OBJECTIVES

• To know the basic concepts about Hemophilia

• How to approach a case of Hemophilia?
• How to Calculate Factor requirement?
• Management in special situations
• Lifestyle modifications of the hemophiliacs
 COAGULATION FACTORS
• Factor I – Fibrinogen
• Factor II - Prothrombin
• Factor III – Tissue factor (Tissue Thromboplastin)
• Factor IV – Calcium
• Factor V – Labile factor (Proaccelerin)
• Factor VII – Serum Prothrombin Conversion Accelerator (SPCA)
• Factor VIII – Anti-Hemophilic Factor
• Factor IX – Partial Thromboplastin Component (PTC); Christmas
Factor
• Factor X – Stuart-Prower Factor
• Factor XI – Plasma Thromboplastin Antecedent (PTA)
• Factor XII – Hagemann factor
• Factor XIII – Fibrin stabilizing Factor
 What is Hemophilia ?
 Hemophilia is an X linked recessive hemorrhagic
disorder due to mutations in F8 gene and the
most common being inversion of intron 22
sequence (Hemophilia A or Classic Hemophilia)
or F9 gene (Hemophilia B).
 Males are usually affected and women who
carry a single mutated gene are generally
asymptomatic.
 Family history of the disease is absent in about
30% cases (for whom the mothers carry a
de novo single mutated allele).
 Degrees of Severity of Hemophilia
Hemophilia A and Hemophilia B are clinically
indistinguishable. The disease phenotype co-
relates with residual activity of Factor VIII & IX
and can be classified as:
 Severe (< 1 %)
 Moderate (1 – 5 %)
 Mild (6 – 30 %)
CLINICAL HIGHLIGHTS
Hemophilia clinically manifests when a child begins
to walk or crawl.
In severe and Moderate forms:
* Bleeding into joints (hemarthrosis), soft
tissues and muscles.
* After Trivial trauma or even spontaneously
In milder forms:
* Infrequent bleeding usually secondary to
trauma.
 FORMS OF BLEEDING

 Acute hemarthroses
are painful
erythematous swelling
which have the
tendency to recur.
Chronic hemarthroses
are debilitating with
synovial thickening and
synovitis in response to
intrarticular bleed.
COMPLICATIONS OF BLEEDING
• Muscle contractures
on adapting a posture
to relieve pain
• Muscle atrophy

JOINT CONTRACTURES
 Hemophilic arthropathy

“Target joint” = irreversibly damaged joint

with vicious cycle of injury and repeated
bleeding
Joint destruction
Hematomas into
muscles of distal
parts of limbs
may lead on to
Compartment
syndrome
 OTHER FORMS OF BLEEDING
 Life threatening bleeding in form of bleeding into oropharyngeal spaces, CNS
or retroperitoneum.

 Retroperitoneal hemorrhages accumalate large quantities of blood

Formation of masses with calcification and inflammatory tissue reaction.

Pseudotumor syndrome with damage to the femoral nerve

 Hematuria a frequent among hemophilia patients, even in the absence of

genitourinary pathology
 LABS

 Prolongation of aPTT
 Normal Bleeding Time and platelet Count
 FVIII and FIX clotting activity determination
TREATMENT
HISTORY OF CLOTTING FACTOR CONCENTRATES:

