PPA News

Posted by: Matthew Helms on Sep 16, 2016

Written by:
Deni Trone, PharmD PGY1 Pharmacy Resident, Kosair Children’s Hospital, Louisville, KY

Hemophilia A is an X-linked recessive bleeding disorder resulting in factor VIII deficiency affecting 1 in 5,000 male births.1 Approximately 50 to 60 percent of these individuals suffer from severe hemophilia A resulting in spontaneous bleeding due to little or no factor VIII activity.1 The strongest predictor for inhibitor development is the type and severity of hemophilia.1 Patients with severe hemophilia A have the highest incidence (30%) versus mild to moderate hemophilia A (2-12%).1,2 Hemophilia B patients have an incidence of approximately 5%.2 Environmental risk factors for inhibitor development correlates with severe hemophilia including early age of exposure to factor VIII, and intensive treatment periods with factor VIII.2-3

Patients with high-titer inhibitors, defined as a Bethesda Inhibitor Assay (BIA) of greater than or equal to 5 BU/mL, require large doses of factor VIII or the use of factor products that bypass the factor VIII pathway, such as recombinant activated factor VIIa (rFVIIa) or factor VIII inhibitor bypassing agent (FEIBA).1,4 Although 80-90% of patients respond to one of these products, some patients will have a decreased response to one agent often requiring dual therapy of rFVIIa and FEIBA. This can increase risk of thrombosis. The use of bypassing products has other limitations including reduced efficacy to stop bleeding and high costs.1

In 2015, the US guidelines for immune tolerance induction (ITI) in hemophilia A patients were published.4 Patients whom ITI is indicated for includes those with severe hemophilia A and one of the following: high-titer inhibitors less than 200 BU/mL with good-risk characteristics, any patient with a titer greater than 200 BU/mL, or patients with high titers and poorly controlled bleeding.4 First-line treatment for ITI is daily administration of factor VIII with a goal of achieving tolerance.4 Reaching tolerance is defined as having an undetectable BIA, reaching peak factor VIII activity of at least 60%, and a factor VIII half-life of at least 6 hours.4

Controversy behind the dosing of factor VIII was made prevalent by two different dosing recommendations provided by the International Immune Tolerance Registry (IITR) and the North American Immune Tolerance Registry (NAITR). The IITR initially recommended dosing of 200 units/kg/day compared to a recommendation of at least 50 units/kg/day by the NAITR.4 A study from the IITR was published in 2012 to compare these dosing recommendations using 200 units/kg/day versus 50 units/kg thrice weekly.5 Although no differences were found in the amount of patients who achieved tolerance between the low-dose and high-dose groups (39% and 41%, respectively), there was a significant difference in the amount of patients who had bleeding episodes requiring hospitalization in the low-dose group.5 The low-dose group was 2.2 times more likely to bleed than the high-dose group requiring the investigators to stop the trial early due to safety concerns.5 Unfortunately, this study did not address the original dosing recommendation by the NAITR of 50 units/kg/day, which could have made a major impact in the results of this study.5

