Micromolar Zinc in Annexin A5 Anticoagulation as a Potential Remedy for RPRGL3-Associated Recurrent Pregnancy Loss

Deficient expression of the placental anticoagulant annexin A5 (ANXA5) has been associated with thrombophilia-related pregnancy complications and ultimately with recurrent pregnancy loss (RPL). Carrier status of M2/ANXA5 ( RPRGL3), common ANXA5 promoter variant, has been identified as genetic cause of reduced ANXA5 levels and proposed as biomarker for successful anticoagulant treatment of RPL women. A murine model of AnxA5 loss of function displayed characteristic placental pathology and fetal loss that was alleviated through anticoagulant intervention. This study identified an alternative means of supplementing anticoagulation, through elevated ANXA5 expression. Physiological micromolar Zn²⁺ stimulated ANXA5 transcription, raising ANXA5 protein expression and surface abundance on BeWo and human umbilical vein endothelial cells (HUVEC), thus resulting in prolonged coagulation times. Zn²-fed AnxA5 functionally deficient pregnant mice showed a trend to increase litter size when primiparous that grew comparable to wild-type progeny in subsequent pregnancies. Elevated AnxA5 signal upon Zn²⁺ treatment was confirmed in murine placentae. Micromolar Zn²⁺ stimulated ANXA5 expression in cell culture directly and alleviated RPL in AnxA5 genetically deficient mice, without notable toxicity effects.