The revised application focuses on complement activation induced by heparin-protamine complexes.
A specific aim of the proposal is to study the relationship of complement activation induced by protamine neutralization of heparin with pulmonary dysfunction. The study will be conducted in patients undergoing first-time cardiopulmonary bypass for coronary artery surgery. A second specific aim is to correlate preoperative complement activation in the presence of heparin and protamine with the actual measurements of in vivo complement activation induced by protamine neutralization of heparin. A third specific aim is to determine whether excessive in vivo complement activation by heparin-protamine is dependent upon the phenotypic or functional differences in C4. Two hundred patients will be entered into the study. Pulmonary shunt fraction will be determined as will pulmonary vascular resistance. Red cell bound C3b/C3d will be determined. IgE and IgG antiprotamine antibodies will be detected using ELISA. Blood samples will be studied at four time points: 1. prior to sternotomy, 2. prior to bypass, 3. before protamine, 4. 10 minutes after protamine. Leukotriene B4 and thromboxane B2 will be determined on samples drawn from pulmonary artery and radial artery lines to represent pre-and post-pulmonary circulation samples. Other studies will be directed at determining the relationship between C3d binding to red cells and subsequent heparin-protamine induced complement activation. Preoperative blood samples will be assessed for C3d binding to red cells. These samples will be used in a series of in vitro assays to determine whether or not the differences in sera with respect to C3d binding are due to differences in the C4b binding to red cells. Statistical analysis will include a number of independent variables such as gender, body surface area, age, number of diseased vessels, number of grafts, heparin dose, time on pump, diabetes, Leukotriene B4 levels, thromboxane B2 levels, changes in C3a during bypass, changes in C3a and C4a during protamine infusion, etc.
| Shastri, K A; Logue, G L; Stern, M P et al. (1997) Complement activation by heparin-protamine complexes during cardiopulmonary bypass: effect of C4A null allele. J Thorac Cardiovasc Surg 114:482-8 |
| Shastri, K A; Logue, G L; Stern, M P et al. (1994) Neutrophil lactoferrin release during open heart surgery is unrelated to complement activation. ASAIO J 40:56-61 |
