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Ann Thorac Surg 2006;82:2315-2322
© 2006 The Society of Thoracic Surgeons

Reviews

Thrombin During Cardiopulmonary Bypass

L. Henry Edmunds, Jr, MD*, Robert W. Colman, MD

Harrison Department of Surgical Research, School of Medicine, University of Pennsylvania, and The Sol Sherry Thrombosis Research Center, Hematology Division, Department of Medicine, Temple University, Philadelphia, Pennsylvania

* Address correspondence to Dr Edmunds, 3440 Market St, Suite 306, Philadelphia, PA 19104-3325 (Email: hank.edmunds{at}uphs.upenn.edu).


   Abstract
Top
 Abstract
Introduction
 Methods
 Heparin
 Thrombin
 Fibrinolysis
 Platelets
 Clinical Consequences
 Control of the Thrombotic...
 Acknowledgments
 References
 
Cardiopulmonary bypass (CPB) ignites a massive defense reaction that stimulates all blood cells and five plasma protein systems to produce a myriad of vasoactive and cytotoxic substances, cell-signaling molecules, and upregulated cellular receptors. Thrombin is the key enzyme in the thrombotic portion of the defense reaction and is only partially suppressed by heparin. During CPB, thrombin is produced by both extrinsic and intrinsic coagulation pathways and activated platelets. The routine use of a cell saver and the eventual introduction of direct thrombin inhibitors now offer the possibility of completely suppressing thrombin production and fibrinolysis during cardiac surgery with CPB.


   Introduction
Top
 Abstract
 Introduction
Methods
 Heparin
 Thrombin
 Fibrinolysis
 Platelets
 Clinical Consequences
 Control of the Thrombotic...
 Acknowledgments
 References
 
Blood is a tissue designed to sustain all cells by continuous circulation within a vast labyrinth paved with endothelial cells. These unique cells simultaneously maintain the fluidity of blood and ensure integrity of the vascular system. Contact with the surgical wound and diversion of blood into the heart-lung machine trigger an angry defense reaction that evolved to protect the body from pathogens, injuries, and noxious substances. The major participants are blood cells and five plasma protein systems, which generate a massive reaction by upregulating cellular receptors and by releasing a potpourri of vasoactive, cytotoxic, and cell-signaling substances into the circulation. Platelets, neutrophils, monocytes, and endothelial cells are the major cellular actors; and complement, contact, intrinsic coagulation, extrinsic coagulation, and fibrinolytic protein systems are the primary plasma participants. When activated, these cells and proteins initiate complex and overlapping reactions and interactions with a multitude of target molecules to create a "whole body inflammatory response" [1]. Anticoagulation is required, and unfractionated heparin has been exclusively used for over half a century with generally satisfactory results.

To simplify presentation, we have arbitrarily separated the defense reaction into thrombotic and acute inflammatory responses. This review does not attempt to catalog the changes in particular hormones, peptides, cytokines, proteases, metalloproteinases, phospholipids, eicosanoids, reactive oxygen and nitrogen species, free radicals, cytotoxins, signaling proteins, and cellular receptors that occur during cardiopulmonary bypass (CPB). Instead we concentrate on the primary mechanisms involved in the generation of thrombin, which is the key enzyme involved in the thrombotic portion of the defense reaction during CPB.


   Methods
Top
 Abstract
 Introduction
 Methods
Heparin
 Thrombin
 Fibrinolysis
 Platelets
 Clinical Consequences
 Control of the Thrombotic...
 Acknowledgments
 References
 
An Internet search was made using the keywords thrombin, thrombosis, tissue factor, and fibrinolysis on Google, Ovid, Pub Med, and Scirus. The number of hits for tissue factor varied between 4826 (Ovid) and "about 24,900,000" (Google). The other keywords produced hits within this range. Thus, we retreated to traditional sources, which included textbooks [2, 3]; original references and reviews (see subsequent sections); and more than three decades of collaborative, government-funded, active research.


   Heparin
Top
 Abstract
 Introduction
 Methods
 Heparin
Thrombin
 Fibrinolysis
 Platelets
 Clinical Consequences
 Control of the Thrombotic...
 Acknowledgments
 References
 
A review of the thrombotic response to CPB and open heart surgery (OHS) is a study of defense reactions to heparinized blood circulated and exposed outside the body. Very high doses of unfractionated, standard heparin are required to maintain the fluidity of blood during CPB and OHS, but even these doses fail to completely inhibit thrombin formation. Standard heparin is required for CPB [4], but acts as a cofactor by accelerating the actions of the natural plasma protease, antithrombin (antithrombin III) [5].

