Oxidative Stress and Preeclampsia-Associated Prothrombotic State

Abstract

Preeclampsia (PE) is a common obstetric disease characterized by hypertension, proteinuria, and multi-system dysfunction. It endangers both maternal and fetal health. Although hemostasis is critical for preventing bleeding complications during pregnancy, delivery, and post-partum, PE patients often develop a severe prothrombotic state, potentially resulting in life-threatening thrombosis and thromboembolism. The cause of this thrombotic complication is multi-factorial, involving endothelial cells, platelets, adhesive ligands, coagulation, and fibrinolysis. Increasing evidence has shown that hemostatic cells and factors undergo oxidative modifications during the systemic inflammation found in PE patients. However, it is largely unknown how these oxidative modifications of hemostasis contribute to development of the PE-associated prothrombotic state. This knowledge gap has significantly hindered the development of predictive markers, preventive measures, and therapeutic agents to protect women during pregnancy. Here we summarize reports in the literature regarding the effects of oxidative stress and antioxidants on systemic hemostasis, with emphasis on the condition of PE.

Keywords: coagulation; hemostasis; oxidative stress; platelets; preeclampsia.

Figure 1

Schematic illustration of human hemostasis. Hemostasis begins at the site of vascular injury. Platelets first adhere to the exposed subendothelium and, through multiple ligand–receptor interactions, are activated and aggregate by fibrinogen crosslinking to form a plug to seal the wound. Anionic phospholipids exposed on the surface of activated platelets also trigger coagulation through a series of enzymatic actions of coagulation factors (e.g., inactive factor X (FX) to activated FX (Fxa)), resulting in the eventual activation of thrombin, which cleaves fibrinogen to generate fibrin fibrils that crosslink and stabilize the platelet plug to arrest bleeding. The fibrin fibrils then activate the fibrinolysis pathway that generates plasmin to cleave these fibrils to re-establish circulation. VWF: von Willebrand factor; TF: tissue factor; PS: phosphatidylserine; HMK: high molecular weight kininogen; PK: prekallibrein; tPA: tissue plasminogen activator; uPA: urokinase.

Figure 2

Pathogenesis of the preeclampsia (PE)-associated prothrombotic state. Placental ischemia–reperfusion injury induces mitochondrial dysfunction and oxidative stress and reduces the antioxidative defense, producing excessive reactive oxygen species (ROS). This oxidative stress propagates placental injury and also disseminates to systemic circulation, where it injures endothelial cells and activates platelets to express procoagulant activities and to produce prothrombotic and proinflammatory extracellular vesicles. The procoagulant cells and molecules initiate and propagate the hypercoagulable and prothrombotic states that result in arterial and venous thrombosis, renal dysfunction, and fetal growth restriction (FGR). eNOS: endothelial nitric oxide synthase; XO: xanthine oxidase; SOD: superoxide dismutase; GSH-Px: glutathione peroxidase; HO-1: heme oxygenase-1; TF: tissue factor; ICAM: Intercellular Adhesion Molecule; NO: nitric oxide; PGI₂: Prostaglandin I₂.