec), 9 of 10 men with severe or moderately
severe hemophilia B (FIX level, ≤2% of normal) maintained FIX activity at a median follow-up of 27.2 months and no longer
required FIX injections. In the patients who responded, FIX levels ranged from 23-260%, depending on their gene therapy dose.
This protocol requires immunosuppression (with glucocorticoids, with or without tacrolimus) to decrease the risk of vector-related
immune responses; of reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression.
[64]
Other gene therapies for hemophilia B include lentiviral and CRISPR (clustered regulatory interspaced short palindromic
repeats)/Cas-9 gene therapy approaches.[65] A proof-of-principle study by Morishige et al demonstrated that gene repair in
hemophilia B can be accomplished with CRISPR technology. Using CRISPR/Cas9 on patient-derived induced pluripotent stem
cells, these researchers repaired an in-frame deletion in exon 2 of the factor IX gene.[66] Chen et al reported long-term
correction of hemophilia B in a rat model, using CRISPR/Cas9-induced homology-independent targeted integration.[67]
Activity
Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk
of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury
rate and severity, and improving psychosocial functioning.
Patients with severe hemophilia can bleed from any anatomic site after negligible or minor trauma, or they may even bleed
spontaneously. Any physical activity may trigger bleeding in soft tissues. Prophylactic factor replacement early in life may help
prevent bleeding during activity, as well as helping to prevent chronic arthritic and muscular damage and deformity.
Consultations
Consultations may be indicated with a hematologist, blood bank, pathologist, or others as indicated by hemorrhagic
complications. Early hematology consultation for management of inhibitors is essential. Annual dental evaluation is
recommended.
A genetic counselor may be consulted. Genetic testing for hemophilia A is available and must be offered to potential carriers.
Prenatal testing is performed by using amniocentesis or chorionic villus biopsy.
Before elective surgery is planned, a hematologist should be consulted to arrange adequate coverage with antihemophilic
factors and to arrange close follow-up to ensure that factor levels are sufficient during the operation and in the recovery and
healing period.
Consult an orthopedic surgeon in cases of permanent joint deformities resulting from recurrent hemarthrosis in relatively
neglected cases or, occasionally, in cases of repetitive bleeding in a single joint despite intensive prophylactic replacement of
factor and physiotherapy. Open surgical or arthroscopic synovectomy may decrease bleeding and pain in the affected joint.
Management should be provided in coordination with a comprehensive hemophilia care center.
Guidelines
Guidelines Summary
United Kingdom Haemophilia Centre Doctors’ Organisation guidelines
Guidelines for the management of acute joint bleeds and chronic synovitis in hemophilia from the United Kingdom Haemophilia
Centre Doctors’ Organisation (UKHCDO) include recommendations for patients with and without inhibitors.[68]
Hemostatic management of patients with inhibitors to factor IX includes the following:
Patients with inhibitors should be encouraged to be on a home treatment program, and bleeds should be treated as early
as possible.
Activated prothrombin complex (aPCC) 50–100 μg kg −1 or recombinant factor VIIa (rFVIIa) 270 μg kg −1 as a single
dose (or 90 μg kg −1 2–3 hourly) are equally acceptable treatments for joint or soft tissue bleeds, with repeated doses as
necessary. The frequency of infusion and duration of treatment should be determined by the clinical response.
The total daily dose of aPCC should not exceed 200 IU kg −1.
Tranexamic acid can be considered as adjunctive therapy to aPCC and rFVIIa.
Sequential alternating treatment of aPCC and rFVIIa can be considered for the management of limb/life-threatening
bleeds.
Hemostatic management of patients without inhibitors includes the following:
All patients with severe hemophilia A and B and other patients at risk of joint bleeding should be offered home treatment.
The initial treatment of early and moderate bleeds should aim for a peak factor IX (FIX) level of 50 to 60 IU dL −1. This is
equivalent to 40 to 60 IU kg −1 for severe hemophilia B, with extended half-life FIX being dosed at the lower end of the
recommended range. Early bleeds often do not require a second infusion, and moderate bleeds often respond to a single
infusion but may require up to 2 infusions.
Children may require more frequent or higher doses, as they have a shorter factor half-life than adults.
For joint-immobilizing bleeds, higher initial doses are recommended, which aim to raise the peak factor IX level to 60 to
80 IU dL −1. Doses should be administered every 24 hr until complete resolution of pain. For severe bleeds, more
frequent administration may be required in the initial 48 hr with standard FIX.
International consensus recommendations
Consensus recommendations on the management of hemophilia B by an international group of hematology experts cover the
following topics[69] :
Factor treatment choice

