Antithrombin III in Infants With Cardiopulmonary Bypass (CPB)

Cardiopulmonary bypass (CPB) and cardiovascular surgery initiate diffuse activation of
coagulation, inflammation and fibrinolysis that often has deleterious effects on patient
outcomes, including bleeding, transfusion, myocardial dysfunction, renal failure, pulmonary
dysfunction, prolonged intubation, ICU and hospital length of stay, stroke and
neurocognitive dysfunction, and mortality.Pediatric patients are especially at risk for
hematologic derangement related to CPB. Not only are infants and children subject to the
same diffuse activations of coagulation, inflammation, and fibrinolysis as adults, but their
size, immaturity, and circulatory abnormalities secondary to congenital heart disease
increase the risk of loss of hematologic homeostasis. Since an infant's blood volume is much
smaller than that of the prime in the CPB pump, hemodilution alone produces impaired
hemostasis related to thrombocytopenia and coagulation factor dilution The incidence of each
of these complications is variable and depends on the diagnosis, operation, time on CPB and
other factors.

Adequate anticoagulation during cardiopulmonary bypass (CPB) is essential to preserve the
hemostatic system and ensure hemostasis after surgery. Heparin has long been the mainstay of
anticoagulation for CPB, due to its ease of use, familiarity, and reversibility. For heparin
to exert its anticoagulant effect, it must bind with an intrinsic cofactor, antithrombin III
(ATIII) to inhibit enzymes of the intrinsic and final common coagulation pathways. It has
been established that neonates have significantly decreased levels of ATIII relative to
adults, and that this relative deficiency continues at least until 6 months of age. Children
with congenital heart disease have further decreases in ATIII and other abnormalities of
coagulation which may contribute to adverse outcomes. Given this ATIII deficiency, it is not
surprising that heparin anticoagulation does not fully suppress coagulation during CPB.
Neonates anticoagulated for CPB with heparin have ongoing activation of humoral and cellular
coagulation with associated activation of inflammation and fibrinolysis. Improved
anticoagulation may reduce activation of these cascades and improve outcomes. In addition,
infants are at high risk for post cardiac surgery intervascular thrombosis. Baseline ATIII
deficiency, and consumption of ATIII during bypass may contribute to a postoperative
prothrombotic state esulting in this often fatal complication. ATIII supplementation may
decrease this risk.

ATIII is available as a lyophilized product derived from pooled human plasma. Treatment with
ATIII has been shown to improve the anticoagulant effects of heparin and attenuate
activation of hemostasis and inflammation during adult CPB, and to decrease the incidence of
thrombosis associated with central venous cannulation in children. The incidence of central
venous thrombosis in infants undergoing cardiac surgery has been reported as 5.8 - 22% in
neonates, with a resultant mortality of 20%.

The biologic half-life of antithrombin in healthy adult volunteers is 2.5 - 3.8 days.
Pharmacokinetic data in neonates is not available, but biologic activity should certainly
persist through the 2 highest risk periods:

CPB, where activation of coagulation produces activation of inflammation, both cellular and
humoral, and fibrinolysis.

The early post-op period when patients typically become hypercoagulable as part of the
stress response to surgery. Hypercoagulability places the patients at high risk for central
line-associated thrombosis despite by heparin-containing flush solutions which are standard
of care. Ensuring a near normal level of antithrombin appears to enhance the ability of the
flush solutions to inhibit thrombin generation on the catheter.

ATIII has been used in infants after cardiac surgery to prophylax against central venous
thrombosis, for infants with necrotizing enterocolitis (NEC), and as treatment for neonates
with congenital ATIII deficiency. Neonates appear to respond as expected to ATIII
supplementation, with clinical efficacy for central venous thrombosis but not NEC. No
complications unique to infants were reported in any of these publications.

It is reasonable to expect that ATIII would be even more beneficial in infants less than 6
months old.

Inclusion Criteria:

- Subjects will be included if they are presenting for elective cardiac surgery using
cardiopulmonary bypass and are 180 days of age or less.

Exclusion Criteria:

Sensitivity to ATIII product (Thrombate, Grifols, Los Angeles, CA)

- Known inherited or acquired coagulation defect

- Current or prior treatment with pro-or anticoagulant medication within past 30 days
(except aspirin or a single dose of heparin, e.g. for catheterization)

- Known central venous thrombosis

- Recent (30 days) transfusion with hemostatic blood products (fresh-frozen plasma,
platelets, cryoprecipitate, whole blood)

- wt less than 3000g