Ann Thorac Surg 2010;89:324-331. doi:10.1016/j.athoracsur.2009.10.043
© 2010 The Society of Thoracic Surgeons
Reviews
Managing Fibrinolysis Without Aprotinin
L. Henry Edmunds, Jr, MD*
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
* Address correspondence to Dr Edmunds, Department of Surgery, University of Pennsylvania School of Medicine, 3440 Market St, Suite 306, Philadelphia, PA 19104-3325 (Email: hank.edmunds{at}uphs.upenn.edu).
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Abstract
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Cardiopulmonary bypass increases perioperative bleeding and produces a consumptive coagulopathy, which is defined as the simultaneous production of thrombin and fibrinolysis. Thrombin formation and fibrinolysis primarily occur in the surgical wound and peak at the time heparin is reversed by protamine. Neither aprotinin nor lysine analogs successfully control bleeding in many complex procedures, reoperations, aortic resections, or in implantations of mechanical circulatory devices. This analysis reviews the mechanisms involved and current treatment protocols, with the conclusion that changes in treatment protocols rather than use of a specific anti-fibrinolytic drug may provide better control of bleeding in these patients.
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Introduction
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Bidstrup and colleagues [1] introduced aprotinin to cardiac surgery in 1989 by showing that very high doses of the drug, commonly known as Trasylol, dramatically reduced perioperative bleeding in patients who had initial operations for coronary artery bypass. Use of this drug expanded both rapidly and widely. Many surgeons became convinced of the superiority of this nonspecific serine protease inhibitor of plasmin in comparison with the synthetic lysine analogs, 
-aminocaproic acid (EACA) and tranexamic acid (TA). EACA was introduced to cardiac surgery in 1962 [2] and was shown to be effective [3]. Aprotinin was aggressively marketed, but as its use spread, concerns regarding renal toxicity [4, 5] and safety issues [6] surfaced, and the superiority of the drug over lysine analogs became vigorously debated. In the fall of 2007, a randomized, controlled trial, BART, designed to settle efficacy issues, was abruptly stopped by the trial Data Safety Monitoring Board [7]. On November 5, 2007, the Food and Drug Administration ordered Bayer Healthcare Pharmaceuticals to stop marketing aprotinin in the United States.
This review addresses the pathophysiology of bleeding associated with use of cardiopulmonary bypass (CPB) and other applications of extracorporeal circulation and re-evaluates the efficacy and protocols for using lysine analogs to control bleeding complications associated with complex and reoperative cardiac surgery, thoracic aortic surgery, and applications of mechanical circulatory assist devices. The efficacy of both aprotinin and the lysine analogs to reduce bleeding in low-risk cardiac operations has been repeatedly demonstrated [5, 8–10], but these operations are rarely associated with massive perioperative bleeding. However, neither aprotinin nor the lysine analogs are consistently effective in more complex operations. Mechanisms and consequences of thrombin formation and platelet activation during extracorporeal circulation have been previously published, and relevant information is summarized, but not repeated, in this review [11].
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Material and Methods
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This review is largely based on more than 3.5 decades of active research on reactions of heparinized blood within extracorporeal circulatory systems and the surgical wound with close collaboration of two highly respected hematologists. It has been supplemented by multiple selected articles, chapters, and reviews written by others and ourselves during this time period and by recent specific internet searches using a variety of key words, such as lysine analogs, d-dimer, thrombin, and platelets combined with cardiac surgery and extracorporeal perfusion. This review is intentionally focused and can not be considered comprehensive.
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Pathogenesis of Bleeding Associated with Cardiopulmonary Bypass
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Blood contact with nonendothelial cell surfaces initiates clotting by generation of thrombin. The endothelial cell is the only known nonthrombogenic surface and maintains the fluidity of blood and the integrity of the vascular network by inducing and producing both anti-coagulants and pro-coagulants [11, 12]. No known synthetic surface or coating is nonthrombogenic; all initiate thrombin formation [13, 14]. Claims of superiority of one commercial product in comparison with another are spurious and unproven [14]. Thus, an anticoagulant is required for extracorporeal circulation. Standard, unfractionated heparin is almost exclusively used, but it is not entirely satisfactory [11].
