COMPLICATIONS OF HEMOPHILIA: INHIBITORS

Nairobi, Kenya

June 25, 2013

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

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

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

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.

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.

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.

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.

PRACTICAL APPLICATIONS OF CANAL

May be benefit to early prophylaxis• Exposure of factor in the absence of inflammation and

immune responseDevelopment of risk stratification • Positive family history (2 points)• High risk mutation (2 points)• Intensive initial treatment (3 points)

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

INHIBITOR FORMATION (CONT’D)

Prevalence of FVIII inhibitorsAll severities: 5-7%Severe FVIII deficiency: 12-13%

Wight J. Haemophilia, vol 9, no 4, July, 2003.

IncidenceFVIII 10-30%FIX 3-4%

Additional challenges faced by people with factor IX inhibitors

SIGNS AND SYMPTOMS

DetectionCareful monitoring during early treatment period Yearly screeningPoor response to treatmentIncreased bleeding frequencyPre- and post-surgical monitoring

MeasurementInhibitory antibodies measured by Bethesda Units (BU)1 BU = the quantity of inhibitor that results in 50% loss of factor activity in 2 hoursInhibitors can be low-responding (<5 BUs) or high-responding (≥ 5 BUs)

Paisley, Haemophilia, 2003

TREATMENT OF INHIBITORS

Goals of treatmentStop acute bleedsPrevent bleeding episodesEradicate inhibitor

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

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®)

ALGORITHM FOR MANAGEMENT OF INHIBITORS

Kasper, C. Treatment of Hemophilia No 34 World Federation of Hemophilia 2004

WHEN BLEEDS DON’T RESPOND….

Consider increasing the dose or frequency of the bypassing agent firstIf unsuccessful, consider switching to another bypassing agentIf still unsuccessful, consider changing dose or frequency of the second agentIf still refractory to treatment, consider sequential therapy or salvage therapy

IMMUNE TOLERANCE THERAPY (ITT)

GoalTreatment with repeated factor concentrate (with or without immunomodulating agents) to reduce or eliminate inhibitorsCan be done using high or low doses of factor of varying frequency (daily versus TIW)

ITT: CONSIDERATIONS FOR INITIATION

Intense, time-consuming Requires increased monitoringFamily readiness/ commitmentAdherence• Interruption decreases success • Can be long term processVenous access• CVAD issues; increased infectionCost

ITT: PROTOCOL SELECTION

Historical high inhibitor titerTiter at initiationAvailability of resourcesCaregiver/patient adherenceHistory of allergic reaction

ITT: PREDICTORS OF SUCCESS

Peak historical BU Yes YesPre-induction titer <10 BU Yes YesAge at induction Yes NoElapsed time w/ inhibitor Yes* NoDose Yes No

* Significance decreased with additional analysis

IITR NAITR

ALTERNATIVES FOR ITT FAILURE

About 30% of patients fail ITTEnhance ITT regimen:• Steroids• Other immunosuppressive agentsRituximab• Anecdotal reports of success • Limited literature • Study in process

Francini, et. al., Haemophilia, 2008; 14: 903-912.

Education about new plan of care, potential new productsReassurance and supportDiscussion about ITT• Evaluating family readiness, venous access• Protocol / Product choice• Considerations of family schedule, ability to adhere to regimen

NURSING CONSIDERATIONS

FIX inhibitors: What’s the big deal?

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, 1997Warrier et al, Journal of Pediatric Hematology/Oncology, 1997

FIX INHIBITORS: ANAPHYLAXIS

18 children in 12 HTCs reported with anaphylaxisMedian age 16 monthsMedian exposure days: 11 12/18 patients had inhibitor detected around time of anaphylaxisMedian titer 48 BU

Warrier et al, Journal of Pediatric Hematology/Oncology, 1997

Warrier et al, Journal of Pediatric Hematology/Oncology, 1997

FIX INHIBITORS: ANAPHYLAXIS (CONT’D)

Genetic analysis on 17/18 patients• 10 with complete deletion• 7 with major derangement2/12 underwent ITI developed nephrotic syndrome 8 months after beginning ITI2/12 achieved toleranceInfusion products included PCC & very high-purity FIX products

Warrier et al, Journal of Pediatric Hematology/Oncology, 1997

FIX INHIBITORS: NEPHROTIC SYNDROME

7 patients on ITI regimens with FIXCommon 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

FIX INHIBITORS: NURSING CONSIDERATIONS

Genetic analysis of all patients with severe hemophilia BGive 1st 10-20 infusions at a medical facilityMaintain venous access for 30 minutes after each infusionDiscuss issues with family at diagnosisITT optionsMonitor for nephrotic syndrome

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

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

JIM MUNN, R.N., M.S.Program Nurse CoordinatorUniversity of Michigan HTCAnn Arbor, MI, USAChair – WFH Nursing Committee

Acknowledgement: Select slides courtesy of Partners in Bleeding Disorders Education Program www.partnersprn.org

MERGER AVEC SLIDE 1