1. COMPLICATIONS OF HEMOPHILIA: INHIBITORS Nairobi, Kenya June 25, 2013

2. OBJECTIVES Discuss inhibitor development List risk factors associated with inhibitors Identify signs and symptoms of inhibitor development Identify methods to treat acute bleeds Discuss treatment modalities for eradication of inhibitors Examine special inhibitor types

3. WHAT ARE INHIBITORS? Inhibitors are the most serious complication of hemophilia treatment Infused FVIII or FIX is destroyed and becomes ineffective at stopping or preventing bleeding

4. THE IMMUNE SYSTEM Immune system fights invading organisms Antibody production is a normal response During fetal development and early childhood, immune system programmed to recognize “self” from “non-self” Individuals who do not make a particular protein or enzyme etc., may recognize it as non-self if exposed to it as a replacement later Antibodies developed against a clotting factor are called inhibitors

5. HOW INHIBITORS NEUTRALIZE TREATMENT PRODUCT When this happens, inhibitors (also called antibodies) form in the blood to fight against the foreign factor proteins. This stops the factor concentrates from being able to fix the bleeding problem. In the case of an inhibitor, a person’s immune system reacts to proteins in factor concentrates as if they were harmful foreign substances, because the body has never seen them before.

6. RISK FACTORS Age First 50 exposure days (more likely in first 10 infusions) Keep track! Genetics African American and Hispanic Family history Intensive periods of therapy Sharathkumar A et al. Thromb Haemost. 2003. van der Bom JG et al. Thromb Haemost. 2003.

7. CANAL STUDY CANAL: Concerted Action on Neutralizing Antibodies in severe hemophilia PUPS 376 patients born between 1990 and 2000 with more than 50 exposure days Evaluated several data points -Age at first exposure to FVIII -Reason for first exposure (intensity of treatment) -Genetic mutation Gouw, S.C., et al. Blood, 1, June 2007. Vol. 109 Num 11.

8. CANAL STUDY FINDINGS Age at first exposure is associated with inhibitor development -Association is explained by intensity of treatment Significant association with surgeries and intensive treatment -Likely related to tissue damage and inflammation Positive family history Gouw, S.C., et al. Blood, 1, June 2007. Vol. 109 Num 11.

9. PRACTICAL APPLICATIONS OF CANAL May be benefit to early prophylaxis –Exposure of factor in the absence of inflammation and immune response Development of risk stratification –Positive family history (2 points) –High risk mutation (2 points) –Intensive initial treatment (3 points)

10. Severe molecular gene defect FVIII: Inversion, nonsense, large deletion or insertion ─No endogenous FVIII synthesis FIX: Large gene deletions Data courtesy of Dr. Johannes Oldenburg INHIBITOR FORMATION Data courtesy of Dr. Johannes Oldenburg

11. INHIBITOR FORMATION (CONT’D) Prevalence of FVIII inhibitors All severities: 5-7% Severe FVIII deficiency: 12-13% Wight J. Haemophilia, vol 9, no 4, July, 2003. Incidence FVIII 10-30% FIX 3-4% Additional challenges faced by people with factor IX inhibitors

12. SIGNS AND SYMPTOMS Detection Careful monitoring during early treatment period Yearly screening Poor response to treatment Increased bleeding frequency Pre- and post-surgical monitoring Measurement Inhibitory antibodies measured by Bethesda Units (BU) 1 BU = the quantity of inhibitor that results in 50% loss of factor activity in 2 hours Inhibitors can be low-responding (<5 BUs) or high- responding (≥ 5 BUs) Paisley, Haemophilia, 2003

13. TREATMENT OF INHIBITORS Goals of treatment Stop acute bleeds Prevent bleeding episodes Eradicate inhibitor

14. TREATMENT OF ACUTE BLEEDS Low-responding inhibitors (< 5 B.U.) Increased dose and frequency of factor replacement may stop bleeding May require bypassing agents for refractory acute bleeds High-responding inhibitors (> 5 B.U.) Life or limb-threatening bleeding −High dose FVIII or IX if current titer is low −Anamnestic response likely after 5-7 days

15. TREATMENT OF ACUTE BLEEDS (CONT’D) High-responding inhibitors (cont’d) Other episodes –Bypassing agents PCC ( FII, VII, IX, X) (Bebulin®, Profilnine ®) aPCC (activated PCC) (FEIBA®) rFVIIa (activated rFVII ) (Novoseven®)

16. ALGORITHM FOR MANAGEMENT OF INHIBITORS Kasper, C. Treatment of Hemophilia No 34 World Federation of Hemophilia 2004

17. WHEN BLEEDS DON’T RESPOND…. Consider increasing the dose or frequency of the bypassing agent first If unsuccessful, consider switching to another bypassing agent If still unsuccessful, consider changing dose or frequency of the second agent If still refractory to treatment, consider sequential therapy or salvage therapy

