What is Factor IX (9) deficiency, also known as Hemophilia B?

From the Guidelines

Factor 9 deficiency, also known as Hemophilia B or Christmas disease, is an inherited bleeding disorder caused by insufficient levels of clotting factor IX in the blood, primarily affecting males and passed down through an X-linked recessive pattern, with severity depending on the amount of factor IX present, and treatment involving replacement of the missing factor IX through intravenous infusions of factor IX concentrates, either on-demand or as prophylaxis, with a dosage ranging from 20-100 IU/kg depending on the severity of bleeding and the patient's weight, as recommended by the international society on thrombosis and haemostasis clinical practice guideline for treatment of congenital hemophilia A and B 1.

Key Points

• Factor 9 deficiency is a congenital X-linked bleeding disorder that affects an estimated 1,125,000 individuals worldwide, with hemophilia B resulting from deficiency of functional coagulation factor IX, and accounting for about 15% to 20% of all hemophilia cases 1.
• The severity of factor 9 deficiency depends on the amount of factor IX present, with levels below 1% causing severe disease, 1-5% moderate disease, and 5-40% mild disease, and individuals with severe forms of hemophilia not treated with prophylaxis may experience spontaneous bleeding, of which the most frequent are joint and muscle bleeding 1.
• Treatment involves replacing the missing factor IX through intravenous infusions of factor IX concentrates, either on-demand when bleeding occurs or as prophylaxis to prevent bleeding episodes, with a dosage ranging from 20-100 IU/kg depending on the severity of bleeding and the patient's weight, and extended half-life products are now available, allowing less frequent infusions 1.
• Some patients develop inhibitors (antibodies) against factor IX, complicating treatment, and gene therapy for Hemophilia B is advancing, with some approved treatments that may provide long-term factor IX production 1.

Management

• Prophylactic treatment in individuals with hemophilia without inhibitors with FVIII and FIX concentrates consists of regular administration of clotting factor concentrates to prevent bleeding and joint damage, with standard prophylaxis referring to dose and dose intervals of 20 to 60 IU/kg of FIX twice per week for hemophilia B, as defined by Srivastava et al. 1.
• The international society on thrombosis and haemostasis clinical practice guideline for treatment of congenital hemophilia A and B recommends prophylaxis with FVIII or FIX concentrates to prevent bleeding and joint damage, with different regimens (dose and dose intervals) of FVIII or FIX concentrates, and low-dose prophylaxis with FVIII was defined as 10 IU/kg, 2 times per week, according to the studies included in recommendation 4 1.

From the Research

Definition and Causes of Factor 9 Deficiency

• Factor 9 deficiency, also known as Hemophilia B or Christmas disease, is a bleeding disorder caused by a deficiency of or defect in blood coagulation factor IX (FIX) 2.
• It is inherited in an X-linked manner, resulting from one of over 1000 known pathogenic variants in the FIX gene, F9 2.
• The disorder can lead to recurrent and spontaneous bleeding into joints, which can cause joint deformity and arthritis at an early age 3.

Symptoms and Treatment

• The hallmark of the severe phenotype is recurrent and spontaneous bleeding into joints 3.
• Treatment typically consists of the administration of recombinant factor IX concentrate on a prophylactic basis to prevent bleeds and minimize disability in the long term 3.
• Gene therapy is also being explored as a potential treatment option, although it is still in the early stages of development 3, 2.
• Patients with factor 9 deficiency may also be at risk of developing antibodies to FIX treatment products (inhibitors), which can make treatment more challenging 2.

Management and Prophylaxis

• The management of factor 9 deficiency often involves individualized dosing of clotting factor concentrates, which can be guided by pharmacokinetic (PK) parameters 4.
• Several alternative dosing strategies have been proposed, including methods using clinical parameters, empirical individual PK-guided methods, and maximum a posteriori (MAP) Bayesian estimation methods 4.
• Prophylactic treatment regimens, including combinations of plasma-derived factor, recombinant factor, desmopressin, and/or tranexamic acid, can be effective in preventing bleeding during invasive procedures such as gastrointestinal endoscopy 5.

Bleeding Risk and Complications

• Patients with factor 9 deficiency may be at risk of bleeding during invasive procedures, although the bleeding risk can be managed with appropriate prophylactic treatment regimens 5.
• The overall bleeding rate after gastrointestinal endoscopy has been reported to be low, with a 72-hour postendoscopy bleeding rate of 0.96% in one study 5.
• However, patients with factor 9 deficiency may still be at risk of developing complications such as joint deformity and arthritis if left untreated or undertreated 3.