The enzyme prothrombinase cleaves prothrombin into 
-thrombin and a fragment produced by cleavage of prothrombin to -thrombin (F1.2), which serves as a measurable marker of thrombin generation. The principal action of thrombin is to cleave fibrinogen into fibrin at sites of vascular injury in conjunction with activated platelets and other enzymes. Multiple pathways initiate thrombin generation [see Fig 1 in Ref. 11], but the enzyme normally does not circulate due to rapid inactivation by super-abundant (140 µg/mL) antithrombin [15]. The normal half-life of thrombin in blood is approximately 30 seconds. However, during CPB and other applications of extracorporeal circulation (eg, ventricular assist devices, extracorporeal membrane oxygenation, dialysis), thrombin is generated continuously and likely circulates in varying amounts despite large doses of heparin [13, 16–18]. Boisclair and colleagues [19] and Chandler and Velan [20] showed that initiation of CPB produces a modest increase in F1.2, which continues to increase gradually until release of the aortic cross clamp (Fig 1A). F1.2 increases sharply thereafter; peaks with the administration of protamine; and remains elevated long after CPB ends [19–21]. Heparin accelerates inactivation of thrombin by antithrombin 1,000-fold, but the drug does not inhibit thrombin within fibrin clots [22]. Direct thrombin inhibitors (ie, bivalirudin, lepirudin, and argatroban) do inhibit thrombin in clots [22], but for a variety of reasons (eg, monitoring, lack of antidote, cost, toxicity, safety) these drugs have not displaced standard heparin in applications of extracorporeal circulation.
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Fig 1. (A) Serial measurements of prothrombin fragment, F1.2, during cardiopulmonary bypass. (ECC = duration of cardiopulmonary bypass; H = heparin injection; P = protamine administration; S = duration of operation.) (Reprinted from Boisclair MD, Lane DA, Philippou H. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993;82:3350–7 [17], with permission. © The American Society of Hematology.) (B) Ten serial measurements of d-dimer during cardiac surgery with cardiopulmonary bypass (CPB) (black bar). Protamine was given at sample 9; sample 10 was taken two hours later. (Reprinted from Chandler WL, Valen T. Plasmin generation and d-dimer formation during cardiopulmonary bypass. Blood Coag Fibroly 2004;15:583–91 [26], with permission.)
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Normally thrombin generation stimulates small vessel endothelial cells at sites of injury to produce tissue-type plasminogen activator, which binds fibrin with high affinity and the zymogen, plasminogen with high specificity [23, 24]. This dual coupling greatly accelerates plasmin formation and lysis of fibrin and serves to maintain blood flow past sites of injury. D-dimer, a useful marker of fibrinolysis, is one of several protein fragments produced by plasmin. During CPB tissue plasminogen activator increases by a factor of 6 and progressively increases for the remainder of bypass and for 2 hours after CPB ends [25]. The inhibitor protein, plasminogen activator inhibitor 1, however, does not increase until the end of cardiopulmonary bypass; thus active tissue plasminogen activator increases rapidly during CPB and begins to fall with the release of the aortic cross clamp [25]. D-dimer concentrations, which reflect fibrinolysis, increase modestly after CPB starts; gradually increase until release of the aortic cross clamp; and then accelerate to peak with the administration of protamine (Fig 1B). D-dimer remains greatly increased in comparison to baseline several hours after CPB ends [19, 26]. Circulating plasmin is normally inactivated by -2 antiplasminm and to a lesser extent -2 macroglobulin.
Ongoing thrombin production and fibrinolysis during extracorporeal circulation (ECC) transforms a complex system designed for local hemostasis into an iatrogenic, systemic, consumptive coagulopathy. Both F1.2 and d-dimer progressively increase during CPB and peak with the administration of protamine [16, 17, 20, 26, 27]. The simultaneous generation of thrombin and plasmin is the definition of a consumptive coagulopathy [28]. This life-threatening process is associated with diffuse intravascular coagulation, which is most commonly observed in patients with overwhelming septicemia or in patients who have suffered massive trauma and require multiple transfusions of blood products. Consumptive coagulopathy occurs in all applications of ECC, but the severity of the pathologic process varies widely between patients. Surface area of nonendothelial cell surfaces, duration of ECC, amounts of blood exposed to the wound, heparin resistance, cachexia, hypothermia, infection, and liver disease are among the variables that affect the magnitude of the consumptive coagulopathy [11].
