Factor IX Deficiency (Hemophilia B) Treatment & Management

Updated: Aug 01, 2019
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
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Treatment

Medical Care

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.

Fibrinolytic inhibitors are used as follows:

  • A dose of EACA, 5 g orally or IV, is administered immediately before the surgical procedure along with a dose of FIX, followed by 1 g per hour postoperatively until the decision is made to taper the dose over the next 5 days.

  • Tranexamic acid can be administered in a dose of 1.5 g every 6-8 hours for 5 days; this drug is not available in the United States.

  • Administration of these fibrinolytic inhibitors is contraindicated in patients with hematuria who are receiving or have recently received an FIX product because of the risk of an acute persistent thrombus obstructing the ureters and causing acute hydronephrosis.

Nonnarcotic and narcotic analgesics are used to relieve pain. Narcotic analgesics are used to manage severe acute pain, such as occurs with joint bleeding or perioperatively. Chronic persistent pain of chronic joint disease can be difficult to manage.

Ideally, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in patients with a bleeding disorder because the addition of platelet dysfunction caused by the drugs can potentiate bleeding. However, because of the persistent demand by individuals with hemophilia, cyclooxygenase 2 (COX-2) inhibitors may be tried with caution because of a lack of efficacy of nonnarcotic pain relievers in severe arthritis. Use of NSAIDs by individuals with hemophilia has increased in an attempt to relieve the severe joint pain of chronic arthritis.

Gene therapy

Several approaches to gene therapy have been undertaken in treating patients with severe hemophilia B. [26] Considerable success has been reported with systemic administration of an adeno-associated virus (AAV) encoding an optimized factor IX construct, although efforts to maintain long-term FIX expression continue. [27] Basal levels of 5-10% significantly ameliorate bleeding in persons with severe hemophilia.

Nathwani et al reported long-term efficacy and safety of gene therapy in 10 patients with severe hemophilia B using an AAV serotype 8 (AAV8) vector, scAAV2/8-LP1-hFIXco, that contains a codon-optimized modified FIX transgene. After a single intravenous infusion of the vector, circulating FIX levels increased to 1% to 6% of normal in all 10 patients over a median of 3.2 years. Four of the seven patients previously on factor replacement were able to discontinue it, and the others were able to decrease the dose. [28]

The most significant toxicity was mild elevation of the alanine amino-transferase level that occurred 7 to 10 weeks after infusion. The increase resolved over a median of 5 days with prednisolone treatment. This contrasts with results of earlier studies that used intrahepatic administration of AAV2 vector, which did not result in long-term expression of FIX and was associated with appreciable hepatic toxicity. [28]

Nevertheless, FIX levels achieved with gene therapy, although above the current usual target trough levels achieved with FIX prophylaxis, fall well short of the level that longer-acting FIX preparations can produce. In addition, the high peak levels provided by FIX infusions permit patients to maintain an active lifestyle.

Widespread adoption of gene therapy also faces the barriers of high cost and a high seroprevalence of antibodies to AAV vectors in the general population. Other new technologies that do not require viral vectors (eg, stem cell therapy) may obviate that difficulty.

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Surgical Care

Appropriate preoperative evaluation includes an activated partial thromboplastin time (aPTT) mixing test after incubation for 1-2 hours at 37°C with pooled normal plasma to exclude an inhibitor, followed by administration of an appropriate preoperative dose of concentrate, followed by appropriate postoperative treatment.

Small studies have established the efficacy of using lower than usually recommended doses of FIX concentrate, administered as an intermittent bolus infusion after major surgical procedures. Preoperatively, FIX was used in a dose of 77 U/kg to achieve a presurgical level of 107% (range 50-104%). Between days 1 and 3 after surgery, an average of 23 U/kg/d was used with an average trough value of FIX of 34% (range 11-52%). After day 4, an average of 18 U/kg/d of FIX was used until wound healing occurred. This resulted in a significant reduction in overall factor used without hemostatic inadequacy. Such data underscore the importance of defining the least amount of factor replacement necessary to obtain and maintain adequate hemostasis.

The use of fibrin sealants (ie, fibrin glue, fibrin adhesive), which consist of fibrinogen and thrombin with variable incorporation of factor XIII (FXIII) and fibrinolytic inhibitors, has helped improve surgical hemostasis markedly, thereby permitting necessary high-risk surgery (eg, pseudotumors, surgery in patients with hemophilia with inhibitors). This technology reduces or eliminates the need for prolonged replacement using expensive clotting factor concentrates and may eliminate or reduce the need for hospitalization.

In total, the measures result in improved quality of life in patients with hemophilia, while achieving a reduction in medical care costs. Bovine thrombin used in these preparations may result in development of inhibitors to several factors, including thrombin and FV, as it has in other postoperative states.

Warn patients to avoid any antiplatelet drug starting 1 week prior to surgery and in the immediate postoperative period to minimize the risk of bleeding.

The use of ice packs at surgical sites may be beneficial to reduce the size of the surgical site hematoma.

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Consultations

See the list below:

  • Hematologist, including general medical evaluation
  • Orthopedist
  • Physical therapist
  • Dentist
  • Surgeon
  • Social worker
  • Psychiatrist, particularly in the management of HIV-related issues [29]
  • Geneticist for genetic testing and counseling for family members
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Activity

Activity recommendations depend on such factors as joint disease and resolution of bleed into joints and muscles. Appropriate use of physical therapy is advised.

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Complications

Despite safe and effective replacement therapy, patients still experience breakthrough bleeding, progressive joint disease. and  high rates of inhibitor development. [30]

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