Data di Pubblicazione:
2013
Citazione:
ADAMTS13-RELATED ASSAYS IN ACQUIRED THROMBOTIC THROMBOCYTOPENIC PURPURA / I. Mancini ; tutor: F. Peyvandi ; coordinatore: P Corradini. DIPARTIMENTO DI SCIENZE CLINICHE E DI COMUNITA', 2013 Feb 14. 25. ciclo, Anno Accademico 2012. [10.13130/mancini-ilaria_phd2013-02-14].
Abstract:
Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening microangiopathic disorder, due to the persistence of highly thrombogenic ultra large (UL) von Willebrand factor (VWF) multimers in the microcirculation. TTP is associated with the severe deficiency of ADAMTS13 (activity <10%), the metalloprotease responsible for the proteolytic regulation of VWF multimers size. In the acquired form of the disease, the severe deficiency of ADAMTS13 is caused by anti-ADAMTS13 antibodies that inhibit ADAMTS13 activity (neutralizing anti-ADAMTS13 antibodies or inhibitors) and/or increase its clearance from the circulation (non-neutralizing anti-ADAMTS13 antibodies). In the absence of ADAMTS13, highly adhesive ULVWF, that spontaneously aggregate platelets, accumulates promoting platelet thrombi formation and eventually leading to the clinical features typical of TTP.
In the past decade, the increasing knowledge regarding the molecular mechanisms involved in the pathogenesis of TTP, yielded to a proliferation of assays for the measurement of ADAMTS13 and anti-ADAMTS13 antibodies. Despite the numerous studies conducted to assess the clinical utility of ADAMTS13-related markers, their prognostic value is still controversial. The finding that severe ADAMTS13 deficiency and the presence of anti-ADAMTS13 antibody is associated with an increased risk of relapse is rather consistent, but studies on larger cohort of patients are needed. More uncertain is the predictive value of immunoglobulin (Ig) class subtype of anti-ADAMTS13 antibodies, whether or not inhibitory. Controversial results may be partially due to differences in the assays used to measure ADAMTS13 activity and anti-ADAMTS13 antibodies, which require further standardization.
With this background, the present research had two main objectives: to evaluate, in a large cohort of acquired TTP patients enrolled in the international Milan TTP Registry (developed and curated at the The Hemophilia and Thrombosis Centre of Milan), the clinical utility of ADAMTS13 related biomarkers and to investigate which ADAMTS13 assay may be more reliable in the management of acquired TTP.
In the first part of this study, we analyzed, during both acute and remission phase, all the biomarkers associated with ADAMTS13 (activity, antigen and class, subclass and titre of anti ADAMTS13 autoantibodies) in acquired TTP patients referred to our centre and we correlated them to episode severity and recurrence. We found that both the Ig class and subclass are of predictive value for acute episode severity in patients with TTP. Disease recurrence seemed to be associated with the presence of IgG antibodies during the acute phase, while alterations in several ADAMTS13 related biomarkers (ADAMTS13 activity or antigen levels <10%, presence of ADAMTS13 inhibitor or IgG) could predict recurrence risk when measured during disease remission.
The results of this study confirmed and extended previous data on the prognostic value of ADAMTS13 testing, providing valuable information for the identification of patients at higher risk requiring closer follow up.
The studies conducted in the second part of this doctorate intended to investigate the performance of two widely used methods, the collagen-binding assay (CBA) and the more recent fluorescence resonance energy transfer (FRET) assay, for the measurement of ADAMTS13 activity and anti ADAMTS13 inhibitors. Given the prognostic value of ADAMTS13-related markers (as demonstrated in the first part of this thesis), it is essential to determine which ADAMTS13 assay is more reliable in the management of patients suffering from this rare but life-threatening disease.
CBA and FRET assay strongly differ from a methodological point of view: they use different substrates
Tipologia IRIS:
Tesi di dottorato
Keywords:
THROMBOTIC THROMBOCYTOPENIC PURPURA ; ADAMTS13 ; ASSAYS
Elenco autori:
I. Mancini
Link alla scheda completa:
Link al Full Text: