Haemophilia A & B

Haemophilia A & B
Theresa Nwagha MD, MPH, FMCPath, MSc
Professor of Haematology
University of Nigeria,
Deputy MAC (Laboratory & Radiology)
Head, coagulation unit, University of Nigeria Teaching Hospital
Director, Southeast Haemophilia treatment center UNTH
VP Medical HFN
Ituku Ozalla, Enugu, Nigeria

Email: theresa.nwagha@unn.edu.ng
Outline
Prophylaxis
Innovation in
Overview of • Low dose prophylaxis
haemophilia
haemophilia
treatment

Inhibitors in
haemophilia A and Diagnosis of
B a practical haemophilia
management
Haemophilia is a
• Hereditary Bleeding Disorder in which a gene that makes a clotting factor is
partially or completely defective

• Clotting factors known by Roman numerals… numbered ..I - XIII

• Types of haemophilia
• Haemophilia A – FVIII (8) deficiency 1:10 000 population
• Haemophilia B – F IX (9) deficiency 1:60 000 population
Degrees of Severity of Hemophilia A or B
• Normal factor VIII or IX level = 50-150%
• Mild hemophilia >5% - <40%
▪ bleeds because of trauma
• Moderate hemophilia 1-5%
▪ bleeds because of trauma
▪ needs treatment for invasive procedures, can have
spontaneous bleeds

• Severe hemophilia <1%

▪ Spontaneous bleeds into muscles and joints
 Family history
Symptoms
• Newborn & Infants
• 30% bleed with circumcision
• 1-2% intracranial hemorrhage
• Toddlers buttock bruises, then leg bruises with
Diagnosis of walking
• Children
Hemophilia • Musculoskeletal
• CNS
• Oral

Laboratory testing
• Screening tests : (CBC - PT - aPTT)
• Factor assay
 • Joint bleeding – hemarthrosis
Clinical Presentation • Muscle hemorrhage
• Soft tissue bleeding
• Life threatening bleeding
Joint Bleeding
• Most common bleeding
manifestation (80%)
• Most common joint
• knees 60%

• elbows
• ankles
26%

1% 13%

Knees Elbows Ankles Shoulders

Manifestations of Synovitis
• Acutebleed
• Bubbling
• Tingling
• Heat

• Repeated subacute bleeds

• Swelling
• Pain
• Heat

• Synovitis hemophilia joint

• Swollen
• Muscle wasting
• Morning Stiffness
• Chronic pain
• Affected joint held in flexed
position
 • Second common
Muscle Bleeds bleeding manifestation
• Bleeding leg, thigh, calf
and forearm, create
pressure on nerves
• Early sign: reluctance to
move, swelling and pain
as bleeding progresses
• Affected extremity held
in flexed position
• Usually no visible
cutaneous bruising
Mouth Bleeding
• Teething
• usually no problem with bleeding
• Tooth extraction
• Mouth bleeds
• need treatment with Cyklokapron
and or Factor Concentrates
 Head / Intracranial

• Nausea, vomiting, headache,

drowsiness, confusion, loss of
consciousness

Neck and Throat

• Pain, swelling,
• difficulty breathing/swallowing

Abdominal / GI

• Pain, tenderness, swelling,

melena or blood in the stools

Iliopsoas Muscle

Life-Threatening Bleeding • Back pain, abdominal pain,

• thigh tingling/numbness,
• decreased hip range of motion
Life threatening haemorrhage
Compression syndrome Pseudotumour
 Aims of therapy

Prevent bleeding

Prevent arthropathy
Management
of Hemophilia: Maintain full musculoskeletal function

Maintain ‘good’ quality of life

-Full integration in society

-No days lost from school or work

Factor Replacement Products and Medications
Replacement of missing clotting protein

• Fresh Frozen Plasma (1 unit factor/ml)

• Cryopreciptate (factor 2-3 units/ml of cryo)
• SD cryopreciptate (factor 7-12 units/ml of SD cryo)
• Factor VIII & Factor IX concentrates
• (factor 25-100 units/ml)
• Anti-hemophilic factor (Recombinant)
• Long Lasting CFCs

