Hemophilia A & B

Definition:

Hemophilia is usually an inherited bleeding disorder

in which the blood does not clot properly.

• Blood contains many proteins called clotting factors

that can help to stop bleeding.
• People with hemophilia have low levels of either
factor VIII (8) or factor IX (9).
• The severity of hemophilia that a person has is
determined by the amount of factor in the blood.
Hemophilia A - (Classic Hemophilia)
➢ This type is caused by a lack or decrease of clotting
factor VIII.

Hemophilia B - (Christmas Disease)

➢ This type is caused by a lack or decrease of clotting
factor IX.
➢ It is named after the first person to be diagnosed
with the disorder in 1952, Stephen Christmas.
Epidemiology:

➢ Hemophilia A is the most common type of the

condition; 1 in 4,000 to 1 in 5,000 males worldwide
are born with this disorder.
➢ Hemophilia B occurs in approximately 1 in 20,000
newborn males worldwide.
➢ Hemophilia A is about four times as common as
hemophilia B, and about half of those affected
have the severe form.
➢ Hemophilia affects people from all racial and
ethnic groups.
Etiology:

➢ Hemophilia is caused by a mutation or change, in

one of the genes, that provides instructions for
making the clotting factor proteins needed to
form a blood clot.
➢ These genes are located on the X chromosome.
Males have one X and one Y chromosome (XY)
and females have two X chromosomes (XX).
Males inherit the X chromosome from their
mothers and the Y chromosome from their
fathers. Females inherit one X chromosome from
each parent.
➢ The X chromosome contains many genes
that are not present on the Y chromosome.
This means that males only have one copy
of most of the genes on the X
chromosome, whereas females have 2
copies.

➢ Females can also have hemophilia, but

this is much rarer. In such cases both X
chromosomes are affected or one is
affected and the other is missing or
inactive.

➢ A female with one affected X chromosome

is a “carrier” of hemophilia. Sometimes a
female who is a carrier can have
symptoms of hemophilia.
 Clinical Manifestations

• Spontaneous hemorrhage
Approximately 30-50% of patients with severe
hemophilia present with manifestations of neonatal
bleeding

• Hematuria
In the genitourinary tract, gross hematuria may occur
in as many as 90% of patients.

• General symptoms
Weakness and orthostasis may occur.
• Musculoskeletal
Tingling, cracking, warmth, pain, stiffness,
and refusal to use the joint among children are
common.

• Central nervous system

Headache, stiff neck, vomiting, lethargy,
irritability, and spinal cord syndromes may
occur.

• Genitourinary
Symptoms may be painless; there may be
hepatic/splenic tenderness and peritoneal
signs.
• Hemophilia can result in:

✓ Bleeding within joints that can lead to

chronic joint disease and pain

✓ Bleeding in the head and sometimes in the

brain which can cause long term
problems, such as seizures and paralysis

✓ Death can occur if the bleeding cannot be

stopped or if it occurs in a vital organ such
as the brain.
PATHOPHYSIOLOGY
Investigation/
Diagnostics
• Screening Tests
Screening tests are blood tests that
show if the blood is clotting properly.

Types of screening tests:

• Complete Blood Count (CBC)
This common test measures the
amount of hemoglobin (the red pigment
inside red blood cells that carries
oxygen), the size and number of red
blood cells and numbers of different
types of white blood cells and platelets
found in blood. The CBC is normal in
people with hemophilia.
• Activated Partial Thromboplastin Time (APTT)
Test
This test measures how long it takes for blood to
clot. It measures the clotting ability of factors VIII
(8), IX (9), XI (11), and XII (12). The results of this
test will show a longer clotting time among people
with hemophilia A or B.
• Prothrombin Time (PT) Test
This test also measures the time it takes for
blood to clot. It measures primarily the clotting ability
of factors I (1), II (2), V (5), VII (7), and X (10). The
results of this test will be normal among most people
with hemophilia A and B.
• Clotting Factor Tests
Clotting factor tests, also called factor assays,
are required to diagnose a bleeding disorder. This
blood test shows the type of hemophilia and the
severity. It is important to know the type and
severity in order to create the best treatment plan.
 Treatment
• The best way to treat hemophilia is
to replace the missing blood
clotting factor so that the blood
can clot properly. This is done by
infusing commercially prepared
factor concentrates.
Management
Medical Management

