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40 years!
Last updated:
9/20/2023
Years published: 1987, 1988, 1989, 1995, 1996, 2000, 2007, 2008, 2012, 2015, 2018, 2023
NORD gratefully acknowledges Amy D. Shapiro, MD, Medical Director, Indiana Hemophilia and Thrombosis Center, for the preparation of this report.
Summary
Hemophilia B is a rare genetic bleeding disorder in which affected individuals have insufficient levels of a blood protein called factor IX. Factor IX is a clotting factor. Clotting factors are specialized proteins needed for blood clotting, the process by which blood seals a wound to stop bleeding and promote healing. Individuals with hemophilia B do not bleed faster than unaffected individuals, they bleed longer. This is because they are missing or have a decreased amount of a protein involved in blood clotting and are unable to effectively stop the flow of blood from a wound, injury or bleeding site. This is sometimes referred to as prolonged bleeding or a bleeding episode.
Hemophilia B is classified as mild, moderate or severe based upon the activity level of factor IX. In mild cases, bleeding symptoms may occur only after surgery, injury or a dental procedure. In some moderate and most severe cases, bleeding symptoms may occur after a minor injury or spontaneously, meaning without an identifiable cause.
Hemophilia B is caused by changes (variants or mutations) in the factor IX gene (F9) on the X chromosome. Hemophilia B is most commonly identified in males; however, females who carry the gene may have mild or, rarely, more severe symptoms of bleeding and should have their factor IX level checked.
Introduction
Hemophilia B, also known as factor IX deficiency or Christmas disease, is the second most common type of hemophilia. The disorder was first reported in the medical literature in 1952 in a patient with the name of Stephen Christmas. The most well-known family with hemophilia B was that of Queen Victoria of England. Through her descendants, the disorder was passed down to the royal families of Germany, Spain and Russia and thus hemophilia B is also known as the “royal disease.”
Although the focus of this report is the genetic, or inherited, form of hemophilia B, it should be noted that another form called acquired hemophilia B can develop, most commonly later in life (see “Related Disorders” section below). An individual with acquired hemophilia B is not born with the condition. Acquired hemophilia B is caused by the body’s production of antibodies against its own factor IX protein. The factor IX antibodies destroy circulating factor IX in the blood causing bleeding symptoms. Acquired hemophilia B is extremely rare; most cases of acquired hemophilia are in those with hemophilia A or factor VIII deficiency.
The symptoms and severity of hemophilia B vary greatly based upon the level of factor IX present. Hemophilia B can range from mild to moderate to severe. Individuals with mild hemophilia have factor IX levels between 5 and 40% of normal; those with moderate hemophilia have factor levels from 1 to 5% of normal; and individuals with severe hemophilia have factor levels less than 1% of normal. The age an individual becomes aware that they have hemophilia B, known as age of diagnosis, and the frequency of bleeding episodes depends upon the amount of factor IX present in the blood and the family history.
In mild cases of hemophilia B, individuals may experience bruising and bleeding after surgery, dental procedures, injury or trauma. Although some bleeding occurs in individuals without hemophilia after injury or trauma, individuals with hemophilia B often have longer and more severe bleeding episodes with these occurrences. Many individuals with mild hemophilia B may go undiagnosed until a surgical procedure is needed, or an injury occurs. Individuals with mild hemophilia may not experience their first bleeding episode until adulthood. Additionally, individuals with the mild form of hemophilia B may go many years between bleeding episodes.
Individuals with moderate hemophilia B may have occasional episodes of spontaneous bleeding from deep tissues such as joints and muscles. Spontaneous bleeding refers to bleeding episodes that occur without an identifiable cause. The individual may not be able to identify an event that may have occurred. Individuals with moderate hemophilia B are also at risk for prolonged bleeding following surgery or trauma. Affected individuals are usually diagnosed by five or six years of age but this may vary as well. The frequency of spontaneous bleeding episodes in individuals with moderate hemophilia B is highly variable.
