Blood Clotting as an Unintended Cytokine Stimulus in Pregnancy: Why Serum and Plasma are Non-Equivalent Immune Matrices.

Circulating cytokines are widely investigated as biomarkers of immune adaptation and adverse outcomes in pregnancy, yet findings remain inconsistent across cohorts. A major under-recognized contributor to this heterogeneity is the biological matrix used for cytokine measurement-serum versus plasma. Serum formation requires ex vivo clotting, a biologically active process involving platelet activation and platelet-leukocyte interactions that can release immune mediators into the fluid phase. Pregnancy is characterized by altered platelet physiology and thrombo-inflammatory priming, suggesting that clot-associated cytokine release may plausibly be accentuated in gestation, although direct paired serum-plasma pregnancy studies remain limited. Plasma collection suppresses coagulation but introduces variability related to anticoagulant chemistry and pre-analytical handling. We argue that serum and plasma should be considered biologically non-equivalent but complementary matrices in pregnancy immunology. A matrix-conscious framework may improve reproducibility and strengthen the translational value of cytokine biomarkers in maternal health.