• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report

Hemophilia B

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Last updated: 02/13/2023
Years published: 1987, 1988, 1989, 1995, 1996, 2000, 2007, 2008, 2012, 2015, 2018


Acknowledgment

NORD gratefully acknowledges Amy D. Shapiro, MD, Medical Director, Indiana Hemophilia and Thrombosis Center, for the preparation of this report.


Disease Overview

 

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 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 (mutations) in the factor IX (F9) gene on the X chromosome. Hemophilia B is mostly expressed in males but some females who carry the gene may have mild or, rarely, severe symptoms of bleeding.

 

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 famous 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.

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Synonyms

  • Christmas disease
  • factor IX deficiency
  • royal disease
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Signs & Symptoms

The symptoms and severity of hemophilia B may vary greatly from one person to another. 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 he has 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 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. These episodes are usually associated with some injury or inciting event. Individuals with moderate hemophilia B are at risk for prolonged bleeding following surgery or trauma. Affected individuals are usually diagnosed by five or six years of age. Spontaneous bleeding refers to bleeding episodes that occur without an identifiable cause. 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 a hemarthrosis. If left untreated, this may result in long-term damage including inflammation of the membrane lining the joints (synovitis) and joint disease (arthropathy), muscle weakness and/or swelling, tightness and restricted movement in the affected joint. Permanent joint damage may occur. Spontaneous joint bleeding is the most common symptom of severe hemophilia B. Additional symptoms affecting individuals with severe hemophilia B include easy, frequent and severe bruising and muscle bleeds, and less commonly, nosebleeds, gastrointestinal and central nervous system bleeding.

Individuals with a moderate or severe form of hemophilia can potentially experience spontaneous bleeding into any organ including the kidneys, stomach, intestines, and brain. Bleeding within the kidneys or stomach and intestines may cause blood in the urine, called hematuria, and stool, 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 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 on the basis of a known family history of hemophilia or after they develop bleeding following circumcision, another neonatal procedure or, in some cases, bleeding within the brain, called an intracranial bleed, resulting from delivery. 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.

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Causes

Hemophilia B is caused by mutations in the F9 gene. The F9 gene is located on the X chromosome and thus is inherited as an X-linked recessive trait. In about 30% of new 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. Mutations 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. Carrier females of hemophilia may experience bleeding symptoms which may be related to their FIX activity level; as carriers have a normal copy of their other X-chromosome carrier levels are most commonly higher than affected males.

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 of their daughters. These daughters will be carriers if the X chromosome they inherit from their mother is normal or 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 mutation 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.

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Affected populations

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 1-2 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.

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Diagnosis

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 mutation in the F9 gene responsible for causing hemophilia may be identified. Identifying the type of mutation 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 mutation can also help identify female carriers within a family as factor IX levels are not adequate to determine carrier status.

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Standard Therapies

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 following childbirth due to postpartum bleeding or for dental and surgical procedures depending on their factor IX activity level.

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 of 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.

Gene Therapy: In 2022, the FDA approved a gene therapy called etranacogene dezaparvovec (Hemgenix) 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. This product is a one-time treatment of a viral vector that carries a gene for factor IX.

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 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 sufficient quantities of 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.

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. 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 Food and Drug Administration. 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.

Complications

Infusion Reactions: Individuals with factor IX deficiency may experience itching, hives, redness of the skin or, uncommonly, wheezing during or immediately after infusion of replacement with FIX. Infusion reactions are most commonly 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 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 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 that does not contain any FIX protein.

In 2020, the FDA approved Sevenfact (recombinant coagulation factor VIIa), another recombinant product that does not contain FIX protein. Sevenfact 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.

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

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Clinical Trials and Studies

Future Treatment Options

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: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

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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References

JOURNAL ARTICLES
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Nathwani AC, Reiss UM, Tuddenham CR, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994-2004.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278802/

Powell JS, Pasi KJ, Ragni MV, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med. 2013;369:2313-2323. http://www.ncbi.nlm.nih.gov/pubmed/24304002

Shapiro AD, Ragni MV, Valentino LA, et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B. Blood. 2012;119:666-672.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265197/

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Coppola A, Favaloro EJ, Tufano A, et al. Acquired inhibitors of coagulation factors: part I-acquired hemophilia a. Semin Thromb Hemost. 2012;38:433-46. http://www.ncbi.nlm.nih.gov/pubmed/22740182

Hamasaki-Katagiri N, Salari R, Simhadri VL, et al. Analysis of F9 point mutations and their correlation to severity of haemophilia B disease. Haemophilia. 2012. http://www.ncbi.nlm.nih.gov/pubmed/22639855

Miller CH, Benson J, Ellingsen D, et al. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012;18:375-82. http://www.ncbi.nlm.nih.gov/pubmed/22103590

Bornikova L, Peyvandi F, Allen G, Bernstein J, Manco-Johnson MJ. Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost. 2011;9:1687-704. http://www.ncbi.nlm.nih.gov/pubmed/21711446

Krishnamurthy P, Hawche C, Evans G, Winter M. A rare case of an acquired inhibitor to factor IX. Haemophilia. 2011;17:712-3. http://www.ncbi.nlm.nih.gov/pubmed/21371188

Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365:2357-65. http://www.ncbi.nlm.nih.gov/pubmed/22149959

Rogaev EI, Grigorenko AP, Faskhutdinova G, Kittler EL, Moliaka YK. Genotype analysis identifies the cause of the “royal disease”. Science. 2009;326:817. http://www.ncbi.nlm.nih.gov/pubmed/19815722