Antithrombin is an abundant (140 µg/mL), large molecule (58 kDa) that binds thrombin to form the thrombin-antithrombin complex (TAT), which is rapidly cleared from the circulation by the liver. Antithrombin also inhibits factor Xa, which forms part of the prothrombinase complex. Earlier in the coagulation cascade, antithrombin inhibits factors XIIa, XIa, and IXa and essentially all serine proteases involved in coagulation [6].

Heparin increases antithrombin-mediated inhibition of thrombin and factors IXa and Xa more than 1000-fold, but the mechanisms of inhibition differ. In the case of thrombin, a bridging effect predominates, whereas with factor Xa and factor IXa, the major effect is an allosteric expanse of a reactive loop [7].

Heparin has advantages and disadvantages. The most notable advantages are rapid thrombin inhibition and reversal by protamine. Protamine does not reverse low-molecular-weight heparins. The major disadvantage of heparin is that it fails to completely prevent thrombin formation during CPB [8, 9] and does not inhibit clot-bound thrombin, which antithrombin cannot reach [10]. Heparin concentrations are difficult to monitor in the operating room, and the most common method, activated clotting time, is crude, indirect, and poorly reproducible [11]. Heparin also interacts with platelets and numerous plasma proteins, activates factor XII [12] and complement [13], and induces immunoglobulin G (IgG) antiplatelet PF4 antibodies in some patients [14].


   Thrombin
Top
 Abstract
 Introduction
 Methods
 Heparin
 Thrombin
Fibrinolysis
 Platelets
 Clinical Consequences
 Control of the Thrombotic...
 Acknowledgments
 References
 
Thrombin is a serine protease that is rapidly inhibited by antithrombin. Its plasma half-life is very short (<1 min) and circulation is evanescent [15]. Normally, the enzyme acts at sites of blood vessel injury and is essential for maintaining the integrity of the vascular network. CPB is unique in that thrombin is continuously generated and circulated to transform a local process into a systemic, iatrogenic disease.

The principal actions of thrombin during applications of extracorporeal circulation are cleavage of fibrinogen into fibrin, activation of factor XIII to crosslink fibrin, activation of platelets by way of the specific thrombin receptors glycoprotein Ib (GPIb) and proteinase activated receptor-1 (PAR-1) and PAR-4, and stimulation of endothelial cells to release tissue plasminogen activator protein (t-PA) and von Willebrand factor [16, 17]. Other important procoagulant and anticoagulant reactions of thrombin are listed in Table 1 and are discussed in the following sections.


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  		Table 1. Hemostatic Actions of Thrombin
 
Thrombin is probably essential to mammalian life [6] and has a wide range of actions beyond the coagulation system. Thrombin mediates production of a variety of growth factors, which stimulate mitogenesis of smooth muscle cells, endothelial cells, and macrophages, and probably other undiscovered targets as well [18]. At injury sites, thrombin induces the production of cytokines, chemoattractants, and vasoactive substances, which promote neutrophil adhesion, attract macrophages, and increase vascular permeability. Thrombin is also involved in angiogenesis and enhances vascular endothelial growth factor (VEGF) in the growth of tumors and metastases.

Generation of Thrombin During CPB
Thrombin is continually produced during CPB and OHS, as evidenced by the progressive increase in thrombin-antithrombin complex (TAT) and prothrombin fragment F1.2 [8, 9, 19]. Historically, the perfusion circuit was considered the major stimulus for thrombin production during CPB and OHS [13]. After contact, plasma proteins are instantly adsorbed onto the biomaterial surfaces to produce a dense monolayer [20], and both protein adsorption [20] and heparin [12] activate factor XII.

As demonstrated during in vitro simulated extracorporeal circulation, activated factor XII produces thrombin by the intrinsic coagulation pathway (Fig 1) [21]. The amounts of activated factor XII measured during CPB and OHS are small [9], however, and bleeding events do not occur in patients with factor XII deficiency, nor do they require replacement therapy [22]. In addition, factor XII knockout mice are protected from thrombosis [23–25].


