Activated Clotting Times, Heparin Responses, and Antithrombin

Abstract

It was recognized early in the development of modern cardiopulmonary bypass (CPB) that the fluidity of blood needed to be maintained for extracorporeal circulation, especially with the evolution of early oxygenators.1 It was not until the anticoagulant properties of heparin were discovered that blood could circulate over nonendothelial surfaces without activating the coagulation cascade. Today, almost a century after its isolation by Howell and McLean in 1916, heparin remains the mainstay agent for cardiac surgery because of several advantages.2 Profound levels of anticoagulation can be quickly obtained (AntiXa levels of 3–5 U/mL) and an antidote, protamine, is readily available. In addition, heparin has a relatively short context-sensitive half-life, and can be used in patients with renal dysfunction. However, an important limiting aspect of heparin is that it requires a cofactor, antithrombin (also referred to as antithrombin III or ATIII), for its anticoagulation effect. Thus, heparin is still used extensively as an anticoagulant despite the development of newer agents that have been the focus of significant clinical interest and consternation.3 The most common method for determining the adequacy of anticoagulation for cardiac surgery is the activated clotting time (ACT), a modified whole blood Lee-White clotting assay that can be affected by multiple factors.4 Although there is not universal agreement on the ideal ACT for CPB, when heparin does not produce the desired ACT increase, “heparin resistance” is said to have occurred.5 The term is misleading, however, because it is really an alteration in the heparin dose response, possibly because of decreased antithrombin. “Heparin resistance” is perhaps more aptly termed “altered heparin responsiveness.”6 Antithrombin levels markedly decrease after CPB.7 These decreased levels may lead to a dangerous increase in thrombin activity.8 It would seem logical that this could lead to postoperative thrombotic complications, suggesting the need for antithrombin not only before CPB, but after it as well. In this issue of the journal, 3 investigations from the same group add further information and pose new questions about the interrelationship of antithrombin and heparin. In the first study, Garvin et al.9 retrospectively evaluated the Hepcon HMS PLUS System (Medtronic Inc., Minneapolis, MN) for its accuracy in predicting heparin dose responses for cardiac surgery with CPB. ACT-measured heparin dose response and heparin concentrations were evaluated in 3880 patients after a heparin dose calculated to achieve a target ACT. The result was wide variability in measurements. A target ACT of 300 seconds was not obtained in 7% of patients, and a target ACT of 350 seconds was not obtained in 17% of patients. The investigators also found that calculated and measured heparin dose responses were not related at any heparin dose. In the second study, the authors examined whether there was a direct association among preoperative antithrombin activity, heparin dose responses, and the heparin sensitivity index from 304 patients after CPB using Hepcon HMS PLUS Systems.10 The authors used multivariate linear regression to identify independent predictors of heparin dose response. The baseline antithrombin activity was normal in this study and was not associated with either baseline or postheparin ACT, heparin dose response, or heparin sensitivity index. Of note, only 16% of patients (49 of 304) in the study presented with low baseline antithrombin levels as defined as <80%. In the third study, the authors prospectively evaluated whether low levels of antithrombin were associated with postoperative major adverse cardiac events in 1403 patients undergoing coronary artery bypass graft.11 Major adverse cardiac events were defined as postoperative death, reoperation for coronary graft occlusion, myocardial infarction, stroke, pulmonary embolism, or cardiac arrest until first hospital discharge. Antithrombin activity levels were measured preoperatively, post-CPB, and on postoperative days 1 to 5. Major adverse cardiac events occurred in 146 patients (10.4%) and were independently associated with postoperative antithrombin but not preoperative antithrombin levels. What do these 3 studies tell us? For starters, they prove that an altered heparin response cannot be predicted by preoperative antithrombin alone. Heparin's effect on coagulation is rather unpredictable, at least as measured by ACT, an important perspective but not a new finding.12,13 For example, Metz and Keats14 gave 193 patients a single dose of heparin (300 U/kg). In 51 patients (26.4%), ACT values were <400 seconds, including 4 patients <300 seconds. The target ACT values of 300 or 350 seconds for the 3 studies may seem relatively low for many clinical practices and the rate of failure to meet those targets may seem unusually high. Previous reports suggest there is a 5% to 10% chance of a patient developing altered heparin responsiveness. The current studies targeted ACT values >350, which may account for the authors finding a 17% incidence of altered heparin responsiveness.14,15 Realistically, we still do not know the ideal ACT to initiate CPB, which is reflected in the widespread variability in clinical practice.4,16 Several studies have demonstrated that thrombin is still activated at ACT values of 400 to 480 seconds during CPB.17,18 As shown by the response of patients with factor XII deficiency, a prolonged ACT does not guarantee anticoagulation.19 All of this calls into question the validity of using ACTs to assess adequate anticoagulation. Clinicians need to understand the factors that influence both anticoagulation and its clinical measurement. The ACT is a relatively primordial tool, consisting only of a tube, some dirt or glass for activation, and some heat and agitation to speed the reaction. As shown in Figure 1, there are a host of other factors besides heparin concentration and antithrombin levels that affect ACT values. Unfortunately, there is no “gold standard” measurement to validate ACTs, complicating assessment of the relationship between ACT and altered heparin responsiveness.Figure 1: The activated clotting time (ACT) is a whole blood point of care coagulation test used extensively in cardiac surgery and in the cardiac catheterization laboratory to monitor the anticoagulant effect of different agents including unfractionated heparin. In the ACT, blood is added to a cartridge or tube that contains an activator, usually celite or kaolin, to speed the process by increasing contact activation by the intrinsic coagulation cascade. Clot formation in the ACT represents the interaction of plasma coagulation components (e.g., factors and fibrinogen), platelets, and red blood cells as this is a whole blood clotting assay. However, clot formation in the ACT is influenced by multiple factors that include platelet count and platelet function, factor deficiencies, fibrinogen levels, pharmacologic agents (anticoagulants in platelet inhibitors), temperature(especially hypothermia), and contact activation inhibitors (e.g., aprotinin).Based on the current studies, is there a role for antithrombin administration to improve heparin responsiveness? Multiple studies report that antithrombin supplementation improves intraoperative anticoagulation, increases ACT, and reduces biochemical markers of hemostatic activation.13,20–22 Although these 3 studies did not investigate antithrombin administration, the authors did find a relationship between postoperative antithrombin levels and major adverse cardiac events. This corroborates the observation by Ranucci et al.,23 that low levels of antithrombin activity in the intensive care unit are associated with a poor outcome in cardiac surgery. However, there are still only a few supporting studies demonstrating that antithrombin supplementation improves clinical outcomes, and these studies were not conducted in patients undergoing cardiac surgery.24,25 In summary, the current 3 studies provide additional data about the complex issues of anticoagulation, heparin responsiveness, and outcomes, including the role of antithrombin. Have we been wrong all these years regarding ACTs, heparin responsiveness, and the role of antithrombin? More than 50 years after the development of CPB, we are still asking many of the questions that the early pioneers confronted. We need better monitors and better understanding of anticoagulation adequacy to treat alterations in heparin response and assess therapeutic efficacy. We hope it will not take another 50 years to find these answers.