Serious thrombotic complications occur in sick neonates, while healthy infants have a very low risk of thrombosis. To better understand the regulation of physiological anticoagulation at birth, components of the protein C pathway were measured in cord plasma samples from 14 full-term healthy newborns and in samples from 10 adult controls. Although zymogen protein C was significantly reduced in cord plasma (mean +/- SEM in cord vs. adult sample 37 +/- 1.4% vs. 90 +/- 5.5%, p < 0.0001), levels of the active enzyme, activated protein C (APC), were not (119 +/- 20% vs. 75 +/- 12%, p = 0.0762). Relative to the protein C level, cord plasmas had a 5.2-fold higher APC level (p < 0.01). The APC increase was partially due to slower inactivation of APC in cord plasma (half-life for APC 50 min in cord plasma vs. 27 minutes in adult plasma). Increased sensitivity of factor V to inactivation by APC in cord plasma was observed since the activated partial thromboplastin time-based APC sensitivity ratio was significantly increased for cord vs. adult plasma samples (2.28 +/- 0.09 versus 1.97 +/- 0.03, p < 0.01). Thus, despite low zymogen protein C, the protein C pathway in newborns seems to be functionally well developed and at an activated stage at birth.