Therapeutic agent laboratory monitoring
Pharmacokinetics considerations
Inhibitor management
Preparing for gene therapy
Factor treatment choice:
Consider FIX prophylaxis in all people with severe hemophilia B, including those who have non-severe disease according
to their basal FIX levels but with a severe bleeding phenotype); initiate prophylaxis as early as possible (ie, before the
onset of joint bleeding) and donot interrupt it.
Both standard half-life FIX and extended half-life recombinant FIX (EHL rFIX) are effective treatment options for
prophylaxis, and can be used to offer adequate hemostatic cover for bleeds, surgery, and invasive procedures; however,
when using EHLs, consider product-specific laboratory requirements for monitoring.
Adapt the dose and frequency of FIX prophylaxis treatment to the clinical phenotype (eg, bleed rates) and lifestyle
considerations, and not plasma trough levels exclusively.
Pharmacokinetics considerations
To determine whether pharmacokinetic analysis may guide individualized prophylaxis dosing, clinicians should review product-
specific characteristics, as well as patient phenotype and joint status. Clinicians should consider population pharmacokinetics
(ie, analysis of pharmacokinetics using a predictive algorithm derived from a large data repository for a given FIX product).
Laboratory monitoring
Recommendations for clinicians include the following:
Chromogenic substrate assays (CSAs) provide higher levels of precision and accuracy in the assessment of FIX activity,
whereas there may be variability with different one-stage assays (OSAs); however, CSAs may not be suitable for routine
monitoring of recombinant FIX–albumin fusion protein (albutrepenonacog alfa).
Insufficient evidence exists for thrombin generation assay or other global assays to guide routine clinical management.
Current FIX gene therapy demonstrates consistently lower FIX activity when measured by CSA than by OSA; it is unclear
which assay should be used to aid clinical decision making in gene therapy recipients.
Inhibitor management
Recommendations for patients with severe hemophilia B include the following:
Determine the causative FIX genetic defect as soon as possible after the diagnosis, to identify the patients at increased
risk of inhibitor development and/or severe allergic reaction.
Perform inhibitor screening routinely, and intensify scrutiny in patients who develop allergic reactions to FIX and/or who
have an inadequate response to FIX replacement therapy.
During the first 20 exposure days, provide FIX infusion and close clinical observation for allergic reaction in the hospital
setting.
Recombinant activated factor VII should be the first choice for bleeding control and/or surgical cover in patientsand high-
responding inhibitors, as well as in those who have developed allergic reactions; aPCC is an option, but the content of
FIX and associated risk of anamnesis and/or worsening of allergic reaction(s) needs to be considered.
Consider immune tolerance induction (ITI) to eradicate persistent inhibitors; however, the relative benefits and risks need
to be taken into account; ITI should be initiated only in a hemophilia treatment center with an experienced team.
Monitor patients closely during ITI for the development of nephrotic syndrome and/or severe allergic reactions.
For those patients who have an allergic reaction, consider desensitization; importantly, further serious allergic reaction(s)
should be anticipated in these patients, and subsequent infusions should occur in the hospital setting with appropriate
resuscitation expertise and equipment.
For FIX inhibitor eradication, first-line treatment consists of ITI protocols with a combination of FIX and
immunosuppressive agents.
Preparing for gene therapy:
Based on current AAV hemophilia B trial data, gene therapy should be considered as a future treatment option in adults
with severe hemophilia B.
As part of the informed consent process, patients should be made aware of the unpredictability of achieved FIX level and
duration of expression.
With liver-directed AAV gene therapy, patients should be aware that pre-existing liver pathology may be an exclusion
criterion, and patients proceeding to gene therapy should be counselled about other potential sources of hepatotoxicity
that may interfere with FIX expression (eg, medication use, alcohol)
Clinicians should be aware that a rise in transaminase levels during the acute phase of gene therapy may indicate an
immune response that can potentially threaten the expression of FIX; close monitoring of transaminase levels is needed
to ensure that timely immunosuppression can be implemented.
Clinicians should consider that the specific geographic pattern of AAV seropositivity may help direct which gene therapy
is chosen.
Medication
Medication Summary
Factor IX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage. Recombinant factor IX is the
preferred source for replacement therapy. The factor IX activity level should be corrected to 100% of normal for potentially
serious hemorrhage (eg, central nervous system, trauma related, gastrointestinal, genitourinary, epistaxis) and to 30-50% of
normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular).
One unit of factor IX is the amount of factor IX in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of factor IX is
approximately 100 mL/kg. To find the number of units of factor IX needed to correct the factor IX activity level, use the following:
Units factor IX = (weight in kg)(100 mL/kg)(1 U factor IX/mL)(desired factor IX level minus the native factor IX level)
The difference between the desired factor IX activity level and the patient's native factor IX activity level is expressed as a
fraction. For example, if 100% activity is desired and the patient’s native activity is 5%, the calculation is as follows:
100% - 5% = 95% or 0.95
As an example, an 80-kg person with hemophilia with known 1% factor IX activity level presents to the emergency department
with a serious upper GI bleed. The desired factor IX activity level is 100%. The dose of factor IX to administer to the patient
would be calculated as follows:
Units factor IX = (80 kg)(100 mL/kg)(1 U factor IX/mL)(.99) = 7920
The next dose should be administered 24 hours after the first and is one half of the initial calculated dose.
Minor hemorrhage requires 1-3 doses of factor IX. Major hemorrhage requires many doses and continued factor IX activity
monitoring with the goal of keeping the trough activity level at least 50%. Continuous infusions of factor IX may be considered for
major hemorrhage.
Factor IX-containing Products
Class Summary
These agents are used to correct the patient's native deficiency, with the goals of achieving a normal hematologic response to
hemorrhage or preventing hemorrhage. Fresh frozen plasma is no longer used in hemophilia because of the lack of safe viral
elimination and concerns regarding volume overload.
Factor IX, recombinant (BeneFIX, Rixubis, Alprolix, Ixinity, Rebinyn)