Factor VIII and FIX concentrates

Desmopressin
Management of bleeding
Prophylactic factor infusions
Pain management
Activity
Radiosynovectomy
Pharmacologic Management

Factor VIII
Antifibrinolytic agents
Factor IX
Coagulation factors
Antihemophilic agents
Monoclonal antibodies
Vasopressin-related
The interventions for a child with
hemophilia are:

Relieve pain
Maintain optimal physical
mobility
Assist in the coping of the family
Prevent bleeding
Prevent injury
Recommendations
Exercise regularly
Avoid certain pain medications
Avoid blood-thinning
medications
Practice good dental hygiene
Get vaccinations
Protect your child from injuries
that could cause bleeding
Case Study
 4-year-old boy presents to the
emergency department complaining of
swelling in his left elbow joint. He and his
mother deny trauma to the elbow. On
further questioning his mother told that she
also experienced swollen joints. It was
also found out that the mother has a
family history of hemophilia.

Note : Some of the hemophilia gene carrier also

experienced symptoms of hemophilia.
 FINDINGS ASSESSMENT RESOLUTION MONITORING

➢ Swollen ➢The patient Pharmacologic: ➢Avoid

elbow joint might inherit his ➢Desmopressin excessive
mother’s disorder ➢Factor VIII / bleeding and
➢His mother with the Factor IX protect your
also symptom of ➢Tranexamic joints
experienced hemarthrosis. Acid
swollen joints ➢Replacement ➢Exercise
and has a ➢The mother is a therapy regularly
family history carrier of
of Hemophilia Hemophilia Non- ➢Avoid certain
gene. pharmacologic: pain
➢Patient should medications
undergo several
types of
screening test
and physical
exam .
Coagulation Disorder – Hemophilia A & B
Definition:

Hemophilia is usually an inherited bleeding disorder in which the blood does not clot properly.

This can lead to spontaneous bleeding as well as bleeding following injuries or surgery.

Blood contains many proteins called clotting factors that can help to stop bleeding.

People with hemophilia have low levels of either factor VIII (8) or factor IX (9).

The severity of hemophilia that a person has is determined by the amount of factor in the blood.

The lower the amount of the factor, the more likely it is that bleeding will occur which can lead to
serious health problems.

Hemophilia A – is also known as (Classic Hemophilia)

• This type is caused by a lack or decrease of clotting factor VIII.

Hemophilia B - aka (Christmas Disease)

• This type is caused by a lack or decrease of clotting factor IX.

• It is named after the first person to be diagnosed with the disorder in 1952, Stephen Christmas.

Both Hemophilia A and B

• Heritable
• X-Linked Recessive – it is a genetic conditions associated with mutations in genes on the X
chromosome. A male carrying such a mutation will be affected, because he carries only
one X chromosome.
• Male Predominant
• Increased PTT

Epidemiology:

➢ Hemophilia A is the most common type of the condition; 1 in 4,000 to 1 in 5,000 males worldwide
are born with this disorder.
➢ Hemophilia B occurs in approximately 1 in 20,000 newborn males worldwide.
➢ Hemophilia A is about four times as common as hemophilia B, and about half of those affected
have the severe form.
➢ Hemophilia affects people from all racial and ethnic groups.

Etiology:

Hemophilia is caused by a mutation or change, in one of the genes, that provides instructions for
making the clotting factor proteins needed to form a blood clot. This change or mutation can prevent
the clotting protein from working properly or to be missing altogether.

These genes are located on the X chromosome. We all know that males have one X and one Y
chromosome (XY) and females have two X chromosomes (XX). Males inherit the X chromosome from
their mothers and the Y chromosome from their fathers. Females inherit one X chromosome from each
parent.

