Von Willebrand disease

Transcription

Von Willebrand disease
Dr. Paul Giangrande
Oxford Haemophilia & Thrombosis Centre
and
Nuffield Department of Clinical Medicine
University of Oxford
[email protected]
Issues to be covered:

Clinical manifestations
Laboratory diagnosis
Genetic basis
Treatment:
• Bleeding episodes
• Surgery
• Pregnancy
1924: Erich von Willebrand described
bleeding disorder in Åland islands.
Ascribed to defect in platelets.
1928: Similar cases described by Minot who
noted prolongation of bleeding time.
1941: Macfarlane claimed disorder was due
to vascular abnormality.
1953: Low level of “antihaemophilic
factor” identified by several workers
(Alexander, Larrieu, Quick)
1959: Nilsson reported that haemostatic
defect is corrected by transfusion of
plasma from haemophiliacs.
1971: Firkin introduced ristocetin as tool
for testing platelet function.
1973: VWF in endothelial cells (Jaffe).
1977: Mannucci reported use of DDAVP.
Clinical features
von Willebrand factor is essential for
platelet adhesion to collagen:
platelet
endothelial cells
collagen
von Willebrand factor (VWF):

VWF can be thought of as the glue which is
needed by platelets to stick to site of injury
Made and stored in cells lining blood vessels
(endothelial cells)
Stored in cylindrical structures called WeibelPalade bodies
Gene on chromosome 12 (not on Xchromosome like factor VIII or IX)
VWF is very large protein which circulates in
plasma as a series of stacked molecules
(multimers)
VWF also binds factor VIII in plasma
Weibel-Palade bodies in endothelial cells
Von Willebrand’s disease:

Common but usually mild bleeding disorder
• Up to 1% of population affected as defined by
reduced plasma level of VWF, although only
• 125 / million have significant bleeding disorder
Sadler JE Thromb. Haemostasis 84: 160-174 (2000)

Autosomal dominant inheritance
Typical features include:
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Easy bruising
Prolonged bleeding from cuts and scratches
Nose bleeds (epistaxis)
Heavy menstrual bleeding (menorrhagia)
Joint bleeding not a typical feature
Inheritance of VWD:
A baby with severe von
Willebrand disease:
Non-accidental injury may be suspected in babies with bruising
Importance of history taking:

Easy bruising
Nose bleeds
Heavy menstrual periods
Bleeding after operations etc:
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operations
dental extractions
after giving birth
Family history
Objective criteria include:

Need for blood transfusion
Anaemia
Prolonged bleeding from trivial wounds
lasting > 15 minutes and requiring
medical attention
Haematoma at site of injections (e.g
vaccination), bleeding from umbilical
stump
Oral cavity bleeding associated with
tooth eruption, bites to lips and tongue
Menorrhagia without uterine disease
Frequency of bleeding disorders in
women with menorrhagia:
Kadir RA et al: Lancet 351: 485-489 (1998)

150 women with menorrhagia but no pelvic
abnormality screened
Inherited bleeding disorder in 26 (17%)
Commonest disorders: von Willebrand’s
disease, platelet disorders, factor XI deficiency.
“Inherited bleeding disorders are found in a
substantial proportion of women with
menorrhagia and a normal pelvis.”
Guidelines on the management of
menorrhagia in secondary care
Royal College of Obstetricians & Gynaecologists, UK (1998)
“The study emphasises the importance of a careful
history specifically with regard to a long history
of menorrhagia since menarche, and a history of
bleeding after tooth extraction, operations and
childbirth. If these factors are present, testing
for bleeding disorders should be carried out.
This should be arranged in conjunction with the
Local haematology department as many of the
necessary tests are not routine.”
2007
A diagnosis of VWD can have
significant adverse social
consequences:

Self-esteem
School
Employment
Participation in sports
Life insurance
Credit rating (e.g mortgage)
Travel insurance
Marriage prospects
Von Willebrand disease (VWD):
…..or would either
“deficiency” or “disorder”
be better?
Laboratory
diagnosis
Tests available for diagnosis of
VWD:
No single test suffices to make a
diagnosis of VWD. Panel of tests include:

