Patogenesi della PTT e della SEU
Elena BresinIRCCS - Istituto Mario Negri, Bergamo
Convegno Microangiopatie Trombotiche UCSC 2016Roma, 19 Febbraio 2016
THROMBOTIC THROMBOCYTOPENIC PURPURA
TTP is a thrombotic microangiopathy characterized by
thrombocytopenia, microangiopathic hemolytic anemia, central
nervous system involvement and/or renal impairment.
In the majority of patients deficiency of ADAMTS13, the von Willebrand
factor-cleaving protease, is associated with autoantibodies to
ADAMTS13.
These cases are at high risk of disease relapse when there is a
persistence of anti-ADAMTS13 autoantibodies.
Congenital deficiency of ADAMTS13 cause Hereditary
THROMBOTIC THROMBOCYTOPENIC PURPURA
Hereditary TTP is very rare (< 10% of all TTP cases) and usually
manifests in the postnatal period or during infancy, although in some
cases (especially women) the onset is later at 20-30 years.
Hereditary TTP is caused by homozygous or double heterozygous
mutations of ADAMTS13 gene that determine congenital deficiency of
ADAMTS13, the von Willebrand Factor (VWF)-cleaving protease.
Patients with hereditary TTP tipically exhibit a relapsing course and need
regular plasma infusions to prevent relapses.
Family A
10
5
4
7
8
7
5
3
2
7
5
3
10
5
4
7
8
7
5
3
2
7
5
3
10
5
4
7
8
7
6
5
/
7
6
7
1
5
/
7
7
7
5
3
2
7
5
3
5
3
2
7
5
3
10
5
4
7
8
7
731 78679 8277
< 6%
1580
6
5
5
7
6
/
1
5
3
7
7
7
108% 62% < 6% 67%< 6%
ADAMTS13 antigen (ng/mL)
ADAMTS13 activity (%)
ADAMTS13 activity (%) < 6%
6
5
3
6
5
4
Family B
ADAMTS13 antigen (ng/mL) < 62.5
Family C
< 6% < 6%
6
5
1
5
6
6
6
5
1
5
6
6
6
5
1
5
6
6
6
5
1
5
6
6
< 62.5 < 62.5
Val88Met(metalloprotease)
Gly1239Val (CUB1)
Heterozygous
6
5
3
6
5
4
Arg1123Cys (TSP8) Arg1219Trp (CUB1)
ADAMTS13 MUTATIONS IN TTP CAUSE SEVERELY REDUCED
PLASMA ADAMTS13 CONCENTRATION
Homozygous Homozygous
43% 47% 45%
REDUCED ADAMTS13 ACTIVITY IN HEALTH AND DISEASE
Mannucci et al., Blood, 2001
- elderly
- newborns
- third trimester of pregnancy
- uremia
- after major surgery
- inflammatory states
- liver cirrhosis
DIFFERENTIAL DIAGNOSIS BETWEEN TTP ASSOCIATED WITH
GENETIC OR IMMUNE-MEDIATED ADAMTS13 DEFICIENCY IS
IMPORTANT TO GUIDE SPECIFIC TREATMENTS
Genetic ADAMTS13 deficiency:
- replacement with plasma of the defective activity
Immuno-mediated ADAMTS13 deficiency:
- plasma exchange to remove anti-ADAMTS13 autoantibodies
and to replace the metalloprotease
- inhibition of the autoantibodies production through treatment
with glucocorticoids, immunosuppressive agents, or rituximab
A multisystem disease with predominant
renal involvement, characterized by a
triad of symptoms:
- microangiopathic hemolytic anemia,
- thrombocytopenia,
- formation of platelet-rich thrombi in the
microcirculation
Definition
Hemolytic Uremic SyndromeTHROMBOTIC MICROANGIOPATHY
Classification of the different forms of Hemolytic Uremic Syndrome
Typical HUS
Infections by E. coli producing Shiga-like toxin/verotoxin and causing hemorrhagic colitis
Typical HUS manifests expecially in children with diarrhea often bloody
Typical HUS usually has a favorable outcome: only 10% of patients progress to ESRD
Atypical HUS
Atypical HUS is rare: 10% of all HUS cases
Atypical HUS may be familial or sporadic and may manifest at all ages.