The X chromosome contains many genes that are not present on the Y chromosome. This means that
males only have one copy of most of the genes on the X chromosome, whereas females have 2
copies. Thus, males can have a disease like hemophilia if they inherit an affected X chromosome that
has a mutation in either the factor VIII or factor IX gene.

Females can also have hemophilia, but this is much rarer. In such cases both X chromosomes are
affected or one is affected and the other is missing or inactive. In these females, bleeding symptoms
may be similar to males with hemophilia.
A female with one affected X chromosome is a “carrier” of hemophilia. Sometimes a female who is a
carrier can have symptoms of hemophilia. In addition, she can pass the affected X chromosome with
the clotting factor gene mutation on to her children. Carrier females have about half the usual amount
of coagulation factor VIII or coagulation factor IX, which is generally enough for normal blood clotting.
However, about 10 percent of carrier females have less than half the normal amount of one of these
coagulation factors; these individuals are at risk for abnormal bleeding, particularly after an injury,
surgery, or tooth extraction..

Clinical Manifestations

People with hemophilia may experience:

Spontaneous hemorrhage - a blood clot that arises in the brain parenchyma in the absence of trauma
or surgery.

➢ Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal
bleeding (eg, after circumcision); other neonates may present with severe hematoma and
prolonged bleeding from the cord or umbilical area or at sites of blood draws or immunizations.

Hematuria - the presence of blood in a person's urine.

➢ In the genitourinary tract, gross hematuria may occur in as many as 90% of patients.

General symptoms

➢ Weakness and orthostasis (normal physiological response of the sympathetic system to

counteract a fall in blood pressure when a person is laying down and assumes the upright
position) may occur.

Musculoskeletal - includes bones, muscles, tendons, ligaments and soft tissues.

➢ Tingling (unusual sensation), cracking, warmth, pain, stiffness (you feel pain in your muscles and
cannot move easily), and refusal to use the joint among children are common.

Central nervous system

➢ Headache, stiff neck, vomiting, lethargy (lack of energy), irritability, and spinal cord syndromes
may occur. - The buildup of blood puts pressure on your brain and interferes with its oxygen
supply. This can quickly cause brain and nerve damage.

Genitourinary - the urinary and genital organs.

 ➢ Symptoms may be painless; there may be hepatic/splenic tenderness and peritoneal signs. -
peritoneum is the tissue that lines your abdominal wall and covers most of the organs in your
abdomen. A liquid, peritoneal fluid, lubricates the surface of this tissue.

Hemophilia can result in:

• Bleeding within joints that can lead to chronic joint disease and pain
• Bleeding in the head and sometimes in the brain which can cause long term problems, such as
seizures and paralysis
• Death can occur if the bleeding cannot be stopped or if it occurs in a vital organ such as the
brain.

Pathophysiology (mechanism, types, stages):

Coagulation cascade

➢ Activated factor VII and tissue factor work together to activate factor 10 to activated factor 10
and i wanted to mention that activation of these factors involves proteolytic cleavage of the
precursor, so when we have activated factor 10, activated factor 10 will proteolytically cleaved
small amounts of prothrombin to small amounts of thrombin, once we had thrombin this has a
wide variety of downstream effects, it will activate factors of XIII, XI, VII and V. So a lot of different
downstream affects. So when we haven't activated factor XI, activated factor XI proteolytically
cleaves factor IX to activated factor IX. In thrombin is acting on factor VIII to form activated
factor VIII and these factors combined to work on factor X again, proteolytically cleaving even
more factor X to activated factor X. With the activated factor V, and activated factor X,
proteolytically cleaves large amounts of prothrombin to thrombin. Thrombin would act to
fibrinogen to produce fibrin and factor XIII will take the soluble fibrin to make it insoluble fibrin. If
the person has low levels or low activities of the factor VIII and IX, will not gonna get proper fibrin
clot formation because we're not getting activations large amounts of thrombin that's the reason
why it inadequate formation of fibrin clots , it get platelet clogs, but we don't quite an adequate
functioning of secondary hemostasis because of defiency of factor VIII and IX.

