Transcript Diapositiva 1

INTERNATIONAL REGISTRY of RECURRENT and FAMILIAL
HEMOLYTIC UREMIC SYNDROME (HUS)
and THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)
HYSTORY:
The Registry was established in 1996.
AIM OF THE REGISTRY:
-
understanding the pathogenesis of HUS/TTP
studying the genetic and biochemical abnormalities of HUS/TTP
finding the best therapeutic approach for patients
collecting clinical and genetic data of patients and their families
giving up-to-date information to physicians and families
THE THROMBOTIC MICROANGIOPATHY (TMA)
The term “thrombotic microangiopathy” (TMA) defines a lesion of vessel
wall thickening (mainly arterioles and capillaries), intraluminal platelet
thrombosis and partial or complete obstruction of the vessel lumina1.
HUS microangiopathic haemolysis, thrombocytopenia and renal failure
TTP microangiopathic haemolysis, thrombocytopenia and cerebral lesions
HUS and TTP are entities pathologically indistinguishable
1 Caprioli J. et al. Human Molecular Genetics, 2003, Vol. 12, No. 24: 3385-3395
FORMS OF HUS/TTP:
The most common form of HUS in children, with predominant renal failure,
is associated with a particular gastro-intestinal infection.
This form usually has an excellent prognosis.
There are also rare forms of HUS/TTP without gastro-intestinal infection,
that have a much poorer prognosis:
- relapsing form (when the patient has severaò relapses of the disease)
- familial form (when there are at least 2 subjects with HUS/TTP in the
same family)
TTP is the most common form of TMA in adults and manifests with
prevailing neurological symptoms.
THERAPY OF HUS/TTP:
Early plasma-exchange or plasma infusion of an health donor
are the current therapies for acute phases of the disease.
Dialysis is necessary if there is an acute renal failure
HOW FAR IS RESEARCH?
There are a lot of research studies ongoing about HUS/TTP to
understand the pathogenesis and to find the specific therapies of
the disease.
Researchers involving are studying the role of substances of the
blood coagulation and particularly some proteins of the
complement system, and are studying the genetic aspects of
HUS/TTP.
As for therapy: research is working on the optimisation of plasma
treatment for patients.
WHAT OUR RESEARCH LABORATORY OF THE REGISTRY IS DOING
TO BETTER UNDERSTAND HUS/TTP?
GENETIC AND BIOCHEMICAL STUDIES ON:
Factor H – CFH - a plasmatic circulating protein produced by the liver
and involved in the regulation of the complement system, that is often
spoiled in patients with HUS.
Membrane Cofactor Protein – MCP - a complement regulatory protein.
Recently our researchers have found a mutation of MCP gene in a family
with HUS.
ADAMTS13 – the Von Willebrand Factor cleaving protease – an
enzyme which degrades the VWF multimers, preventing platelet
adhesion and aggregation in the microcirculation.
The plasma levels of ADAMTS13 protease in some patients (particularly
with TTP) are absent or very low, due to a constitutive or acquired
defective activity.
2 Noris M. et al. Lancet, 2003, Vol. 362: 1542-1547
WHAT THE REGISTRY RESEARCHERS ARE DOING?
Recently* our researchers found 17 different mutations in the
factor H gene of 33 patients with HUS referred to the Registry.
3 Caprioli et al. Human Molecular Genetics, 2003, Vol. 12, No. 24: 3385-3395
MUTATIONS FOUND IN FACTOR H GENE FROM
PATIENTS REFERRED TO THE REGISTRY
R
L
Trp1183Arg
H
G
STOP
Arg60Gly
H
W
Tyr951His
Cys1163Trp
Gln950His
del A1494-1496
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
NH2
COOH
WT A K
R
Q
L
K
A
L
I
Y
N
S
Y
STOP
R
N
D Gly1194Asp
T
Glu1172Stop E
G
M
STOP
E
I
A
S
Val1197Ala
E
A
V
R
E
K LE Y
S
G
I
F P
D
A Glu1198Ala
V T
V
W
C
C C
NH2 H P C
T
K A
K
T
R
R COOH
R
G
L
Y
Q
Q
T
R
STOP
Arg1215Gln H
L
SR S S
24 bp deletion
C
C
C
Arg1210Cys
PARTICIPATING CENTERS OF THE INTERNATIONAL
REGISTRY OF HEMOLYTIC UREMIC SYNDROME AND
THROMBOTIC THROMBOCYTOPENIC PURPURA:


Italian Centers: 72
Abroad Centers: 39
Bergamo
DENMARK
U.S.A
UK
CANADA
BELGIUM
ARGENTINA
RSA
SAUDI ARABIA
ISRAEL
GERMANY
SWITZERLAND
PORTUGAL
SPAIN
THE INTERNATIONAL REGISTRY OF HUS/TTP:
PATIENTS DATA
Atypical forms
HUS
TTP
Familial forms
54 (within 29 families)
8 (within 6 families)
Recurrent forms
51
36
Sporadic forms
106
22
Tot. 211
Tot. 66
CONTACTS
We perform biochemical and genetic analyses for
patients with atypical form of HUS/TTP.
For information and for other questions and for any
other questions, please contact:
Clinical Research Center for Rare Diseases Aldo e Cele Daccò
Mario Negri Institute for Pharmacological Research
Via G.B. Camozzi, 3 -24020- Ranica (BG) Italy
Phone: +39-035-4535304
Fax: +39-035-4535373
E-mail: [email protected]
Contact persons:
Elena Bresin, MD
Erica Daina, MD
Sara Gamba, RN