Figure 1
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  		Fig 1. Diagram illustrates the five pathways for generation of thrombin during cardiopulmonary bypass (CPB) and open heart surgery (OHS). The protein or proteins that start each pathway appear at the top of the diagram. Plus signs (+) designate the principal substrate, and arrows show the enzyme produced by the reaction. The contact pathway (far left) is initiated by activation of factor XII, which with cofactors high molecular kininogen (HK) and pre-kallikrein (PK) activates factor XI to factor XIa. Thrombin, once produced, also directly activates factor XI. Factor XIa activates factor IX in the next reaction, which forms part of the intrinsic tenase complex. Although animal studies indicate that factor XIIa activates factor VII, this pathway has not been studied in patients with OHS and CPB. Both cellular tissue factor (TF) and soluble plasma tissue factor (pTF) activate factor VII in the extrinsic coagulation pathway to form the factor VIIa/tissue factor complex or extrinsic tenase. pTF requires a phospholipid cofactor (monocyte, platelet or microparticle). Extrinsic tenase activates both factors IX and X. Activated factor IX (factor IXa) complexes with thrombin activated factor VIII to form intrinsic tenase, which activates factor X. Tissue factor pathways and extrinsic tenase initiate thrombin formation, but once begun, the intrinsic coagulation pathway, aided by activated platelets, is the dominate source of factor Xa. Factor Xa with factor Va forms prothrombinase, which cleaves prothrombin to form {alpha}-thrombin and prothrombin fragment, F1.2.

 
Because factor XIIa can directly activate factor VII to factor VIIa, this reaction may enhance the generation of thrombin [24], but this has not been documented during OHS and CPB. Cumulative data indicate that factor XII initiates low-level thrombin formation that may or may not be controlled by antithrombin within perfusion circuits; however, the surgical wound is the main source of thrombin during CPB and OHS.

Thrombin is designed to act locally, but continuous exposure of the entire blood mass to the surgical wound, biomaterials and air converts a local reaction into a systemic, "whole body" reaction. At sites of injury, thrombin is produced by the extrinsic coagulation pathway in minute amounts by the formation of the FVIIa/tissue factor complex, which directly activates platelets and small amounts of factors IX and X (Fig 1). Low concentrations of thrombin also activate factors V and VIII. Activated platelets release partially activated factor V/Va, which readily combines with factor Xa to form prothrombinase [26]. This is the "initiation phase" of thrombin formation and produces small amounts of thrombin [6]. Furthermore, tissue factor pathway inhibitor (TFPI), produced by thrombin-stimulated endothelial cells, rapidly inhibits both FVIIa/tissue factor complex and factor Xa [27].

These mechanisms suppress thrombin production, but activation of platelets and factor XI, which activates factors IX and VIII during the initiation phase, triggers the intrinsic coagulation pathway and the "propagation phase" of explosive thrombin production [28]. Once thrombin formation is initiated, the intrinsic pathway, which generates thrombin 50 times faster than the extrinsic pathway, dominates. These reactions primarily relate to local injuries and the formation of the platelet-fibrin clot. Quantitative measurements of proteins involved in thrombin formation during OHS and CPB do not exist, but the probable pathways are illustrated in Figure 1 and are described below.

It is now clear that the extrinsic and intrinsic coagulation pathways are both involved in the generation of factors IXa and Xa in the pericardial wound [9, 29, 30] (Fig 1). Tissue factor protein exists as either cell-bound tissue factor or circulating soluble plasma tissue factor in the wound [31]. Both forms of tissue factor activate factor VII to form the factor VIIa/tissue factor complex (extrinsic tenase), which activates factors IX and X. Epicardium, myocardium, adventitia, muscle, fat, and bone constitutively express cellular tissue factor, but pericardium does not [32].

Soluble plasma tissue factor, which contains the 166 amino acids of the extracellular domain of cellular tissue factor, circulates in 1 to 3 pM concentrations in normal individuals [31, 33–35]. However, plasma tissue factor increases severalfold in a wide variety of diseases, including acute coronary syndromes [36, 37], sepsis [37], trauma, gastrointestinal and gynecologic tumors, and some lymphomas [37] as well as in OHS with CPB [30, 35, 38]. Plasma tissue factor requires monocytes, platelets, or microparticles [30, 35, 38, 39] to provide a phospholipid surface for activating factor VII. In the pericardial wound, concentrations of both soluble plasma tissue factor and microparticles, derived primarily from platelets and red cells, are elevated [30, 31, 35, 38, 40, 41] and microparticles are procoagulant [30, 38]. At the concentrations of soluble plasma tissue factor measured in patients, however, activated monocytes in combination with wound soluble plasma tissue factor more efficiently activate both factors VII and X in the cardiac surgical wound than either platelets or microparticles [35, 39].

