Von Willebrand disease

Von Willebrand disease (vWD) is the most common hereditary coagulation abnormality
described in humans, although it can also be acquired as a result of other medical conditions. It
arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a multimeric
protein that is required for platelet adhesion. It is known to affect humans and dogs (notably
Doberman Pinschers), and rarely swine, cattle, horses, and cats. There are three forms of vWD:
inherited, acquired, and pseudo or platelet type. There are three types of hereditary vWD: vWD
Type I, vWD Type II, and vWD III. Within the three inherited types of vWD there are various
subtypes. Platelet type vWD is also an inherited condition.
vWD Type I is the most common type of the disorder and those that have it are typically
asymptomatic or may experience mild symptoms such as nosebleeds although there may be
severe symptoms in some cases. There are various factors that affect the presentation and
severity of symptoms of vWD such as blood type.
vWD is named after Erik Adolf von Willebrand, a Finnish pediatrician who first described the
disease in 1926.

Signs and symptoms

The various types of vWD present with varying degrees of bleeding tendency, usually in the
form of easy bruising, nosebleeds and bleeding gums. Women may experience heavy menstrual
periods and blood loss during childbirth.
Severe internal or joint bleeding is uncommon (which mostly occurs in type 3 vWD).

Diagnosisa
When suspected, blood plasma of a patient needs to be investigated for quantitative and
qualitative deficiencies of vWF. This is achieved by measuring the amount of vWF in a vWF
antigen assay and the functionality of vWF with a glycoprotein (GP)Ib binding assay, a collagen
binding assay, or a ristocetin cofactor activity (RiCof) or ristocetin induced platelet
agglutination (RIPA) assays. Factor VIII levels are also performed because factor VIII is bound
to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of
vWF can therefore lead to a reduction in factor VIII levels. Normal levels do not exclude all

forms of vWD, particularly type 2 which may only be revealed by investigating platelet
interaction with subendothelium under flow (PAF), a highly specialized coagulation study not
routinely performed in most medical laboratories. A platelet aggregation assay will show an
abnormal response to ristocetin with normal responses to the other agonists used. A platelet
function assay (PFA) will give an abnormal collagen/adrenaline closure time and in most cases
(but not all) a normal collagen/ADP time. Type 2N can only be diagnosed by performing a
"factor VIII binding" assay. Detection of vWD is complicated by vWF being an acute phase
reactant with levels rising in infection, pregnancy and stress.
Other tests performed in any patient with bleeding problems are a complete blood count
(especially platelet counts), APTT (activated partial thromboplastin time), prothrombin time,
thrombin time and fibrinogen level. Testing for factor IX may also be performed if hemophilia B
is suspected. Other coagulation factor assays may be performed depending on the results of a
coagulation screen. Patients with von Willebrand disease will typically display a normal
prothrombin time and a variable prolongation of partial thromboplastin time.
Laboratory findings in various platelet and coagulation disorders (V - T)
Condition

Vitamin K deficiency or
warfarin

Partial
Prothrombi
Bleeding
thromboplastin
n time
time
time
Normal or
Prolonged mildly
prolonged

Disseminated
Prolonged Prolonged
intravascular coagulation

Platelet
count

Unaffecte
Unaffected
d
Prolonge
Decreased
d

Von Willebrand disease Unaffected

Prolonged or
unaffected

Prolonge
Unaffected
d

Hemophilia

Unaffected

Prolonged

Unaffecte
Unaffected
d

Aspirin

Unaffected

Unaffected

Prolonge
Unaffected
d

Thrombocytopenia

Unaffected

Unaffected

Prolonge
Decreased
d

Liver failure, early

Prolonged Unaffected

Unaffecte
Unaffected
d

Liver failure, end-stage

Prolonged Prolonged

Prolonge Decreased

Laboratory findings in various platelet and coagulation disorders (V - T)

