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ADAMTS-13 and thrombotic microangiopathies: Pathophysiology, diagnosis and treatment

English title ADAMTS-13 and thrombotic microangiopathies: Pathophysiology, diagnosis and treatment
Applicant Lämmle Bernhard
Number 108261
Funding scheme Project funding
Research institution Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor Inselspital
Institution of higher education University of Berne - BE
Main discipline Clinical Cardiovascular Research
Start/End 01.07.2005 - 30.06.2009
Approved amount 296'000.00
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All Disciplines (3)

Discipline
Clinical Cardiovascular Research
Biochemistry
Molecular Biology

Keywords (5)

THROMBOTIC THROMBOCYTOPENIC PURPURA; TTP; thrombotic microangiopathy; von Willebrand factor-cleaving protease; ADAMTS-13

Lay Summary (English)

Lead
Lay summary
Our research focuses on the disease “thrombotic thrombocytopenic purpura” (TTP) which is characterized by a severe decrease of the platelet count (thrombocytopenia), destruction of red blood cells (hemolytic anemia) and often dysfunction of several organs, such as the brain and kidneys. Thrombocytopenia is caused by intravascular platelet clumping in the arterioles and capillaries leading to red blood cell fragmentation in the partially occluded small blood vessels (microcirculation) and to ischemic organ damage (damage by deficient blood supply).Until the 1970ies more than 90% of patients with acute TTP died. The empirical introduction in the 1970ies of plasma exchange and replacement of the exchanged blood plasma with fresh frozen plasma from healthy blood donors dramatically improved the outcome. However, even today, mortality remains high and 10-20% of affected patients still succumb.One main pathophysiological factor in TTP is the inability of processing large, highly polymeric von Willebrand factor (vWF) molecules secreted from endothelial cells into the blood. These unusually large vWF multimers (ULvWF) are highly adhesive and seem to be responsible for the platelet clumping in the microcirculation.In 1996, our laboratory detected a protease, now called ADAMTS13, that cleaves ULvWF to generate normal-sized vWF. In 1997-1998 we detected that most patients with acute TTP had a severe deficiency of ADAMTS13, either due to a constitutional, inherited defect or, more commonly, caused by autoantibodies inhibiting the ADAMTS13 activity.Our institute is an international reference laboratory for measuring ADAMTS13, studying the genetic defects of ADAMTS13 and advising physicians on the treatment of their TTP patients. Over the past 10 years we have received some 3000 blood samples from from many hospitals all over the world for analysis.Our current research addresses several topics:1.Improvement of assays for studying ADAMTS13, autoantibodies and vWF.2.Study of the defects of the ADAMTS13 gene in patients and families with hereditary TTP in order to understand whether specific mutations explain the highly variable clinical course, for instance the variable age at disease onset. An international registry is being set up.3.We investigate why patients may develop autoantibodies against ADAMTS13. We also aim to find out whether repeatedly measuring ADAMTS13 and inhibitors in surviving patients will allow to detect those patients at risk of disease relapse.4.Special effort focuses at understanding the factors leading to TTP in patients not having a severely decreased ADAMTS13 activity as measured by current methods.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
124892 Acquired and hereditary thrombotic microangiopathies - clinical presentation, pathophysiology and treatment with a focus on ADAMTS13 01.09.2009 Project funding
66756 von Willebrand factor-cleaving protease and thrombotic micro- angiopathies: Pathophysiology, Diagnosis and Treatment. 01.05.2002 Project funding

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