Although it is much rarer, a girl
can have hemophilia, but she would
have to have the defective gene on
both of her X chromosomes or have
one hemophilia gene plus a lost or
defective copy of the second X
chromosome that should be carrying
the normal genes. If a girl has one
copy of the defective gene on one of
her X chromosomes and a normal
second X chromosome, she does not
have hemophilia but is said to be
A. OVERVIEW heterozygous for hemophilia (a
carrier). Her male children have a
Hemophilia is not one disease 50% chance of inheriting the one
but rather one of a group of inherited mutated X gene and thus have a
bleeding disorders that cause 50% chance of inheriting hemophilia
abnormal or exaggerated bleeding from their carrier mother.
and poor blood clotting. The term is
most commonly used to refer to two Hemophilia A occurs in about 1
specific conditions known as out of every 5000 live male births.
hemophilia A and hemophilia B, Hemophilia A and B occurs in all
which will be the main subjects of this racial groups. Hemophilia A is about
article. Hemophilia A and B are four times more common than B. B
distinguished by the specific gene occurs in about 1 out of 20- 30,000
that is mutated (altered to become live male births.
defective) and codes for a defective
clotting factor (protein) in each Hemophilia has been called the
disease. Rarely, hemophilia C (a Royal Disease because Queen
deficiency of Factor XI) is Victoria, Queen of England from
encountered, but its effect on clotting 1837 to 1901, was a carrier. Her
is far less pronounced than A or B. daughters passed the mutated gene
on to members of the royal families
Hemophilia A and B are inherited of Germany, Spain, and Russia.
in an X-linked recessive genetic Alexandra, Queen Victoria's
pattern and are therefore much more granddaughter, who became Tsarina
common in males. This pattern of of Russia in the early 20th century
inheritance means that a given gene when she married Tsar Nicholas II,
on the X chromosome expresses was a carrier. Their son, the
itself only when there is no normal Tsarevich Alexei, suffered from
gene present. For example, a boy hemophilia.
has only one X chromosome, so a
boy with hemophilia has the
defective gene on his sole X
chromosome (and so is said to be
hemizygous for hemophilia).
Hemophilia is the most common
X-linked genetic disease.
16
B. PATHOPHYSIOLOGY calnexin and calreticulin, enhance
both FVIII secretion and degradation.
A part of the factor FVIII protein in
Factor VIII production, processing,
the endoplasmic reticulum is
and structure
degraded within the cell. The other
Primary sites of factor VIII (FVIII) part enters the Golgi apparatus,
production are thought to be the where several changes occur to
vascular endothelium in the liver and produce the heavy and light chains
the reticuloendothelial system. Liver and to modify the carbohydrates.
transplantation corrects FVIII The addition of sulfates to tyrosine
deficiency in persons with residues of the heavy and light
hemophilia. chains is necessary for full
FVIII messenger RNA has been procoagulant activity, with the
detected in the liver, spleen, and sulfated region playing a role in
other tissues. [2]Studies of FVIII thrombin interaction. This
production in transfected cell lines posttranslational sulfation of tyrosine
have shown that following synthesis, residues impacts the procoagulant
FVIII moves to the lumen of the activity of factor VIII and its
endoplasmic reticulum, where it is interaction with von Willebrand factor
bound to several proteins that (vWF).
regulate secretion, particularly von Willebrand factor
immunoglobulin binding protein, from FVIII circulates in plasma in a
which it has to dissociate in an noncovalently bound complex with
energy-dependent process. vWF, which plays significant roles in
Cleavage of FVIII's signal peptide the function, production, stabilization,
and the addition of oligosaccharides conformation, and immunogenicity of
also occur in the endoplasmic FVIII. [3] VWF has been termed
reticulum. The chaperone proteins, FVIII-related antigen (FVIII-R);
17
related terminology for FVIII is
FVIII-coagulant (FVIII-C). Other: Epistaxis, oral mucosal
VWF appears to promote assembly hemorrhage, hemoptysis,
of the heavy and light chains of FVIII dyspnea (hematoma leading to
and more efficient secretion of FVIII airway obstruction),
from the endoplasmic reticulum. It compartment syndrome
also directs FVIII into the symptoms, and contusions;
Weibel-Palade bodies, which are the excessive bleeding with routine
intracellular storage sites for vWF.
dental procedures
In plasma, vWF stabilizes FVIII and
protects it from degradation. In the
DIAGNOSIS
presence of normal vWF protein, the
half-life of FVIII is approximately 12
hours, whereas in the absence of Laboratory studies for suspected
vWF, the half-life of FVIII-C is hemophilia include the following:
reduced to 2 hours.
Complete blood cell count
Screening coagulation studies
C. SIGNS AND SYMPTOMS
(prothrombin time [PT], activated
Depending on the level of FVIII partial thromboplastin time
activity, patients with hemophilia may [aPTT])
present with easy bruising;
FVIII assay
inadequate clotting of traumatic or
even mild injury; or, in the case of
FVIII inhibitor assay (Bethesda
severe hemophilia, spontaneous
assay, Nijmegen modified
hemorrhage.