Condition

Partial
Prothrombi
Bleeding
thromboplastin
n time
time
time

Platelet
count

d
Uremia

Unaffected

Unaffected

Prolonge
Unaffected
d

Congenital
afibrinogenemia

Prolonged Prolonged

Prolonge
Unaffected
d

Factor V deficiency

Prolonged Prolonged

Unaffecte
Unaffected
d

Factor X deficiency as
seen in amyloid purpura

Prolonged Prolonged

Unaffecte
Unaffected
d

Glanzmann's
thrombasthenia

Unaffected

Unaffected

Prolonge
Unaffected
d

Bernard-Soulier syndrome Unaffected

Unaffected

Prolonge Decreased or
d
unaffected

Factor XII deficiency

Unaffected

Prolonged

Unaffecte
Unaffected
d

C1INH deficiency

Unaffected Shortened

Unaffecte
Unaffected
d

The testing for vWD can be influenced by laboratory procedures. There are numerous variables
in the testing procedure that may affect the validity of the test results and may result in a missed
or erroneous diagnosis. The chance of procedural errors are typically greatest during the
preanalytical phase (during collecting storage and transportation of the specimen) especially
when the testing is contracted out to an outside facility and the specimen is frozen and
transported long distances.[2] Diagnostic errors are not uncommon, and there is a varying rate of
testing proficiency amongst laboratories with error rates ranging from 7% to 22% in some
studies to as high as 60% in cases of misclassification of vWD sub-type. To increase the
probability of a proper diagnosis testing should be done at a facility with immediate on-site
processing in their own specialized coagulation laboratory.

 Classification and types

Classification

The four hereditary types of vWD described are type 1, type 2, type 3, and pseudo or platelettype. Most cases are hereditary, but acquired forms of vWD have been described. The
International Society on Thrombosis and Haemostasis's (ISTH) classification depends on the
definition of qualitative and quantitative defects.[5]
Type 1

Type 1 vWD (60-80% of all vWD cases) is a quantitative defect which is heterozygous for the
defective gene. The production of von Willebrand factor vWF is decreased. Decreased levels of
vWF are detected at 10-45% of normal, i.e. 10-45 IU.
Many patients are asymptomatic or may have mild symptoms and not have clearly impaired
clotting which might suggest a bleeding disorder. Often the discovery of vWD occurs
incidentally to other medical procedures requiring a blood work-up. Most cases of Type 1 vWD
are never diagnosed due to the asymptomatic or mild presentation of Type I and most people
usually end up leading a normal life free of complications with many being unaware that they
have the disorder.
Trouble may however arise in some patients in the form of bleeding following surgery (including
dental procedures), noticeable easy bruising, or menorrhagia (heavy menstrual periods). There
are also a minority of cases of Type 1 which may present with severe hemorrhagic symptoms.
Type 2

Type 2 vWD (20-30%) is a qualitative defect and the bleeding tendency can vary between
individuals. There are normal levels of vWF, but the multimers are structurally abnormal, or
subgroups of large or small multimers are absent. Four subtypes exist: 2A, 2B, 2M and 2N.
Type 2A

The vWF is quantitatively normal but qualitatively defective. Its ability to bind to the
glycoprotein1 (GP1) receptor on the platelet membrane is diminished, resulting in decreased
platelet adhesiveness and aggregation and abnormally low ristocetin cofactor activity. The ability
of the defective von Willebrand factors to coalesce and form large vWF multimers is also
impaired, resulting in decreased quantity of large vWF multimers. Only small multimer units are
detected in the circulation. Therefore von Willebrand disease type 2A is characterized by
qualitatively defective von Willebrand factor with decreased ability to bind to platelet
glycoprotein1(GP1) and decreased capability at multimerization. Von Willebrand factor antigen
assay is normal. Ristocetin co-factor activity is low and large vWF multimers are reduced or
absent.

