Factor IX Deficiency (Hemophilia B) Medication

Updated: Jun 05, 2017
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
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Medication

Medication Summary

Currently, highly purified preparations — recombinant factor IX (rFIX) or purified monoclonal antibody and solvent-detergent–treated FIX products — are used for the treatment of hemophilia B. rFIX products are free of the usual viral contaminants and are the only products free of parvovirus B19. These products have significantly reduced risks of viral transmission; however, a report exists of contamination of first-generation recombinant products with TT virus due to the use of human serum albumin. [21]

Recombinant products result in 20-30% less factor recovery, possibly because of the presence of nonneutralizing antibodies. These products can cause severe allergic reactions, especially in patients who are severely deficient in FIX. These potentially life-threatening reactions are associated with development of inhibitors. Young children can experience such reactions, especially at the start of treatment.

Serious allergic reactions to FIX preclude further use of FIX or prothrombin-complex concentrates (PCCs) or activated prothrombin-complex concentrates (aPCCs); desensitization may be attempted. PCCs/aPCCs are crude plasma preparations containing concentrates of vitamin K–dependent factors, some in an activated form. Liver disease diminishes clearance of activated coagulation factors and synthesis of physiologic inhibitors. Rapid infusion increases risk of thromboembolic complications, especially disseminated intravascular coagulation (DIC), in patients with liver disease. The addition of very small amounts of heparin (1 U of heparin for every 100 U of FIX activity) has been used to minimize the effect of activators present in the aPCCs.

Most data suggest an approximate 50% drop in FIX level within approximately 24 hours. However, the actual in vivo FIX level that is achieved varies. Peak and trough levels following bolus dosing dictate the amount and timing of subsequent doses. Generally, an appropriate second dose is approximately one half of the initial dose, which is administered every 24 hours for moderate or minor bleeds and more often for severe or life-threatening bleeds. Ideally, FIX levels should be monitored in any serious situation to assess adequacy of dose and response.

Home care on-demand factor replacement therapy doses depend on the individual's response to the product and on the type of bleed. The goal of prophylactic therapy is to maintain the basal FIX level in an approximate 5% range, which reduces frequency and risk of spontaneous bleeding. Attempts are underway to determine the lowest level of FIX necessary for adequate hemostasis and to reduce dose requirements by using continuous infusion of FIX concentrates.

Dosing guidelines relate to the in vivo level of FIX needed. Different products have different in vivo recovery. Dosing guidelines require verification for each patient. Educating patients regarding their response to specific products is important so that the information does not have to be generated repeatedly, and patients can advise an emergency department physician regarding personal dose response to a specific product.

Current products are safer in regards to viral and HIV infection. However, contamination with previously unknown pathogens may occur. Currently, blood from donors who have new variant Creutzfeldt-Jacob disease (nvCJD) has been withdrawn from the manufacturing process. Potential risk of nvCJD or transmissible spongiform encephalopathies remains a concern when plasma-derived products are used. Patients should be vaccinated for hepatitis A and B.

DIC and thromboembolism are complications that have occurred using PCCs and aPCCs. Fibrinolytic inhibitors should not be used concomitantly with these products because of the risk of accelerating thrombosis.

FIX inhibitors develop in 3-5% of patients with hemophilia B who are receiving concentrates. An inhibitor should be suspected if FIX levels do not rise to predicted (expected) levels following treatment with concentrates, a hemorrhage does not respond to previously adequate doses, or severe allergic reactions occur soon after starting a patient on a replacement product. Laboratory confirmation of the presence of an inhibitor is essential.

Treatment of patients with FIX inhibitors is complex, requiring the services of a competent hematologist. Patients with low titers of inhibitors of 10 Bethesda units can be treated using PCCs, starting with a dose of 75 U/kg q6-12h, or recombinant activated factor VIIa (rFVIIa) can be used to treat patients with FIX inhibitors; doses vary from 30-90 mcg/kg IV q2-3h, with 1 additional dose after hemostasis is achieved.

Availability of rFVIIa resulted in another leap forward in the ability to treat patients with inhibitors to FIX or factor VIII coagulant activity (FVIII-C), allowing them to undergo previously impossible major surgical procedures, such as joint replacements or pseudocyst excisions, which require extensive procedures. As a result of its cost, rFVIIa previously was used as backup therapy when other products failed, but as experience with this product grows, it is being used more often as first-line therapy. The starting dose can vary from 30-90 mcg/kg IV every 2-3 hours.

Excellent or effective response may be seen in patients with inhibitors within 12 hours of starting therapy. Data from compassionate-use experience shows that hemostasis was obtained in approximately 92% of patients with inhibitors within 2-3 doses using 90 mcg/kg, suggesting an up-front use of the larger dose.

A decline of inhibitor titer to approximately one third of the original level was seen in patients who had received repeated doses of rFVIIa for treatment of bleeding. A continuous infusion regimen, rather than administration of an intermittent bolus, has been used successfully in patients with inhibitors. Since FVIIa in concert with TF, phospholipids, and calcium activates FX to FXa, thereby leading to thrombin generation, fibrinogen levels were monitored in treated patients and found to be similar to baseline values in the majority.

