4. How Bleeding Stops
• Vasoconstriction
• Platelet plug formation
• Clotting cascade activated to form fibrin clot
5. Turecek PL et al. Vox Sang 1999; 77 (suppl 1): 72-79.
PL = Phospholipids
FV
FVIIa FVII
TF
Extrinsic
Pathway
Blood
coagulation
Common Pathway
Leading to Clot
FII FIIa (Thrombin)
FVa
Fibrinogen Fibrin
CLOT
Fibrin Polymer
FXIIIa
FXIII
FX
Intrinsic
Pathway
FXII FXIIa
FXI FXIa
FIX FIXa
Ca++-PL
FVIII FVIIIa
FXa
Initiation
Amplification
on activated
platelets
Propagation
Clotting cascade
6. Types of Bleeding Disorders
• Hemophilia A (factor VIII deficiency)
• Hemophilia B (factor IX deficiency)
• von Willebrand Disease (vWD)
• Other
7. What is Hemophilia?
• Hemophilia is an inherited bleeding disorder
in which there is a deficiency or lack of factor
VIII (hemophilia A) or factor IX (hemophilia B)
• Etymology: Greek “haima” meaning blood,
“philia” meaning to love
8. Inheritance of Hemophilia
• Hemophilia A and B are X-linked recessive
disorders
• Hemophilia is typically expressed in males and
carried by females
• Severity level is consistent between family
members
• ~30 % of cases of hemophilia are new
mutations
12. 20th Century
• Harvard doctors Patek and Taylor isolate anti-
hemophilic globulin from plasma.
– Prove that problem not with vessel or platelet
structures.
• Argentinean doctor Pavlosky clinically
differentiated between types A and B.
– Blood from one could help another with a
different protein deficiency.
13. • Hemopilia A (deficiency of factor VIII):
1 - 2 of 10 000 male newborns in all ethnic
groups
– Severe: 50-60%
• Hemophilia B (deficiency of factor IX):
1 - 2 of 50 000 male newborns in all ethnic
groups
– Severe: 44%
Incidence of Hemophilia
14. Hemophilia A: Is it rare?
• An estimated 250,000 patients in the world
population.
• Estimated 72 000 in India (6/100 000 )
• 2500 new cases per year in India (1 in 10000
male births)
• Only about 15% receive some treatment.
• Estimation formula: (Population X 1.33)/20,000*
Rajesh Kashyap and VP Choudhry, Indian J Pediatr, 2001, 68(2, 151-157), Ghosh K. Indian J Med Res 130, 2009, pp 87-88
* WFH guidelines
15. Detection of Hemophilia
• Family history
• Symptoms
– Bruising
– Bleeding with circumcision
– Muscle, joint, or soft tissue bleeding
• Hemostatic challenges
– Surgery
– Dental work
– Trauma, accidents
• Laboratory testing
17. Severity of Hemophilia
Type VIII:C (%) IX: C (%) Bleed
Hemophilia A
Severe
Moderate
Mild
<1
1-5
6-40
100
100
100
+++
+
(+)
Hemophilia B
Severe
Moderate
Mild
100
100
100
<1
1-5
6-40
+++
+
(+)
White et al. Thromb Haemost. 2001;85:560.
18. Hemophilia A
Clinical Classification
White et al. Thromb Haemost. 2001;85:560.
Classification Severe Moderate
Cause of bleeding
episodes
Spontaneous
Minor
trauma
Major trauma
Surgery
Pattern of bleeding
episodes
24–48
per year
4–6
per year
Uncommon
FVIII activity1
(% of normal)
<1% 1%–≤5% >5%–<40%
Mild
19. Clinical manifestations of hemophilia
Hemophilia can affect any organ in the body
Joints (70% – 80%)
Muscles and soft tissues (10% - 20%)
Mouth and gums (10%)
Others ( 5%)
20. Early symptoms
From childhood
• Blue patches and bruises on the skin.
• Gum bleeds
• Frenulum bleeds.
• Cuts and Wounds which Bleed a long time.
21. Early symptoms
• Un bearable pain in Muscles and joints
• Swelling.
