TREATMENT OF HEMOPHILIA WITH INHIBITORS:AN ADVANCE IN OPTIONS FOR

PEDIATRIC PATIENTS

Authors: Joan McCarthy, RN, and Prasad Mathew, MD, New York, NY, Albuquerque, NM

Hemophilia is a rare genetic (X-linked) bleedingdisorder caused by lack of specific clotting factorsin blood. It is estimated to affect around 18,000

persons in the United States.1 There are 2 forms: hemophi-lia A, caused by a deficiency in clotting factor VIII (FVIII),and hemophilia B, in which factor IX (FIX) is deficient.Most patients (around 90%) have hemophilia A, and70% of these patients will have a severe form of the disor-der (<1% of normal clotting factor levels).1 Patients withsevere hemophilia may have frequent and spontaneousbleeding episodes in response to even minor trauma.1,2

Treatment is aimed at replacing the missing clotting factorwith regular or as-needed infusions. Complicating thetreatment of patients with congenital hemophilia A andB is the development of neutralizing alloantibodies (“inhi-bitors”) to FVIII and FIX, respectively. FVIII inhibitordevelopment is estimated to occur in approximately 20%to 40% of patients with severe hemophilia A3-5 and1% to 13% of patients with mild or moderate type Adisease.3,6,7 Patients are at the highest risk for the devel-opment of alloantibody inhibitors during the first 50 to

100 days of exposure to therapeutically administeredFVIII or factor FIX, so this period typically occurs duringchildhood; however, inhibitors can develop at any age,and a second peak period of risk occurs in patients agedin their 50s and 60s.7 Risk factors reflect a mix of patient-and treatment-related factors and include, but are not lim-ited to, age at first treatment,8 hemophilia severity,5 thegenetic mutation associated with hemophilia,9 black orHispanic race,10 and a family history of inhibitors.9 Devel-opment of inhibitors makes management of bleeding epi-sodes difficult, because regular factor infusions are notefficacious in treating or preventing a bleed. Bypassingagents are used to manage these patients. Two currentlyavailable bypassing agents are Factor Eight InhibitorBypassing Activity Anti-inhibitor Coagulant Complex(FEIBA; Baxter Healthcare, Deerfield, IL) and recombi-nant activated coagulation factor VII (NovoSeven; NovoNordisk, Princeton, NJ).

ED Presentation

Pediatric hemophilia patients initially present to the emer-gency department with excessive bruising or bleeding,which—in the absence of a positive family history—maybe mistaken for or suspected as a case of child abuse/neglect.Male infants may present with excessive or persistent bleed-ing after circumcision. Previously diagnosed hemophiliapatients who visit the emergency department are oftenyoung. In a Colorado study, 48.8% of hemophilia patientstreated in the emergency department were aged under 21years.11 Bleeding in hemophilia patients can occur in thejoints, muscles, soft tissue, and mucous membranes, butintracranial hemorrhage can also occur. The most commonreason for ED visits in the Colorado study was hemorrhage(64.8%), with traumatic hemorrhage being slightly morecommon (37.6%) than hemorrhage of unknown cause(27.2%).11 In another study 48% of ED visits by pediatrichemophilia patients were the result of soft-tissue hemato-mas, 24% were the result of hemarthrosis, and 12% weredue to head injuries.12 Severe and/or repeated bleeding epi-sodes into joints increase the risk of joint deterioration andpermanent disability; therefore consultation with a hema-tologist is warranted upon presentation.

Joan McCarthy, Nurse Clinician, Mount Sinai Hemophilia Center,New York, NY.

Prasad Mathew, Associate Professor, University of New Mexico, Albuquer-que, NM.

Financial disclosure: Editorial assistance was provided by PHOCUS, (Lam-bertville, NJ), through financial support from Novo Nordisk.

Conflicts of interest: Ms. Joan McCarthy was a member of the NursingAdvisory Board at Novo Norodisk and received an honorarium. Dr. PrasadMathew serves on Advisory Boards for and has received research funding atUNM for the following companies: Bayer Pharmaceuticals, Baxter Health-care Corporation, CSL Behring, Novo Nordisk, Inc., Wyeth Pharmaceuti-cals, Pfizer; advisor for Octapharma.

For correspondence, write: Joan McCarthy, RN, Mount Sinai Medical Cen-ter, One Gustave L. Levy Place, New York, NY 10029; E-mail: johanna.mccarthy@mssm.edu.

J Emerg Nurs 2011;37:474-6.

Available online 15 May 2010.

0099-1767/$36.00

Copyright © 2011 Emergency Nurses Association. Published by Elsevier Inc.All rights reserved.

doi: 10.1016/j.jen.2010.03.004

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Management

In the past, whole blood transfusions, fresh-frozen plasma,and cryoprecipitate were used to stem hemophilia-asso-ciated bleeding, but currently, recombinant formulationsof FVIII and FIX, which are stable at room temperature,are generally used.13 Such preparations have the advantageof being easy to use, portable, and convenient, improvingboth patient and caregiver quality of life. In addition, theiravailability means that hemophilia A and B patients inwhom inhibitors do not develop can now receive ongoingprophylactic therapy with FVIII or FIX. Meanwhile, forpatients in whom inhibitors develop, bypassing agents arethe treatments of choice. The rest of this article will focuson an advancement in this treatment using one of thesebypassing agents.