Atypical HUS has a poor outcome: 50 to 60% of patients reach ESRD at the 1st episode
Atypical HUS
In the last 15 years, extensive research
has established a clear link between
aHUS and defects in regulation of the
alternative complement pathway
resulting in uncontrolled activation of
the complement system
10
COMPLEMENT ACTIVATION PATHWAYS
CR1
Factor I
DAF
MCP
AP dysregulation on endothelial cells resulting in endothelial injury and loss of anti-thrombogenic properties.
C5a
C5b-9
Lectin pathwayClassical pathway
Mannose
residues
IgM, IgG
Immune complexes
C1q,C1r,C1s
C4,C2
C4bC2a
C3 convertase
C3
C3b
C3a
C4bC2aC3b
C5 convertase
MBL, MASP
C1-est inhib
C4bp
C5
Factor H
Alternative pathway
bacteria, bacterial toxin,
LPS, tick-over
C3
C3b
C3a
C3bBb
C3 convertase
C3
C3b
C3a
(C3b)2Bb
C5 convertase
Factor B
Bergamo
Trento
Padova
Treviso
Vicenza
ParmaGenova
Torino
Pavia
Milano
Varese
MonzaBrescia
Firenze
Roma
Foggia
BariSalerno
Reggio Calabria
Palermo
Cagliari
Sassari
UK9 cases
USA58 cases
Argentina23 cases
Belgium
1 case
Israel14 cases
Portugal11 cases
Canada4 cases
Switzerland22 cases
South Africa2 cases
Germany19 cases
Denmark3 cases
Saudi Arabia4 cases
Czech R.11 cases
Esthonia1 case
Serbia5 cases
Italy765 cases
Greece4 cases
Australia14 cases
Malaysia2 cases
Turkey
8 cases
IRAN49 cases
Spain5 cases
Poland13 cases
Russia
6 cases
UAE
1 caseIndia
5 cases
Japan
2 cases
Chile3 cases
Participating Centers
HUS/TTP patients
Italian cases
Foreign cases
180
1160
780
380
INTERNATIONAL REGISTRY OF
HUS/TTP
09/2015
http://www.marionegri.it
Brazil2 cases
Croatia2 cases
FIMAC SRCR LRDR-1 LRDR-2 S-S SP
H Chain L Chain
C43FT72SP50A
P230E
A240G
G243fs46X
C247G
G261D
G349R
W399R
I416L
G424D
A431T
I433V
K441R
W456L
D519N
W546X
MG2 MG3 MG4 MG5
MG
6β
LNK
β-chain α-chain
α’NT
MG
6α
MG7
CU
B g
TED MG8AN
A
CU
B f
Anchor
C345C
R592WR592Q
R1042WK1051MS1063RA1094VI1095SD1115NI1157TC1158W
T1383NH1461D
1 2 3
SCRslinker
Ba Bb
R138W
1 2 3
SCRslinker
VWA SP
S298Lfs2X
R317W
c.884-7T>C
T162RT162KR161W
Q185E
Regulatory
domain
C3b
Recognition
domain
C3bproteoglycansproteoglycans C3b proteoglycans
