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Ann Thorac Surg 2001;72:S1814-S1820
© 2001 The Society of Thoracic Surgeons

Supplement: Mechanisms and attenuation of abnormalities in hemostasis/inflammation and neurologic injury: implications for patient outcomes

Pharmacologic preservation of the hemostatic system during cardiac surgery

Jerrold H. Levy, MD*a

a Division of Cardiothoracic Anesthesiology and Critical Care, Emory University School of Medicine, Emory Healthcare, Atlanta, Georgia, USA

* Address reprint requests to Dr Levy, Department of Anesthesiology, Emory University Hospital, 1364 Clifton Rd, NE, Atlanta, GA 30322, USA
e-mail: jerrold_levy{at}emoryhealthcare.org

Presented at Mechanisms and Attenuation of Abnormalities in Hemostasis/Inflammation and Neurologic Injury: Implications for Patient Outcomes, Vancouver, BC, Canada, May 6, 2001.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Anticoagulation strategies
 Summary
 References
 
Bleeding after cardiac surgery remains a major potential problem. Numerous pharmacologic approaches to attenuating hemostatic system activation in cardiac surgery patients have been studied to further improve patient management. Therapeutic approaches studied include inhibiting thrombin generation or activation, preserving platelet function, and decreasing the need for transfusion of allogeneic blood products. Pharmacologic approaches to reduce bleeding and transfusion requirements in cardiac surgery patients are based on either preventing or reversing the defects associated with the CPB-induced coagulopathy. The increasing use of platelet inhibitors (clopidogrel and IIb/IIIa receptor antagonists) and new anticoagulants (low–molecular weight heparins, pentasaccharide, recombinant hirudin, bivalirudin, and argatroban) also pose interesting problems in managing cardiac surgery patients. Aprotinin and lysine analogues ({epsilon}-aminocaproic acid and tranexamic acid) have become mainstay therapeutic agents to prevent bleeding and the potential need for allogeneic transfusion. Newer therapies that are important to consider include the potential of recombinant activated factor VIIa as a therapy for refractory bleeding after cardiac surgery.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Anticoagulation strategies
 Summary
 References
 
Cardiopulmonary bypass (CPB) can alter normal hemostatic balance and predispose patients to the risk of excessive postoperative bleeding [1]. In addition to the effects of hypothermia and hemodilution, activation of the coagulation, fibrinolytic, and inflammatory pathways all contribute to postoperative bleeding and other potential complications [2–5]. As part of humoral amplification pathways, the hemostatic system is activated by means of multiple pathways [2–5]. Attention has focused primarily on interaction of blood with the foreign, nonendothelialized surface of the bypass circuit, resulting in factor XII activation and amplification of contact activation of the intrinsic pathway. However, activation of the extrinsic pathway secondary to surgery tissue trauma, release of tissue factor, and generation of factor VIIa is now recognized also to be an important cause of hemostatic activation. The endpoint of both pathways is the generation of thrombin, a pivotal enzyme in the control of hemostasis. Thrombin not only converts fibrinogen to fibrin but also acts on platelets, inflammatory cells, and endothelium to modulate both hemostasis and inflammation. Platelet dysfunction is thought to be a major mechanism of bypass-related bleeding, although the pathophysiology of the platelet defect is still poorly understood and remains the subject of investigation. Additional factors may relate to the use of heparin and protamine [5–10].

Numerous pharmacologic approaches to attenuating hemostatic system activation, preserving platelet function, and decreasing the need for transfusion of allogeneic blood products have been used and are under evaluation, as shown in Tables 1 and 2. Strategies that clinicians can develop to reduce bleeding and transfusion requirements include recognizing risk factors, developing transfusion practices, conserving red cells, new alternatives to red blood cells, and altering inflammatory responses and potentially improving anticoagulation/reversal. Pharmacologic approaches to reduce bleeding and transfusion requirements in cardiac surgery patients are based on either preventing or reversing the defects associated with CPB-induced coagulopathy. Furthermore, the use of new anticoagulants and platelet inhibitors also may potentiate bleeding. Other novel pharmacologic therapies and considerations will be reviewed.