Both tenases require a phospholipid surface, which is provided by activated monocytes or endothelial cells for the extrinsic pathway and by activated platelets for the intrinsic and common coagulation pathways [28]. Activated platelets provide receptors for zymogens and active enzymes of factors V, VIII, IX, X, and XI; prothrombin; and thrombin plus negatively charged membrane phosphatidylserine for localizing enzymes, cofactors, and substrates.

After initiation of thrombin production by the factor VIIa/tissue factor complex, the explosive production of thrombin by the intrinsic pathway is mediated by platelets, which accelerate each step in the coagulation cascade by factors of 105 to 108 [28]. In addition, platelets provide protection from inhibitors such as antithrombin and TFPI [6, 28]; secrete adhesive proteins, fibrinogen, and factor V/Va to support fibrin production; and facilitate localization at sites of injury [26]. The massive burst of thrombin formation also activates thrombin activatable fibrinolysis inhibitor (TAFI), which slows fibrinolysis in the fresh clot [42].

During CPB and OHS, it is likely that sufficient thrombin circulates to directly activate factor XI [43] and augment the small amount of factor XIa produced by factor XIIa and the contact proteins. Activated factor XIa on surfaces of activated platelets directly activates factor IX (Fig 1) [44] and bypasses the extrinsic coagulation pathway completely. Although both tenases independently generate activated factor X; most likely, intrinsic tenase predominates during OHS and CPB, as it does in local reactions.

Factor Xa, the important product of the tenase reactions, forms the prothrombinase complex with factor Va on a platelet phospholipid surface and cleaves prothrombin into {alpha}-thrombin, the active enzyme, and prothrombin fragment F1.2 [2].


   Fibrinolysis
Top
 Abstract
 Introduction
 Methods
 Heparin
 Thrombin
 Fibrinolysis
Platelets
 Clinical Consequences
 Control of the Thrombotic...
 Acknowledgments
 References
 
In 1984, Stibbe and colleagues [45] reported that fibrinolysis occurred in patients who had cardiac surgery with CPB. Blood contains two major proteins that lead to cleavage of plasma plasminogen to produce plasmin, which is the active fibrinolytic enzyme. Urinary-type plasminogen activator (u-PA) is produced by numerous cells, binds poorly to fibrin, and acts primarily outside the vasculature in the extracellular matrix [46]. This system is involved in inflammation, cell migration, and cancer and has a minor role in CPB.

The tissue-type plasminogen activator (t-PA) fibrinolytic system is designed similar to that of the coagulation cascades and features protein activators, zymogens, inhibitors and the active enzyme, plasmin, that are harmoniously balanced to act locally to clear blood paths of clot without disrupting sites of vessel repair [42]. Thrombin initiates fibrinolysis by stimulating local endothelial cells to produce and release t-PA, which circulates briefly and binds to fibrin with high affinity and to plasminogen with high specificity [46]. The combination of fibrin and plasminogen binding greatly increases the rate of plasminogen cleavage to produce plasmin [47]. Plasmin then cleaves fibrin and produces several degradation products, the smallest of which is D-dimer. D-dimer is specific for plasmin degradation of fibrin as opposed to degradation of fibrinogen [48].

Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of t-PA (PAI-2 primarily inhibits u-PA), and relatively large amounts are stored in platelets [49]. When platelets are activated at sites of vascular injury, PAI-1 is released into the fibrin clot and helps to regulate the balance between fibrin formation and fibrinolysis.

TAFI is a plasma protein primarily activated by the thrombin-thrombomodulin complex but is also activated by high concentrations of plasmin and thrombin, which is produced by the propagation phase of thrombin formation [50]. Activated TAFI directly inhibits plasmin and prolongs clot lysis by attaching to cross-linked fibrin [18].

Circulating plasmin is inactivated by {alpha}2-antiplasmin, but is partially protected from this enzyme when bound to fibrin [46]. {alpha}2-Macroglobulin is a slower acting, nonspecific plasmin inhibitor.

Fibrinolysis occurs continuously during CPB and OHS, both in the pericardial wound and in the perfusion circuit [51, 52].