Room Temperature–Stable Recombinant Activated

Coagulation Factor VII

In May 2008 the US Food and Drug Administrationapproved a recombinant clotting factor that is stable atroom temperature in a manner identical to the recombi-nant forms of FVIII and FIX. The room temperature–stable recombinant activated coagulation factor VII pro-duct (rFVIIa-RT) (NovoSeven RT; Novo Nordisk) workssimilar to its previous formulation (NovoSeven) throughactivated platelets at the site of injury, bypassing the needfor FVIII and FIX. The recommended storage tempera-ture is between 2°C and 25°C (35.6°F and 77°F), and ithas a shelf-life of up to 2 years before reconstitution andup to 3 hours after reconstitution.14 Room temperaturestability has been achieved by adding 2 new excipientsto the lyophilized powder (a stabilizing sucrose excipientand the antioxidant methionine) and by creating a newreconstitution medium (a histidine-containing sterilewater diluent). During experiments, both lyophilizedand reconstituted rFVIIa-RT remained stable across awide range of storage conditions, including those thatsimulated the changing storage temperatures that mightoccur in a home setting.15

To aid rapid and accurate dose calculations in theemergency department and at home, rFVIIa-RT is nowavailable in single-use vials containing 1, 2, or 5 mg ofrFVIIa-RT per vial (previous preparations contained 1.2-,2.4-, and 4.8-mg doses), with an overall 1-mg/mL concen-tration once reconstituted. The formulation changes makethe rFVIIa-RT formulation 40% more concentrated thanthe original product, thus allowing for a lower infusionvolume and shorter infusion time while remaining phar-macokinetically equivalent to the original recombinantactivated coagulation factor VII product.16 A further

improvement, to allow quick and easy medication discri-mination and to help avoid errors, has been to color codethe rFVIIa-RT vials’ caps to match to their correspondingpremeasured diluents.

ED Implications

From an ED viewpoint, the availability of rFVIIa-RT mayprevent waste and facilitate portability. Product portabilityin turn provides the opportunity for earlier infusion, facil-itating very early treatment of episodes and avoiding theadverse consequences of delayed treatment. In the eventof diluent bottle breakage or loss, research has shown thatreconstitution in saline solution or sterile water for injec-tion may not adversely affect product activity.17 This canconfer an advantage to the emergency nurse, who may haveonly 1 of these products, such as saline solution, availablefor reconstitution.

A further advantage of rFVIIa-RT is its reduced infu-sion volume compared with the original formulation.Because vial sizes are now simple numbers, even miscalcu-lating the volume of an incorrect diluent should not be anissue if entire vials are used. To achieve a correct concen-tration of rFVIIa-RT, it should be reconstituted with theappropriate solvent at the correct volume.17 It is impor-tant to note that there may be minor changes in thevolumes of reconstituted drug administered because ofthe alteration in vial sizes. This will require updated pre-scriptions for patients with ongoing therapy, as well as areorientation for hospital-based prescribers currently usingvial-based dosing. Particularly for children, the number ofvials used per acute bleed will change over time as patientsget older and gain weight, and the amount of the round-ing will continue to vary over time. The change to simplervial sizes (1, 2, and 5 mg) should make dosing calculationseasier for patients and the emergency nurse but should notsignificantly change the recommended dosing (90-μg/kgbolus injection every 2 hours until hemostasis is achieved;doses between 35 and 120 μg/kg have been used success-fully in clinical trials) that the patient receives on anongoing basis.14

Refrigerator storage in the pharmacy or blood bank isat a premium, so a 2-year shelf life at room temperatureallows for placement in a PYXIS distribution system (Care-Fusion, San Diego, CA) in the emergency department oroperating room. In addition, the unreconstituted rFVIIa-RT product can be used weeks or months later. Even afterreconstitution, according to the US labeling, the productcan be used within 3 hours when stored at either 5°C(4°F) or room temperature. Maintaining reconstitutedrFVIIa-RT for 6 hours at room temperature, or 24 hours

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if refrigerated, may also not adversely affect the product.17

Bypassing agents such as rFVIIa-RT are prescribed by spe-cialists, so ED personnel need to work closely with theirprescribers when using these agents.

Conclusion

Hemorrhage in the pediatric hemophilia patient is a trueemergency, particularly if the patient has developed inhibi-tors to clotting factors. The recent availability of the roomtemperature–stable formulation of recombinant activatedcoagulation factor VII will improve treatment for patientsand their families by improving portability, reducingwastage and making dosing calculations easier.

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13. Key NS, Negrier N. Coagulation factor concentrates: past, present, andfuture. Lancet. 2007;370(9585):439-48.

14. NovoSeven RT. US prescribing information. http://www.novosevenrt.com/pdfs/PI_novosevenrt.pdf. Accessed November 11, 2008.

15. Nedergaard H, Vestergaard S, Jensen PT, et al. In vitro stability of lyo-philized and reconstituted recombinant activated factor VII formulatedfor storage at room temperature. Clin Ther. 2008;30(7):1309-15.

16. Bysted BV, Scharling B, Moller T, Hansen BL. A randomized, double-blind trial demonstrating bioequivalence of the current recombinantactivated factor VII formulation and a new robust 25 degrees C stableformulation. Haemophilia. 2007;13(5):527-32.

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