Chinese Medical Journal, 2000, Vol
Chinese Medical Journal, 2000, Vol. 113 No. 8 : 677-680 Review
Article
von Willebrand disease in China WANG Yingchun , LI Zhenyu , GU
Jianming , RUAN Changgeng WANG Yingchun First Affiliated Hospital
of Suzhou Medical College, Thrombosis and Hemostasis Research Unit
Jiangsu Institute of Hematology Suzhou 215006, China; LI Zhenyu
First Affiliated Hospital of Suzhou Medical College, Thrombosis and
Hemostasis Research Unit Jiangsu Institute of Hematology Suzhou
215006, China; GU Jianming First Affiliated Hospital of Suzhou
Medical College, Thrombosis and Hemostasis Research Unit Jiangsu
Institute of Hematology Suzhou 215006, China; RUAN Changgeng First
Affiliated Hospital of Suzhou Medical College, Thrombosis and
Hemostasis Research Unit Jiangsu Institute of Hematology Suzhou
215006, China
Correspondence to: Changgeng Ruan First Affiliated Hospital of
Suzhou Medical College, Thrombosis and Hemostasis Research
UnitJiangsu Institute of Hematology Suzhou, 215006, China
(Tel:0512-5101708 Fax:86-512-5192662
Email:[email protected] ) Keywords: von Willebrand
factorvon Willebrand factor genevon Willebrand diseasepoint
mutation polymorphismChinese population Abstract: Purpose To review
the molecular pathogenesis in Chinese patients with von Willebrand
disease (vWD) and polymorphisms of von Willebrand factor (vWF) in
Chinese population. Data sources Both Chinese and English language
literature search using MEDLINE (1985-1998), and original articles
published in main Chinese and international journals.Study
selection and data extraction After reviewing of the literature, 19
articles of them were selected that specifically addressed the
stated purpose. Results The molecular pathogenesis of vWD was
variant. Six cases of point mutation have been found in Chinese
patients with vWD. The system of site-directed mutagenesis and
expression of vWF gene was constructed. The polymorphisms of vWF
gene are very different between Chinese and Gaucasians. Conclusion
Combining to gene mutant in vWD patients, the use of site- directed
mutagenesis and expression of vWF will help to understand the vWF
function. The polymorphisms of vWF gene are useful marker in
Chinese for carrier detection and prenatal diagnosis of vWD.
CMJ2000;113(8):677-680
von Willebrand disease (vWD), which is caused by qualitative and
quantitative defects in von Willebrand factor (vWF), is one of the
most common inherited human bleeding disorders. vWF plays an
important role in primary hemostasis by mediating the adhesion of
platelets to sites of vascular damaged by binding to specific
platelet membrane glycoproteins and to constituents of exposed
connective tissue. In addition, vWF is a carrier protein for blood
clotting factor (F) and this interaction is required for normal F
survival in the circulation.
The human vWF gene is localized to chromosome 12
(12p12-pter),[1,2]spans approximately 180 kb and is composed of 52
exons.[3]The 8.9 kb mRNA encodes a primary translation product is
composed of a 22 amino acid signal peptide, a 741 residue
pro-peptide and a 2050 amino acid mature vWF subunit. vWF is
synthesized in megakaryocytes and endothelial cells by a complex
multistep process that results in the assembly of multimers of up
to 100 subunits. These high molecular weight (HMW) multimers appear
to be most effective in platelet binding.
The increase in information about the molecular structure of vWF
has led to a simplified classification of vWD. In 1994, according
to the clinical phenotype, pathological characteristics and
molecular pathogenesis of vWD, the International Thrombosis and
Hemostasis Committee proposed a new classification standard that
divides vWD into 3 categories ( Table 1 ).[4]Type 1 refers to a
partial quantitative deficiency of vWF and autosomal dominant
inheritance. Type 1 is characterized by a concordant reduction in
vWF antigen, ristocetin cofactor activity, and F activity, but vWF
multimers are normal. Type 2 refers to qualitative deficiencies of
vWF and is generally inherited in a dominant manner although rare
cases of apparently recessive inheritance have been reported. Type
2 contains subtype 2A, 2B, 2N and 2M, and is characterized by
defect in vWF function and often also quantity. Type 2A and 2B are
frequently associated with a disproportionately low level of
ristocetin cofactor activity relative to vWF antigen, and a
decrease or absence of the largest vWF multimers. Type 2M and 2N
are associated with specific defects in platelet and F binding
functions, respectively. Type 3 is characterized by a virtually
complete deficiency of vWF. Type 3 is usually defined as autosomal
recessive, this is not a completely consistent finding.