• With out Injury
22. Types of Bleeds….
• Joint bleeding - hemarthrosis
• Muscle hemorrhage
• Soft tissue
• Life threatening-bleeding
• Other
….and their management
23. Management
• RICE Therapy
– R – Rest
– I – Ice Fomentation
– C – compression (Crepe – Bandages)
– E – Elevation & Exercise
• A.H.F Replacement
– Route of Administration – IV
– Dosage
• Factor VIII 1 unit/ kg will raise 2% (14-15 hours half life)
• Factor IX 1 unit / kg will raise 1% (18-24 hours half life)
– Routine bleeds 20 – 40% level
– Surgery and Emergencies 100% level
• PHYSIOTHERAPY
• PSYCHOLOGICAL COUNSELLING
30. Life-Threatening Bleeding
• Head / Intracranial
– Nausea, vomiting, headache, drowsiness,
confusion, visual changes, loss of
consciousness
– Factor replacement required: 80 -100%
• Neck and Throat
– Pain, swelling, difficulty
breathing/swallowing
– Factor replacement required: 80 -100%
• Abdominal / GI
– Pain, tenderness, swelling, blood in the
stools
– Factor replacement required: 40 -60%
• Trauma & Surgery
– Factor replacement required: 50 -100%
31. Other Bleeding Episodes
• Mouth bleeding
• Nose bleeding
• Ecchymoses
• Scrapes and/or minor cuts
Factor replacement required:
1. Minor bleeds (gums ) 20-40%
2. Dental extractions 60-80%
3. Retroperitoneal bleed 80-100%
4. Hematuria 30-40
32. Type of bleed/
surgery
Required max.
activity of FVIII
Frequency of infusions
Bleeds Milder 20-40%
Every 12-24 hrs
1-3 days
Moderate 30-60%
Every 12-24 hrs
More than 3 days
Severe or life
threatening
60-100%
Every 8-24 hrs
until resolved
Surgery
Minor surgery
incl. dental
extraction
60-80%
1 Infusion plus
antifibrinolytic agent
Major surgery 80-100% Every 8-24 hrs
Treatment : Factor replacement
33. Hemophilia - Surgery
Protocol
* Factor dose IU kg ID Mean Dose / Surg
Factor VIII Factor IX ( IU / kg)
Pre-Op 80-100 50-80
1-3D 80-100 50-80
4-6D 60-80 40-50
7-10 30-60 30-40
10+D 20-40 20-30 600-1000
Low Dose**
Pre-Op 80-100 50-80
1-3D 20-40 15-30
4+D 15-30 10-20 300
*Richard. K Hemophilia 1995 **Srivastava A. Hemophilia 1998
34. Hemophilia Management Goals
Pathogen Safety
Optimal Therapy
Cure
Product Supply
Uninterrupted
supply
rFVIII, PFM
Evidence-based
medicine
Ease of use
Quality of Life
35. Product Supply
World has moved over to rFVIII therapies
Plasma derived and recombinant Factor VIII actual global consumption and projections
As per estimates consumption of plasma derived factor would not grow because of supply
issues and recombinant factors to provide growth in consumption
36. Product Supply
Just a thought:
– With 1.2 Billion population in India
– With a prevalence of 1-2 per 10,000 males
– With approximately 25% of PWH treated
– With a bare minimum of 10,000 IU/patient/year
– Will plasma derived factor therapy be able to
meet the demand of 15000 patient X 10,000
IU/year = 150,000,000 IU?
– And it is expected to only go up as per the trends
worldwide……
37. 1975
1980
1985
1988
1990
1992
1995
1999
Time
HBV ELISA testing of blood donations became mandatory in the US
First experimental HBV inactivation method described
HIV screening of plasma donations began and all new lots of FVIII and
FIX are subjected to some virus inactivation procedure
(50% of hemophilia population already infected)
First mab purified Factor VIII concentrate with S/D
viral inactivation
First HCV ELISA licensed (nearly all patients
treated with products before 1985 were
infected)
First recombinant Factor VIII concentrate
and double virus inactivated pdFVIII
Baxter Immuno as first
company started PCR
screening of plasma pools
on HIV, HBV and HCV
HCV PCR
mandatory in EU
The development of hemophilia therapies
was driven by safety needs
HIV
HCV
HAV
Prions
(vCJD)
Treatment of choice: cryoprecipitate
First plasma-derived factor concentrates
First
plasma/albumin
free rFVIII conc.
2003
38. HIV / AIDS
1980/81 First infections
reported
1984 Virus isolated and
characterized
1985 HIV ELISA for donors and
donations and virus
inactivation for final products
implemented
Consequence of 5 years delay:
50% of hemophilia population
infected and died
HCV / hepatitis C
1978 First infections reported
(hepatitis non A non B)
1989 first infection reported
(Hepatitis C)
1989 Virus isolated and
characterized
1990 HCV ELISA for donors
and donations implemented
Consequence of 12 years delay:
Nearly 100% of hemophilia
population infected
Prions / vCJD
1980-83 transmission of BSE
on humans
1986 prions identified as
causing agent
2004 first cases of possible
transmission of prions via
blood products
2007 still no prion detection
test for donors available
2007 still no validated prion
removal study done for any
rFVIII product
Consequence of 27 years delay:
???
