HEMOPHILIA

Presented by;
Saveena Nadab
Ayesha Kalsoom
Maria Tahir
Komal Nawaz
Munaza Rana
Hemophilia

 Hemophilia is a bleeding disorder that results from a congenital

deficiency in a plasma protein.
Etiology
EPIDEMIOLOGY
• Hemophilia occurs in 400000 male worldwide.
• About 1/3 of the patients having hemophilia have negative family
history.

Hemophilia A Hemophilia B

 1 in 5000 male births  1 in 30000 male births

 Constitutes 80-85 % of total  Constitutes 15-20%of all
cases patients.
Pattern of inheritance

 Both hemophilia A and B are recessive X˗linked disease.

 The disease primarily affects males while females are carriers.
 Female carriers have one normal allele and therefore they don’t
usually have a bleeding tendency.
 there is a ̎skipped generation ̎ mode of inheritance.
Pathophysiology

 The pathophysiology of hemophilia is based on the factor VIII or

factor IX deficiency resulting in inadequate thrombin generation
and an impaired intrinsic pathway coagulation cascade.
 Over 2 million point mutations, deletions, inversions have been
identified as result of single gene mutation.
Factor VIII gene

 In 1984, researcher isolated and cloned the human factor VIII gene.
It is a large gene, consisting of 186 kilobases (kb). More than 2000
mutations in factor VIII gene, including point mutations, deletions,
and inversions, have been identified.
 In 1993, researchers identified an inversion in the factor VIII gene at
intron 22 that accounts for almost 50% of severe hemophilia A gene
abnormalities.
Factor IX gene

 The factor IX gene, cloned and sequenced in 1982, consists of only

34 kb and is significantly smaller than the factor VIII gene.
 Direct gene mutation analysis in hemophilia B is simpler because of
smaller gene size, and to date more than 1,000 different mutations
have been reported.
Hemophilia B Leyden

 It is a rare variant in which factor IX levels are initially low

but rise at puberty.
 The mechanism of this disorder is controversial.
 mechanisms for age related gene regulations have been
recently discovered and implicated in factor IX Leyden.
Clinical presentation
Signs and symptoms
Signs and symptoms
Ecchymoses
Hemarthroses (especially knee, ankle, and
elbow)
Joint pain
Joint swelling and erythema
Decreased range of motion
Muscle hemorrhage
Swelling at the site of muscle bleeding
Pain with motion of affected muscle
Sign of nerve compression
Significant anemia
Oral bleeding with dental extractions or
trauma
Hematuria
Intracranial hemorrhage (spontaneous or
following trauma)
Excessive bleeding with surgery
 Activity of clotting factors is measured in units/ml
 Normal plasma range is 0.5 -1.5 units/ml.
severe moderate mild
Plasma level <0.01 units/ml 0.01-0.05 >0.05 units/ml
units/ml
Age at <1 year 1-2 years 2 years to adult
diagnosis
neonatal symptoms
Oral Usually common common
hemorrhage
ICH occasionally uncommonly rarely
CNS spontaneous Moderate risk uncommon
hemorrhage
post-surgical High risk Moderate risk uncommon
hemorrhage
Muscle/joint spontaneous Minor trauma Minor to
hemorrhage moderate
trauma
Diagnosis

 The diagnosis should be considered in any male if there is

i. Unusual bleeding
ii. Family history
 Male siblings should be screened.
 Sisters should also be screened for carrier testing.
 In severe hemophilia A, Factor VIII gene inversion is tested.
 Gene can also be sequenced to determine exact mutation.

 In hemophilia B, similar techniques are applied but direct DNA mutational

analysis is also done.

 Prenatal diagnosis, can also be done by chorionic villus sampling in

gestational weeks 9 to 14 or by amniocentesis after 15 to 17 weeks of
gestation.
Laboratory testing

 activated partial thromboplastin time (aPTT)

 factor VIII or factor IX level
 prothrombin time (PT)
 platelet count
 bleeding time
Treatment of Hemophilia
Treatment of Hemophilia A