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  		Table 1. Novel Anticoagulant Agents Affecting the Hemostatic System

 

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  		Table 2. Agents That Improve Hemostatic Function in the Bleeding Patient

 

   Anticoagulation strategies
Top
 Footnotes
 Abstract
 Introduction
 Anticoagulation strategies
Summary
 References
 
Antithrombotic therapy is based on inhibiting thrombus formation due to both thrombin activation and platelet activation [2–5]. Thrombin formation exhibits major procoagulant effects by generating fibrin from soluble fibrinogen, activating factors V and VIII, and activating platelets. Activated platelets adhere to injured vascular endothelia, express IIb/IIIa receptors, aggregate, and contribute to further generation of thrombin [6, 7]. Because of the complex humoral amplification system linking both hemostatic and inflammatory responses, there are multiple pathways to generate thrombin and prothrombotic effects [8–10]. Furthermore, during cardiac surgery, blood interfacing with large nonendothelial circuits of the extracorporeal system provides multiple mechanisms for thrombin generation. Understanding the final common pathway is important when developing therapeutic agents to attenuate the pathologic procoagulant effects. Despite the ability of different antithrombins to suppress thrombin activity, the ability of platelets to be activated and other hemostatic activation pathways has limited the effectiveness of intravenous antithrombins.

Heparin
Heparin, isolated from either porcine intestine or from bovine lung as an unfractionated array of different molecules, is the most commonly used anticoagulant to prevent clotting during cardiac or vascular surgery [11–13]. Heparin is an acidic polysaccharide with side groups, either sulfates or N-acetyl groups, attached to individual sugar groups. Heparin acts indirectly as an anticoagulant by binding to antithrombin III (AT III) enhancing the rate of thrombin–AT III complex formation by 1,000 to 10,000 times. Several other steps in coagulation cascade, including clotting factor X are also inhibited to a lesser degree by AT III [13]. Anticoagulation thus depends on the presence of adequate amounts of circulating AT III. The advantage of this is that heparin anticoagulation can be re versed immediately by removing heparin from AT III with protamine. Heparin also binds to a number of other blood and endothelial proteins including high molecular weight kininogen, von Willebrand factor, plasminogen, fibronectin, lipoproteins, and platelet and endothelial receptors. Heparin can also produce platelet dysfunction after acute or constant administration, especially with high dose administration during cardiac surgery. Despotis and colleagues [14, 15] reported that the maintenance of patient-specific heparin concentrations during cardiopulmonary bypass (CPB) was associated with more effective suppression of hemostatic activation. Furthermore, Mochizuki and colleagues [16] have shown that excess protamine can further alter coagulation and coagulation tests, and the careful exact titrated reversal of heparin avoiding excess protamine may be an important contribution to prevent coagulopathy.

Low–molecular weight heparin
Low–molecular weight heparin (LMWH) is formed by depolymerization of unfractionated heparin producing fragments with a mean molecular weight of approximately 5000 Da [17–19]. A pentasaccharide sequence is required for attachment of a heparin fragment to antithrombin, and an additional 13 saccharide residues are necessary to allow the heparin fragment to simultaneously attach itself to the heparin-binding domain of thrombin [17–19]. Low–molecular weight heparin fragments of less than 18 saccharides retain the critical pentasaccharide sequence required for formation of a Xa:antithrombin complex; LMWH inhibits both factor Xa and thrombin, but the ratio of factor Xa:thrombin is increased [17–19]. The LMWHs have been suggested to provide a therapeutic benefit because factor Xa generation occurs several steps earlier in the coagulation cascade than thrombin generation, inhibition of Xa has a profound effect on the later steps in coagulation. The use of LMWH is rapidly growing and evolving in cardiovascular medicine because of the long half-life and ease of dosing, yet it may pose a potential problem for surgery patients because commonly used hemostatic tests are not affected by LMWH. Furthermore, because these agents are not readily reversible with protamine, they are not suitable anticoagulants for CPB.

Heparin reversal
Heparin’s advantage as an anticoagulant consists of its rapid offset of action upon administration of a neutralizing agent. Protamine, the only clinically available neutralizing agent, is a basic polypeptide isolated from salmon sperm. Comprised mostly of arginine, protamine reverses heparin by a nonspecific acid–base interaction (polyanionic–polycationic) [20]. Neutralization by protamine is immediate; it is the only drug that is widely available for clinical use. A spectrum of adverse reactions to protamine ranging from minimal cardiovascular effects to life-threatening cardiovascular collapse have been reported; however, life-threatening reactions to protamine probably represent true anaphylactic reactions, mediated by immunospecific antibodies [21]. In insulin dependent diabetics who were also receiving neutral protamine Hagedorn insulin preparations, Levy and colleagues [22, 23] reported the incidence of life-threatening reactions in cardiac surgery patients following protamine administration NPH ranges from 0.6% to 2%. Life-threatening reactions to protamine represent true allergic reactions. Unfortunately, despite clinical trials with recombinant platelet factor 4, a peptide normally found in platelets, and heparinase, an enzyme that degrades heparin into biologically inert fragments, no alternatives are currently available for the patient with a protamine allergy [24–26].

