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VWF and ADAMTS 13: Physiopathology
Alberto Tosetto
Centro Malattie Emorragiche e Trombotiche
Dipartimento di Terapie Cellulari ed Ematologia
ULSS 6 Vicenza
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The Atlantic hagfish has
circulating VWF
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…but its closest
Urochordata, the sea squirt,
doesn’t
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VWF evolved in the ancestral
vertebrate following the
divergence of the urochordates
some 500 million years ago
Grant et al. Blood, 2017.
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S-S
Multimers
22
Peptide Signal
763
Propeptide
GP Ib
Collagen VI
FVIII
H2N
D2 D3 D1D’
A1 A2
D2 D3
ADAMTS-13
The hagfish Von Willebrand Factor (VWF)
Grant et al. Blood, 2017.
S-SDimer
2813 GP IIb/IIIa
COOHB1 C1 C2 CK
B3B2 C3
C4 C5
C6
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S-S
Multimers
Collagen I & III
22
Peptide Signal
763
Propeptide
GP Ib
Collagen VI
FVIII
H2N
D2 D3
A3
D1D’
A1 A2 D4
D2 D3
A3
ADAMTS-13
The human Von Willebrand Factor (VWF)
S-SDimer
2813 GP IIb/IIIa
COOHB1 C1 C2 CK
B3B2 C3
C4 C5
C6
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S-S
Multimers
Collagen I & III
22
Peptide Signal
763
Propeptide
GP Ib
Collagen VI
FVIII
H2N
D2 D3
A3
D1D’
A1 A2 D4
D2 D3
A3
ADAMTS-13
The human Von Willebrand Factor (VWF)
S-SDimer
2813 GP IIb/IIIa
COOHB1 C1 C2 CK
B3B2 C3
C4 C5
C6
High-shear stress component
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The revised VWF-related activities nomenclature
Test Explored function
VWF:Ag VWF antigen as measured by a polyclonal Ab
VWF:FVIIIB FVIII Binding: all assays measuring D’ domain binding to FVIII
VWF:Rco Ristocetin Cofactor activity: all assays that use platelets and Ristocetin (A1 domain)
VWF:GPIbR All assays that are based on the Ristocetin induced binding of VWF to a recombinant WT GPIb fragment
VWF:GPIbM All assays that are based on the spontaneous binding of VWF to a gain-of-function Mutant GPIb fragment.
VWF:Ab All assays that are based on the binding of a monoclonal antibody (mAb) to a VWF A1 domain epitope
VWF:CBA All assays measuring A3 domain binding to collagen
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VWF promotes growth factor recruitment and wound healing
Ishihara et al, Blood, 2019
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D1D2
COOH
D3
A3
D’
A1 A2 D4 B1 C1 C2 CK
B3B2
D3
A3
In the ER, propeptide is released and VWF dimerized
-S
–S
-
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VWF dimers are stored in Weibel-Palade bodies as ultra-large multimers
- S – S - - S – S -- S – S
-- S – S -
Mutations in CK and D3 domains are associated with defective (di)multimerization
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VWF is secreted from the endothelial cells as long VWF “strings”
A3A1 A2
CK D3
A3
A3A1 A2
CK D3
A3
`Weibel-Palade bodies
` ` `
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VWF “strings” are cut by ADAMTS at the A2 domain
A3A1 A2
CK D3
A3
A3A1 A2
CK D3
A3
`Weibel-Palade bodies
` ` `
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ADAMTS proteolysis is responsible for “triplets” in high-resolution gels
14
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VWF clearance
15
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VWF clearance: the role of the D3-A1 domain
16
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Σ =
Sinthesis Proteolisis Steady state
(ADAMTS-13) (Normal Plasma)
EC → Plasma
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Mechanisms in VWD
• Decreased biosynthesis
– Type 1 VWD
18
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• Patient SS, a 34 yo male
• Mild mucocutaneous bleeding
diathesis
• FVIII:C: 19 IU/dL
• VWF:Ag: 8 IU/dL
• VWF:RCo 9 IU/dL
• FVIII:C/Ag ratio = 2.4
Mechanisms in VWD: FVIII/VWF:Ag ratio
19 Eikenboom, et al. Thromb Haemost, 2002
Increased FVIII/VWF ratio is
suggestive for presence of reduced
VWF biosynthesis
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Mechanisms in VWD
• Decreased biosynthesis
– Type 1 VWD
• Increased clearance
– Type 1 VWD (“Vicenza”)
– Type 2B (increased affinity for GpIb)
20
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0
20
40
60
80
100
120
140
0 2 4 6 8 10 12 14
VW
F:R
Co
Hours
Vicenza VWD Type 1 VWD Increased clearance:
• Reduced response
to DDAVP
• Multimeric pattern
more closely
resembling storage
pools
• Increased
propeptide/Ag
ratios
Increased clearance is present in many
type 1 VWD patients (type 1C)
21
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Normal VWD 2A VWD 2B
1 min. 1 min.
1 min.
Tra
nsm
iss
ion
Ris
toceti
n m
g/m
l
VON WILLEBRAND FACTOR: RIPA
Ristocetin induced platelet agglutination
Platelet Rich Plasma from Patients + RISTOCETIN [0.2-2.0 mg/ml]
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Mechanisms in VWD
• Decreased biosynthesis
– Type 1 VWD
• Increased clearance
– Type 1 VWD (“Vicenza”)
– Type 2B (increased affinity for GpIb)
• Defective multimerization (biosynthesis and clearance
abn.)
