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Ann Thorac Surg 2000;70:1434-1443
© 2000 The Society of Thoracic Surgeons

Current review

Cardiopulmonary bypass in humans: bypassing unfractionated heparin

James W. Frederiksen, MDa

a Division of Cardiothoracic Surgery, Department of Surgery, Northwestern University Medical School, Chicago, Illinois, USA

Address reprint requests to Dr Frederiksen, Division of Cardiothoracic Surgery, Department of Surgery, Northwestern University Medical School 251 East Chicago Ave, Suite 1030, Chicago, IL 60611;
e-mail: jwf{at}nwu.edu


   Abstract
Top
 Abstract
Introduction
 Overview of cardiopulmonary...
 Unfractionated heparin
 Alternative anticoagulants
 Conclusion
 Future studies of alternative...
 References
 
Seven anticoagulants besides unfractionated heparin have been used for human cardiopulmonary bypass (CPB), mainly in patients with heparin-induced thrombocytopenia. The collective experience with these alternative anticoagulants provides a perspective on current efforts aimed at improving CPB anticoagulation. Unfortunately, each alternative currently lacks a standard dosing schedule and a reliable method of monitoring the adequacy of its anticoagulant effect during CPB. Most also lack proven antidotes. Thus, unfractionated heparin remains the anticoagulant of choice for standard CPB.


   Introduction
Top
 Abstract
 Introduction
Overview of cardiopulmonary...
 Unfractionated heparin
 Alternative anticoagulants
 Conclusion
 Future studies of alternative...
 References
 
Seven anticoagulants besides unfractionated heparin (UFH) have been used for cardiopulmonary bypass (CPB) in humans to date. They are nadroparin [1], enoxaparin [2–7], dalteparin [8, 9], danaparoid [10–20], ancrod [21–26], recombinant hirudin (r-hirudin) [27–35], and argatroban. Most recipients have been adult patients in whom a history of heparin-induced thrombocytopenia (HIT) was believed to contraindicate the use of UFH. In addition, factor IXa inhibitor (IXai) [36] has been used for anticoagulation in a patient with presumed HIT undergoing treatment with extracorporeal membrane oxygenation and a biventricular assist device.

Each of these alternatives has drawbacks, and none has superseded UFH for standard CPB [24, 37]. However, their use in selected patients has demonstrated that human CPB can be achieved with anticoagulants that act through mechanisms distinct from UFHs. This review evaluates these mechanisms and the published use of alternative anticoagulants for human CPB. A brief description is included of the anticoagulant mechanism of UFH to facilitate comparisons between UFH and the alternatives. The goal is to provide a perspective on some of the current efforts aimed at improving CPB anticoagulation.

The review does not discuss UFH-bonded circuits, for example, Duraflo (Baxter Healthcare Corp, Irvine, CA) or Carmeda (Medtronic Inc, Minneapolis, MN) or drugs that have been used to modify the effects of UFH-induced CPB anticoagulation, for example, the antifibrinolytics epsilon-aminocaproic acid and tranexamic acid, the serine protease inhibitor (serpin) aprotinin, or the platelet "anesthetics" aspirin, tirofiban, eptifibatide, iloprost, and L-arginine.


   Overview of cardiopulmonary bypass anticoagulant mechanisms
Top
 Abstract
 Introduction
 Overview of cardiopulmonary...
Unfractionated heparin
 Alternative anticoagulants
 Conclusion
 Future studies of alternative...
 References
 
Figure 1 [38] shows the intrinsic and extrinsic coagulation pathways, and indicates the coagulation protein(s) that UFH and the alternative anticoagulants are known to affect. Unfractionated heparin becomes bound to two constitutive plasma serpins, antithrombin (formerly called antithrombin III) and heparin cofactor II (HCII) [39]. Antithrombin inhibits thrombin (IIa) and Xa and, to a lesser degree, IXa, XIa, and XIIa. Antithrombin’s inhibition of IXa, XIa, and XIIa is not shown in Figure 1. Heparin cofactor II inhibits IIa [39] (Fig 1). When bound to UFH, antithrombin and HCII undergo conformational changes that significantly augment antithrombin’s inhibition of IIa and Xa [39, 40] and HCII’s inhibition of IIa [39]. The ratio of anti-Xa to anti-IIa activity produced by UFH is 1.



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  		Fig 1. Overview of the coagulation pathways and the mechanisms through which unfractionated heparin (UFH) and the alternative anticoagulants are known to act. Anticoagulants are displayed within black rectangular backgrounds. Physiologic inhibitors are indicated in italics. Dashed arrows indicate inhibition. Antithrombin’s inhibition of IXa, XIa, and XIIa is not shown. For abbreviations of anticoagulants see text. (HK = high molecular weight kininogen; LMWHs = low molecular weight heparins; RES = reticulo-endothelial system; TFPI = tissue factor pathway inhibitor. Redrawn and modified from the Coagulation pathways poster, printed by Enzyme Research Laboratories, South Bend, IN.)