Bleeding time
Factor VIII
VWF antigen
VWF:RCo (ristocetin-induced platelet
aggregation)
VWF:CB (collagen binding assay)
VWF multimer analysis
VWF levels:

Normal level in range of 40-240 iu/dl
Various genetic and environmental factors
influence the plasma level: e.g. blood
group, age, race, hormones.
The presence of VWD, or at least the
severity, are frequently determined by a
combination of these factors
These may also obscure the diagnosis in
some cases
Bleeding time:

Measure time to stop
bleeding after skin incision
with 40 mmHg pressure
applied to forearm (normal <9 min)
Limited sensitivity: frequently
normal in mild VWD
BT also prolonged with
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low platelet count
platelet disorders
aspirin treatment
low haematocrit
Poor reproducibility
Use of the PFA-100 in VWD:

Uses 800 μl citrated blood: test within 4
hours of collection
Prolonged closure time using both
collagen/ADP and collagen/epinephrine
cartridges in VWD
Higher sensitivity than bleeding time
Better consistency of results
Useful for initial screening
May also be of value in monitoring treatment
Types of von Willebrand disorder (VWD):
ISTH Classification: Thromb. Haemostasis 71: 520-525 (1994)
Type 1: Partial quantitative deficiency [reduced
level of qualitatively normal VWF]
Type 2: Qualitative deficiency [absolute level of
VWF may be normal or low, but VWF
present is qualitatively defective]
Type 3: Total quantitative deficiency
[no VWF produced]
Multimer analysis in VWD:
1
3
2A 2B
2D Å normal samples Æ
Factors which influence VWF
level:

ABO group
Secretor status
Age
Race
Difficult venepuncture
Physical exertion
Mental stress
Oestrogen therapy
Menstrual cycle

Pregnancy
Systemic disease:
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Malignancy
Infection
Inflammation
Pre-eclampsia
Postoperative state
Hypothyroidism
Diabetes mellitus
Effect of blood group on VWF
level:
Gill JC et al. Blood 69: 1691-1695 (1987)
VWF:Ag (iu/dl)
140
120
100
80
60
40
20
0
O
A
B
AB
Blood group
(data derived from analysis of 1117 volunteer blood donors)
Changes in VWF during the menstrual
cycle:
Kadir RA et al. Thromb. Haemost 82: 1456-61 (1999)
Hypothyroidism and acquired
VWD:
Dalton R et al: Lancet i: 1007-1009 (1987)

Hypothyroidism may be associated
with menorrhagia
Hypothyroidism may also be
associated with reduction in von
Willebrand factor level
Secondary VWD is associated with an
acquired bleeding tendency
VWF level rises with thyroxine therapy
Summary of key
recommendations for diagnosis:

No single test suffices
Normal APTT does not exclude mild form
Take note of bleeding history
Repeat tests if borderline
Beware of conditions which modify VWF levels
PFA-100 test and functional tests of VWF
activity (VWF:RCo & VWF:CB) particularly
important
Molecular basis
Molecular basis of VWD:

No mutation identified in majority of case of
type 1
Postulated that most cases of type 1 VWD
result from defect in a linked gene which
controls gene transcription
Several defects described in type 3 VWD e.g.
large deletions
Single cytosine deletion in exon 18, resulting
in frameshift causing a stop codon, identified
in original pedigree of type 3 VWD
Type 1 VWD is certainly not simply due to
heterozygosity for type 3 VWD
Molecular basis of type 2 VWD:
D1
D2
D’ D3A1 A2 A3
B
pro-VWF
chrom. 12p
178 kb
52 exons
D4
C1 C2
type 2N
mutations
aa497
909
A1
type 2B
mutations
A2
exon 28
type 2A
mutations
VWD mutation database: www.sheffield.ac.uk/vwf
Treatment
General measures:

Ask for medical card with details of your
condition
Suggest screening of other family
members
Avoid aspirin and related antiinflammatory drugs:
• Paracetamol is fine

