Download von Willebrand`s Disease

von Willebrand’s Disease
vWD
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Family of bleeding disorders
Caused by a deficiency or an abnormality of von
Willebrand Factor
VWF gene : short arm of chromosome 12
vWF Production
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Vascular endothelial cells
Megakaryocytes
Most vWF is secreted
Some vWF is stored
 Weibel-Palade bodies
in endothelial cells
 Alpha granules of
platelets
Constitutive and stimulusinduced pathways
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Release stimuli (EC)
 Thrombin
 Histamine
 Fibrin
 C5b-9 (complement
membrane attack
complex)
Release stimuli (platelets)
 Thrombin
 ADP
 Collagen
vWF Function
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Adhesion
 Mediates the adhesion of
platelets to sites of vascular
injury (subendothelium)
 Mediates platelet to platelet
interaction
 Binds GPIb and GPIIb-IIIa
on activated platelets
 Stabilizes the hemostatic
plug against shear forces
vW Factor Functions
in Hemostasis
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Carrier protein for Factor VIII (FVIII)
 Protects FVIII from proteolytic degradation
 Localizes FVIII to the site of vascular injury
vWD History
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1931: Erik von Willebrand
described novel bleeding
disorder
 Hereditary
pseudohemophilia
 Prolonged BT and
normal platelet count
 Mucosal bleeding
 Both sexes affected
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1950s: Prolonged BT
associated with reduced
FVIII
1970s: Discovery of vWF
1980s: vWF gene cloned
Frequency
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Most frequent inherited bleeding disorder
Autosomal inheritance pattern
 Males and females are affected equally
vWD Classification
1.
Disease is due to either a quantitative deficiency of
vWF or to functional deficiencies of vWF
1.
Due to vWF role as carrier protein for FVIII,
inadequate amount of vWF or improperly
functioning vWF can lead to a resultant decrease in
the available amount of FVIII
vWD Classification
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3 major subclasses
 Type I: Partial quantitative deficiency of vWF
 Mild-moderate disease
 70%
 Type II: Qualitative deficiency of vWF
 Mild to moderate disease
 25%
 Type III: Total or near total deficiency of vWF
 Severe disease
 5%
Additional subclass
 Acquired vWD
Clinical Manifestations
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Most with the disease
have few or no symptoms
For most with symptoms,
it is a mild manageable
bleeding disorder with
clinically severe
hemorrhage only with
trauma or surgery
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Types II and III: Bleeding
episodes may be severe and
potentially life threatening
Disease may be more
pronounced in females
because of menorrhagia
Bleeding often worsen by the
ingestion of aspirin
Severity of symptoms tends
to decrease with age due to
increasing amounts of vWF
vWD Screening
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PT
aPTT
(Bleeding time)
1- aPTT:
1. Mildly prolonged in approximately 50% of patients
with vWD
2. Normal PTT does not rule out vWD
3. Prolongation is secondary to low levels of FVIII
2-PT: Usually within reference ranges
 Prolongations of both the PT and the aPTT
signal a problem with acquisition of a proper
specimen or a disorder other than or in addition
to vWD
3-Bleeding time is prolonged.
4-vWF level : When suspected, blood plasma of a
patient needs to be investigated for quantitative
and qualitative deficiencies of vWF.
vWD Diagnostic Difficulties
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vWF levels vary greatly
 Physiologic stress
 Estrogens
 Growth hormone
vWF levels may be normal irregularly in patients with vWD
 Measurements should be repeated to confirm abnormal
results
 Repeating tests at intervals of more than 2 weeks is
advisable to confirm or definitively exclude the diagnosis,
optimally at a time remote from hemorrhagic events,
pregnancy, infections, and strenuous exercise
vWF levels vary with blood type??
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5. vWF Antigen: Quantitative immunoassay or an
ELISA using an antibody to vWF
5-Multimer analysis
6- FVIII activity assay: Factor VIII and vWF levels
arc reduced (Factor VIII levels are also performed as
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).
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Defective platelet function, reduced
aggregation with ristocetin,
A platelet aggregation assay will show
an abnormal response.
Mild thrombocytopenin may occur
Other tests performed in any patient
with bleeding problems are a full blood
count (especially platelet counts),
thrombin time and fibrinogen level.
vWD Treatment
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DDAVP
Cryoprecipitate
FVIII concentrate
Factor VIII Concentrates
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Concentrates are purified to reduce the risk of bloodborne disease
Contain a near-normal complement of high molecular
weight vWF multimers
vWD Treatment
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Platelet transfusions
 May be helpful with vWD refractory to other therapies
Cryoprecipitate
 Fraction of human plasma
 Contains both FVIII and vWF
 Medical and Scientific Advisory council of the National
Hemophilia Foundation no longer recommends this
treatment method due to its associated risks of infection
FFP
 An additional drawback of fresh frozen plasma is the large
infusion volume required
Haemophilia A
Haemophilia
B
VW Disease
Inheritance
Sex-linked
Sex-linked
Dominant
Main sites of haemorrhage
Muscles, joints, post
trauma or operative.
Muscles, joints,
post trauma or
operative.
Mucous
membranes,
skin cuts, post
trauma or
operative
Platelet count
Normal
Normal
Normal
Bleeding Time
Normal
Normal
Prolonged
PT
Normal
Normal
Normal
PTT
Prolonged
Prolonged
Prolonged or
normal
Factor VIII
Low
Normal
Low
Factor IX
Normal
Abnormal
Normal
Restoctin induced platelet
aggregation
Normal
Normal
Impaired
Platelet aggregation
Normal
Normal
Abnormal