Von Willebrand Disease - Haematology
Transcript of Von Willebrand Disease - Haematology
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Von Willebrand Disease
Alison Street
Malaysia April 2010
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OUTLINE
• Physiology of VWF
• Clinical presentation of VWD
• Classification of VWD with emphases on Type 1, 2B and 2N disease
• Testing for VWD
• Treatment
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Pedigree of the original family described by Erik von Willebrand in 1926
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VWF Gene
• Located at chromosome 12p13.2
• 52 exons spanning 178 kb
• 9kb mRNA
• Partial pseudogene at chromosome 22
– VWF and pseudogene diverge by 3.1% in
sequence
– Probable relatively recent origin of
pseudogene by partial gene duplication
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5’ 3’
N C
--S--
N N
C
C
C
C
C CC
CC C
--S--
--S----S--
--S-- --S--
--S--
VWF mRNA
Pro-VWF
Pro-VWF dimer
Pro-VWF
multimers
Propeptide
dimer
VWF
multimers
RER
Golgi
VWF biosynthesis and processing
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VWF synthesis and processing
• VWF synthesised in endothelial cells and megakaryocytes
• Primary translation product processed in ER to form pro-VWF dimers
• In Golgi apparatus VWF propolypeptide mediates assembly of dimers into multimers of molecular wt. up to 20 x 106
• Mature VWF secreted directly into plasma or subendothelium, or stored in endothelial cell Weibel-Palade bodies and platelet alpha granules
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VWF FUNCTION
• Platelet-dependent function in primary
haemostasis
– High shear stress
– High molecular weight multimers
• Carrier for FVIII
• VWF plasma half-life ~12 h
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VWF gene and protein – structure / function
relationships
VWF gene (chromosome 12)
VWF primary translation product
Mature secreted VWF protomer - functional sites
Region duplicated in partial VWF
pseudogene (chromosome 22)
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VWF binds via A3 domain to
collagen inducing a
conformational change
Which allows GP1b to bind to
VWF A1 domain
This slows the platelet travel
and allows activation of FVIII
Activation of platelets leads to
the binding of GPIIb/IIIa to VWF
C2 domain which is slower but
has higher affinity
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VWF functionality - high molecular
weight multimers
• Essential to promote platelet-vessel wall
and platelet-platelet interactions at high
shear
• Circulating VWF multimer size is
controlled by proteolytic cleavage by
ADAMTS13
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ADAMTS 13
• A specific plasma protease which
proteolyses the bond between Tyr 1605
and Met 1606 (Tyr 842 and Met 843 of
mature sub-unit)
• Generates a spectrum of circulating vWF
species (single – twenty dimer multimers)
of which larger ones have most affinity for
platelet Gp1b and Gp11b/111a receptors
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VWF multimer analysis
Normal
High MW
Crucial for
normal function
Low MW
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Von Willebrand Disease
• Inherited deficiency or dysfunction of VWF
• Bleeding results due to impaired platelet
adhesion and lower levels of FVIII
• VWD prevalence haemostasis centres :
0.0023-0.01%
• Abnormal VWF prevalence (screening):
0.6-1.3%
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Clinical presentations
• Bleeding: mucous membrane and skin sites
• Personal history of bleeding
• Family history of bleeding
• Bleeding: severity, site, duration, type of
injury or insult, ease of stopping, concurrent
medications e.g. aspirin, clopidogrel, warfarin,
heparin
• Liver,kidney, bone marrow disorder
• Examination: bruising/bleeding & exclude
other diagnoses
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Bleeding symptoms are common
in people with normal levels of
VWF!
• 23%of healthy controls, replying to a bleeding questionnaire, report at least one symptom of bleeding compared with 88% of patients with a diagnosis of VWD Type 1.
• Standardised bleeding scores do not predict VWF gene or plasma levels within families but do predict for post-operative bleeding
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1994 Classification of VWD
• Type 1 VWD (~ 70% of cases??)