In severe cases of hemophilia B, frequent, spontaneous bleeding episodes are the most common symptom. Spontaneous bleeding episodes may include bleeding into the muscles and joints. This often causes pain and swelling and restricts movement of the joint. Bleeding into a joint is called hemarthrosis. If left untreated, this often results in long-term damage including inflammation of the membrane lining the joints (synovitis) and joint disease (arthropathy) and muscle weakness and/or swelling, tightness and restricted movement around the affected joint. Permanent joint damage may occur. Additional symptoms affecting individuals with severe hemophilia B include easy bruising and bleeding into deep tissues such as the muscles, in addition, nosebleeds, gastrointestinal and central nervous system bleeding.
Individuals with a moderate or severe form of hemophilia can potentially experience spontaneous bleeding into other areas including the kidneys, stomach, intestines and brain. Bleeding within the kidneys or stomach and intestines may cause blood in the urine, called hematuria and stomach/intestines, called melena or hematochezia, respectively. Bleeding within the brain may cause headaches, stiff neck, vomiting, seizures and mental status changes including excessive sleepiness and poor arousability, and may result in permanent neurologic damage and/or death if left untreated.
Severe cases of hemophilia B usually become apparent early during infancy or childhood. Without preventative treatment, called prophylaxis, a young child may experience two to five spontaneous bleeding episodes per month. Infants are diagnosed with hemophilia B based on a known family history of hemophilia or after they develop bleeding due to a bleeding event which may but not always occur with circumcision, a neonatal procedure; bleeding within the brain or around the head, called an intracranial bleed or extracranial bleed, resulting from delivery may also occur. If an infant is not diagnosed at birth, hemophilia may be suspected if the child develops excessive bruising or deep tissue bleeding in areas such as the buttock muscles from falling while learning to walk; bleeding into the joints; or prolonged bleeding in the mouth due to an injury such as a fall or abnormal bruising or bleeding with immunizations.
Hemophilia B is caused by a change (variant or mutation) in the F9 gene. The F9 gene is located on the X chromosome and thus is inherited in an X-linked recessive pattern. In about 30% of cases of hemophilia B, the altered gene occurs spontaneously without a previous family history.
The F9 gene contains instructions for creating the factor IX protein. Variants in the F9 gene can lead to deficient levels of functional factor IX protein. The bleeding symptoms associated with hemophilia B occur due to this deficiency.
X-linked recessive disorders are conditions caused by an altered gene on the X chromosome. Females have two X chromosomes (XX). If only one of their X chromosomes contains a disease-causing variation on a gene, they are called “carriers” of that disorder, and carriers with FIX activity level <40% are now diagnosed as having hemophilia. Males have one X chromosome and one Y chromosome (XY). Thus, if a male inherits an X chromosome from his mother that contains a disorder-causing gene, he will develop the disorder. Males with an X chromosome containing the disorder-causing gene will pass that gene on to all their daughters. These daughters will be carriers if the X chromosome they inherit from their mother is normal. They will have hemophilia if they inherit another disorder-causing gene from their mother; this is rare. A male cannot pass an X-linked gene on to his sons because males only pass their Y chromosome on to their sons. With each pregnancy, female carriers of an X-linked disorder have a 25% chance for each daughter to be a carrier; a 25% chance of having a non-carrier daughter; a 25% chance of having a son with the disorder; and a 25% chance of having an unaffected son. Hemophilia B Leyden: There is an unusual form of factor IX deficiency called hemophilia B Leyden. Hemophilia B Leyden is named after the place in the Netherlands where it was first described. Depending upon the particular hemophilia B Leyden variant present, there are undetectable levels of factor IX present early in life that increase over time. By midlife, these patients have factor IX levels at the low end of the normal range and thus may no longer require treatment for bleeding episodes. Hemophilia B Leyden represents approximately 3% of all hemophilia B cases.
