The state of development of coagulation alternatives for cardiopulmonary bypass

U'ufractionatcd heparin (UFH) is currently the most common anticoagulant used for cardiopulmonary bypass (CPB). Heparin was first used clinically in the 1930s and is widely prescribed due to rapid action and ready reversibility. The pharmacodynamics and pharmacokinetics of UFH are well studied and almost all research related to CPB utilizes UFH as the primary anticoagulant. Until recently, there have been no viable alternatives to heparin for anticoagulation during CPB. In recent years, a number of issues have emerged related to the use of UFH, particularly involving the immunological reaction of heparininduced thrombocytopenia (HIT). A search began for alternate anticoagulants with more favorable biological profiles and for different techniques that could minimize immunological reactions to heparin, particularly in cardiac surgery patients. Adverse effects of UFH during cardiopulmonary bypass may include significant inflammatory and hemostatic derangements as well as sensitization to future immunological reactions. Indeed, the problems seen with heparin in HIT may well be the "tip of the iceberg" with more subtle and often unrecognized immunologic and inflammatory changes occurring in most patients receiving heparin, particularly for CPB. I The ideal anticoagulant for CPB should meet several criteria: predictable onset and action, doserelated effect, easy and reliable monitoring with rapid point-of-care testing in the operating room, easy reversibility, minimal or no antigenic properties, minimal hemodynamic effects, and minimal effect on normal hemostasis. 2 Heparin is currently the "gold standard" for anticoagulation during cardiopulmonary bypass and is monitored by the activated clotting time (ACT), with well-established parameters for safe anticoagulation. However, heparin is unable to inhibit thrombin bound in an existing clot or bound to fibrin in the CPB circuit. Heparin's mechanism of action is dependent on anti-thrombin III (AT-lID, which can be problematic in AT-III deficient or depleted patients. Heparin decreases the concentration of AT-III either from chronic administration or acutely during CPB. The levels of AT-III seen during CPB are most often in the 40-60% of normal range but significant numbers of patients encounter levels of 20-30%. Levels below 40% are those that are seen during shock and diffuse intravascular coagulation. The implications of such low AT-Ill levels (2040%) during CPB is still under investigation. Finally, heparin is bound by plasma proteins and has a wide range of effect, so each patient's response to the drug must be monitored closely. Accurate ACT monitoring is affected by hemodilution, hypothermia and the use of aprotinin. Problems with heparin itself, heparin-induced thrombocytopenia, and monitoring of heparin effect lead to the development of new agents that could more effectively inhibit thrombin and reduce the risk of HIT) Alternate techniques that reduce or avoid the use of heparin include extreme hemodilution and heparin-bonded cardiopulmonary bypass circuits. Currently available pharmacological alternatives to heparin include: low molecular weight heparins (enoxaparin), heparinoids (danaparoid), ancrod, and the direct thrombin inhibitors recombinant hirudin (lepirudin), bivalirudin and argatroban. Also, standard doses of unfractionated heparin may be used in conjunction with the "platelet anesthesia" agents including prostaglandins (iloprost and prostacyclin) and the glycoprotein IIa-Illb inhil~itor tirofiban. Each alternative anticoagulant has attendant difficulties with its use related to availability, dosing and monitoring, antigenic cross-reactivity, excessive bleeding and thrombotic complications. Although alternative anticoagulant strategies are