Factor IX Treatment & Management

A review of the global experience with plasma derived factor IX (pdFIX; Immunine and Mononine) products or rFIX showed that the 2 types of products are comparable with regards to reliability, tolerability, and clinical efficacy, with rare occurrences of serious adverse effects in 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, 2001^[14] ; in children < 15 y according to Roth, 2001^[15] ).

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).

Worldwide, only 25 patients with allergic reactions have been reported to the manufacturer of rFIX, with mild-to-moderate skin and respiratory reactions in most of the patients. Of 5 patients with anaphylaxis, some developed an inhibitor, and no fatalities were reported. Three thrombotic events were reported, of which 2 were catheter related and the third patient, aged 14 years, had a transient ischemic event but did well when continued on rFIX. Seventeen of 4500 patients had red cell agglutination when blood was withdrawn into the catheter or syringe containing rFIX; this practice must be avoided.

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.

Both pdFIX and rFIX are highly effective, but rFIX is believed to be free of blood-borne pathogens.

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.^[16]

It is important to understand the pharmacokinetics of factor IX.^[17] 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. Highly purified FIX concentrates (monoclonal antibody purified FIX or rFIX) are now available (first dose: 20-80 IU/kg depending on 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 EACA or tranexamic acid (Cyklokapron) administered orally or IV 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 the surgical procedure, the drugs are continued, then tapered as the wound heals. Such treatment allows use of a single dose 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.

  • 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 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 are being 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.
• Several approaches to gene therapy have been undertaken in treating patients with hemophilia B or A with severe deficiency. Basal levels of 5-10% significantly ameliorate bleeding in persons with severe hemophilia.

  • The most successful and least toxic method of introducing the gene remains to be determined. The use of an attenuated adenoviral vector, although associated with high short-term expression in a canine model of hemophilia, led to liver toxicity, thrombocytopenia, and an antibody to the factor due to an immunologic response to the vector.
  • An additional question is the appropriate in vivo–vector dose to be administered; evidence is emerging for the need for a minimum threshold dose.
  • Short-term correction resulting from high gene expression in the neonatal period following in utero injection of an adenoviral murine vector has been accomplished with FVIII.
  • Use of a parvovirus, use of transduced endothelial cells, or the possibility of cutaneous gene therapy are being explored in animal models and in humans.
  • Development of antibodies to replaced proteins is a major problem, and the possibility of using CTLA4-Ig to block T-cell function to prevent antibody response has been explored in murine models of hemophilia A.
  • Several possible approaches to gene therapy include ex vivo gene therapy, in which the cells to be injected are modified to secrete FIX or FVIII and then are reimplanted into the recipient, and in vivo gene therapy, in which cells modified to secrete the missing factor are packaged in immunoprotected devices and implanted in recipients.
  • Gene therapy with a variety of vectors has been tested in humans, with the most successful method still to be determined. Gene therapy studies were halted following the death of a patient treated for a metabolic disorder. Reevaluation of the type of vector, dose, route, and toxicity of the different approaches to gene therapy was undertaken. Oligonucleotides possibly can be used in vivo to correct point mutations. Advantages and disadvantages of several approaches to gene therapy in individuals with hemophilia and other patients have been updated in two recent publications.^{[18, 19]}
  • Gene therapy with viral-based vectors has had efficacy limited by immune responses against the viral components.^[20]

Gene therapy remains promising.^{[7, 21, 20]} In humans, one hemophilia B patient achieved 10% of normal activity after liver-directed gene therapy with a single-stranded adeno-associated virus vector expressing human factor IX, but expression fell at 1 month. Thus, gene therapy may be viewed as successful in a patient with hemophilia B, but expression was unstable probably due to an immune response. Abrogating immune responses may be the next important hurdle for achieving long-lasting gene therapy.

Appropriate preoperative evaluation includes an 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.

Recent 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.

• Hematologist, including general medical evaluation
• Orthopedist
• Physical therapist
• Dentist
• Surgeon
• Social worker
• Psychiatrist, particularly in the management of HIV-related issues^[22]
• Geneticist for genetic testing and counseling for family members

Encourage a generally healthy and nutritious diet.

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