DDAVP / Stimate/Minirin

Antifibrinolytic Agents
• Tranexamic acid (cyclokapron)
Factor VIII & IX Concentrate
• Intravenous infusion
▪ IV push
▪ Continuous infusion (surgical prophylaxis)
• Dose varies depending on type of bleeding
▪ Factor VIII Ranges from 10-50 units/kg. body weight
▪ Factor IX Ranges from 20-100 units/kg. body weight
• Half-life
▪ Factor VIII 8-12 hours
▪ Factor IX 12-24 hours
• Each unit infused raises
▪ plasma factor VIII level by 2 %
▪ plasma factor IX level by 1%
-Pharmaceutical grade SD/F cryoprecipitate

-Possibility of FI, FVIII, VWF & FXIII dose labeling

DDAVP (Desmopressin acetate)

• Synthetic vasopressin
• Method of action
• Release of stores from endothelial cells
raising factor VIII (in mild and moderate
cases) and vWD plasma levels
• Administration
• Intravenous
• Subcutaneously
• Nasally (Stimate)
• Side effects
• Facial flushing
• headache
Management of Severe Hemophilia
Factor Replacement

Episodic Prophylactic
 Usually in severe hemophilia

Scheduled infusions of factor concentrates

to prevent spontaneous bleeding
Prophylaxis Frequency: 1 to 3 times weekly to keep
trough factor VIII or IX levels at 2-3%

Use of Implantable venous access device

(IVAD) necessary in some patients
 Treating hemarthrosis
with first aid
• REST: The arm or leg should rest on a pillows or be
put in a sling or bandage.
• ICE: Wrap an ice pack in a damp towel and put it
over the bleed. This may help decrease
• pain and limit bleeding.
• COMPRESSION: Joints can be wrapped in a tensor
bandage or elastic Stocking
• ELEVATION: Raise the area that is bleeding above the
level of the heart. This may slow blood loss by
lowering pressure in the area.
Management of pain
 Prophylactic replacement therapy,
Treatment in Surgery before and after surgery

The objective is to prevent bleeding

Should be continued until complete

wound healing

Should be supervised by consultant

hematologist

Screening for clotting factor

inhibitors & use of anti-fibrinolytics
FVIII & FIX Inhibitors

• Patients with severe hemophilia may develop inhibitors against FVIII

concentrates
• Incidence of inhibitors:
• HA ≅ 30%
• HB ≅ 3%
• Even patients with moderate and mild hemophilia may develop inhibitors
Measuring an Inhibitor
• Measured in Bethesda Unit: BU
▪ low titer <5 BU
▪ high titer >5BU

• One Bethesda unit is the amount of

inhibitor that will neutralize 50% of factor
activity when 1 ml of hemophilic plasma is mixed with 1 ml of normal
plasma and incubated for two hours at 37° C

Inhibitor •••••••••••••• Factor concentrate

Each BU of inhibitor
consumes a 50% level
 Treatment of acute bleeds
• Low responding: Higher doses of factor
• High responding: by-pass agents
Treatment of • APCCs (activated prothrombin complex
concentrates)
Inhibitors • Recombinant FVIIa
Long term treatment to eradicate inhibitor
• Immune tolerance
• High and frequent doses of factor reduces
the inhibitor
• ~80%
• Immunosuppressive
• IV Ig
• www.wfh.org
Innovations in the treatment of
Haemophilia
« Classical » treatment of hemophilia
Injection of missing
Factor VIII or IX

Replacement or substitutive
therapy by regular intravenous
infusions of exogenous clotting
Factor VIII or Factor IX
to correct clotting
factor deficiency in order to
treat or prevent bleeding
episodes
Residual clottingFactor Phenotype – clinical symptoms
Levelmeasured in blood Annual bleeding rate (ABR)
(%) without replacement

50–150%
0
Normal Range

25–49% Rare

6–24% Mild 0–1

1–5% Moderate 1–5

Severe Haemophilia
The difference in clinical phenotype between severe and moderate
haemophilia provides the rationale for prophylaxis