The impact of new viruses on hemophilia community
39. Evolution of F VIII / IX therapy
Source Pathogen
removal
TTI Risk Storage Inhibitor
risk
FFP Single unit
Plasma
None ↑↑↑↑ - 200 C ++++
Cryo Single unit
Plasma
None ↑↑↑↑ -200 C ++++
Low –
intermediate
purity factors
Pooled Plasma Heat ↑↑ Refrigerator +++
High purity
factors
Pooled Plasma Heat + SD ↑ Refrigerator ++
Ultra High purity
factors
Pooled Plasma Heat + SD +
Monoclonal
purification
↑ Refrigerator +
rDNA
(recombinant)
factors
CHO
Cell culture
Not
required
No Refrigerator/
6 M at RT
+
40. Evolution of F VIII / IX therapy
FFP Cryo Low
Purity F
Conc
High Purity
F Conc
r DNA
F Conc
Available
Factors
1 IU/ 1mL 80-100 IU/
Bag
250 IU/
10-15 mL
250-500
IU/10-15 mL
250-1000
IU/10 mL
Volume e.g.,
1000 IU
1000 mL 10-12 Bags
(250 mL)
40-50 mL 20-40 mL 10 mL
Unwanted
Proteins
+++++ +++++ + ± --
Protein load ++++ ++ ± Nil Nil
Transfusion
reactions
++ + Nil Nil Nil
41. The Answer
• Ultra High Purity Plasma Derived Factor VIII
– Three Viral Inactivation Processes
• Solvent Detergent
• Monoclonal Purification
• Electro Chromotography
• Recombinant (rDNA) Factor VIII
42. Purity of the products
• Purity refers to the percentage of the desired
ingredient (e.g., FVIII) in concentrates, relative
to other ingredients present. Based on purity
the products are classified as:
– Low purity is less than 10 IU per mg of protein.
– Intermediate purity is 10–100 IU per mg of
protein.
– High purity is 100–1,000 IU per mg of protein.
– Very/Ultra high purity is more than 1,000 IU per
mg of protein.
Guidelines for the Management of Hemophilia, World Federation of Hemophilia, 2005, Page 30-32
43. Concerns with Cryoprecipitate and Fresh
Frozen Plasma
• Though the Cryopreciptitate, generally has an activity approximating to 100 IU/bag,
the coagulation factor content of individual pack of Cryoprecipitate is variable and
is usually not controlled. 1,4
• Cryoprecipitate is not subjected to viral inactivation procedures (such as heat or
solvent/detergent treatment) and this inevitably translates into a risk of
transmission of viral pathogens, which is not insignificant with repeated exposure.4
• Much of what has been said about cryoprecipitate applies to the use of fresh
frozen plasma (FFP)4
• The risks of FFP include disease transmission, anaphylactoid reactions,
alloimmunization, and excessive intravascular volume. The potential viral infectivity
of FFP probably is similar to that of whole blood and red blood cells. 2,3
1. de Grauchy’s Clinical Hematoloty in Medical Practice, Chapter 15, Coagulation Disorders, Blackwell Publishing, 5th Edition, Page 430
2. Fresh Frozen Plasma: Indications and Risks, NIH Consensus Statements - NCBI Bookshelf: http://www.ncbi.nlm.nih.gov/books/NBK15119/
accessed, 07/01/2011
3. Guide to the preparation, use and quality assurance of blood components: recommendation no. R (95) 15. Council of Europe. pp. 157–. ISBN
9789287161376. http://books.google.com/books?id=huNgp2KJ-wQC&pg=PA157. Accessed 07/01/2011
4. Guidelines for the Management of Hemophilia, World Federation of Hemophilia, 2005, Page 30-32
44. The Answer: rDNA FVIII
– “Recombinant FVIII is the treatment of choice”
UK Haemophilia Centre Doctors’ Org. (Haemophilia 2003;9:1-23)
UKHCDO has moved to recombinant factor therapy since 2003
– “…recombinant factor VIII products are the recommended treatment of choice for
patients with hemophilia A”
MASAC (Document #190, March 2009)
US has moved to recombinant factor therapy since 1998 (MASAC Document #169,)
– “PUPs must be treated with recombinant FVIII and HCV and HIV negative patients with
the aim of minimizing the residual risk of viral infections, these patients should be
treated with recombinant FVIII”
Santagostino et al. (Haemophilia 2000;6:1-10)
Based on these recommendation Italy has moved to recombinant factor therapy since 2000
– “rVIII concentrate… is recommended for the management of hemophilia A”
Assoc. of Hemophilia Clinic Directors of Canada (http://www.ahcdc.ca)
Canada has moved to recombinant factor therapy since 1999