Type 2B

This is a "gain of function" defect. The ability of the qualitatively defective von Willebrand
factor to bind to glycoprotein1 (GP1) receptor on the platelet membrane is abnormally enhanced,
leading to its spontaneous binding to platelets and subsequent rapid clearance of the bound
platelets and of the large vWF multimers. Thrombocytopenia may occur. Large vWF multimers
are reduced or absent from the circulation.
The ristocetin cofactor activity is low when the patient's platelet-poor plasma is assayed against
formalin-fixed, normal donor platelets. However, when the assay is performed with the patient's
own platelets (platelet-rich plasma), a lower-than-normal amount of ristocetin causes aggregation
to occur. This is due to the large vWF multimers remaining bound to the patient's platelets.
Patients with this sub-type are unable to use desmopressin as a treatment for bleeding, because it
can lead to unwanted platelet aggregation and aggravation of thrombocytopenia.
Type 2M

Type 2M von willebrand disease is a qualitative defect of von Willebrand factor characterized by
its decreased ability to bind to glycoprotein1 (GP1) receptor on the platelet membrane and
normal capability at multimerization. The vWF antigen levels are normal. The ristocetin cofactor
activity is decreased and high molecular weight large vWF multimers are present in the
circulation.[6]
Type 2N (Normandy)

This is a deficiency of the binding of vWF to coagulation factor VIII. The vWF antigen test is
normal indicating normal quantity of vWF. the ristocetin cofactor assay is normal. Assay for
coagulation factor VIII revealed marked quantitative decrease equivalent to levels seen in
hemophilia A. This has led to some vWD type 2N patients being misdiagnosed as having
hemophilia A.
Type 3

Type 3 is the most severe form of von Willebrand disease (homozygous for the defective gene)
and is characterized by complete absence of production of vWF. The von Willebrand factor is
undetectable in the vWF antigen assay. Since the von Willebrand factor protects coagulation
Factor VIII from proteolytic degradation, total absence of vWF leads to extremely low Factor
VIII level, equivalent to that seen in severe hemophilia A with its clinical manifestations of life
threatening external and internal hemorrhages. The inheritance pattern of vWD type 3 is
autosomal recessive while the inheritance pattern of hemophilia A is x-linked recessive.
Platelet-type

(also known as pseudo-vWD or platelet-type vWD)

Platelet-type vWD is an autosomal dominant genetic defect of the platelets. The von Willebrand
factor is qualitatively normal and genetic testing of the von Willebrand gene and vWF protein

reveals no mutational alteration. The defect lies in the qualtatively altered glycoprotein1 (GP1)
receptor on the platelet membrane which increases its affinity to bind to the von Willebrand
factor. Large platelet aggregates and high molecular weight vWF multimers are removed from
the circulation resulting in thrombocytopenia and diminished or absent large vWF multimers.
The ristocetin cofactor activity and loss of large vWF multimers are similar to vWD type 2B.

Acquired von Willebrand disease

Acquired vWD can occur in patients with autoantibodies. In this case the function of vWF is not
inhibited but the vWF-antibody complex is rapidly cleared from the circulation.
A form of vWD occurs in patients with aortic valve stenosis, leading to gastrointestinal bleeding
(Heyde's syndrome). This form of acquired vWD may be more prevalent than is presently
thought. In 2003 Vincentelli et al. noted that patients with acquired vWD and aortic stenosis who
underwent valve replacement experienced a correction of their hemostatic abnormalities but that
the hemostatic abnormalities can recur after 6 months when the prosthetic valve is a poor match
with the patient.[7] Similarly, acquired vWD contributes to the bleeding tendency in people with
an implant of a Left Ventricular Assist Device (LVAD), a pump that pumps blood from the left
ventricle of the heart into the aorta. Large multimers of vWF are destroyed by mechanical stress
in both conditions.
Thrombocythemia is another cause of acquired von Willebrand disease, due to sequestration of
von Willebrand factor via the adhesion of vast numbers of platelets.
Acquired vWD has also been described in the following disorders: Wilms' tumour,
hypothyroidism and mesenchymal dysplasias.

