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Case & Journal Reading

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Kai-Fu Chuang

on 23 October 2013

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Transcript of Case & Journal Reading

Case to
Journal Reading

Hemophilia A
The CANAL Study
Concerted Action on Neutralizing Antibodies in severe hemophilia A
Describe the relationship between treatment characteristics and inhibitor development in previously untreated patients with severe hemophlilia A
Multicenter retrospective cohort study
366 consecutive patient born between 1990 and 2000
Teatment-related risk factors of inhibitor development in previously untreated
patients with hemophilia A:
the CANAL cohort study

Backgound knowledge


Reveiw of system
clinically relevant inhibitor development
occurrence of at least 2 positive inhibitor titers combined with a decreased recovery
87(24%) developed inhibitors
Incidence of inhibitor appeared to be age at first treatment
41% for treated in first month of age

18% in those treated after 18 months
adjustment for treatment intensity, this association largely disappeared
Surgical procedures and Peak treatment moment at start of treatment
Increasing inhibitor risk
RR 3.7, CI 95% 2.0-7.1 / RR 3.3, CI 2.1-5.3
Regular prophylaxis was associated with a 60% lower risk than on-demand treatment
RR, 0.4: CI, 0.2-0.8
Our findings suggest the previously reported associated bewteen an early age at first exposure and the risk of inhibitor development is largely explained by early, intensive treatment
**Early and regular prophylaxis may protect patients with hemophilia against the development of inhibitors**
Patient and methods
Hemophilia A is an X-link inherited bleeding disorder characterized by a deficiency of functional clotting factor VIII
Looking forward to a favorable outcome and high level of health-related quality of life
25% children with severe hemophilia A develop inhibitory antibodies against infused factor VIII
Patients with high-titer inhibitors have a particularly increased risk of potential life-threatening bleeds and, furthermore, treatment of these patients is complex and costly
patient-related factors
family history of inhibitors
factor VIII gene mutation type
HLA complex genotype polymorphisms in the promoter regions of the interleukin-10 gene and tumor necrosis factor-alpha
observations of discordant inhibitor status in monozygotic twins suggest that environmental risk factors also affect inhibitor development
Some studies observed a higher risk in patients who were first treated with factor VIII at a younger age than those first treated at a later age
Intensive treatment was suggested to be a risk factor in patients with mild hemophilia A, who appeared to develop inhibitors more frequently after surgery
protective effect has been suggested for prophylactic treatment, but additional studies are required to confirm this association
Modifiable risk factors of inhibitors provide the key to predict and perhaps even prevent inhibitor development in hemophilia patients
13 European and 1 Canadian hemophilia treatment centers
Exam previously untreated patients with severe hemophilia A
age at first exposure
intensity of treatment
regular prophylaxis
study population
376 patients with severe hemophilia A born in 1990 and 2000 (residual factor VIII activity of < 0.02 IU/mL )
Treated in single center from first clotting factor administration on ward
Ten patients were excluded
1 because of an unknown baseline factor VIII activity
2 because of treatment with a particular factor VIII product that was reported to be clearly associated with an increased risk of inhibitor development
1 because of treatment with desmopressin
6 because they were lost to follow-up before they received treatment with factor VIII on a total of 50 exposure days
collect data from medical record and clotting factor logbook
date of birth
residual factor VIII activity level
family history of hemophilia and inhibitors
duration of breastfeeding
factor VIII gene mutation
Record details on all clotting factor infusion up to 50 exposure days or until inhibitor development
dates of infusion
doses and types of factor VIII product
reasons of treatment
types of bleeds
For correct assessment
collect detail on all performed inhibitor tests and recovery measurements
body weights
infused doses of clotting factor
preinfusion and postinfusion factor VIII activity level