The prevalence of von Willebrand disease ranges from 3 or 4 per
100 000 to as h igh as 1.3% of the population.[5-7]Precise
determination of prevalenc e is difficult because of the variable
expression and reduced penetrance. The e xact prevalence estimate
of vWD in China is unknown. In the past years, patient s with
various types of inherited bleeding disorders, such as hemophilia A
(HA), hemophilia B (HB), Glanzman's thrombasthenia (GT) and vWD
were assessed in our hospital. Ninety-one (42.13 %) of them were
vWD patients. Of all the vWD pat ients, 56 (61.5%) were type 1, 26
(28.6%) type 2 and 9 (9.89%) type 3. Genet ic analysis was
performed in some of patients with type 2 and type 3 vWD by dena
turing gradient gel electrophoresis (DGGE) and sequencing.
Mutations of von Willebrand factor gene in Chinese patients with
vWD Given the complexity of vWF biosysthesis, section and function,
defects at a number of genetic loci could potentially result in a
vWD phenotype. Analysis of the vWF gene was performed in some type
2 and type 3 vWD patients by denaturing gradient gel
electrophoresis and sequencing. From 1996 to 1998 we found six
cases of point mutation in these patients with vWD ( Table 2 ).
Type 2A vWD is the most common qualitative variant, accounting
for approximately 10%-15% of all vWD diagnosis. Most of the
mutations responsible for type 2A vWD cluster within exon 28, which
is 1.4 kb in length, and is the largest of all vWF exons. It
encodes the entire A1 and A2 repeats, including the proteolysis
site of vWF. Analysis of the type 2A vWD phenotype and study of its
molecular pathogenesis will contribute to further understanding of
vWF structure and function and direct gene diagnosis.
Three mutations have been found in these 14 patients with type
2A vWD.[8 9]They are Arg611His, Ala737Glu and Arg834Trp and all are
hot point mut ations locating on the GpC island. Arg611His
substitution has been reported i n 2 unrelated families[10]and
locates on the A1 domain of vWF. Most type 2B vWD mutations have
been found in this domain, but the mutation reported here is
associated with decreased ristocetin cofactor activity and the
absence of la rge and intermediate vWF multimers. Arg611His
mutation resulted in a decrease d affinity of vWF for glycoprotein
Ib. This type is often identified as a type 2A vWD variant.
Arg834Trp is the most common mutation in 2A vWD. In vitro
expression confirmed that Arg834Trp did not disturb the assembly
and secretion of multimers of vWF in cells, but the absence of
large and intermediate vWF multimers was due to the high
susceptibility of vWF to proteolysis in plasma.[11]
Two patients from the same hemorrhagic family showed prolonged
bleeding times, markedly decreased ristocentin induced platelet
aggregation, decrease of vWFAg and FVIIIAg, and the absence of
large and intermediate molecular weight form of von Willebrand
factor multimers in plasma, were studied recently. A novel missense
mutation of C to A transition was detected, which resulted in
Ala737Glu substitution. The type 2A vWD family with Ala737Glu
mutation showed the characteristics of autosomal dominant
inheritance. Among 19 members within 4 generations 9 possessed
similar bleeding symptoms. The mutation located within the A2
domain of vWF, within which most type 2A vWD were clustered. The
Ala737Glu substitution is considered a new mutation in the vWD
database.[12]
We constructed an expression plasmid pSVA737EvWF containing the
full length cDNA of vWF which included the Ala737Glu substitution
by site-direct mutagenesis. Recombinant vWF containing the
candidate mutation was transitorily expressed in COS-7 cells.
Compared with wild type, recombinant vWF expressed in conditioned
media was 76.4%, while in cell lysate was 98.8%. The multimer
pattern of extracellular pSVA737EvWF was indistinguishable from
that of the wild type, and both were comprised of a variety of
molecular weights. The existence of many molecular weight multimers
in platelets from patients indicated that the mutant didn't disturb
the conformation of structure and secretion of vWF. The absence of
large and intermediate multimers in plasma is possibly due to
mutation in the vWF gene where a neutral amino acid is replaced by
an acidic amino acid, resulting in a conformational change and an
abnormally increased susceptiblity to proteolysis in plasma.
