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Other Factor Deficiencies
Factor I ·
Factor II · Factor
V · Factor VII ·
Factor X · Factor
XI · Factor XII ·
Factor XIII |
| There are ten clotting factors that are
necessary in forming a blood clot. Deficiencies in factors
VIII and IX are well known to most people, but what of the
other factor deficiencies? Not everyone is as familiar with
these conditions because they are diagnosed so rarely. To
date, deficiencies in eight of the lesser known coagulation
factors have been documented in the medical literature.
Many of these disorders were only discovered or described
within the last 40 years.
In most cases, rare factor deficiencies
are not genetically sex-linked. They occur in equal
frequency among men and women. By and large the gene is
passed down in an autosomal recessive fashion. This means
that when the factor deficiency is inherited from only one
parent, the child will be a carrier of the condition, but
usually not have symptoms. It is possible for people to
inherit a gene from both parents, but this happens very
rarely and usually means a more severe manifestation of the
disease.
Obtaining a detailed family history is an
important component to diagnosing the condition. Most
people with rare factor deficiencies are best seen by
hematologists at hemophilia treatment centers. Making a
proper diagnosis for some of these rare conditions requires
a quality lab and an experienced hematologist. To find a
treatment center located closest to you, click here.
Not all factor deficiencies have the same
severity. Not everyone with these disorders needs
treatment. However for those who do, the treatments
available for people with rare factor deficiencies are not
optimal. Many people in the United States with rare factor
deficiencies need to take fresh frozen plasma, prothrombin
complex concentrates (PCCs) or cryoprecipitate.
Since there are such a small number of
patients with these conditions, there are few clinical
studies regarding the use of products to treat them.
Without solid clinical data, obtaining FDA approval for
products is extremely difficult. Very few pharmaceutical
companies will choose to invest the research dollars needed
to produce such products for so few patients. |
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Factor I Deficiency |
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(can also
be known as Fibrinogen deficiency,
afibrinogenemia, dysfibrinogenemia, or
hypofibrinogenemia)
Factor I
deficiency is actually a collective term for
several rare inherited fibrinogen deficiencies.
Fibrinogen may be absent from the blood
altogether (afibrinogenemia), present in only
very low levels in the blood (hypofibrinogenemia),
or measurable in normal quantities but defective
(dysfibrinogenemia).
The incidence of
Factor I deficiency is estimated at 1 to 2 per
million. It is inherited in an autosomal
recessive fashion, which means it affects men
and women equally.
Fibrinogen helps
platelets to glue together to form the initial
“plug” in response to an injury. Therefore,
people with factor I deficiency, have a combined
bleeding disorder because both platelets and
clotting are abnormal. The severity of the
disorder is directly related to the amount of
fibrinogen present.
Afibrinogenemia
and hypofibrogenemia are usually diagnosed in
newborns who can present with head bleeds,
bleeding after circumcision and from the site of
the umbilical cord. Easy bruising, nose and
mouth bleeds, and soft tissue bleeds are also
common. Joint bleeding is relatively uncommon.
Women with afibinogenemia have an increased risk
of spontaneous abortion. Persons with
dysfibrinogenemia may have a disposition to
thrombosis.
Diagnosis is made
by measuring the amount of fibrinogen in the
blood, prothrombin time (PT) test, activated
partial thromboplastin time (aPTT) test, and
thrombin clotting time (TCT) test.
Treatment
For now,
cryoprecipitate is the treatment of choice in
the United States. FFP may be given, but
cryoprecipitate is used more often to avoid
volume overload. There are no Factor I
concentrates available for use in the U.S.
However, there are three fibrinogen concentrates
being used in Europe and Japan. There have also
been some reports of adverse reactions with use
of these concentrates.
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Factor II Deficiency |
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(Can
also be known as prothrombin deficiency)
Factor II
deficiency is quite rare, with only 26 cases
reported in the medical literature. The
incidence is estimated at 1 in 2 million. It is
inherited in an autosomal recessive fashion,
which means it affects men and women equally.
Prothrombin is a
precursor to thrombin, which converts fibrinogen
into fibrin which in turn strengthens a
protective clot. Factor II deficiency usually
takes the form of an abnormality in the
structure of prothrombin rather than a lack of
the protein itself. People with a more severe
factor II deficiency have severe bruising,
bleeding from the nose and mouth, menorrhagia,
as well as muscle bleeds, head bleeds and
bleeding after trauma.
