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1
European Haemophilia Consortium Round Table of Stakeholders
Orthopaedic Aspects in Haemophilia Care
What are the goals of
treatment?
A Haematologist’s perspective
Professor Cedric HERMANS
MD PhD FRCP (Edin, Lon)
Haemostasis and Thrombosis Unit
Haemophilia Clinic
Division of Haematology
Cliniques Universitaires Saint-Luc
Catholic University of Louvain
1200 Brussels, Belgium
Speaker disclosures
Shareholder No relevant conflicts of interest to declare
Grant / Research Support
No relevant conflicts of interest to declare
ConsultantPfizer, Bayer, Shire, Novo Nordisk, CSL Behring, Octapharma, Sobi, LFB, CAF-CDF, OctaPharma
Employee No relevant conflicts of interest to declare
Paid Instructor No relevant conflicts of interest to declare
Speaker bureau No relevant conflicts of interest to declare
Other
3
THE MOST FAMOUS HAEMOPHILIA PATIENT
TSARÉVITCH ALEXIS (1904-1918)
4 year-old
8 year-old
10 year-old
4
HAEMOPHILIA TODAY : NOT LONGER A ROYAL
DISEASE BUT A DISEASE THAT CAN BE
TREATED
This young boy with severe
haemophilia can now be
treated safely and have a
normal life.
HAEMOPHILIA
Blood Coagulation Defect Debilitating Arthropathy
6
Bleeding complications in patients with
haemophilia
Intra-Cranial
Hip
Ilio-psoas Muscle
7
Factor Level(%)
PhenotypeAnnual bleeding rate (ABR)
without Replacement
Moderate
Severe<1%
1–5%
6–24%
25–49%
50–150%
>150%
Mild
52
1–5
0–1
0
0
0
The Most Affected Joints in Haemophilia
• 90% of bleeding episodes affect MSK system
• Up to 80% in ankles, knees and elbows
• 10% of hematomas
• Begin by age 2
• Nonvital tissues express low levels of TF.
• These tissues appear to rely more on the intrinsic pathway of coagulation to maintain hemostasis.
• This may explain why hemophilia A and B patients exhibit spontaneous hemorrhages into skeletal muscle and joints.
Mackman N. Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):1015-22.
Why do patients with haemophilia bleed in
their joints ? Haemotological reason
Elbows, knees and ankles are the
most susceptibe to acute
haemarthrosis
« hinge joint » synovium gets stuck
in the joint
Shoulders and hips are less
susceptible to acute
haemarthrosis
Why do patients with haemophilia bleed in
their joints ? Anatomical reason
Interleukin-1Interleukin-6
TNF-alpha
Consequence of hemarthrosis: Inflammation and hypertrophy of the Synovium
Source: S. Lobet
Source: Novo Nordisk
Musculoskeletal bleeding episodes in patients with haemophilia
Features
Location Joint Muscle
Reason Spontaneous Induced (trauma, physical activity)
Presentation Clinically patent Suclinical
Symptomatic
Asymptomatic
Clinical haemarthrosisLarge amount of blood
Clinically patent
Subclinical haemarthrosisSmall amount of blood
Clinically silent
Treatment of haemophilia
Replacement or substitutive
therapy by regular intravenous
infusions of exogenous clotting
F8 or F9 to correct clotting
factor deficiency in order to
treat or prevent bleeding
episodes
Injection of missing
Factor VIII or IX
Treatment of haemarthrosis
should not be delayed
WITH A JOINT BLEED, TIME LOST IS JOINT
AND CARTILAGE LOST
Visit our Website: http://www.hemophilie-ucl.be and discover our
computer-generated movie on blood coagulation and haemophilia
The benefits of early treatment : a well-known
