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. 2023 Apr 9;24(8):6960.
doi: 10.3390/ijms24086960.

Endothelial Injury Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation: Angiopetin-2 as a Novel Predictor of the Outcome and the Role of Functional Autoantibodies against Angiotensin II Type 1 and Endothelin A Receptor

Dionysios Vythoulkas  1 , Ioanna Lazana  1 , Christos Kroupis  2 , Eleni Gavriilaki  3 , Ioannis Konstantellos  1 , Zoi Bousiou  3 , Spiros Chondropoulos  1 , Marianna Griniezaki  1 , Anna Vardi  3 , Konstantinos Gkirkas  1 , Aggeliki Karagiannidou  1 , Ioannis Batsis  3 , Maria Stamouli  1 , Ioanna Sakellari  3 , Panagiotis Tsirigotis  1
Affiliations

Endothelial Injury Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation: Angiopetin-2 as a Novel Predictor of the Outcome and the Role of Functional Autoantibodies against Angiotensin II Type 1 and Endothelin A Receptor

Dionysios Vythoulkas et al. Int J Mol Sci. .

Abstract

Transplant-associated thrombotic microangiopathy (TMA) occurs in a significant percentage of patients after allogeneic stem cell transplantation (allo-SCT) and is associated with significant morbidity and mortality. The aim of the present study was to examine the association of serum angiopoetin-2 (Ang2) levels and the presence of antibodies against angiotensin II type 1 (AT1R) and ndothelin A Recreptor (ETAR) with the outcome of patients with TMA and/or graft-versus-host disease (GVHD) after allo-SCT. Analysis of our data showed that elevated serum Ang2 levels at the time of TMA diagnosis are significantly associated with increased non-relapse mortality and decreased overall survival. To our knowledge, this is the first study demonstrating an association between raised Ang2 levels and poor outcomes in patients with TMA. Antibodies against AT1R (AT1R-Abs) and ETAR (ETAR-Abs) were detected in 27% and 23% of the patients, respectively, but there was no association between the presence of autoantibodies and the outcome of patients with TMA. However, a significant finding was the strong positive correlation between the presence of AT1R-Abs with the occurrence of chronic fibrotic GVHD, such as scleroderma and cryptogenic organizing pneumonia, raising the possibility of the contribution of autoantibodies in the pathogenesis of fibrotic GVHD manifestations.

Keywords: angiopoetin-2; angiotensin II type 1 receptor; endothelial injury syndromes; endothelin A receptor; graft-versus-host disease; transplant-associated thrombotic microangiopathy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Serum Ang2 levels and non-relapse mortality (all patients).
Figure 2
Figure 2
Spearman’ rank analysis (n = 52 patients): (a) positive correlation between AT1R-Abs and ETAR-Abs titers (patients with high AT1R-Abs have also high ETAR-Abs titers), (b) positive correlation between AT1R-Abs titers and serum Ang2 levels (patients with high AT1R-Abs titers also have high serum Ang2 levels).
Figure 3
Figure 3
Non-relapse mortality (n = 52 patients): (a) patients with TMA and concurrent GVHD versus patients with GVHD in the absence of TMA (increased NRM in the group of patients with TMA and concurrent GVHD), (b) patients with serum Ang2 levels above versus below the median (increased NRM in the group of patients with serum Ang2 levels above the median).
Figure 4
Figure 4
Patients with TMA and serum Ang2 levels (n = 20 patients): (a) non-relapse mortality (increased NRM in the group of patients with serum Ang2 above the median), (b) overall survival (decreased OS in the group of patients with serum Ang2 above the median).
Figure 5
Figure 5
(a) AT1R-Abs and chronic GVHD with fibrotic manifestations (9 patients with scleroderma and 3 patients with COP have higher AT1R-Abs titers in comparison with patients without fibrotic GVHD manifestations), (b) the predictive value of AT1R-Abs titers.
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