{Reference Type}: Journal Article
{Title}: VE-Cadherin is involved in endothelial cell detachment during Thrombotic Thrombocytopenic Purpura.
{Author}: Cauchois R;Lagarde M;Muller R;Faccini J;Leroyer A;Arnaud L;Poullin P;Dignat-George F;Kaplanski G;Tellier E;
{Journal}: J Thromb Haemost
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 29
{Factor}: 16.036
{DOI}: 10.1016/j.jtha.2024.06.012
{Abstract}: <B>OBJECTIVE: </B>Immune Thrombotic thrombocytopenic purpura (i-TTP) is a life-threatening thrombotic microangiopathie linked to ADAMTS13 deficiency. It has long been assumed that the activation of endothelial cells is the triggering factor for the TTP crisis. Circulating endothelial cells (CEC) have been shown to be a biomarker of vascular damage and are associated with the clinical severity of i-TTP. However, the mechanisms leading to endothelial cell detachment remain unclear.<BR><B>OBJECTIVE: </B>We have investigated junctional destabilization and the mechanisms underlying cell detachment in TTP.<BR><B>RESULTS: </B>In plasma from i-TTP patients, we show that CEC count is associated with severity and correlated to intracellular calcium influx (p<0.01). In vitro, serum from i-TTP patients induced stronger detachment of human umbilical vein endothelial cells (HUVECs) than serum from control patients (p<0.001). Plasma from i-TTP patients induced a higher calcium-dependent phosphorylation (p<0.05) and internalization (p<0.05) of VE-cadherin compared to plasma from control patients. This effect could be reproduced by IgG fraction isolated from patient plasma and in particular by the F(ab)'2 fragments of the corresponding IgG. In addition, subcutaneous injection of i-TTP plasma into mice resulted in higher vascular permeability than plasma from control patients. An inhibitor of endothelial calcium influx, ITF1697, normalized this increase in permeability.<BR><B>CONCLUSIONS: </B>Our results suggest that plasma-induced endothelial activation also leads to an increase in vascular permeability. They contribute to the understanding of the mechanisms behind the presence of elevated CECs in patients' blood by linking endothelial activation to endothelial injury.