Abstract
Immune thrombotic thrombocytopenic purpura (iTTP) is caused by severe deficiency of
plasma ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1
motif, member 13) activity. Despite advances in early diagnosis and management, the
mortality rate of acute iTTP remains high in a large part of world where access to
some of the most novel therapies is limited. To determine the role of plasma big endothelin-1
(bigET-1) or its bioactive product ET-1 as a biomarker and/or a pathogenic factor
in acute iTTP, plasma levels of bigET-1 were determined using an immunoassay in patients
with iTTP on admission and during remission, as well as in healthy controls; moreover,
the biological effect of ET-1 in thrombus formation was determined by a microfluidic
assay. We show that plasma levels of bigET-1 were dramatically increased in patients
with acute iTTP on admission, which was significantly decreased during clinical response/remission;
elevated admission levels of plasma bigET-1 were associated with low estimated glomerular
filtration rate, the need for intensive care unit admission or intubation, and in-hospital
mortality. Moreover, an addition of a bioactive product ET-1 to cultured endothelial
cells in a microfluidic channel significantly accelerated the rate of thrombus formation
under arterial flow. Our results demonstrate for the first time a potential role of
measuring plasma bigET-1 in patients with acute iTTP in assessing the disease severity
and risk of in-hospital mortality, which may help stratify patients for a more aggressive
monitoring and therapeutic strategy; also, the bioactive ET-1, derived from bigET-1,
may result in acute renal injury in TTP patient, likely through its vasoconstriction
and prothrombotic properties.
Keywords
endothelial ET-1 - TTP - renal injury - mortality - outcome
