HAEMOPHILIA

Dr Y S Vishnu Vardhan,
PG
 HISTORY

Best Known of the Bleeding Disorders

First Coined by Schonlein in 1820's

Originally termed Hemorraphilia – love for

hemorrhages

Often called the disease of the kings.

Queen Victoria - carrier
 WHAT'S HEMOPHILIA?
Inherited hemorrhagic disorder caused by deficiency of
Factor VIII or Factor IX

X linked recessive inheritance hence affect males exclusively

Incidence in Hemophilia A 1 in 5000 live male births

Incidence in Hemophilia B 1 in 30,000 live male births

Females who carry single mutated gene are generally asymptomatic

 TYPES

Disease Factor Deficiency Inheritance

Hemophilia A VIII X linked Recessive

Hemophilia B IX X linked Recessive

Hemophilia C XI Autosomal Recessive

Parahemophilia V Autosomal Recessive

 Factor
Activity

Defined as the activity present in 1ml of fresh plasma

from normal donors

Expressed in terms of Units

Concentration of all coagulation factors in native plasma is

thus 1 U/ml or 100 U/dl or 100% activty

Levels in blood bank plasma – 80 U/dl

because of dilution with anticoagulants

Normal Factor VIII & IX activity in patients older than infants

range between 50% - 150%
 Severity of Hemophilia –
Defined by the measured level of clotting factor activity

Distribution Clotting Factor Activity

Severe Hemophilia 50% <1%

Moderate Hemophilia 10% 1 - 5%

Mild Hemophilia 30% - 40% 5-40%

In Hemophilia
 Causes

Mutations in F8 gene Mutations in F9 gene

Deficiency of Deficiency of
Factor VIII Factor IX

Hemophilia A Hemophilia B
 PATHOPHYSIOLOGY

The Classic representation of hemostasis shows

factor VII
together with tissue factor activating factor X

Recent studies suggest that

the primary physiologic pathway
of factor X activation by tissue factor and
factor VII is through the activation of Factor IX

Activated Factor IX complexes with Factor VIIIa,

calcium and phosphatidyl serine on
physilogic membranes to generate
Factor Xa
 PATHOPHYSIOLOGY

Thus, physiologically, the tissue factor pathway of

Factor X activation requires Factor VII and IX
and the absence of either protein - severely impairs the ability
to generate thrombin and Fibrin

The division of hemostasis into

distinct Intrinsic and Extrinsic pathways is
no longer accurate

Because thrombin generation in hemophilia is

markedly delayed,
Hemorrhage occurs after minimal or unknown trauma.
Also the clot formed is friable,
Making rebleeding common
 GENETICS

X- linked recessive inheritance

30% of hemophilias present as spontaneous mutations

Gene for Factor VIII or IX located on fragile and

mutation prone region of
X Chromosome

Most common Mutation of Factor VIII gene – Inv of Intron 22

(acc. For 45% of severe hemophilia)

Moderate and mild severity hemophilia A are mainly the result of missense mutations
INHERITANCE
 Hemophilia in Females

Lyonization of
Factor VIII or IX alleles in carriers

Hemizygosity of X Chr
in females with Turner syndrome

Female progeny of hemophilia carriers &

affected hemophiliac male
Clinical Manifestations
 DIFFERENCE B/N PLATELET & COAGULATION DISORDERS

PLATELET DISORDERS COAGULATION FACTOR

DISORDERS

SITE OF BLEEDING SKIN, MUCOUS JOINTS, MUSCLES

MEMBRANE, SOFT
TISSUE

PHYSICAL FINDING PETECHIAE, HEMATOMA,

ECHHYMOSES, HEMARTHROSIS

BLEEDING AFTER CUTS YES NO

& SCRATCHES

BLEEDING AFTER IMMEDIATE, USUALLY DELAYED, 1- 2 DAYS,

SURGERY & TRAUMA MILD SEVERE
 MUSCULOSKELETAL BLEEDING

Hallmark -
Deep bleeding into joints & muscles

Begins when the child reaches the toddler age

In toddlers – Ankle is the Most common site

Later,
knees & elbow become the most common

Hematomas
into muscles of distal part of limbs
leads to external compr of Ar.s, Veins, nerves
– evolve into – compartment syndrome
 Target Joint

A particular joint that has experienced

repeated bleeds

At least 4 times within a At least 3 bleeds within a

6 month period (USA) 3 months period (Canada)
 ILIOPSOAS BLEEDING

Hidden,
Lumbosacral Plexopathy

Vague abdominal and upper thigh

Discomfort and a characteristic gait
(hip is flexed and internally rotated)

