1. health and fitness
2. disorders

Hemophilia and HTCs
How to tell our story
Mark T. Reding, MD
Associate Professor of Medicine
Division of Hematology, Oncology, and Transplantation
Director, Center for Bleeding and Clotting Disorders
University of Minnesota Medical Center
Minneapolis, MN
Hemophilia Alliance – Spring Members Meeting
Washington, DC – April 27, 2015
Basic Approach
1. Assume they know nothing
about hemophilia
2. Show them what it really looks
like – a picture with a story
attached is a powerful tool
3. Don’t be afraid to brag a little
4. Set the expectation for an
ongoing dialogue
Topic Outline
1. What is hemophilia?
2. Clinical manifestations
3. Treatment of hemophilia
4. HTC care model
Magnitude of the Problem
How many people are affected?
Obesity…………………90,500,000
Diabetes………………..25,800,000
COPD…………………..15,000,000
MS………………………….300,000
Hemophilia………………….20,000
Sources: Centers for Disease Control and Prevention (www.cdc.gov)
National Institute of Neurological Disorders and Stroke (www.ninds.nih.gov)
What is Hemophilia ?
• Congenital bleeding disorder
• Due to deficiency or absence of a
coagulation cascade protein
• Hemophilia A = factor VIII deficiency
• Hemophilia B = factor IX deficiency
Hemophilia A
• Factor VIII deficiency
• Classical hemophilia
• 1 in 5,000 to 10,000
male births
Hemophilia B
• Factor IX deficiency
• Christmas disease
• 1 in 30,000 male
births
• 80% of total cases
• 20% of total cases
• Spontaneous
• Spontaneous
mutations = 30%
mutations = 20%
Clinical phenotypes are indistinguishable
•
Hemophilia affects all
racial and
socioeconomic groups
equally
•
There are ~20,000
hemophiliacs in the
United States
•
~500,000 hemophiliacs
worldwide
Age Distribution of the US
Hemophilia Population
2 – 19
8584
48%
20 – 44
6418
36%
45 – 64
2274
13%
65+
524
3%
Percent
Age (y) Number Percent
50
45
40
35
30
25
20
15
10
5
0
2 to 19
Source:
20 to 44 45 to 64
Age
Centers for Disease Control and Prevention
Summary Report of UDC Activity (National)
Report Date – May 30, 2011
65+
Genetics of Hemophilia
• Genes for factors VIII and IX are located
on the X chromosome
• Females are carriers, males are affected
High rate of spontaneous mutations:
• Unaware female carriers
• New mutation in baby boy
• ~30% have no family history of hemophilia
Diagnosis of Hemophilia
+ Family History
• Identify carriers
• Pre-conception
counseling
• Cord blood testing of
male newborns
• Defer testing of
females until sx or
considering pregnancy
No Family History
• Bleeding with birth
trauma, circumcision,
immunizations
• Suspected child
abuse
• Joint bleeds and
hematomas start to
occur when learning
to walk
Clinical Features of Hemophilia
Severity of bleeding tendency depends on the factor level
•
•
Mild ( > 5% )
Moderate (1-5%)
Bleed only
after severe
injury, trauma,
or surgery
•
Bleed after
injury, surgery
•
May have
occasional
spontaneous
bleeding
May not be
diagnosed until
adulthood
Severe ( < 1 %)
•
Frequent
spontaneous
bleeding
•
Diagnosis
made in early
childhood
Clinical Features of Hemophilia
Joint bleed (hemarthrosis)
©2009
Rush University Medical Center
The Clinical Problem of Joint Bleeding
• Hemarthrosis, primarily involving the ankles, knees, and
elbows, is the most common complication of hemophilia
• 45% experience first joint bleed within the first year of life
• 90% have at least one joint bleed by 4 years of age
• 90% of those with severe hemophilia have chronic
degenerative changes involving at least 1 joint by age 25
• 40% report restricted physical activities due to arthropathy
Lafeber et al., Haemophilia 2008; 14(Suppl. 4):3-9
Valentino et al., Semin Hematol 2008; 45(Suppl. 1):S50-S57
Blood in joint
Recurrent
bleeding
Inflammation
Synovitis
Normal knee
Normal knee
47 year old with severe hemophilia B
MD
Clinical Features of Hemophilia
Joint bleed (hemarthrosis)
• 36 year old
• Severe hemophilia A
• Recurrent left knee bleeds
• Severe hemophilic
arthropathy
TS
Clinical Features of Hemophilia
Joint bleed (hemarthrosis)
• 36 year old
• Severe hemophilia A