Recombinant factor IX (rFIX) uses no human products for stabilization. Each of the brands is FDA-approved for control and
prevention of bleeding episodes, and for perioperative management in adults and children. Rixubis, Ixinity, and Alprolix are also
approved for routine prophylaxis in adults and children. Alprolix is a long-acting product, it may be administered for routine
prophylaxis once weekly or every 10 days. Rebinyn is a glycopegylated long-acting rFIX. Pegylation slows removal of FIX from
the blood circulation.
Factor IX, recombinant/albumin fusion protein (Idelvion)

Recombinant protein that temporarily replaces missing coagulation Factor IX needed for effective hemostasis. Comprised of
genetically fused recombinant coagulation Factor IX and recombinant albumin, which extends the half-life of Factor IX. It is
indicated for on-demand control and prevention of bleeding episodes, management of postoperative bleeding, and as
prophylaxis to reduce the frequency of bleeding episodes.
Factor IX (Mononine, AlphaNine SD)

Human blood-derived Factor IX indicated for control and prevention of bleeding episodes, and for perioperative management in
adults and children.
Factor IX Complex (Bebulin, Bebulin VH, Profilnine SD)

Human plasma-derived prothrombin complex concentrates. These pooled plasma products (high purity) replace deficient FIX
and other coagulation factors.
Coagulation Factor VIIa
Class Summary
These agents can activate coagulation factor X to factor Xa as well as coagulation factor IX to IXa.
Factor VIIa, recombinant (NovoSeven RT, Sevenfact)

This agent is indicated to treat bleeding episodes in patients with hemophilia A or B and inhibitors. It promotes hemostasis by
activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor, and promoting activation of
factor X to factor Xa, factor IX to factor IXa, and factor II to factor IIa.
Antifibrinolytics
Class Summary
These agents are used in addition to factor IX replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa is
rich in native fibrinolytic activity. These agents are used in prophylaxis for oral surgery and in the treatment of excessive bleeding
in the oral mucosa that results from local fibrinolytic activity. Their use is contraindicated as initial therapies for hemophilia-
related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria. They should
not be used in combination with prothrombin complex concentrate (PCC).
Epsilon aminocaproic acid (Amicar)