Antithrombin III
Despite high-dose heparin for patients undergoing cardiac surgery, thrombin generation and activity continues during cardiopulmonary bypass (CPB). Antithrombin levels, which are lower in patients receiving heparin before the procedure, and decrease further by 40% to 50% after initiation of CPB, may be critical in determining the extent of thrombin inhibition [27]. Despotis and colleagues have suggested that better anticoagulation during CPB may be associated with less bleeding postprocedure, presumably related to preservation of critical coagulation components [15]. One promising therapy currently under investigation is the use of purified antithrombin III (AT III or AT) [28–31]. Supplemental AT, through improved heparin sensitivity and enhanced anticoagulation, may preserve hemostasis during CPB [14, 15]. Because maintaining normal or elevated plasma AT levels during cardiopulmonary bypass could potentially improve thrombin inhibition, we have investigated the role of increasing doses of AT from transgenic recombinant sources as a potential source of AT. Currently, there is a shortage of AT available for clinical use and for the potential treatment of heparin resistance.

New anticoagulants
New intravenous antithrombins currently available are listed in Table 1 [2–5, 32–39]. Thrombin may be inhibited with direct thrombin inhibitors (r-hirudin, bivalirudin, argatroban), AT-dependent inhibitors such as unfractionated heparin, low–molecular weight heparins, pentasaccharide, and warfarin. Currently available direct thrombin inhibitors include recombinant hirudin (Refludan), bivalirudin (Hirulog), and argatroban, which inhibit fibrin-bound thrombin independent of AT. This property is thought to represent a therapeutic advantage, because thrombus acts as a potent stimulus for coagulation [40]. The direct thrombin inhibitors do not require access to the heparin binding site of thrombin, and therefore remain potent inhibitors of fibrin-bound as well as fluid-phase thrombin [41]. Direct thrombin inhibitors have been evaluated in percutaneous coronary interventions, unstable angina, and myocardial infarction [20].

Hirudin is produced by the salivary glands of the medicinal leech (Hirudo medicinalis), and represents the most potent and specific thrombin inhibitor currently known. Unlike heparin, hirudin can inhibit thrombin bound within the clot [41]. Recombinant hirudin (lepirudin), a 65–amino acid polypeptide, is the most potent antithrombin that produces anticoagulation at nanomolar concentrations. Although lepirudin has been used as an anticoagulant for cardiac surgery in patients with HIT, problems with hirudin include the lack of an antidote, difficulty monitoring its anticoagulant effect during CPB, renal excretion, and potential antigenicity in the surgical environment. Argatroban is a synthetic intravenous direct thrombin inhibitor with a relatively short elimination half-life that is approved for use in patients with HIT. Argatroban requires hepatic elimination and can be used in patients with renal failure [19, 39].

Bivalirudin (Angiomax) is another hirudin analogue that has been studied in six trials that included 4,603 patients undergoing elective percutaneous coronary revascularization and 1,071 patients with acute coronary syndromes [37]. Bivalirudin has a much shorter elimination time that hirudin, and requires an infusion for therapeutic effects. Monitoring the newer thrombin inhibitors using routine hemostatic tests, especially for cardiac surgery patients may require different testing [42].

Heparin-induced thrombocytopenia (HIT) is an adverse effect of heparin produced by antibodies (IgG) to the composite of heparin–platelet factor 4 (PF4) that leads to the formation of immune complexes [43]. These immune complexes bind to platelets through platelet Fc-receptors (CD 32) producing intravascular platelet activation, thrombocytopenia, and platelet activation with potential thromboembolic complications that can result in limb loss or death. When patients with HIT require CPB, danaparoid (Orgaran), ancrod, recombinant hirudin (Refludan), and several other drug combinations have been used with various degrees of success [43–47]. One of the major problems with these drugs is their lack of reversibility and thus potential to produce bleeding. Danaparoid has a long half-life (t1/2 of anti–factor Xa activity of 24 hours), and monitoring that is complicated by the need to measure anti–factor Xa. Recombinant hirudin, a direct thrombin inhibitor modified from a leech salivary protein, is the most potent and specific thrombin inhibitor currently known. It acts independently of cofactors such as antithrombin. Potzsch and colleagues [36] have reported using Lepirudin during cardiopulmonary bypass for patients with HIT using a 0.25-mg/kg bolus and then 5-mg boluses when hirudin concentration was less than 2500 ng/mL as determined by ecarin clotting time.

