Circulating Endothelial Cells As a Reliable Marker Of Endothelial Damage In Children Undergoing Hematopoietic Stem Cell Transplantation
Authors: Touzot Fabien , Moshous Despina , Cros Guilhem , Frange Pierre , Heritier Sebastien , Neven Benedicte , Cavazzana-Calvo Marina , Fischer Alain , Blanche Stephane , Helley Dominique 
Published: October 2019

Abstract
The endothelial dysfunction associated with Hematopoietic Stem Cell Transplantation (HSCT) is responsible for pleomorphic complications that arise during the post-tranplant period: sinusoidal obstruction syndrome (SOS), pulmonary arterial hypertension (PAH), capillary leak syndrome (CLS) and transplantation-associated thrombotic microangiopathy (TA-TMA). Numerous factors may induce these endothelial damages. Circulating endothelial cells (CEC) emerge as a potent marker of endothelial lesion in a variety of disorders but their monitoring in HSCT has been little investigated so far.

Methods
Thirty-six pediatric patients treated in the department of Immuno-Hematology at the Necker-Enfants-Malades Hospital who received allogeneic HSCT after full intensity conditioning regimen for non-malignant disorders including inherited immunodeficiencies, metabolic diseases or hemoglobin disorders were enrolled in the study between April 2011 and December 2012. CEC were monitored at 5 time points: before conditioning (day -15), at time of transplant (day 0) and during the post-transplantation period (at day +15, day +30 and eventually day +60 if the patient was still hospitalized). Blood samples were not collected in period of sepsis to avoid any confounding factor7.

Results
Among the thirty-six patient enrolled, four patients were excluded because of incomplete follow-up. Thirty-two patients completed the study, and their data were analyzed.
Vascular complications occurred in 10 patients (31% patients) and are detailed in Figure 1C. Of note, all patients who developed SOS were under defibrotide prophylaxis. Two patients developed CLS in association with grade IV GVH. TA-TMA occurred in two patients and resolved in both after cyclosporine withdrawal.
Patients with vascular events (VE) had significant higher CEC counts as compared to patients without endothelial complication at day +15 (p = 0.0122) and day +30 (p=0.0046). The increase of CEC counts was significantly higher in patients with VE during the first 15 days (p=0.0175) and during the first month post transplantation (p=0.0005) as compared to patient without VE. Strikingly, detection of high CEC counts in patients with major vascular events (ie. PAH, CLS and TA-TAM) was preceding the onset of clinical manifestations by a median of 18.5 days (range, 8-42).
We didn’t find any correlation on univariate analysis between CEC counts and the following variables: the underlying disease, the intensity of conditioning regimen, the existence of CMV reactivation, graft versus host disease or death.

Conclusion
We observed that the occurrence of vascular complications is associated with an early rise (in the first 15 days) of CEC count. Interestingly, the increase in the number of CEC is preceding the onset of major endothelial complications. Thus, monitoring of CEC in routine could be a useful prognostic tool that could allow early therapeutic intervention.

Disclosures:
No relevant conflicts of interest to declare.