This is a lysine analog that binds to natively produced plasmin, reducing its fibrinolytic activity.
This agent inhibits fibrinolysis by inhibiting plasminogen activator substances and, to a lesser degree, antiplasmin activity. The
principal drawbacks of this agent are that thrombi formed during treatment are not lysed, and its effectiveness is uncertain. It has
been used to prevent recurrence of subarachnoid hemorrhage.
This agent is widely distributed. Its half-life is 1-2 hours. Peak effect occurs within 2 hours. Hepatic metabolism is minimal.
Tranexamic acid (Cyklokapron)

Tranexamic acid is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin.
Antihemophilic Agents
Class Summary
These agents are used to control bleeding in patients with hemophilia B or FIX deficiency who have inhibitors to FIX. They are
also used to prevent and/or control bleeding in patients with hemophilia A and inhibitors to FVIII, and in those with some forms of
von Willebrand disease.
Human antihemophilic factor (Hemofil M, Koate-DVI)

FVIII is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X in conjunction with
activated FIX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII,
forms a stable clot.
Anti-inhibitor coagulant complex (Feiba, Feiba NF)

This agent is a freeze-dried sterile human plasma fraction with factor VIII inhibitor bypassing activity. It contains factors II, IX,
and X, mainly nonactivated; and factor VII, mainly in the activated form. It may shorten the activated partial thromboplastin time
of plasma containing factor VIII inhibitors. Anti-inhibitor coagulant complex is indicated for prevention and control of spontaneous
hemorrhage or bleeding during surgical interventions in hemophilia patients who have autoantibodies or alloantibodies to
coagulation factors. It is also indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in
patients with hemophilia A or B who have developed inhibitors.
Monoclonal Antibodies
Class Summary
These agents are monoclonal antibodies directed against the CD20 antigen on B cells. They are recommended as second-line
therapy in the treatment of factor IX inhibitors, especially in cases with high inhibitor titers.
Rituximab (Rituxan)
Rituximab binds to, and mediates destruction of, B-cells, thereby decreasing production of inhibitors and autoimmunization.
Gene Therapy, Hematologics
Class Summary
The first adeno-associated virus-5 (AAV5)-based gene therapy designed to deliver a copy of a gene encoding the Padua variant
of human coagulation factor IX (hFIX598 Padua) was approved by the FDA in late 2022. A second gene therapy gain approval in
April 2024. A single IV infusion results in cell transduction and increase in circulating factor IX activity in patients with hemophilia
B.
Etranacogene dezaparvovec (Hemgenix)

Indicated for adults with hemophilia B (congenital factor IX deficiency) who currently use factor IX prophylaxis, have current or
historical life-threatening hemorrhage, or repeated serious spontaneous bleeding episodes.
Fidanacogene elaparvovec (Beqvez)

One-time gene therapy for adults with moderate-to-severe hemophilia B who currently use factor IX prophylaxis therapy or have
current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes and do not have
neutralizing antibodies to adeno-associated virus serotype Rh74var capsid.
Questions & Answers

