Management of coagulation during cardiopulmonary bypass

Abstract

During normal haemostasis, a platelet plug forms at the site of vessel injury. This is stabilized by fibrin produced from enzymatic reactions of coagulation factors. These reactions can only proceed at a sufficient rate on the phospholipid surface of activated platelets. This requirement for platelet phospholipid, plus a series of inhibitors, and the fibrinolytic system restrict clot production to the site of injury. Historically, coagulation was considered as two separate pathways of factors, denoted by Roman numerals, arranged in cascades. The ‘intrinsic’ (contact activation) and ‘extrinsic’ (tissue factor) pathways join to form a common pathway at factor Xa that activates thrombin, which in turn converts fibrinogen to fibrin. Although not an accurate representation of in vivo coagulation, this scheme remains useful when trying to understand laboratory tests. The prothrombin time (PT) is a test of the extrinsic pathway. The activated partial thromboplastin time (APTT) is a test of the intrinsic pathway. Modern understanding is that in vivo haemostasis begins with tissue factor (TF) and circulating factor VII. A network of reactions is triggered with platelets playing a central role, rather than a unidirectional enzyme cascade. TF is a transmembrane glycoprotein expressed on cells outside the bloodstream. Coagulation is initiated when TF becomes exposed at the site of vessel injury, binds and activates circulating factor VII. The resulting TF–VIIa complex activates factors X and IX. Activated factor X (Xa) then binds cofactor V. This TF– Xa/Va complex cleaves prothrombin to thrombin. Thrombin is an important enzyme in coagulation as it cleaves fibrinogen to fibrin and activates platelets, factor XI, and cofactors V and VIII. Thrombin also activates control mechanisms such as the inhibitor protein C and the fibrinolytic enzyme plasmin. The small amount of thrombin produced thus far is not sufficient to produce a fibrin clot. Amplification of thrombin production is achieved by accelerating enzyme reactions on the platelet surface. Platelets are activated and localized via receptors for substances such as collagen and thrombin. They release procoagulant factors and change shape, exposing negatively charged membrane phospholipid. Factors IXa, Xa, and XIa also have negatively charged sites that attach to platelet phospholipid via calcium ions acting as a sandwich-like buffer. XIa activates IX, an additional source of IXa to that derived by TF–VIIa. Two key enzyme–cofactor complexes form on the platelet surface. IXa joins with its cofactor VIIIa to form a ‘tenase’ complex that activates X. Similarly, a ‘prothrombinase’ complex is formed by Xa and Va. The combination of enzyme, cofactor, calcium, and phospholipid surface increase the speed of these reactions many thousand-fold. This produces an explosive increase in thrombin production sufficient to produce fibrin. Platelets become linked together in this platelet-fibrin clot via their fibrin-receptor glycoprotein IIbIIIa (GpIIbIIIa). Coagulation overlaps with inflammatory pathways; for example, activated platelets release inflammatory cytokines and thrombin activates monocytes. Coagulation can activate the inflammatory system and vice versa. This becomes relevant with extreme activation of either system, such as in systemic inflammation. During CPB for OHS, heparin is required to prevent blood clotting within the CPB circuit. By facilitating the action of antithrombin III, heparin inhibits thrombin. Despite heparin anticoagulation, some activation of coagulation still occurs and increases with the duration of CPB. Contact activation occurs on foreign surfaces within the bypass circuit. In addition, there is exposure of blood to air and TF in the wound and recirculation of this blood via cardiotomy suction. Thrombin bound to fibrin deposited on surfaces within the CPB circuit is resistant to inhibition by heparin–antithrombin III. Consumption of clotting factors and platelets follows their activation by thrombin. Thrombin-induced fibrinolysis by plasmin not only lyses fibrin clot, but plasmin also degrades platelet surface receptors such as GpIIbIIIa. Key points Coagulation and inflammatory pathways are triggered by contact of blood with the cardiopulmonary bypass (CPB) circuit and surgical wound during open heart surgery. Heparin remains the standard anticoagulant for CPB; despite inconsistent relationships between coagulation tests, thrombin inhibition, and plasma concentrations. Activated clotting time is the standard test of coagulation during CPB. Thromboelastography is a point of care coagulation test that gives rapid, qualitative information about coagulation factors, platelets, and fibrinolysis. Following protamine reversal of heparin, failure to re-establish normal haemostasis can occur and may result in postoperative bleeding.