Hypochromic red cells as a prognostic indicator of survival among patients with systemic sclerosis screened for pulmonary hypertension

Abstract

Background Patients with systemic sclerosis (SSc) are frequently affected by iron deficiency, particularly those with pulmonary hypertension (PH). The first data indicate the prognostic importance of hypochromic red cells (% HRC) > 2% among patients with PH. Hence, the objective of our study was to investigate the prognostic value of % HRC in SSc patients screened for PH. Methods In this retrospective, single-center cohort study, SSc patients with a screening for PH were enrolled. Clinical characteristics and laboratory and pulmonary functional parameters associated with the prognosis of SSc were analyzed using uni- and multivariable analysis. Results From 280 SSc patients screened, 171 could be included in the analysis having available data of iron metabolism (81% female, 60 ± 13 years of age, 77% limited cutaneous SSc, 65 manifest PH, and 73 pulmonary fibrosis). The patients were followed for 2.4 ± 1.8 (median 2.4) years. HRC > 2% at baseline was significantly associated with worse survival in the uni- (p = 0.018) and multivariable (p = 0.031) analysis independent from the presence of PH or pulmonary parenchymal manifestations. The combination of HRC > 2% and low diffusion capacity for carbon monoxide (DLCO) ≤ 65% predicted was significantly associated with survival (p < 0.0001). Conclusion This is the first study reporting that HRC > 2% is an independent prognostic predictor of mortality and can possibly be used as a biomarker among SSc patients. The combination of HRC > 2% and DLCO ≤ 65% predicted could serve in the risk stratification of SSc patients. Larger studies are required to confirm these findings.

Biomarkers in Systemic Sclerosis: An Overview

“…Local secretion of the von Willebrand factor causes platelet aggregation, hypercoagulability, and fibrin deposition leading to terminal vascular injury [126][127][128][129][130][131][132][133]151]. The endothelialmesenchymal transition also favors the formation of myofibroblasts [128][129][130][131][132][133]152,153].…”

“…Local secretion of the von Willebrand factor causes platelet aggregation, hypercoagulability, and fibrin deposition leading to terminal vascular injury [126][127][128][129][130][131][132][133]151]. The endothelialmesenchymal transition also favors the formation of myofibroblasts [128][129][130][131][132][133]152,153]. The activated endothelium also expresses an increase in adhesion molecules and specific chemokines, recruiting immune cells and perivascular infiltrates leading to further inflammation and fibrosis [128][129][130][131][132][133]152,153].…”

“…The endothelialmesenchymal transition also favors the formation of myofibroblasts [128][129][130][131][132][133]152,153]. The activated endothelium also expresses an increase in adhesion molecules and specific chemokines, recruiting immune cells and perivascular infiltrates leading to further inflammation and fibrosis [128][129][130][131][132][133]152,153]. Specifically, the imbalance of cytokines, including endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-9, endoglin, endothelin-1 (ET-1), and the angiostatic pentraxin 3 (PTX3), MMP-12, endostatin, angiostatin and semaphorin3E (Sema3E) cause dysfunction in angiogenesis and an alteration in endothelial progenitor cell (EPC) recruitment [116][117][118][119].…”

“…Specifically, the imbalance of cytokines, including endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-9, endoglin, endothelin-1 (ET-1), and the angiostatic pentraxin 3 (PTX3), MMP-12, endostatin, angiostatin and semaphorin3E (Sema3E) cause dysfunction in angiogenesis and an alteration in endothelial progenitor cell (EPC) recruitment [116][117][118][119]. Endothelin-1 is secreted by endothelial cells and activated smooth muscle cells, fibroblasts, epithelial cells, and inflammatory cells [128][129][130][131][132][133]152,153]. An increase in ET-1 is present in SSc-PAH compared to SSc patients without PAH and healthy controls [116][117][118][119].…”

“…Hemoglobin and ferritin are significantly lower in patients with pulmonary hypertension (PH) in SSc than in those with pulmonary hypertension, while uric acid and NT-proBNP are significantly higher [116][117][118][119]. CCL21 circulating in SSc is a biomarker associated with PAH and the development of PAH [128][129][130][131][132][133]152,153]. SSc-PAH is associated with elevated metalloproteinase inhibitors, including TIMP-4 levels, indicating a cardiopulmonary vasculature-specific role of TIMP-4 activation in SSc [116][117][118][119].…”