– Partial quantitative deficiency of VWF
• Type 2 VWD
– Qualitative deficiency of VWF
– Sub-types 2A, 2B, 2M, 2N
• Type 3 VWD
– Virtual complete deficiency of VWF
Sadler, Thromb Haemost 1994, 71, 520-5
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Clinical assessment
• Bleeding: mucous membrane and skin sites
• Personal history of bleeding
• Family history of bleeding
• Bleeding: severity, site, duration, type of injury or insult, ease of stopping, concurrent medications e.g. aspirin, clopidogrel, warfarin, heparin
• Exclusion of liver, kidney or bone marrow disorders
• Examination: bruising/bleeding & exclusion of other diagnoses
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Classificationtype description inheritance prevalence bleeding
1* partial quantitative deficiency AD up to 1% Mild-mod
2A VWF-dep platelet adhesion
Loss high & int MW multimers
AD or AR
uncommon variable-
usually
moderate
2B affinity for platelet GPIb
Loss high MW multimers
AD
2M VWF-dep platelet adhesion
without selective loss high
MW multimers
AD or AR
2N binding affinity for FVIII AR
3* almost complete deficiency AR rare high
* Quantitative deficiency vs qualitative deficiency
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Laboratory testing
• Skin Bleeding Time
• Platelet Function Analyser/ Aggregation
• Plasma testing for VWF antigenic and
activity levels
• Activity measured by Ristocetin Co Factor
and Collagen Binding assays
• Full Blood Examination
• F VIII levels/ F VIII binding
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Summary of criteria for diagnosis and classification of VWD
Type 1
Type 3
Type 2A
Type 2B
Type 2M
Type 2N
VWF:Ag Decreased < 5% Decreased (Normal)
Decreased (Normal)
Variable Normal
VWF activity
Decreased Absent Markedly decreased
Decreased (Normal)
Decreased relative to VWF:Ag
Normal
RIPA Reduced (Normal)
Absent Markedly reduced
Increased Reduced (Normal)
Normal
Multimers Essentially normal
Absent HMW absent
HMW usually absent
Normal Normal
VWF: FVIIIB
Normal NA Normal Normal Normal Reduced
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Approach to classification of VWD
Quantitative defect Qualitative defect
Type 1 or Type 3 VWD Type 2 VWD
Normal platelet-dependent Defective platelet-
VWF function & dependent VWF function
defective FVIII binding
Type 2N VWD
Gain in function Reduced function
Type 2B VWD
Loss of HMW multimers HMW multimers present
Type 2A VWD Type 2M VWD
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Laboratory features of Type I VWD
• Partial quantitative deficiency of VWF
• Concordant VWF:Ag & CBA/RistoCoF
• Normal multimer pattern
• When VWF <20 IU/dL may identify mutations which interfere with intracellular transport of dimeric proVWF or promote rapid clearance of VWF from circulation
• Lower VWF levels, more likely to have VWF gene mutations, significant bleeding history + strong Family History*
*Goodeve et al. Blood 2007;109:112-121, James et al. Blood 2007;109:145-154
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Many diagnoses of Type 1 VWD
are false positives
• Past bleeding history is a better guide to
risk assessment for future bleeding
particularly when the VWF is between
30 and 50 IU/dl (RR 50-200%)
• Neither symptoms nor VWF level are
predicted by VWF genetic testing at this
level of deficiency
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50% 0%VWF Level
eg. Dominant Negative
VWF MutationsVWF Mutations
missense
splicing
transcriptional
+ABO Blood Group
+Other Genetic Modifiers
~35% of cases
Incomplete Penetrance Highly Penetrant
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Is it just a low VWF level or
VWD?