Combined with gene mutantion in vWD patients, the use of site-
directed mutagenesis and expression of vWF will help us understand
the function of vWF and give us a model for studying the molecular
pathology in other bleeding disorders.
Type 2N vWD patients have a phenotype similar to mild hemophilia
A. The FVIII binding domain has been localized to the N-terminal
fragment composed of 272 amino acid residues, encoded by exon 18-23
of the vWF gene. Mutations detected in type 2N vWD were all located
within exon 18-20 of the vWF gene. We found two novel candidates
with missense mutations in this type. One abnormal pattern is in
exon 18 of the vWF gene of the type 2N pedigree. DNA sequencing
demonstrated a heterozygous G to A transition, substituting
glutamic acid to glycine in position 22.[13]This novel missense
mutation creates a new restriction site for the enzyme SacI. The
family study showed that the mutation originated from the mother.
For another candidate, we screened exon 18-20 of the vWF gene from
22 patients with mild phenotypes of hemophilia A by DGGE and found
that one fragment of exon 18 showed an abnormal electrophoretic
pattern. DNA sequencing demonstrated an A to G transition at
nucleotide 2398 in exon 18, substituting Met to Val at position 37
in the mature vWF subunit.
Type 3 vWD represents a severe form of the disease with a nearly
complete deficiency of vWF in plasma. Most of the identified
mutations in type 3 vWD gene deletions are nonsense mutations. A
mutation was detected in a type 3 vWD patient by our lab[14]and was
a nonsense mutation of C to A transition at nucleotide 212 in exon
3 of the vWF gene, introducing a stop codon at 71. This mutation
created a Xba 1 restriction enzyme site and eliminated a Taq 1
restriction site. The patient was homozygous for the mutation and
his parents were heterozygous, whose FVIIIAg, vWFAg and bleeding
time were normal.
Polymorphism of von Willebrand factor in Chinese population The
vWF gene is one of the most polymorphic genes with more than 40
polymorphic sites having been reported.[15]Wu et al[16]first found
the restriction fragment length polymorphism (RFLP) of Xba 1 and
BamH 1 in the 5' end of the vWF gene using Southern blot and found
that the heterozygous rate is 0.49 and 0.46, respectively. In
addition, there are many variable number tandem repeats (VNTR) in
intron 40 of the vWF gene, and the heterozygous rate is high. The
study of 142 chromosomes in 71 Chinese people in the Suzhou and
Kunming area showed that there are ATCT tandem repeated sequences
in the vWF gene of Chinese people, with 8 alleles in the area of
the nt 1880-1980 in the vWF gene. The total theoretical
heterozygous rate is 79.4%.[17]DNA samples from 112 normal people
in Shanghai area were also assayed and 7 and 5 types of VNTR were
identified on nt 1890-1990 and nt 2215-2380, respectively. The
heterozygous rates were 75% and 74%, respectively.[18]
The vWF gene from 52 unrelated individuals of Han Nationality,
44 of the Yi tribe, and 42 of the Dai tribe were amplified by PCR
and subsequently analysis with restriction enzyme digestion with
Sma I, Hha I, Msp I and Rsa I ( Table 2 ).[19]
The allele frequencies of Sma I, and Hha I of the vWF gene are
very different between Chinese and Caucasians, though the
theoretical heterozygous rates in the two populations are similar.
In the three races of Chinese, allele frequencies and theoretical
rates show very little difference. Allele frequencies and
theoretical rates of MspI in the vWF gene in Chinese are lower than
these of Caucasians. These gene markers are useful for carrier
detection and prenatal diagnosis of vWD. As for Ras I RFLP of the
vWF gene, the theoretical rate is much lower in Chinese Hans than
that in Caucasians, it has a lower diagnostic value in family
analysis of vWD in people of Chinese origin.
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von Willebrand disease
DefinitionVon Willebrand disease is caused by a deficiency or an
abnormality in a protein called von Willebrand factor and is
characterized by prolonged bleeding.