concept in various therapeutic areas
CARDIOLOGY
Acute myocardial infarction
Saves cardiac
muscle
NEUROLOGY
Acute ischemic stroke
Saves
neurones
HAEMOPHILIA
Acute haemarthrosis
Saves
cartilage
PATIENT
Education
Good understanding
Rapid recognition
Good venous access
HEALTH CARE
SYSTEM
Home-treatment
Education
TREATMENTReplacement or
Bypassing
Haemostatic efficacy
Convenience of use
Requirements for early treatment of bleeding
episodes in patients with haemophilia
Better than early treatment,
PREVENTION of haemarthrosis is
the optimal option
20
Ideal treatment of Severe Haemophilia :
Prevention of bleeding episodes by regular
infusions
Regular self-administration of
F8 or F9 concentrate in order
to prevent bleeding episodes
(20-40 units/kg – 3x/week or
1x/2days)
Time
FVIII
1%
F8 correction by regular infusion
21
The Concept of Prophylaxis
<1%
1–5%
6–24%
25–49%
50–150%
>150%
• Patients with moderate hemophilia
(FVIII / FIX 2–5%) have much less
frequent haemarthrosis than
patients with severe disease (<1%)
• The rationale for prophylaxis is to
maintain FVIII / FIX >1% in order to
prevent spontaneous bleeding
episodes, especially haemarthrosis
• Regular infusions of FVIII
concentrates aim to convert
severe into moderate
• No consensus on optimal
prophylaxis regimen
• Considering a recovery of 2, and
a half-life of 9-13 hours for
currently available FVIII
concentrates, 2-3 infusions per
week are needed
10 %
20 %
30 %
40 %
50 %
60 %
Monday Tuesday Wednesday Thursday Friday Saturday Sunday
Fact
or
VII
I m
easu
red
in
blo
od
1 %
Infusions of concentrate
Prophylactic Treatment of Haemophilia A:
Basic Principles
23
Choices of Treatment Regimens and Different Ages at
Which They Are Implemented
A. Coppola. Blood transfusion, 2008.
0 5 10 15 20 25 30 35 40
Prevention of
Life-
threatening
Bleeding
Reduction of
Progression of
Arthropathy
and Disability
Enable Normal
Activities of
Daily Life and
Physical
Exercise
Enable
Practically
Normal
Psychosocial
Development
without
Overprotection
Primary Prophylaxis
Early Secondary Prophylaxis
Late Secondary Prophylaxis
Secondary Prophylaxis in
Adolescents and Adults
Short-term Prophylaxis
On-demand Treatment
Age (years)
• To all boys with severe haemophilia A/B
• Around the age of one year
• At a low dose, i.e. usually 25 U/kg
• Frequency of every 2nd day/trough guided
• Avoiding “immunological danger signals” first 20 ED
• As “prophylaxis” during first 20 ED instead of “on demand”
How should prohylaxis be started in 2017 ?
DATA SUPPORTING PROPHYLAXIS: RETROSPECTIVE AND PROSPECTIVE STUDIES
Author Outcome Prophylaxis On-Demand
Liesner et al. 19961 All bleeds/year (median) 1.5 14.7
Szucs et al. 19982 Joint bleeds/6 mos(mean)
3.1 8.8
Yee et al. 20023 Joint bleeds/year (median)
0.5 3.5
Panicker et al. 20034 Major bleeds/year (mean) 1.9 15.5
Feldman et al. 20065
(Interim results: prophylaxis only)
Joint bleeds/year (mean) 1.2 N/A
N/A = not available.
1. Liesner et al. Br J Haematol. 1996;92(4):973-978 2. Szucs et al. Haemophilia. 1998;4(4):498-501 3. Yee et al. Haemophilia. 2002;8(2):76-82.
4. Panicker et al. Haemophilia. 2003;9(3):272-278 5. Feldman et al. J Thromb Haemost. 2006;4(6):1228-1236.
26
Prophylaxis Reduces the Occurrence of
Bleedings
Manco-Johnson M. et al, NEJM, 2007; 357:535-44.