Kurachi S, Huo JS, Ameri A, Zhang K, Yoshizawa AC, Kurachi K. An age-related homeostasis mechanism is essential for spontaneous amelioration of hemophilia B Leyden. Proc Natl Acad Sci USA. 2009;106:7921-6. http://www.ncbi.nlm.nih.gov/pubmed/19416882

de Moerloose P, Neerman-Arbez M. Congenital fibrinogen disorders. Semin Thromb Hemost. 2009;35:356-66. http://www.ncbi.nlm.nih.gov/pubmed/19598064

Peyvandi F. Results of an international, multicentre pharmacokinetic trial in congenital fibrinogen deficiency. Thromb Res. 2009;124 Suppl 2:S9-11. http://www.ncbi.nlm.nih.gov/pubmed/20109654

Acharya SS, Dimichele DM. Rare inherited disorders of fibrinogen. Haemophilia. 2008;14:1151-8. http://www.ncbi.nlm.nih.gov/pubmed/19141154

Mauser-Bunschoten E. Symptomatic Carriers of Hemophilia. A World Federation of Hemophilia Publication. 2008;46.

Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357:535-44. http://www.ncbi.nlm.nih.gov/pubmed/17687129

Lillicrap D. Von Willebrand disease – phenotype versus genotype: deficiency versus disease. Thromb Res. 2007;120 Suppl 1:S11-6.
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Schulman S. Mild Hemophilia. A World Federation of Hemophilia Publication. 2006;41.

Mitchell M, Keeney S, Goodeve A, Network UKHCDOHGL. The molecular analysis of haemophilia B: a guideline from the UK haemophilia centre doctors’ organization haemophilia genetics laboratory network. Haemophilia: the official journal of the World Federation of Hemophilia 2005;11:398-404. http://www.ncbi.nlm.nih.gov/pubmed/16011594

Franchini M, Gandini G, Di Paolantonio T, Mariani G. Acquired hemophilia A: a concise review. Am J Hematol. 2005;80:55-63. http://www.ncbi.nlm.nih.gov/pubmed/16138334

Giangrande P. Haemophilia B: Christmas disease. Expert Opin Pharmacother. 2005;6:1517-24. http://www.ncbi.nlm.nih.gov/pubmed/16086639

Bolton-Maggs PH, Perry DJ, Chalmers EA, et al. The rare coagulation disorders–review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation. Haemophilia. 2004;10:593-628. http://www.ncbi.nlm.nih.gov/pubmed/15357789

Powell JS, Ragni MV, White GC, et al. Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion. Blood. 2003;102:2038-45. http://www.ncbi.nlm.nih.gov/pubmed/12763932

Manno CS, Chew AJ, Hutchison S, et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood. 2003;101:2963-72. http://www.ncbi.nlm.nih.gov/pubmed/12515715

Von Depka M. NovoSeven: mode of action and use in acquired haemophilia. Intensive Care Med. 2002;28 Suppl 2:S222-7. http://www.ncbi.nlm.nih.gov/pubmed/12404090

Boggio LN, Green D. Acquired hemophilia. Rev Clin Exp Hematol. 2001;5:389-404; quiz following 31. http://www.ncbi.nlm.nih.gov/pubmed/11844135

Soucie JM, Nuss R, Evatt BL, et al. Mortality among males with hemophilia: relations with source of medical care. Blood. 2000;96:437-42. http://www.ncbi.nlm.nih.gov/pubmed/10887103

Hay CR. Acquired haemophilia. Baillieres Clin Haematol. 1998;11:287-303. http://www.ncbi.nlm.nih.gov/pubmed/10097808

Dioun AF, Ewenstein BM, Geha RS, Schneider LC. IgE-mediated allergy and desensitization to factor IX in hemophilia B. The Journal of allergy and clinical immunology 1998;102:113-7. http://www.ncbi.nlm.nih.gov/pubmed/9679854

Williamson LM, Allain JP. Virally inactivated fresh frozen plasma. Vox Sang. 1995;69:159-65. http://www.ncbi.nlm.nih.gov/pubmed/8578727

Berntorp E. Methods of haemophilia care delivery: regular prophylaxis versus episodic treatment. Haemophilia. 1995;1:3-7.

Briet E, Bertina RM, van Tilburg NH, Veltkamp JJ. Hemophilia B Leyden: a sex-linked hereditary disorder that improves after puberty. N Engl J Med. 1982;306:788-90. http://www.ncbi.nlm.nih.gov/pubmed/7062952

Breen FA Jr, Tullis JL. Prothrombin concentrates in treatment of Christmas disease and allied disorders. JAMA. 1969;208:1848-52. http://www.ncbi.nlm.nih.gov/pubmed/5818828

Pool JG, Gershgold EJ, Pappenhagen AR. High-potency antihaemophilic factor concentrate prepared from cryoglobulin precipitate. Nature. 1964;203:312.
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Biggs R, Douglas AS, Macfarlane RG, et al. Christmas disease: a condition previously mistaken for haemophilia. Br Med J. 1952;2:1378-82. http://www.ncbi.nlm.nih.gov/pubmed/12997790

INTERNET
Konkle BA, Huston H, Nakaya Fletcher S. Hemophilia B. 2000 Oct 2 [Updated 2017 Jun 15]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1495/ Accessed June 6, 2018.

Genetics Home Reference. F9. http://ghr.nlm.nih.gov/gene/F9 Reviewed May 2010. Accessed June 6, 2018.

MASAC Recommendations Concerning Products Licensed for the Treatment of Hemophilia and Other Bleeding Disorders. MASAC. 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 April 23, 2018. Accessed June 6, 2018.

National Hemophilia Foundation. Medical and Scientific Advisory Council (MASAC) recommendation regarding the use of recombinant clotting factor products with respect to pathogen transmission. 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 May 6, 2014. Accessed June 6, 2018.

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