1. 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 INTERNATIONAL REGISTRY of RECURRENT and FAMILIAL HEMOLYTIC UREMIC SYNDROME (HUS) and THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)

2. 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 lumina 1. 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

3. 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.

4. 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

5. 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.

6. 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

7. 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

8. 1234567891011121314151617181920 COOH NH 2 W G Gln950His Tyr951His Cys1163Trp Arg60Gly STOP del A1494-1496 H H MUTATIONS FOUND IN FACTOR H GENE FROM PATIENTS REFERRED TO THE REGISTRY

9. PARTICIPATING CENTERS OF THE INTERNATIONAL REGISTRY OF HEMOLYTIC UREMIC SYNDROME AND THROMBOTIC THROMBOCYTOPENIC PURPURA: U.S.A CANADA ARGENTINA UK DENMARK BELGIUM SWITZERLAND SPAIN PORTUGAL SAUDI ARABIA RSA GERMANY Bergamo Italian Centers: 72 Italian Centers: 72 Abroad Centers: 39 Abroad Centers: 39 ISRAEL

10. THE INTERNATIONAL REGISTRY OF HUS/TTP: PATIENTS DATA Atypical forms HUSTTP Familial forms 54 (within 29 families) 8 (within 6 families) Recurrent forms 5136 Sporadic forms 10622 Tot. 211 Tot. 66

11. 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: raredis@marionegri.it raredis@marionegri.it Contact persons: Elena Bresin, MD Erica Daina, MD Sara Gamba, RN 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: