Hemophilia B

Hemophilia B is a lifelong bleeding disorder in which the blood does not clot properly because of an inherited deficiency of factor IX (FIX).1

As with Hemophilia A, the gene for encoding FIX is on the X chromosome (recessive), which means Hemophilia B occurs primarily in males.1 Females are typically carriers of the gene and can pass it on to their children, but can occasionally be symptomatic carriers.

Hemophilia B illustration

Epidemiology

Globally, it is estimated that more than 1.1 million males have hemophilia, including 418,000 with severe hemophilia.1 Hemophilia B accounts for an estimated 15-20% of cases worldwide.

Within the U.S., it is estimated that 1 in 19,283 males are born with Hemophilia B.2 Data from the U.S. Centers for Disease Control and Prevention (CDC) estimated that the total number of patients with Hemophilia B in the U.S., between 2012 and 2022, was 7,253.3

According to the hemophilia treatment centers population profile (HTC PP), about 28.1% of male patients with Hemophilia B have mild disease, 40.9% have moderate disease, and 30.0% have severe disease.4

Diagnosis

The diagnosis of hemophilia is based on 3 principles:1

  • Suspecting hemophilia when the following symptoms are present: easy bruising, spontaneous bleeding, excessive bleeding post-trauma or -surgery, or early symptoms of joint bleeds in children
  • Screening tests: abnormally prolonged activated partial thromboplastin time (aPTT) with normal prothrombin time (PT) and normal platelet count
  • Confirming tests: specific factor assays to determine level of FVIII or FIX in the blood. Severe Hemophilia B is defined as <1% of normal FIX, moderate is 1-5% of normal FIX, and mild is 5-40% of normal FIX

A surveillance project evaluating 864 male infants with hemophilia seen at U.S. hemophilia treatment centers (aged 0 to 2 years) found that 73% of them were diagnosed by 1 month of age.5 The diagnosis in these cases was prompted by a known carrier mother (47.2% of cases), a family history (23.2% of cases), and a bleeding event or unusual bruising (28.8% of cases).

In approximately one-third of severe cases there is no known family history, suggesting a spontaneous mutation.1,5

Pathophysiology

Hemophilia B is caused by a variety of inherited or spontaneous mutations in the gene encoding FIX.1

FIX plays a key role in the contact activation pathway, or intrinsic pathway, for blood coagulation following an injury.6 Following damage to endothelial surface, FIX is cleaved by Factor VIIa into its active form, FIXa. FIXa, in turn, cleaves Factor X to create Factor Xa, which is instrumental in the generation of thrombin, necessary for the formation of fibrin clots.

The level of deficiency in functional FIX, as detected in factor assays, is associated with the severity of bleeding symptoms in Hemophilia B.1

Navigating Hemophilia B

Joints (most commonly the elbow, knee, and ankle) are the site of approximately 92% of bleeds in severe hemophilia.1,7 Other common sites of bleeding are the muscles, the brain, and mucosal tissues (mouth, epistaxis, gastrointestinal, and genitourinary tract).1 Recurrent bleeding into the same joint may eventually cause hypertrophic synovitis, progressive cartilage degradation, hemophilic arthropathy, and significant impairment of joint function.7,8

Treatment of Hemophilia B involves replacement therapy in which the deficient endogenous FIX is replaced via intravenous infusion.9,10 The standard of care in Hemophilia B has shifted towards prophylactic treatment, with the goal of preventing all bleeds, rather than on-demand or episodic treatment in response to a bleeding episode. World Federation of Hemophilia (WFH) guidelines recommend individualized prophylaxis based on bleeding phenotype, joint status, individual pharmacokinetics, and patient self-assessment and preference.1

The most severe treatment-related complication in hemophilia is the development of inhibitors, which are alloantibodies to administered factor replacement therapy.11 The lifetime incidence of inhibitors is lower in Hemophilia B than in Hemophilia A (3-5% of severe Hemophilia B patients vs 25-30% of severe Hemophilia A patients). In contrast with FVIII inhibitors, FIX inhibitors are associated with severe anaphylactic reactions to the infusion of FIX-containing products in about half of patients with inhibitors.