E847V
C853T
C864SK474Nfs6X
N516K
Q950H
T956M
I970V
P968Lfs7X
G1011Vfs4X
D1119G
D1119N
Q1137L
Y1142C
C1163W
P166L
E1172X
R1182S
W1183L
W1183R
W1183X
T1184A
T1184R
K1188del
L1189F
L1189R
S1191L
S1191W
G1194D
V1197A
E1198A
F1199A
V1200L
R1210C
R1215Q
R1215G
C1218R
c.3546_3581dup
c.3675-3699del
R53CR78GQ81PT30Nfs10X
11 12 13 145 6 7 8 9 10 17 1815 162 3 41 2019
F242C
Y248X
T267Nfs4X
c.745_751del
c.800_820del
SCRs
STP
TM
CT
2
3
4
1
C35X
C35Y
R59X
K65DfsX39
c.286+1G>C
c.286+2T>G
A353V
C99R
R103Q
R103W
G130V
c.287-2A>G
c.390-11G>C
MG1
R478L
CFH 25%
MCP 7%
CFI 6%
C3 5%
CFB 1%
Anti-CFH Ab 8%
COMPLEMENT ABNORMALITIES IN aHUS PATIENTS (Noris et al CJASN 2010; Bresin et al 2013)
A43TD53GV81L
D486YP495SP501L
CT
Lectin-Like
domain
TME1
TME2
TME3
TME4
TME5
TME6
ST-rich
peptide
TM
TM 5%
R735WV762I
Y854X V1658A
I340T
I357M
L484Vfs3X
Y459S
D524V
c.1429+1G>C
T538X
P553S
E554V
G119R
W145X
N177I
H118R
H183R
N151S
F286LK323EV455I
Y534F
E179Q
D185N
Y189D
G196R
G240R
S206P
P165S
I208Y
C210F
c.902-2A>G
c.1027+2T>C
Q1076E
S890I
H893R
Y899D
Y899X
W920R
Q925X
c.2686_2700del
E762X
N767Kfs7X
K768Kfs7X
G786fs871X
C673YC569XK584XC623S
G397R
Q400K
S411T
C431Y
V111EW134Rc.351delG
A161S
G218E
R341H
13
1 2 3 4 20
19
18
17
16
15
14
13
12
11
10
98765
Dragon-Durey et al, JASN, 2005
Jozsi et al., Blood, 2007
HUS associated factor H autoantibodies (described in 10% of aHUS
cases, mainly in children) mimic the effect of C-terminal factor H
mutations, as they inhibit the regulatory function of factor H at cell
surfaces by blocking its C-terminal recognition region
FACTOR H AUTOANTIBODIES IN aHUS
14
Blanc C. et al. J Immunol, 2012
RECOGNITION SITES OF THE ANTI-FH AUTOANTIBODIES
TO CFHR1 AND FH IN aHUS
Factor H
1 2 3 4 98765 10 11 12 13 14 15 16 17 18 19 20
(94%)
(94%)
(100%)
1 2 3 4 5
CFHR1
(80%)
Among 104 aHUS patients tested both for the CFHR1
deletion and anti-CFH autoantibodies, 23 out of 27
patients with autoantibodies (85%) were also homozygous
for the CFHR1 deletion.
15
Valoti et al. Immunobiology 2012
The Hom ∆CFHR1 is a strong predisposing factor for the
generation of anti-CFH autoantibodies.