Overview
What is hemophilia B?
What are the signs and symptoms of hemophilia B?
What are the signs of hemorrhage in hemophilia B?
Which lab tests are performed in the workup of hemophilia B?
Which imaging studies are performed in the workup of hemophilia B?
What is the treatment of choice for hemophilia B?
Which medications are used to treat hemophilia B?
When was hemophilia B first identified?
How is the severity of hemophilia B classified?
What is the pathophysiology of hemophilia B?
What is the role of factor IX in the pathophysiology of hemophilia B?
What is the role of the coagulation system in the pathophysiology of hemophilia B?
What is the role of genetics in the pathophysiology of hemophilia B?
What is the pathophysiology of hemorrhage in hemophilia B?
What is the pathophysiology of inhibitor development in hemophilia B?
What causes hemophilia B?
What is the prevalence of hemophilia B?
What are the racial predilections of hemophilia B?
What are the sexual predilections of hemophilia B?
At what age do the symptoms of hemophilia B initially appear?
What is the prognosis of hemophilia B?
What is included in patient education about hemophilia B?
Presentation
Which clinical history findings are characteristic of hemophilia B?
Which physical findings are characteristic of hemophilia B?
How is hemophilia B classified?
DDX
Which conditions are included in the differential diagnoses of hemophilia B?
How is hemophilia B differentiated from hemophilia A?
What are the differential diagnoses for Hemophilia B (Factor IX Deficiency)?
Workup
What is the role of lab testing in the workup of hemophilia B?
What is the role of imaging studies in the workup of hemophilia B?
When is testing for inhibitors indicated in the workup of hemophilia B?
What is the role of genetic testing in the workup of hemophilia B?
What is the role of radiography in the workups of hemophilia B?
Treatment
How is hemophilia B treated?
What is included in prehospital care for acute bleeding in patients with hemophilia B?
What is included in treatment of hemophilia B in the emergency department (ED)?
What types of factor IX concentrates are used in the treatment of hemophilia B?
What are the dosing guidelines for factor IX concentrates to treat hemophilia B?
How is hemophilia B musculoskeletal bleeding treated?
How is hemophilia B oral bleeding treated?
How is hemophilia B GI bleeding treated?
How is hemophilia B intracranial bleeding treated?
What is the role of concizumab in the treatment of hemophilia B?
How is hemophilia B treated in patients with inhibitors?
What is the role of recombinant activated FVIIa in the treatment of hemophilia B?
What is the role of desensitization in the treatment of hemophilia B?
What is the role of immune tolerance induction in the treatment of hemophilia B?
What is the role of prophylaxis in the treatment of hemophilia B?
How is prophylaxis adherence assessed in patients with hemophilia B?
How is pain managed in hemophilia B?
What are the possible complications of hemophilia B?
How are bleeding episodes prevented in hemophilia B?
What is the role of gene therapy in the treatment of hemophilia B?
Which activity modifications are used in the treatment of hemophilia B?
Which specialist consultations are beneficial to patients with hemophilia B?
Medications
What is the role of medications in the treatment of hemophilia B?
Which medications in the drug class Monoclonal Antibodies are used in the treatment of Hemophilia B (Factor IX Deficiency)?
Which medications in the drug class Antihemophilic Agents are used in the treatment of Hemophilia B (Factor IX Deficiency)?
Which medications in the drug class Antifibrinolytics are used in the treatment of Hemophilia B (Factor IX Deficiency)?
Which medications in the drug class Coagulation Factor VIIa are used in the treatment of Hemophilia B (Factor IX Deficiency)?
Which medications in the drug class Factor IX-containing Products are used in the treatment of Hemophilia B (Factor IX
Deficiency)?
Contributor Information and Disclosures
Author
Robert A Zaiden, MD Adjunct Associate Professor, Division of Cancer Medicine, Baptist MD Anderson Cancer Center
Robert A Zaiden, MD is a member of the following medical societies: American College of Physicians, American Society of
Clinical Oncology
Disclosure: Nothing to disclose.
Specialty Editor Board
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-
Chief, Medscape Drug Reference
Chief Editor
Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical
Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine
Srikanth Nagalla, MD, MS, FACP is a member of the following medical societies: American Society of Hematology, Association
of Specialty Professors
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion;
Sanofi; Dova; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel.
Acknowledgements
Dimitrios P Agaliotis, MD, PhD, FACP Consulting Staff, Department of Medicine, Baptist Health System
Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and
American College of Physicians
Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell
Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American
College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American
Society of Hematology, and New York Academy of Sciences
Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of
Pediatrics, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of
Hematology
Brendan R Furlong, MD Clinical Chief, Department of Emergency Medicine, Georgetown University Hospital.
Brendan R Furlong is a member of the following medical societies: American College of Emergency Physicians and Society for
Academic Emergency Medicine
Mary A Furlong, MD Associate Professor and Program/Residency Director, Department of Pathology, Georgetown University
School of Medicine
Mary A Furlong, MD is a member of the following medical societies: United States and Canadian Academy of Pathology
William G Gossman, MD Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine;
Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center
William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine
Lawrence F Jardine, MD, FRCPC Associate Professor, Department of Pediatrics, Schulich School of Medicine and Dentistry,
University of Western Ontario; Head, Section of Pediatric Hematology and Oncology, Children's Hospital of Western Ontario;
Associate Scientist, Child Health Research Institute
Lawrence F Jardine, MD, FRCPC is a member of the following medical societies: American Society of Hematology, American
Society of Pediatric Hematology/Oncology, Canadian Medical Protective Association, Children's Oncology Group, College of
Physicians and Surgeons of Ontario, Hemophilia and Thrombosis Research Society, Ontario Medical Association, and Royal
College of Physicians and Surgeons of Canada
Disclosure: Baxter Honoraria Consulting; Bayer Honoraria Consulting; Novartis Honoraria Speaking and teaching
Adonis Lorenzana, MD Consulting Staff, Department of Pediatric Oncology, St John Hospital and Medical Center
Adonis Lorenzana, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of
Pediatric Hematology/Oncology
Saduman Ozturk, PA-C Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute
Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center,
University of Cincinnati Academic Health Center
Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the
Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American
Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood
Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching
Hadi Sawaf, MD Director, Pediatric Hematology Oncology, Van Elslander Cancer Center; Clinical Assistant Professor, Wayne
State University School of Medicine
Hadi Sawaf, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Clinical
Oncology, and American Society of Hematology
Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College
of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Novartis Consulting fee Speaking and teaching; Ariad Honoraria
Speaking and teaching; Celgene Honoraria Speaking and teaching
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
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Hemophilia B (Factor IX Deficiency)