 
Nadroparin, enoxaparin, and dalteparin, three types of low molecular weight heparins (LMWHs), also induce conformational changes in antithrombin and HCII that augment the inhibitory effects of these serpins (Fig 1). However, by a mechanism to be described, they affect IIa much less than Xa [40]. Protamine can reverse completely the anti-IIa activity, but only incompletely the anti-Xa activity, produced by LMWHs [3].

Danaparoid, a byproduct of UFH production [11], comprises a mixture of three heparinoids: heparan, dermatan, and chondroitin sulfates, approximately 84%, 12%, and 4%, respectively [10]. Danaparoid induces predominantly anti-Xa activity and some anti-IIa activity through the action of heparan sulfate, 5% of which possesses binding affinity for antithrombin [10] (Fig 1). Dermatan sulfate also augments HCII’s inhibition of IIa [41] (Fig 1) through a mechanism different from that of UFH. Danaparoid’s anti-Xa to anti-IIa activity ratio—at least 22—significantly exceeds the anti-Xa to anti-IIa ratios of the LMWHs and UFH [10]. However, its induced inhibition of these two serine proteases is responsible for only about half of its anticoagulant effect, the other half being due to an unknown mechanism or mechanisms [10]. Like UFH and the LMWHs, danaparoid produces immediate anticoagulation following intravenous administration. Neither protamine nor any other drug can reverse danaparoid’s anticoagulant effects.

Ancrod catalyzes the breakdown of fibrinogen through a mechanism that prevents fibrin generation [42] (Fig 1). The details of this mechanism are described below. Cardiopulmonary bypass anticoagulation can be achieved by lowering the fibrinogen concentration to 0.2 to 0.8 g/L [21–26] (normal range 2.0 to 4.0 g/L) with an infusion of ancrod administered over 12 hours [21–26]. Exogenous fibrinogen, usually administered in fresh frozen plasma or cryoprecipitate, will reverse ancrod’s anticoagulant effect.

r-Hirudin blocks the action of IIa through direct and specific 1:1 binding to that protease [43] (Fig 1). Thus, r-hirudin’s anticoagulant effect does not require the action or the presence of antithrombin, HCII, or any other plasma cofactor. r-Hirudin produces no known effects on any other coagulation protein [43]. Like UFH, LMWHs, and danaparoid, r-hirudin’s anticoagulant effect occurs immediately following intravenous administration. Recombinant meizothrombin has been proposed as an antidote to r-hirudin [35].

Argatroban, a synthetic thrombin inhibitor [44], inhibits IIa (Fig 1) through direct 1:1 binding to IIa’s catalytic site. Hence, like r-hirudin, argatroban does not require the action of antithrombin. Argatroban has been used for CPB anticoagulation in only two unpublished NYHA class IV patients with HIT, both of whom bled excessively and died shortly following their operations. IXai competitively inhibits IXa’s catalytic conversion of X to Xa [36]. It thereby blocks the formation of Xa via the intrinsic coagulation pathway, but theoretically allows formation of Xa through the action of VIIa via the extrinsic coagulation pathway [36] (Fig 1).


   Unfractionated heparin
Top
 Abstract
 Introduction
 Overview of cardiopulmonary...
 Unfractionated heparin
Alternative anticoagulants
 Conclusion
 Future studies of alternative...
 References
 
Unfractionated heparin comprises a heterogeneous mixture of linear polysulfated polydisaccharide chains [45] that "cannot be separated into pure compounds" because of their structural similarity [46]. The chains are prepared from a proteoglycan synthesized exclusively within connective tissue mast cells [47]. The sulfate to disaccharide ratio varies between 2.4 and 2.8 to 1 [47], and the in vivo molecular weights vary between 60,000 and 100,000 daltons [45]. During preparation of UFH from porcine intestinal mucosa or bovine lung the chains become cleaved to fragments having molecular weights between 5,000 and 30,000 daltons, and the remaining tissue components become degraded. The mean molecular weight of UFH is approximately 12,000 daltons [47]. The average chain contains approximately 40 monosaccharide units.

A specific sequence of five monosaccharide units that possesses binding affinity for antithrombin [45] occurs in only about one third of the chains [47]. The structure of this catalytic pentasaccharide sequence (CPS) has been determined [48]. Chains without the CPS do not become bound to or augment the inhibitory effects of antithrombin. Some of the drawbacks of UFH as an anticoagulant may result from the predominance of non-CPS containing chains and from the presence of small quantities of retained animal tissue [49]. A detailed discussion of UFH’s drawbacks is beyond the scope of this article, but may be found elsewhere [49–52].