Hemophilia B occurs in approximately 1 in 25,000 male births. It is less prevalent than hemophilia A which occurs in approximately 1 in 5,000 male births. Although many hemophilia B carrier females do not have symptoms, an estimated 10-25% will develop mild symptoms and females have also been reported with moderate and severe symptoms. All races and ethnic groups are affected equally. Individuals with severe hemophilia B are usually diagnosed around birth or within the first few years of life; those with moderate hemophilia B, five to six years of age; and individuals with mild hemophilia B may not be diagnosed until later in life and even into adulthood.
Diagnosis of hemophilia B is made with attention to the following: the patient’s personal history of bleeding, the patient’s family history of bleeding and inheritance and laboratory testing. Several different specialized tests are necessary to confirm a diagnosis of hemophilia B.
To determine if an individual has hemophilia B, specialized blood coagulation tests are used that measure how long it takes the blood to clot. The initial test is the activated partial thromboplastin time (aPTT). If the results of the aPTT test are abnormal, more specific blood tests must be used to determine if the cause of the abnormal aPTT is due to a deficiency of factor IX/hemophilia B, factor VIII/hemophilia A or another clotting factor. A specific factor assay also determines the severity level of the factor deficiency. It should be noted that the aPTT is not consistently sensitive to detect mild hemophilia B. If this diagnosis is suspected, a specific factor IX activity level should be performed even in the face of a normal aPTT.
Once an individual is diagnosed with hemophilia B, the specific variant in the F9 gene responsible for causing hemophilia may be identified. Identifying the variant may assist in determining an individual’s risk of developing an inhibitor, a serious complication in those with severe hemophilia (see “Complications” section below). Understanding the specific F9 gene variant is important to identify female carriers within a family as factor IX levels are not adequate to determine carrier status.
Treatment
The fundamental treatment of hemophilia B is to replace factor IX to achieve adequate blood clotting and to prevent complications associated with the disorder. Currently, replacement of factor IX to achieve a sufficient level is commonly done utilizing recombinant products or with products derived from human blood or plasma. Many physicians and voluntary health organizations favor the use of recombinant factor IX because it does not contain human blood proteins. Human blood donations carry a very small risk of transmitting viral infections such as hepatitis and HIV; however, newer techniques for screening and treating blood donations have this risk extremely low to negligible.
Carrier females that have bleeding symptoms may need factor replacement therapy in a variety of circumstances such as for bleeding episodes, following childbirth due to postpartum bleeding or for dental and surgical procedures depending on their factor IX activity level.
Federally Recognized Hemophilia Treatment Centers: Evidence has shown that individuals with hemophilia significantly benefit from receiving care from a federally recognized hemophilia treatment center. These specialized centers provide comprehensive care for individuals with hemophilia including the development of specific treatment plans, monitoring and follow-up of affected individuals and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team including physicians, nurses, physical therapists, social workers and genetic counselors experienced in treating individuals with hemophilia. To locate a hemophilia treatment center, visit the Centers for Disease Control and Prevention website at: https://www.cdc.gov/ncbddd/hemophilia/HTC.html
Current Treatment Options
Recombinant Factor IX: Recombinant factor IX products are manufactured in a laboratory. These genetically engineered products do not contain animal or human protein and are not derived from human blood; they are theoretically considered to be free of the risk of transmitting viruses. Recombinant factor IX therapy is the recommended treatment for individuals with hemophilia B. In the U.S., the currently available recombinant factor IX products are BeneFIX, Rixubis, Ixinity, Alprolix, Idelvion and Rebinyn.
Plasma-Derived Factor IX Concentrates: There are two main categories of plasma-derived factor IX concentrates available; highly purified plasma-derived products and intermediate purity plasma-derived products. Plasma-derived products come from human donations of blood or plasma. Highly purified products are essentially free of other clotting factor proteins and are virally inactivated using various methods. There are two high purity products available in the U.S., AlphaNine SD and Mononine. Intermediate purity products contain factor IX and variable amounts of other clotting factor proteins and are virally inactivated; however, they are rarely used in the United States and not recommended for treatment of FIX deficiency.