Joint bleeding is rare.
Diagnosis is made with a prothrombin time (PT)
test and an activated partial thromboplastin
time (aPTT) test. Levels of prothrombin
deficiency can range from 2% to 50% of normal.
Patients with levels reaching 50% of normal have
little to no bleeding problems. The inherited
condition must be distinguished from the
acquired form of Factor II, which is also
associated with bleeding. Hereditary Factor II
deficiency has also been reported as part of a
combined disorder with factor VII, IX, X and
protein C and S.
Treatment
Moderate bleeding
can be treated with Fresh Frozen Plasma.
Correction of prothrombin can also be achieved
with the use of Prothrombin complex concentrates
(PCCs). However, there are differences in the
amount of factor II present in PCCs, depending
upon the product. There are reported risks of
thromboembolic complications with certain use of
PCCs.
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Factor V Deficiency |
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(Can also be
known as Owren’s disease,
labile factor deficiency,
proaccelerin deficiency or
parahemophilia. Not to be
confused with Factor V
Leiden, which is a type of
thrombophilia.)
The
deficiency was first
described in a Norwegian
patient in 1944. The
incidence of Factor V
deficiency is estimated at 1
per 1 million. It is
usually inherited in an
autosomal recessive fashion,
which means it affects men
and women equally. There
are some case reports of a
dominant pattern of
inheritance in some
families.
The role of
the factor V protein is to
be a catalyst or
“accelerator” in the process
by which prothrombin is
converted to thrombin.
Common characteristics of
factor V deficiency are
bruising, nose and mouth
bleeds. Severe deep tissue
bleeds are uncommon. Among
people with severe forms of
factor V deficiency, there
can be joint bleeding and
risks of head bleeds in
newborns. Women can also
present with menorrhagia.
Diagnosis is
made through activated
partial thromboplastin time
(aPTT) test, prothrombin
time (PT) test and thrombin
clotting time (TCT) test.
Diagnosis can be confirmed
with a factor V assay.
Factor V is found in both
plasma and platelets, so
platelets function may also
be affected. A very rare
condition, known as combined
factor VIII and Factor V is
characterized by more severe
bleeding episodes. The
combined FVIII+FV deficiency
is a separate disorder that
can be mistaken for either
mild factor V or mild factor
VIII deficiency.
Treatment
There are no
available factor V
concentrates. Fresh frozen
plasma (FFP) is the only
treatment available. In
acute cases of severe
bleeding, the addition of
platelet concentrates may be
helpful. Depending upon
availability,
solvent-detergent FFP may
contain a more reliable
level of Factor V than
standard FFP.
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Factor VII
Deficiency |
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(Can
also be known as Alexander’s
disease, stable factor
deficiency, or proconvertin
deficiency. Not to be
confused with acquired
factor VII deficiency, which
is associated with liver
disease.)
Factor VII
was first recognized in
1951, and originally named
serum prothrombin version
accerlerator (SPCA)
deficiency. Although the
published incidence of
Factor VII deficiency is
estimated at 1 in 500,000,
the disorder may be more
common. It is inherited in
an autosomal recessive
fashion, which means it
affects men and women
equally.
The factor
VII protein is part of the
cascade of clotting factors
that form the chain leading
to a protective blood clot.
Factor VII deficiency is
usually severe. In fact
patients with less than 1%
Factor VII activity
experience similar symptoms
to hemophilia. People with
severe factor VII are prone
to joint bleeds. In
addition to spontaneous
nosebleeds, people can
experience bleeds in the
stomach, intestines and
urinary tract. Head bleeds
and muscle bleeds have also
been reported. Women can
have severe menorrhagia.
Diagnosis
is made through activated
partial thromboplastin time
(aPTT) test, prothrombin
time (PT) test and thrombin
time (TT) test. Diagnosis
can be confirmed with a
factor VII assay. There
have been instances of
combined Factor VII
deficiencies with cases of
Factors II, IX and X.
Treatment
In July
2005, Novo Nordisk received
FDA-approval for a new usage
indication of its
recombinant factor VIIa
product Novoseven® to treat
bleeding episodes in
patients with factor VII
deficiency.