• Genetic factors account for minority of
heritable variation in VWF levels
• No linkage to VWF locus when VWF >30
• Other inheritable and environmental factors
influence plasma VWF
*Mannucci et. al. Blood 1989;74:2433-2436
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ISTH VWF mutation database(www.vwf.group.shef.ac.uk)
• Pre-Canadian, EU, and UK studies - 14
different VWF gene mutations reported
in association with type 1 VWD
• By 31 July 2007 - 117 different mutations
or candidate mutations reported
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D1 D2 D’ D3 D4A2 A3A1
NH2 COOH
1 2813
B1-3
preproVWF VWF Monomer
22aa 741aa 2050aa
CKC1 C2
5’ Regulatory Sequence Mutations
-2731C>T
-2714G>A
-2639G>A
-2615A>G
-2533G>A
-2522C>T
-2487G>A
-2328T>G
-1896C>T
-1886A>C
-1873A>G
-1665G>C
-1522del13
Propeptide Sequence Mutations
G19R
L129M
D141G
G160W
N166I
c.1109+2T>C (splice)
c.1534-3C>A (splice)
M576I
A641V
W642X
D’-D3 Mutations
K762E c.3072delC
M771I c.3108+5G>A (splice)
c.2435delC I1094T
R816W C1111Y
R854Q c.3379+1G>A (splice)
c.2685+2T>C (splice) Y1146C
c.3537+1G>A (splice) C1190R
c.2686-1G>C (splice) R1205H
R924Q
R924W
C996E
D3, A1-A3 Mutations
1546_1548del3 P1413L
V1229G N1421K
N1231T Q1475X
P1266L R1583W
V1279I Y1584C
c.3839_3845dup7 c.4944delT
R1315C R1668S
L1361S
R1379C
K1405del
A3-D4 Mutations
c.5180insTT E2233G
V1760I c.6798+1G>T (splice)
L1774S R2287W
K1794E
N1818S
V1850M
P2063S
R2185Q
c.6599-20A>T (splice)
T2104I
B1-B3,C1,C2 Mutations
C2304Y T2647M
R2313H C2693Y
C2340R P2722A
G2343V c.8412insTCCC
R2379C
R2464C
c.7437+1G>A (splice)
S2497P
G2518S
Q2544X
Candidate VWF mutations in type 1 VWD – Canadian, EU and UK studies
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Genetics of type 1 VWD (2010)
• Molecular mechanisms more clearly understood
• But functional studies assessed in only about 10% of reported candidate mutations
• A proportion of type 1 VWD likely to be due to defects away from VWF locus
• Definition of type 1 VWD not restricted to VWF mutations
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Type 2 VWD
• Qualitative variants of VWF
• The proportion of large VWF multimers is reduced in Types 2A and B with consequent loss of function in 2A and gain in 2B
• Mutations lead to interference with assembly or secretion of large multimers or increased susceptibility to proteolytic degradation
• Type 2N results in impaired binding of FVIII and may be confused with mild haemophilia
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Proposed model of VWF synthesis and catabolism
Sadler et al, JTH 2006, 4, 2103-14
Normal
VWD variants
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Summary of criteria for diagnosis and classification of VWD
Type 1
Type 3
Type 2A
Type 2B
Type 2M
Type 2N
VWF:Ag Decreased < 5% Decreased (Normal)
Decreased (Normal)
Variable Normal
VWF activity
Decreased Absent Markedly decreased
Decreased (Normal)
Decreased relative to VWF:Ag
Normal
RIPA Reduced (Normal)
Absent Markedly reduced
Increased Reduced (Normal)
Normal
Multimers Essentially normal
Absent HMW absent
HMW usually absent
Normal Normal
VWF: FVIIIB
Normal NA Normal Normal Normal Reduced
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Genetic diagnosis in type 2 VWD
• Generally well-characterised genetic disorders
• Screening for type 2N VWD in non X-linked mild or
moderate FVIII deficiency
• Differentiation of type 2B VWD and platelet-type
pseudo VWD
• Differential diagnosis of type 1 and type 2M VWD
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Type 2B VWD
• Increased affinity of mutant VWF for platelet glycoprotein 1b
• Circulating platelets coated with mutant VWF - may prevent platelet adhesion at sites of injury
• Variable thrombocytopenia - reversible sequestration of VWF-platelet aggregates in microcirculation
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Type 2B VWD
• VWF bound to platelets susceptible to proteolysis by ADAMTS13 → high molecular weight multimers usually absent in plasma
• VWF activity usually reduced
• VWF:Ag reduced or normal
• Increased Ristocetin Induced Platelet Aggregation.
• May be confused with platelet type or “pseudo” VWD
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Genetics of Type 2B VWD
• Autosomal dominant inheritance
• “Gain of function” missense mutations
confined to VWF A1 domain (containing
platelet GP1b binding site)
• 4 VWF gene mutations account for
~ 90% of type 2B VWD
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Type 2N VWD
(VWD Normandy)
• Reduced affinity of VWF for factor VIII
• Phenotype similar to mild or moderate haemophilia A or haemophilia A carriers.