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Primary Sources of Thrombin and Plasmin
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During cardiac surgery using CPB, thrombin is primarily generated in the surgical wound [29] (Fig 2A); the amount generated through the activation of contact proteins by nonendothelial cell surfaces is relatively very small [30]. Wound thrombin is initiated by the tissue factor (TF) pathway, which involves two forms of TF: (1) cell bound and (2) soluble [11]. Cell bound TF does not circulate, but it is expressed by most wound cells [31]. Cell bound TF combines with plasma factor VII to form the factor VIIa-TF complex, which activates factors IX and X and the remainder of the coagulation cascade. Plasma (soluble) TF normally circulates in 1 to 3 picomolar concentrations, but is increased two to three times during cardiopulmonary bypass [32, 33] and is likely to be elevated in other applications of ECC. Soluble TF is increased in a wide range of inflammatory diseases, including acute coronary syndromes, trauma, diffuse intravascular coagulation, and some cancers [34, 35]. Plasma TF requires a phospholipid surface (preferably activated monocytes) to activate factor VII [33, 35]. To a lesser extent, platelet and microparticle surfaces also assemble the FVIIa/TF complex [36]. However, the monocyte–plasma TF pathway is highly correlated (r = 0.944) with generation of wound F1.2, and this is the major site of thrombin generation during cardiac surgery with CPB [33].
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Fig 2. (A) Concentrations of F1.2, taken from the perfusion circuit during cardiac surgery. Thirty to 45 minutes after beginning cardiopulmonary bypass (CPB), simultaneous samples were drawn from the pericardial well surrounding the heart (PERC) and the circuit (PERF). (HEP = heparin injection; POST = immediately after CPB stopped; PROT at the time of protamine administration.) (Reprinted from Chung JH, Gikakis N, Drake TA, Colman RW, Edmunds LH Jr. Pericardial blood activates the extrinsic coagulation pathway during clinical cardiopulmonary bypass. Circulation 1996;93:2014–2018 [29], with permission.) (B) Simultaneous measurements of fibrinogen degradation products (FgDP), fibrin degradation products (FbDP), and tissue-type plasminogen activating factor drawn from the perfusion circuit (black bars) and from the wound (gray bars). (Reprinted from Tabuchi N, Haan J, Boonstra PW, van Oeveren W. Activation of fibrinolysis in the pericardial cavity during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;106:828–33 [37], with permission.)
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The wound is also the site of extensive fibrinolysis (Fig 2B) [37]. In a study of 6 patients who had primary coronary arterial bypass, Tabuchi and colleagues [38] found 23.5 times more fibrin split products in the wound than what appeared in simultaneous samples of perfusate. High concentrations of fibrin and fibrinogen degradation products are present in blood shed after wound closure [39]. Axford and colleagues [40] found that d-dimer levels in collected mediastinal blood exceeded 2 µg/mL as compared with less than 0.5 µg/mL in stored autologous or homologous blood.
Although both thrombin and plasmin are generated in the perfusion circuit during CPB, the wound is the primary site of both thrombin formation and fibrinolysis. The importance of the surgical wound in the pathogenesis of the consumptive coagulopathy offers novel opportunities to diminish and perhaps prevent the bleeding diathesis associated with complex cardiac surgery and use of mechanical circulatory assist devices.