Prothrombin complex
concentrates (PCCs) can also
be used to treat Factor VII
deficiency. However, the
amount of factor VII
contained in these products
vary considerably among PCCs.
Not only is there a marked
difference in factor content
between the different
commercial preparations, but
factor content can also vary
between product lots
produced by the same
manufacturer.
Patients
with factor VII deficiency
can also be treated with
fresh frozen plasma (FFP).
However, volume constraints
may limit the amount of FFP
that can be used. There have
been cases of thrombosis
reported in people with
factor VII deficiency.
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Factor X
Deficiency |
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(Can also be
known as Stuart-Prower
Factor Deficiency)
Factor X
deficiency was first
discovered in a man with the
surname Stuart from North
Carolina. While his doctors
had originally thought he
might have factor VII
deficiency, a woman with the
surname Prower was
determined to have the same
clotting abnormality.
Researchers realized that
this was a new factor and
called it the Stuart-Prower
factor. It was later
renamed Factor X
deficiency.
The
incidence of Factor X is
estimated at 1 in 500,000
births. It is inherited in
an autosomal recessive
fashion, which means it
affects men and women
equally.
The factor
X protein activates the
enzymes that help to form a
clot. Several genetic
variations of Factor X with
varying degrees of severity
have been described in the
medical literature. People
with mild forms of the
deficiency, usually do not
experience bleeding
episodes, but do have
bleeding after trauma or
surgery. Patients with
severe forms of the disease,
commonly have joint
bleeding, gastrointestinal
bleeds, and hematomas.
Spontaneous head bleeds,
spinal cord bleeds and
bleeding at the site of the
umbilical cord have also
been reported. Women with
Factor X deficiency may have
menorrhagia or be
susceptible to first
trimester miscarriage.
Diagnosis
is made through a bleeding
time test, prothrombin time
(PT) test, and partial
thromboplastin time (PTT)
test. Diagnosis can be
confirmed by a factor X
assay, or a ruffle viper
venom time assay.
Treatment
There are
no factor X concentrates
available and fresh-frozen
plasma is normally used as
treatment. Prothrombin
Complex concentrates (PCCs)
have been used in patients,
but it is important to know
that the amount of factor X
in each product in not
consistent. There has also
been a reported risk of
thromboembolic complications
with PCC product usage.
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Factor XI
Deficiency |
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(Can
also be
known as
Hemophilia
C,
Plasma
Thromboplastin
Antecedent
(PTA)
Deficiency,
Rosenthal
Syndrome)
Factor
XI was
only
first
recognized
in
1953.
The
incidence
of
Factor
XI is
estimated
at 1 in
100,000.
It is
inherited
in an
autosomal
dominant
fashion,
which
means it
affects
men and
women
equally.
It can
occur
with
greater
frequency
in
people
of
Ashkenazi
Jewish
descent
because
intermarriage
among
this
group
has been
more
prevalent.
In
Israel,
factor
XI
deficiency
has been
estimated
to be
around
8% among
Ashkenazi
Jews,
making
it one
of the
most
common
genetic
disorders
in this
group.
Factor
XI is
another
part of
the
cascade
of
clotting
factors
that
form the
chain
leading
to a
protective
clot.
Some
people
with
Factor
XI
deficiency
may have
milder
symptoms
that
those of
hemophilia,
but
there
can be
quite a
bit of
variability
with
this
deficiency.
Individuals
are not
likely
to bleed
spontaneously,
and
hemorrhage
normally
occurs
after
trauma
or
surgery.
Certain
procedures
carry an
increased
risk of
bleeding
such as,
dental
extractions,
tonsillectomies,
surgery
in the
urinary
and
genital
tracts
and
nasal
surgery.
Joint
bleeds
are
uncommon.
Patients
are more
prone to
bruising,
nosebleeds,
or blood
in the
urine.
Woman
may
experience
menorrhagia
and
prolonged
bleeding
after
childbirth.
Diagnosis
is made
through
bleeding
time
test,
platelet
function
tests
and
prothrombin
time
(PT) and
activated
partial
thromboplastin
time (aPTT)
tests.
A
specific
Factor
XI assay
is
extremely
useful
in
ruling
out
combined
deficiencies.
Treatment
In the
United
States,
there
are no
factor
XI
concentrates
available
and
fresh-frozen
plasma
is
normally
used for
treatment.
