Anticoagulation and reversal for cardiopulmonary bypass

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Anticoagulation and reversal for cardiopulmonary bypass

Brian S. Donahue, MD, PhD

Heparin

Heparin (MW 750-1000 kDa) is a glycosaminoglycan, or mucopolysaccharide, composed of alternating D-glucuronic N-acetyl-D-glucosamine acid residues. Heparin has one of the highest negative charge-to-size ratios of any known biologic compound. Heparan sulfate is a related biologic compound that has fewer sulfate groups than heparin and, therefore, has less potency. Heparin inhibits coagulation by serving as a catalyst—antithrombin III (AT) binds to its surface, inducing a conformational change in AT, making its active site more accessible to any of several proteases involved in the intrinsic and common coagulation pathways (thrombin [IIa], factor Xa, factor XIa, factor XIIa, and factor IXa). However, the anticoagulant effects of heparin are primarily mediated by the inhibition of thrombin and factor Xa that occurs when thrombin and factor Xa are bound by AT. Once these covalent bonds are established, the heparin moiety is released and available to bind to another molecule of AT. Heparin also induces the release of tissue factor pathway inhibitor from intravascular endothelium. Fragments of tissue factor pathway inhibitor may contribute to post-CPB coagulopathy.

Administration and monitoring of heparin during cardiopulmonary bypass

Heparin is administered intravenously as a bolus dose of 300 to 400 units/kg. Traditionally, the extent of inhibition of coagulation has been monitored using the whole-blood activated clotting time (ACT). With this technique, the patient’s blood is mixed in a test tube with an activator (e.g., diatomite or kaolin), and the time until clot forms is recorded as the ACT. Although practice varies markedly, most surgeons require an ACT of 400 to 450 sec before they will allow initiation of CPB; however, these limits were established with very little data. The ACT is widely used because it has several advantages: the prolongation of the ACT is generally linear with the heparin level, and the test is widely available, is inexpensive, is easy to perform, and has stood the test of time. However, the ACT has many drawbacks—there is wide variability not only between tests of blood run on different instruments, but also between aliquots of the same blood run on the same instrument. Other methods of anticoagulation monitoring include the measurement of heparin concentration by protamine titration, high-dose thrombin time, and the heparin concentration test. The most popular of these non-ACT methods is the heparin-concentration test, which has been compared with the ACT in efforts to arrive at the most optimal evidence-based management. In a few randomized trials, the heparin-concentration test, compared with the ACT, was found to be associated with greater suppression of the coagulation pathway, decreased perioperative transfusion requirements, and greater total heparin dosing. Overall, a 2006 best-evidence review of point-of-care coagulation testing during CPB concluded that using the heparin-concentration test results in higher heparin and lower protamine dosing, with possible sparing of coagulation system activation and decreased transfusion requirements.

Problems associated with the use of heparin

Heparin-induced thrombocytopenia

The occasional patient with heparin-induced thrombocytopenia presents a challenge to the cardiac surgical team. Heparin-induced thrombocytopenia is caused by IgG antibodies that bind to heparin–platelet factor (PF) 4 complexes on platelets, thus activating the platelets and leading to microaggregate formation, thrombocytopenia, and vascular thrombosis (usually arterial). Even without the existence of thrombocytopenia, the very presence of antibodies directed against heparin-PF4 complexes is a risk factor for the occurrence of major adverse events in patients with cardiovascular disease. Currently, many patients with acute heparin-induced thrombocytopenia will undergo plasmapheresis before surgery to effectively reduce antibody levels to zero; however, if plasmapheresis is not available or an emergency arises that does not allow time to perform plasmapheresis, the use of thrombin inhibitors is indicated to anticoagulate the patient.

Problems associated with heparin manufacture

In 2007, lots of heparin were removed from the market because several syringes were found to be contaminated with Serratia marcescens. In 2008, Baxter withdrew all of its heparin from the market after more than 80 deaths were associated with its use. The heparin, imported from China, had a contaminant—oversulfated derivatives of chondroitin sulfate, a shellfish-derived supplement.

In 2009, the U.S. Food and Drug Administration notified physicians of a new reference standard to measure the potency of heparin so as to bring the U.S. pharmacopeia unit dose in compliance with the World Health Organization international standard unit dose. This change resulted in an approximately 10% reduction in the potency of the heparin sold in the United States.

Heparin alternatives for cardiopulmonary bypass

Alternatives to the use of heparin in CPB include direct thrombin inhibitors, such as lepirudin and bivalirudin; platelet glycoprotein inhibitors; danaparoid and other heparinoids; and ancrod. Because a specific reversal agent, such as protamine, is lacking for these agents, bivalirudin is the most commonly used heparin alternative because it has the shortest duration of action. The ACT is typically not sensitive enough to the effects of thrombin antagonists to be useful during CPB; therefore, a similar test, the ecarin clotting time, has been developed. In medical institutions in which the ecarin clotting time is not available, success has been reported with the use of a modified ACT.