time between infusion of clotting factor
blood sampling for postinfusion factor VIII activity level
Definition of inhibitor development
the development of “all clinically relevant inhibitors” was defined as the occurrence of at least 2 positive antibody titers combined with a decreased factor VIII recoverywithin the first 50 exposure days
the development of “high-titer inhibitors” occurred when the peak inhibitor titer was at least 5 Bethesda units/mL.
A positive inhibitor titer was defined according to the inhibitor assay used and the cutoff level of the respective laboratory
The factor VIII recovery was considered to be decreased, when it was less than 66% of the expected level
The expected level of factor VIII activity was calculated according to Lee et al. 26
Data analyses
Aim: whether potential determinants were associated with inhibitor development
1/2 all inhibitors occur before the 15th exposure day
the other 1/2 occur with a sharply decreasing incidence rate relatively early afterward
At 50 exposure days, < 1%
take into account if risk factors occurring at various time points during the early treatment with factor VIII
Potential determinants of inhibitor development
Fixed potential risk factors of inhibitor development
baseline factor VIII activity
family history of inhibitors
factor VIII gene mutation type
age at first exposure to factor VIII
reason for first factor VIII treatment (prophylaxis, bleeds, or surgical procedures)
peak treatment moments at first treatment episode
We studied inhibitor incidences in
high-risk mutations (large deletions [ > 200 base pairs] nonsense mutations intron 22 or 1 inversions)
low-risk mutations (small deletions/insertions [ < 200 base pairs], missense mutations, and other mutations [splice site defects or promoter mutations])
Time-varying potential determinants:
peak treatment moments
major peak treatment moments
major surgical procedures
duration between exposure days
dose of factor VIII product
regular prophylaxis
“Peak treatment moment” was defined as an episode of treatment with factor VIII for a bleed or surgery on at least 3 consecutive days
“Major peak treatment moment” was defined as a peak treatment moment during which treatment was given on at least 5 consecutive days
“major surgical procedures” for which replacement therapy lasting at least 3 consecutive days was given
corresponding time-dependent variables were defined as
“after peak treatment moment”
“after major peak treatment moment”
“after major surgical procedure”
“Duration between exposure days” was our measure for frequency of exposures, defined as
the time period between the current exposure day and the fifth exposure day prior to this exposure day (or in the first 4 exposure days, the time period was converted to a total of 5 exposure days)
For example, if a patient had developed an inhibitor at the 20th exposure day, the time period between the days at which he had his 15th and 20th exposure day was his duration between exposure days at the 20th exposure day
“Dose of factor VIII product” was defined as
the mean dose of factor VIII product per kilogram body weight of the last 5 exposure days prior to each exposure day (or in the first 4 exposure days, mean dose of all previous days)
We defined “regular prophylaxis” as
regular factor VIII infusions at least once a week aimed at preventing bleeds,
as we expected that one exposure to factor VIII a week could have an immunologic effect.
Since prophylaxis influences these variables to a large extent, we restricted the analyses of duration between exposure days and dose of factor VIII product to the subgroup of patients who never received regular prophylaxis
All patients contributed were classified into the on-demand group until they started prophylaxis, plotted the cumulative incidences of inhibitor development in
on-demand treatment
prophylactic treatment
To illustrate the association of treatment regimen and the risk of inhibitor development
All associations were adjusted for factor VIII gene mutation type categorized as
low-risk mutation types
as specified earlier
All associations were also adjusted for the type of factor VIII product, categorized as recombinant factor VIII products, monoclonal antibody purified plasma-derived products, and other plasma-derived products
fever off and on with body temperature around 38-38.5' C for 10 days
skin rash and itching over four limbs and face
cough and rhinorrhea

