Two-Chain Factor VIIa Generated in the Pericardium During Surgery With Cardiopulmonary Bypass

Abstract

Abstract-Several recent studies have proposed that coagulation is triggered during cardiopulmonary bypass surgery by extrinsic pathway activation involving factor VIIa generation, but the methodology was indirect. Therefore, 12 patients were studied during routine cardiac and cardiopulmonary bypass surgery. Samples were taken before, during, and after bypass from the perfusate, from the aorta (retrograde cardiac drainage), pericardium, and collected suction fluid originating from the whole operative field. These samples were analyzed by enzyme-linked immunosorbent assay for 2-chain factor VIIa, by prothrombin F 1ϩ2 assay, by thrombin-antithrombin (TAT) assay, and for heparin concentration. Factor VIIa, F 1ϩ2 , and TAT levels in samples from the pericardium were greatly elevated (mean, 0.92 to 1.01, 227 to 334, and 399 to 526 g/L, respectively; preoperative mean, 0.33, 32.3, and 1.90 g/L, respectively; PϽ0.05 for all), whereas levels in suction fluid were less consistently high. Factor VIIa and both F 1ϩ2 and thrombin-antithrombin levels in samples from the aorta, pericardium, and suction fluid were significantly correlated (rϭ0. 57, PϽ0.001, nϭ111; and rϭ0.51, PϽ0.001, nϭ105, respectively), and all were inversely correlated with heparin levels (rϾϪ0.35, PϽ0.001, nϾ92). There was no evidence of factor VIIa generation in the circuit during bypass surgery, and both F 1ϩ2 and thrombin-antithrombin levels rose only Ϸ2-fold, probably because heparin levels were higher than they were in the pericardium (PϽ0.05). We concluded that appreciable activation of factor VII occurs on the pericardium and that this is associated with increased thrombin generation. Ineffective local heparinization may be partly responsible. These results suggest that pericardium-induced activation of factor VII should be the target of anticoagulant strategies during cardiopulmonary bypass surgery. (Arterioscler Thromb Vasc Biol. 1999;19:248-254.)

Relationships Between Homocysteine, Factor VIIa, and Thrombin Generation in Acute Coronary Syndromes

“…19,22,23 The assay for F1ϩ2 was performed as originally described 23 and has intra-and interassay coefficients of variation of Ϸ10% and Ϸ15%, respectively. The normal laboratory mean (ϮSEM) is 31.0Ϯ3.7 ng/mL, which corresponds to 0.88Ϯ0.11 nmol/L.…”

“…The normal laboratory mean (ϮSEM) is 31.0Ϯ3.7 ng/mL, which corresponds to 0.88Ϯ0.11 nmol/L. The Factor VIIa assay was modified, as described 22 by replacement of the standard, which altered the normal mean to 0.25Ϯ0.10 ng/mL (0.005Ϯ0.003 nmol/L). The intraand interassay coefficients of variation are Ϸ4% and Ϸ10%, respectively.…”

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

“…However, there is controversy regarding this source of thrombin generation during CPB, since patients with congenital factor XII deficiency still generate comparable amounts of thrombin during CPB [32]. Several workers found a strong association between the generation of thrombin during CPB and activation of the tissue factor-factor VIIa complex, [16,109,151,189] but others did not [106,149]. The bulk of evidence supports the concept that activation of the tissue factor/factor VII pathway (e.g., from monocytes and endothelial capillaries) is an important source of thrombin generation during CPB presumably from exposure of tissue in the open surgical wound and from contact of blood with synthetic surfaces of the CPB circuit [37,179].…”

Coagulation and fibrinolytic protein kinetics in cardiopulmonary bypass

“…Shortly after the initiation of CPB, there is a rapid rise in thrombin-antithrombin III complexes, modified antithrombin and thrombomodulin plasma levels [67]. Thrombin generation is particularly robust on the pericardial surface and within the suction fluid, reflecting a marked increase of factor VII activation and TF expression [68].…”