Hemophilia a

WHAT IS
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 male live births.
Incidence in Hemophilia B 1 in 30,000 male live births.
Female who carry a single mutated gene, are generally
asymtomatic. 2

TYPES
Disease Factor deficiency Inheritance
Hemophilia A VIII X linked recessive
Hemophilia B IX X linked recessive
3www.ihtc.org/patient/blood-disorders/hemophilia-a-and-b/

CAUSES
Mutations in F8
gene
Deficiency of
factor VIII
Hemophilia A
Mutations in F9
gene
Deficiency of
factor IX
Hemophilia B
4
www.ihtc.org/patient/blood-disorders/hemophilia-a-and-b/

 Accurate diagnosis of hemophilia is essential
to inform appropriate management.
Hemophilia should be suspected in patients
presenting with a history of
 Easy bruising in early chilhood
 “Spontaneous” bleeding (bleeding for no
known reason, particularly into the joints,
muscles, and soft tissues
 Excessive bleeding following trauma or
surgery
 A family history of bleeding is obtained in
about two-thirds of all patients
 A definitive diagnosis depends on factor assay
to demonstrate deficiency of FVIII or FIX
5Guidelines For The Management of Hemophilia

CLINICAL MANIFESTATIONS
 bleeding can happen
anywhere in the body.
 following an
injury / surgery or
spontaneous.
6

PATHOPHYSIOL
OGY
7http://accesmedicine.net/pathophysiology

8www.studyblue.com/notes/note/b-11-coagulation-cascade/

STAGES OF HEMOSTASIS
INJURY
VESSEL WALL+PLATELET
FORMATION OF PLT PLUG
ACTIVATION OF PLASMA COAGULATION
FACTORS
FORMATION OF STABLE FIBRIN CLOT
PRIMARY
SECONDARY
DISSOLUTION OF FIBRIN CLOT BY
FIBRINOLYSIS
9www.hemostasis.com/hemostasis/

10
www.eclinpath.com/hemostasis/physiology/primary/hemostasis

Type of hemorrhage Hemophilia A Hemophilia B
Hemarthrosis 40 IU/kg on day1; then 20 IU/ kg on days 2, 3, 5
until joint function is normal or back to baseline.
Consider additional treatment every other day
for 7-10 days. Consider prophylaxis.
60-80 IU/kg on day 1; then 40 IU/kg on days 2,
4. Consider additional treatment every other
day for 7-10 days. Consider prophylaxis.
Muscle or significant
subcutaneous hematoma
20 IU/kg; may need every-other-day treatment
until resolved.
40 IU/kg; may need treatment every 2-3 days
until resolved.
Mouth, deciduous tooth or
tooth extraction
20 IU/kg; antifibrinolytic therapy; remove loose
deciduous tooth.
40 IU/kg; antifibrinolytic therapy; remove
loose deciduous tooth.
Epistaxis
Apply pressure for 15-20 min; pack with
petroleum gauze; give antifibrinolytic therapy;
20 IU/kg if this treatment fails.
Apply pressure for 15-20 min; pack with
petroleum gauze; give antifibrinolytic
therapy; 30 IU/kg if this treatment fails.
Major surgery, life
threatening hemorrhage
50-75 IU/kg, then initiate continuous infusion of
2-4 IU/kg/hr to maintain FVIII >100 IU/dL for
24hr, then give 2-3 IU/kg/hr continuously for 5-
7d to maintain the level at >50 IU/dL and an
additional 5-7d at a level of >30 IU/dL
120 IU/kg, then 50-60 IU/kg every 12-24 hr to
maintain FIX >40 IU/dL for 5-7 d and then
>30 IU/dL for 7 d.
Hematuria Bed rest; 1.5 times maintenance fluids; if not
controlled in 1-2 d, 20 IU/kg FVIII.
Bed rest; 1.5 times maintenance fluids; if not
controlled in 1-2 d, 40 IU/kg FIX
Prophylaxis 20-40 IU/kg FVIII every other day to achieve a
trough level of > 1%.
30-50 IU/kg FIX every 2-3 days to achieve a
trough level of > 1%.
14

 Acute bleeds should be treated as quickly as
possible.
 In emergency situations, all patient should
carry easily accesible identification indicating
the diagnosis, severity of the bleeding, type
of treatment product used, initial dosage for
treatment.
 Administration of desmopressin can raise
FVIII level adequately (3 to 6 times baseline
level) to control bleeding.

