Complication of Hemophilia:

inhibitor & transfusion

related infection

Novie Amelia Chozie

Divisi Hematologi-Onkologi Dept IKA FKUI/RSCM
Jakarta
 What is inhibitor ?

 Inhibitors are antibodies that neutralize the

activity of a clotting factor.

 Inhibitor antibodies to factor VIII or IX may

arise as allo-antibodies in patients with
hemophilia A or B who have been transfused
with exogenous factor VIII or IX
 Incidence

 The incidence of inhibitors to factor VIII in

patients with severe hemophilia A within the
first few years of life has been reported in
various series as 10-50% (typically, 20-30%).

 The prevalence of inhibitors in severe

hemophilia B is about 4%.
 Inhibitor F VIII Epidemiology Study
(Jakarta, 2013)

Titer N (%)
< 0,5 BU 96/157 (61.1%)
(negative)
0,5 - <5 BU 50/157 (31.8%)
(low titer)
≥ 5 BU 11/157 (7%)
(high titer)
 Characteristics

 Inhibitors are IgG antibodies.

 Anti-factor VIII antibodies react with

active sites of the factor VIII molecule,
primarily with epitopes in the A2, A3, C1
and C2 domains.
Anti-FVIII inhibitors
Risk factors

Blood. 2009;113:11-17
 Risk factors
 Severe hemophilia > mild or moderate hemophilia.

 FVIII genotype and the risk of developing inhibitor:

- large deletion ( 88%)
- nonsense mutations ( 60%)
- intron-22 inversion ( 21%)
- small deletions/insertions ( 20%)
- missense mutations ( 5%)
Clinical presentation

Inhibitor is suspected when a

patient’s hemorrhage is not
promptly controlled with usual
dose of clotting factor
concentrate.
 Inhibitor measurement

Inhibitors are quantified by the so-

called Bethesda method, and are
expressed in Bethesda units (BUs)
1 BUs ≈ 50% of the total FVIII activity is
inhibited
Charles & Hay Brit J Haematol 2006;133:591–605; WFH. Guidelines for the
Management of Hemophilia. 2005; AHCDO. Guidelines for the Treatment of Inhibitors in Haemophilia A
and Haemophilia B. 2010; Scharrer et al. Haemophilia 1999;5:145–54
Laboratory examination

Inhibitor titre assayed using the Bethesda

method:
High & low responder
 Screening for Inhibitor

 WFH
 Children: every (first) 10-20 exposure
days or every 3-12 months.
 Adult : as clinically indicated
Lack of response to adequate FVIII
infusion.
Before surgery

WFH guidelines 2012

 Diagnosis

 Inhibitor patients are distinguished on the

basis of the anamnestic response to FVIII
exposure : low vs high responder

 Low titre inhibitor (< 5 BU) usually transient :

 disappear spontaneously
 no relevant impact on clinical management
 Treatment

1. Acute bleeding episodes

2. Eradication of antibody : immune
tolerance induction (ITI)

WFH, 2000
Management of acute bleeding

 Low titre inhibitor : Replacement therapy

 Human FVIII (high-dose)
 Recombinant FVIII (2nd and 3rd generation)
 Porcine FVIII
 High titre inhibitor : Bypassing agent
 Recombinant fVIIa
 Prothrombin complex concentrate (PCC)
 Activated PCC
WFH Guideline for inhibitor
management
 Mechanism of action FVIIa

Normal Hemophilia

Blood.2004;104:3858-3864
TF independent mechanism of rFVIIa
 rFVIIa
 Facilitates hemostasis by activating factor X
directly on the platelet surface thereby
bypassing the tenase complex.
 The half-life is 2.3 hours in adults but
potentially shorter in children
 No potential for anamnesis to fVIII (small
amounts of fVIII can be found in PCCs/FEIBA )
 rF VIIa Dose

 Typical joint bleeds :

 Dose : 90 - 120 mcg/kg every 2 to 3 hours.
 Effective in 92% of treated bleeds after a
mean of 2.2 injections

 Target joints :
 A single dose of 270 mcg/kg or 3 doses of 90
mcg/kg
 New drugs : re-balancing
hemostasis