DescriptionThe Finnish physician Erik von Willebrand was the
first to describe von Willebrand disease (VWD). In 1926 Dr. von
Willebrand noticed that many male and female members of a large
family from the Aland Islands had increased bruising (bleeding into
the skin) and prolonged episodes of bleeding. The severity of the
bleeding varied between family members and ranged from mild to
severe and typically involved the mouth, nose, genital and urinary
tracts, and occasionally the intestinal tract. Excessive bleeding
during the menstrual period was also experience by some of the
women in this family. What differentiated this bleeding disorder
from classical hemophilia was that it appeared not to be associated
with muscle and joint bleeding and affected women and men rather
than just men. Dr. von Willebrand named this disorder hereditary
pseudohemophilia.
Pseudohemophilia, or von Willebrand disease (VWD) as it is now
called, is caused when the body does not produce enough of a
protein called von Willebrand factor(vWF) or produces abnormal vWF.
vWF is involved in the process of blood clotting (coagulation).
Blood clotting is necessary to heal an injury to a blood vessel.
When a blood vessel is injured, vWF enables blood cells called
platelets to bind to the injured area and form a temporary plug to
seal the hole and stop the bleeding. vWF is secreted by platelets
and by the cells that line the inner wall of the blood vessels
(endothelial cells). The platelets release other chemicals, called
factors, in response to a blood vessel injury, which are involved
in forming a strong permanent clot. vWF binds to and stabilizes
factor VIII, one of the factors involved in forming the permanent
clot.
A deficiency or abnormality in vWF can interfere with the
formation of the temporary platelet plug and also affect the normal
survival of factor VIII, which can indirectly interfere with the
production of the permanent clot. Individuals with VWD, therefore,
have difficulty in forming blood clots and as a result they may
bleed for longer periods of time. In most cases the bleeding is due
to an obvious injury, although it can sometimes occur
spontaneously.
VWD is classified into three basic types: type 1, 2, and 3 based
on the amount and type of vWF that is produced. Type 1 is the most
common and mildest form and results when the body produces slightly
decreased amounts of typically normal vWF. Type 2 can be classified
into five subtypes (A,B,M,N) and results when the body produces an
abnormal type of vWF. Type 3 is the rarest and most severe form and
results when the body does not produce any detectable vWF.
Approximately one out of 100 people are affected with VWD,
making it the most common inherited bleeding disorder (hemophilia).
VWD affects people of all ethnic backgrounds. Approximately
70-80% of people with VWD have type 1 and close to
20-30% have type 2. Type 3 is very rare and occurs in
less than one percent of people with VWD.
Causes and symptomsThe genetics of VWD are complex and involve a
gene that produces vWF and is found on chromosome 12. Since we
inherit two of each type of chromosome we inherit two vWF genes.
There are different types of changes in the vWF gene that can
affect the production of vWF. Some types of changes can cause the
vWF gene to produce decreased amounts of normal vWF, while other
changes can cause the gene to produce abnormal vWF. Most of the
gene changes are significant enough that a change in only one vWF
gene is sufficient to cause VWD. Some gene changes only cause VWD
if both genes are changed, which often leads to more severe
symptoms. Type 1 VWD is called an autosomal dominant condition
since it is caused by a change in only one vWF gene. Since type 1
VWD results in only a slight decrease in the amount of vWF
produced, the symptoms are often mild and even non-existent in some
patients. Most cases of Type 2 VWD are autosomal dominant since
they are caused by a change in only one vWF gene that results in
the production of an abnormal protein. An autosomal dominant form
of VWD can be inherited from either parent or can occur
spontaneously in the embryo that is formed when the egg and sperm
cells come together during fertilization.
Some cases of type 2 VWD and all cases of type 3 VWD are
autosomal recessive since they are caused by changes in both vWF
genes. A person with an autosomal recessive form of VWD has
inherited a changed gene from his or her mother and a changed gene
from his or her father. Parents who have a child with an autosomal
recessive form of VWD are called carriers, since they each possess
one changed vWF gene and one unchanged vWF gene. Many carriers for
the autosomal recessive forms of type 2 VWD and type 3 VWD do not
have any symptoms, although some people with type 3 VWD are born to
parents who have type 1 VWD and may have symptoms. Each child born
to parents who are both carriers for VWD has a 25%
chance of having VWD, a 50% chance of being a carrier,
and a 25% chance of being neither a carrier nor affected
with VWD disease. A person with an autosomal dominant form of VWD
has a 50% chance of passing the changed gene on to his
or her children who may or may not have symptoms.
