Complement activation by heparin-protamine complexes during cardiopulmonary bypass: effect of C4A null allele.
OBJECTIVE
The first objective was to determine the effect of inherited differences in the classic pathway complement protein C4 on complement activation by heparin-protamine complexes in cardiac surgery. Specifically, we hypothesized that patients with heterozygous C4A null phenotype (A0BB), who have decreased amounts of C4A, may have increased complement activation because of reduced clearance of heparin-protamine complexes. The second objective was to determine whether heparin-protamine-induced complement activation correlated with postoperative pulmonary shunt fractions.


METHODS
C4 typing was performed by agarose gel immunofixation and crossed immunoelectrophoresis. Complement activation was measured by radioimmunoassay of C3a and C4a before cardiopulmonary bypass, after bypass, and after protamine infusion. Shunt fractions were calculated from blood gases.


RESULTS
Of the 79 patients, 18 expressed heterozygous C4A null allele (A0BB), 16 had heterozygous C4B null allele (AAB0), three had homozygous C4B null alleles (AA00), and the rest expressed both C4A and C4B alleles (AABB). Patients with heterozygous C4A null allele had significantly increased plasma levels of C4a after protamine neutralization of heparin (C4a of 2862 +/- 375 ng/ml; mean +/- standard error of the mean) when compared with patients with normal expression of C4 alleles (AABB) (C4a of 1580 +/- 141 ng/ml) or heterozygous C4B null allele (C4a 1526 +/- 208 ng/ml). Pulmonary shunt fractions obtained after the operation correlated with the classic pathway complement activation by heparin-protamine complexes, but not with alternative pathway complement activation during cardiopulmonary bypass.


CONCLUSIONS
Patients with heterozygous C4A null phenotype have increased complement activation by heparin-protamine complexes during cardiac operations, possibly because of their defective clearance. The classic pathway complement activation by heparin-protamine interaction correlates with postoperative pulmonary shunt fractions.
Shastri
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KA
Medical Service, Department of Veterans Affairs, Western New York Health Care System, Buffalo, N.Y., USA.
Logue
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GL
Stern
M P
MP
Rehman
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Raza
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D000483:Alleles; D000925:Anticoagulants / Q000494:pharmacology*; D002315:Cardiopulmonary Bypass; D003167:Complement Activation / Q000187:drug effects*; D015926:Complement C3a / Q000032:analysis; D015934:Complement C4a / Q000032:analysis / Q000235:genetics*; D003171:Complement Pathway, Classical / Q000187:drug effects; D001026:Coronary Artery Bypass; D005260:Female; D006493:Heparin / Q000494:pharmacology*; D006494:Heparin Antagonists / Q000494:pharmacology*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011479:Protamines / Q000494:pharmacology*
D000925:Anticoagulants; D006494:Heparin Antagonists; D011479:Protamines; D015926:Complement C3a; D015934:Complement C4a; D006493:Heparin