 Drugs affect platelet function : ASA and
NSAID should be avoided.
Paracetamol/acetaminophen is a safe
alternative for analgesia
 Factors level should be raised to appropriate
levels prior to any invasive procedures
 Good oral hygiene prevents periodontal
disease and dental caries, which predispose
to gum bleeding
16
Guidelines For The Management of Hemophilia

Acute and chronic pain are common in patients
with hemophilia. Adequate assesment of the
cause of pain is essential to guide proper
management.
1.Pain caused by venous access
2.Pain caused by joint or muscle bleeding
3.Post-operative pain
4.Pain due to chronic hemophilic arthropathy

 Pre-operative assesment should include
inhibitor screening and inhibitor assay.
 Adequate quantities of clotting factor
concentrates should be available for the
surgery itself and to maintain adequate
coverage post-op.
 The dosage and duration of clotting factor
concentrate coverage depends on the type of
surgery performed.

 Platelet count, BT, PT, and APTT may be used
to screen a patient suspected of having a
bleeding disorder
 Bleeding time lacks sensitivity and specifity
and is also prone to performance-related
error. Therefore other test of platelet function
such as platelet aggregometry are preferred
when available.

 Based of the result of these test, the category
of bleeding disorder may be partially
characterized to guide subsequent analysis
 These screening test may not detect
abnormalities in patients with mild bleeding
disorders including some defect of platelet
function, FXIII deficiency, and those rare
defects of fibrinolysis, which may be
associated with a bleeding tendency.

 Clotting factor concentrates
The WFH strongly recommends the use of viral
inactivated plasma-derived or recombinant
concentrates in preference to cryoprecipitate or
fresh frozen plasma for thr treatment of
hemophilia and other inherited bleeding
disorders.
Product selection
1. Purity of product
2. Viral inactivation/elimination

Purity
1. Purity of concentrates refers to the percentage of the
desired ingredient (e.g FVIII),relative to the other
ingredients present.
2. Concentrate of lower purity give rise to allergic
reaction
3. Products with higher purity tend to be associated with
low manufaturing yields.these concentrates are,
therefore, costlier.
4. Plasma-derived FVIII concentrates may contain
variable amounts of von willebrand factor (VWF)
5. For treatment of FIX deficiency, a product containing
only FIX is more appropriate than prothrombin
complex concentrates, which also contain other
clotting factors such as factor II,VII, and X, some of
which may become activated during manufacture.
Products containing activated clotting factors may
predispose to thromboebolism

Viral inactivation/elimination
1. In process viral inactivation is the single largest
contributor to the safety of plasma-derived
concentrate.
2. There is growing tendency to incorporate two
specific viral-reducing steps in the manufacturing
process of concentrate
 Heat treatment is generally effective aganinst
broad range of viruses, both with or without a
lipid envelope, including HIV, HAV, HBV, and HCV
 Solvent/detergent treatment is effective against
HBV, HCV, and HIV but does not inactivate non-
enveloped viruses such as HAV
3. Some viruses (such as human parvovirus B19) are
relatively resistent to both types of process.

4. Nano (ultra) filtration can be used to remove
small viruses such as parvovirus.
FVIII concentrate
FVIII concentrates are the treatment of choice
hemophilia A
Dosage/administration
1. Vials of factor concentrates are available in
dosage ranging from 250 to 3000 units each.
2. In the absence of inhibitor,each unit of FVIII per
kilogram of BW infused IV will raise the plasma
FVIII level approximately 2 IU/dl.
3. The half-life of FVIII is approximately 8-12
hours

4. The patient’s factor level should be
measured 15 minutes after the infusion to
verify the calculated dose
5. The dose is calculated by multiplying the
patient’s BW in kg by the desired rise in
factor level in IU/dl, multiplied by 0.5
Ex: 50 kg x 40 (IU/dl) x 0.5 = 1000 units of
FVIII
4. FVIII should be infused by slow IV injection at
a rate not to exceed 3 ml per minute in
adults and 100 units per minute in young
children

4. Subsequent dose should ideally be based
on the half-life of FVIII and on the
recovery in an the individual patient
5. Continous infusion avoids peaks and
troughs and is considered by some to be
advantageous and more convenient.
6. Continous infusion may lead to a
reduction in the total quantity of clotting
factor concentrates used and can be more
cost-effective in patients with severe
hemophilia.

1. The WFH supports the use of coagulation factor
concentrates in preference to cryoprecipitate or
fresh frozen plasma (FFP) due to concerns about
their quality and safety.
2. Cryoprecipitate and FFP are not subjected to viral
inactivation procedures, leading to an increased
risk of transmission of viral pathogens, which is
significant with repeated infusions.
3. Allergic reaction more common following infusion
of cryoprecipitate than concentrate.

1. As FFP contains all the coagulation factors, it is
sometimes used to treat coagulation factor
deficiencies
2. Cryoprecipitate is preferable to FFP for the
treatment of hemophilia A
3. Due to concerns about the safety and quality of
FFP, its use is not recomended
4. It is posssible to apply some forms of virucidal
treatment to packs of FFP (including
solvent/detergent treatment), and the use of
treated packs is recommended.