VWD is usually a relatively mild disorder characterized by easy
bruising, recurrent nosebleeds, heavy menstrual periods, and
extended bleeding after surgeries and invasive dental work. There
is a great deal of variability in the severity of symptoms, which
can range from clinically insignificant to life threatening. Even
people within the same family who are affected with the same type
of VWD may exhibit different symptoms. An individual with VWD may
exhibit a range of symptoms over the course of his or her lifetime
and may experience an improvement in symptoms with age. The
severity of the disease is partially related to the amount and type
of vWF that the body produces, but is also influenced by other
genetic and non-genetic factors.
Type 1Type 1, the mildest form of VWD, is usually associated
with easy bruising, recurrent nosebleeds, heavy menstrual periods,
and prolonged bleeding after surgeries and invasive work. Many
people with type 1 VWD do not have any noticeable symptoms or only
have prolonged bleeding after surgery or significant trauma. The
amount of vWF produced by the body increases during pregnancy, so
prolonged bleeding during delivery is uncommon in people with type
1 VWD.
Type 2People with type 2 VWD usually have symptoms from early
childhood and symptoms may even be present at birth. They usually
experience prolonged bleeding from cuts, easy bruising, nose
bleeds, skin hematomas, and prolonged bleeding from the gums
following teeth extraction and minor trauma. More than
50% of women with type 2 VWD experience heavy periods
that may require a blood transfusion. Gastrointestinal bleeding is
rare but can be life-threatening. Some women with type 2 VWD
exhibit prolonged bleeding during delivery.
Type 3Type 3 VWD can be quite severe and is associated with
bruising and bleeding from the mouth, nose, intestinal, genital and
urinary tracts. Type 3 is also associated with spontaneous bleeding
into the muscles and joints, which can result in joint deformities.
Some women with type 3 VWD experience prolonged bleeding during
delivery.
DiagnosisDiagnostic testingMany people with VWD have mild
symptoms or symptoms that can be confused with other bleeding
disorders making it difficult to diagnose VWD on the basis of
clinical symptoms. VWD should be suspected in any person with a
normal number of platelets in their blood and bleeding from the
mucous membranes such as the nose, gums and gastrointestinal tract.
Testing for an individual with suspected VWD often includes the
measurement of:
how long it takes for the bleeding to stop after a tiny cut is
made in the skin (the bleeding time)
the amount of vWF (vWF antigen measurement)
the activity of vWF (ristocetin co-factor activity)
the amount of factor VIII (factor VIII antigen measurement)
activity of factor VIII
People with type 1 VWD usually have an increased bleeding time
but they may have an intermittently normal bleeding time. They also
have a decreased amount of vWF, and decreased vWF activity and
usually have slightly decreased factor VIII levels and activity.
People with type 2 VWD have a prolonged bleeding time, decreased
activity of vWF and may have decreased amounts of vWF and factor
VIII, and may have decreased factor VIII activity. Type 3
individuals have undetectable amounts of vWF, negligible vWF
activity, factor VIII levels of less than 5-10%, and
significantly reduced factor VIII activity. The activity of vWF is
reduced for all types of VWD, making it the most sensitive means of
identifying all three types of VWD. Patients with borderline
results should be tested two to three times over a three month
period.
Once a patient is diagnosed with VWD, further testing such as
vWF multimer analysis and ristocetin-induced platelet aggregation
(RIPA) may need to be performed to determine the subtype. Multimer
analysis evaluates the structure of the vWF, and RIPA measures how
much ristocetin is required to cause the clumping of platelets in a
blood sample. The vWF multimer analysis is able to differentiate
people with a structurally normal vWF (type 1) from people with a
structurally abnormal vWF (type 2) and is often able to identify
the subtype of patients with type 2 VWD. People with type 1 VWD
usually have normal to decreased RIPA concentrations. Depending on
the subtype, patients with type 2 VWD either have increased or
decreased RIPA. RIPA is usually absent and the multimer analysis
shows undetectable vWF in people with type 3 VWD.
In some cases DNA testing can be a valuable adjunct to
biochemical testing. The detection of gene alteration(s) can
confirm a diagnosis and can determine the type and subtype of VWD.
It can also help to facilitate prenatal testing and testing of
other family members. Unfortunately, as of 2001, many people with
VWD possess DNA changes that are not detectable through DNA
testing. A person who has a mother, father, or sibling diagnosed
with VWD should undergo biochemical testing for VWD. If the
relative with VWD possesses a detectable gene change, then DNA
testing should also be considered.
