Contribution of endogenous bradykinin to fibrinolysis, inflammation, and blood product transfusion following cardiac surgery: a randomized clinical trial

Abstract

Bradykinin increases during cardiopulmonary bypass (CPB) and stimulates the release of nitric oxide, inflammatory cytokines, and tissue-type plasminogen activator (t-PA), acting through its B2 receptor. This study tested the hypothesis that endogenous bradykinin contributes to the fibrinolytic and inflammatory response to CPB and that bradykinin B2 receptor antagonism reduces fibrinolysis, inflammation, and subsequent transfusion requirements. Patients (N = 115) were prospectively randomized to placebo, ε-aminocaproic acid (EACA), or HOE 140, a bradykinin B2 receptor antagonist. Bradykinin B2 receptor antagonism decreased intraoperative fibrinolytic capacity as much as EACA, but only EACA decreased D-dimer formation and tended to decrease postoperative bleeding. Although EACA and HOE 140 decreased fibrinolysis and EACA attenuated blood loss, these treatments did not reduce the proportion of patients transfused. These data suggest that endogenous bradykinin contributes to t-PA generation in patients undergoing CPB, but that additional effects on plasmin generation contribute to decreased D-dimer concentrations during EACA treatment.

Trial registration: ClinicalTrials.gov NCT00223704.

Conflict of interest statement

CONFLICT OF INTEREST

The authors declared no conflict of interest.

Figures

Figure 1

Enrollment. HOE 140 is a specific bradykinin B2 receptor antagonist.

Figure 2

Fibrinolytic response to surgery as measured by (a) tissue-type plasminogen activator (t-PA) antigen concentrations, (b) plasminogen activator inhibitor-1 (PAI-1) antigen concentrations, (c) PAI-1 to t-PA antigen molar ratio, and (d) D-dimer concentrations in the three study groups. “30 min” indicates 30 min of cardiopulmonary bypass (CPB), “60 min” indicates 60 min of CPB, and “post” indicates postbypass. The intraoperative PAI-1 to t-PA molar ratio was decreased in the placebo group as compared with either active treatment group (P = 0.05 as compared with EACA and P = 0.04 as compared with HOE 140, a specific bradykinin B2 receptor antagonist), indicating enhanced fibrinolysis. Data are presented as mean ± SEM. EACA, ε-aminocaproic acid; POD, postoperative day.

Figure 3

Inflammatory response as quantified by (a) interleukin (IL)-6, (b) IL-8, and (c) IL-10 concentrations in the three study groups. Data are presented as mean ± SEM. “Post” indicates postbypass. HOE 140 is a specific bradykinin B2 receptor antagonist. EACA, ε-aminocaproic acid; POD, postoperative day.

Figure 4

Antifibrinolytic drugs’ mechanisms of action. Activation of the kallikrein–kinin system results in the release of bradykinin from HMWK through the action of kallikrein. Bradykinin activates the B2R and stimulates the release of tissue-type plasminogen activator (t-PA) from the endothelium. Bradykinin is inactivated by ACE to its inactive metabolite, BK1-5. Other substances such as thrombin and substance P can also stimulate t-PA release through specific membrane-bound receptors. Free active t-PA converts plasminogen to plasmin, which subsequently degrades fibrinogen and fibrin to fibrin degradation products that include D-dimer. Endogenous antifibrinolytics include PAI-1, α2AP, and TAFI. The antifibrinolytic drug aprotinin, a nonspecific serine protease inhibitor, inhibits kallikrein, plasmin, and thrombin. EACA inhibits plasmin and increases α2-antiplasmin. HOE 140 is a specific bradykinin B2 receptor antagonist. α2AP, α2-antiplasmin; ACE, angiotensin-converting enzyme; B2R, bradykinin B2 receptor; EACA, ε-aminocaproic acid; HMWK, high-molecular-weight kininogen; PAI-1, plasminogen activator inhibitor-1; TAFI, thrombin activatable fibrinolysis inhibitor.