The anti-IIa and anti-Xa activities of an UFH chain that contains the CPS depend on the total number of monosaccharide units in the chain. Augmenting antithrombin’s inhibition of IIa requires the simultaneous binding of antithrombin by the CPS and IIa by the remainder of the chain. Only CPS-containing chains that have a total of 18 or more monosaccharide units are long enough to form this ternary complex [40]. In contrast, augmenting antithrombin’s inhibition of Xa does not depend on chain length, but only on the presence of the CPS [40]. Indeed, an isolated CPS will augment antithrombin’s inhibition of Xa. As mentioned earlier, the ratio of anti-Xa to anti-IIa activity produced by UFH is 1.

To form the ternary complex with IIa, the UFH–antithrombin complex must bind IIa at the same site that fibrin binds IIa [52]. Hence, an UFH–antithrombin complex cannot inhibit the catalytic activity of a IIa molecule that has become bound to fibrin [50, 52].

Unfractionated heparin’s augmentation of HCII’s catalytic activity does not require the presence of the CPS, but does require an UFH chain that has at least 26 monosaccharide units [53].


   Alternative anticoagulants
Top
 Abstract
 Introduction
 Overview of cardiopulmonary...
 Unfractionated heparin
 Alternative anticoagulants
Conclusion
 Future studies of alternative...
 References
 
Low molecular weight heparins
Low molecular weight heparins are prepared from UFH by controlled depolymerization [40]. Nadroparin and dalteparin, having mean molecular weights of 4,500 and 6,000 daltons, respectively, are prepared by nitrous acid depolymerization of UFH. Enoxaparin, having a mean molecular weight of 4,200 daltons, is prepared by benzylation and alkaline depolymerization of UFH [40]. Thus, these LMWHs are not identical mixtures. However, their antithrombin binding occurs through the same CPS present in UFH. Low molecular weight heparins have higher anti-Xa to anti-IIa activity ratios than UFH because they have relatively fewer CPS-containing polydisaccharide chains with 18 or more monosaccharide units than UFH. LMWHs also augment HCII’s inhibition of IIa less than UFH because they have fewer chains with 26 or more monosaccharide units than UFH. Like UFH, the LMWHs cannot inhibit fibrin-bound IIa. The half-lives of LMWHs following intravenous injection range between 2 and 4 hours [40], compared with an average half-life of 90 minutes for UFH.

Nadroparin is not available in the United States. Enoxaparin and dalteparin are approved by the United States Food and Drug Administration (FDA) for the prevention of thrombosis. Enoxaparin is also approved by the FDA for the treatment of thrombosis.

The indications for the use of LMWHs in CPB are unclear. Cross-reactivity of HIT antibodies with an LMWH may be found in approximately 90% of patients with HIT [54], making a LMWH a potentially dangerous alternative to UFH in these patients. Nevertheless, four letters [1, 2, 7, 8], one abstract [6], three case reports [4, 5, 9], and one study [3] have documented 28 patients, 6 of whom had HIT, who received a LMWH for CPB.

In 1983 Gounault-Heilmann and coworkers [1] reported the first successful use of nadroparin for CPB in a 66-year-old man with HIT undergoing an emergency pulmonary thrombectomy. These researchers gave a pre-CPB intravenous dose of 25,000 U and a priming fluid dose of 12,500 U.

The following year Massonnet-Castel and coworkers [2] reported the use of enoxaparin for CPB in a pilot study of six patients undergoing elective cardiac operations. These researchers gave initial individual pre-CPB doses of 160, 150, 120, 110, 100, and 90 mg/m2, a 20-mg priming fluid dose, and 90 mg/m2 after 1 hour of bypass. They based this dosing regimen on a study showing that 80 mg/m2 had produced satisfactory CPB anticoagulation in sheep. In a subsequent group of 15 elective cardiac surgical patients, Massonnet-Castel and associates [3] found that a lower dose of enoxaparin, 70 to 80 mg/m2 per hour plus a 10-mg priming fluid dose, also produced satisfactory CPB anticoagulation. Following these reports they [4] and three other groups of investigators [5–7] successfully used enoxaparin to perform cardiac operations on three patients with HIT and one with an idiosyncratic reaction to UFH [7]. One of the patients with HIT underwent bypass with a UFH-bonded (Carmeda; Medtronic Inc, Minneapolis, MN) circuit [5]. Another received aprotinin [6].

Párama and coworkers [8] and Altés and coworkers [9] successfully used dalteparin to perform mitral valve replacements in 2 patients with HIT. Each patient received a pre-CPB dose of 10,000 U and a priming fluid dose of 5,000 U.

No clots were observed during CPB in 27 of the 28 patients who were anticoagulated with a LMWH. In one, a 65-year-old man who had had the idiosyncratic reaction to UFH and was undergoing an aortic valve replacement [7], clots did form in the extracorporeal circuit following 108 minutes of CPB. Cardiopulmonary bypass was terminated successfully 2 minutes later. The patient subsequently required mediastinal reexploration to control postoperative bleeding.

