Background

Hemophilia B, also called factor IX deficiency or Christmas disease, is the second most common type of hemophilia. The disease was first described in the literature in 1952 in a patient named Stephen Christmas. The most famous family afflicted with hemophilia B was that of Queen Victoria of England. The disease was transferred through her descendants to the royal families of Russia, Germany, and Spain, and therefore hemophilia B is also called the royal disease.1

Hemophilia B is an X-linked recessive inherited disorder characterized by a deficiency of plasma coagulation factor IX. It may also develop through acquired immunologic mechanisms and spontaneous mutations. Hemophilia B accounts for 20% of all cases of hemophilia; in approximately 50% of these cases, levels of factor IX are higher than 1%.2

Prevalence 

The prevalence of hemophilia B is 1 in 40,000 live males. Hemophilia B is distributed equally among all ethnic groups, but rates are higher in specific communities, such as Egyptians and Ashkenazi Jews, because of a higher incidence of consanguineous marriages among them.3 Episodes of bleeding are more common in children and adolescents than in adults.4

Factor IX and the Coagulation System

Factor IX, a vitamin K–dependent single-chain glycoprotein, is synthesized in the hepatocytes. The precursor protein undergoes many post-translational modifications before it is released into the blood.2

For the fibrin mesh that stabilizes the platelet plug to form, 2 coagulation pathways must be activated: an intrinsic pathway, which is activated by collagen, basement membrane, activated platelets, and high-molecular-weight kininogen (HMWK), including factors XII, XI, IX, and VIII, and an extrinsic pathway, which is activated by tissue factor (TF), which includes factor VII. Both pathways activate the combined pathway, consisting of factors X, V, II, and I, ultimately resulting in the formation of a stable fibrin mesh.3 Factor IX is therefore a main component of the intrinsic pathway, and a deficiency of factor IX causes defects in the coagulation cascade and inadequate fibrin mesh formation.5

Clinical Presentation of Hemophilia B 

The severity of hemophilia is described according to either the clinical bleeding symptoms or the plasma procoagulant levels, more frequently the latter. Disease in which factor levels are below 1% of normal (<0.01 IU/mL) is classified as severe hemophilia. When factor levels are 1% to 5% of normal (0.01-0.05 IU/mL), the hemophilia is classified as moderately severe. Disease in which factor levels are above 5% but below 40% of normal (>0.05 to <0.40 IU/mL) is considered mild hemophilia.2

The characteristic clinical feature of hemophilia B is spontaneous bleeding from a joint (hemarthrosis), which occurs in severe cases. Severe disease is commonly diagnosed during the first 2 years of life. Without prophylactic treatment, patients who have severe hemophilia B experience 2 to 5 episodes of spontaneous bleeding each month. Patients with moderate hemophilia B rarely experience spontaneous bleeding, but delayed or prolonged oozing occurs after relatively minor trauma. Moderate disease is commonly diagnosed before 5 to 6 years of age. The number of episodes of bleeding ranges from 1 per month to 1 per year. Episodes of  spontaneous bleeding do not occur in mild hemophilia B, but without pre- and postoperative treatment, abnormal bleeding accompanies surgery or tooth extractions. The number of episodes of bleeding can range from 1 per year to 1 every 10 years. Mild hemophilia B is generally not diagnosed until later in life.4

Diagnosis and Evaluation

Hemophilia B is diagnosed with an evaluation of the patient’s personal history of bleeding, the family history of bleeding and pattern of inheritance, and laboratory tests. Many specialized tests are required to confirm the diagnosis.1

Prolongation of the activated partial thromboplastin time (aPTT) indicates disruption in the intrinsic pathway of coagulation; however, a normal aPTT cannot rule out hemophilia. A complete blood cell count may show normal or low hemoglobin levels with normal platelet levels.3 A specific factor assay evaluates the severity of the factor deficiency. When a diagnosis of hemophilia B is suspected, the specific factor IX activity level must be tested even if the aPTT is normal.1 The other types of hemophilia are also caused by coagulation factor abnormalities, such as hemophilia A (factor VIII) and hemophilia C (factor XI). They are differentiated through the clinical presentation, coagulation factor assays, and genetic testing. Hemophilia A and B are inherited in an X-linked recessive pattern, whereas the inheritance of hemophilia C is not X-linked; inheritance is autosomal-recessive.3

Hemophilia B Treatment

Factor IX replacement is the basis of hemophilia B treatment. This maintains adequate blood clotting and prevents complications associated with the disease.1 Current treatment options are recombinant factor IX, plasma-derived factor IX concentrates, and fresh frozen plasma.1

References

  1. Hemophilia B. NORD (National Organization for Rare Disorders), Accessed July 26, 2021.
  2. Zaiden RA. Hemophilia B. Practice Essentials. Medscape, Updated Oct 02, 2020. Accessed July 26, 2021.
  3. Alshaikhli A, Rokkam VR. Hemophilia B. StatPearls. Updated February 6, 2021. Accessed July 26, 2021.
  4. Konkle BA, Huston H, Nakaya Fletcher S. Hemophilia B. GeneReviews. Published October 2, 2000. Updated June 15, 2017. Accessed July 26, 2021.
  5. Zimmerman B, Valentino LA. Hemophilia: in review. Pediatr Rev. 2013;34(7):289-295. doi:10.1542/pir.34-7-289.

Reviewed by Debjyoti Talukdar, MD, on 8/10/2021.