In two open-label safety trials of bivalirudin in patients with heparin-induced thrombocytopenia who were undergoing either on-pump or off-pump cardiac procedures, the authors reported procedural success rates equivalent to those from cases in which heparin was used. Investigators of the EVOLUTION study—a randomized, open-label, multicenter trial comparing heparin and bivalirudin—reported similar procedural success rates and hemostatic outcomes in patients undergoing either on-pump or off-pump cardiac operations. Koster and colleagues reported acceptable hemostatic results with the use of bivalirudin as an anticoagulant in a series of 141 patients undergoing on-pump or off-pump operations.

Reversal of heparin following cardiopulmonary bypass

Protamine is a polyanionic peptide that binds rapidly and noncovalently to circulating heparin to inactivate the anticoagulant effect. Although protamine is the chief heparin-reversal agent used in clinical practice, other agents—such as heparinase and heparin-ecarin clotting time 4—have been used.

Excess protamine impairs postoperative platelet function, increases ACT, and may contribute to coagulopathy following CPB. Insufficient protamine results in residual circulating heparin that is too low in concentration to be detected by ACT, yet is high enough to impair coagulation. Ideally, the dose of protamine should be determined by measuring residual heparin concentration or by titrating the protamine dose response. If these techniques are not an option, most clinicians use weight-based dosing as opposed to a fixed dose.

Protamine administration has been associated with a range of systemic cardiovascular reactions, such as vasodilation, pulmonary hypertension, bronchospasm, anaphylaxis, myocardial depression, and circulatory collapse. These reactions may range from mild and clinically inconsequential to severe and ultimately fatal. The immunologic mechanism responsible for protamine reactions is complex and probably involves release of anaphylatoxins and eicosanoids, complement activation, histamine, and preformed antiprotamine or antiprotamine–heparin-complex antibodies. Fish or shellfish allergy, prior use of NPH insulin, and previous vasectomy have been classically taught as risk factors for protamine reactions, although the evidence supporting these associations is weak or anecdotal. Previous exposure to protamine appears to increase the incidence of protamine-induced pulmonary vasoconstriction, whereas preoperative aspirin use seems to decrease it. Treatment of protamine reactions is generally supportive and aimed at restoring normal hemodynamics. The use of inhaled nitric oxide to manage pulmonary hypertension and right-sided heart failure associated with protamine use has been reported.

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Anticoagulation and reversal for cardiopulmonary bypass

Brian S. Donahue, MD, PhD

Heparin

Heparin (MW 750-1000 kDa) is a glycosaminoglycan, or mucopolysaccharide, composed of alternating D-glucuronic N-acetyl-D-glucosamine acid residues. Heparin has one of the highest negative charge-to-size ratios of any known biologic compound. Heparan sulfate is a related biologic compound that has fewer sulfate groups than heparin and, therefore, has less potency. Heparin inhibits coagulation by serving as a catalyst—antithrombin III (AT) binds to its surface, inducing a conformational change in AT, making its active site more accessible to any of several proteases involved in the intrinsic and common coagulation pathways (thrombin [IIa], factor Xa, factor XIa, factor XIIa, and factor IXa). However, the anticoagulant effects of heparin are primarily mediated by the inhibition of thrombin and factor Xa that occurs when thrombin and factor Xa are bound by AT. Once these covalent bonds are established, the heparin moiety is released and available to bind to another molecule of AT. Heparin also induces the release of tissue factor pathway inhibitor from intravascular endothelium. Fragments of tissue factor pathway inhibitor may contribute to post-CPB coagulopathy.

Administration and monitoring of heparin during cardiopulmonary bypass

Heparin is administered intravenously as a bolus dose of 300 to 400 units/kg. Traditionally, the extent of inhibition of coagulation has been monitored using the whole-blood activated clotting time (ACT). With this technique, the patient’s blood is mixed in a test tube with an activator (e.g., diatomite or kaolin), and the time until clot forms is recorded as the ACT. Although practice varies markedly, most surgeons require an ACT of 400 to 450 sec before they will allow initiation of CPB; however, these limits were established with very little data. The ACT is widely used because it has several advantages: the prolongation of the ACT is generally linear with the heparin level, and the test is widely available, is inexpensive, is easy to perform, and has stood the test of time. However, the ACT has many drawbacks—there is wide variability not only between tests of blood run on different instruments, but also between aliquots of the same blood run on the same instrument. Other methods of anticoagulation monitoring include the measurement of heparin concentration by protamine titration, high-dose thrombin time, and the heparin concentration test. The most popular of these non-ACT methods is the heparin-concentration test, which has been compared with the ACT in efforts to arrive at the most optimal evidence-based management. In a few randomized trials, the heparin-concentration test, compared with the ACT, was found to be associated with greater suppression of the coagulation pathway, decreased perioperative transfusion requirements, and greater total heparin dosing. Overall, a 2006 best-evidence review of point-of-care coagulation testing during CPB concluded that using the heparin-concentration test results in higher heparin and lower protamine dosing, with possible sparing of coagulation system activation and decreased transfusion requirements.

Problems associated with the use of heparin

Heparin-induced thrombocytopenia

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