The 6 patients who received enoxaparin in the initial pilot study [2] bled between 500 and 1,800 mL during the first 6 hours following CPB. Three required reoperation to control bleeding. The researchers acknowledged that the volume of bleeding and the incidence of reoperation were unacceptable. However, for safety reasons they deliberately gave the patients higher doses of enoxaparin than were previously shown to produce satisfactory CPB in sheep. One of the patients died on the third postoperative day from a myocardial infarction the researchers believed was not due to the use of enoxaparin. Each of the 15 subsequent patients undergoing cardiac operations with a lower dose of enoxaparin survived the operation, and none required reoperation [3].

Of the 7 patients with either HIT or an idiosyncratic reaction to UFH [1, 4–9], 4 [5–8] required multiple transfusions of blood, fresh frozen plasma, and platelets to treat a postoperative coagulopathy.

The LMWHs elevated activated clotting time (ACT) [5–7] and activated partial thromboplastin time (aPTT) [3, 7, 8], and produced anti-Xa [3, 6–9] and anti-IIa [3, 7] activity. However, none of these researchers used the results of ACT, aPTT, anti-Xa assays, or anti-IIa assays to determine the dosing schedule. In fact, no current coagulation assay or set of assays has been shown to indicate whether satisfactory CPB anticoagulation has been achieved with any LMWH.

Although 17 of the 28 patients received protamine, the dose bore no consistent relationship to the dose of LMWH [2–9]. Because protamine cannot completely reverse anti-Xa activity [3], it is not an ideal antidote for any of the LMWHs. For example, the in vitro study of Massonnet-Castel and coworkers [3] showed that whereas anti-IIa activity was completely reversed with a gravimetric protamine: enoxaparin ratio of 2:1, anti-Xa activity was only 60% reversed even with a ratio of 5:1.

Low molecular weight heparins did not produce platelet aggregation in any of the 6 patients with HIT, including the patient in whom a UFH-bonded circuit was used [5]. However, as mentioned earlier, LMWHs can cross-react with HIT antibodies [54]. Unfractionated heparin-bonded surfaces can also cross-react with HIT antibodies [55], and UFH-bonded bypass circuits are not recommended for patients with HIT.

The published experience to date indicates that CPB anticoagulation can be achieved with LMWHs. However, reliable dosing schedules have not been established, the clinical experience with each LMWH is empirical and limited, and methods for monitoring and reversing their anticoagulant effects have not been determined.

Danaparoid
Like UFH and the LMWHs, each of danaparoid’s three components is a heterogeneous mixture of linear polysulfated polydisaccharide chains obtained from porcine intestinal mucosa. The average molecular weight of the mixture is approximately 6,500 daltons. The molecular weights of the individual components have not been published. The half-lives of danaparoid’s anti-Xa and anti-IIa activities are, respectively, 25 and 7 hours [16]. Danaparoid is approved by the FDA for the prevention of thrombosis.

Each of danaparoid’s components is less sulfated than UFH [47]. As mentioned earlier, approximately 5% of heparan sulfate possesses binding affinity for antithrombin. Dermatan sulfate’s augmentation of HCII’s inhibition of IIa has been shown to occur through the binding of HCII by a specific hexasaccharide sequence whose structure has been determined [41]. The dermatan sulfate–HCII complex cannot inhibit Xa. However, unlike the UFH–antithrombin complex, the dermatan sulfate–HCII complex can inhibit fibrin-bound IIa [52]. Dermatan sulfate alone has been used successfully for CPB anticoagulation in pigs [52]. Chondroitin sulfate’s anticoagulant mechanism, if one exists, is unknown.

Weak cross-reactivity between danaparoid and HIT antibodies has been demonstrated in only 17% of patients with HIT [54], making this agent considerably safer than the LMWHs for these patients. One letter [14], eight case reports [11–13, 15–18, 20], one study [19], and one book chapter [10] have documented 65 patients, each with a history of HIT, who received danaparoid for CPB. One of these patients [20] also received ancrod and is discussed in the section describing that agent.

In 1997 Magnani and coworkers [10] reported that 53 patients had received danaparoid for CPB in an uncontrolled and nonrandomized compassionate-use trial conducted in several European centers between 1985 and 1996. The researchers reported the clinical outcomes of 47 of those patients, whose operations included 31 coronary artery bypass graft (CABG) operations, 10 valve replacements, 4 cardiac transplants, 1 ascending aortic repair, and 1 pulmonary embolectomy. These researchers recommended a pre-CPB dose of 8,750 anti-Xa U and a priming fluid dose of 7,500 U for patients weighing between 60 and 90 kg [10]. They recommended weight-adjusted doses for patients with weights outside this range. After clots developed during CPB in some of the initial patients, the researchers recommended giving additional bolus doses of 1,500 U/h during CPB if clots were observed. From the sometimes incomplete dosing information Magnani and coworkers received from the study sites, they were able to determine that only 23 (49%) of the 47 patients received both the pre-CPB and priming fluid doses of danaparoid they had recommended [10]. Table 1 shows the actual mean, mode, and range values of the prebypass doses, the priming fluid doses, and the doses given during CPB for the patients whose data were reported [10].


