von Willebrand Disease

DEFINITION:
A coagulation disorder characterized by a deficiency in Factor VIIIvW resulting in a
bleeding diathesis (this type is the classic von Willebrand Disease).
the most common hereditary bleeding disorder
present in 12% of the population.
inherited autosomally,
more women than men. Since menorrhagia is a major symptom, it may cause more
women to seek diagnosis
von Willebrand disease is classified on the basis of whether the protein is =
quantitatively reduced but not absent (type 1),
qualitatively abnormal (type 2),
totally absent (type 3)
PATHOPHYSIOLOGY.
. Background
Factor VIII is a complex of two components each with a different genetic control and
biochemical function:
1. Factor VIIIc - coagulation protein
2. Factor VIIIvW - platelet adhesion protein
Factor VIIIvW is a large polymeric protein necessary for normal platelet adhesion and
acts as a bridge between a receptor on the platelet surface and the exposed basement
membrane or subendothelial collagen
Factor VIIIc is complexed with Factor VIIIvW in the plasma, the latter acting as a carrier
protein
there are at least 5 variants of von Willebrand Disease
. Genetic Defect
genetic defect -> reduced Factor VIIIvW protein and function but normal multimeric
structure -> clinical features
von Willebrand factor (vWf) is a large glycoprotein
synthesized in megakaryocytes and endothelial cells
stored in granules and Weibel-Palade bodies
During normal hemostasis, vWf adheres to the sub-endothelial tissue following vascular
damage. -- the structure of vWf is changed -- it causes platelets to adhere to vWf through
their glycoprotein IB (GPIB) receptor.
platelets are then activated, exposing phosphatidylserine, which is an important
regulatory step for factor V and factor VIIIdependent steps in the clotting cascade.
vWf is the carrier protein for plasma factor VIII.

Deficiency of vWf may cause deficiency in factor VIII, even though the gene for factor
VIII is normal.
This is the cause of autosomal deficiency of factor VIII, now known to be a molecular
abnormality of vWf.
CLINICAL MANIFESTATIONS.
symptoms of mucocutaneous hemorrhage, including excessive bruising, epistaxis,
menorrhagia, and postoperative hemorrhage, after mucosal surgery such as tonsillectomy
or wisdom tooth extraction.
Since a teenager's menstrual history is usually put in the context of other family
members, excessive menstrual bleeding is not always recognized as being abnormal,
because others in the family may be affected with the same disorder.
If a menstruating female presents with iron deficiency,
a detailed history of bruising and bleeding should be elicited and further
evaluation undertaken, if indicated.
Since vWf is an acute-phase protein, stress will increase its level.
Thus patients may not bleed with procedures that incur major stress, such as
appendectomy and childbirth, but may bleed excessively at the time of cosmetic or
mucosal surgery.
Bruising symptoms may diminish during pregnancy, since the vWf levels may double or
triple during pregnancy.
patients with von Willebrand disease may have gastrointestinal telangiectasias. This
combination results in major bleeding and accounts for numerous hospital admissions for
patients with severe disease.
In patients with type 3 or homozygous von Willebrand disease, bleeding symptoms are
much more profound.
These patients are usually diagnosed early in life and may have severe epistaxis or
menorrhagia that results in major blood loss and possibly shock.
Rarely, patients with severe type 3 von Willebrand disease may have joint hemorrhages
or spontaneous central nervous system hemorrhages.
1. Hematological Manifestations
spontaneous bleeding is rare
bleeding from mucous membranes (epistaxis, gums)
menorrhagia
prolonged oozing from cuts
increased bleeding after surgery or trauma
INVESTIGATIONS:
1. Serum
prolonged bleeding time
decreased Factor activity
Factor VIIIvW
Factor VIIIc

also have reduced ristocetin cofactor and reduced ristocetin-induced platelet aggregation
(agglutination)
normal or prolonged PTT
normal PT, thrombin time, platelet count

LABORATORY FINDINGS.
long bleeding time
a long PTT.
These tests are not always prolonged except in patients with type 3 von Willebrand
disease.
Therefore, normal screening tests do not preclude the diagnosis of von Willebrand
disease.
If the history is suggestive of a bleeding disorder,
von Willebrand testing must be undertaken,
1. quantitative assay for vWf antigen
2. vWf activity (ristocetin cofactor activity, or vWf R:Co
3. plasma factor VIII activity
4. determination of vWf structure (vWf multimers),
5. platelet count.
While the platelet count is usually normal in most patients, those with type 2B disease or
platelet-type (pseudo-) von Willebrand disease may have lifelong thrombocytopenia.
GENETICS.
Chromosome 12 contains the gene for vWf.
The phenotype can guide the genetic diagnosis of the specific mutation.
TREATMENT.
Treatment of von Willebrand disease
increasing the plasma level of vWf and factor VIII.
gene for factor VIII is normal in patients with von Willebrand disease,
elevating the plasma concentration of vWf will permit the normal recovery and survival
of the endogenously produced factor VIII.
The most common form of von Willebrand disease is type 1. In these patients the
synthetic drug DDAVP induces the release of vWf from the endothelial cells.
In type 2 variants, DDAVP may similarly be effective, but released vWf may be
dysfunctional.
In patients who are unresponsive to DDAVP, who have a variant in which DDAVP
release of vWf is not effective, or who have type 3 disease in which there is no vWf to be
released, replacement therapy must be used.

vWf distributes only to the intravascular space, because it is so large.