Blanc C. et al. J Immunol 2012
1616
The formation of hybrid genes is a recently described
mechanism for CFH abnormalities in HUS
High degree of sequence identity between the gene for factor H (CFH)
and the genes for the five factor H-related proteins (CFHR1-5)
CFH consists of 20 SCR and CFHR1 of 5 SCR. CFH SCR20 and
CFHL1 SCR 5 differ at only 2 aminoacids
17
ATYPICAL HEMOLYTIC UREMIC SYNDROME ASSOCIATED WITH A
HYBRID COMPLEMENT GENE
Affected individuals carry a heterozygous CFH/CFHL1 hybrid protein in
which SCR 1-18 are derived from CFH and SCR 19/20 from SCR 4/5 of
CFHR1 by non allelic homologous recombination
The protein product of the hybrid gene is a protein that lacks any
complement regulatory activity on endothelial cell surface
4
Venables et al., PLoS Med, 2006
Noris et al., CJASN, 2010
CFH mutations: 48%
MCP mutations: 53%
CFI mutations: 50%
C3 mutations: 56%
INCOMPLETE PENETRANCE OF aHUS IN CARRIERS OF COMPLEMENT
GENE MUTATION
#01 HUS
I
II
III
2
F34
4yr, dialysis
F82F35F70
F83*
*
*
•3 subjects in the III generation developed aHUS in infancy: 2 died and 1 reached ESRD
•father F35 never developed aHUS
•grandfather F83, carrier of the R1215Q/CFH mutation, developed aHUS and died at 82 years of age
Noris et al., CJASN 2010
Incomplete penetrance of aHUS indicates that
additional genetic and/or environmental hits are
necessary for disease manifestation
T30Nfs10X
G1194D
G1194D
R1210C
R1210C
R1210C
R1215Q
N767Kfs7X
P968fs947X
S1191L
V1197A
R341H
R1210C
R1210C19
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
S
I
I
F
I
I
S
F
S
I
I
F
F
F
S
S
S
I
S
S
UK
F
F
F
F
I
H183R
I340T
E554V
P50A
H118R
N151S
N151S
C247G
L484V+Q485G+
W486X
T538X
T538X
P553S
D524V
Y459S
P553S
I357M
G1094R
R161W
H1464V
P1114L
V455I
Cohort CFH MCP CFI C3 CFB#
I208Y
F242C
F242C
Y29X
C35Y and R59X
C35Y and R59X
R103Q
R103W
IVS2+2
R103W
R103W+c.800-820del
C210F
(96-129)del+
G130I+Y131I+Y132T+L133X
P165S
P165S
A353V
A353V
Y29X
IVS2+2 Bresin et al, JASN 2013
20
Combined complement gene mutations were found in 3% of aHUS patients, more
frequently in those with MCP or CFI mutation than in patients with CFH or C3 or CFB
mutations.
8.7% 8.2% 10%
22.6% 27%
Bresin et al, JASN 2013
COMBINED complement gene MUTATIONS in aHUS
21Caprioli et al., Hum Mol Gen, 2003
-257T Promoter
2089G/SCR11, 2881T/SCR16
Promoter + SCR16
Genotypes Odds Ratios (95 % C.I.) P value
1 2 3 4 5 6 8 97
High risk
0.0015
< 0.0001
< 0.0001
Risk haplotype CFH-tgt
22
A specific SNP haplotype block, spanning the MCP gene in the regulators of
complement activation gene cluster, which is over-represented in aHUS patients and
strongly associates with the severity of the disease.
IMPACT of presence of CFH and MCP RISK HAPLOTYPES on aHUS PENETRANCE
Overall
0-1 risk haplotype
2 risk haplotype
0
20
40
60
80
100P
en
etr
an
ce (
%)
Two mutations Three mutations
55.2
35.7
73.3
100
Risk haplotypes
CFH-tgt:
c.1-332C>T (rs3753394) and c.2808G>T, p.E936D (rs1065489)
MCPggaac:
c.*897T>C (rs7144)
*
*P<0.05 vs 0-1 risk haplotype
The concomitant presence of CFH
and MCP risk haplotypes
increased aHUS penetrance in
carriers of combined mutations
Bresin et al, JASN 2013
Abnormalities of complement
regulators in aHUS: how do they
impact clinical phenotype and
management of patients?