Diagnosis confirmed by
USG or CT scan
 Life threatening Hemorrhages

Intracranial hemorrhage, bleeding into and around

The oropharyngeal spaces and exsanguinating
hemorrhage

Retroperitoneal hemorrhages can accumulate

large quantities of blood with formation of masses
with calcification & inflammatory tissue reaction
(Pseudomotor Syndrome)

Trt: Achieving a Factor level of 100 U/dL,

Maintenance of adequate hemostatic levels
(>50-60 U/dL)
For minimum 14 days
and a more prolonged period of prophylactic therapy
for additional 1-2 wk
 MISCELLANEOUS HEMORRHAGES

Hematuria – May arise spontaneously

Rx: Bed rest, increased fluid intake,
if not controlled in 1-2 days,
then Factor VIII replacement.

Traumatic Bleeding –
Bleeding may persist as
slow continuous ooze for days to months
or it may be massive and life threatening.
Delayed bleeding is common
 HEMOPHILIC ARTHROPATHY

Three phases

1. Following first episodes of hemarthrosis,

absorption of blood is incomplete,
the retained blood produces
chronic inflammation.
Iron is deposited into the synovium
and chondrocytes of the articular cartilage.
 2. Chronic proliferative synovitis

Characterised by presence of
Chronic synovitis,
Pain,
Fibrosis &
Progressive joint disease
 3. Chronic Hemophilic Arthropathy -
Characterised by
progressive and erosive destruction of joint cartilage,
narrowing of joint space, subchondral cyst formation
and eventual collapse and ankylosis of the joint

MRI is superior to
standard x ray
for assessment of
early arthropathy
 INVESTIGATIONS

BASELINE SPECIAL

Complete hemogram Factor VIII assay

Coagulation time Synovial fluid
PT & aPTT Carrier state genetic
X ray of joint testing
 BASELINE INVESTIGATIONS

1. Complete Hemogram 2. X ray of joint

a. Hb count – decreased Knee joint

b. TLC – normal Elbow joint
c. DLC – normal Ankle joint
d. Platelet count - normal
 Coagulation time – Prolonged
PT – Usually normal
Activated PTT – Prolonged 2-3 times

In mild to moderate F IX deficiency, it may be normal.

Thus if Hemophilia is suspected,
a F IX assay should be performed even if PTT is normal

APTT correction studies

With control plasma – confirms Factor deficiency

and not circulating inhibitors as the cause of APTT prolongation.

With Factor VIII deficient plasma (from known patients) –

suggests Factor IX deficiency

With Factor IX deficient plasma (from known patients) –

suggests Factor VIII deficiency
 INTERPRETATION OF SCREENING TEST

POSSIBLE PT APTT BT PLATELET

DIAGNOSIS COUNT

NORMAL NORMAL NORMAL NORMAL NORMAL

HEMOPHILIA NORMAL PROLONGED NORMAL NORMAL

A OR B

vWD NORMAL NORMAL OR NORMAL OR NORMAL OR

PROLONGED PROLONGED REDUCED

PLATELET NORMAL NORMAL NORMAL OR NORMAL OR

DEFECT PROLONGED REDUCED
 SPECIAL INVESTIGATIONS

Factor VIII assays

Types
To determine diagnosis
Monitor treatment
Performing pre and post infusion clotting factor levels.
Factor levels prior to surgery.
To test quality of cryoprecipitate

Detection of Inhibitors

When to suspect –
PTT not correcting to normal when mixed with normal plasma
and incubated for 2hrs
One Bethesda unit is defined as
the amount of antibody that will inactivate
50% of the normal Factor VII or Factor IX
in 2hr when the residual F VIII or IX level is between 25 – 75 U/dL
Carrier and Genetic Testing

1. Patient and Family H/o

2. Coagulation – based assays

3. DNA testing
 Carrier state and Genetic Testing

A woman is a definite carrier if

(1) her father has hemophilia

(2) she has one son with hemophilia and
a 1st degree male relative with hemophilia
(3) she has two sons with hemophilia

A possible carrier if

(1) she has one or more maternal relatives with hemophilia

(2) she has one son with hemophilia & no other affected relative
 Carrier status –
solely based on Factor levels – NOT reliable,
significant overlap

In Severe Hemophilia A,
perform Intron 22 gene Inversion analysis and,
If negative, then proceed with full F VIII gene sequencing