Secondary hemostasis refers to the cascade of enzymatic reactions that ultimately results in the
conversion of fibrinogen to fibrin monomers. Fibrin monomers are then cross-linked into insoluble strands
that serve to stabilize the loose platelet clot formed in primary hemostasis.

Investigation/ Diagnostics:

To make a diagnosis, doctors would perform certain blood tests to show if the blood is clotting
properly. If it does not, then they would do clotting factor tests, also called factor assays, to diagnose
the cause of the bleeding disorder. These blood tests would show the type of hemophilia and the
severity.

Screening Tests

Screening tests are blood tests that show if the blood is clotting properly.

Types of screening tests:

Complete Blood Count (CBC)

This common test measures the amount of hemoglobin (the red pigment inside red blood cells
that carries oxygen), the size and number of red blood cells and numbers of different types of white
blood cells and platelets found in blood. The CBC is normal in people with hemophilia. However, if a
person with hemophilia has unusually heavy bleeding or bleeds for a long time, the hemoglobin and
the red blood cell count can be low.

Activated Partial Thromboplastin Time (APTT) Test

This test measures how long it takes for blood to clot. It measures the clotting ability of factors VIII
(8), IX (9), XI (11), and XII (12). If any of these clotting factors are too low, it takes longer than normal for
the blood to clot. The results of this test will show a longer clotting time among people with hemophilia
A or B.

Prothrombin Time (PT) Test

This test also measures the time it takes for blood to clot. It measures primarily the clotting ability of
factors I (1), II (2), V (5), VII (7), and X (10). The results of this test will be normal among most people with
hemophilia A and B.

Clotting Factor Tests

Clotting factor tests, also called factor assays, are required to diagnose a bleeding disorder. This
blood test shows the type of hemophilia and the severity. It is important to know the type and severity
in order to create the best treatment plan.

Severity Levels of Hemophilia

• Severe hemophilia – FVIII or FIX level less than 1% of normal (< 0.01 IU/mL)

• Moderate hemophilia – FVIII or FIX level 1-5% of normal (0.01-0.05 IU/mL)

• Mild hemophilia – FVIII or FIX level more than 5% but less than 40% of normal (>0.05 to < 0.40 IU/mL)

Treatment

The best way to treat hemophilia is to replace the missing blood clotting factor so that the blood
can clot properly. This is done by infusing (administering through a vein) commercially prepared factor
concentrates. People with hemophilia can learn how to perform these infusions themselves so that
they can stop bleeding episodes and, by performing the infusions on a regular basis (called
prophylaxis), can even prevent most bleeding episodes.

Management: Non- Drug & Drug Treatment

Medical Management

The treatment of hemophilia may involve prophylaxis, management of bleeding episodes, treatment
of factor VIII (FVIII) inhibitors, and treatment and rehabilitation of hemophilia synovitis.
Factor VIII and FIX concentrates

Various FVIII and FIX concentrates are available to treat hemophilia A and B; besides improved
hemostasis, continuous infusion decreases the amount of factor used, which can result in significant
savings; obtain factor level assays daily before each infusion to establish a stable pattern of
replacement regarding the dose and frequency of administration.

Desmopressin

Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), is considered

the treatment of choice for mild and moderate hemophilia A; DDAVP stimulates a transient increase in
plasma FVIII levels; DDAVP may result in sufficient hemostasis to stop a bleeding episode or to prepare
patients for dental and minor surgical procedures.

Management of bleeding

Immobilization of the affected limb and the application of ice packs are helpful in diminishing
swelling and pain; early infusion upon the recognition of initial symptoms of a joint bleed may often
eliminate the need for a second infusion by preventing the inflammatory reaction in the joint; prompt
and adequate replacement therapy is the key to preventing long-term complications.

Treatment of patients with inhibitors

Inhibitors are antibodies that neutralize factor VIII (FVIII) and can render replacement therapy
ineffective; the treatment of patients with inhibitors of FVIII is difficult; assuming no anamnestic
response, low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be
overcome with high doses of factor VIII; there is no established treatment for bleeding episodes in
patients with high-titer inhibitors.