• Recurrent left knee
bleeds
• Severe hemophilic
arthropathy
• Underwent total knee
arthroplasty
TS
Normal ankle
Severe hemophilia A, morbidly obese
RS
Normal elbow
•
•
36 year old, severe hemophilia A, followed by HTC
since birth
Target joint in childhood, no longer bleeds (or moves)
NJ
Clinical Features of Hemophilia
Deep muscle bleeds
• 52 year old with severe
hemophilia B
•
Spontaneous bleed
Clinical Features of Hemophilia
Deep muscle bleeds
• 20 year old with
mild hemophilia A
•
•
No trauma
Bled after light
jogging
Clinical Features of Hemophilia
Intracranial bleeds
•
6 year old with severe
hemophilia A
• Bumped head on school
playground equipment,
did not appear to have
any significant injury
• Parents noted change in
behavior later that
evening
Clinical Features of Hemophilia
Intracranial bleeds
• 52 year old with severe hemophilia A
• Tripped coming out of restaurant, hit
head on curb
•
•
Received factor VIII within 30
minutes
Presented to ER 2 days later
because he had blood on Q-tip
• No neurologic symptoms
• No headache
DD
Clinical Features of Hemophilia
Intracranial bleeds
•
58 year old with severe
hemophilia A, on regular
factor VIII prophylaxis
• Fell at grocery store,
didn’t think he had
significant injury, refused
transfer to ER
•
Found unresponsive at
home several hours later
• Died of massive subdural
hematoma
TD
Inhibitors in Congenital Hemophilia
Inhibitors in Congenital Hemophilia
• Some hemophilia patients “see” factor VIII
or factor IX as a foreign protein
• Infusion of factor concentrate to prevent
or treat bleeding triggers an immune
response
• Antibodies (“inhibitors”) directed against
factor VIII or factor IX neutralize the
procoagulant effect and render standard
treatment useless
Inhibitors in Congenital Hemophilia
• Development of inhibitors is currently the most
serious complication of factor replacement therapy
• Typically seen in those with severe hemophilia
• May occur in those with mild or moderate
hemophilia, usually after intense factor exposure
related to trauma or surgery
• No longer associated with increased mortality
However . . .
 Bleeding more difficult to control
 Devastating joint disease and disability
 Major clinical and economic challenges
Clinical Features of Hemophilia
Joint bleed (hemarthrosis)
• 26 yo with severe
hemophilia A and fVIII
inhibitor
• Recurrent traumatic
and spontaneous knee
bleeds
• Left side surgically
replaced
• Note severe muscular
atrophy
• Following right TKA he
became fully
ambulatory (again)
SK
22 yo male with severe hemophilia A and fVIII inhibitor
Rapid progression of arthropathy
March 2008
May 2010
June 2010
LF
Clinical Features of Hemophilia
Joint bleed (hemarthrosis)
•
28 yo severe hemophilia A with inhibitor and end stage
arthropathy, severe pain even when non-weight bearing
•
Excellent functional outcome with right total hip arthroplasty
SK
Clinical Features of Hemophilia
Soft tissue bleeding
• Inhibitor patient, presented to ER with left elbow bleed
• Failed attempts to place IV in right arm
LF
Clinical Features of Hemophilia
Soft tissue bleeding
•
56 year old with severe
hemophilia A and inhibitor
• Fell on icy sidewalk
• Did not treat aggressively
enough
• Required transfusion of 6
units RBCs
GR
Clinical Features of Hemophilia
Soft tissue bleeding
Severe hemophilia A with inhibitor,
neck bleed provoked by coughing
GR
Inhibitors in Congenital Hemophilia
Unique Challenges
• Factor replacement therapy not possible; treatment
options currently limited to bypassing agents
• Bypassing agents only have 75 – 90% efficacy in
stopping acute bleeds
• High degree of variability in response between
patients and bleeding episodes
• No established routine method of lab monitoring
• Risks of thrombosis with bypassing agents
• Extreme cost
• Very small number of patients
Treatment of Hemophilia
1. Historical perspectives
2. Clinical challenges
3. On-demand vs. prophylaxis
4. Treatment of inhibitor patients
5. New factor products
Treatment of Hemophilia
What happens if you don’t treat bleeds?