oral ulcer
eczema was diagnosed but condition did not improve
Present illness
Physical examination
skin rash
itching over four limbs
oral ulcer
skin rash over the four limb
oral ulcers
1.General: Fever
2.HEENT:oral ulcers
3.Cardio-Respiratory system:Normal
4.Gastrointestinal system:Normal
5.Genito-urinary system:Normal
6.Neuro-Psychiatric system:Normal
7.Musculoskeletal system:Normal
8.Skin: Rash

MCV   76.7 fL [80.0-99.0]
%Basophil  0.0 % [0.0-1.5]
%Eosinophil   4.0 % [0.0-7.0]
%Monocyte  11.0 % [3.4-9.0]
%Lymphocyte 62.0 % [19.0-48.0]
WBC   6.90 10^3/uL [4.80-10.80]
RBC   4.38 10^6/uL [4.70-6.10]
HGB   11.2 g/dL [14.0-18.0]
HCT   33.6 % [42.0-52.0]
MCH   25.6 pg [27.0-34.0]
MCHC   33.4 g/dL [31.0-37.0]
Platelet  264 x10^3 /uL [130-400]
%Neutrophil   23.0 % [40.0-74.0]
APTT   > 180.0 sec [23.9-35.5]
MNPT sec   10.5 sec
PT_FIB_INR   0.89 [0.85-1.15]
PT_FIB   9.4 sec [8.0-12.0]
CRP   0.80 mg/dL [<1.00]
H-F-M disease
seborrheic dermatitis
erythema multiforme
erythema infectiosum
checked his PT/aPTT due to echymosis of bilateral legs for a long time
prolong aPTT
consult hematologist
for coagulopathy
mixed aPTT
mixed aPTT
showed normal ranged
Hemophilia profile factor VIII & IX
swelling and echymosis improved after medication and FFP transfusion, hand-foot-mouth also improved
Discharge at 1020408
Factor VIII activity: 1.2%
19-21 deletion
prolong mixed APTT
Factor VIII activity: 0.9%
Severe hemophilia A
with inhibitor development
Chart No: 04xxxx47
Age: 1-year old
Gender: male
Residence: Taiwan
2007 109: 4648-4654
Prepublished online February 8, 2007;
Samantha C. Gouw,1,2 Johanna G. van der Bom,3 and H. Marijke van den Berg,1 for the CANAL Study group
1Van Creveldkliniek, University Medical Center Utrecht, Utrecht, the Netherlands; 2Department of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands; 3Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
Age at first exposure
5 previous reports observed a higher incidence of inhibitors among boys who were treated with factor VIII at a young age, but did not adjust for treatment intensity.
We found this association is explained by intensity of treatment.

Intensity of treatment
surgical procedures and major peak treatment moments carried a markedly increased inhibitor risk

Regular prophylaxis
Factor VIII infusions in absence of immunologic danger signals, like in prophylactic treatment, may lead to inhibition of the immune response through peripheral anergy of factor VIII–specific T lymphocytes
60% decreased risk of inhibitor development in patients on regular prophylaxis
Patient characteristics
our study confirmed previous reports of an increased risk of inhibitor development in patients with a
positive family history of inhibitors
and patients with large deletions, nonsense mutations, or intron 22 inversion in their factor VIII gene
No relation about breastfeeding
Strength and limitations
Include patient treated in single center
98% treated at least 50 exposure days, so little chance of bias due to being still at risk of Inhibitor development
time-dependent determinants
Young age at first exposure to factor VIII was associated with an increased risk ofinhibitor development, disappeared after adjustment for intensity of treatment
Intensive treatment (early surgical procedures, early major peak treatment moments, and high dosing of factor VIII) was related to a higher risk
Regular prophylaxis was related to a 60% lower risk of inhibitor development
Major bleeds or surgeries cause tissue damage and inflammation
Danger signals released from injured cells
Activate antigen-
presenting cells
subsequently present factor VIII antigen with up-regulated costimulatory signals to T lymphocytes
Enhance antibody formation in B lymphocytes
More prone to inhibitor development during periods of intensive treatment
Int. Kai-Fu Chuang
Dr. Shu-Huey Chen Dr. Sheng-Chieh Lin

X-linked recessive diseases
1 in 5,000 males: 85% hemophilia A, 10-15% hemophilia B
Severe (<1% factor activity), moderate (1-5%), mild (5-25%)

S/S: bleeding from circumcision, neonatal ICH (1-2%), easy bruising, oral bleeding, hemarthroses, intramuscular hemorrhages, hematuria, GI bleeding

Complication: avascular necrosis of femoral head, chronic arthropathy, muscular contracture, pseudotumor
Life-threatening hemorrhages: CNS, iliopsoas
Prolonged PTT, low factor VIII or IX, genetic testing
Factor replacement,antifibrinolytic
Arthropathy: surgery, radionuclide synoviorthesis
Median life expectance: 11.3 yrs (early 1990s) to 60-70 yrs now

Mixed aPTT
For differential diagnosis of aPTT prolong
Factor deficiency(ex: Hemophilia factor VIII, IX deficiency)
Inhibitors(ex:antiphospholipid antibodies/lupus anticoagulant, inhibitors directed against thrombin, factor inhibitors)
Anticoagulants(ex: heparin)

plasma concentrates of coagulation factors 1970:*hepatitis B and C 1980:*HIV
Prophylaxis in Hemophilia
To prevent chronic joint disease
Prohylaxis is optimal therapy in severe hemophilia (MASAC)
Start early (1-2 yrs)
Keep >1%
For hemophilia A: 25-40 units/kg 3 times per week
For hemophilia B: 25-40 units/kg 2 times per week
Evaluations: joint, cost, complications
Full transcript