Prenatal testingIf one parent has been diagnosed with an
autosomal dominant form of VWD or both parents are carriers for an
autosomal recessive form of VWD, then prenatal testing can be
considered. If the parent with an autosomal dominant form of VWD
possesses a detectable gene change or both parents who are carriers
for an autosomal recessive form of VWD possess detectable
mutations, then DNA testing of their fetus would be available. DNA
testing can be performed through amniocentesis or chorionic villus
sampling. If the DNA change in the parent(s) is unknown then
prenatal testing can sometimes be performed through biochemical
testing of blood obtained from the fetal umbilical cord, which is
less accurate and is associated with a higher risk of pregnancy
loss.
TreatmentVWD is most commonly treated by replacement of vWF
through the administration of blood products that contain vWF or
through treatment with desmopressin (DDAVP, 1-deamino-8-D-arginine
vasopressin). DDAVP functions by increasing the amount of factor
VIII and vWF in the bloodstream. Treatment with blood products or
DDAVP may be started in response to uncontrollable bleeding or may
be administered prior to procedures such as surgeries or dental
work. The type of treatment chosen depends on the type of VWD and a
patient's response to a preliminary treatment trial.
Treatment with desmopressinDDAVP is the most common treatment
for people with type 1 VWD. About 80% of people with
type 1 VWD respond to DDAVP therapy. Treatment with DDAVP can also
be used to treat some people with type 2 VWD. Patients with Type 2B
VWD should not be treated with this medication since DDAVP can
induce dangerous platelet clumping. Type 3 VWD should not be
treated with DDAVP since this medication does not increase the
level of vWF in type 3 patients. DDAVP should only be used in
people who have been shown to be responsive through a pre-treatment
trial transfusion with this medication.
DDAVP can be administered intravenously or through a nasal
inhaler. DDAVP has relatively few side effects although some people
may experience facial flushing, tingling sensations, and headaches
after treatment with this medication. Often treatment with this
medication is only required prior to invasive surgeries or dental
procedures.
Treatment with blood productsPatients who are unable to tolerate
or are unresponsive to drug-based treatments are treated with
concentrated factor VIII obtained from blood products. Not all
factor VIII concentrates can be used since some do not contain
enough vWF. The concentrate is treated to kill most viruses,
although caution should be used since not all types of viruses are
destroyed. If the factor VIII concentrates are unable to manage a
severe bleeding episode, then blood products called
cryoprecipitates, which contain concentrated amounts of vWF, or
platelet concentrates should be considered. Caution should be used
when treating with these blood products since they are not treated
to kill viruses.
Other treatments and precautionsMedications called fibrinolytic
inhibitors can be helpful in the control of intestinal, mouth, and
nose bleeding. Estrogens such as are found in oral contraceptives
increase the synthesis of vWF and can sometimes be used in the
long-term treatment of women with mild to moderate VWD. Estrogens
are also sometimes used prior to surgery in women with type 1 VWD.
Some topical agents are available to treat nose and mouth bleeds.
Patients with VWD should avoid taking aspirin, which can increase
their susceptibility to bleeding and people with severe forms of
VWD should avoid activities that increase their risk of injury such
as contact sports.
PrognosisThe prognosis for VWD disease is generally fairly good
and most individuals have a normal lifespan. The prognosis can
depend, however on accurate diagnosis and appropriate medical
treatment.
Key TermsAmniocentesisA procedure performed at 16-18 weeks of
pregnancy in which a needle is inserted through a woman's abdomen
into her uterus to draw out a small sample of the amniotic fluid
from around the baby. Either the fluid itself or cells from the
fluid can be used for a variety of tests to obtain information
about genetic disorders and other medical conditions in the
fetus.
Autosomal dominantA pattern of genetic inheritance where only
one abnormal gene is needed to display the trait or disease.
Autosomal recessiveA pattern of genetic inheritance where two
abnormal genes are needed to display the trait or disease.
Biochemical testingMeasuring the amount or activity of a
particular enzyme or protein in a sample of blood or urine or other
tissue from the body.
CarrierA person who possesses a gene for an abnormal trait
without showing signs of the disorder. The person may pass the
abnormal gene on to offspring.