Prior to 1950: whole blood

1952: Hemophilia A distinguished from B
1950-1960: FFP and Cryoprecipitate
Early 1970s: Commercial plasma-derived factor concentrates
Mid-late 1970’s: Home infusion practices
1981: First AIDS death in the Hemophilia community
Mid-1983: Factor concentrates heat treated for hepatitis
1985: All products heat treated for viral inactivation
1987: Monoclonal factor concentrates
1992: Recombinant factor VIII
1994: Recombinant factor IX-albumin free
2001: 2nd generation recombinant factor VIII
 HOME THERAPHY
Advantages:
Immediate access to the treatment
It is achieved with clotting factor concentrates or
other lyophilised products that are safe and can be
stored in a domestic fridge that can be reconstituted
easily
Cryoprecipite can also be kept in fridge but it should
not be frozen.
 Monitoring of home therapy
1. It should be supervised by a comprehensive care centre with
adequate education and training to the pt. Teaching should include
recognising a bleed and its complications, dosage calculation,
preparation and storage.
2. Administration of clotting factor with aseptic techniques,
performing venipuncture, record keeping, as well as proper
storage and disposal of needles and handling of blood spills
3. Patients or parents should keep bleeding records that include
date and site of bleeding, dosage and lot no. of product used, as
well as any adverse effects.
4. Home care can be instituted for young children having adequate
venous access and motivated family members undergone adequate
training. Self infusion can be encouraged to older children and
teenagers.
5. Implanted venous access device (PORT-A-CATH) can also be
used but this will be associated with complications like infection
and thrombosis.
FACTOR REPLACEMENT THERAPY

 It can be started in response to a bleeding episode or as

a prophylactic treatment.
 Primary Prophylaxis: a tool for maintaining the missing
clotting factor at levels >1% or higher on a regular basis
in order to prevent bleeds, especially at the onset of
hemarthroses.
 Hemophiliac boys receiving regular infusions of FVIII
of 25-40 IU/kg (3 days /week) or FIX( 2 days/week) can
reach puberty without detectable joint abnormalities
 How to calculate Factor requirement?
Factor VIII concentrate increases factor VIII activity approximately 2% for every
1 IU/kg infused. A 50 IU/kg IV bolus raises factor VIII activity approximately
100% over baseline. Extended treatment should follow with 25-IU/kg IV bolus
q12h to maintain sufficient levels.

FVIII dose (IU) = (Target FVIII levels – FVIII baseline levels) x

Body weight (kgs) x 0.5 unit/kg

Half life of FVIII is 8 to 12 hours, hence requires BD dose

to maintain therapautic range
 FACTOR IX REQUIREMENT
FIX dose (IU) = (Target FIX levels – FIX baseline levels) x
Body weight (kgs) x 1 unit/kg

• FIX recovery postinfusion is usually only 50% of predicted value

• half life of FIX is 24 hours and hence given an OD dose.
 TREATMENT OF BLEEDS
GOAL OF TREATMENT

Mild Bleeds Uncomplicated Hemarthroses or Maintain factor level at 30 -

superficial hematomas 50%
Severe On Target joint Same as mild bleeds with
hemarthroses additional doses to maintain
levels of 15 -25% for 2 – 3 days.
Large Maintain factor level at 50%
hematomas and factor replacement
required for a period of 1 week
or longer
Severe bleeds Oropharyngeal spaces Maintain factor level at 30 -
CNS or retroperitoneum 100% for 7 days
Prophylactic Maintain factor level at 100%
replacement for 7 days
for surgery
 MANAGEMENT OF BLEEDING WITH
INHIBITORS
1. Patients with inhibitors must be in consultation with centers
experienced in management of such patients before and all
serious bleeds should be managed in such centres
2. Choice of product should be based on the titre of the inhibitor,
records of clinical response to products, site & nature of
bleeding.
3. Patient with a low responding inhibitor should be treated with
a high dose of specific factor replacement at a much higher
dose, if possible to neutralize the inhibitor with excess factor
activity
 NON TRANSFUSION THERAPHY IN
HEMOPHILIA

Mild-to-moderate hemophilia A with minor bleeding:

* DDAVP (0.3 mg/kg IV in 50 to 100 mL NS infused over 30 minutes, or 300

mg intranasally [Stimate, 1.5 mg/mL] dosed every 12 hours). Increases factor VIII
activity threefold to fivefold and has a half-life of 8 to 12 hours. Tachyphylaxis
may occur after several doses

•ANTI-FIBRINOLYTIC AGENTS: EACA or Tranexemic acid.