Aprotinin
Aprotinin is a naturally occurring polypeptide with a molecular weight of 6,512 Da, which reversibly complexes with the active serine site in various proteases in plasma to inhibit the serine proteases, trypsin, kallikrein, plasmin, and elastase [48, 49]. Multiple mechanisms are responsible for aprotinin’s ability to reduce bleeding after cardiopulmonary bypass. Aprotinin is the most potent antifibrinolytic agent. The propagation of the "intrinsic" fibrinolysis through factor XII–mediated kallikrein activation and the generation of plasmin through "extrinsic" or t-PA–mediated activation of plasminogen is effectively inhibited by approximately 4 µmol/L of aprotinin, which is maintained in plasma with a high-dose regimen [50]. Aprotinin also has multiple antiinflammatory effects, and inflammation and hemostasis are closely linked [8]. Finally, aprotinin has been studied in multiple placebo-controlled studies, for both safety and efficacy, and is the only agent approved by the United States Food and Drug Administration to reduce bleeding in cardiac surgery patients [48–52].

Antifibrinolytic agents and desmopressin
The synthetic lysine analogue {epsilon}-aminocaproic acid (EACA; Amicar) and tranexamic acid inhibits fibrinolysis by attaching to the lysine binding site of the plasmin(ogen) molecule, displacing plasminogen from fibrin. Levi and colleagues [53] reported a metaanalysis of all randomized, controlled trials of the three most frequently used pharmacological strategies to decrease perioperative blood loss (aprotinin, lysine analogues [aminocaproic acid and tranexamic acid], and desmopressin). Studies were included if they reported at least one clinically relevant outcome (mortality, rethoracotomy, proportion of patients receiving a transfusion, or perioperative myocardial infarction) in addition to perioperative blood loss. In addition, a separate metaanalysis was done for studies concerning complicated cardiac surgery. A total of 72 trials (8,409 patients) met the inclusion criteria. Treatment with aprotinin decreased mortality almost 2-fold (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34 to 0.90) compared with placebo. Treatment with aprotinin and with lysine analogues decreased the frequency of surgical reexploration (OR 0.37; 95% CI 0.25 to 0.55), and OR 0.44; 95% CI 0.22 to 0.90, respectively). These two treatments also significantly decreased the proportion of patients receiving any allogeneic blood transfusion. The use of desmopressin resulted in a small decrease in perioperative blood loss, but was not associated with a beneficial effect on other clinical outcomes. Aprotinin and lysine analogues did not increase the risk of perioperative myocardial infarction; however, desmopressin was associated with a 2.4-fold increase in the risk of this complication. Studies in patients undergoing complicated cardiac surgery showed similar results.

Acquired platelet dysfunction
One of the major problems confronting the cardiac surgery patient is acquired functional platelet disorders due to the multitude of potent antiplatelet agents that patents receive for coronary artery disease or during percutaneous interventions [54–56]. Clopidogrel (Plavix), a drug that selectively interferes with ADP induced platelet aggregation, is commonly used in patients with ischemic heart disease and in those undergoing angioplasty [55]. Clopidogrel requires 3 to 5 days for the onset to occur, and a similar length of time for the effect to disappear [55]. Because of the pivotal role of the platelet glycoprotein (GP) IIb/IIIa complex in platelet-mediated thrombus formation, three different GP IIb/IIIa antagonists are currently available, but they differ in antagonist affinity, reversibility, and receptor specificity. Glycoprotein (GP) IIb/IIIa (IIbß3) is a receptor on platelets that binds to key hemostatic proteins, including fibrinogen and von Willebrand factor, to allow cross-linking of platelets and platelet aggregation. By blocking this final common pathway using GP IIb/IIIa antagonists, these drugs function as inhibitors of platelet participation in acute thrombosis [54]. Various antagonists of GP IIb/IIIa are available and include the monoclonal antibody abciximab (ReoPro), tirofiban (Aggrastat), a nonpeptide fiban molecule, and eptifibatide (Integrelin), a cyclic peptide [54]. Tirofiban and eptifibatide are cleared predominantly through renal mechanisms and have a circulating plasma half-life of approximately 2 to 4 hours; whereas abciximab has a relatively short plasma half-life, the monoclonal antibody avidly binds to platelets with a relatively longer duration of action [54].

Antiplatelet agents are used primarily to treat and prevent arterial thrombosis. Ticlopidine and clopidogrel are believed to inhibit the binding of adenosine 5'-diphosphate (ADP) to its platelet receptor; this ADP receptor blockade led to direct inhibition of the binding of fibrinogen to the glycoprotein IIb/IIIa complex [55]. Clopidogrel was approved by the FDA for the reduction of ischemic events in patients with recent myocardial infarction, stroke, or peripheral arterial disease with no added risk for neutropenia [55]. The combination of clopidogrel and aspirin, as well as the growing use of clopidogrel in coronary stenting, is rapidly growing. Many heart centers now administer clopidogrel before anticipated stenting procedures. The variability in bleeding in patients receiving these agents for cardiac surgery may relate to the time and duration of therapy.