• Severe hemophilia, no access to factor concentrate
• Recurrent bleeds may lead to pseudotumors
Historical Overview
•
•
•
•
•
•
•
•
1900 – 1940s: Hemophilic life expectancy 25 – 30 years,
usually disabled by age 20
1960: Life expectancy increased to 40 years due to
transfusions of whole blood and plasma, but most
hemophiliacs still severely disabled and unemployed
1968: First commercially available factor VIII concentrate
1980: Life expectancy reaches 60 years
1982: First reported cases of AIDS in hemophilia patients.
More than 50% ultimately infected with HIV and more than
75% infected with viral hepatitis
1985: Virally inactivated factor concentrates introduced
1992: Recombinant factor VIII
1997: Recombinant factor IX
Historical Perspective
Diabetes vs. Hemophilia
First human
treated with
insulin (1922)
First human
pancreas
transplant (1966)
1900
Commercially
available insulin
pump (1978)
2010
Commercially
available factor
concentrate
(1968)
Viral inactivation of
factor concentrates
(1985)
Recombinant
factor concentrates
(1992, 1997)
Ongoing Clinical Challenges
• Managing orthopedic complications
in those with already existing
arthropathy
• Managing medical co-morbidities
(liver disease, HIV, cardiovascular
health, weight management)
• The aging hemophiliac
• Inhibitor patients
Factor Replacement Therapy
• Plasma derived and recombinant factor VIII
and factor IX concentrates are available
• 1st, 2nd, and 3rd generation recombinant
factor concentrates
• No documented case of viral transmission in
more than 25 years
• Goal is for every child
to learn self-infusion
Factor Replacement Therapy
On-Demand
• Treatment of bleeds when they occur
• Good at stopping bleeds after they start,
but does not prevent bleeds
• Does not prevent arthropathy
Prophylaxis
• Regular administration of factor to prevent
bleeds form occurring
• Goal is elimination of all bleeds
• Current standard of care
Summary of Prophylaxis Studies
(in adolescents and adults)
Median ABR
Study
On-demand
Prophylaxis
Zero bleeds
Collins 2010
41
0
53%
Fischer 2011
n/a
2.1 – 3.3
17 – 31%
Valentino 2012
43.9
1.0 – 2.0
27 – 41%
Manco-Johnson 2013
27.9
0
52%
Mahlangu 2014
33.6
1.6 – 3.6
17 – 45%
ABR = annualized bleed rate (how many bleeds per year)
Economic Burden of Hemophilia
• Proper treatment of hemophilia is expensive, but
the long term economic impact of poorly managed
hemophilia is even greater
• Factor concentrates account for the majority of the
cost of treating hemophilia
• Routine prophylaxis for severe hemophilia A, dosed
at 25-40 u/kg 3x/week:
Age
Weight
Annual factor consumption (units)
5y
20 kg
78,000 – 124,800
15 y
60 kg
234,000 – 374,400
Adult
80 kg
312,000 – 499,200
(Rough estimate of the cost of factor – $1 per unit)
Treatment of Inhibitor Patients
1. This is very complicated
2. This can be extremely expensive
3. This absolutely requires HTC expertise
Why?
• These patients are rare
• Treatment options have significant
limitations
Treatment of Inhibitor Patients
Immune Tolerance Therapy
• Costs approximately $ 1 million per patient
• Only 70% effective, BUT . . .
• The effects of a long-term inhibitor can be
devastating
Bypassing Agents
• 2 options: aPCC and rfVIIa
• Efficacy is incomplete (75 - 90%) and
unpredictable
• No standard laboratory monitoring exists
• Thrombosis is a real risk
Treatment of Hemophilia
Where are we headed?