Bleeding in gums, GIT or during oral surgery. EACA – loading dose of
200mg/kg followed by 100 mg/kg per dose every 6th hourly. Tranexemic Acid – 25 mg/kg 3
to 5 times a day.
Not indicated to control hematuria because of the risk of formation of occlusive clot in the
lumen of genitoruinary tract structues
COMPLICATIONS DUE TO
FACTOR REPLACEMENT
 Inhibitor formation
Formation of alloantibodies to the factor, that is the leading complication of
Hemophilia treatment.

High risk groups:

1. Severe deficiency of factor
2. Family history of inhibitor
3. Mutation in FVIII or FIX
4. Gene derangements
5. Need for intensive replacement therapy ( major surgeries, intracranial
bleeding or trauma)

Clinically, hemophilia is diagnosed when patients do not respond to factor

replacement at therapeutic levels
 LABS
 The laboratory test to conform the presence of an inhibitor is
an aPTT with a mix ( with normal Plasma).

 A 1:1mix with normal plasma normally corrects the aPTT but

in patients with inhibitor the aPTT is abnormally prolonged.

 Bethedsa assay – to define the specificity of the inhibitor and

its titer.
 Bethesda Assay for Inhibitors
• Serial dilutions of patient plasma in normal plasma
• Incubate 2 hours
• Assay residual factor activity
• 1 Bethesda Unit neutralizes 50% of factor in an
equivalent volume of normal plasma
• Example: 1:100 dilution of patient plasma + normal
plasma → 50% residual factor activity, so inhibitor
titer is 100 BU
 Bethesda Assay

Residual factor activity

50%

100 BU

1:1 1:10 1:100 1:1000

dilution pt plasma
 Inhibitor patients

High responders Low responders

Initial inhibitor titer >10 BU, do Initial inhibitor titer <10 BU responds
Not respond to FVIII or FIX conc- Well to human or Porcine FVIII with
entrates Minimal/no increase in inhibitor titres
 TREATMENT OF HEMOPHILIACS WITH INHIBITORS

• Recombinant factor VIIa

– Enhances TF-driven thrombin formation
• FEIBA (Factor Eight Inhibitor Bypassing Activity)
– Mixture of partially activated vitamin K-
dependent clotting proteases including VIIa
• High dose factor VIII (if low titer inhibitor)
• Induction of tolerance with daily factor VIII infusions
– Optimal dose not established
– Role for concomitant immunosuppression?
Patients with severe hemophilia A and inhibitors resistant to ITI: use of
anti CD20 monoclonal Antibody with FVIII is effective but transitional.
 INFECTIOUS DISEASES
• HCV infection – major cause of morbidity and 2nd
leading cause of death in hemophilia patients
exposed to older clotting factor concentrates.
• Co-morbidity of underlying liver diseases is clear
in these individuals.
• Response to HCV antiviral therapy is also
restricted with even more proportion among co-
infected with HIV.
• End stage liver disease requiring liver
transplantation may be curative for both liver
disease and for hemophilia.
Cardiovascular diseases & malignancy
 Though the early assumption that hemophilia
would protect against occlusive vascular disease
because of the underlying hypocoagulablility
but Physical inactivity, hypertension, CKD and HIV
co-infection on ART (commonly observed in
hemophiliacs) points more in favor of
cardiovascular risk.
 At risk for HIV and HCV related malignancies.
Hepatocellular cancer (HCC) – most prevalant
among HIV negative hemophiliacs.
LIFE STYLE MODIFICATIONS
OF HEMOPHILIACS
 Goal is to avoid excessive bleeding to protect joints
 Avoid contact sports – football, hockey or wrestling
 Can indulge in activities like swimming, bicycle riding
 Avoid medications – aspirin, ibuprofen, use alternatives like
acetaminophen
 Heparin, warfarin, clopidogrel should also be avoided

