MANAGEMENT OF HEMOPHILIA

DR. ZOONA QAZI

POST GRADUATE RESIDENT
PRINCIPLES OF CARE

• Prevent and treat bleeding

• Treated as quickly as possible, preferably within two hours
• Identify the site of bleeding (if not clinically obvious) and administration
of appropriate clotting factor
• In severe bleeding episodes, treatment with factor should be initiated
immediately, even before diagnostic assessment is completed.
CONT....
• Measurement of clotting factor levels
• Inhibitor testing
• Prophylactic factor replacement
• Home therapy
• Avoid activities likely to cause trauma
• Drugs that affect platelet function, particularly acetylsalicylic acid (ASA) and non-
steroidal anti-inflammatory drugs (NSAIDs), except certain COX-2 inhibitors, should
be avoided.
• Factor levels should be raised to appropriate levels prior to any invasive procedure.
• Good oral hygiene
COMPREHENSIVE CARE
• Promotes physical and psychosocial health and quality of life while decreasing morbidity
and mortality.
• Multidisciplinary team of healthcare professionals
• The core team should consist of the following members:
° Medical director (preferably a pediatric and/ or adult hematologist, or
a physician with interest and expertise in hemostasis)
° Nurse coordinator

° Musculoskeletal expert (physiotherapist, occupational therapist, physiatrist,

orthopedist, rheumatologist)
° Laboratory specialist
° Psychosocial expert (preferably a social worker, or a psychologist) familiar with
available community resources.
° chronic pain specialist
° dentist
° geneticist
° hepatologist
° infectious disease specialist
° immunologist
ADJUNCTIVE MANAGEMENT
• Clotting factor concentrates are limited or not available, and may lessen the
amount of treatment product required.
• Clotting factor concentrates (or desmopressin in mild hemophilia A), protection
(splint), rest, ice, compression, and elevation (PRICE) may be used as
adjunctive management for bleeding in muscles and joints.
• Physiotherapy/rehabilitation is particularly important for functional
improvement and recovery after musculoskeletal bleeds and for those with
established hemophilic arthropathy.
CONT...

• Antifibrinolytic drugs (e.g. tranexamic acid, epsilon aminocaproic acid) for

mucosal bleeds and dental extractions.
• Certain COX-2 inhibitors for joint inflammation after an acute bleed and in
chronic arthritis.
PROPHYLACTIC FACTOR REPLACEMENT THERAPY

• Intravenous injection of factor concentrate in order to prevent anticipated

bleeding
• Prevents bleeding and joint destruction and should be the goal of therapy to
preserve normal musculoskeletal function
• Useful even when factor levels are not maintained above 1 IU/dl at all times
CONT...
• In patients with repeated bleeding, particularly into target joints, short-term
prophylaxis for four to eight weeks can be used to interrupt the bleeding cycle. This
may be combined with intensive physiotherapy or synoviorthesis.
• Two prophylaxis protocols:
■ The Malmö protocol: 25-40 IU/kg per dose administered three times a week for
those with hemophilia A, and twice a week for those with hemophilia B.
■ The Utrecht protocol: 15-30 IU/kg per dose administered three times a week for
those with hemophilia A, and twice a week for those with hemophilia B.
• Prophylactic administration of clotting factor concentrates is advisable prior to
engaging in activities with higher risk of injury
HOME THERAPY
• Immediate access to clotting factor and early treatment, resulting in decreased pain,
dysfunction, and long term disability and significantly decreased hospital admissions
for complications.
• Close supervision by the comprehensive care team and should only be initiated after
adequate education and training.
• An implanted venous access device (Port-ACath) can make injections much easier and
may be required for administering prophylaxis in younger children.
• Risks of surgery, local infection, and thrombosis associated with such devices need to
be weighed against the advantages of starting intensive prophylaxis early.
PAIN MANAGEMENT
• Pain caused by venous access in general, no pain medication is given.
• Pain caused by joint or muscle bleeding drugs are often needed for
pain control alongwith cold packs, immobilization, splints, and crutches.
• Post-operative pain Intramuscular injection of analgesia should be
avoided, intravenous morphine or other narcotic analgesics can be given,
followed by an oral opioid such as tramadol, codeine, hydrocodone, and
others.
CONT...