Chorionic villus sampling (CVS)A procedure used for prenatal
diagnosis at 10-12 weeks gestation. Under ultrasound guidance a
needle is inserted either through the mother's vagina or abdominal
wall and a sample of cells is collected from around the early
embryo. These cells are then tested for chromosome abnormalities or
other genetic diseases.
ChromosomeA microscopic thread-like structure found within each
cell of the body and consists of a complex of proteins and DNA.
Humans have 46 chromosomes arranged into 23 pairs. Changes in
either the total number of chromosomes or their shape and size
(structure) may lead to physical or mental abnormalities.
Deoxyribonucleic acid (DNA)The genetic material in cells that
holds the inherited instructions for growth, development, and
cellular functioning.
Desmopressin (DDAVP)A drug used in the treatment of von
Willebrand's disease.
Diagnostic testingTesting performed to determine if someone is
affected with a particular disease.
DNA testingAnalysis of DNA (the genetic component of cells) in
order to determine changes in genes that may indicate a specific
disorder.
Endothelial cellsThe cells lining the inner walls of the blood
vessels.
Factor VIIIA protein involved in blood clotting that requires
vWF for stability and long-term survival in the bloodstream.
GeneA building block of inheritance, which contains the
instructions for the production of a particular protein, and is
made up of a molecular sequence found on a section of DNA. Each
gene is found on a precise location on a chromosome.
MutationA permanent change in the genetic material that may
alter a trait or characteristic of an individual, or manifest as
disease, and can be transmitted to offspring.
PlateletsSmall disc-shaped structures that circulate in the
blood stream and participate in blood clotting.
Prenatal testingTesting for a disease such as a genetic
condition in an unborn baby.
ProteinImportant building blocks of the body, composed of amino
acids, involved in the formation of body structures and controlling
the basic functions of the human body.
Skin hematomaBlood from a broken blood vessel that has
accumulated under the skin.
von Willebrand factor (vWF)A protein found in the blood that is
involved in the process of blood clotting.
For Your InformationBooks Handin, Robert I. "Disorders of the
Platelet and Vessel Wall." In Harrison's Principles of Internal
Medicine, edited by Anthony S. Fauci, et al. New York: McGraw-Hill,
1998.
Sadler, J.E. "Von Willebrand Disease." In The Metabolic and
Molecular Basis of Inherited Disease, edited by C.R. Scriver, et
al. New York: McGraw Hill, 1995.
Periodicals Ginsburg, David. "Molecular Genetics of von
Willebrand Disease." Thrombosis and Haemostasis 82, no. 2 (1999):
585-591.
Nichols, William C., and David Ginsburg. "Von Willebrand's
Disease." Medicine 76 (Jan. 1997): 1.
Voelker, Rebecca. "New Focus on von Willebrand's Disease."
Journal of the American Medical Association 278 (October 8, 1997):
1137.
Organizations National Hemophilia Foundation. Soho Building, 110
Greene Street, Suite 406, New York, NY 10012. (212) 219-8180.
http://www.hemophilia.org/home.htm.
Other Mannucci, Pier "Desmopressin (DDAVP) in the Treatment of
Bleeding Disorders: The First Twenty Years." The Treatment of
Hemophilia Monograph Series. No. 11 (1998).
Paper, Renee. "Gynecological Complications in Women with
Bleeding Disorders." The Treatment of Hemophilia Monograph Series.
No. 5 (1996).
World Federation of Hemophilia. "Protocols for the Treatment of
Hemophilia and von Willebrand Disease." No. 14 (1998).
Source: Gale Encyclopedia of Medicine, Published December, 2002
by the Gale Group
The Essay Author is Lisa Maria Andres MS, CGC.
Von Willebrand Disease
by Laurie Rosenblum, MPHEn Espaol (Spanish
Version)Definition
Von Willebrand disease (VWD) is an inherited blood disorder. It
decreases the bloods ability to clot. As a result, bleeding lasts
longer than usual. V
Von Willebrand's disease is the most common hereditary bleeding
disorder affecting at least 1% of the population. It affects both
sexes approximately equally. There are no racial or ethnic
associations with this disorder.
Causes
VWD is caused by a reduced amount of a protein called von
Willebrand Factor (vWF) or an abnormality in this protein. This
protein helps blood to clot. When a person is bleeding, blood cells
called platelets form a plug to stop the bleeding. Normally, vWF
allows platelets to adhere to the cells that line the inside of the
blood vessels (endothelium), a process necessary for successful
clotting. If there is not enough vWF or if it is defective,
platelets cannot properly grip onto the injured area and bleeding
does not stop as quickly as it should.