Cost must be a consideration when contemplating ITI in these patients, which may sway decisions regarding dosing and choice of therapy. A cost-analysis was performed through a decisions analytic model to compare three different treatment strategies (on-demand therapy to treat acute bleeding events, prophylaxis with bypassing agents, and ITI) in hemophilia A patients with inhibitors.6 This cost-analysis compared costs and outcomes over the course of patients lifetime.6 It concluded that not only did patients receiving ITI live approximately 4.3 years longer, but also lifetime costs were significantly lower in the ITI group compared to the on-demand and prophylaxis groups ($19,904,815 vs. $21,562,055 vs. $43,106,359, respectively).6 This analysis was completed utilizing the factor VIII dosing of 200 units/kg/day..7 However, when running the analysis using 100 units/kg/day of factor VIII dosing the article did report a lower total cost of $18,957,325..6 The International Registry of Immune Tolerance reported a dosing threshold of at least 100 units/kg/day for successfully achieving induction in the 1994 update..7 These two dosing regimens have not been directly compared to assess efficacy and adverse effects of each. Although, it has been suggested when comparing past literature that using a higher dosing regimen of 200 units/kg/day will achieve induction more quickly than the lower dosing regimens.8 Three years after the IITR study was initiated, 70 percent of all patients achieved tolerance..5 Therefore, almost one third of patients were still refractory to daily factor VIII treatment.5 Rituximab, a monoclonal anti-CD20 antibody, is an agent that has been recently utilized for ITI..4,9 A systematic review analyzed its use for ITI in hemophilia A patients. Unfortunately, there are wide variances regarding its dosing, frequency, and whether it’s used concomitantly with factor VIII administration.9 Although the review concluded that rituximab was well tolerated and 75% achieved tolerance at 15 months, prospective, long term studies are necessary to assess its place in therapy.9

Additionally, other immunosuppressant agents may have benefits. Sirolimus was recently studied as conjunctive therapy with factor VIII products to induce tolerance in male mice.10 The study showed promising results with significantly lower BIA and anti-factor VIII titers in the mice that received sirolimus and factor VIII compared to the factor VIII monotherapy group.10 Of note, the mice included in the study did not have inhibitors at baseline.10 Therefore, the study did not truly assess immune tolerance induction, but instead assessed prevention of factor VIII inhibitor formation.10 Currently, sirolimus use has not been formally reported for use in humans with hemophilia A.

To conclude, daily factor VIII is an effective, yet costly, first-line therapy for severe hemophilia A patients that develop high-titer inhibitors. Although the current dosing recommendations state 200 units/kg/day should be utilized, lower dosing regimens should be explored to assess efficacy in hopes to reduce costs for these patients. Further studies are necessary to investigate the proper dosing regimen in patients with a BIA > 200 BU/mL due to the large number of studies excluding these patients who have a high risk of treatment failure. The final area that requires further exploration is the use of immunomodulators. With sparse literature and studies, immunomodulators place in therapy has yet to be determined at this time. However, the results are promising that these agents could enhance immune tolerance in patients who have developed inhibitors in hemophilia A.


  1. Zimmerman B, Valentina LA. Hemophilia: in review. Peds in Review. 2013; 34(7):289-95.
  2. Sharathkumar AA, Carcao M. Clinical advances in hemophilia management. Pediatr Blood Cancer. 2011;57:910-20.
  3. Carr ME, Tortella BJ. Emerging and future therapies for hemophilia. J Blood Med. 2015;6:245-55.
  4. Valentino LA, Kempton CL, Kruse-Jarres R, et al. US guidelines for immune tolerance induction in patients with haemophilia A and inhibitors. Haemophilia. 2015; 21(5):559-67.
  5. Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012;119(6):1335-44.
  6. Earnshaw SR, Graham CN, Mcdade CL, Spears JB, Kessler CM. Factor VIII alloantibody inhibitors: cost analysis of immune tolerance induction vs. prophylaxis and on-demand with bypass treatment. Haemophilia. 2015;21:310-19.
  7. Mariani G, Ghirardini A, Belloco R. Immune tolerance in hemophilia-principal results from the International Registry. Report of the factor VIII and IX subcommittee. Thromb Haemost. 1994;72(1):155-8.
  8. Colowick AB, Bohn RL, Avorn J, Ewenstein BM. Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper. Blood. 2000;96(5):1698-702.
  9. Franchini M, Mengoli C, Lippi G, et al. Immune tolerance with rituximab in congenital haemophilia with inhibitors: a systematic literature review based on individual patients’ analysis. Haemophilia. 2008;14(5):903-12
  10. Moghimi B, Sack BK, Nayak S, Markusic DM, Mah CS, Herzog RW. Induction of tolerance to factor VIII by transient co-administration with rapamycin. J Thrombo Haemost. 2011; 9(8):1524-33.