Thrombin Generation in Neonates

Neonates are unique due to maturational differences in their coagulation systems. During the first few months of life, distinct differences exist between the coagulation system of a neonate and that of an adult including differences between the concentration of coagulation proteins, the ability to generate thrombin and the ability to inhibit thrombin once it is formed (1). One important coagulant protein that is quantitatively deficient in the first several months of life is prothrombin. In the coagulation cascade, prothrombin is converted into thrombin, a major regulator of hemostasis. In healthy newborns mean prothrombin values are less than 70% of adult mean values (1), and investigators have found that neonatal prothrombin level is directly proportional to the amount of thrombin generated (1). In fact, the impaired ability of newborn plasma to generate thrombin in the face of deficient prothrombin has been shown to be similar to adults who are being treated therapeutically with an anticoagulant (2). Therefore, low prothrombin levels in neonates have important implications when considering anticoagulant therapy.

For neonates with congenital heart disease presenting for cardiac surgery, anticoagulation for cardiopulmonary bypass (CPB) is necessary to prevent clotting as blood comes into contact with the unphysiologic surfaces of the extracorporeal circuit. This is achieved by the use of high dose heparin, which is used to inhibit the formation and activation of thrombin. Since neonatal prothrombin levels are low, rendering them unable to generate large amounts of thrombin, neonates with congenital heart disease requiring anticoagulation for CPB have historically been considered heparin sensitive (3). However, in a recent investigation conducted by this group, elevated baseline levels of thrombin production and activity were consistently found in neonates presenting for cardiac surgery (4). Additionally, despite routine heparin dosing, elevated markers of thrombin production were also found in these neonates during CPB when compared to their adult counterparts (4). Perhaps the assumption that neonates with congenital heart disease are similar to other healthy neonates in their impaired ability to generate thrombin is incorrect. Contact activation may occur preoperatively from the presence of indwelling umbilical catheters and central lines or from interventional manipulations in the cardiac catheterization lab and stimulate their coagulation systems to generate more thrombin than anticipated. Elevated thrombin levels in neonates presenting for cardiac surgery would consequently have important implications in determining the optimal heparin dose needed to provide adequate anticoagulation for CPB.

A technique has been developed to monitor the thrombin generating capacity of plasma (5). A thrombin generation curve (TGC) can be constructed from a sample of plasma and the area under the TGC, called the endogenous thrombin potential (ETP), is a good indicator of the coagulability of the sample. Currently, we have found no published data addressing the TGC in the neonatal population. Therefore, we propose a prospective study between neonates with congenital heart disease presenting for cardiac surgery and other healthy neonates to compare their respective abilities to generate thrombin by measuring TGCs.