Since
Factor
XI is
not
concentrated
in fresh
frozen
plasma,
considerable
amounts
of
plasma
may be
required
to
maintain
the
factor
level.
In the
case of
mouth
bleeds,
antifibrinolytic
products
such as
Amicar
can be
helpful.
Currently
there
are two
factor
XI
concentrates
produced
in
Europe.
One is
manufactured
through
Bioproducts
Laboratories
(BPL) in
the UK.
The
other
product
is
produced
in
France
through
LFB and
only for
limited
patient
use.
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Factor XII
Deficiency |
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(Can
also be
known as
Hageman
factor
deficiency)
This
somewhat
mysterious
deficiency
was
first
discovered
in 1955
and
named
after
John
Hageman,
the
first
patient
diagnosed
with the
condition.
The
incidence
of
Factor
XII
deficiency
is
estimated
at 1 in
1
million.
This
deficiency
is
inherited
in an
autosomal
recessive
fashion,
which
means it
affects
men and
women
equally.
It has
been
reported
that
factor
XII
levels
seem to
be lower
among
Asians,
than any
other
ethnic
group.
The
mystery
of
Factor
XII
centers
on how
the
protein
is a
step in
the
process
of
forming
a clot,
but
people
with the
deficiency
usually
do not
experience
bleeds
and
normally
do not
require
treatment.
Having a
low
factor
XII
level
has
little
to no
clinical
significance.
Even
with
major
surgery,
bleeding
manifestations
are
extremely
rare.
In fact,
most
people
only get
diagnosed
by
chance,
or
during
pre-screening
blood
tests
for
surgery.
Since
bleeding
time is
usually
normal,
diagnosis
is made
by a
prolonged
activated
partial
thromboplastin
time (aPTT)
test. A
specific
factor
XII
assay is
necessary
to
confirm
the
initial
diagnosis.
Treatment
Treatment
is
usually
unnecessary.
There is
some
indication
that
Factor
XII
deficiency
may
predispose
people
to
thrombosis,
but this
has not
been
clearly
established
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Factor XIII
Deficiency |
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(Can
also be
known as
Fibrin
Stabilizing
Factor
deficiency)
This
condition
is
perhaps
the
rarest
of all
factor
deficiencies.
The
incidence
of
Factor
XIII
deficiency
is
estimated
at one
in five
million
births.
It is
inherited
in an
autosomal
recessive
fashion,
which
means it
affects
men and
women
equally.
No
racial
or
ethnic
group is
disproportionately
affected.
Factor
XIII is
the
protein
responsible
for
stabilizing
the
formation
of a
blood
clot.
In the
absence
of
Factor
XIII, a
clot
will
still
develop
but it
will
remain
unstable.
When
someone
has a
deficiency
of
Factor
XIII,
the
tenuously
formed
clot
will
eventually
break
down and
cause
recurrent
bleeds.
The
prolonged
bleeding
that is
associated
with
Factor
XIII is
usually
associated
with
trauma.
Among
severe
patients
there is
a high
risk of
head
bleeds
with or
without
trauma.
Bleeding
immediately
after
surgery
is
usually
not
excessive,
but can
be
delayed.
Women
who go
untreated
risk
spontaneous
abortion.
Men with
the
deficiency
may show
signs of
infertility.
Common
characteristics
include
soft
tissue
bleeds,
menorrhagia,
joint
bleeding,
and
persistent
bleeding
during
circumsicion
or at
the site
of the
umbilical
cord.
Diagnosis
is made
by
normal
coagulation
screening
tests
and a
detailed
family
history.
Specific
factor
XIII
assays
can
confirm
the
diagnosis.
The
condition
can also
be
defined
by a
clot
solubility
test.
Treatment
There
are
currently
two
commercially-produced
factor
XIII
concentrates
produced
in
Europe.
One is
manufactured
by Bio
Products
Laboratory
(BPL)
and is
only
available
in the
United
Kingdom.
The
other
product
is
called
Fibrogammin-P,
produced
by
Beringwerke
of
Germany.
It is
only
available
under
IND or
through
clinical
trial in
the
United
States.
Neither
of these
products
is FDA
approved
for use
in the
United
States.
For the
time
being,
cryoprecipitate
or
fresh-frozen
plasma
is used
to treat
factor
XIII
deficiency.
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