World has moved over to recombinant therapies
45. Optimal Therapy
• On-demand therapy
– Whenever there is a bleed
– Until the bleed stops
• Prophylaxis therapy
– Regular prophylaxis
• 25–40 IU/kg every other day (minimum 3x per week)1
– Low Dose prophylaxis
• 15 – 25 IU/kg 2 – 3 times per week2
1. Nilsson IM et al. J Intern Med. 1992;232:25-32
2. Fischer et al. Haemophilia 2002;8:745-52
46. On Demand
0 6 12 18 24 30 36 42 48 Time (hours)
0
20
80
60
40
100
F
V
III
L
e
v
el
(%
)
single infusion
47. Prophylaxis
0 6 12 18 24 30 36 42 48 Time (hours)
0
20
80
60
40
100
F
V
III
L
e
v
e
l
(
%
)
Multiple infusions
Goal of
prophylaxis:
keep FVIII levels
>1% all the time
48. Image source:
www.emedicine.com
Goals in Prophylaxis
1. To prevent hemarthroses and their structural and functional
consequences
2. To prevent other life-threatening and major hemorrhages
3. Prophylaxis: Long-Term Goals
• Prevention of life-threatening bleeds
• Prevention of chronic disease (target joint)
• Improvement in individual/family quality of life
• Reduction in long-term societal costs through prevention of disability,
improved outcome, maximization of human potential
Fischer et al. Haemophilia. 2003;9(suppl 1):75-82.
49.
50. Prophylactic Treatment in Hemophilia:
Revised Definitions
Berntorp E et al. Haemophilia. 2003;9(suppl 1):1-4.
Short-term treatment to prevent bleeding
Short-term prophylaxis
Long-term continuous* treatment not
fulfilling the criteria for primary prophylaxis
Secondary prophylaxis
Revised Definition
Model
Long-term continuous* treatment started
prior to the onset of joint damage,†
irrespective of age
Primary prophylaxis determined by
first bleed
†Presumptively defined as having had no more than one joint bleed.
Long-term continuous* treatment started
before 2 years of age and prior to clinically
evident joint bleeding
Primary prophylaxis determined
by age
*With intent of treating 52 weeks/yr up to adulthood, minimum treatment of 46 weeks/yr.
51. 62%
53%
40%
31%
19% 17%
41%
28%
18%
80%
65%
57%
31%
41%
46%
40% 60%
58%
17%
31%
37%
3%
7%
8%
5% 5%
6%
21%
19%
19%
29%
36%
35%
9%
15%
23%
2% 1%
1%
8%
2% 6%
13%
5% 10% 8%
9%
12%
7% 4%
< 3 years 3 to <13 years 13 to <18 years 18+ years
*
Significantly
higher/lower
than 2006
*
*
*
2003 (292) 2006 (249) 2008 (249) 2003 2006 (771) 2008 2003 (499) 2006 (473) 2008 (512) 2003 2006 2008
On-demand FVIII Primary prophylaxis
Continuous secondary prophylaxis Intermittent secondary prophylaxis
No bleeds/ no treatment Not stated
(1020) (1005) (1686) (1424) (1903)
Khair et al., Acta Haematol 2008; 119: 115-123.
2003 – 2008
Prophylaxis Use Increasing in All Age
Groups
52. Prophylaxis in the Literature
• Retrospective Studies
Study Outcome Prophylaxis On-Demand
Panicker et al. 2002 Major bleeds 1.9 15.5
Yee et al. 2002 Median annual joint bleeds 0.5 3.5
Szucs et al. 1998 Joint bleeds/year (mean) 3.1 8.8
Liesner et al. 1996 Bleeding episodes/year
(median)
1.5 14.7
Aledort et al. 1994 Joint bleeds/year (mean) 5.7 16.5
53. Prophylaxis in the Literature
• Prospective Studies
Study Outcome Prophylaxis On-Demand
Gringeri 2003
randomized trial
Bleeds/patient/month
Joint bleeds/pt/month
0.52
0.20
1.02
0.52
Manco-Johnson et al. 2007
prospective, controlled study
Joint bleeds/year (mean) 0.63 4.89
Feldman et al. 2006
interim results: prophylaxis only
Joint bleeds/year (mean) 1.2 N/A
Aronstam et al. 1976
9 hemophilia subjects
once-weekly prophylaxis
Overall bleeding frequency Reduced overall bleeding 15%
54. Outcomes of Prophylaxis
Regular/Low dose
• Prevention of life threatening bleeds
• Prevention of chronic disease (target joint)
• Improvement in individual/family quality of life
• Reduction in long-term societal costs through
prevention of disability, improved outcome,
maximization of human potential
55. Guidelines for the management of Hemophilia, World Federation of
Hemophilia (2005)
“Prophylaxis is the administration of clotting factors at regular intervals to
prevent bleeding and must be the goal of all hemophilia care programs until
a cure is available“.