AGE AT ONSET%
of
pati
en
ts
% o
f p
ati
en
ts
% o
f p
ati
en
ts
MCPCFI
CFH
05
101520253035404550
0 - 2 3 - 10 11 - 16 17 - 34 35 - 54
05
101520253035404550
0 - 2 3 - 10 11 - 16 17 - 34 35 - 54 >55
05
101520253035404550
0 - 2 3 - 10 11 - 16 17 - 34 35 - 54 >55
% o
f p
ati
en
ts
C3
0
5
10
15
20
25
30
35
40
45
50
0 - 2 3 - 10 11 - 16 17- 34 35 - 54
*
% o
f p
ati
en
ts THBD
0
5
10
15
20
25
30
35
40
50
60
0 - 2 3 - 10 11 - 16 17 - 34 35 - 54 >55
45
% o
f p
ati
en
ts
Non mut
0
5
10
15
20
25
30
35
40
45
50
0 - 2 3 - 10 11 - 16 17 - 34 35 - 54 >55
>55
>55
- aHUS manifested during infancy in most patients
- The earliest onset was in subjects with CFH or THBD mutations
- A second pick was at 20-30 years of age, often in association with post-partum
Years of age Years of age
Noris et al CJASN 2010
TRIGGERING /UNDERLYING CONDITION%
of
HU
S p
ati
en
ts
CFH MCP CFI
40
30
20
0
No mutation
10
C3
Upper respiratory
tract infection
Diarrhea
Post-partum
Noris et al, CJASN 2010
OUTCOME OF THE FIRST EPISODE
Noris et al CJASN 2010
*P<0.05 vs MCP
0
10
20
30
40
50
60
70
80
no mut CFH CFI C3
% o
f even
ts
(ES
RF
or
death
)
THBD
**
**
*
MCP
Overall population
Children (40%)
Adults (60%)
2828
LONG TERM OUTCOME OF aHUS PATIENTS
CFH mutation
Patients
fre
e o
f events
Death
or
ES
RD
(%
)
100
80
60
40
20
0
0 2 4 6 8 10 12
CFI mutation
C3 mutation
Follow up (years)
MCP mutation
Noris et al CJASN 2010
TM mutation
Mutations in CFH, CFI, C3 and THBD were associated with a worse long-term outcome than mutations in MCP.
Patients with:
- CFH mutations 60/76 49/76 (64%) 40 out 49 (82%)
- CFI mutations 23/26 19/26 (73%) 18 out 19 (95%)
- C3 mutations 18/30 16/30 (53%) 12 out 16 (75%)
- CFB mutations 3/4 4/4 (100%) 4 out 4 (100%)
Noris & Remuzzi, Am J Transplant 2010
Zuber Jet al. Nat Rev Nephrol 2011
Le Quintrec M et al. Am J Tranpl 2013
RENAL TRANSPLANTATION OUTCOMES
graft failure for
aHUS recurrence
In patients with alterations in circulating complement proteins, the risk of graft failure
for aHUS recurrence is high since the altered protein is produced by the liver and
persists in the circulation after kidney transplantation.
recurrences
(% grafts)patients/grafts
SURVIVAL TIME OF THE KIDNEY GRAFT IN PATIENTS
WITH SINGLE MCP MUTATIONS
Noris and Remuzzi, Am J Transplant 2010
Follow up (years)
100
80
60
40
20
00 105
Surv
ival (%
)MCP
No HUS recurrence in 10 out of 12 kidney grafts.
MCP is a membrane-bound protein highly expressed in the kidney.
A dysfunction in MCP can be corrected by transplanting a normal kidney.
OUTCOME OF KIDNEY TRANSPLANTATION OF COMBINED AND
SINGLE MUTATED PATIENTS FROM 4 COHORTS OF aHUS PATIENTS
Kid
ne
yg
raft
los
tfo
rre
cu
rre
nc
e(%
)
Single mutated patients
Combined mutated patients
Single mutated patients considered overall
Combined mutated patients considered overall
77 14 37 8 13 12 Number of transplanted
kidney for each group
Bresin et al, JASN 2013
Recurrence of HUS after live-related renal transplantation
associated with subsequent de novo disease in the donor
Proband: a 4 month-old female with ESRD following an episode of
aHUS and no familial history of the disease
Living-related renal transplant from the father with graft loss in 7 weeks
for HUS
The donor developed HUS 10 months after donation and subsequently
progressed to ESRD
Genetic screening revealed that both the proband and her donor father
carried a heterozygous S1191L mutation in CFH
Donne et al., Am J Kidney Dis, 2002
In the case of CFH associated HUS, living related kidney transplant is
risky not only for the recipient, but also for the donor
SCR 1
Paziente
c.286+2T>G
SCR 1
Madre
c.286+2T>G
c.286+2T>G
c.286+2T>G
Patiente con mutazione MCP e
recidiva di SEU post-trapianto
La paziente aveva ricevuto il rene
dalla madre, portatrice dello stessa
mutazione MCP.