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Hemophilia B (Factor IX Deficiency)

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6/21/24, 5:50 PM emedicine.medscape.

The hemostatic pathway: role of factor IX.

Signs and symptoms

See Presentation for more detail.

Systemic: Tachycardia, tachypnea, hypotension, and/or orthostasis

Laboratory studies for suspected hemophilia B include the following:

Screening tests for HIV and hepatitis

Genetic carrier and fetal testing

Ultrasonography: To assess joints affected by acute or chronic effusions

See Workup for more detail.

Management of hemophilia B includes the following:

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

See Treatment and Medication for more detail.

For related information, see Hemophilia A, Acquired Hemophilia, and Hemophilia C.

Factor IX structure, production, and half-life

The hemostatic pathway: role of factor IX.

Cell surface–directed hemostasis

Racial, sexual, and age-related differences in incidence

For patient education information, see Hemophilia.

Signs of hemorrhage include the following:

General - Weakness and orthostasis

Genitourinary - Hematuria, renal colic, and postcircumcision bleeding

Organ system–specific signs of hemorrhage include the following:

Classification Factor Activity, % Cause of Hemorrhage

Mild >5-40 Major trauma or surgery

Moderate 1-5 Minor trauma or surgery; occasional spontaneous hemarthrosis

Severe <1 Lifelong spontaneous hemorrhages and hemarthroses starting in infancy

von Willebrand disease (autosomal dominant transmission)

For related information, see Hemophilia A, Acquired Hemophilia, and Hemophilia C.

Factor VII Deficiency

Factor XIII Deficiency

Hemophilia A (Factor VIII Deficiency)

Physical Child Abuse

von Willebrand Disease

Mild - Greater than 5% to 40%

Imaging studies for acute bleeds

Testing for Inhibitors

Carrier Testing and Fetal Testing

For related information, see Hemophilia A, Acquired Hemophilia, and Hemophilia C.

Apply aggressive hemostatic techniques

Emergency Department Care

The type and severity of factor deficiency

Target levels by hemorrhage severity are as follows:

Factor level FIX Dose,

Severe epistaxis; mouth, lip, tongue, or

Joint (hip or groin) 40 40 Repeat transfusion in 24-48 h

No therapy if site small and not enlarging

Muscle (calf and forearm) 30-40 40 None

Neck or throat 50-80 50-80 None

Hematuria 40 40 Transfuse to 40% then rest and hydration

Laceration 40 40 Transfuse until wound healed

GI or retroperitoneal bleeding 60-80 60-80 None

Head trauma (no evidence of CNS

Trauma with bleeding, surgery 80-100 100 10-14 d

Management of Bleeding Episodes by Site

Treatment of Patients with Inhibitors

Recombinant activated FVIIa

Immune tolerance induction

Prophylactic Factor Infusions

Assessing adherence to prophylaxis

Day 1 (0-24 hours) - 0.80-1.00 IU/mL −1

Currently use factor IX prophylaxis therapy, or

Investigational gene therapies

Management should be provided in coordination with a comprehensive hemophilia care center.