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  		Table 1. Danaparoid for Cardiopulmonary Bypass

 
Because danaparoid’s antithrombotic effects are not entirely related to its anti-Xa activity [10], Magnani and coworkers did not recommend intraoperative anti-Xa activity assays. In fact, anti-Xa assays were performed on less than half of the study patients, the assay results were unavailable during the operations, and no assay result was used to determine how much danaparoid a patient should receive.

Clots were observed in either the CPB circuit or the operative field in 18 of the 47 patients (38%), although clot formation necessitated termination of CPB in only 2. Twenty-six patients (55%) required more than eight units of postoperative "transfusion fluids" (presumably blood, fresh frozen plasma, and platelets), and 6 (13%) required more than 20 units. Four (8.5%) required reoperation to control mediastinal hemorrhage. The 48-hour and 6-week mortality rates were 6% and 23%, respectively [10].

Nine other groups of authors [11–19] used danaparoid as the only anticoagulant for 11 other patients undergoing CPB (Table 2). Most of these groups gave pre-CPB and priming fluid doses similar to those recommended by Magnani and coworkers [10]. Seven of the nine groups measured anti-Xa activity during CPB in an effort to identify an anti-Xa level that would indicate adequate CPB anticoagulation. The peak anti-Xa levels for the patients in whom they were measured are shown in Table 2. All 11 patients survived their operations, although 5 [11, 12, 15, 19] had excessive postoperative bleeding and 1 [15] required reoperation for this complication.


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  		Table 2. Danaparoid for CPB in 11 Patients

 
During 3 of the 11 operations the CPB circuit and the operative field remained free of clots. During the other 8, clots formed in either the pericardial sac or in a CPB circuit filter (Table 2). Six of those eight were given additional doses of danaparoid, following which no further clots were observed. The 2 patients not given additional danaparoid were being weaned from CPB when the clots were noticed. One was weaned quickly and uneventfully following 38 minutes of CPB [17]. The other was also weaned quickly and decannulated following 123 minutes of CPB, at which time the entire CPB circuit clotted [18]. However, this patient required readministration of danaparoid 7,500 U, recannulation, and reinstitution of CPB because of post-CPB hemodynamic instability. Small clots also formed in the second CPB circuit, although the patient was eventually weaned with the aid of an intra-aortic balloon pump.

The 2 patients reported by Wilhelm and coworkers [16] received pre-CPB doses of only 5,250 and 5,000 U, respectively, no priming fluid dose, and no dose during CPB (Table 2). Although these doses are well below the doses recommended by Magnani and coworkers [10], clots did not form during CPB and excessive postoperative bleeding did not occur in either patient. Wilhelm’s experience raises the possibility that danaparoid doses lower than those originally recommended may provide satisfactory CPB anticoagulation.

Antibody-induced platelet dysfunction has not occurred in any patient who received danaparoid for CPB. However, the published clinical experience to date indicates that no standard dose for CPB anticoagulation has been established [13], no method of monitoring its anticoagulant effects has been devised, and no antidote exists. In addition, the half-lives of danaparoid’s anti-Xa and anti-IIa activities are long relative to the operating time required for cardiac operations [17]. These disadvantages are reflected by the frequent development of clots during CPB, and by the excessive and prolonged postoperative bleeding observed in many patients who received this agent.

Ancrod
Ancrod is a glycosylated 234-amino acid fibrinogenolytic serine protease isolated from the venom of the Malayan pit viper Calloselasma rhodostoma (formerly called Akistrodon rhodostoma). Its amino acid sequence has been determined [56], as have the structures of several of its oligosaccharide side chains [57]. However, to date its complete structure has not been published. Its initial half-life is 3 to 5 hours [42]. Its half-life becomes prolonged as the concentration decreases, however, because it is eliminated by the reticuloendothelial system (RES). By 4 days, 90% of ancrod is cleared. As a foreign protein it is potentially antigenic, although to date antibody formation has not been reported in patients who have received the agent for CPB. Ancrod is not approved by the FDA and is available only by compassionate-use protocol.

Ancrod’s mechanism of action can be understood by comparing its effects on fibrinogen with those of IIa [42], as shown in Figure 2 [21]. Ancrod cleaves the A-fibrinopeptides, but not the B-fibrinopeptide, from fibrinogen [42]. The fibrin monomers generated following this selective cleavage form end-to-end, but not end-to-side, linkages. The end-to-end linked monomers form linear 1- to 2-micron fibrin polymers [42] that are removed from the circulation by plasmin-induced fibrinolysis and reticuloendothelial phagocytosis. To effect a reduction in fibrinogen concentration that is sufficient to permit CPB, ancrod should be infused over a 12-hour period so that the RES does not become overwhelmed with the products of fibrinolysis [21].



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  		Fig 2. Schematic comparison of the actions of ancrod and IIa on fibrinogen. (Redrawn from Zulys VJ, Teasdale SJ, Michel ER, et al. Ancrod (Arvin) as an alternative to heparin anticoagulation for cardiopulmonary bypass. Anesthesiology 1989;71:870–7.)

