Association of Placenta Growth Factor with Hemolysis and Inflammation in Sickle Cell Disease (SCD)

BACKGROUND: Placenta Growth Factor (PlGF) is a member of the vascular endothelial growth factor family of cytokines. Although expressed at high levels by the placenta during pregnancy, PlGF is also released by immature erythrocytes and is elevated in SCD. PlGF appears to play a role in inflammation and may be associated with the frequency of pain episodes in SCD. More recently, PlGF has been reported to increase the expression of endothelin-1 and endothelin-B receptor in human pulmonary microvascular endothelial cells and monocytes, and therefore may play a role in the development of SCD-associated pulmonary hypertension (PHT).

OBJECTIVE: We have previously reported that SCD patients with PHT exhibit higher levels of inflammatory markers compared to patients without PHT. The purpose of this study was to evaluate the association of PlGF with PHT (and other SCD-related complications), and to explore the link between PlGF and laboratory markers of hemolysis and inflammation in SCD patients.

METHODS: We performed a cross-sectional study of patients followed at the Sickle Cell Clinic at UNC-Chapel Hill. Doppler echocardiography was used to determine the pulmonary artery systolic pressure, and PHT was subsequently defined using an age-, sex-and BMI-adjusted reference range. Nitric oxide metabolites (NOx), PlGF and soluble VCAM (all quantified by ELISA), as well as laboratory markers of hemolysis were obtained at the time of patient evaluation. Student’s t-tests (a = 0.05) were used to compare mean values of PlGF in patients with SCD-related complications. Furthermore, Spearman’s correlation coefficient was used to assess for correlations between PlGF and laboratory variables.

RESULTS: Plasma samples were available in 71 of the 74 subjects evaluated. Levels of PlGF were significantly higher in patients with PHT (12.3 ng/ml vs. 8.9 ng/ml, p = 0.005), and patients with a history of stroke (12.8 ng/ml vs 9.3 ng/ml p = 0.027) compared to those patients without these complications. There was however no association of PlGF with the frequency of acute pain episodes, acute chest syndrome, leg ulcers, priapism or retinopathy. We observed significant positive correlations between lactate dehydrogenase (r² = 0.13, p = 0.002), reticulocyte counts (r² = 0.08, p = 0.02), soluble VCAM (r² = 0.09, p = 0.009), NT-proBNP (r² = 0.13, p = 0.003), and absolute monocyte count (r² = 0.08, p = 0.02) with PlGF. There were significant negative correlations between PlGF and hemoglobin (r² = 0.19, p < 0.0001), and borderline significant negative correlations between PlGF and NOx (r² = 0.05, p = 0.08).

CONCLUSIONS: Our results indicate that PlGF is strongly associated with PHT and stroke, and correlates with soluble VCAM in SCD patients. This suggests that inflammation may play a role in the pathogenesis of SCD-associated vasculopathy. The correlation of PlGF with laboratory measures of hemolysis and NOx suggests that hemolysis, possibly with associated scavenging of nitric oxide, contributes to the inflammatory state in SCD.