Additionally, follow-up samples obtained in patients treated with rFVIIa did not detect any antibody levels above the cutoff value, and no new antibodies were found to baby hamster kidney cells or to murine IgG. Despite these data, further studies are needed to refine dosing for the treatment of different types of bleeding in patients with inhibitors. Duration of therapy depends on adequacy of control of bleeding as balanced against possible adverse effects. Thromboembolic complications are infrequent, based on currently available information.

Advantages of rFVIIa are that it is a recombinant protein with no risk of transmission of the usual viruses, hemostasis is localized to the site(s) of injury, anaphylactic reactions have not occurred in patients with FIX deficiency, and rFVIIa does not induce an anamnestic rise in FIX antibody titer. rFVIIa can be used at home, postoperatively. Disadvantages are its expense, the need for good venous access, frequent repetitive administration, and activation of coagulation with possible DIC and rare thromboembolic events.

Immune tolerance induction (ITI) using prolonged gradually increasing doses of IV FIX concentrate, IV IgG, Cytoxan, other immunosuppressives, and inhibitor-antibody column has been used to treat patients with FIX inhibitors. ITI can be associated with development of nephrotic syndrome, which usually is steroid resistant and requires withdrawal of the antigenic protein. Disadvantages of ITI are that it is time intensive (6-24 mo), requires a high degree of patient compliance and daily venous access, is expensive, and has a significant failure rate.

The use of PCC/aPCC products in patients with inhibitors has several disadvantages. They have a poorly defined mode of action and an unpredictable hemostatic response. Since they are derived from pooled plasma, they carry a greater potential for transmission of viral and other illnesses. In addition, response is variable, frequent administration is required (at least q12h), and they are associated with significant failure rate, induce an anamnestic response with increase in antibody titer, and are not for use in patients who have developed anaphylaxis to FIX products.

To reduce factor usage and cost, the potential use of FIX variants with enhanced specific clotting activity has been investigated. [26] One of seven tested appeared to be a possible candidate for protein replacement therapy as well as gene-based therapeutic strategies.

In practice, administration of concentrates must be individualized by the evaluation of the extent, site, and cause of bleeding, response to therapy, current laboratory data, and the patient's history.

Table 2. Rough Guidelines for Treatment Using Factor IX Concentrates (Open Table in a new window)

Type of Hemorrhage Desired FIX Activity, % of Normal Duration of Therapy, Days
Minor -



Uncomplicated



hemarthroses



superficial large



hematomas



20-30 1-2
Moderate -



Hematoma with dissection



Oral/mucosal hemorrhages and epistaxis hematuria*



25-50 3-7



(2-5 in oral hemorrhages)



Dental extraction(s)* 50-100 2-5
Major -



Pharyngeal/retropharyngeal,



retroperitoneal,



GI tract bleeding,



CNS bleeding surgery



~100 until bleeding is controlled; then taper to minimum required to prevent rebleed 7-10



(5-10 in



oral hemorrhages)



*Concomitant administration of EACA or tranexamic acid (both fibrinolytic inhibitors) can help reduce the dose of clotting factor replacement required to treat such bleeds.

 

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Coagulation Factors

Class Summary

For use in patients with FIX deficiency.

Factor IX, recombinant (BeneFIX, Rixubis, Alprolix, Ixinity, Rebinyn)

Recombinant factor IX (rFIX) is indicated for control and treatment of spontaneous or surgery-related bleeding or prevention of bleeding in patients proven to be deficient in FIX. It is used as first-line therapy, particularly in previously untreated patients, owing to its safety regarding common virally transmitted illnesses associated with nonrecombinant products.

In vivo recovery of rFIX is lower than that obtained with plasma-derived products.

Factor IX (AlphaNine SD, Mononine)

Factor IX prevents and treats spontaneous or surgery-associated bleeding in patients with proven FIX deficiency. As with any factor replacement therapy, documenting actual recovery for a given dose and product is essential in every patient.

Factor IX complex (Bebulin, Profilnine SD, Bebulin VH)

Factor IX complex is standardized in terms of factor IX content, and each vial is labeled for the factor IX content. One IU of factor IX corresponds to the activity of factor IX in 1 mL of fresh normal human plasma. It also contains factor II, factor X, and low (nontherapeutic) levels of factor VII.

Factor VIIa, recombinant (NovoSeven RT)

Factor VIIa is used in patients with FIX inhibitors to control spontaneous or anticipated surgical bleeding. The dose range that has been used has varied from 35-120 mcg/kg. Dose generally is tapered after hemostatic efficacy has been obtained, depending on clinical context.

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Antifibrinolytics

Class Summary

Use together with single-dose factor replacement for minor surgical procedures, such as dental extractions or sinus surgery, so that the procedures can be accomplished on an outpatient basis with the use of a single dose of product.

Aminocaproic acid (Amicar)

Hemostatic agent that diminishes bleeding by inhibiting fibrinolysis of hemostatic plug. Can be used PO or IV.

Tranexamic acid (Cyklokapron, Lysteda)

Fibrinolytic inhibitor used with FIX replacement to reduce need for hospitalization and more than 1 dose of FIX concentrate in patients with hemophilia B requiring dental or sinus procedures. Can be used similarly in patients with hemophilia A. Also used to inhibit fibrinolysis in other conditions.

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