• Pain due to chronic hemophilic arthropathy functional training,

adaptations, and adequate analgesia, COX-2 inhibitors have a greater role
in this situation, other NSAIDs should be avoided. When pain is disabling,
orthopedic surgery may be indicated.
STRATEGIES FOR PAIN MANAGEMENT IN PATIENTS WITH HEMOPHILIA
SURGERY AND INVASIVE PROCEDURES
• Consultation with a comprehensive hemophilia treatment centre
• Pre-operative assessment should include inhibitor screening and inhibitor assay
• Patients with mild hemophilia A, as well as patients receiving intensive factor
replacement for the first time, are at particular risk of inhibitor development
and should be re-screened 4–12 weeks post-operatively.
• Infusion of factor concentrates/hemostatic agents before invasive diagnostic
procedures such as lumbar puncture, arterial blood gas determination, or any
endoscopy with biopsy
DENTAL CARE AND MANAGEMENT
• Infiltration, intrapapillary, and intra-ligamentary injections under factor cover
(20-40%) though it may be possible for those with adequate experience to
administer these injections without it
• Dental extraction or surgical procedures within the oral cavity with a plan for
hemostasis management, in consultation with the hematologist
• Tranexamic acid or epsilon aminocaproic acid (EACA) after dntal procedures
to reduce the need for replacement therapy
• Non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin must be avoided.
• An appropriate dose of paracetamol/acetaminophen every six hours for two
to three days will help prevent pain following an extraction.
 HEMOSTATIC AGENTS

CLOTTING FACTOR CONCENTRATES

• FVIII concentrates:
FVIII concentrates are the treatment of choice for hemophilia A.
Vials of factor concentrates are available in dosages ranging
from approximately 250 to 3000 units each.
In the absence of an inhibitor, each unit of FVIII per kilogram of body
weight infused intravenously will raise the plasma FVIII level approximately 2
IU/dl.
The half-life of FVIII is approximately 8-12 hours.
CONT...

• The patient’s factor level should be measured 15 minutes after the infusion to
verify the calculated dose.
• The dose is calculated by multiplying the patient’s weight in kilograms by the
desired rise in factor level in IU/dl, multiplied by 0.5.
• FVIII should be infused by slow IV injection at a rate not to exceed 100 units
per minute in young children.
• FIX concentrates:
Treatment of choice for hemophilia B.
Two classes:
■ Pure FIX concentrates (plasma derived or recombinant)
■ FIX concentrates: factors II, VII, IX, and X, also known as
prothrombin complex concentrates (PCCs), rarely used.
Pure FIX products are free of the risks of thrombosis or disseminated
intravascular coagulation (DIC), which may occur with large doses of PCCs.
Vials of FIX concentrates in doses ranging from approximately 250 to 2000
units each.
In absence of an inhibitor, each unit of FIX per kilogram of body weight infused
intravenously will raise the plasma FIX level approximately 1 IU/dl.
The half-life is approximately 18–24 hours.
The patient’s FIX level should be measured approximately 15 minutes after
infusion to verify calculated doses.
To calculate dosage, multiply the patient’s weight in kilograms by the desired
rise in factor level in IU/dl multiplied by 1.5
Infusion by slow IV injection at a rate not to exceed 100 units per minute in
young children
OTHER PLASMA PRODUCTS
• Fresh frozen plasma (FFP)
As FFP contains all the coagulation factors, it is sometimes used to treat
coagulation factor deficiencies.
Cryoprecipitate is preferable to FFP for the treatment of hemophilia A.
One ml of fresh frozen plasma contains 1 unit of factor activity.
It is generally difficult to achieve FVIII levels higher than 30 IU/dl with FFP
alone. FIX levels above 25 IU/dl are difficult to achieve.
An acceptable starting dose is 15−20 ml/kg
• Cryoprecipitate
Cryoprecipitate contains significant quantities of FVIII (about 3-5 IU/ml), VWF,
fibrinogen, and FXIII but not FIX or FXI.
Not recommended in the treatment of congenital bleeding disorders and can
only be justified in situations where clotting factor concentrates are not
available.
A bag of cryoprecipitate made from one unit of FFP (200-250ml) may contain
70–80 units of FVIII in a volume of 30–40 ml.
OTHER PHARMACOLOGICAL OPTIONS