Fresh Frozen Plasma: Fresh frozen plasma is derived from human blood and is used to treat patients with factor IX deficiency only if factor IX concentrate is not available. Fresh frozen plasma contains all the coagulation factors in the blood but is not virally inactivated. In addition, fresh frozen plasma is inefficient in raising factor IX activity to a hemostatic level.
In 2020, the FDA approved recombinant coagulation factor VIIa (Sevenfact), another recombinant product that does not contain FIX protein. Sevenfact also has been approved for the treatment and control of bleeding episodes in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors.
In 2022, etranacogene dezaparvovec (Hemgenix) was approved by the FDA as the first gene therapy to treat adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes.
The document in the link below from the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation provides recommendations for the treatment of hemophilia:
https://www.hemophilia.org/sites/default/files/document/files/259_treatment.pdf
History of Hemophilia Treatment Options
Whole Blood: Until the 1960s, highly reliable treatment for hemophilia did not exist. Patients experiencing bleeding episodes were treated with whole blood transfusions. This was an ineffective treatment option as whole blood does not contain enough clotting factor to increase the level to a hemostatic range to effectively control bleeding. During this time, individuals often had repeated bleeding into the joints or central nervous system which led to permanent joint damage, seizures and a variety of permanent intellectual and movement disorders. The average life expectancy of a male with severe hemophilia during this time was 12 years of age.
Cryoprecipitate: In the mid-1960s, Dr. Judith Pool discovered cryoprecipitate, a human plasma-derived material rich in clotting factor VIII, the clotting factor that is deficient in those with hemophilia A. Cryoprecipitate settles to the bottom of containers of frozen plasma when thawed at refrigerator temperature. Upon warming to room temperature, the cryoprecipitate returns to solution. In its frozen form, cryoprecipitate was stored in blood banks and administered to persons with hemophilia A in place of whole blood or plasma. The effect of the more concentrated factor VIII found in cryoprecipitate, compared to whole blood, was more rapid blood clot formation and decreased problems associated with bleeding episodes. Cryoprecipitate does not contain factor IX and is not recommended for use in the United States anymore for treatment of hemophilia A.
Plasma-Derived Clotting Factor Concentrates: In the late 1960s and early 1970s clotting factors became available in more concentrated forms that remained stable as powders when stored at refrigerator temperature. This allowed hemophilia patients to store and administer the clotting factor at home without medical supervision. The first available factor IX product was an intermediate purity (PCC) and was approved for use in the U.S. in 1969.
One of the main problems with early factor therapy was that the products available came from human plasma from many donors. This carried the risk of transmitting viruses such as hepatitis A, B and C and human immunodeficiency virus (HIV) from the donor to the patient. Until the mid-1980s many individuals receiving factor products became infected with one or more of these viruses due to inability to effectively screen donors or treat the concentrate to inactivate viruses.
Recombinant Products: It was not until the late 1980s to the early 1990s, that the efficacy of recombinant factor products was reported, and products made commercially available. In 1992, the first genetically engineered factor VIII concentrate was approved by the U.S. Food and Drug Administration (FDA). It was not until 1997 that the first recombinant factor IX product became available. Use of genetically engineered factor concentrates may eliminate the risk of blood borne infections or transmittable diseases dependent on the method of manufacturing and exposure or use of human or animal proteins in the manufacturing process.
Treatment Regimens for Hemophilia
Individuals with mild or moderate hemophilia B may be treated with replacement therapy as needed to treat a bleeding episode. This is called episodic infusion therapy and is used to stop a bleed that has already started. Individuals with severe hemophilia B may receive regular infusions to prevent bleeding episodes. This is called prophylactic therapy and is intended to prevent bleeds before they occur. Prophylactic therapy has been shown to reduce many complications associated with recurrent bleeding such as joint damage and intracranial hemorrhage in patients with severe hemophilia A and B. Parents and affected individuals can be trained to administer factor IX at home. Home therapy is especially important for individuals with severe disease but is also important for moderate and mild hemophilia as infusion of factor IX concentrate is most effective at limiting bleeding when administered within one hour of the onset of a bleeding episode. Some patients with moderate or mild hemophilia B receive prophylaxis for prevention of bleeding during activities either short or longer term (e.g., before a specific activity such as skiing or during basketball or baseball season etc.)