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The Bleeding Problem in Contemporary Cardiac Surgery
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In the majority of patients who have cardiac surgery with CPB, native platelets, procoagulants, and plasma inhibitors are sufficient to sustain wound clotting after heparin is neutralized by protamine. Nevertheless, CPB increases postoperative wound bleeding and the need for transfusion of blood products. In a randomized, controlled trial of 200 patients who had first time coronary artery revascularization, wound drainage from the time of closure until removal of drainage tubes averaged 943 ± 105 mL when CPB was used versus 687 ± 66 mL when CPB was not used (p < 0.05) [41]. Transfusion requirements of blood products were significantly greater in the CPB group (p < 0.05), and 5 patients required reoperations for nonsurgical bleeding in the CPB group versus none for those not exposed to CPB [41]. The findings of a meta-analysis of 52 trials comparing antifibrinolytic drugs versus placebo in patients who had cardiac surgery using CPB revealed that mean blood losses in control (placebo) patients ranged from 750 mL to 1250 mL postoperatively [10]. The number of units of homologous packed red cells transfused in placebo groups ranged from 1.5 to 2.2 units.
Reoperations, complex procedures, and many aortic operations with or without deep hypothermia are associated with increased postoperative bleeding [42–44]. Mehta and colleagues [44] reviewed 528,279 patients who had first time coronary arterial revascularization and found that 2.4% required reoperation to control bleeding. The percentages of reoperative patients who received red cell and platelet transfusions were 93.2% and 74.8%, respectively, as compared with 53.0% and 20.7% of those who did not return to the operating room [44]. Mean blood losses after operations on the thoracic aorta ranged from 612 mL to 2114 mL in 24 hours in five studies of a total of 536 patients [45–49]. In four studies of 1,070 patients, 5.6% to 14.7% were returned to the operating room to control bleeding [48, 50–52]. Transfusions of red cell units, fresh frozen plasma units, and platelet packs in these aortic operations ranged from 1.2 to 3.9, 1.7 to 11.7, and 0.2 to 9.2, respectively [45–47, 50, 53–55].
Bleeding is a major adverse event both at the time of implantation of a ventricular assist device [56–59] and also afterward. The consumptive coagulopathy continues for the entire duration of mechanical circulatory support, irrespective of anticoagulation schema [18]. After implantation of a device, the incidence for early return to the operating room to control bleeding ranges from 32% to 36% [56–59]. Often the initial wound is packed with gauze and closed 1 or more days later when excessive bleeding has stopped. During the period of mechanical circulatory assistance, bleeding, infection, and to a lesser extent thromboemboli, are the most common, major adverse events [57, 59–61].
These data document the ineffectiveness of contemporary measures to control bleeding after heparin is neutralized by protamine. Studies by Engoren and colleagues [62] and Koch and colleagues [63] have shown that patients who received transfusions at the time of heart surgery have a reduced life expectancy as compared with those who did not require transfusions [62, 63].
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Contemporary Measures to Control Bleeding in Patients Requiring Complex Cardiac Surgery or Ventricular Assist Devices
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Standard laboratory tests in the operating room include the activated clotting time to monitor heparin dosage, prothrombin time, and activated partial thromboplastin time. The latter tests reflect the initiation phase of thrombin generation, which accounts for approximately 5% of total thrombin formation and are not relevant to the propagation phase [64]. Blood samples are often sent for platelet counts and occasionally fibrinogen concentrations, but a severe deficit in coagulation factors or fibrinogen is seldom related to the bleeding problem. Platelet concentrates are prescribed for bleeding patients if counts are less than 100,000/µL, and fresh frozen plasma is prescribed for bleeding patients if either prothrombin time or activated partial thromboplastin time is abnormal [65]. However, in practice, if the patient has diffuse nonsurgical bleeding, platelets and fresh frozen plasma are given regardless of laboratory data. In addition, topical sealants are used, and cryoprecipitate is sometimes given empirically.
More recently, NovoSeven (recombinant factor VIIa) (Novo Nordisk A/S, Bagsverd, Denmark) has been used "off label" to control severe, persistent bleeding after cardiac surgery that can not be controlled by conventional measures [66–68]. A bolus dose (90 µg/kg) acutely increases plasma factor VIIa from 1% of factor VII to approximately 15% [69]. A randomized trial of 172 patients treated with a placebo or 40 or 80 µg/kg recombinant activated factor VII (rFVIIa) showed that significantly fewer patients required reoperations or allogeneic transfusions in the two rFVIIa treatment groups. The observed number of severe adverse events was higher in the treatment groups, but did not reach statistical significance, perhaps because the study was underpowered. Adverse thrombotic events have been reported [68, 70], and the drug probably should not be used in patients who require sustained mechanical assistance [71].
