Abstract
Background: The neonatal hemostatic system exhibits a fragile balance featuring lower levels of clotting factors as well as inhibitors. Neonatal platelets show in-vitro hypoaggregability, but neonates exhibit well-functioning primary and secondary hemostasis despite this impairment. Recently, polyphosphate shed by activated platelets has been shown to induce a prothrombotic shift on the plasmatic coagulation system of adults. The impact of platelet derived polyphosphate might differ in neonates due to aforementioned peculiarities.Aims: We aimed to comparatively determine polyphosphate content and release from adult and neonatal platelets and to determine its impact on thrombin generation in plasma from adult and cord blood.Methods: Polyphosphate was extracted from adult and neonatal platelet lysates and releasates using silica spin-columns and quantified with a DAPI based fluorescence assay. The impact of exogenous polyphosphate in various concentrations (208–0.026 μg/ml) on thrombin generation was evaluated in plasma from adult and cord blood as well as in adult plasma with reduced tissue factor pathway inhibitor (TFPI) levels using calibrated automated thrombography.Results: Polyphosphate content was comparable in both groups, but the fraction of released polyphosphate upon stimulation with thrombin receptor activating peptide was lower in neonatal samples (adult: 84.1 ± 12.9%; cord: 58.8 ± 11.2%). Relative impact of polyphosphate on lag time of thrombin generation was higher in adult samples compared to samples from cord blood (adult: 41.0% [IQR: 35.2–71.8%] of vehicle; cord: 73.4% [IQR: 70.2–91.4%] of vehicle). However, in samples from cord blood, lower concentrations of polyphosphate were required to obtain maximal impact on thrombin generation (adult: 26 μg/ml; cord: 0.814 μg/ml). PolyP affected thrombin generation in adult plasma similarly to cord plasma, when the TFPI concentration was reduced to neonatal levels.Conclusion: Differences in the impact of polyphosphate on adult and neonatal coagulation are largely caused by differences in TFPI levels. Lower polyphosphate release from neonatal platelets, but lower optimum concentration to drive neonatal plasmatic hemostasis emphasizes the well-matched, but fragile interplay between platelets and coagulation in newborns. A potential developmental mismatch should be considered when transfusing adult platelets into neonates.
Highlights
Hemostasis of healthy full-term neonates exhibits peculiarities that cannot be observed in adults
We showed that peak levels of prostaglandin E2 at birth provide a modest inhibitory effect on platelets in neonates, potentially protecting against preactivation during accouchement (Schlagenhauf et al, 2015). This effect is lost within the first hours of life. These findings argue for a neonatal platelet phenotype that is well-adapted to special requirements before, during and after birth, providing an optimal interplay with the neonatal plasmatic hemostatic system
Our data show a lower PolyP-release by neonatal platelets, but a higher disposition of plasma from cord blood to undergo a prothrombotic shift at low PolyP concentrations
Summary
Hemostasis of healthy full-term neonates exhibits peculiarities that cannot be observed in adults. The activated partial thromboplastin time (aPTT) is prolonged when compared to adult reference ranges. This is most likely attributed to the lower concentrations of coagulation factors after birth (Andrew et al, 1987). Despite this peculiarity, neonates show no increased bleeding during surgery and good wound healing, which is in contrast to results from in-vitro testing (Manco-Johnson, 2008). The concomitant action of low levels of tissue factor pathway inhibitor (TFPI) and antithrombin (AT) results in shorter clotting times as well as faster factor Xa and thrombin generation in cord as compared to adult plasma when small amounts of lipidated tissue factor (TF < 10 pm) are applied to initiate clotting. The impact of platelet derived polyphosphate might differ in neonates due to aforementioned peculiarities
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