Il rene trapiantato produceva la
stessa proteina MCP disfunzionale
come il rene nativo e non era
abbastanza protetto dalla
iperattivazione del complemento.
Alberti M. et al. Am J Transpl 2013
La SEU tipica ha un basso tasso di recidiva post-trapianto (0-5%)
Caso
Una giovane donna con IRT dopo
grave episodio di SEU tipica aveva
ricevuto un trapianto di rene da
cadavere che era fallito dopo 1
anno, per ricorrenza della SEU.
Lo screening genetico eseguito
prima di pianificare 2° trapianto
rivelava una mutazione di CFI.
Alberti M. et al. Am J Transpl 2013
Questo caso indica che lo screening dei geni associati alla SEU si dovrebbe eseguire anche
in pazienti in dialisi a seguito di gravi episodi di SEU tipica.
Ci possono essere casi non diagnosticati di SEU atipica, innescati da infezione da
Escherichia Coli che hanno una predisposizione genetica.
Light
Chain
Val412Met
FIMAC SRCR LRDR-1 LRDR-2 S-S Serine Protease
Heavy Chain
3535
C3b
C3
C3b CFB
C3b
Bb
C3C3
convertase
C3b
C5
C3b
Bb
C5b
C5b-9
formation
EculizumabA humanized monoclonal antibody
that binds to C5
Endothelial cell
C5a
Eculizumab was safe and well tolerated in patients with Paroxistic Nocturnal Hemoglobinuria
(PNH).
This antibody against terminal complement protein 5 reduced intravascular hemolysis,
hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life.
TRIALS OF ECULIZUMAB IN ATYPICAL HUS (62 weeks data)
Patients resistant to plasma therapy
-Platelet normalization
-TMA event-free status
-Change in renal function
One-stage improvement
>25% creatinine reduction
Patients on chronic plasma therapy
-TMA event-free status
-Hematological normalization
-One-stage renal function improvement
Licht et al., J Am Soc Nephrol (Abstract), 2011
Greenbaum et al., J Am Soc Nephrol (Abstract), 2011
Nester CM and Brophy PD, Curr Opin Pediatr, 2013
Legendre CM et al., NEJM, 2013
15/17 patients
15/17 patients
11/17 patients
13/17 patients
17/20 patients
18/20 patients
9/20 patients
Ten patients had no identified genetic abnormalities or anti-CFH antibodies
Managing and preventing aHUS recurrence after kidney tx
Patients with aHUS recurrence in the kidney graft (n=13)
Mutation Response to plasma Response to Ecu Loss
CFH 2/8 6/8 *1/8
C3 2(partial)/2 2/2 0/2
not identified 0/3 *1/3 2/3
Patients with post-transplant Eculizumab prophylaxis (n=10)
Mutation Plasma therapy Recurrence Loss
-CFH 4/9 0/9 1/9
-C3 0/1 0/1 0/1
Two pts received PEX just before tx and were switched to eculizumab at day 5 and 10 post-tx.
In 3 pts eculizumab was started 1 week or more before tx, preceded (in 2 pts) by PEX.
The more common strategy was based on eculizumab alone, started immediately before tx.
Only one patient lost the graft for immediated arterial thrombosis at day 1 post-tx.
*Single dose of Eculizumab
Two patients were plasma-dependent whereas the other had plasma-resistant forms.
A single-dose eculizumab and eculizumab discontinuation after several months were associated with
subsequent relapses and graft loss in 3 patients despite re-initiation of eculizumab.