 
In contrast to ancrod, IIa cleaves both the A-fibrinopeptides and the B-fibrinopeptide from fibrinogen (Fig 2). The fibrin monomers generated by this double cleavage, through the catalytic action of XIIIa, become joined through end-to-end and end-to-side linkages that form a stable fibrin polymer lattice.

Ancrod-induced defibrinogenation not only prevents coagulation, but also decreases blood viscosity [42]. Thus, it may improve microcirculatory flow and flow to stenotic vascular beds. During CPB this effect may add to the viscosity-reducing effect of hemodilution in counteracting the viscosity-increasing effect of hypothermia.

Five case reports [22–26] and one study [21] have documented 33 patients, 11 of whom had HIT, who received ancrod for CPB. The manufacturer has collected data on 42 additional patients who received ancrod for CPB under a manufacturer-sponsored investigational protocol. To date those data have not been published.

In 1989 Zulys and coworkers [21] reported the use of ancrod for CPB in a pilot study of 20 patients undergoing elective CABG operations. Using an intravenous infusion of 1.65 ± 0.55 (mean ± SD) U/kg given over 13.3 ± 2.5 hours, these researchers reduced the fibrinogen concentration from 2.96 ± 0.47 g/L to a pre-CPB level of 0.41 ± 0.20 g/L. Hemodilution during CPB further reduced the fibrinogen concentration to 0.14 ± 0.10 g/L. The CPB time was 92 ± 17 minutes, during which no clots formed in either the operative field or the CPB circuit. No changes occurred in either the resistance to flow through the oxygenator or the efficiency of gas exchange. All patients survived their operations, and none had neurologic complications, wound infections, or delayed wound healing. Subsequently Zulys and coworkers [21] used ancrod successfully for CPB in 6 patients with HIT and in 2 with an allergy to protamine.

The postoperative blood loss for the pilot study patients who received ancrod was 2,286 ± 131 mL during the 37.6 ± 11.8 postoperative hours the chest tubes remained in place. One patient required reoperation to control bleeding. In a nonrandomized group of 20 age- and sex-matched patients on whom the authors performed elective CABG operations with UFH, postoperative blood loss was similar, 1,737 ± 973 ml, p = 0.15. However, the patients who received ancrod required significantly more intra- and postoperative transfusions of fresh frozen plasma, cryoprecipitate, packed red cells, and albumin than did the patients who received UFH [21].

Subsequently five groups of researchers reported the successful use of ancrod for CPB in 5 patients with HIT [22–26]. Each group administered doses of ancrod similar to the dose used by Zulys and coworkers [21] during a 12- to 24-hour period preceding the operation. They achieved pre-CPB fibrinogen concentrations that ranged between 0.15 and 0.45 g/L, and they performed serial measurements of intra- and postoperative fibrinogen concentrations. None of their patients developed clots during CPB and none had a postoperative neurologic complication. Spiess and coworkers [26] administered aprotinin during CPB initiated following ancrod-induced defibrinogenation, apparently without ill effects.

Zulys and coworkers [21] pointed out that ACT, prothrombin time (PT) and aPTT tests all depend on "... a mechanical endpoint, namely the conversion of fibrinogen into a thrombus, and are either extremely prolonged or infinite in the presence of hypofibrinogenemia" [21]. They and the other groups believe that CPB can be conducted safely if fibrinogen concentration is sufficiently reduced, and that ACT, PT, and aPTT measurements before and during CPB are not helpful.

Spiekermann and coworkers [24] performed four consecutive precannulation celite ACT determinations in their patient at a time when the fibrinogen concentration was 0.33 g/L. Each determination, performed in a Hemochron 801 test unit (International Technidyne, Edison, NJ), was normal—110 to 140 seconds. Because the surgeon also noted "loose clot" in the operative field, the researchers gave additional ancrod, 0.25 U/kg, which lowered the fibrinogen concentration to 0.18 g/L. The ACT still remained normal, although the PT and the aPTT each rose to over 200 seconds. The surgeon cannulated the patient and initiated CPB, whereupon the ACT rose immediately to more than 1,000 seconds. No clots formed during CPB. Based on their consultation with the Hemochron manufacturer, the researchers believe that ancrod-induced fibrin polymers may form a "loose thrombus" that is clinically insignificant, yet viscous enough to impede the rotating magnet of the test unit. They concluded that a "normal" ACT signaled by the device may be misleading in the presence of ancrod-induced hypofibrinogenemia.