 Hemophilia A
 Recombinant factor VIII
 Plasma derived factor VIII

PdFVIII RFVIII
Made from human blood Made from animal cells
Low cost Premium pricing
Contamination fears fatal diseases Seen as less immunogenic
 Recombinant factor VIII
Currently first, second and third generation rF VIII are available commercially.
First generation rFVIII products contain human albumin as stabilizing protein
e.g. Recombinate®
Second generation rFVIII products add sugar instead of human albumin, but
human albumin is used in the culture process e.g. Kogenate®
Third generation rFVIII do not contain human protein either in the culture or in
the stabilization process.
 Plasma derived factor VIII
Factor VIII concentrates can be classified according to their level of purity.
Low-purity products
e.g. Cryoprecipitate
Intermediate-purity products
Factor VIII activity of 5 units/mg of proteins
High-purity products
Factor VIII activity of 2000 units/mg
Ultrahigh-purity products
Specific activity of 3000 units/mg
 Factor VIII concentrate replacement
Dosing of factor VIII concentrate depends on:
• Half life of the infused factor
• Patient’s body weight
• Location of bleed
• Severity of bleed
Serious or life threatening bleeding
Require peak factor level of greater than 0.75 to 1 units/ml
Less severe bleeding
Require peak plasma level of 0.3 to 0.5 units/ml
 Each ml of factor VIII concentrate infused per kg of actual body weight
results in 2% rise in plasma factor vIII levels.
 Initial dose of factor VIII is calculated

Factor VIII (units) = (desired level – baseline level) × 0.5 × (weight in kg)

 The half life of factor VIII is 8 to 15 hours.

 It is generally necessary to administer 50% of the initial dose about every 12
hours to sustain the desired level.
 Factor VIII can be administered as continuous infusion in prolong treatment
e.g. perioperative period or for serious bleeding episodes
 Infusion rate ranges from 2 to 4 units/kg/hr are given in fixed dose
continuous infusion protocols with the aim of maintaining the stedy state
level of 60 to 100%
Other Pharmacologic Therapy

 Desmopression
 For minor bleeding episodes in patients with mild hemophilia A
 Most effective in patients with higher baseline factor VIII level (0.1-0.15
units/ml)
Dose :
 0.3 mcg/kg diluted in 50 ml of normal saline and infused IV over 15 to 30
minutes
 Patients with mild to moderate hemophilia A should undergo a
Desmopression trial.
 Adequate response is twofold rise in factor VIII to minimul level of 0.3
units/ml within 60 minutes
 Intranasally
Less than 30kg weight
One spray (150 mcg) in one nostril.
More than 50 kg
Two spray (300 mcg) one in each nostril.
Adverse effects:
 Facial flushing
 Less frequnently reported: headache, increase heart rate, decrease BP
 Severe hyponatremia
 Antifibrinolytic therapy
 Beneficial for treatment of oral bleeding because of high concentration
of fibrinolytic enzymes in saliva.
 Also helpful as adjuvant therapy in GI bleeding, epistaxis and menorrhagia.
Examples
 Aminocaproic acid
100 mg/kg (maximum 6g) every 6 hr can be given orally or IV
 Tranexamic acid
25 mg/kg ( maximum 1.5g ) orally 6 to 8 hr.
Treatment of Hemophilia B
Factor IX Concentrates
Brand name Product type Viral inactivation or exclusion method Other contents

1)Alphanine SD Plasma Solvent detergent, nanofiltration Heparin

2)Alprolix Fc Fusion Nanofiltration, chromatography
Recombinant Sucrose,
3)rixubis mannitol,IgG
Chromatography, nonofiltration, solvent
Recombinant detergent
Sucrose, mannitol

aPCC

Feiba VH Immuno plasma Vapor heat IIa,VIIa, VIIIa,IXa, Xa

PCC

Bebulin VH plasma Vapor heat Heparin, II, IX, X

 Recombinant Factor IX
 Not Available until 1998.
 Produced in chinese hamster ovary cells.
 Has excellent viral safety.
 Clinical trial have shown it to be safe and efficacious.
 Recovery is 30% less so dose must be higher.
 Recovery and survival studies should be performed.
 Considered to be the treatment of choice.
 Plasma-Derived Factor IX Product
 Available in US since 1990s.
 Derived through biochemical purification and monoclonal
immunoaffinity techniques.
 Other viral inactivation measures also used.
 Excellent efficacy.
 Risk of thromboembolic complication is low.
 Treatment with factor IX concentrates.
 Prothrombin complex concentrates (PCCs).
 Use associates with thrombotic complications.
 Risk of complication is higher in various patients.
 Concomitant use of PCCs and antifibrinolytics should be
avoided.
 Factor IX Concentrate Replacement

 It is relatively small protein.