On-demand
(n=33)
Prophylaxis
(n=32)
Total Bleeds/year 18 1.9
Joint Bleeds/year 5 0.5
(90% less)
(90% less)
PK of FVIII and the risk of haemarthrosis
Peak
Trough
Monday FridayWednesday
Reduced bleeding risk zone
Collins PW: Plenary lecture „Personalized Prophylaxis“ WFH congress July, 10 2012
FVII
I lev
el (
%)
time
Peak / time spent in reduced bleeding risk zone:
Important to prevent activity related and traumatic bleeds
Trough Important to prevent spontaneous break through bleeds
AUC Important to prevent subclinical bleeds, maximizing the window of protection
RISKS OF STOPPING PROPHYLAXIS IN ADULTS
• Haemophiliacs do not lose the risk of joint bleeding at the age of 18
• Switching to “on-demand” will lead to haemarthroses –how many before haemophilic arthropathy develops ?
• Risk of losing the benefits of the financial and human resource invested in childhood
SECONDARY PROPHYLAXIS
• Introducing prophylaxis in adulthood is effective in reducing joint bleeding and improving joint function
Median (interquartile
range) number of bleeds per
patient
On-demand treatment*
Prophylactic treatment†
P value‡
Months 1–6 (n = 20)
Months 7–13 (n = 19)
Joint bleeds 15.0 (11–26) 0 (0–3) < 0.001
All bleeds 20.5 (14–37) 0 (0–3) < 0.001
Spontaneous bleeds
13.5 (7–29) 0 (0–1) < 0.001
Trauma bleeds 2.5 (0–9) 0 (0) < 0.001
NUMBER OF BLEEDS ON SECONDARY PROPHYLAXIS
Median observation period was 192 days. †Median observation period was 177 days. ‡Wilcoxon test.
Collins et al JTH 2009 8, 83-89
Patients receiving prophylaxis had 15.2 times fewer bleeds
Note: Median treatment duration at time of data analysis was 1.4 years; data shown are for all nondiscontinued patients who completed at least
1 study year.
*On demand vs prophylaxis; adjusted for stratification variables (presence/absence of target joints and number of previous BEs).
References: 1. Kempton C, et al. Presented at: XXXth International Congress of the World Federation of Hemophilia; July 8-12, 2012; Paris, France.
2. Manco-Johnson MJ, Kempton CL, Reding MT, Lissitchkov T, Goranov S, Gercheva L, Rusen L, Ghinea M, Uscatescu V, Rescia V, Hong W.
Randomized, controlled, parallel-group trial of routine prophylaxis versus on-demand treatment with rFVIII-FS in adults with severe hemophilia A
(SPINART) [published correction appears in J Thromb Haemost. 2014;12:119–122.] J Thromb Haemost. 2013;11:1119-1127.
40.7
29.2
1.93.5
52.7
36.9
2.0*4.2*
P<0.001, on demand vsprophylaxis*
Mea
n B
Es, n
Total BEs per yearTotal BEs
Mea
n B
Es, n
10
20
30
40
50
60
0 0
10
15
25
30
40
45
20
35
5
Joint BEs per yearJoint BEs
On demand (n=42)Prophylaxis (n=42)
31G.SM.HEM.03.2014.0146
SPINART (Secondary Prophylaxis in Adults, Randomized Trial)
One year mean efficacy results1,2
Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens.
• Current prophylactic regimens, although very effective, do not completely prevent joint disease in a long-term perspective.
• Joint arthropathy in primary prophylaxis develops over many years, sometimes over a decade or even longer time periods.
• The ankle joints are the first and most severely affected joints in those patients and thus may serve in outcome assessment as an indicator of early joint arthropathy when followed by ultrasound or magnetic resonance imaging.
J. Oldenburg Blood. 2015 Mar 26;125(13):2038-44.
Patients with Different Lifestyle and Activity Level may need Different FVIII Trough Levels
>3% ?
10% ?
33
34
• Based on FVIII PK parameters
• Based on bleed pattern
• (presence of target joints/joint damage)
• Tailored to activity level (sports)
• Tailored to personal circumstances
• Based on all available information
• Efficient
Hemostasis
Joint Status
Activity Level
Valentino LA. Considerations in individualizing prophylaxis in patients with haemophilia A. Haemophilia 2014 Sep; 20(5): 607-15.