Kanagasabay and coworkers [20] recently reported the combined use of ancrod and danaparoid for CPB in a 50-year-old woman who had HIT, and who underwent aortic valve replacement for fungal endocarditis. Despite lowering the patient’s fibrinogen concentration to 0.6 g/L with a slow ancrod infusion, these researchers identified clots in the aortic cannula and elsewhere in the operative field as they were about to initiate CPB. Like Spiekermann and coworkers [24], they found that the ACT was normal. They removed the cannula and lowered the fibrinogen concentration to 0.2 g/L with additional ancrod. When the surgeon continued to observe clots and the ACT remained normal, they gave a 3,750-U bolus of intravenous danaparoid and added an identical dose to the priming fluid. The surgeon observed no further clots, initiated CPB, and replaced the aortic valve. No intra- or postoperative complications occurred. The researchers attributed the clots to the action of "adhesive acute phase proteins (fibronectin, von Willebrand factor)" they believed were elevated because of the endocarditis. They suggested that danaparoid may enhance ancrod’s anticoagulant effect in a patient with HIT and ongoing sepsis who requires CPB [20].

For patients requiring emergency cardiac operations the time required for ancrod to produce adequate defibrinogenation safely makes this agent an unsuitable CPB anticoagulant. However, except for the patient reported by Kanagasabay and coworkers [20], ancrod used as a single agent has provided satisfactory CPB anticoagulation in all patients in whom its use for this purpose has been reported. It has not induced platelet aggregation or otherwise adversely affected platelet function.

Because ancrod’s action depends on plasmin, the concomitant administration of plasmin inhibitors such as epsilon-aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron) during ancrod infusion is contraindicated [42]. As already noted, however, Spiess and colleagues [26] reported that aprotinin can be given safely during CPB to a patient already defibrinogenated with ancrod.

r-Hirudin
The recombinantly produced hirudin protein (r-hirudin) is a 65-amino acid polypeptide that was originally isolated from the saliva of the medicinal leech, Hirudo medicinalis [43]. r-Hirudin has the same amino acid sequence as natural hirudin. However, the Tyr-63 residue of natural hirudin is sulfated, while the corresponding Tyr residue of r-hirudin is not [43]. Eliminated by the kidneys, r-hirudin’s half-life is between 30 and 60 minutes if renal function is normal [35]. As a foreign protein it is potentially antigenic, although no reports of antibody formation have appeared in patients who have received it for CPB.

Each molecule of r-hirudin has an identical structure. Hence, unlike UFH, the LMWHs, and danaparoid, r-hirudin does not have noncatalytic molecules or retained animal tissue components. Like the dermatan sulfate–HCII complex, r-hirudin cannot inhibit Xa but can inhibit fibrin-bound IIa [43]. Reversal of r-hirudin’s anticoagulant effect is not easily achieved. r-Hirudin (Refludan; Hoechst Marion Rousel, Frankfurt am Main, Germany) is approved by the FDA for anticoagulation in patients with HIT and associated thrombosis.

Four abstracts [27, 29–31], three case reports [28, 32, 35], one study [33], and one book chapter [34] have documented approximately 26 patients, each with a history of HIT, who received r-hirudin for CPB. Koster and coworkers [35] reported on 5 of those patients. Pötzsch, Riess, and their coworkers [27–34] reported on the other patients. The exact number of other patients is difficult to determine, because several patients appear in more than one of their reports.

In 1994 Pötzsch and coworkers [27] reported the first use of r-hirudin for CPB in a 29-year-old man undergoing a pulmonary thromboendarterectomy. Subsequently Riess, Pötzsch, and their coworkers [28–34] reported the use of r-hirudin for approximately 10 aortic valve replacements, approximately 8 primary isolated CABG operations, 1 redo CABG operation, and 1 CABG operation with concomitant repair of a postinfarction ventricular septal defect. They gave most of their patients pre-CPB doses of 0.25 mg/kg (range 0.16 to 0.93 mg/kg) and priming fluid doses of 0.20 mg/kg (range 0.10 to 0.46 mg/kg). Using a chromogenic IIa-based assay, the researchers assessed the adequacy of anticoagulation by monitoring the plasma concentration of free r-hirudin before and every 10 minutes during CPB. Along with each r-hirudin concentration measurement they measured ecarin clotting time (ECT), a recently described clot-based assay [58] that has been reported to reflect r-hirudin concentration [59]. To maintain the r-hirudin concentration above 2.0 µg/mL they gave additional 5.0- or 2.5-mg bolus doses as needed during CPB. Because of hirudin’s relatively short half-life, they did not administer a reversal agent to any patient following CPB. However, in 2 patients they reduced the r-hirudin concentration to approximately 2.0 µg/mL [27, 32] with hemofiltration shortly before discontinuing CPB. All patients survived their operations. No clots were observed in any patient during CPB, and no patient had a thromboembolic complication. Two patients required reoperation to control early postoperative bleeding, which in each case the researchers attributed to a surgical cause. Early postoperative ADP- and collagen-induced platelet aggregation studies showed that r-hirudin did not adversely affect platelet function.