 Also present in the extravascular compartment.
 Vol. of distribution is twice.
 Rise in plasma level at each unit per kg.
 Range is 0.67%-1.28%
 Equation to calculate initial dose:

 Baseline level is omitted if negligible in case of factor VIII dose

calculation..
For recombinant factor IX:
• Pediatric dosing:

• 𝑅𝑒𝑐𝑜𝑚𝑏𝑖𝑛𝑎𝑛𝑡 𝑓𝑎𝑐𝑡𝑜𝑟 𝐼𝑋(𝑢𝑛𝑖𝑡𝑠) = (𝑑𝑒𝑠𝑖𝑟𝑒𝑑 𝑙𝑒𝑣𝑒𝑙 −

 Recovery study to determine optimal dosing is
recommended.
 Half life is 24 hours.
 Guidelines for Factor Replacement therapy for
Hemorrhage in Hemophilia A and B
Site of Desired hemostatic factor Comments
hemorrhage level(% of normal)

Joint 50%-70%, 2-3 days Rest/immobilization/physical therapy rehabilitation

following bleed; several doses necessary to prevent or
treat target joint

muscle 30%-50% for most sites Risk of significant blood loss with a thigh or iliopsoas
70%-100% for thigh,iliopsoas ,or bleed: bed rest for iliopsoas bleeding
nerve compression

Oral mucosa 30%-50% May try antifibrinolytic or topical thrombin prior to factor
replacement for minor bleeding. Higher factor levels are
needed for tongue swelling or risk of airway compromise.
GI Initially 100% ,then 40%-60% Endoscopy is highly recommended; antifibrinolytic
therapy may be useful. Continue until healing occurs

Hematuria 30%-50% if no trauma
70%-100% if traumatic
If no pain or trauma, consider bed rest and fluids for 24
hours;factor should be given if hematuria
persist;evaluate if hematuria persist; if trauma to
abdomen or back, perform imaging and give
aggressive factor replacement

CNS Initially 100%, then 50%-100%for Lumber puncture requires prophylactic factor
10-20 days coverage

Trauma or Initially 100%, then 50%-100% Perioperative and postoperative management plan
Surgery until wound healing complete must be in place preoperatively, medicine for inhibitors
is crucial prior to elective surgery
Prophylaxis versus on demand therapy

 Administer the necessary factor only.

 development of severe physical disability.
 Avoid the damage by preventing bleeding episodes.
 Prophylactic replacement therapy: maintain minimum factor
level at or above 0.01 units/mL(1%) with regular infusion of factor
products.
 Considered standard of care.
 Also recommended by WHO and World federation of Hemophilia.
 Rarely used in patients with mild hemophilia.
 Converts severe hemophilia into a
milder form of disease.
 Rarely experience spontaneous
hemarthroses,
 and have lower risk of arthropathy.

 Pediatric clinical trial study:

 Efficacy in pediatric patients.
 Demonstration about prophylaxis prevention by first pediatric randomized
clinical trials.
 Efficacy in preventing bleeds and arthropathy by eurpeon clinical trial.
Dosing for prophylactic regimen:
• Varies considerably and no one proven to be superior.
• hemophilia A:
• Common regimen is 20 to 40 units/kg of factor VIII every other day or 3 times
a week.
• Fc fusion product can be given at a dose of 25 to 65 units/kg at 3 to 5 day
intervals.
• Hemophilia B:
• dosage ranges between 25 and 60 units/kg of factor IX given twice weekly.
• Fc fusion product either 50 units/kg once weekly or 100 units/kg every 10
days.
• A more feasible approach
• Controversy regarding the initiation of prophylaxis.
• Primary prophylaxis is started at young age prior to onset of joint bleeding.
• Secondary prophylaxis begin after significant joint bleeding has occurred.
• Recommendation of primary prophylaxis according to Medical Scientific
advisory Council of the National Hemophilia Federation of the US.
• Administration guidelines.
 Challenges to prophylaxis therapy

High cost of this approach

Inconvenience to families and difficulty with adherence.

Potential complications of CNS include surgical risks, infection, and

catheter-related deep vein thrombosis.

Routine use of primary prophylaxis may overtreat some patients with

severe hemophilia who do not have severe clinical phenotype.
 Neutralizing antibodies to factor VIII and IX ,known as inhibitors
develop in a subset of patient with hemophilia.
 The development of inhibitors is the serious complication of factor
replacement therapy.
 Inhibitors is a polyclonal high affinity immunoglobulin G directed
against factor VIII and IX.
 Inhibitors develop in about 20-30% of people who have severe
hemophilia A and 2-5% who have hemophilia B.
 Inhibitors are measured with the Bethesda assay and titers are reported in
Bethesda units.
 Bethesda assay:Patient plasma is serially diluted in normal plasma,and after
incubation for 2 hrs at 37° factor activity is measured.
 Normanl BU = 5 BU/ml
 One BU is the amount of inhibitors needed to inactivity half of the factors VIII and
factor IX in a mixture of inhibitor containing plasma and pooled Normal plasma.
Patient with inhibitor to factor VIII and factor IX are divided into 2
groups.