– Type 2
23
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“Variants” of type 2 VWD: defective
multimerization and/or ADAMTS interaction
24 Zimmerman et al. J Clin Invest, 1986.
• Odd dimerization (IID): CK
defects
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“Variants” of type 2 VWD
25
CBA
RCo
Reduced VWF:CBA activity is
the hallmark of missing HMW
Multimers
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A1, A2, A3 domains are available only when VWF is elongated by shear stress
Crawley et al. Blood, 2011.
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ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin 1 repeats)
• Synthetized in the liver, endothelium and platelets
• Up-regulated upon activation by inflammatory cytokines
• Secreted as a constitutively active protease, no inhibitor identified to date.
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ADAMTS13 structure
MP Dis 1 2 3 4 5 6 7 8Cys spacer CUB CUB
Active site Binds to linear A2 D4-CK binding
to globular VWF
Trombospondin repeats
Zheng JTH, 2013.
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ADAMTS13 TSP repeats bind to globular VWF
Crawley et al. Blood, 2011.Zheng JTH, 2013.
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Shear-stress elongated A2 permitsbinding and cleavage
Crawley et al. Blood, 2011.Zheng JTH, 2013.
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Shear-stress elongated A2 permitsbinding and cleavage
Crawley et al. Blood, 2011.Zheng JTH, 2013.
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ADAMTS13 cleavage is promoted by FVIII:C and GpIb binding
Binding of FVIII or GpIbdiscloses cleavagesite in A2
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Disorders of the VWF/ADAMTS system
Normal
TTP
Malaria, DIC
Stroke risk
Normal
Bleeding risk factor
Mild VWD
Severe VWD
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Multimeric pattern in TTP
EC: endothelial cell lysate
NP: normal plasma
TTP plasma during remission
Day 1, 18: after one or 18 days of plasma exchange
Moake et al. Blood, 1984.
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In TTP, antibodies directed against Cys and spacer domains clear ADAMTS13 from circulation
MP Dis 1 2 3 4 5 6 7 8Cys spacer CUB CUB
Zheng JTH, 2013Joly et al Blood 2017.
• Associated with SLE, APA, pregnancy, drugs (cyclosporine, quinine, clopidogrel, ticlopidine), HIV infection, cancer
• 50% of cases are idiopathic
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TTP: pathophysiology
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TTP: a thrombotic microangiopathy
• Incidence: 1 new case/106
• Neurologic manifestations
• Hemolytic anemia
• Thrombocytopenia (but few bleeding)
• Marginal renal involvement
• Fever
• Mortality: 10-20%
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Disorders of the VWF/ADAMTS system
VWF multimers
Mulltimers are:
Increased: relative ADAMTS13 deficiency• TTP• Upshaw-Shulman• DIC, malaria, sepsis
Decreased: von Willebrand disease• Congenital• Acquired (antibody, ECMO, MPD)
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Disorders of the VWF/ADAMTS system
VWF multimers
Mulltimers are: Measured with:
Increased: relative ADAMTS13 deficiency• TTP• Upshaw-Shulman• DIC, malaria, sepsis
Multimer analysisADAMTS13
Decreased: von Willebrand disease• Congenital• Acquired (antibody, ECMO, MPD)
VWF:AgVWF:RCoVWF:CBA
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Potential mechanisms ofADAMTS13 deficiency
Mediator Mode of action
Adamts13 deficiency
Inhibition IL6 Delays the rate of UL-VWF cleavage under flow
Free haemoglobin/TSP Competitive binding to VWF A2/A3 domain
Leukocyte elastes, bacteria, thrombin
Proteolysis of ADAMTS13
FVIII deficiency FVIII accelerates VWF cleavage
Exhaustion ULVWF multimers consuming ADAMTS13 molecules
Increased clearance Non-neutralising antibodies
Adapted from Schwameis et al. Thrombosis and haemostasis, 2015.
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Potential mechanisms ofVWF iper-release
Mediator Mode of action
VWF release
Cytokines TNF, interleukin-8
Endotoxin LPS
Biogenic amine Histamine, Epinephrine
Clotting factor FVIIa
Adapted from Schwameis et al. Thrombosis and haemostasis, 2015.
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VWF and ADAMTS13 in non-acute conditions
Andersson et al. Blood, 2012.
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Relative Risk of Stroke or IMA
0
1
2
3
4
5
6
7
Quartile 1 Quartile 2 Quartile 3 Quartile 4
Od
ds
rati
os
VWF-IS VWF-MI ADAMTS-IS ADAMTS-MI
Andersson et al. Blood, 2012.
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ADAMTS13 knockout mice has impaired neovascularization after stroke
Xu et al. Blood, 2017.
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Infusion of rADAMTS-13 is capable of restoring VEGFR expression
Xu et al. Blood, 2017.
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Conclusions
• HMW VWF multimers play an essential role in bleeding and thrombotic disorders
• Increase of HMW multimers is strongly associated with subsequent development of TMA
• Measurement of ADAMTS13 levels is still unfrequent in clinicallabs, but required for hospitals in which a plasma exchangefacility is available