• PRACTICE GOOD DENTAL HYGIENE

Goal is to prevent excessive bleeding
• PROTECT FROM INJURIES :
 Knee pads, elbow pads, helmets safety belts all may help in
preventing injuries. Keep your home free of furniture with sharp
corners.
• CARRY IDENTIFICATION AT ALL TIMES:
Always carry a card mentioning the fact that the person is suffering
from hemophilia , the type of treatment & the drugs prescribed etc.
• TRAVEL WITH CARE :
While on travel carry all medications and store information about
hemophilia clinics around the place.
 MANAGEMENT OF
HEMOPHILIA IN SPECIAL
SITUATIONS
 1. Surgical intervention may be elective or emergency. Whenever possible pt. is
shifted to the hemophilic treatment center.
2. Surgery is undertaken in a place(OT) where reliable and adequate laboratory
facilities should be available for monitoring clotting factor level.
3. Pre-operative assessment of inhibitor screen
4. Surgery to be scheduled early in the week and early in the day for optimal
laboratory and blood bank support.
5. Availability of sufficient quantities of clotting factor concentrates..
6. Dosage and duration of clotting factor concentrate coverage depends on type of
surgery performed.
PLANNING FOR SURGERY : Adequate coagulation factor should be available. If
bleeding is very high elective surgery should be postponed. Antiplatelet should
be avoided peri-operatively.
• Adult – 70kg – with severe hemophilia A – taken for major surgery – factor 8
requirement is 50,000 – 80,000 units
Major Minor
Abdominal SURGERY Removal of skin lesions
Intracranial Dental problems
Spinal Arthroscopy
Joint replacement
• Coagulation factor replacement for surgery is based on
1) Through factor level : minimum factor level measured immediately
before next bolus
2) Peak factor level – maximum factor level measured in 1hr of bolus
injection

Minor procedures – continuous infusion of factor is enough

ADULT - MAJOR SURGERY - CONTINOUS INFUSION

Pre-op : 80 – 100IU/Kg

Day Factor 8 level Dose(IUKg)

1-6 More than 50% 2.5 – 3.0 IU/Kg/hr
More than 7 Often change to bolus
• ADULTS – MAJOR SURGERY – BOLUS DOSING

Day Factor 8 Factor 9

Pre-op 40-50
1-3 80 - 100 80 - 100
4-6 60- 80 60- 80
More than 7 40- 60 40- 60

MINOR SURGERY

Day Factor 8 Factor 9

Pre-op 20 - 30
1-3 40-50 40-50
More than 4 20- 30 20- 30
• LIVER BIOPSY : Transjugular liver biopsy is necessary for
hemophiliac & the factor replacement should be done as explained
above, Pt should be hospitalised for 48 hrs
• DENTAL PROCEDURE : After factor 8 replacement for pt.
undergoing dental procedures, antifibrinolytic agent is also strongly
recommeded due to alteration of mucosa in these procedures
• TRANEXEMIC ACID – ANTIFIBRINOLYTIC OF CHOICE
Dose- 15- 20mg/kg

 DELIVERY : Deliver the baby by the least traumatic method

Avoid ventouse
Avoid mid cavity forceps
Avoid prolonged labour
Replace factor if necessary for the mother during labour
Check CBC, aPTT,, Factor level & X-matching
POSTPARTUM : Keep more than 50% for 3 days
Prophylactic OCP should be started from delivery continued for 1
month
FOR BABIES : Vit. K – to prevent HDN
Hep B vaccination mandatory
All newborns delivered by hemophiliac should be screened by cord
blood
HEMOPHILIAC WOMEN PRESENTED WITH MENORRHAGIA
• Antifibrinolytic agent – Tranexamic acid – 1g Q6H during menstrual
bleed
• DDAVP – Desmopressin – intranasal(1.5mg/ml) or SC
(0.3microgram/Kg)
• Should begin with DDAVP when menstrual bleeding starts & can
be repeated every 12-24hrs
• S/E – facial flushing
• ADH effect (+) hence avoid excess fluid intake