Low responder High responder

< 5BU/ml > 5 BU /ml
Low level of inhibitors High level of inhibitors
No rise in antibodies production Rise in antibodies production
There are two types of treatment
modalities that is actually done in
hemophilic patients.
1. Control bleeding episodes
2. Eradication of inhibitors
 Patients with low inhibitors
 high dose of specific factors can often control the acute bleeding
episodes.
 Patient with high inhibitors
 by passing agents are used.These are
Activated prothrombin complex concentrate
Recombinant factor VIIa
 Control bleeding episodes
Local measures: apply direct pressure,elevate or ice compress

Epistaxsis sit up lean forward

 Prevent joint degeneration
Immobilize joint during acute bleeding
Progressive excercise
 Avoid contact sports
 Contain greater quantity of activated factors primarily X and
Prothrombin
 Only available aPPC product in US is FEIBA*
 Recommended dose: 50-100 u/kg every 12 hrs
 Dose≥200u/kg/d associated with serious complications like
thrombotic complications,pulmonary emboli, MI and Deep vein
thrombosis.
 is hemostaticallly active only at the site of injury where tissue factor is
present.
 Recommended dose: 90ug/kg every 2 hrs until hemostasis is achieved.
 Higher dose upto 300ug/kg can also be used.
 Draw back is that it has short half life.
 Each alone is effective in about 70-90% OF bleeds.
 Both recombinant favtor VIIa and aPPC have been demonstared to be
effective in treatment of bleeding for patient with inhibitor.
 In patient with newly diagnosed inhibitors,it is prudent to use rFVIIa because
aPPC contain a small amount of factor VIII or IX and have ben shown to
increase the inhibitor titer.
 Due to risk of developing thrombosis this therapy should be used with
caution.
 2.

 The ideal therapy for patients with an inhibitor is total eradication so that optimal
hemostatic treatment is achieved.
 Only proven method for inhibitor eradication is immune tolerance induction.

immue system is
Immune system no
Regular administration No production of trained and patient
longer identifies them
of factor concentrate antibody inhibitors responds normally to
as foreign entities
tratment

Process flow of ITI therapy

 Since hemophilia is an inherited disorderd attributed to gene
mutation.
 In gene therapy functional copy of gene is delivered inthe patient on
cell that produce the normal protien .
 Goal of gene therapy would be to achieve a sustainable factor level of
over 5% which convert the severe disease to much milder phenotype.
 If factor activity level 50%,it would be considered curative.
 Removal of certain Reinsertion of Increase in
Genetic
cels from the genetically factor level in
modifications of
patient(usually modified cells the blood,curing
the cells
liver cells) into the patient the condition.

Benefits of gene therapy

• patient convenience ,viral safety and decreased cost
Draw backs
• Risk of inhibitor formation
 Pain management
 Acute pain

 Cause: bleeding

 Treatment:

1)Factor replacement therapy

2)RICE
3)Acetaminophen(mild)
4)Narcotics(severe)
5)Cyclo-oxygenase inhibitors

Warning: Do not give non steroidal anti inflammatory drugs

 Pain management
 Chronic pain

 Cause: Hemophilic arthropathy

 Treatment:

1)Cyclo-oxygenase 2 inhibitors
2)Surgical interventions(Synovectomy)
3)Joint replacement
 Surgery in hemophilia

 2 weeks before surgery: asses t1/2 of infused factor

 Perioperative stage: factor activity maintained at 50% to 100%(1u/ml plasma level)

 5-7 weeks after surgery:0.5u/ml plasma level is maintained

 Personalized Pharmacotherapy

 Standard prophylaxis: weight based calculation to increase factor level to 0.1uml

 Personalized prophylaxis

 Factors effecting breakthrough bleeding:

1)patients activity level

2)individual pharmacokinetics
3)presence of target joint
 Personalized Pharmacotherapy

4)synovial hypertrophy
5)degree of hemophilic arthropathy

 Inhibitor formation

 Targeted pharmacotherapy
Evaluation of therapeutic outcomes

 Outcomes:

1) Control and prevent bleeding

2) Chronic Arthropathies

 Monitor:

1) Bleeding
2) Plasma factor levels
3) Development of inhibitors
4) Joint range motion
 Evaluation of therapeutic outcomes

 Home Therapy:

1) Patient education
2) Personal records
3) Assessing bleeds
4) Treating bleeds