In mild to moderate Hemophilia A,

full sequencing of the F VIII gene is recommended

In Hemophilia B, perform full sequencing of F IX gene

 Prenatal Diagnosis

Offered,
when termination of pregnancy would be considered
if affected fetus identified

Obtain chorionic villi samples in 10th-11th gestational wk

and perform genotype testing

Test duration 1wk/2wk

 TREATMENT

FUNDAMENTALS
Replacement therapy –
Replacement of F VIII or IX to hemostatically adequate plasma levels
for prevention or treatment of acute bleeding is the basis of the management

Knowledge of Half-life, volume of distribution, patient's inhibitor status

and appropriate replacement is necessary

Factor Hemostatic level (U/dL) Half life (hr)

Factor VIII 25 - 30 24

Factor IX 15 - 30 12
 CALCULATION OF DOSE

ONE unit is defined as amount of Factor VIII (1000ng/ml)

Or Factor IX (5 microg/ml) in 1 ml of normal plasma

Factor VIII dose (IU) =

Target Factor VIII levels – Factor VIII baseline levels x body wieght (kg) x 0.5 unit/kg

Factor IX dose (IU) =

Target Factor IX levels – Factor IX baseline levels x bowdy wt x 1 unit/kg

Types of Factor replacement

-Treatment on demand
-Prohylaxis
 Treatment on Demand

For mild to moderate hemorrhages, achieve

Factor VIII levels of 30 – 40 U/dL or
Factor IX levels of 30 U/dL

For life threatening hemorrhages,

immediately correct Factor level to 100 – 150 U/dL and
Maintain the level between 80 – 100 U/dL for 5 – 7 days
Followed by vigorous maintenance
 Type of Hemophilia A Hemophilia B
Hemorrhage

Hemarthrosis 40 IU/kg on day 1: then 20 60 – 80 IU/kg on day 1;

IU/kg on days 2, 3, 5 until then 40 IU/kg on days 2, 4.
joint function is normal or Consider additional
back to baseline. Consider treatment every other day
additional treatment every for 7-10 days.
other day for 7 – 10 days.
Muscle or significant 20 IU/kg; may need every 40 IU/kg; may need
subcutaneous other day treatment until treatment every 2-3 days
resolved until resolved
hematoma

Mouth, deciduous 20 IU/kg; antifibrinolytic 40 IU/kg; antifibrinolytic

tooth or tooth therapy; remove loose therapy; remove loose
deciduous tooth deciduous tooth
extraction
Types of Hemophilia A Hemophilia B
Hemorrhage

Epistaxis Apply pressure for 15 – 20 min; Apply pressure for 15-20 min;
pack with petroleum gauze; pack with petroleum gauze;
give antifibrinolytic therapy; 20 give antifibrinolytic therapy; 30
IU/kg if this treatment fails IU/kg if this treatment fails

Major surgery, life 50-75 IU/kg then initiate 120 IU/kg then 50-60 IU/kg
threatening hemorrhage continuous infusion of 2-4 every 12-24 hr to maintain F IX
IU/kg/hr to maintain F VIII > > 40 IU/dL for 5-7 days and
100 IU/dl for 24hr, then give 2- then >30 IU/dL for 7 days
3 IU/kg/hr continuously for 5-7
days to maintain the level at
>50 IU/dl and an additional 5-7
days at a level of >30 IU/dL

Hematuria Bed rest; 1.5 times Bed rest; 1.5 times

maintenance fluids; if not maintenance fluid; if not
controlled in 1-2 days, 20 IU/kg controlled in 1-2 days, 40 IU/kg
F VIII F IX

Prophylaxis 20-40 IU/kg F VIII every other 30-50 IU/kg F IX every 2-3
day to achieve a trough level of days to achieve a trough level
> 1% of >1%
 Prohylactic Factor VIII therapy - Evidence

Manco – Johnson et al in their perspective,

randomised, controlled clinical trial showed
83% reduction in risk for joint damage (evaluated by MRI)
In the prophylaxis group as compared to on-demand group.
In 14% cases of MRI changes, there was no evidence of
Any previous clinical hemarthrosis.
 Prophylactic Factor VIII therapy - Evidence

Fischer et al in their long term outcome study over 22yr

Showed that prophylaxis improves clinical outcome
without significantly increasing treatment cost
 Prohylactic Factor VIII therapy

Administered by subcutaneous access port

of a central venous line

Dose of 20 – 40 U/kg of Factor VIII

administered every other day or thrice weekly.
Dose and rate adjusted to ensure that nadir
before next infusion is > 1 U/dL

Prevents spontaneous bleeding;

Hemorrhages caused by trauma
may still require additional replacement
 Prophylactic Factor VIII therapy

Primary prophylaxis –

therapy initiated in young patients who have Hemophilia

before joint damage

High cost of primary prophylaxis –

hindrance for developing countries.
However,
the long term cost savings may be greater with Primary prophylaxis
as joints are preserved,
lives are more productive,
expensive surgical interventions are avoided
 When to start Primary Prophylaxis?

