Platelets link coagulation and complement in regulating murine placental vascular development

Smid, Arno, Schumann, Lisa, Oleshko, Olga, Peters-Bernard, Ulrike, Flächsig-Schulz, Kerstin, Whitehead, Melissa, Arndt, Emma, Brand, Korbinian, Werwitzke, Sonja, Klos, Andreas, Morgan, Bryan Paul ORCID: https://orcid.org/0000-0003-4075-7676, Zelek, Wioleta M., Tiede, Andreas and Abeln, Markus 2026. Platelets link coagulation and complement in regulating murine placental vascular development. Journal of Clinical Investigation 10.1172/jci200372

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Abstract

During early pregnancy, maternal blood surrounds the embryo before the placenta is fully developed, requiring tight regulation of maternal blood flow into the placental vasculature. We identify placental microthrombi (PMTs) as essential structures guiding this process. PMTs contain platelets, coagulation factors, and complement proteins, and their formation depends on maternal platelet activation by thrombin through the protease-activated receptor PAR4 (F2rl3). Deficiency of PAR4 abolished PMTs and caused excessive bleeding at the implantation site. C3 deficiency also led to increased bleeding events, indicating that complement activation contributes to thrombosis in the placental circulation. Conversely, dysregulated complement activation in CMP-sialic acid synthase-deficient (Cmas-/-) mice led to widespread thrombosis and failed placental development. Strikingly, platelet activation via PAR4 was necessary to localize complement activation to trophoblast surfaces, thereby coupling coagulation and complement in PMT formation. Depletion of maternal platelets mitigated complement-driven thromboinflammation in Cmas-/- pregnancies, restoring placental growth. These findings uncover a critical cooperation between platelets, coagulation, and complement in establishing maternal blood flow to the placenta. Successful pregnancy therefore requires not only activation but also tight regulation of these systems to balance necessary PMT formation with the prevention of pathological thrombosis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	American Society for Clinical Investigation
ISSN:	0021-9738
Date of First Compliant Deposit:	27 July 2026
Last Modified:	27 Jul 2026 11:30
URI:	https://orca.cardiff.ac.uk/id/eprint/188468

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