Understanding "Heparin Resistance" in Cardiac Surgery

This study uses a prospective, randomized, open-label cross-over design to evaluate the
responses to recombinant human AT (rhAT) and/or supplemental heparin for restoration of
heparin-responsiveness in the presence of biomarkers of acute inflammation, so called acute
phase reactants. Our ultimate goal is, of course, to apply this knowledge to optimize
perioperative management of anticoagulation in patients undergoing cardiopulmonary bypass.

We will first identify enrolled patients with altered heparin responsiveness (AHR) as
defined by an ACT < 450 seconds (the MGH standard target ACT after the initial dose of
heparin for CPB). Patients who achieve an ACT > 450 sec will not enter the randomization
phase of the study, their participation in the study will be complete and their routine
clinical care will continue unaltered. Those with AHR (post-heparin ACT < 450 sec) will be
randomized to receive either supplemental heparin or supplemental AT. Those that fail to
achieve an adequate ACT after the first supplementation will cross-over to receive the
alternate supplement. Blood samples (totaling at most 20 ml) will be taken at each step to
measure heparin level, AT level, AT activity. Once a patient is placed onto cardiopulmonary
bypass their participation in the study will be complete.

By design, this study replicates routine clinical management of heparin anticoagulation for
cardiopulmonary bypass at the MGH. Most patients (80%) coming to cardiac surgery who will
undergo CPB respond adequately to a routine initial bolus dose of heparin (ACT > 450 after
350 U/kg); as noted, subjects in this study that achieve the target ACT will be managed
according to routine clinical practice without further testing or intervention.

Under routine care, patients with an inadequate initial response to heparin receive either
supplemental heparin (150 U/kg) or pooled human antithrombin (1000 Units), or both. In this
study, subjects with inadequate heparin response (ACT < 450) after the initial heparin
bolus, will be randomly assigned to two comparison groups; half will receive supplemental
heparin (150 U/kg) and half will receive AT (1000 IU). Subjects who fail to respond to their
assigned first intervention will cross-over to receive the alternate intervention.

Some subjects may not achieve the target ACT despite receiving both supplemental heparin and
AT comprising a group of patients with "true heparin resistance" whose coagulation profiles
can be further characterized to better understand the mechanisms of the resistance. These
subjects will be considered to have completed the study even though they are not yet on
cardiopulmonary bypass and will be managed according to the best clinical judgment of their
physicians. They may receive additional heparin, additional AT, fresh-frozen plasma, or any
combination of these. These patients may be at risk for thrombotic complications during the
post-operative period. Accordingly, when clinically appropriate, these individuals may be
referred for further evaluation of their coagulation status, but these evaluations will not
be done as part of this study.

This is a pathophysiological risk-factor association study that seeks to better understand
the phenomenon of altered heparin responsiveness. Accordingly, there is no specific study
endpoint apart from achieving an ACT of > 450 sec. In all enrolled subjects we will measure
the levels of three acute phase reactants, Factor VIII, fibrinogen and CRP, heparin levels
(anti Xa), AT level (immunofixation) and AT activity after the initial heparin dose. For all
subjects who do not achieve and ACT of > 450 we will also measure additional heparin levels
(anti Xa), AT level (immunofixation), and AT activity after each intervention in the
randomization/crossover phase. The total amount of blood taken for the research-specific
laboratory test is less than 20 ml.

Inclusion Criteria:

- Patients scheduled for elective cardiac or aortic surgery requiring CPB for which
heparin will be used for systemic anticoagulation

- Patients scheduled for urgent surgery who are hemodynamically stable and capable of
giving voluntary consent

- Patients with platelet factor 4 antibody positivity (antiPF4+) for whom heparin
anticoagulation will be used

Exclusion Criteria:

- Patients for whom heparin will not be used for anticoagulation

- Patients with known congenital AT-deficiency

- Patients with known goat milk allergy