- Author: Robert A Zaiden, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP more...
Hemophilia B, or Christmas disease, is an inherited, X-linked, recessive disorder that results in deficiency of functional plasma coagulation factor IX. Spontaneous mutation and acquired immunologic processes can result in this disorder as well. Hemophilia B constitutes about 20% of hemophilia cases, and about 50% of these cases have factor IX levels greater than 1%.
The role of the coagulation system is to produce a stable fibrin clot at sites of injury. See the image below.
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.
With mild hemophilia, 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 and symptoms of moderate and severe hemophilia include the following:
Neonates: Prolonged bleeding and/or severe hematoma following procedures such as circumcision, phlebotomy, and/or immunizations; intracranial hemorrhage
Toddler: Trauma-related soft-tissue hemorrhage; oral bleeding during teething
Children: Hemarthrosis and hematomas with increasing physical activity; chronic arthropathy (late complication); traumatic intracranial hemorrhage (life threatening)
There may also be signs and symptoms of infectious disease related to HIV/AIDS or hepatitis.
See Clinical Presentation for more detail.
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 with 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 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
Factor IX (FIX) assay: Mild disease, result is over 5%; moderate, 1-5%; severe, below 1%
von Willebrand factor (vWF) and factor VIII levels: To exclude vWF deficiency as primary diagnosis (low vWF and low FVIII)
Screening tests for HIV and hepatitis
Genetic carrier and fetal testing
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.
Factor IX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage in patients with hemophilia B. Recombinant factor IX 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).
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)
Hemophilia B is an inherited, X-linked, recessive disorder resulting in deficiency of functional plasma coagulation factor IX. Spontaneous mutation and acquired immunologic processes can result in this disorder as well. Hemophilia B comprises approximately 20% of hemophilia cases. Approximately 50% of persons with hemophilia B have factor IX levels of greater than 1% (ie, mild to moderate hemophilia).
Morbidity and death are primarily the result of hemorrhage, although infectious diseases (eg, HIV, hepatitis) became prominent, particularly in patients who received blood products prior to 1985.
Laboratory studies for suspected hemophilia B include a complete blood cell count, coagulation studies, and a factor IX assay (see Workup). 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 hemophilia synovitis (see Treatment).
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 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).
In 1952, Christmas disease was described and named after the surname of the first patient who was examined in detail. Mixing plasma from a patient with "true hemophilia" and with plasma from a patient with Christmas disease corrected the clotting time; thus, hemophilia A and B were differentiated.
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.
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.
Factor IX deficiency, dysfunctional factor IX, or factor IX inhibitors lead to disruption of the normal intrinsic 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. Patients who acquired HIV, hepatitis, or other viruses suffer from maladies associated with those infections.
Factor IX, a vitamin K–dependent single-chain glycoprotein, is synthesized first by the hepatocyte. The precursor protein undergoes extensive posttranslational modification before being secreted into the blood.
Factor IX 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 factor IX in plasma is normal. Since factor IX is smaller than albumin, it distributes in both the extravascular and intravascular compartments.
The role of the coagulation system, as depicted in the image below, is to produce a stable fibrin clot at sites of injury. The clotting mechanism has two pathways: intrinsic and extrinsic.
The intrinsic system is initiated when factor XII is activated by contact with damaged endothelium. The activation of factor XII can also initiate the extrinsic pathway, fibrinolysis, kinin generation, and complement activation.
In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa converts prekallikrein (PK) to kallikrein and activates factor XI. Activated factor XI, in turn, activates factor IX in a calcium-dependent reaction. Factor IXa can bind phospholipids. Then, factor X is activated on the cell surface; activation of factor X involves a complex (tenase complex) of factor IXa, thrombin-activated FVIII, calcium ions, and phospholipid.
In the extrinsic system, the conversion of factor X to factor Xa involves tissue factor (TF), or thromboplastin; factor VII; and calcium ions. TF is released from the damaged cells. It is thought to be a lipoprotein complex that acts as a cell surface receptor for FVII, with its resultant activation. It also adsorbs factor X to enhance the reaction between factor VIIa, factor X, and calcium ions. Factor IXa and factor XII fragments can also activate factor VII.
