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ResearchIn-Press PreviewImmunologyReproductive biology Open Access | 10.1172/JCI200372

Platelets link coagulation and complement in regulating murine placental vascular development

Arno Smid,1 Lisa Schumann,1 Olga Oleshko,2 Ulrike Peters-Bernard,1 Kerstin Flächsig-Schulz,1 Melissa Whitehead,1 Emma Arndt,1 Korbinian Brand,3 Sonja Werwitzke,3 Andreas Klos,4 Bryan Paul Morgan,5 Wioleta M. Zelek,5 Andreas Tiede,2 and Markus Abeln1

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Smid, A. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Schumann, L. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Oleshko, O. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Peters-Bernard, U. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Flächsig-Schulz, K. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Whitehead, M. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Arndt, E. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Brand, K. in: PubMed | Google Scholar |

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Werwitzke, S. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Klos, A. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Morgan, B. in: PubMed | Google Scholar |

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Zelek, W. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Tiede, A. in: PubMed | Google Scholar

1Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

2Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplanta, Hannover Medical School, Hannover, Germany

3Institute of Clinical Chemistry and Central Laboratory, Hannover Medical School, Hannover, Germany

4Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

5Division of Infection and Immunity and UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Find articles by Abeln, M. in: PubMed | Google Scholar |

Published July 23, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI200372.
Copyright © 2026, Smid et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 23, 2026 - Version history
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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.

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