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Anti-Fibrinolytic Synthetic Lysine Analogs
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The two synthetic lysine analogs have an identical mechanism of action [72], but differ in potency. The drugs have no substantial differences in clinical efficacy, renal clearance, or costs. Tranexamic acid is approximately 10 times more potent than EACA. Both drugs have a half-life in plasma of approximately 2 hours [73, 74]. Approximately 75% of both drugs are excreted by the kidneys and the rate of clearance is approximately that of creatinine [73, 74]. The toxicity of both drugs is considered low; however, a recent single, retrospective study found a higher incidence of seizures and atrial fibrillation associated with high doses of TA (> 4 g) [75]. Previous experience has not reported these complications, but concerns have been raised regarding possible renal toxicity in patients who undergo CPB [5], which is also associated with renal injury independent of either drug.
Although neither drug is advised for patients with severe renal dysfunction, Stafford-Smith has shown that total doses of EACA (15 gm) does not disproportionately affect postoperative renal clearance during cardiac surgery with CPB in patients with normal renal function (plasma creatinine < 133 µmol/L) or in patients with moderate elevations above 133 µmol/L and who are not considered high risks for postoperative renal failure [76]. EACA may produce a microglobulinuria due to a nonharmful, reversible, blocking effect on the renal tubular reuptake system, but the 1 and β2 microglobulinuria is not indicative of renal dysfunction or injury [77]. Intravascular thrombosis of fresh coronary artery bypass grafts does not increase after administration of anti-fibrinolytic agents [78].
EACA has been widely used in total doses up to 30 gm [79], but in a retrospective study of 774 cardiac surgical patients, Lambert and colleagues [3] reported administering up to 60 g of EACA within 1 hour "without adverse sequelae" to 159 cardiac surgical patients in which "excessive hemorrhage because of hyperfibrinolytic activity" developed. Lambert and colleagues [3] further stated that "Amicar [EACA] in doses up to 90 gm within a two hour period have been employed, without demonstrable ill effects." According to Horrow and colleagues [80] and Fiechtner and colleagues [81], some patients have received up to 20 g of tranexamic during cardiac surgery with CPB. Unfortunately the literature fails to establish dosage toxicity limits of lysine analogs with and without CPB.
Horrow and colleagues [80] studied dosing schedules for TA and recommends 10 mg/kg TA for 30 minutes after anesthesia before skin incision followed by 1 mg/kg/hr for 12 hours (total,1.54 g/70 kg) [80]. Higher doses do not reduce d-dimer levels measured in fibrinogen equivalent units nor further reduce blood losses. According to Fiechtner and colleagues [81], the in vitro concentration of TA to inhibit fibrinolysis is 10 µg/mL [81]. Using the dosing protocol recommended by Horrow and colleagues [80], Fiedhtner found that TA concentrations ranged between two and three times the in vitro inhibitory concentration during and for one hour after clinical CPB [81].
Daily used a total dose of 30 gm EACA in a randomized controlled trial [79] of 40 patients who had first time cardiac revascularization as follows: 10 gm in 40 mL of saline intravenously after anesthesia before incision; 10 gm in the pump prime after heparin; and 10 g in 40 mL intravenously after protamine. Greilich and colleagues [8] infused a loading dose of 100 mg/kg EACA over 15 minutes after full heparinization, added 5 g to the pump prime, and infused 30 mg/kg/hr until reaching the intensive care unit (total, 20.4 gm/70 kg) [8]. Plasma EACA concentrations measured in 14 patients were all greater than 260 µg/mL at the time protamine was given, and > 130 µg/mL 4 hours after CPB ended [8]. Using an approximately similar total dose and dosing protocol Bennett-Guerrero found that mean plasma EACA concentrations during CPB in 27 unselected patients were 593 µg/mL at baseline and between 302 µg/mL to 317 µg/mL during CPB [82]. All measurements remained above the effective in vitro inhibitory concentration of 130 µg/mL, but measurements between patients varied by a factor of six.