Previous recommendations for managing patients receiving antiplatelet agents and requiring cardiac surgery have been made and are summarized in Table 3 [54]. Patients receiving antiplatelet agents should not preclude urgent revascularization. Platelets may be need and should be available when operating on abciximab-treated patients. Platelets should not be administered prophylactically. Although recommendations have been made on reducing heparin dosing, we believe there are no data to support reductions in heparin dosing during cardiopulmonary bypass and for cardiac surgery. Therefore, standard-loading doses should be considered and additional heparin doses, based on time and duration of bypass or on actual heparin levels, should be maintained. Further, the heparin is reduced at the end of CPB.


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  		Table 3. Recommendations for Managing Patients Receiving Platelet Inhibitors for Cardiac Surgery

 
Recombinant coagulation products
Coagulation products used to manage bleeding in patients with hemophilia, von Willebrand’s disease (vWD), or acquired inhibitors to antihemophilic factor (AHF) include AHF concentrates, factor IX concentrates, factor VIIa concentrate, factor IX complexes, antiinhibitor coagulant complexes, and desmopressin acetate. These commercially available products are used to manage acute bleeding or to prevent excessive bleeding during cardiac and noncardiac surgery in patient with hematologic disorders. Recombinant activated factor VIIa (rFVIIa; NovoSeven, Novo Nordisk A/S) has been used as a novel and effective treatment for patients with hemophilia with inhibitors for the treatment of bleeding, and to secure hemostasis in complex clinical situations [57, 58].

The role of rFVIIa in the treatment of bleeding was evaluated in an open pilot study in patients with complicated cardiac surgical procedures. Blood loss and hemostatic effects and safety after rFVIIa administration were evaluated [59]. Five patients undergoing closure of atrial septal defect, De Vega’s procedure (mitral valve replacement with tricuspid valve repair), and arterial switch (2.5-year-old) were evaluated. Four patients received rFVIIa intraoperatively, whereas the fifth received it postoperatively. Satisfactory hemostasis was achieved with a single dose (30 µg/kg) of rFVIIa. Four hours after treatment mean blood loss was 262 ml for adults (220 to 334 ml) and 85 ml for the child. No significant adverse events were reported. Laboratory values indicated a mean 18.5-fold (range 3.7- to 42-fold) increase in FVII levels 30 minutes postinjection and a mean reduction of 12 seconds (range 3 to 39 seconds) in prothrombin time.

The mode of action of rFVIIa are multiple, including tissue-factor–dependent mechanisms and generation of factors Xa and IXa on the surface of activated platelets. These studies relate thrombin generation on activated platelets to the high level of recombinant factor VIIa binding to platelet surfaces. Therapeutic doses of recombinant factor VIIa are not established; different doses have been used during surgery in patients with hemophilia and inhibitors, and with refractory bleeding after cardiac surgery. The use of recombinant factor VIIa has been reported to control bleeding in patients with thrombocytopathies, liver disease, liver transplantation, and patients undergoing cardiac surgery. Recommended dose ranges for rFVIIa usually vary from 60 to 120 µg/kg, although 90 µg/kg is usually the initial starting dose [57–59].


   Summary
Top
 Footnotes
 Abstract
 Introduction
 Anticoagulation strategies
 Summary
References
 
The potential for bleeding after cardiac surgery and cardiopulmonary bypass remains a major problem. Current and future pharmacologic approaches to attenuating hemostatic system activation in cardiac surgery patients need to be designed to decrease coagulopathy and the potential need for allogeneic blood administration. Novel antiinflammatory strategies are under investigation, targeting multiple pathways to reduce the potential for perioperative complications, and to potentially make CPB safer. The increasing use of platelet inhibitors and newer anticoagulants will continue to pose new paradigms and potential problems in managing cardiac surgery patients. Newer therapies including recombinant factor VIIa as a therapy for refractory bleeding after cardiac surgery need to be considered as potential therapies. Additional understanding of the risk of bleeding for off pump patients may represent additional important considerations in the future.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Anticoagulation strategies
 Summary
 References
 
Dr Levy discloses that he has a financial relationship with Bayer Corporation, Genzyme Corporation, and Sanofi-Synthelabo Inc.


   References
Top
 Footnotes
 Abstract
 Introduction
 Anticoagulation strategies
 Summary
 References
 

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