Therefore, 1U/kg will increase the plasma level by 2U/dL (2%).
The plasma half-life of both factor VIII and vWf is 12hr.
If only vWf is replaced, the endogenous correction of the factor VIII level takes 1224hr.
Dental extractions and sometimes nosebleeds can be managed with both DDAVP and an
antifibrinolytic agent such as epsilon amino caproic acid (amicar).
von Willebrand Variants
Type 1 von Willebrand disease is the most common form
accounts for 85% of cases.
Bleeding symptoms include epistaxis, bruising, and menorrhagia.
DDAVP administration at a dose of 0.3mg/kg given intravenously will increase the level
of vWf and factor VIII by three to five fold.
Intranasal DDAVP (Stimate) is particularly helpful for the outpatient treatment of
bleeding episodes.
Type 2A von Willebrand disease is due to the abnormal proteolysis of vWf
This results in a reduction in vWf antigen with a reduction in vWf activity.
While DDAVP is safe in these patients, it is not always effective, because normal
molecules of vWf are not seen in plasma.
Significant bleeding should be treated with vWf replacement therapy.
Type 2B von Willebrand disease may be caused by one of several mutations resulting in
hyperactive vWf.
The abnormal vWf binds spontaneously to platelets, causing platelet activation and
clumping.
The larger molecular weight multimers of vWf are cleared from the circulation, and
moderate to severe thrombocytopenia is common.
The laboratory diagnosis is based on demonstration that the hyperactive 2B vWf binds
to platelets and agglutinates them at low concentrations of ristocetina concentration
that would not agglutinate normal platelets.
If one administers DDAVP to these patients, the abnormal hyperactive 2B vWf would
be released, and thrombocytopenia might occur. These patients usually respond to the
infusion of vWf.
Type 2M von Willebrand disease is caused by mutations that result in the loss of the
platelet-binding function of vWf.
The binding of this protein to factor VIII is normal, so that the factor VIII levels will be
equal to the vWf levels, but the platelet-dependent interaction of vWf is reduced
significantly.
DDAVP will increase vWf and factor VIII levels, but the released type 2M vWf may not
have sufficient activity to cause cessation of bleeding.
Thus, vWf replacement therapy may need to be employed.

Type 2N von Willebrand disease is due to the loss of factor VIII binding by vWf. This
has also been termed autosomal hemophilia.
platelet interaction with vWf is normal, but the 2N vWf binds weakly (or not at all) to
factor VIII, resulting in rapid clearance of normal factor VIII.
the factor VIII level is reduced much more than the vWf levels.
patients who have symptomatic bleeding are heterozygote who have inherited a gene for
type 1 von Willebrand disease from one parent and one for type 2N von Willebrand
disease from the other.
2N mutations are inherited from both parents and the vWf levels are normal.
In the patient who is compound heterozygous of type 1 and type 2N, the one allele makes
no protein and the other allele makes a functionally abnormal protein, resulting in all of
the vWf being dysfunctional.
While DDAVP will release the 2N vWf, the factor VIII levels occasionally may be
inadequate for normal hemostasis.
von Willebrand factor replacement therapy is usually effective.
Platelet type (pseudo-) von Willebrand disease is actually an abnormality of the GPIB
receptor on platelets.
the GPIB receptor on platelets is hyperfunctional and binds plasma vWf spontaneously.
This results in thrombocytopenia and a loss of high molecular weight multimers that are
indistinguishable from 2B type von Willebrand disease.
Specific testing, however, will demonstrate that this is a platelet abnormality rather than a
plasma abnormality.
Type 3 von Willebrand disease is the homozygous inheritance of vWf deficiency.
Patients exhibit undetectable plama levels of vWf and only low, but measurable, levels of
factor VIII.
These patients will have major hemorrhage, only rarely have joint hemorrhages.
This severe form occurs in approximately 1:500,000 individuals, so it is rare.
Intracranial hemorrhage, major epistaxis, and menorrhagia in women are the major
features.
Treatment must be with vWf-containing concentrates. DDAVP is not effective.
MANAGEMENT:
1. Supportive
avoid trauma and anticoagulants (i.e., ASA)
pressure and cold compresses to bleeding sites
2. Replacement Therapy
. Cryoprecipitate
treatment of choice for severe hemorrhages and major surgical procedures
2-4 bags/10 kg IV q12-24h
. Others
fresh frozen plasma
DDAVP
EACA (Amicar)