Complex interplay of factors that can cause bleeding after cardiac surgery with cardiopulmonary bypass

Interplay between coagulation, anticoagulation, and the fibrinolytic systems. In a simplified model, coagulation factors are illustrated upon the activated platelet surface. Through the activation of factor X (Xa) via intrinsic (Factor IXa, VIIIa) and extrinsic tenase (Xase) complexes, factors Xa and Va convert factor II (prothrombin) to factor IIa (thrombin). Thrombin then cleaves fibrinogen into fibrin. Fibrin polymerization is facilitated by the activation of factor XIII that forms cross links leading to clot stabilization. Factor II, VII (not pictured), IX (not pictured), and X are targeted for repletion with prothrombin complex concentrate (PCC) administration. Factor VIIa is targeted for repletion with administration of recombinant factor VIIa (rFVIIa). Simultaneously, anticoagulants negatively modulate clot formation. Antithrombin III (ATIII) modulates factor IIa (primarily) and factor Xa (secondarily), but ATIII-dependent inhibition of factor IXa, XIa, and VIIa-TF complex occurs to a lesser extent (not pictured). Other important anticoagulants include TFPI-modulation of tissue factor and factor VIIa, and activated protein C (APC) which, through activation of protein S, inhibits factor Va, weakening the prothrombinase complex and impairing thrombin generation. Upstream, APC inhibits factor VIIIa of the intrinsic Xase complex. Factor IIa complexes with thrombomodulin (TM) to activate PC. Of note, the thrombin-TM/PC/PS system is primarily localized to the endothelium but can be expressed on platelets and monocytes. This complex initiates thrombin-activatable fibrinolysis inhibitor (TAFI), which prevents plasmin production by inhibiting tissue-plasminogen activator and through direct inhibition of plasminogen (not pictured). Plasmin is a serine protease and, as the primary driver of fibrinolysis, results in clot destabilization, degradation of fibrin cross linkage, and production of fibrin degradation products, which include D-dimers. Plasmin triggers platelet activation (not pictured) thereby competing with TAFI at the local level.