Congenital TTP and eculizumab
A 12-year-old Italian boy was admitted to the Hospital with hemolytic
anemia, thrombocytopenia, acute renal failure requiring hemodialysis
and generalized seizures, preceded by an upper respiratory tract
infection
Absence of prodromal diarrhoea and negative results (by stool culture
and sierology) for Shiga-like toxin-producing E.coli
Elevated plasma levels of the terminal complement complex sC5b-9
(520 ng/ml, n.v.<400 ng/ml)
Diagnosis of complement-mediated atypical hemolytic uremic syndrome
(aHUS)
38
Pla
tele
t count
(10
3/m
icro
lite
r)
days
Lower limit of
normal range
EculizumabHD
Relapse
900 mg
1200 mg
Pecoraro C, Remuzzi G, 2015
renal function
normalized
in 3 days
0
6000
12000
18000°
* *
pre-
Ecu
3 days
post-
Ecu
C5
b-9
fo
rme
d(p
ixe
l2/f
ield
)
15 days
post-
Ecu
normal range
Serum-induced C5b-9 deposits on HMEC-1 ex-vivo normalized after Eculizumab
40
No mutations in CFH, MCP, CFI, C3, CFB, THBD, and no anti-CFH antibodies.
Undetectable plasma ADAMTS13 activity (<6% by CBA, without inhibitory
antibodies).
Two compound heterozygous ADAMTS13 mutations:
CUB1 CUB2TSP-1
1Metalloprotease Disintegrin Cys Spacer TSP-1
3
TSP-1
4
TSP-1
5
TSP-1
6
TSP-1
7
TSP-1
2TSP-1
8
c.3251G>A
p.C1084Y
N-term C-term
vWF binding
c.4049delC
p.E1351STOP
Vessel wall
Shear
Folded vWF
Vessel wall
Platelet rolling Platelet adhesion
Platelet
Platelet
Shear Unfolded vWF
Vessel wall
Platelet adhesion and
aggregation
Platel
et
ADAMTS13
Platelet
Unfolded vWF
TTP
Pecoraro C, Remuzzi G, 2015
41
The clinical evolution of this patient and the
intense C5b-9 deposits suggested a role of
complement activation in the pathogenesis of
TTP and opens a perspective for the treatment of
this disease
42
Disease presentation before the age of 1 year, with multiple relapsing
episodes, often progressing to CKD by the second decade of life.
Mutations in DGKE encoding diacylglycerol kinase ɛ. Recessive
inheritance. Explained 27% of aHUS cases in the first year of life.
No evidence linking DGKE deficiency to complement cascade.
One of 7 patients with DGKE mutation on maintenance Eculizumab
therapy had an HUS relapse.
Renal transplantation can be efficacious in patients with DGKE
mutations. No aHUS recurrence after transplantation in 3/3 subjects.
Lemaire M et al, Nature Genet 2013
RECESSIVE MUTATIONS IN DGKE CAUSE
ATYPICAL HEMOLYTIC-UREMIC SYNDROME
Conclusioni
• La PTT è causata da deficienza acquisita o congenita di ADAMTS13 ed è
importante definire la causa per scegliere la terapia appropriata.
• Importante lo screening di mutazioni del complemento nella SEU atipica,
e nelle forme severe di SEU tipica.
• Elevato rischio di recidiva post-tx in pazienti con mutazioni in geni che
codificano per proteine del complemento circolanti (CFH, CFI, C3, CFB).
• Pazienti con mutazioni in MCP e DGKE hanno una prognosi favorevole e mostrano buon esito del trapianto.
Laboratory
ClinicalMarina Noris
Roberta Donadelli
Elisabetta Valoti
Rossela Piras
Caterina Mele
Marta Alberti
Matteo Breno
Serena Bettoni
Giuseppe Remuzzi
Erica Daina
Piero Ruggenenti
Sara Gamba
Paraskevas Iatropoulos
Manuela Curreri
Collaborations
Santiago Rodriguez DeCordoba
Veronique Fremeaux-Bacchi
Tim Goodship
Peter Zipfel