• Patients with moderate hemophilia (FVIII

50–150% /FIX 2–5%) experience much less
frequent haemarthrosis than patients with
severe disease (<1%)
25–49%
• The rationale for prophylaxis is to maintain
6–24% FVIII / FIX >1% in order to prevent
spontaneous bleeding episodes,
especially haemarthrosis
1–5%

How can this be achieved ? 6

“Classical” treatment of severe hemophilia:
prevention / ideally abolition of bleeding episodes by
regular self-infusions – prophylaxis

FVIII correction by regular

infusions
FVIII

Hemophilia Tx Goals 1%
• Treat/avoid/abolish
bleeding Time
• complications
• Avoid joint disease
Avoid
• side effects
• Inhibitors
• Infections
Achieve the life the patient
chooses
WFH. About Bleeding Disorders: http://www.wfh.org /en/page.aspx?pid=642 (Accessed
October 2018).
 RAPIDCLEARANCEOF FVIII FROMTHEBLOOD
AFTERIV ADMINISTRATION

Circulating concentration of FVIII or FIX

Peak 30-40 %

Trough 0-1 %
Frequency

DAY 1 DAY2 or 3
C URRENT TREATMENT OF HAEMOPHILIA
Intravenous Infusions

Monday - Thursday
Monday – Wed - Friday
Monday – Wed – Friday
- Sunday

104 infusions/year (10-50 IU/kg)

176 infusions/year (10-50 IU/kg)

• The treatment regimen (amount of FVIII per infusion– frequency of infusions) should be

individualized

• Take into account many variables

Progress inhemophilia therapy

Haematologica 2020 Volume 105(3):545-

M. Makris and C.Hermans

“Over the yearsa number of developments led to majorimprovements in haemophilia care; these
include the introduction of clotting factor concentrates, home treatment as well as primary
prophylaxis. The result of these developments is that in countries that can afford the cost of
replacement therapy and primary prophylaxis, the quality of life of persons with haemophilia is high
andlife expectancy is close to normal”

CH
 New and future treatment options
for hemophilia

Non-factor
Standard Extended therapies
Bispecific Gene
half-life half-life that
antibody therapy*
FVIII FVIII rebalance
hemostasis

Replacement therapy Non-replacement therapy

*Gene therapy for haemophilia is currently under development and is not yet approved by the EMA, FDA or other regulatory agen cies. Gene therapy for haemophilia has not been proven
safe or effective.
TFPI, tissue factor pathway inhibitor.
Laffan M. Br J Haematol 2016;172:23–31.
 Innovations
1. Extended half-life FVIII-FIX concentrates by produced biotechnology

2. Bispecific antibody mimicking the action of FVIII

3. Rebalancing agents of the degree inhibition of natural

(reduction the coagulation process

4. Subcutaneous treatments

5. Gene therapy
 Modifications of FVIII and FIX
to increase half-life

FVIII FIX
Factor + Fc Fragment + +
Factor + Albumin 0 +
Factor+ Pegylation + +

These improve PK of FVIII and FIX modifications by different

mechanisms
Fc: Fragment crystallizable region; PK: Pharmacokinetic.
Lambert T, et al. Ther Adv Hematol 2018;9(9):295–308.
 EXTENSION OF HALF - LIFE IS MUCH
HIGHER FOR FIX (4-5 X), ALLOWING
MUCH L E S S INFUSIONS (1X/WEEK, 1/10
DAYS, 1X/14 DAYS)
New and future treatment options for haemophilia

Non-factor
Standard half- Extendedhalf-
Bispecific therapies that
life life Gene therapy
antibody rebalance
FVIII FVIII
haemostasis

Replacemen therap Non- therap

t y replacement y

TFPI, tissue factor pathway

inhibitor
EMICIZUMAB IS A BISPECIFIC ANTIBODY MIMICKING E ACTION
THOF FVIIIA IN THE
COAGULATIONPROCESS

FVIIIa FXa
A2

A1
FIXa A3
FX
C1 C2

Phospholipid membrane

Bispecific antibody (=ACE910)