When travelling abroad:
• Find out where nearest treatment centre is
• Take out medical/travel insurance
Tranexamic acid:

Stops clots from being broken down
(“fibrinolysis”)
Widely used for treatment of menorrhagia,
recurrent nosebleeds, oral bleeding etc.
Do not use in cases of blood in the urine
(“haematuria”)
Risk of venous thrombosis not increased
Minor and infrequent side-effects: nausea,
diarrhoea, abdominal pain, skin rash
Lancet i: 869-872 (1977)
Desmopressin (DDAVP):
Mannucci PM: Blood 2515-2521 (1997)

Chemical analogue of natural hormone called
antidiuretic hormone (ADH)
Boosts levels of factor VIII and VWF
No effect on factor IX level
Cheap and free of risk of viral transmission
Choice of administration:
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subcutaneous injection
intravenous infusion
nasal spray
Peak effect seen after one hour
May be used during pregnancy
Various formulations of DDAVP exist:
make sure you use the correct one!
“Octim” is the correct intranasal spray product for
the treatment of haemostatic disorders!
Response to desmopressin in
different types of VWD:
Type
1
2A
2B
2M
2N
3
Response
Usually effective
Usually ineffective
May be contraindicated
Predicted to be ineffective
Rarely effective
Ineffective
Mannucci PM: Blood 97: 1915-1919 (2001)
Side-effects of DDAVP:

Minor:
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headache
flushing
tachycardia
tremor
sweating
dizziness
rhinitis (runny nose)
abdominal cramps

Major:
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hyponatraemia (low
sodium level)
marked hypotension
(very low blood
pressure)
myocardial infarction
(heart attack)
other arterial thrombosis
Response in VWD:
Mannucci PM: Br. J. Haematol. 82: 87-93 (1992)
Surgery in VWD:

Major procedures that require prolonged correction
of factor VIII level are unlikely to be feasible with
DDAVP alone
FVIII level predictive risk of bleeding
Raise factor VIII level to around 100 iu/dl perioperatively, and maintain at or above 50 iu/dl until
wound healing is complete
Correction of bleeding time is not always observed
and is not vital
Cases of DVT have been reported in some
patients with VWD
Makris MT et al. Thromb. Haemostasis 88: 387-388 (2002).
Blood products:

Used in type 2 & 3, and in type 1 if DDAVP
unsuitable.
No recombinant VWF product yet
High-purity plasma or recombinant FVIII
products of no value
Commonly used plasma-derived
concentrates include: Wilate (Octapharma);
Haemate-P (CSL Behring), Alphanate
(Grifols); VHP-VWF (LFB), 8Y (BPL)
Cryoprecipitate may be used but is far from
ideal
Haemostasis in normal pregnancy:
Factor level iu/dl
Thrombosis & Haemostasis 52: 176-182 (1984)
450
400
350
300
250
200
150
100
50
0
FVIII:C
VWF Ag
13
18
23
28
33
Weeks gestation
38
Post
Basal
Changes during pregnancy in
VWD:

VWF levels start to rise by sixth week of
gestation in VWD types 1 and 2
Level often well within normal range at
term in type 1 VWD
VWF level does not rise in the rare type 3
VWD subtype
Levels drop down to original baseline
within a few days after delivery
Pregnancy in women with VWD:
NHLBI Guidelines (USA). Haemophilia 14: 171-232 (2008)
www. www.nhlbi.nih.gov/guidelines/vwd

Check factor levels at 34-36 weeks
Vaginal delivery generally regarded as safe if
VWF activity is ≥50 iu/dl
Similar threshold for Caesarean section and
epidural anaesthetic
DDAVP may be used
Avoid aspirin-like analgesics
Cord blood screening of baby is unlikely to yield
reliable results in type 1 VWD
Increased risk of post-partum haemorrhage
(≈20%)
WFH 2010:
abstract 36P05
Conclusions:

VWD is the commonest inherited bleeding
disorder
No single test exists for diagnosis
Repeat testing may be need in borderline
cases
DDAVP is a very useful agent
No recombinant VWF concentrate
available yet