Prophylactic factor infusions

The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in
particular to joints; in December 2013, the US Food and Drug Administration (FDA) expanded the
indication for anti-inhibitor coagulant complex (Feiba NF) to include routine prophylaxis in patients with
hemophilia A or B who have developed inhibitors; approval was based on data from a pivotal phase III
study in which a prophylactic regimen resulted in a 72% reduction in median annual bleed rate
compared with on-demand treatment.

Pain management

Hemophilic chronic arthropathy is associated with pain; narcotic agents have been used, but
frequent use of these drugs may result in addiction; nonsteroidal anti-inflammatory drugs may be used
instead because their effects on platelet function are reversible and because these drugs can be
effective in managing acute and chronic arthritic pain; avoid aspirin because of its irreversible effect
on platelet function.

Activity

Generally, individuals with severe hemophilia should avoid high-impact contact sports and other
activities with a significant risk of trauma; however, mounting evidence suggests that appropriate
physical activity improves overall conditioning, reduces injury rate and severity, and improves
psychosocial functioning.

Radiosynovectomy

In patients who develop synovitis from joint bleeds, intra-articular injection of radioisotopes to
ablate the synovium (radiosynovectomy) can be used to decrease bleeding, slow progression of
cartilage and bone damage, and prevent arthropathy- a joint disease, of which arthritis is a type.
Pharmacologic Management

Medications of choice for patients with hemophilia:

Factor VIII

(FVIII) is the treatment of choice for acute or potential hemorrhage in hemophilia A; recombinant
FVIII concentrate is generally the preferred source of factor VIII; prophylactic administration of FVIII is
often recommended for pediatric patients with severe disease.

A prophylactic is a medication or a treatment designed and used to prevent a disease from

occurring.

Antifibrinolytic agents

Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, are especially useful for
oral mucosal bleeds but are contraindicated as initial therapies for hemophilia-related hematuria
originating from the upper urinary tract because they can cause obstructive uropathy or anuria.

A type of drug that helps the blood clot. It prevents the breakdown of a protein called fibrin,
which is the main protein in a blood clot.

Factor IX

Factor IX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage in
hemophilia B. Recombinant factor IX is the preferred source for replacement therapy.

Coagulation factors

FVIII concentrates replace deficient FVIII in patients with hemophilia A, with the goal of achieving
a normal hematologic response to hemorrhage or preventing hemorrhage; recombinant products
should be used initially and subsequently in all newly diagnosed cases of hemophilia that require
factor replacement; agents that bypass FVIII activity in the clotting cascade (eg, activated FVII) are
used in patients with FVIII inhibitors.

Antihemophilic agents

These agents are used to control bleeding in hemophilia B or FIX deficiency and to prevent
and/or control bleeding in patients with hemophilia A and inhibitors to FVIII.

Monoclonal antibodies

Monoclonal antibodies are used to bind to one specific substance in the body (eg, molecules,
antigens); this binding is very versatile and can mimic, block, or cause changes to enact precise
mechanisms (eg, bridging molecules, replacing or activating enzymes or cofactors, immune system
stimulation).

Vasopressin-related

Desmopressin transiently increases the FVIII plasma level in patients with mild hemophilia A.

The interventions for a child with hemophilia are:

Relieve pain

Immobilize joints and apply elastic bandages to the affected joint if indicated; elevate affected
and apply a cold compress to active bleeding sites, but must be used cautiously in young children to
prevent skin breakdown.

Maintain optimal physical mobility

Provide gentle, passive ROM exercise when the child’s condition is stable; educate on preventive
measures, such as the application of protective gear and the administration of factor products; and
refer for physical therapy, occupational therapy, and orthopedic consultations, as required.
Assist in the coping of the family

Encourage family members to verbalize problem areas and develop solutions on their own;
encourage family members to express feelings, such as how they deal with the chronic needs of a
family member and coping patterns that help or hinder adjustment to the problems.

Prevent bleeding

Monitor hemoglobin and hematocrit levels; assess for inhibitor antibody to factor VIII; anticipate
or instruct in the need for prophylactic treatment before high-risk situations, such as invasive diagnostic
or surgical procedures, or dental work; and provide replacement therapy of deficient clotting factors.