No consensus!!
Start before 3 years of age,
Usually around 14- 18 months,
At that time the child begins to walk

Secondary prophylaxis

In patients with target joints who are having recurrent events.

Coagulation factors are administered as in
Primary prophylaxis but over limited period of 3 – 6 months
 Tailored prophyaxis

Basic Idea

Tailored to patient's bleeding pattern,

joint involvement and individual needs

Once weekly infusion of Factor concentrate has been studied,

Thus reducing the need for CVC placement

The indwelling venous access devices are the cause of

most of the complications associated with prophylaxis
(Systemic infections, catheter related thrombosis, etc.)

The long term effect on joint outcome using this approach

warrants further scrutiny
 TREATMENT PRODUCTS

PLASMA

a. Difference b/w Fresh frozen and frozen

b. 1 Unit FFP contains about 160 – 250ml

Plasma with activity of ~ 80%

c. Rate & total dose limited by the risk of

Acute or chronic circulatory overload

d. How to use
 CRYOPRECIPITATE

Prepared by slowly thawing Fresh Frozen Plasma at 2-4 'C

Then harvesting the precipitate by centrifugation

Cryo prepared from 200 ml of FFP contains

80 – 100 Units of Factor VIII, ~250 mg of fibrinogen
And useful amounts of Factor XIII and vWF
Per 10 – 15ml of precipitate

Use thawed cryo within 4hr

Can be stored at -18'C for ~1 yr
 FACTOR CONCENTRATES

Two sources/types
1. Human plasma
2. Genetically engineered - Recombinant

Dose
1 unit/kg of F VIII – rise by 2%
Slow I.V push

Example
50 units/kg will increase F VIII level by ~100%

Factor IX
1 unit/kg of Factor IX – rise by 0.7 - 1%
 ADJUVANT TREATMENT OPTIONS

Desmopressin (DDAVP)

Increases plasma F VIII and vWF levels

In mild & moderate Hemophilia A who have shown

Response in therapeutic trial

I.V dose –0.3 mcg/kg in 25-50 mL NS over 20-30 min

For OPD Mx – Intra Nasal

Dose 150 mcg (1 puff) for <50 kg
300 mcg (1puff both nostrils) >50kg

Tachyphylaxis
S/E – Headache, Flushing, Hyponatremia

Peak effect
I.V – 30 -60 min
Intra nasal 60 – 90 min
 ANTIFIBRINOLYTIC THERAPY

Inhibits fibrinolysis of thrombus by Plasmin

Uses – Mucosal, oral, nasal and menstrual bleeds

Tranexamic acid
Oral – 25mg/kg/dose every 6-8hr
I.V – 10mg/kg/dose every 6-8hr
EACA
Oral – 100-200 mg/kg f/by
50-100mg/kg/dose 6th hrly
I.V – 100mg/kg/dose 6th hrly
 TREATMENT COMPLICATIONS

Inhibitors
Alloantibodies directed against F VIII or F IX
Clinical hallmark – Failure to respond to routine replacement therapy

Incidence – Hemophilia A ~30% ; Hemophilia B ~3%

Risk factors: Severity of Hemophilia, age, race, Fam H/o of inhibitors, genes
Low titer (<5 BU); usually transient
High titer (>5 BU); persistent

Screen once every 3-12 months

or every 10-20 exposure days and prior to surgery
or when clinical response to adequate treatment is sub-optimal
 MANAGEMENT OF INHIBITORS

Low titer-

high dose factor replacement

High titer -

Continuous F VIII infusion

Bypassing agents – Recombinant F VIIa or Activated PT complex conc

Immune tolerance Induction (ITI)
Rituximab – limited data
 ITI -Immune Tolerance Induction

Immune system desensitization technique intended to eradicate inhibitor

No general agreement on optimal dose and frequency of dosage for ITI.