Complications
Infusion Reactions: Individuals with factor IX deficiency may experience itching, hives, redness of the skin or, uncommonly, coughing, tight throat or wheezing during or immediately after infusion of replacement with FIX. Infusion reactions are most seen in individuals using fresh frozen plasma where the reaction is typically an allergic-like reaction to some part of the donor’s blood. These reactions can usually be treated with antihistamines and corticosteroids; however, a physician should always be notified of such an event. An important infusion reaction in hemophilia B can occur with the use of factor IX concentrates; these are uncommon but must be recognized promptly for patient safety and monitoring. If symptoms develop or are severe, the infusion should be stopped, and the patient should notify their hemophilia care provider immediately as well as be seen in the emergency room. Infusion reactions in patients with severe factor IX deficiency may be associated with the development of inhibitors.
Inhibitors: It is estimated that < 5% of individuals with severe hemophilia B develop “inhibitors” against factor IX replacement therapy. Inhibitors are antibodies, created by the body’s immune system that is usually targeted to combat foreign or invading substances such as toxins or bacteria. The immune system may recognize replacement factor IX as “foreign” and create antibodies, or “inhibitors”, against it. These antibodies destroy the replacement factor. This complication negatively impacts the effectiveness of standard treatment. In such cases, alternate treatment is used to treat bleeding. In addition, therapy to eradicate these antibodies may be instituted. The therapy is called immune tolerance induction therapy. Immune tolerance induction therapy is less commonly attempted in patients with hemophilia B and inhibitors than in hemophilia A with inhibitors due to the risk of allergic reactions, kidney disease and decreased rate of success. Inhibitor development is considered the most severe problem in hemophilia care today as it affects patient treatment, risk of developing joint disease, cost of hemophilia care, morbidity and mortality. Genetic testing can help determine whether an individual with factor IX deficiency is at a higher risk of developing an inhibitor. NovoSeven RT (recombinant coagulation factor VIIa) is a recombinant product used for treatment and prevention of bleeding in individuals with factor IX deficiency with an inhibitor that does not contain any FIX protein.
The goal of hemophilia B therapy is to provide a treatment that allows for long-term expression of the missing or deficient factor in a patient’s blood without continuous medical intervention; a so-called “cure.” Gene therapy has the potential to be a cure. In hemophilia B gene therapy, the addition of a new gene would allow an individual to produce enough of the factor IX protein. Ideally, the addition of a new gene could be long lasting, and an individual will no longer have to infuse with clotting factor concentrate based upon the level achieved, or if required would only be used quite infrequently.
Other novel agents being investigated in clinical trials include fitusran and anti-TFPI inhibitors such as concizumab, among others.
To obtain information on hemophilia B clinical trials visit www.clinicaltrials.gov. Studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site. For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office at:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com.
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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INTERNET
Konkle BA, Nakaya Fletcher S. Hemophilia B. 2000 Oct 2 [Updated 2023 Feb 9]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1495/ AccessedSept 19, 2023.
MedlinePlus. F9. Reviewed May 2010. https://ghr.nlm.nih.gov/gene/F9 Accessed Sept 19, 2023.
MASAC Recommendations Concerning Products Licensed for the Treatment of Hemophilia and Other Bleeding Disorders. MASAC. August 20, 2023. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendations-Concerning-Products-Licensed-for-the-Treatment-of-Hemophilia-and-Other-Bleeding-Disorders Accessed Sept 19, 2023.
National Hemophilia Foundation. Medical and Scientific Advisory Council (MASAC) recommendation regarding the use of recombinant clotting factor products with respect to pathogen transmission. May 6, 2014. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendation-Regarding-the-Use-of-Recombinant-Clotting-Factor-Products-with-Respect-to-Pathogen-Transmission Accessed Sept 19, 2023.
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