1. One ml of FFP contains 1 unit of factor activity
2. It is difficult to achieve FVIII levels higher than 30
IU/dl with FFP alone
3. FIX levels above 25 IU/dl are difficult to achieve.
4. An acceptable starting dose is 15-20 ml/kg

1. Cryoprecipitate is prepared by slow thawing of FFP
at 4°C for 10-24 hours
2. Cryoprecipitate contains significant quantities of
FVIII (about 3-5 IU/ml),VWF,fibrinogen and FXIII but
not FIX or FXI.
3. Due to concerns about safety and quality of
cryoprecipitate, its use in the treatment of
congenital bleeding disorders is not recommended
and can only be justified in situations where clotting
factor concentrate are not available

A bag of cryoprecipitate made from unit of FFP (200-
250 ml) may contain 70-80 units of FVIII in a volume of
30-40 ml
Other pharmacological options
In addition to conventional coagulation factor
concentrates, other agents can be of great value in a
significant proportion of cases. These include :
1.Desmopressin
2.Tranexamic acid
3.Epsilon aminoproic acid

Desmopressin
1. Desmopressin is a synthetic analogue of
vasopressin that boosts plasma levels of FVIII
and VWF
2. DDAVP may be the treatment of choice for
patients with mild or moderate hemophilia A
when FVIII can be raised to an appropriate
theraupetic level because it avoids the expense
and potential hazards of using a clotting factor
concentrate
3. Desmopressin does not affect FIX levels and is
no value in hemophilia B
4. DDAVP is particularly useful in the treatment or
prevention of bleeding in carriers of
hemophilia.

4. Although DDAVP is not licensed for use in
pregnancy, there is evidence that it can be safely
used during delivery and in the post-partum
period in an otherwise normal pregnancy. Its
use should be avoided in preeclampsia because
of the already high levels of VWF.
5. Obvious advantages of DDAVP over plasma
products are the much lower cost and the
absence of any risk of transmission of viral
infections.
6. DDAVP may also be useful to control bleeding
and reduce the prolongation of bleeding time
associated with disorders of hemostasis,
including congenital platelet disorders.

1. Desmopressin is given subcutaneously in
most patients, it can also be administered
by intravenous infusion or by nasal spray.
2. Appropriate preparations include :
 4 μg/ml for iv use
 15 μg/ml for iv and sc use
 150 μg/ml per meterd dose as nasal spray
3. A single dose of 0.3 μg/ml BW, either by iv
or sc route, can be expected to boost the
level FVIII three to six fold

4. For iv use, DDAVP is usually diluted in a least 50-
100 ml of physiological saline and given by slow iv
infusion over 20-30 minutes
5. The peak response is seen approximately 60
minutes after administration either intravenously
or subcutaneously
6. Closely spaced repetitive use of DDAVP over
several days may result in decreased response
(tachyphylaxis). Factor concentrates may be
needed when higher factor levels when higher
factor levels are required for a prolonged period
7. Rapid infusion may result in tachycardia,flushing,
tremor and abdominal discomfort

1. Tranexamic acid is an antifibrinolytic agent that
competitively inhibits the activation of
plasminogen to plasmin.
2. It promote clot stability and is useful as
adjunctive therapy in hemophilia and some
other bleeding disorders.
3. Regular treatment with tranexamic acid alone is
of no value in the prevention of hemarthroses
in hemophilia
4. It is valuable in controlling bleeding from skin
and mucosal surfaces (e.g. Oral bleeding,
epistaxis, menorrhagia)

1. Tranexamic acid is given is an tablet 3-4
times daily. It can also be given by iv
infusion 2-3 times daily, and also available
as a mouthwash
2. GI upset (nausea, vomitting, or diarrhea)
may rarely occur as a side effect, resolve if
the dosage is reduced. Rapid injection may
result dizziness and hyotension.
3. A syrup formulation is for pediatric use.

4. Tranexamic acid is commonly prescribed for
seven days following dental extractions to
prevent post-op bleeding.
5. Tranexamic acid may be given
alone/together with standard of coagulation
factor concentrates.

Epsilon aminocaproic acid (EACA)
EACA is similar to tranexamic acid but is less widely used as
it has a shorter plasma half-life, is less potent, more toxic
1. EACA is typically administered to adult orally or
intravenously every 4-6 hours up to a max of 24 g/day
in an adult
2. A 250 mg/ml syrup is also available
3. GI upset is common complication, reducing the dose
often helps
4. Myopathy is a rare adverse reaction specifically reported,
typically occuring after administration of high doses for
several weeks
5. The myopathy is often painful and associated levels of
creatine kinase and even myoglobinuria
45
Guidelines For The Management of Hemophilia

Hemophilia a

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