18. IMMUNE TOLERANCE THERAPY (ITT) Goal Treatment with repeated factor concentrate (with or without immunomodulating agents) to reduce or eliminate inhibitors Can be done using high or low doses of factor of varying frequency (daily versus TIW)

19. ITT: CONSIDERATIONS FOR INITIATION Intense, time-consuming Requires increased monitoring Family readiness/ commitment Adherence –Interruption decreases success –Can be long term process Venous access –CVAD issues; increased infection Cost

20. ITT: PROTOCOL SELECTION Historical high inhibitor titer Titer at initiation Availability of resources Caregiver/patient adherence History of allergic reaction

21. ITT: PREDICTORS OF SUCCESS Peak historical BU Yes Yes Pre-induction titer <10 BU Yes Yes Age at induction Yes No Elapsed time w/ inhibitor Yes* No Dose Yes No * Significance decreased with additional analysis IITR NAITR

22. ALTERNATIVES FOR ITT FAILURE About 30% of patients fail ITT Enhance ITT regimen: –Steroids –Other immunosuppressive agents Rituximab –Anecdotal reports of success –Limited literature –Study in process Francini, et. al., Haemophilia, 2008; 14: 903-912.

23. Education about new plan of care, potential new products Reassurance and support Discussion about ITT –Evaluating family readiness, venous access –Protocol / Product choice –Considerations of family schedule, ability to adhere to regimen NURSING CONSIDERATIONS

24. FIX inhibitors: What’s the big deal?

25. FIX INHIBITORS WHY? Hypothesis: –Small molecular weight causes distribution in extravascular and intravascular spaces contributing to hypersensitivity –Exposed to a higher protein load 200-400 mcg vs 2.5-5 mcg per exposure to FVIII –Absence of tolerance due to complete gene deletion or stop codon and thus lack of any FIX gene product Warrier et al, Journal of Pediatric Hematology/Oncology, 1997

26. FIX INHIBITORS: ANAPHYLAXIS 18 children in 12 HTCs reported with anaphylaxis Median age 16 months Median exposure days: 11 12/18 patients had inhibitor detected around time of anaphylaxis Median titer 48 BU Warrier et al, Journal of Pediatric Hematology/Oncology, 1997

27. FIX INHIBITORS: ANAPHYLAXIS (CONT’D) Genetic analysis on 17/18 patients –10 with complete deletion –7 with major derangement 2/12 underwent ITI developed nephrotic syndrome 8 months after beginning ITI 2/12 achieved tolerance Infusion products included PCC & very high-purity FIX products Warrier et al, Journal of Pediatric Hematology/Oncology, 1997

28. FIX INHIBITORS: NEPHROTIC SYNDROME 7 patients on ITI regimens with FIX Common feature <12 years, history of reaction to FIX, exposure to high doses of FIX (100-200 U/kg/d) 6/7 with total gene deletion or major derangement 5/7 presented with edema, 2 with asymptomatic proteinuria Consider alternate therapy for those who have reacted to FIX (rFVIIa) Warrier et al., Haemophilia, 1998

29. FIX INHIBITORS: NURSING CONSIDERATIONS Genetic analysis of all patients with severe hemophilia B Give 1st 10-20 infusions at a medical facility Maintain venous access for 30 minutes after each infusion Discuss issues with family at diagnosis ITT options Monitor for nephrotic syndrome

30. SUMMARY Inhibitors can develop in patients with either factor VIII or IX deficiency, and in all severities Certain racial groups and patients with intensive exposure to factor appear to have a higher risk for inhibitor development Suspect an inhibitor when usual treatment for bleeding seems poor or unresponsive, or when patients continue to have more bleeding despite adequate treatment Inhibitor patients need a plan on how to treat acute bleeding and should be considered for ITT Factor IX patients with inhibitors and allergic reactions may be difficult to tolerize

31. ADDITIONAL WFH RESOURCES What are Inhibitors? Inhibitors in Hemophilia: A Primer Diagnosis and Management of Inhibitors to Factor VIII and IX: An Introductory Discussion for Physicians Dental Management of Patients with Inhibitors to Factor VIII or Factor IX Guidelines for the Management of Hemophilia Visit the Publications Library at www.wfh.org/publications for free copies www.wfh.org/publications

32. JIM MUNN, R.N., M.S. Program Nurse Coordinator University of Michigan HTC Ann Arbor, MI, USA Chair – WFH Nursing Committee Acknowledgement: Select slides courtesy of Partners in Bleeding Disorders Education Program www.partnersprn.org MERGER AVEC SLIDE 1