The pathophysiology of preeclampsia and HELLP syndrome relies on systemic vascular endothelial dysfunction, resulting from angiogenic imbalance due to abnormal uteroplacental vascular remodeling and placental ischemia/reperfusion. Recent studies demonstrated that HELLP syndrome falls within the spectrum of secondary microangiopathy due to abnormal complement activation. However, to date, the link between angiogenic imbalance, endothelial dysfunction, and complement activation remains unclear. Building upon current understanding of complement regulation, this paper proposes a novel pathophysiological approach, suggesting a new understanding of HELLP syndrome and preeclampsia, including the undebatable role of sFlt-1/PlGF and the knowledge of maternal systemic endothelial and renal diseases. We hypothesize that endothelial glycocalyx may be the missing link between angiogenic factors, inflammatory regulation, and endothelial maternal lesions. Targeting the glycocalyx-endothelium axis may enable novel therapeutic strategies that delay delivery and reduce maternal-neonatal morbidity in preeclampsia and HELLP syndrome.