Platelet-leukocyte activation and modulation of adhesion receptors in pediatric patients with congenital heart disease undergoing cardiopulmonary bypass.

Cardiopulmonary bypass has been shown in adults to activate platelets and leukocytes, lead to the formation of circulating platelet-leukocyte conjugates, and alter adhesive receptors on both cell types. Pediatric patients with congenital heart disease undergoing cardiopulmonary bypass, however, have not been extensively studied and may represent a group at particular clinical risk for bleeding and pulmonary dysfunction. We studied 13 patients with congenital heart disease undergoing operations necessitating bypass, 7 with cyanotic and 6 with noncyanotic congenital heart disease. We determined that (1) the surface density of platelet glycoprotein Ib was significantly lower at baseline and throughout bypass in patients with cyanotic heart disease than in noncyanotic patients; (2) platelet glycoprotein Ib in both cyanotic and noncyanotic congenital heart disease decreased significantly during bypass, with a nadir of 75% of baseline values; (3) platelets were activated to a high degree, comparable with that seen in adults; (4) mean circulating monocyte-platelet conjugates rose significantly during bypass, increasing from 36% to 66% by the end of bypass, whereas neutrophil-platelet conjugates and lymphocyte-platelet conjugates declined; and (5) both monocytes and neutrophils were activated by cardiopulmonary bypass, as assessed by increased surface expression of CD11b and, in the case of monocytes, CD11b expression continued to increase even after termination of bypass. Patients with cyanotic and noncyanotic heart disease did not differ with respect to platelet or leukocyte activation or the formation of platelet-leukocyte conjugates. We conclude that in children with congenital heart disease cardiopulmonary bypass causes loss of platelet adhesion receptors, activation of platelets, formation of platelet-leukocyte conjugates, and leukocyte activation. Cyanotic and noncyanotic patients are qualitatively similarly affected; however, cyanotic patients demonstrate a baseline deficit in the platelet adhesion receptor glycoprotein Ib. These cellular changes may contribute to both the hemostatic and inflammatory complications associated with cardiopulmonary bypass.

Aspirin does not inhibit adenosine diphosphate-induced platelet alpha-granule release.

The involvement of metabolites of arachidonic acid in platelet-dense granule secretion and secondary platelet-platelet interactions is well characterized. However, their role in heterotypic interactions dependent on alpha-granule secretion is less well understood. Using platelet-surface expression of P-selectin as a marker of alpha-granule secretion, we have shown that: (1) aspirin treatment of platelets at doses that block dense granule secretion does not inhibit alpha-granule secretion to adenosine diphosphate (ADP); (2) synergism between epinephrine and ADP in the induction of P-selectin expression is similarly unaffected by aspirin; and (3) the ability of P-selectin to mediate adhesion of activated platelets to monocytes and polymorphonuclear lymphocytes in whole blood is also unchanged by aspirin treatment. To further explore the mechanisms responsible for platelet alpha-granule secretion, we have shown that inhibition of Na+/H+ exchange by either acidification of the extracellular medium or amiloride treatment blocked ADP-induced P-selectin expression. In contrast, incubation with the platelet lipoxygenase inhibitor 5,8,11-eicosatrynoic acid, by itself and with aspirin, did not decrease ADP-induced P-selectin expression. We conclude that platelet alpha-granule secretion in response to ADP is dependent on intact Na+/H+ exchange but is independent of the lipoxygenase- and cyclooxygenase-dependent metabolites of arachidonic acid.