Subsequently Koster and coworkers [35] reported the use of r-hirudin for five emergency operations: three isolated CABG operations, one redo CABG operation with a concomitant aortic valve replacement, and one isolated aortic valve replacement in a patient with acute endocarditis and alcoholic cirrhosis. These authors measured the ECT before and every 5 minutes during CPB. To assess the adequacy of anticoagulation, they relied on a calibration curve indicating that an ECT of approximately 400 seconds corresponded to an r-hirudin concentration of 4.0 µg/mL or more. Their pre-CPB and priming fluid doses of r-hirudin were similar to those recommended by Pötzsch and coworkers [29, 31]. During CPB, however, they infused r-hirudin continuously at an approximate rate of 0.5 mg/min, which they adjusted to maintain the ECT slightly above 400 seconds.

None of their 5 patients developed clots or thromboembolic complications during CPB [35]. Thus, their limited experience suggests that an ECT of longer than 400 seconds indicates adequate CPB anticoagulation. Their first 4 patients survived their operations and had unremarkable postoperative courses. The patient with endocarditis, who had been anticoagulated with danaparoid prior to undergoing aortic valve replacement, died 6 hours following his operation from excessive bleeding and multiple organ failure.

In a 1997 study Pötzsch and coworkers [59] showed that ECT reflects r-hirudin concentration during CPB more accurately than either ACT or aPTT. However, the simultaneous ECT and r-hirudin concentration measurements in 5 patients published in a book chapter by three of these authors [34] reveal considerable patient-to-patient variation in the r-hirudin concentration indicated by a given ECT. For example, in 3 different patients, r-hirudin concentrations of approximately 2.6, 2.7, and 2.8 µg/mL corresponded to ECTs of approximately 750, 330, and 60 seconds, respectively. Thus, despite the encouraging experience of Koster and coworkers [35], the usefulness of ECT to assess the adequacy of r-hirudin-induced CPB anticoagulation in a large group of patients remains to be demonstrated.

Table 3 summarizes the alternative CPB anticoagulants vis-a-vis their incidence of cross-reactivity with HIT antibodies, monitoring tests, methods of reversal, and approval by the FDA.


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  		Table 3. Comparison of Alternative CPB Anticoagulants

 

   Conclusion
Top
 Abstract
 Introduction
 Overview of cardiopulmonary...
 Unfractionated heparin
 Alternative anticoagulants
 Conclusion
Future studies of alternative...
 References
 
The use of alternative anticoagulants for human CPB constitutes an early phase of an ongoing investigation of CPB anticoagulation strategies. One or more of these strategies may ultimately replace UFH, which has several drawbacks [43, 49–52] besides its potential for inducing thrombocytopenia. However, to date no investigator has published a controlled study comparing any alternative anticoagulant with UFH for human CPB. For now, therefore, the alternative anticoagulants reviewed herein should be used for human CPB only in patients who cannot safely receive UFH.

Because of their potential for cross-reactivity with HIT antibodies [54], LMWHs should probably not be used for CPB in patients with HIT. However, the published clinical experience with danaparoid, ancrod, and r-hirudin does not indicate which of these alternatives, if any, should be used for CPB in these patients. The best CPB anticoagulant for an individual patient with HIT depends on the knowledge and the experience of that patient’s surgeon, anesthesiologist, and consulting hematologist. Cooperation and communication among these three physicians is necessary for the successful use of any alternative CPB anticoagulant. For some patients with HIT, especially those whose operations can be postponed until their antibody titers become low or undetectable, UFH may be the safest CPB anticoagulant. A patient with a history of HIT who receives UFH for CPB should not receive UFH for any other purpose, such as for purging intravascular catheters.


   Future studies of alternative cardiopulmonary bypass anticoagulants
Top
 Abstract
 Introduction
 Overview of cardiopulmonary...
 Unfractionated heparin
 Alternative anticoagulants
 Conclusion
 Future studies of alternative...
References
 
No alternative anticoagulant has been studied extensively in any animal model of CPB. In fact, two of the alternative anticoagulants—nadroparin and dalteparin—were not used for CPB in a published animal study before they were used for CPB in humans. The others were used for CPB or for extracorporeal membrane oxygenation in only one [60–62], two [63, 64], or three [65–70] published animal studies before they were used for human CPB. More in-depth studies of these alternatives in animal models of CPB may help to determine their suitability—or lack thereof—for human CPB.

Alternative anticoagulants that have been used for CPB in animals but not in humans include the aforementioned dermatan sulfate in pigs [52] and a thrombin aptamer in dogs [71]. Recombinant tick anticoagulant peptide [72] and Vasoflux [73, 74] have been used to anticoagulate human blood circulating through an in vitro extracorporeal circuit, but have not been used for CPB. Other newly available anticoagulants, such as pentasaccharide (SR90107/ORG31540), recombinant nematode anticoagulant peptide, antitissue factor antibodies, active site inhibited factor VIIa, and recombinant tissue factor pathway inhibitor await evaluation in animal models of CPB.


   References
Top
 Abstract
 Introduction
 Overview of cardiopulmonary...
 Unfractionated heparin
 Alternative anticoagulants
 Conclusion
 Future studies of alternative...
 References
 

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