N Engl J Med 2017;377:809-818

 Eradication of inhibitor

 Immune tolerance induction (ITI)

- may take up to 1 – 3 years to achieve tolerance
- very high cost
- successfully eradicating up to 90% of FVIII inhibitor
 Immunomodulation
+ cytostatics: cyclophosphamide, 6-mercaptopurine
+ immunosuppressant: azathioprine, cyclosporin
+ corticosteroids
+ gamma globulin
+ plasmapheresis
Immune tolerance induction
Immune tolerance induction
Poor prognostic factors in ITI

 Pre-ITI inhibitor titer >10 BU

 Peak historic inhibitor titer >200 BU
 Presence of inhibitor >2 years

Hematology 2006;421-5
 In patient (pediatric ward, PICU)
Tahun No ID Diagnosis Clinical problems Treatment
Hemofilia A
Pseudotumor abdomen ec
1 JP berat, inhibitor rVIIa (Novo7) ke-1: 54 vial
hematoma abdomen, appendistis
titer tinggi
Burst abdomen, perdarahan luka
rVIIa ke-2: 136 vial
operasi
2017 Hemofilia A
Faktor VIII (Koate) 168 vial
Abd berat, inhibitor Perdarahan iliopsoas pro operasi
@500IU/vial, FEIBA
2 titer rendah
Hemofilia A
Faktor VIII (Koate) 82 vial
R berat, inhibitor Perdarahan intrakranial
@500IU/vial, CPA
3 titer tinggi
Hemoiflia A
berat, inhibitor Hyfema Novo7 30 vial
1 G titer tinggi
2015
Hemofilia A
berat, inhibitor Pseudotumor vesica urinaria Novo7 120 vial
2 MN titer tinggi
Transfusion-related infections

Data in Child Health Dept, 2000 - 2002

 Hepatitis C : 51%
 Hepatitis B : 3%
 HIV : 4 cases

Handryastuti, Djajadiman G, Arwin AP Akib. Karakteristik klinis penderita hemofilia A dengan hemartrosis, 2002
Partiwi, Zuraida, Rulina S. Hepatitis C infection in hemophilia patients : prevalence and risk factors. Jakarta, 2000
 Utilization of Cryoprecipitate vs
Factor VIII Concentrate

3.500.000
F VIII Concentrate
3.051.600
3.000.000 Cryoprecipitate
2.484.640
2.500.000
IU

2.293.600

2.000.000

1.500.000 1.249.200
1.213.360
1.000.000

500.000 572.400
488.400
201.600
0
2003 2004 2005 2006

Year
 Prevalence of hepatitis C infection
in hemophilia A patients (n=72)

Variabel Anti HCV (+) Anti HCV (-)

n = 41 n = 31

Age (mean) year 13.5 6.4

Transfusion period :
> 10 years 28 0
< 10 years 13 31
Cryoprecipitate
(mean) U/year 9123.9 5337.3

Partiwi, Zuraida, Rulina S. Hepatitis C infection in hemophilia patients : prevalence and risk factors. Jakarta, 2000
 Correlation of donor screening and
HCV infection in hemophilia A patients (n=72)
Variabel Outcome Total
Anti HCV (+) Anti HCV (-)

Before screening 39 14 53

40% screening 2 7 9

100% screening 0 10 10

Total 41 31 72

Partiwi, Zuraida, Rulina S. Hepatitis C infection in hemophilia patients : prevalence and risk factors. Jakarta, 2000
OR = 0.1 (95%CI 0.01;0.65)
 Transfusion-related infections

Detection/regular monitoring of transfusion-

related infection
Treatment of hemofiliac with HCV with α-
interferon  poor response:
 HCV genotype 1
 High titer of HCV-RNA
 Advanced age  chronic liver disease/liver
cirrhosis
 Hepatitis leads to chronic liver disease
 Complications specific bleeding due to liver disease:
variceal bleeding, DIC
 Limited access to clotting factor concentrate (“JKN”)
 Available treatment for (chronic active) hepatitis
by “JKN”
 HIV: education and counselling
Thank you