VWF has a separate function of protecting against the break down
of another protein involved in clottingfactor VIII:C. The relative
absence of functioning vWF, therefore, can lead to minor clotting
problems through this mechanism as well.
Von Willebrand disease can often be traced through several
generations in a family. Some have symptoms while others just carry
the gene. Most people with VWD inherit only one gene with the VWD
defect. They have one of the milder forms of the disordereither
type 1 or type 2. This means they have some blood clotting ability.
The small percent of people who inherit two defective genestype 3
VWDhave little clotting ability and experience severe bleeding
episodes.
Types 1 and 2 are usually inherited in what is known as a
"dominant" pattern. A man or woman with the disease has a 50%
chance of passing the gene on to his or her child. This means that
if even one parent has the gene and passes it onto a child, the
child gets the disease. Whether the child has no symptoms, mild
symptoms, or, less commonly, severe symptoms, he or she definitely
has the disease. Regardless of severity of the symptoms, the child
can still pass the gene on to his or her own offspring.
Type III von Willebrand disease, however, is usually inherited
in a "recessive" pattern. This type occurs when the child inherits
the gene from both parents. Even if both parents have mild or
asymptomatic disease, their children are likely to be severely
affected.
Risk Factors
A risk factor is something that increases your chances of
getting a disease or condition. The only risk factor for VWD is
having family members with this disease.
Symptoms
Many people with the VWD gene have very mild symptoms or none at
all. When symptoms do occur, the severity varies from person to
person. Many people only notice symptoms after taking aspirin or
similar medications that interfere with clotting. Symptoms usually
begin in childhood and fluctuate throughout life. Common symptoms
include:
Easy bruising
Frequent or prolonged nosebleeds
Prolonged bleeding from the gums and minor cuts
Heavy or prolonged bleeding during menstrual periods
Bleeding in the digestive system
Prolonged bleeding after injury, childbirth, surgery, or
invasive dental procedures
Diagnosis
Your doctor will ask about your symptoms and medical history,
and perform a physical exam. Blood tests may be done to check the
following:
Bleeding time in VWD it will be prolonged, particularly after
the administration of aspirin
Factor VIII antigen indirectly measures levels of vWF in your
blood; in VWD it will be reduced
Ristocetin cofactor activity shows how well your vWF works; in
VWD it will be decreased
von Willebrand factor multimer examines the different structural
types of vWF in the blood; in VWD it will be reduced
Treatment
Many people with VWD do not need treatment. If you do, your
treatment will depend on the type and severity of your VWD. In many
cases, treatment is only necessary if you are having a surgical or
dental procedure that is likely to cause bleeding.
Treatment may include:
Desmopressin a medicine that usually controls bleeding in mild
cases of type I VWD by raising the level of vWF in the blood. It
can be taken as:
Nasal spray (Stimate)
Injection (DDAVP)
Intravenous infusions to control your bleeding these infusions
are concentrates that contain:
Factor VIII
von Willebrand Factor
Birth control pills may be used to control heavy menstrual
periods in women with type 1 VWD.
Antifibrinolytic medicine (often, Amicar) can be used for
bleeding in the nose or mouth. It helps keep a clot that has
already formed from being dissolved.
Prevention
There are no guidelines for preventing VWD. Genetic counseling
can be helpful to review a detailed family history and discuss
risks and tests available for von Willibrand disease.
RESOURCES:
National Heart, Lung, and Blood Institute
http://www.nhlbi.nih.govNational Hemophilia Foundation
http://www.hemophilia.orgReferences:
Bleeding Disorders. MedlinePlus website. Available at:
http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html. Accessed
October 7, 2005.
Longe JL and Blanchfield DS. The Gale Encyclopedia of Medicine,
2nd ed. Farmington Hills, MI: Gale Research Company; 2001.
Von Willebrand Disease. National Hemophilia Foundation website.
Available at: http://www.hemophilia.org/bdi/bdi_types3.htm.
Accessed October 7, 2005.
Von Willebrands disease: what you need to know about this
inherited disorder. American Journal of Nursing. 2000 Feb.
Last reviewed September 2005 by Mark A. Best, MD, MPH, MBA,
FCAP, FASCP