A hematocrit test measures the proportion of red blood cells in your blood. Red blood cells carry
oxygen throughout your body. Having too few or too many red blood cells can be a sign of certain
diseases.

Prevent injury

Utilize appropriate toys (soft, not pointed or small sharp objects); for infants, may need to use
padded bed rail sides on crib; avoid rectal temperatures; provide appropriate oral hygiene (use of a
water irrigating device; use of a soft toothbrush or softening the toothbrush with warm water before
brushing; use of sponge-tipped toothbrush); and avoid contact sports such as football, soccer, ice
hockey, karate.

Recommendations/ Monitoring:

To avoid excessive bleeding and protect your joints:

• Exercise regularly

o Activities such as swimming, bicycle riding and walking can build muscles while
protecting joints. Contact sports — such as football, hockey or wrestling — are not safe for
people with hemophilia.

• Avoid certain pain medications

o Drugs that can make bleeding worse include aspirin and ibuprofen (Advil, Motrin IB,
others). Instead, use acetaminophen (Tylenol, others), which is a safer alternative for mild
pain relief.
People with haemophilia should not take aspirin (ASA or acetylsalicyclic acid), or
anything containing aspirin, because it interferes with the stickiness of the blood platelets
and adds to problems with bleeding.
Aspirin is non-selective and irreversibly inhibits both forms (but is weakly more selective for
COX-1). It does so by acetylating the hydroxyl of a serine residue. Normally COX
produces prostaglandins, most of which are pro-inflammatory, and thromboxanes, which
promote clotting.

• Avoid blood-thinning medications

o Medications that prevent blood from clotting include heparin, warfarin (Jantoven),
clopidogrel (Plavix), prasugrel (Effient), ticagrelor (Brilinta), rivaroxaban (Xarelto),
apixaban (Eliquis), edoxaban (Savaysa) and dabigatran (Pradaxa).

• Practice good dental hygiene

o The goal is to prevent tooth and gum disease, which can lead to excessive bleeding.

• Get vaccinations

o People with hemophilia should receive recommended vaccinations at the appropriate

ages, as well as hepatitis A and B. Requesting use of the smallest gauge needle and
 having pressure or ice applied for 3 to 5 minutes after the injection can reduce the risk of
bleeding.
Why should my child get the hepatitis A shot? Protects your child from hepatitis A, a
potentially serious disease. Protects other people from the disease because children
under 6 years old with hepatitis A usually don't have symptoms, but they often pass the
disease to others without anyone knowing they were infected.

• Protect your child from injuries that could cause bleeding

o Kneepads, elbow pads, helmets and safety belts all help prevent injuries from falls and
other accidents. Keep your home free of furniture with sharp corners.

Good quality medical care from doctors and nurses who know a lot about the disorder can
help prevent some serious problems. Often the best choice for care is to visit a comprehensive
Hemophilia Treatment Center (HTC). An HTC not only provides care to address all issues related to
the disorder, but also provides health education that helps people with hemophilia stay healthy.

Case presentation and PCot Plan –FARM

4-year-old boy presents to the emergency department complaining of swelling in his left
elbow joint. He and his mother deny trauma to the elbow. On further questioning his mother told
that she also experienced swollen joints. It was also found out that the mother has a family history
of hemophilia.

Note : Some of the hemophilia gene carrier also experienced symptoms of hemophilia.

FINDINGS ASSESSMENT RESOLUTION MONITORING

➢ Swollen ➢ The patient Pharmacologic: ➢ Avoid excessive

elbow joint might inherit his bleeding and
➢ Desmopressin
mother’s protect your
➢ His mother
disorder with the ➢ Factor VIII / joints
also
symptom of Factor IX
experienced ➢ Exercise
hemarthrosis.
swollen joints ➢ Tranexamic Acid regularly
and has a ➢ The mother is a
➢ Replacement ➢ Avoid certain
family history carrier of
therapy pain
of Hemophilia Hemophilia
medications
gene.

Non-pharmacologic:

➢ Patient should
undergo several
types of
screening test
and physical
exam .