New Factor Products
• Long-acting factor concentrates have been in
development for several years
• Extended half-life should result in similar or improved
protection from bleeds with fewer infusions
• Methods to prolong half-life:
PEG-ylation
Fc fusion
Albumin fusion
Degree of success
Old products
New products
Factor VIII
12 h
18-20 h
Factor IX
18-24 h
80-90 h
New Factor Products
Where are we now?
• The following all have long-acting factor VIII and/or
factor IX products in late stage clinical development:
Bayer, Baxter, CSL Behring,
Novo Nordisk
• First long-acting factor products recently approved,
both made by Biogen Idec:
Factor IX – Alprolix (March 2014)
Factor VIII – Eloctate (June 2014)
New Factor Concentrates
What we know . . .
• Highly effective for prophylaxis, acute bleeds, surgery
• Safety comparable to existing products
• Longer half-life allows for fewer infusions to maintain
protective factor levels
What is expected . . .
• More effective treatment and improved adherence for
a greater number of those with hemophilia
To be determined. . .
• How other long acting products will compare
• Role in immune tolerance therapy
• Economic implications (for all involved!)
What’s New for Inhibitor Patients?
Obizur (OBI-1)
• Recombinant porcine fVIII
• FDA approved October 2014 for use in
acquired hemophilia
• Hopefully will expand to use in
congenital inhibitor patients
Other products…
• Several drugs are in pre-clinical or
early phase development
• Cautiously optimistic
Center for Bleeding and
Clotting Disorders
Program History
•
•
•
•
•
•
Began in 1977 as one of 145 federally funded
Hemophilia Treatment Centers in the US
One of the first such programs in the upper Midwest
There are currently 135 HTCs in the US, with 3 in
Minnesota
Our program was broadened to include serving
thrombosis patients in 1996
Children’s Hospitals and Clinics of Minnesota
separated from our program in 2007, making us an
adult focused program
Name changed to the Center for Bleeding and
Clotting Disorders in 2008
Center for Bleeding and
Clotting Disorders
Hemophilia &
Other Bleeding
Disorders
Thrombosis
Women’s
Hemostasis
Program
Patient Centered Care Delivery
Comprehensive Care Model
Guiding Principles:
• The center exists to promote patient care, teaching, and research related to bleeding
and clotting disorders
• We serve as a learning laboratory for the latest in diagnosis and treatment
• Our care delivery is seamless and timely
• We provide an environment that promotes the development of the next generation of
care providers
Program Description
Who we are . . .
Interdisciplinary team: physician, advanced practice providers,
nurse clinicians, social worker, physical therapist, genetic counselor,
coagulation laboratory, pharmacy coordinator, program manager,
administrative support (~120 years of combined experience)
What we do . . .
1. Comprehensive clinic visits
2. Problem focused clinic visits
3. Pre-op planning and care coordination
4. Inpatient care coordination and discharge planning
5. Patient, provider, and community education
6. Patient counseling and advocacy
7. Research and clinical trials
8. Consultation for other health care providers (local, regional, national)
Care Planning
• Weekly care planning
meetings are held with
the interdisciplinary
team
• Discuss previous week’s
clinic visits, upcoming
week’s clinic visits
• Review current inpatient
admissions and any
recent ED / UC visits
• Review recent visits and plan for
upcoming visits to other specialty
clinics
• Update care plans, identify need for
additional referrals, community
resources
Patient Type
Number
Severe hemophilia A / B
8
Severe von Willebrand
disease
2
Moderate hemophilia A / B
2
Inhibitors
4
Note: These are the BCBS patients actively followed / managed by our HTC. There
may be other BCBS patients who have prescriptions filled by Fairview who are not
included on this list.