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Suppression of Fibrinolysis in the Wound
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In 1993, Tatar and colleagues [83] recommended using topical aprotinin to reduce wound fibrinolysis. Fifty elective patients undergoing coronary artery bypass grafting surgery were randomly assigned to receive saline or 1 million KIU aprotinin in 100 mL saline poured into the surgical wound immediately before closure. Drainage tubes were clamped during wound closure in the experimental group and then opened to gravity drainage. Chest drainage within the first 24-hour period was 650 ± 225 mL in the control group and 420 ± 150 mL in the aprotinin group (p < 0.05). Total wound drainage was 1,283 ± 226 and 723 ± 231 mL (p < 0.01), respectfully. Subsequently, De Bonis and colleagues [84] found that 1 g of TA poured into the wound at closure significantly reduced blood loss in a randomized controlled trial of patients having primary coronary arterial bypass [84]. Two hours after CPB ended, no TA could be detected in the circulation. A meta-analysis of seven trials (525 first-time cardiac operations) concluded that topical TA or aprotinin significantly reduced 24-hour blood drainage by 222 and 220 mL, respectively [85].
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Considerations
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Current dosing protocols of the lysine analogs are "front loaded." During the pump run surgeons are not generally concerned regarding the rise of F1.2 or d-dimer; blood is anticoagulated and shed blood is routinely aspirated, washed, and conserved during complex operations. After release of the aortic cross clamp, rates of F1.2 and d-dimer formation increase to peak at the time protamine is given [19, 20, 26] (Figs 1A and 1B). Logic supports the idea of synchronizing efforts to inhibit fibrinolysis by addressing both the location and timing of plasmin formation and activity (Table 1). "Back loading" EACA or TA dosing is not a new idea; in 1962, Gans wrote "Since maximum plasminogen activator activity is observed at the end of cardiac bypass ... , EACA is presently no longer given preoperatively. Instead it is administered at the end of cardiac bypass" [2].
Onsite serial measurements of d-dimer using a point-of-care device may facilitate efforts to suppress fibrinolysis with EACA during complex cardiac surgery [86], even though the protein fragment is not specific for EACA effectiveness and is subject to error. Qualitative serial measurements may or may not prove helpful in regulating EACA dosage in the immediate, post-protamine period. However, since the fibrinolytic process continues [87] in the wound for hours after the operation (there is no other logical site for plasmin formation), EACA inhibition of fibrinolysis should continue as long as bleeding is a problem and routinely as long as 12 hours after protamine. Parolari and colleagues [21] observed that plasma d-dimer and F1.2 remain above baseline levels up to 1 month after cardiac surgery with CPB [21].
Other, procoagulant topical agents, such as recombinant factor VIIa, should also be evaluated and considered; however, safety considerations mandate simultaneous systemic measurements of thrombin generation (eg, F1.2) or drug to estimate amounts absorbed into the circulation. TA is not absorbed [84]; there are no data regarding absorption of EACA or other topical agents.
Theoretically, the use of a cell saver and both topical and systemic administration of an antifibrinolytic drug, combined with complete suppression of circulating thrombin by a direct thrombin inhibitor, such as bivalirudin, may greatly diminish or suppress the consumptive coagulopathy associated with CPB. In a pilot study of 10 patients, who had primary coronary arterial bypass, Koster and colleagues [88] provided "proof of concept." Using bivalirudin anticoagulation, Koster and colleagues evaluated use or nonuse of a cell saver and found no increase in plasma F1.2, thrombin-antithrombin complex, or d-dimer above baseline levels after CPB when a cell saver was used [11, 88] (Table 2).
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Conclusion
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A mechanistic approach to the management of consumptive coagulopathy in patients with complex cardiac surgery, reoperations, aortic surgery, and implantation of mechanical circulatory devices offers a means to control the excessive bleeding associated with these operations. Revision of protocols for administering synthetic lysine inhibitors based on the pathogenesis of thrombin and plasmin formation during and after applications of extracorporeal circulation may well be more important than the choice of an antifibrinolytic drug.
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Acknowledgments
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The author thanks Dr John Hammon for managing the blinded peer review of this article.
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Abstract
Introduction
