Thrombin Inhibition Is Impaired in Plasma of Sick Neonates

ABSTRACT: The sick neomate may develop spontaneous or catheter-related thromboses, which must in part reflect poor regulation of the formation and activities of the coagulation enzyme, thrombin. We hypothesized that the balance between the generation and inhibition of thrombin may differ in sick neonates compared with healthy neonates. Fifty neonates with respiratory failure requiring mechanical ventilation and 40 healthy neonates were studied on d 1 of life. All neonates had normal coagulation screening tests and a platelet count greater than 150 × 10°/L. Plasma pools from neonates with similar gestational age (GA), birth weight, and health status were prepared. Eight plasma pools from 40 healthy neonates of GA 30–38 wk were compared with six plasma pools from 30 sick neonates of GA 30–38 wk. An additional four plasma pools prepared from 20 sick neonates of GA <30 wk were studied. Thrombin generation was measured by amidolysis of a chromogenic substrate, S2238, after defibrination, contact activation, and recalcification of the test plasmas. The contributions of antithrombin III, heparin cofactor II, and α2-macroglobulin as inhibitors of 125I-thrombin were quantitated by SDS-PAGE followed by autoradiography and densitometry. Thrombin generation was similar for both healthy and sick neonates of GA 30–38 wk. However, the inhibition of thrombin was impaired in plasma from sick neonates of GA 30–38 wk compared with plasma from healthy neonates of GA 30–38 wk (4.37 ± 0.22 versus 5.21 ± 0.21 nmol; p < 0.05). Plasma levels of antithrombin III and αγ-macroglobulin were significantly lower in sick neonates of GA 30–38 wk compared with healthy neonates of GA 30–38 wk (0.30 ± 0.03 versus 0.41 ± 0.03 U/mL; p < 0.05 and 0.93 ± 0.07 versus 1.29 ± 0.10 U/mL; p < 0.05, respectively). The sick neonates of GA <30 wk had values similar to sick neonats of GA 30–38 wk for the generation and inhibition of thrombin and for plasma levels of inhibitors antithrombin III and αγ-macroglobulin. Thus, sick neonates are able to generate thrombin as well as healthy age-matched neonates, but their ability to inhibit thrombin is significantly decreased. This acquired imbalance between the generation and inhibition of thrombin may place the sick neonate at risk for thrombotic complications in the immediate postnatal period.