How is factor IX deficiency (FIX) (hemophilia B) treated?

Updated: Mar 09, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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Answer

Highly purified factor IX (FIX) concentrates are now available. These include monoclonal antibody–purified plasma-derived FIX (pdFIX; Immunine and Mononine) and recombinant FIX (rFIX).

A review of the global experience with pdFIX and rFIX products showed that the two types of products have comparable reliability, tolerability, and clinical efficacy. Serious adverse effects occur rarely with either product. The major difference was variable pharmacokinetics, with a similar half-life but an approximately 25-30% lower in vivo recovery after rFIX, particularly in younger children (in children < 16 y, according to Poon [18] ; in children < 15 y, according to Roth et al [19] ).

Data obtained from a survey of several French hemophilia centers and presented at the International Society of Thrombosis and Haemostasis meeting in July 2001 showed an average recovery of 61% for rFIX use versus 85% for pdFIX. Initial dosing of FIX for both inpatient and outpatient treatment is on the basis of standard guidelines (Indiana Hemophilia & Thrombosis Center).

Development of inhibitors is a serious matter affecting 1.5–3% of patients with hemophilia B. Thus, successful eradication of inhibitor may be challenging and require rituximab, with or without desensitization therapy. [20]  

Inhibitors in hemophilia B patients have been associated with the development of severe allergic or anaphylactic reaction. [21] Given the risk of potentially life-threatening reactions, close monitoring of infants and small children with severe hemophilia B for their first 20 or more infusions with any FIX-containing product has been recommended, with the infusions performed in a facility equipped to treat anaphylactic shock. [22]

Although many reports exist of the successful use of different continuous infusion regimens of FIX, ongoing data collection and studies will allow development of a standardized regimen in the future. Potential benefits include the ability to mimic the physiologic state and reduction in product usage, providing much-needed economic savings.

Although administration of clotting factor in prophylaxis has been shown to be beneficial for both hemophilia A and B, it is more commonly used with hemophilia A than hemophilia B. The reasons for this are unclear. [23]

In children who are starting therapy for the first time or in persons with hemophilia who are HIV negative, recombinant products are used whenever possible because of their presumed higher viral safety. Note that approximately 25% of the lots of human albumin containing first-generation recombinant factor VIII (rFVIII) concentrates have been found to be positive for transfusion-transmitted virus (TTV) from contaminated human serum albumin. All of the second-generation rFVIII preparations (free from human albumin) were negative for the virus. [24]

It is important to understand the pharmacokinetics of factor IX. [25] Factor IX in vivo recovery is also relatively short, possibly due to its reversible binding to endothelium and possibly to platelets. There is considerable pharmacokinetic variability of factor IX between products (particularly between plasma-derived factor IX and recombinant factor IX), and between individuals.

Factor replacement in patients with hemophilia B should be guided by an experienced hematologist who is familiar with treating patients with coagulation disorders.

The location and severity of bleeding determine the dose and duration of factor replacement therapy.

The first dose should be 20-80 IU/kg, depending on the FIX level necessary to treat the specific clinical condition. Approximately 50% of the first dose is administered approximately every 24 hours to maintain the initial level of FIX

If therapy is to last for more than 2 days or is occurring for the first time, FIX levels should be obtained immediately after the first dose, with a subsequent trough level taken to determine appropriate dose and frequency of replacement therapy based on in vivo response to a specific product. Children and surgical patients require closer monitoring of FIX levels because of known variable pharmacokinetics and a lack of a steady state, respectively.

Preservation of the hemostatic plug formed in the presence of adequate levels of FIX at the time of surgery (ie, dental extraction) can be achieved by inhibiting fibrinolysis with epsilon-aminocaproic acid (EACA) or tranexamic acid (Cyklokapron) administered orally or intravenously as needed. Inhibitors of fibrinolysis, such as EACA or tranexamic acid, can be used in combination with factor replacement to prevent bleeding from mucosal sites, including after dental extractions or sinus surgery.

Following a surgical procedure, fibrinolytic inhibitors are continued, then tapered as the wound heals. A single dose can be used to prevent bleeding from minor procedures. However, fibrinolytic inhibitors are not of value in the treatment of hemarthroses or deep-seated bleeding. The prolonged use of fibrinolytic inhibitors in joint and deep hematomas can lead to persistence (lack of absorption) of the clot with negative consequences.


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