Individualized prophylaxis should be
Standard prophylaxis not optimal for everybody
35
Patient with an average half-life (25 IU/kg every other
day)
Patient with a short half-life (25 IU/kg every other
day) Time spent with FVIII plasma
levels <1%
Increased risk for
break through bleeds
1%
1%
FV
III
leve
l (%
)F
VII
I le
ve
l (%
)
PHARMACOKINETIC DOSINGFV
III:
C (
U/d
L)
6,000 IU/week
1,575 IU/week
770 IU/week
100
10
1
0.1
100
10
1
0.1100
10
1
0.1
0 3 6 9 12 15 18
Time (days)
2000 IU, 3 times a week
450 IU, every 2 days
110 IU, daily
Carlsson et al. Eur J Haematol 1993;51:247–52. JA
« ZERO » bleed world
A new ambition in haemophilia therapy
Not only an issue of treatment availability and intensity
Only achievable with major collaboration of the patient and his family
Aiming for zero bleeds
Lifetime joint bleeds
Joint scores
Normal joints
Moderate damage
Substantial damage
Joint health
Patient impact
Patient–doctor relationship
Funk M et al. Haemophilia 2002; 8:98–103.
4 or more 3 0–2
Physical examination 3–7 0–2 0
X-ray 7–12 0–3 0
MRI 3–8 2 0
Which FVIII Trough Levels are needed for Zero Joint Bleeds?
Den Uijl et al. Haemophilia 2011; 6: 849-53
3%
12%
39
Correlation of endogenous FVIII level and annual
number of joint bleeds
INTEGRATION OF REAL WORLD-DATA COLLECTION, TAILORED CARE AND PATIENT EMPOWERMENT
Personalized Medicine
1. PK profiling
2. Bleeding risk profiling
1. Bleeding phenotype
2. Target joints
3. Joint status
4. Work and sport activity
5. Lifestyle
6. Compliance
3. Bleeding recognition
Patient Empowerment
1. Disease and treatmentunderstanding (adherence) / psychological support
2. Shared treatment and goals decision making (GAS)
3. Life-style and activity adjustment
4. Promotion of self-management
Real-World Data Collection
Treatment tracking
(recording of bleedingepisodes and factor
consumption)
Outcome tracking
Patient-centricprophylaxis
Adapted from Gringeri A, Doralt J, Valentino LA, Crea R, Reininger AJ. Expert Rev Pharmacoecon Outcomes Res. 2016 Jun;16(3):337-45.
Haematological treatment of hemophilia
TODAY TOMORROW
Compensation of defectiveproduction of FVIII or FIX
"Cure"
Factor replacement therapy withplasma-derived or recombinant concentrates
Gene therapy
Non-factor replacement / Disruptive therapy
Endogenous production of natural/unmodified FVIII or FIX
Could IL-1 blockers prevent
blood-induced joint damage in
hemophilia ?
• It would be ideal if there were oral
drugs which could be taken soon
after a joint bleed for a short period
of time during the period
associated with damaging
inflammatory responses along with
CFC replacement to prevent
further bleeding.
• This could be particularly
significant for the vast majority of
patients in the world who do not
have access to prophylaxis with
CFC.
Srivastava A. Blood. 2015 Nov 5;126(19):2175-6.
Antibodies to block TNF-a / IL-1
antiangiogenesisdrugs
Impact of innovation on haemophilia care
More efficient treatments
Persistent control of FVIII or FIX deficiency
Cure of the disease
No BLEEDS
More time and resources for assessing and following non-
bleeding consequences of haemophilia
CONCLUSION
• The goal / ambition of the haematological treatment of haemophilia should be a complete abolition of all bleeding episodes and a full preservation of the musculo-skeletal system
• This is now achievable with current treatment options in a large proportion but not all patients with severe haemophilia
• The focus should be on patients with an Annual Bleeding Rate (ABR) > 0 . In these patients, different strategies should be implemented to better control their disease.
Thank you for your attention