• Should be considered and tested in all cases of spontaneous mild haemophilia
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VWF-FVIII binding assay (VWF:FVIIIB)
Normal
Patient
Heterozygous
control
Homozygous control
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Functional domains and mutations reported in VWF up to 2006
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Type 2N VWD
• Recognition and differentiation of type 2N
VWD from haemophilia A important for:
– Precise genetic counselling
– Accurate carrier or prenatal diagnosis
– Appropriate treatment of bleeding episodes
• Consider type 2N VWD as a possible
diagnosis in patients with FVIII deficiency
which is not clearly X-chromosome linked
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Treatment of VWD
Selected according to
• Past bleeding experiences
• Level of VWF activity
• Type of procedure
• Product availabilty (need to use VWF
containing concentrates, not recombinant
Factor VIII)
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DDAVP
• Stimulates endothelial production and secretion of VWF from endothelial cells. Can give for 4-5 days
• Of particular value in Type 1 disease where baseline level >10%
• Should give a trial dose to assess effect and tolerability (need to monitor Na+)
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Special considerations
• Beware all cases of “mild” Haemophilia, it might be VWD Type 2N
• It is important to develop and communicate care plans for delivery and post partum management in women with VWD, secondary bleeding is common.
• Acquired VWD may complicate lymphoproliferative disorders (Type 2A like)
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THANK YOU
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Plasma VWF levels rise with
• Increased age
• Non-O blood group
(mean VWF O=75U/dL, 95% VWF levels for O blood donors = 36-157 U/dL* due to reduced vWFsurvival)
• Lewis blood group (secretor)
• Adrenaline, Thrombin (DDAVP)
• Inflammatory mediators
• Endocrine hormones (periods/pregnancy/OCP)
*Gill et. al. Blood 1987;69:1691-1695
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Von Willebrand Factor cleavage
Chromosome 12, 178kb, 52 exons
Sadler et. al. J Thromb & Haemost 2006, 4: 2103-2114
ADAMTS13 cleavage site
Platelet GPIb binding site
THBS-1 binding site
Probable ADAMTS13 binding site
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Normal physiology of ADAMTS13
Adapted from Moake JL. NEJM 2002;347:589-600
Weibel
Palade body
Endothelial cellSecretion of multimers
Binding
site
Unusually large von
Willebrand multimers
ADAMTS13
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ADAMTS13 processing & VWF: a delicate
balance between thrombosis and bleeding
ULvWF Monomers
vWF
ADAMTS13 ULvWF:
Congenital or
acquired deficiency
of ADAMTS13
TTP
Monomers vWF:
Mutations in vWF
cleavage by ADAMTS13
Type IIA vWD
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Normal conditions
• FVIII-VWF circulates but doesn’t strongly interact with platelets or endothelial cells
NHLBI Guideline VWD 2007
FVIII
VWF
multimers
Resting platelets
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Vascular injury
• VWF adheres to vessel subendothelial matrix
• With shear, VWF multimers uncoil, platelets adhere and become activated
NHLBI Guideline VWD 2007
VWF
multimers
activated platelets
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Platelet-fibrin plug
• Activated platelets expose phosphatidyl serine and bind and activate FVIII clotting
• Platelet-fibrin plug thrombolysis tissue repair
NHLBI Guideline VWD 2007
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Platelet type pseudo-VWD
(pVWD)• Rare autosomal dominant disorder
• Mutations in platelet GpIb/IX receptor
cause increased platelet-VWF binding
• Clinical presentation variable
• Laboratory presentation very similar to
type 2B VWD (mild thrombocytopenia,
increased RIPA, decreased HMW
multimers)
• Potential for misdiagnosis
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Differentiation of type 2B VWD and
platelet-type pseudo-VWD (pVWD)
• Genotyping– Targeted screening of VWF gene exon 28 and platelet
GpIb/IX receptor gene
• Plasma / platelet mixing studies– Patient platelets (PRP) + normal VWF (cryoprecipitate)
• Spontaneous aggregation in pVWD
• Absence of platelet aggregation in type 2B VWD
(reliability?)
– Patient VWF (PPP) + normal platelets (PRP)
• Enhanced RIPA in type 2B VWD
• RIPA not enhanced in pVWD
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A Disintegrin and Metalloprotease with
ThromboSpondin motifs 13
Levy,G.G. et al. Blood 2005;106:11-17