In the common pathway, factor Xa (generated through the intrinsic or extrinsic pathways) forms a prothrombinase complex with phospholipids, calcium ions, and thrombin-activated factor Va. The complex cleaves prothrombin into thrombin and prothrombin fragments 1 and 2. Thrombin converts fibrinogen into fibrin and activates FVIII, factor V, and factor XIII.
Fibrinopeptides A and B, the results of the cleavage of peptides A and B by thrombin, cause fibrin monomers to form and then polymerize into a meshwork of fibrin; the resultant clot is stabilized by factor XIIIa and the cross-linking of adjacent fibrin strands. Because of the complex interactions of the intrinsic and extrinsic pathways (factor IXa activates factor VII), the existence of only one in vivo pathway with different mechanisms of activation has been suggested.
FVIII and FIX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of either of these factors may significantly impair clot formation and, as a consequence, result in clinical bleeding.
The gene for factor IX—like the gene for factor VIII—is located on the long arm of chromosome X, within the Xq27 region. The factor IX gene (F9) has 34 kb and comprises eight exons and seven intervening sequences. The mature protein is composed of 415 amino acids. Point mutations and deletions in the factor IX gene are the most common causes of hemophilia B.
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.
Human synovial cells synthesize high levels of tissue factor pathway inhibitor, resulting in a higher degree of factor Xa inhibition, which predisposes hemophilic joints to bleed. Synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage progress, with eventual subchondral bone-cyst formation.
Approximately 3-5% of patients with severe hemophilia B develop alloantibody inhibitors that can neutralize factor IX. 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.
Hemophilia B is an X-linked recessive disease caused by an inherited or acquired mutation in the factor IX gene or by an acquired factor IX inhibitor. The gene for factor IX 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.
Several hundred mutations with different amino acid substitutes have been described in hemophilia B. 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. Evaluation and knowledge of the specific gene defect in families with severe hemophilia enables accurate gene tracking, carrier analysis, and prenatal diagnosis.
The defect results in the insufficient generation of thrombin by the factor IXa and factor VIIIa complex by means of the intrinsic pathway of the coagulation cascade. This mechanism, in combination with the effect of the tissue-factor pathway inhibitor, creates an extraordinary tendency for spontaneous bleeding.
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, African Americans, and Hispanic males in the US are similar.
Because hemophilia is an X-linked, recessive condition, it occurs predominantly in males. Females usually are asymptomatic carriers. However, mild hemophilia may be more common in carriers than previously recognized. In one study, 5 of 55 patients with mild hemophilia (factor levels 5-50%) were girls.
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 FVIII may be evident in the neonatal period. It continues 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.
Significant deficiency in FIX 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.
The Leyden phenotype of hemophilia B manifests as severe childhood disease, which subsequently improves at the onset of puberty, likely due to androgen effect.
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 d 6-18 years have below-normal motor skills and academic performance and have more emotional and behavioral problems than others.
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. The life expectancy rose from 11 years or less for patients with severe hemophilia before the 1960s to almost 60 years prior to HIV epidemic in the 1980s.[3, 4]
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, hepatitis B, or hepatitis 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 seroconversion were more than 75% for severe disease, 46% for moderate disease, and 25% for 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. AIDS remains the most common cause of death in patients with severe hemophilia. Indeed, HIV-infected individuals are likely to die of that disease rather than from hemophilia.
With improved screening of donors, new methods of factor concentrate purification, and recombinant concentrates, infectious complications 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).
Overall, the mortality rate for patients with hemophilia is twice that of the healthy male population. For severe hemophilia, the rate 4-6 times higher. If hepatitis and cirrhosis are excluded, the overall mortality rate of patients with severe hemophilia is 1.2 times that of the healthy male population.
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.
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|Classification||Factor Activity, %||Cause of Hemorrhage|
|Mild||>5-40||Major trauma or surgery|
|Severe||< 1||Spontaneous, hemarthrosis|
|Indication or Site of Bleeding||Factor level Desired, %||FIX Dose, IU/kg*||Comment|
|Severe epistaxis; mouth, lip, tongue, or dental work||20-50||20-50||Consider aminocaproic acid (Amicar), 1-2 d|
|Joint (hip or groin)||40||40||Repeat transfusion in 24-48 h|
|Soft tissue or muscle||20-40||40||No therapy if site small and not enlarging (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 bleeding)||50||50||None|
|Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs)||100||100||Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented†|
|Trauma with bleeding, surgery†||80-100||100||10-14 d|