   Platelets
Top
 Abstract
 Introduction
 Methods
 Heparin
 Thrombin
 Fibrinolysis
 Platelets
Clinical Consequences
 Control of the Thrombotic...
 Acknowledgments
 References
 
The normal platelet count is between 150,000 and 350,000/µL. During CPB and OHS, platelets are diluted by priming fluids and activated by low concentrations of thrombin in the pericardial wound and in the perfusion circuit [21]. Thrombin is not the only agonist to activate platelets during CPB and OHS, however. Collagen, heparin, plasmin, surface contact, adenosine diphosphate, and a host of inflammatory response mediators also active platelets, such as the terminal complement complex C5b-9, leukotrienes, eicosanoids, and collagenases [53–55]. Hypothermia reversibly inhibits platelets [56].

Activated platelets adhere to surface-adsorbed fibrinogen, von Willebrand factor, vitronectin, and fibronectin on biomaterial surfaces [57]. Platelets also adhere to each other by way of fibrinogen bridges anchored by GPIIb/IIIa receptors and to leukocytes by P-selectin or GPIb{alpha} receptors to P-selectin glycoprotein ligand-1 (PSGL-1) or CD11b/CD18 counter-receptors to form circulating aggregates [54].

Some surface-adsorbed platelets partially detach, leaving adherent membrane fragments and producing microparticles [30, 40, 41, 58]; others are destroyed by segments of high shear stress within the perfusion circuit. Some platelets appear intact; others have released some or all granules.

A few new platelets enter the circulation from the bone marrow. The heterogeneity of the circulating platelet mixture varies between patients and perfusion systems, but in all patients, bleeding times are increased, markers of granule release rise, and platelet function is diminished [59].


   Clinical Consequences
Top
 Abstract
 Introduction
 Methods
 Heparin
 Thrombin
 Fibrinolysis
 Platelets
 Clinical Consequences
Control of the Thrombotic...
 Acknowledgments
 References
 
The clinical consequences of the thrombotic response are thrombosis, fibrin-platelet microemboli, and bleeding. OHS and CPB reduce platelet numbers and function and also produce a consumptive coagulopathy that may vary between patients and between operations. Off-pump revascularization operations generally use heparin, salvage wound blood, and are less complex procedures; however, they still generate thrombin, albeit to a lesser extent than CPB and OHS.

The large dose of heparin that is routinely given during CPB and OHS to maintain activated clotting times of more than 400 seconds, and often more than 480 seconds, prevents macroscopic clotting. Microscopic emboli are produced, however, and some are related to the production of thrombin. These include platelet, leukocyte, and platelet-leukocyte aggregates; fibrin, and platelet-fibrin emboli. These microemboli can develop in stagnant areas of the perfusion circuit, the surgical wound, and in stored blood. Most microemboli produced during CPB arise from other sources including blood (eg, fat emboli) [60, 61].

Bleeding is the most vexing problem and the potential causes are numerous and are not here reviewed in depth. A careful history and routine preoperative screening tests, including prothrombin time, activated partial thrombin time (aPTT), platelet count, and bleeding time, are used to detect congenital deficiencies in coagulation proteins (eg, factor XI deficiency) and use of antiplatelet drugs (eg, clopidogrel, aspirin). Possible bleeding related to heparin administration and reversal are managed by repeat activated clotting times, measurement of aPTT, or various versions of protamine titration tests in the operating room and intensive care unit. Surgical bleeding is managed by rigorous surgical hemostasis and topical agents after termination of CPB [62].

Platelet counts of less than 80,000/µL in bleeding patients necessitate transfusions of platelet concentrates. Fresh frozen plasma is recommended for bleeding patients with an abnormal prothrombin time or aPTT test results [62]. Cryoprecipitate, which is rich in fibrinogen, factors VIII and XIII, and von Willebrand factor, is not generally recommended, because CPB-induced deficiencies in coagulation proteins are uncommon. Administration of antifibrinolytics—aprotinin, {varepsilon}-aminocaproic acid, tranexamic acid—after CPB is not as effective as that given before and during CPB, but may be indicated (see below). Persistent bleeding after closure of the wound requires reexploration [62].

The traditional management of excessive bleeding after OHS and CPB, sketched above, reflects the inadequacy of functional tests of coagulation, which only assess the initiation phase of thrombin generation and do not reflect the more important propagation phase [6]. The simultaneous generation of thrombin and D-dimer during CPB is a manifestation of a consumptive coagulopathy that is mild in most patients, who lose between 200 and 600 mL of blood postoperatively.