A trial is ongoing to compare 50 IU/kg 3 times a week to 200 IU/kg daily

Success of ITI – 90% over 6-12 months for allo F VIII Ab inhibitors

Consolidate inhibitor eradication with prolonged prohylaxis

 TRANSFUSION TRANSMITTED INFECTIONS

Viral attenuated plasma derived factor conc. are free from lipid enveloped
Viruses – HIV, Hep B, Hep C,

Non – lipid enveloped viruses – Hep A, Parvo virus B19 are not
susceptible to these techniques, outbreaks reported

Recombinant factor concentrates contain albumin as stabilizer;

Theoretical risk of transmission of prions

Immunization to Hep B and Hep A is important for all persons with Hemophilia
(can be given as S/c but not I.M)

Family members handling treatment products should also be vaccinated

 NEWER THERAPEUTICS FOR
PATIENTS WITH INHIBITORS

FEIBA – Factor Eight Inhibitor Bypassing Agents

OBIZUR – Recombinant B-domain truncated porcine F VIII

Alb-rFVII a-FP- Alb-rFVIIa-FP

TheraPEG-Factor VIIa
 NEWER THERAPEUTIC TARGETS FOR
HEMOPHILIA

Longer acting F VIII & IX – Once weekly Targeting TFPI

1. rF IX-Albumin – Half life is 5-6 times 1. Concizumab – anti TFPI antibody

2. Eftrenonacogalfa – rF IX:Fc (of IgG1) 2. NASP- Non Anticoagulant
3. Nonacog beta pegol: Sulfated Polysacharides – Fucoidanare
GlycoPEGylatedF IX 3. PEGylated version of BAX499
4. PEGylated rF VIII 4. PEGylated anti-human TFPI – JBT2329
5. GlycoPEGylation of rF VIII
6. TheraPEG

Factor 8 Mimetics RNAi Therapeutic Targeting Antithrombin

1. Emicizumab – binds to F IX and X ALN-AT3 (Alnylam) – reduces production of

Helps in progression of Antithrombin-3 proteins –
coagulation cascade preventing the inhibition of FXa
leading to thrombin generation
 NEWER TREATMENT MODALITIES

Activated PT complx concentrates Polyethylene glycol conjugation

(pegylation)
Have increased amounts of
Activated F VIIa, F X & Throbin Increases size,
decreases renal excretion,
APCC are effective even in patients Extends half life
With high titer inhibitors
Polysialic acid polymers
Risk of thrombosis
Forms a watery cloud around the
Target molecule

Biodegradable
 RECOMBINANT FACTOR VIIa

Marketed & manufactured by

NovoNordisk, Denmark
As Novoseven

Bypasses
the F VIII dependent step in FX activation
Primary use – Hemophilia with Inhibitors

Other uses – Controls bleeding in traumatic coagulopathies, thrombocytopathies, liver

disease, liver transplantation, spontaneous intracerebral hemorrhage
And patients undergoing cardiac surgery
Dose – 90 mcg/kg 2 hrly till hemostasis
Cost – Rs 35,000/1.2mg vial; Rs 75,000/2.4 mg vial
 GENE THERAPY

Involves transfer of genes that express a

particular product into human cells
Adeno associated Viral vectors – delivery of
F IX gene to hematocytes

Hemophilia – Ideal candidate

Caused by mutations in single identified gene

Wide range of safety if there's an overshoot

To date, the promise of gene therapy

and a cure for the hemophilia patient have not been realized
Continues to be a topic of intensive investigation
 COMPREHENSIVE CARE

Comprehensive team: Hemophilia specialist, nurse coordinator, social worker,

Psychologist, physiotherapist, Orthopedic surgeon, PCP,
Financial counsellor and Infectious disease specialist

Provided primarily through comprehensive Hemophilia Treatment centers

 HOME THERAPY

Allows immediate access to treatment

Teach –

recognizing a bleed, dosage calculation,

preparation, storage, and administration of
clotting factor, aseptic techniques, record
Keeping, proper storage and disposal of
Needles and handling of blood spills
 PREVENTION OF BLEEDING

Avoid trauma by adjusting their lifestyle

Contact sports should be avoided,

but swimming and cycling with appropriate gear sgould be encouraged

Avoid use of drugs that affect platelet function – NSAID”s

I.M injections, difficult phlebotomy and arterial punctures must be avoided

Regular exercise should be encouraged to promote strong muscles,

Protect joints, and improve fitness
 HEMOPHILIA ID BADGE

A person with Hemophilia should carry

information about his health,
including the type of Hemophilia,
treatment needed and allergies

An International medical card is available

free
Through the World Federation of Hemophilia.
 THANK YOU

References:

1. Harrison's Internal Medicine 19th edition

2. William's Hematology 9th edition