FXa

FIXa FX

Phospholipid membrane

Kitazawa et al. Nat Med 2012;18:1570

 Emicizumab mode of action
*
Emicizumab is a therapeutic antibody This allows the
designed to bridge FIXa coagulation
and FX, cascade to continue
replacing the function of without FVIIIa1,2
FVIIIa1
Emicizumab

FIXa FX

Cell membrane

*Emicizumab is an investigational product andis notapproved or licensed for the treatment of patients withhaemophilia A or any other 1. Kitazawa T, et al. Nat Med 2012;18:1570–4;
medication 2. Sampei Z, et al. PLoS One 2013;8:e57479
FVIIIa, activated factor VIII; FIXa, activated factor IX; FX, factor X
 Emicizumab versus FVIII
A ParadigmShift – from peaks and troughs to steady state hemostatic correction

80
FVIII 70
Emicizumab
60
concentration

50

concentration
40

emicizumab
Mean(SD)

(µg/mL)
30
FVIII

20

1% 10

0
Time 0 4 8 12 16 20 24 28 32 36 40
Time
(weeks)
Fluctuating F8 correction with regular infusions HAVEN 1:Emicizumab trough
concentrations

Louvain Médical - 2015 - Édition spéciale l’hÉmophilie : 150 ans d’histoire et 15 ans de prise en charge aux
cliniques Oldenburg J, et al. N Engl J Med 2017;377:809–
Universitaires saint-luc 818
 Emicizumab
• Bispecific antibody mimicking the action of FVIIIa in the
coagulation process
• Subcutaneous administration
• Prolonged effect (1–4 week(s))
• Efficient in patients with and without INH against FVIII
• High efficacy in clinical studies, especially in patients with INH
•
Several cases of thrombosis (1 death) in patients co-treated
with emicizumab + FEIBA (combined used prohibited)
•
Co-treatment required (FVIII or bypassing agent)
FEIBA: factor eight inhibitor bypass activity; INH: Inhibitor.
Strengths of Emicizumab compared to FVIII

Strengths Practical implications

Subcutaneous administration No needfor venous access

FVIII function but no FVIII structure No inhibition by antibodies against endogenous

FVIII Can be used in INH patients
Long half-life Infrequent administrations Once a week to once
every 4 weeks
Nopeaks and troughs Steady protection after loading phase
Nosignificant inter- andintra-individual PK Homogenous andpredictable treatment regimen
and variations use of ressources
Reduced immunogenicity Only few cases of ADAreported

Personal views – C Hermans

HEMLIBRA : potential uses and
indications
• Salvage therapy in PTPS with a persistent INH who failed ITI or who never treated with ITI
• Hemlibra is used to bypass
• FVIII
• rVIIa if bleeds
FVIII if low-titre INH
• Bypassing agent given during ITI
• In placeof FEIBA or rVIIagiven on-demand or prophylactically during ITI to prevent bleeding
• episodes
Should facilitate ITI andallowdifferent ITI regimens (low-dose regimen)
• Bypassing agent to post-pone ITI
• In children who developed an INH and ITI is not started, Hemlibra could be
• given rVIIa in case of bleed, surgery
• Initial treatment in PUPs
• Haemostatic treatment in PUPs not treated with FVIII
• FVIII might still be needed in case of bleed, trauma / concentration of exposure could increase risk of
INH
• Prophylaxis in PTPS patients without INH
• Subsitution of prophylaxis with FVIII (adults or children)
• Initiation of prophylaxis in patients treated on demand with FVIII
• FVIII would still be needed in case of surgery, breakthrough
bleed,…
Patients on Emicizumab
Novel therapies
of haemophilia
 Inhibiting antithrombin or TFPI:
New strategies to treat hemophiliaA/B
FXII
FXI
FX - TFPI
FIX
Antithrombi
n
- FVIII
FV
FII
Fibrin

AT and TPFI inhibit the coagulation cascade

Blocking AT or TFPI promotes the formation of thrombin
AT: Antithrombin; TFPI: Tissue factor pathway inhibitor .
Laffan M. Br J Haematol 2016;172:23–31.