“…primary prophylaxis, as currently practiced, is an expensive treatment and
can be accomplished only if significant resources are allocated to hemophilia
care, as in developed countries, and for a few patients in developing
countries who can afford it. However, prophylaxis has been shown to
decrease joint bleeding with preservation of joint function and improve
quality of life. Therefore, it is cost-effective in the long term because it
eliminates the high cost associated with subsequent management of
damaged joints. “
Prophylaxis recommended by WFH
http://www.wfh.org/2/docs/Publications/Diagnosis_and_Treatment/Gudelines_Mng_Hemophilia.pdf
56. Inhibitors
• Definition
– IgG antibody to infused factor VIII or IX concentrates,
which occurs after exposure to the extraneous VIII or
IX protein.
• Prevalence
– 20-30% of patients with severe hemophilia A
– 1-4% of patients with severe hemophilia B
• Inhibitors to FVIII develop in about 30% of patients with
severe hemophilia
– in 1-3% in PTPs
– In up to 50% in PUPs
• Inhibitors are measured in Bethesda units (BU)
Scandella D. Human anti-factor VIII antibodies: epitope localization and inhibitory function. Vox Sang.1996;70(suppl 1):9-14.
Scandella DH. Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients.Semin Thromb Hemost. 2000;26:137-142.
57. Inhibitor risk factors – confirmed or
under discussion
Predisposing genetic factors
FVIII mutation type
Family history of inhibitors
Severity of hemophilia
Race/ethnicity
Polymorphism in immune response
genes (IL10 134 positive; TNF-alpha A2 positive
CTLA4-318 T negative)
Predisposing environmental factors
Age at 1st exposure
Immunological challenges (HIV, HCV,
infections, vaccination)
Treatment regimen (prophylaxis/on
demand)
Intensity of treatment (FVIII doses and
intervals)
Invasive clinical procedures (surgery,
CI)
Socioeconomic aspects (family income)
Abnormal FVIII molecules
(immunogenicity)
Infant diet (breast feeding)
EMEA/CHMP/BPWP/123835/2006. Report on expert meeting on FVIII products and inhibitor development. Feb 28-Mar 2, 2006
58. Correlated FVIII inhibitor risk
Correlated inhibitor risk
For patients with 1-150 ED cumulative risk is 20-30%
– 50% for patients with 1-20 ED (high inhibitor risk)
– 45% for patients with 21-50 ED (high inhibitor risk)
– 4% for patients with 51-150 ED (moderate inhibitor risk)
– 0.3-3% for PTPs with >150 ED (low-risk patients)
EMEA/CHMP/BPWP/123835/2006. Report on expert meeting on FVIII products and inhibitor development. Feb 28-Mar 2, 2006
59. 1. Giangrande PLF. Haemophilia 2003; 9(Suppl.1):50-56. 2. Gouw SC et al. Blood 2007; 109:4648-4654.
Protective role of prophylaxis
– General consensus is that prophylaxis does not increase
inhibitor risk in patients1
– Prophylaxis acts to protect patients against inhibitor
development2
• 60% lower risk; RR = 0.4 (95% CI, 0.2-0.8)
60. Kurnik K et al. Haemophilia 2010; 16:256-262.
Early prophylaxis - avoidance danger signals
• Inhibitor development was significantly reduced in study
group compared to control group (P = 0.0003; OR: 0.048; 95%
CI: 0.001-0.372)
– Control group: 14/30 (47%) developed an inhibitor
– Study group: 1/26 (3.8%) developed an inhibitor
61. Psychosocial Issues
• Guilt
• Challenge of hospitalizations
• Financial / insurance challenges
• Feeling different / unable to do certain activities
• Counseling needs
