Heparin sensitivity and resistance in the neonate: An explanation

Based on in vitro tests, newborns are reported to be both sensitive and resistant to standard heparin (SH) compared to adults. The sensitivity to SH occurs in assays based on de novo thrombin generation, and SH resistance occurs in systems where exogenous thrombin is added to newborn plasma. We hypothesized that this apparent paradox is related to the antithrombin III to (pro) thrombin ratio associated with each test. Since SH catalyses the activity of antithrombin III, any imbalance in the antithrombin III/(pro)thrombin ratio in newborns compared to adults would be amplified by SH. If the ratio of antithrombin III/(pro)thrombin is defined as 1 in adults, in comparison newborns have a ratio of 1.5. We compared how various doses of SH (0.1 to 0.6 u/ml) inhibited the generation of endogenous thrombin in defibrinated newborn (N) and adult (A) plasma. Following contact activation and recalcification of each plasma, thrombin activity was measured using a chromogenic substrate and quantitated by measuring the area under the curve. In the presence of SH, newborn plasma was more sensitive to SH than adult plasma and generated relatively less thrombin (N:6.1 vs A:9.1% sec/u/ml; p less than 0.01). When the ratio of antithrombin III/(pro)thrombin in newborns was altered to 2.5 by exogenous antithrombin III, the SH sensitivity was increased. This plasma now generated no detectable thrombin in the presence of only 0.1 u/ml of SH. In contrast, when the ratio of antithrombin III/(pro) thrombin of the newborn was altered by exogenous prothrombin to 0.6, this plasma now became resistant to SH and generated more thrombin than adults in the presence of SH (N:11.6 vs A:9.1; p less than 0.01). Because of the potential use of low molecular weight heparins (LMWH) in newborns, a LMWH, Choay 222, was also tested in a similar fashion and gave similar results to SH. Thus, the ratio of antithrombin III/(pro)thrombin likely determines the in vitro sensitivity or resistance of newborn plasma to SH and LMWH. There are no clinical studies that determine if newborns require more or less SH than the adult to successfully treat thrombotic complications. Current practice is a simple extrapolation of therapeutic ranges from adults. We speculate that the efficacy and safety of SH in the newborn in vivo can be improved by altering the antithrombin III/(pro)thrombin ratio.