Bethesda assay)
Signs of hemorrhage include the
following:
General: Weakness, orthostasis, D. CAUSES
tachycardia, tachypnea
As mentioned above, hemophilia
Musculoskeletal (joints): Tingling, is caused by a genetic mutation. The
cracking, warmth, pain, stiffness, mutations involve genes that code
for proteins that are essential in the
and refusal to use joint (children)
blood clotting process. The bleeding
symptoms arise because
CNS: Headache, stiff neck,
bloodclotting is impaired. The
vomiting, lethargy, irritability, and process of blood clotting involves a
spinal cord syndromes series of complex mechanisms
involving 13 different proteins,
Gastrointestinal: Hematemesis, classically termed factors I through
melena, frank red blood per XIII and written with Roman
rectum, and abdominal pain numerals. If the lining of the blood
vessels becomes damaged, platelets
Genitourinary: Hematuria, renal are recruited to the injured area to
colic, and post circumcision form an initial plug. These activated
bleeding platelets release chemicals that start
18
Hemophilia A is more common
than hemophilia B. About 80% of
people with hemophilia have
hemophilia A. Hemophilia B occurs
in about 1 out of every 20,000 to
30,000 people. A subgroup of those
with hemophilia B has the so-called
Leyden phenotype, which is
characterized by a severe
hemophilia in childhood that
improves at puberty.
E. TREATMENT
The mainstay of treatment is
replacement of the blood clotting
factors. Clotting factor concentrates
can be purified from human donor
blood or made in the laboratory using
methods that do not use donor blood.
This type of therapy is known as
replacement therapy. Clotting factor
replacement therapy is carried out by
infusing the clotting factor
the clotting cascade, activating the
concentrates into a vein, much like
series of 13 proteins known as
a blood transfusion. This type of
clotting factors. Ultimately, fibrin is
therapy can be administered at home
formed, the protein that crosslinks
with proper instruction and training.
with itself to form a mesh that makes
up the final blood clot. The protein
Depending upon the severity of
involved with hemophilia A is factor
the condition, replacement therapy of
VIII (factor 8) and with hemophilia B
the deficient clotting factor may be
is factor IX (factor 9).
carried out on an as-needed basis
(called demand therapy) or on a
Hemophilia A is caused by a
regular basis to prevent bleeding
mutation in the gene for factor VIII,
episodes (known as prophylactic
so there is deficiency of this clotting
therapy).
factor. Hemophilia B (also called
Christmas disease) results from a
People who have mild cases of
deficiency of factor IX due to a
hemophilia A are sometimes treated
mutation in the corresponding gene.
with the drug desmopressin, also
known as DDAVP. This drug
A condition referred to as
stimulates release of substances
hemophilia C involves a deficiency of
from platelets that help form the
clotting factor XI. This condition is
platelet plug. It is administered either
much rarer than hemophilia A and B
slowly through the intravenous route
and typically leads to mild symptoms.
(IV) or, occasionally, in nasal spray
It is also not inherited in an X-linked
form.
manner and affects persons of both
sexes.
19
Pain relievers may be prescribed tolerance therapy (ITT) or immune
for symptom relief, but pain relievers tolerance induction (ITI). In cases of
other than aspirin or non-steroidal severe hemophilia A with persistence
anti-inflammatory medications (such of inhibitors, other factor
as naproxen, ibuprofen) must be concentrates, such as activated
used, since these types prothrombin complex concentrate or
of drugs further inhibit the blood's recombinant factor VIIa, are
ability to administered to attempt to help
clot. Acetaminophen (Tylenol and control bleeding.
others) is often given for pain relief.
The development of inhibitors to
Inhibitors factor IX is much less common and
occurs in about 1% of those with
A major complication of hemophilia B. However, these can
treatment is the development of cause a very serious allergic
so-called inhibitors to the clotting reaction when factor IX concentrates
factors. Inhibitors (antibodies) are are given. Immune tolerance therapy
produced because the body sees the to eliminate inhibitors is less
factor concentrates used to treat successful than with hemophilia A.
patients to reduce or prevent
bleeding, as foreign and activates an F. PROGNOSIS
immune response in the patient to
destroy the foreign substances
Before factor concentrates were
(factor VIII or factor IX).
developed, those with hemophilia
had a significantly decreased life
Inhibitors to factor VIII are the
expectancy. Life expectancy before
most common and occur in about
the 1960s for those with severe
one-third of those with severe
hemophilia was limited to 11 years.
hemophilia A and about 1 out of
Currently, the mortality (death) rate
every 50 people with mild or
for males with hemophilia is twice
moderate hemophilia A. They
that of healthy males. As mentioned
typically develop in childhood in
before, the increase in HIV
those with severe hemophilia A and
and hepatitis infections associated
later in life in milder cases. Inhibitors
with therapy during the 1980s led to
destroy both the replacement factor
a corresponding increase in death
VIII concentrates as well as any
rates.
factor VIII that is present in the body.
This is a serious complication of
Currently, prompt and adequate
treatment because the factor
treatment can greatly reduce the
concentrates are no longer effective
risks of life-threatening bleeding
in treating the condition. The action
episodes and the severity of
of inhibitors to destroy factor VIII
long-term damage to joints, but joint
concentrates shows different
deterioration remains a chronic
degrees of severity among
complication of hemophilia.
individuals and can even vary over
time in the same individual.
In about two-thirds of cases, the
inhibitors disappear on their own or
with treatment known as immune
20