The 16 BCBS patients actively followed / managed by our HTC represent the broad range of
diagnoses, severity, and health care utilization typical of the bleeding disorders population as a whole
Diagnosis
Number
Hospital / ED
visits
(last 5 years)
Severe HA/HB
(age <26)
4
None
Severe vWD
(age <26)
Severe HA/HB
(age 26-55)
Moderate HA/HB
(age 26-55)
Severe HA with
past h/o inhibitor
2
None
4
• 2 with none
• 1 appendectomy
• 23 ED visits and
2 hospitalizations
all unrelated to
hemophilia
2
• 3 ED visits, all
unrelated to
hemophilia
• 1 ankle fusion
• 1 hernia repair
1
2 hospitalizations
(elbow surgery,
iliopsoas bleed)
Prophylaxis
Employment
Co-morbid
conditions
Functional
status
Yes
All in school or
completed and
working
HIV –
HCV –
No limitations;
3 competitive
athletes
Yes
Both in school
or completed
and working
HIV –
HCV –
No limitations
3 on prophy
1 on-demand
All working full
time
2 HIV / HCV –
1 HIV / HCV +
1 HCV +
(both HCV +
on study)
Some
limitations but
all able to
maintain full
employment
1 prophy
1 on-demand
1 getting
doctorate in
nursing
1 unemployed
1 HCV + (on
study)
1 morbid
obesity, DM,
HTN
1 with minor
limitations, 1
with major
limitations
prophylaxis
Works full
time, selfemployed
HIV –
HCV –
Works full
time, physical
job
Individuals with active inhibitors
Diagnosis
Mild HA with
inhibitor to
exogenous fVIII
Severe HA with
high titer inhibitor
Severe HA with
high titer inhibitor
Number
Hospital / ED
visits
(last 5 years)
Prophylaxis
Employment
Co-morbid
conditions
Functional
status
College
graduate,
working full
time
HIV –
HCV –
No limitations
1
None
On-demand
with PCC
1
4 hospitalizations
(iliopsoas bleed,
THA, arthropathy,
arthropathy / pain)
On-demand
with aPCC and
rfVIIa
Works full time
for BCBS
HIV –
HCV +
Major
limitations but
very active
after joint
replacements
1
Multiple
admissions for
bleeds /
uncontrolled pain:
2005-2010 = 26
2011-present = 4
(and 1 ED visit)
On-demand
with rfVIIa
Completed
college, on
disability, does
some web
design from
home
HIV –
HCV +
Chronic pain
Severe
limitations,
wheelchair
bound
Importance of the 340B Pharmacy Program
• HTCs offer unmatched expertise and comprehensive care for
•
•
•
•
hemophilia patients, along with the most competitive factor
pricing
Proceeds from the 340B program allow us to offer expert
nursing, physical therapy, genetic counseling, and social work
services, as well as 24/7 on-call hematologists and pharmacy
access
The 340B program funds tailored, personalized, and
coordinated medical care for our patients
The 340B program also supports activities and services such
as educational events and support groups through partnership
with our local hemophilia foundation
By providing customized and comprehensive care, we are able
to improve health outcomes while reducing treatment costs
How Can We Improve the
Management of Hemophilia?
1. The Easy Stuff
• Effective factor replacement therapy 
• Safe factor products 
• Access to factor 
How Can We Improve the
Management of Hemophilia?
2. Every patient followed by an HTC
• Approximately 30% of hemophilia patients in the
US receive care outside of an HTC
• HTCs offer multidisciplinary team approach to care
for these complex patients
• 40% reduction in mortality among those who
receive HTC care vs. those who do not
• We need to educate patients, community providers,
and managed care organizations about the benefits
of HTC-based care, and eliminate barriers
Soucie JM et al. Blood 2000; 96:437-42
How Can We Improve the
Management of Hemophilia?
3. Address cost issues
• Factor accounts for 45 - 93% of the total health
care cost of hemophilia, depending on severity
and treatment regimen
• 340B pricing is generally 20 - 40% lower than
non-340B pricing
• We must take action to eliminate barriers to
accessing HTC / 340B programs
Johnson KA, Zhou ZY. Hematology, Am Soc Hematol Educ Prog 2011; 437-42
Take Home Points
 Hemophilia is a rare condition, with a large
economic burden on our healthcare system
 We have made great progress in the
management of hemophilia, but we still
have work to do
 HTC-based care is key to the optimal
management of this complex condition
 We need more collaboration across the
boundaries of academia, industry, and
managed care
Questions and Discussion