Blood transfusion in cardiac surgery patients has warranted and generated much investigation and discussion. Significant perioperative blood loss requiring transfusion of blood products has been associated with increased morbidity and mortality in cardiac surgery (1). In the quest for reducing the inherent risks and significant costs of transfusion, many aspects of the perioperative course have been examined. Factors which contribute to the requirement for blood transfusion in the perioperative period include preoperative antiplatelet medication, the nature of the surgery, hemolysis by extracorporeal circuits, hemodilution, and heparin use. Up to 50% of patients undergoing cardiac procedures receive no blood transfusion (2). However, there is a subset of “high risk” patients who require substantial perioperative blood transfusion. One review suggested an overall blood transfusion rate of 57% in patients with a packed red blood cell (RBC) transfusion rate of 49% and a non-RBC component transfusion rate of 27% (3). An audit by the European Association for Cardio-thoracic Surgery estimated that cardiac surgery accounted for 5% of blood donated in the United Kingdom (4). Perioperative transfusion of packed RBCs has been associated with increased risk for a broad spectrum of postoperative morbidity after cardiac surgery, including renal failure, prolonged ventilation, infection, neurologic events, and mortality (1). Karkouti et al. (5) demonstrated that massive blood loss after cardiac surgery resulted in an 8-fold increase in mortality. Blood transfusion of even minimal amounts has been associated with increased morbidity and mortality for on-pump coronary artery bypass surgeries (6). Studies have linked perioperative blood transfusion during cardiac surgeries with mediastinitis leading to increased cost and mortality (7). Increased risk of delirium in the postoperative period has been linked to duration of storage of packed RBCs (8). A review of 42 studies showed an association between intraoperative blood transfusion and wound infection in cardiac surgical patients (9). In a large prospective study, Horvath et al. (10) identified pneumonia and bloodstream infections as the most common manifestations of infection and the incremental risk associated with each unit of packed RBCs was 29%. Since the early 1990s, antifibrinolytic drugs have played a major role in blood conservation strategies in cardiac surgery. Perioperative blood conservation strategies play an important role in the reduction of blood transfusion. This chapter will focus on the key prophylactic role played by antifibrinolytic drugs in reducing blood loss and transfusion.

Hemostasis is the process of clot formation at the exposure site of subendothelial collagen in a blood vessel. The hemostatic system consists of four components: coagulation system, endothelium and regulatory proteins, platelets, and fibrinolysis (11). Nonendothelial surfaces in the cardiopulmonary bypass (CPB) circuit initiate contact activation of the intrinsic coagulation pathway resulting in nonhemostatic thrombin generation (12). Under normal hemostatic conditions, soluble fibrin accounts for 1% of total fibrin formation. CPB leads to dysregulation of fibrin resulting in an increase in soluble fibrin of up to 35% (13). Thrombin generation and soluble fibrin formation increase at initiation of CPB, at CPB cessation, and after protamine administration (14). High-dose unfractionated heparin, via antithrombin III, decreases thrombin activity and fibrin generation, thereby preventing clot formation within the extracorporeal circuit (15). However, thrombin has also been widely recognized as a key amplifier protein of inflammation, coagulation, and fibrinolysis. Thrombin causes the release of tissue plasminogen activator (tPA) from endothelium which promotes plasminogen conversion to plasmin, an enzyme that proteolytically degrades fibrin (16). The plasminogen molecule contains specific lysine-binding sites that interact with both fibrin and the major inhibitor, α₂-antiplasmin. Urinary plasminogen activator (uPA) and tPA are the two main serine protease activators (17). Vascular endothelial cells secrete tPA, while uPA is secreted by a variety of cell types including nonvascular cells. Bradykinin has been shown to play an important role stimulating the release of tPA via β₂ receptors (18). Activators convert plasminogen to plasmin, generating soluble degradation products and exposing carboxy-terminal lysine residues (19).

Other factors contribute to the initiation of fibrinolytic activity during cardiac surgery. Surgical trauma, such as sternotomy alone, can activate fibrinolysis. There is contact activation of fibrinolysis by the CPB circuit, resulting in a 5-fold increase
in tPA activity (14). Peak tPA levels occur early during CPB within 30 to 60 minutes. Increased soluble fibrin is a powerful stimulator of tPA (12). Unfractionated heparin in itself is also a mild stimulator of vascular plasminogen activators, thereby contributing to fibrinolytic augmentation (20). This hyperfibrinolytic state consumes fibrinogen, thereby impairing coagulation postoperatively. In addition to fibrin, plasmin cleaves fibrinogen and a variety of plasma proteins. The breakdown of fibrin strands by plasmin results in the release of fibrin degradation products that include D-dimers. D-Dimer levels have been used as indicators of fibrinolysis in many studies.

Plasmin activity is regulated both by plasminogen activators and inhibitors. Inhibitors of plasminogen activation are plasminogen activator inhibitor-1 (PAI-1), α₂-antiplasmin, and thrombin-activated fibrinolysis inhibitor (TAFI). PAI-1 is a member of the serine protease inhibitor family. It is produced by vascular endothelial and smooth muscle cells and is the primary physiologic regulator of uPA and tPA activity (21). PAI-1 is an acute phase reactant and levels are increased following surgery (14). α₂-antiplasmin is manufactured in the liver and is the major inhibitor of plasmin in plasma. TAFI is activated by thrombin and removes carboxy-terminal lysine residues, thereby attenuating plasmin generation. The resultant overall hyperfibrinolytic state consumes fibrinogen impairing coagulation postoperatively, and increasing postoperative hemorrhagic complications and blood transfusion requirements (22). When antifibrinolytic agents are prophylactically administered during CPB, they reduce the susceptibility of fibrin clots to plasmin-mediated degradation.

Plasmin and plasminogen bind at lysine-binding sites onto fibrinogen. The lysine analogs e-aminocaproic acid (ACA) and tranexamic acid (TXA) competitively inhibit the fibrin-binding site on plasminogen and prevent the degradation of fibrin and the dissolution of clot (Fig. 21.1, Table 21.1).