These include:
■ desmopressin
■ tranexamic acid
■ epsilon aminocaproic acid
• Desmopressin (DDAVP)
Treatment of choice for patients with mild or moderate hemophilia A when FVIII
can be raised to an appropriate therapeutic level
Does not affect FIX levels and is of no value in hemophilia B
Useful in the treatment or prevention of bleeding in carriers of hemophilia
A single dose of 0.3 µg /kg body weight, either by intravenous or
subcutaneous route, can be expected to boost the level of FVIII three- to six-
fold.
• Tranexamic acid
No value in the prevention of hemarthroses in hemophilia
Valuable in controlling bleeding from skin and mucosal surfaces (e.g. oral
bleeding, epistaxis, menorrhagia)
Given as an oral tablet three to four times daily or intravenous infusion two to
three times daily, and is also available as a mouthwash
May be given alone or together with standard doses of coagulation factor
concentrates
Should not be given to patients with FIX deficiency receiving prothrombin
complex concentrates, as this will exacerbate the risk of thromboembolism
• Epsilon aminocaproic acid
Similar to tranexamic acid but is less widely used as it has a shorter plasma
half-life, is less potent, and is more toxic.
TREATMENT OF SPECIFIC HEMORRHAGES

TREATMENT OF SPECIFIC HEMORRHAGES

INHIBITORS
• “Inhibitors” in hemophilia refer to IgG antibodies that neutralize clotting factors.
• Inhibitors to FVIII or FIX are considered to be the most severe treatment related
complication in hemophilia
• Should be suspected in any patient who fails to respond clinically to clotting factors,
particularly if he has been previously responsive
• More frequently encountered in persons with severe hemophilia
• In severe hemophilia, inhibitors do not change the site, frequency, or severity of
bleeding. In moderate or mild hemophilia, the inhibitor may neutralize endogenously
synthesized FVIII, thereby effectively converting the patient’s phenotype to severe.
• Should be done in all patients treated for more than five days, within four
weeks of the last infusion.
• Assessed prior to surgery or if recovery assays are not as expected, and
when clinical response to treatment of bleeding is sub-optimal in the post-
operative period.
• Highly purified factor IX or recombinant factor IX seems to increase the
frequency of inhibitor development
• Management of bleeding:
• Based on titre of inhibitor, records of clinical response to product, and site and
nature of bleed
• Low-responding inhibitor treated with specific factor replacement at a much
higher dose, if possible, to neutralize the inhibitor with excess factor activity and
stop bleeding
• High responding inhibitor but with low titres treated similarly in an emergency until
an anamnestic response occurs, usually in three to five days, precluding further
treatment with concentrates that only contain the missing factor
TREATMENT OF TRANSFUSION-TRANSMITTED AND OTHER
INFECTION-RELATED COMPLICATIONS
• HIV infection:
The diagnosis, counselling, initiation of treatment, and monitoring of HIV, as well as the
treatment of HIV-associated complications in infected people with hemophilia, should be the
same as in the non-hemophilic population.
HCV infection:
Pegylated interferon (PEG-INF) and ribavirin, which give sustained virological response in
61% of people with hemophilia.
HBV infection
Those without HBV immunity should be given the anti-HBV vaccine. Protective seroconversion
should be rechecked following vaccination. People with hemophilia who do not seroconvert
should be revaccinated with double the hepatitis B vaccine dose.
Management of bacterial infection:

Risk factors are venous access catheter insertion, surgical arthroplasty, and
other surgical interventions.
Joint aspiration to treat hemarthrosis should be avoided, unless done early
under appropriate cover of factor replacement and with strict aseptic
precautions to prevent infection.