Endothelial Dysfunction in Hematopoietic Cell Transplantation

Abstract

The goal of this review is to look at the role of endothelial damage and dysfunction in the initiation and development of early complications that appear after hematopoietic cell transplantation (HCT). These early complications share overlapping clinical manifestations and the suspicion of underlying endothelial damage. Several studies using different approaches, such as animal and in vitro models, the analysis of soluble biomarkers and clinical findings have provided evidence of this endothelial dysfunction. Historically, the first complication in which the role of endothelial damage was elucidated was the veno-oclusive disease/sinusoidal obstructive syndrome. In the last two decades, increasing evidence of the implication of the endothelium in the pathophysiology of other syndromes such as capillary leak syndrome, transplant-associated microangiopathy, or even graft versus host disease has accumulated. This knowledge opens up potential pharmacologic interventions to prevent/and/or treat endothelial damage and, therefore, to improve the outcome of patients receiving HCT.

Keywords: Endohtelium; Endothelial dysfunction; GvHD; Hematopoietic stem cell transplantation; Inflammation; TA-TMA.

Figure 1

Endothelial damage markers follow a different kinetics when comparing the in vitro effect of auto and allo-HCT sera over endothelial cells. Bar diagrams summarize changes in adhesion receptor expression (VCAM-1, ICAM-1, and E-selectin) on the surface of endothelial cells exposed to sera from patients receiving auto (left) or allo (right) HCT. These experiments were performed exposing endothelial cells in culture to the sera from patients receiving autologous or allogeneic HCT for 48 hours. The cells were then fixed, and adhesion receptor expression was assessed by immunofluorescence.

Figure 2

Prothrombotic phenotype of the extracellular matrices (ECM) generated by endothelial cells (ECs) in response to sera from patients with acute graft versus host disease (aGvHD). Representative images of platelet adhesion after exposing ECM to flowing blood (800/s, 5 minutes) (upper images) and presence of von Willebrand Factor (vWF, green staining) on the ECM produced by ECs exposed to sera from both GvHD and No-GvHD patients at day 21 after allo-HCT. Original magnification of × 400 for all micrographs obtained with a fluorescent microscope (LEICA DM4000B).

Figure 3

Enhanced expression of the adhesion receptors VCAM-1 and ICAM-1 on endothelial cells exposed to sera from patients developing acute graft versus host disease (GvHD). Micrographs of VCAM-1 and ICAM-1 staining (with red and green colors, respectively) on cell surfaces of microvascular endothelial cells exposed to sera from both GvHD and No-GvHD patients at day 21 after allo-HCT. Original magnification of × 400 for all micrographs obtained with a fluorescent microscope (LEICA DM4000B).