Heparin Responses in Pediatric Patients Undergoing Cardiopulmonary Bypass.

Introduction

Anticoagulation during cardiopulmonary bypass (CPB) is necessary to prevent clotting as blood comes in contact with the unphysiologic surfaces of the extracorporeal circuit, and is achieved by administration of unfractionated heparin which binds to antithrombin III (ATIII) to potentiate and accelerate its inhibition of thrombin and other activated coagulation factors. In adults, heparin dose responses are decreased as ATIII concentrations fall. Findings in adults indicate that the administration of supplemental ATIII as concentrations fall below 80 u/dl may help to preserve heparin's effectiveness during CPB(1). Since ATIII levels in infants do not reach 80 u/dl until 3-6 months of age (2), one would likewise anticipate that heparin dose-response relationships would be affected. However, preliminary investigations in children less than one year of age show that there is no correlation between preoperative ATIII concentrations with the projected heparin dose-response (HDR) curve or with changes in the activated clotting time (ACT) value after heparin administration(3). The lack of correlation of ATIII levels with these heparin dose responses in infants raises important questions for pediatric patients regarding the mechanism by which heparin exerts its anticoagulant effects as well as the adequacy of heparinization during CPB.

Another coagulation inhibitor, heparin cofactor II (HCII), forms a stable enzyme-inhibitor complex that inhibits thrombin in a reaction enhanced by heparin(4). Although in the adult population, the exact role of HCII is unclear, perhaps in neonates its role is more significant. Alpha-2-macroglobulin (2M), a less important inhibitor of thrombin in adults, has concentrations well above adult values in newborns and continues to increase in concentration during the first 6 months of life(2). In neonates, 2M has been shown to have an important role as a thrombin inhibitor although its association with heparin responses during CPB is unknown.

The adequacy of anticoagulation during CPB can be assessed by the extent to which heparin attenuates the formation and activation of thrombin. However, the very short half-life of thrombin in the presence of heparin and ATIII prohibits the direct measurement of thrombin concentration while on CPB. The peptide prothrombin fragment 1.2 (PT1.2), which is formed as prothrombin is converted to thrombin, is readily measurable and provides a way of evaluating thrombin formation during CPB(5). One of thrombin's major actions, the conversion of fibrinogen to fibrin, releases another measurable peptide, fibrinopeptide A (FPA), thereby providing a means of assessing thrombin activity during CPB(5).

In an attempt to determine the mechanism by which heparin exerts its anticoagulant effect in children, this investigation proposes to evaluate the relationship between preoperative ATIII, HCII and 2M levels in pediatric patients of varying age groups with clinical measurements of heparin response in the operating room, specifically changes in ACT values with heparin administration and a generated heparin dose-response curve. We also propose to evaluate the adequacy of heparinization in neonates, whom are known to have a quantitative deficiency in ATIII, by measuring PT1.2 and FPA that is produced during CPB as compared to an adult population.