Is thrombin a “toxin” in the pathogenesis of preeclampsia?

Abstract

Preeclampsia (PE) is a significant obstetric risk factor and multi-organ complication of pregnancy characterized by high blood pressure and proteinuria, occurring in 2% of all pregnancies and resulting in maternal and fetal morbidities. Although the etiology of PE remains unclear, impaired trophoblastic invasion into the inner myometrial portion of spiral arteries causes these vessels to retain their musculoelastic properties, thereby inducing hypoperfusion, hypoxia and the subsequent systemic release of inflammatory cytokines that promote the excess production of soluble fms-like tyrosine kinase 1 (sFLT1). These pro-inflammatory cytokines may also enhance maternal inflammatory responses and systemic endothelial dysfunction, leading to maternal syndrome. Furthermore, the produced inflammatory cytokines induce tissue factor (TF), a receptor for coagulation factor VIIa / VII that subsequently initiates the TF-dependent coagulation pathway. Furthermore, hypoperfusion and hypoxia are responsive to vasoactive substances, which consequently results in vasospasms and vasoconstriction of the uterine artery. These vascular responses may activate the coagulation system in the intervillous space and induce further ischemic damage to trophoblastic cells in a hypercoagulable state, in which the serine protease thrombin plays various important roles. In this review, the pathogenesis of PE is discussed in the context of thrombin as a potential "toxin" by focusing on its role in the activation of coagulation.