Pathophysiology
For the normal function of the coagulation factor, see von Willebrand factor.

vWF is mainly active in conditions of high blood flow and shear stress. Deficiency of vWF
therefore shows primarily in organs with extensive small vessels, such as the skin, the
gastrointestinal tract and the uterus. In angiodysplasia, a form of telangiectasia of the colon,
shear stress is much higher than in average capillaries, and the risk of bleeding is increased
concomitantly.
In more severe cases of type 1 vWD, genetic changes are common within the vWF gene and are
highly penetrant. In milder cases of type 1 vWD there may be a complex spectrum of molecular
pathology in addition to polymorphisms of the vWF gene alone. The individual's ABO blood

group can influence presentation and pathology of vWD. Those individuals with blood group O
have a lower mean level than individuals with other blood groups. Unless ABO groupspecific
vWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I
vWD, and some individuals of blood group AB with a genetic defect of vWF may have the
diagnosis overlooked because vWF levels are elevated due to blood group.

Genetics

von Willebrand disease types I and II are inherited in an autosomal dominant

pattern.

von Willebrand disease type III (and sometimes II) is inherited in an autosomal
recessive pattern.

The vWF gene is located on chromosome twelve (12p13.2). It has 52 exons spanning 178kbp.
Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal
recessive. Occasionally type 2 also inherits recessively.

Epidemiology
The prevalence of vWD is about 1 in 100 individuals. However the majority of these people do
not have symptoms. The prevalence of clinically significant cases is 1 per 10,000. Because most
forms are rather mild, they are detected more often in women, whose bleeding tendency shows
during menstruation. It may be more severe or apparent in people with blood type O.

Therapy
For patients with vWD type 1 and vWD type 2A, desmopressin (DDAVP) is recommended for
use in cases of minor trauma, or in preparation for dental or minor surgical procedures. DDAVP
stimulates the release of von Willebrand factor (vWF) from the Weibel Palade bodies of
endothelial cells, thereby increasing the levels of vWF (as well as coagulant factor VIII) 3 to 5fold. DDAVP is available as a preparation for intranasal administration (Stimate) and as a
preparation for intravenous administration.
DDAVP is contraindicated in vWD type 2b because of the risk of aggravated thrombocytopenia
and thrombotic complications.

DDAVP is probably not effective in vWD type 2M and is rarely effective in vWD type 2N. It is
totally ineffective in vWD type 3.
For women with heavy menstrual bleeding, estrogen-containing oral contraceptive medications
are effective in reducing the frequency and duration of the menstrual periods. Estrogen
compounds available for use in the correction of menorrhagia are Ethinyl Estradiol and
Levonorgestel (levona, Nordette, Lutera, Trivora). Administration of Ethinyl Estradiol
diminishes the secretion of luteinizing hormone and follicle stimulating hormone from the
pituitary, leading to stabilization of the endometrial surface of the uterus.
Desmopressin (DDAVP) is a synthetic analog of the natural antidiuretic hormone vasopressin.
Overuse of Desmopressin (DDAVP) can lead to water retention and dilutional hyponatremia with
consequent convulsion.
For patients with vWD scheduled for surgery and cases of vWD disease complicated by
clinically significant hemorrhage, human derived medium purity Factor VIII concentrates, which
also contain von Willebrand factors, are available for prophylaxis and treatment. Humate P,
Alphanate and Koate HP are commercially available for prophylaxis and treatment of von
Willebrand disease. Monoclonally purified Factor VIII concentrates and recombinant Factor VIII
concentrates contain insignificant quantity of VWF and are therefore not clinically useful.
Development of alloantibodies occur in 10-15% of patients receiving human derived medium
purity Factor VIII concentrates and the risk of allergic reactions including anaphylaxis must be
considered when administering these preparations. Administration of the latters is also associated
with increased risk of venous thromboembolic complications.
Blood transfusions are given as needed to correct anemia and hypotension secondary to
hypovolemia.
Infusion of platelet concentrates is recommended for correction of hemorrhage associated with
platelet-type von Willebrand disease.
The antifibrinolytic agents Epsilon amino caproic acid and Tranexamic acid are useful adjuncts
in the management of vWD complicated by clinical hemorrhage.
The use Topical thrombin JMI and Topical Tisseel VH are effective adjuncts for correction of
hemorrhage from wounds.