Bleeding can, however, be excessive and difficult to control in problem patients who require extended and difficult surgery, reoperations, or who are exceptionally high risk because of preoperative events or comorbid disease. Therapy for these patients is essentially blind without sequential measurements of F1.2 and D-dimer. The laboratory costs of measuring these markers by enzyme-linked immunosorbent assays are high but are small compared with the hospital costs of controlling bleeding in patients who require massive transfusions and postoperative mechanical circulatory support. Timely results of these tests would better guide management of the consumptive coagulopathy in these difficult patients.

Recombinant factor VIIa (rfVIIa) is approved by the Food and Drug Administration as replacement therapy for hemophilia patients with antibodies against factors VIII or IX. In recent years, the drug has been used off-label to control intracranial or massive bleeding in trauma or surgical patients [63]. The mechanism of action is not entirely settled, but hematologists agree that bolus doses (90 µg/kg) abruptly increase plasma fVIIa from 1% of fVII to about 15% [64]. Factor VIIa complexes either with small amounts of tissue factor on platelets or with cellular tissue factor expressed at bleeding sites. In either event, rfVIIa greatly accelerates factor Xa formation, which, with activated factor V, forms prothrombinase [64]. Although intravascular thrombosis has been feared, the rfVIIa does not produce intravascular thrombosis independent of injury sites [65]. The drug has been used successfully as rescue therapy anecdotally and in a small series of cardiac surgical patients [66].


   Control of the Thrombotic Response
Top
 Abstract
 Introduction
 Methods
 Heparin
 Thrombin
 Fibrinolysis
 Platelets
 Clinical Consequences
 Control of the Thrombotic...
Acknowledgments
 References
 
Cumulative evidence does not show that either covalent or ionic-bonded heparin-coated perfusion circuits reduce the rate of thrombin formation [19, 67], protect platelets [19, 68], or reduce postoperative bleeding or transfusion requirements [69]. There is evidence that heparin coated circuits reduce some biochemical aspects of the inflammatory response, but no clinical benefits are recognized [61]. Other commercial circuit coatings also have not shown reduced thrombin formation, preservation of platelets, or reduced bleeding when a cell saver is not used [61].

Aprotinin is a nonspecific protease inhibitor derived from bovine lungs that directly inhibits plasmin and weakly inhibits kallikrein but does not inhibit thrombin at the doses used in vivo [70]. Aprotinin also binds to the platelet thrombin receptor, PAR-1, to prevent platelet activation by thrombin [71]. The {omega}-aminocarboxylic acids, {varepsilon}-aminocaproic acid, and tranexamic acid, occupy a lysine-binding site on plasminogen that, after cleavage of plasminogen to plasmin, prevents plasmin binding to fibrin [70]. The kidney excretes all three drugs. Aprotinin is immunogenic and occasionally produces anaphylactic reactions after repeat exposure. Numerous clinical trials have shown the efficacy of all three drugs in reducing blood losses and sometimes reducing transfusion requirements in various subsets of cardiac surgical patients [72–74]. All three drugs are effective, and advantages of one over another have not been proven [70].

Platelet anesthesia is a method to temporally prevent or attenuate platelet activation, adhesion, and consumption by a short-acting, reversible platelet inhibitor during CPB. The feasibility of this approach has been demonstrated in a baboon model using nitric oxide and eptifibatide [75].

Blood aspirated from the surgical field contains high concentrations of TAT, F1.2, fibrin degradation products, and inflammatory cytokines, which often are filtered and returned to the circulating perfusate from the cardiotomy reservoir [29, 51, 76]. The use of a cell saver to first dilute this aspirated field blood, concentrate red blood cells, and reinfuse packed cells, discards plasma, but significantly reduces circulating enzymes of thrombin generation and fibrinolysis and mediators of the acute inflammatory component of the defense reaction [77–79]. A deficiency of plasma proteins from the use of a cell saver is rare and, if suspected, can be treated by transfusions of fresh frozen plasma.

Three direct thrombin inhibitors—Argatroban (GlaxoSmithKline), lepirudin, and bivalirudin—are in restricted clinical use, but have been used for CPB and OHS for special indications [80–82] and in a clinical trial [83]. None of the three have fast, effective antidotes analogous to protamine, but all inhibit clot-bound thrombin.

Argatroban is a synthetic inhibitor of thrombin with a plasma half-life of about 45 minutes and is metabolized in the liver [82]. In low doses, Argatroban is monitored with the partial thromboplastin time, but the activated clotting time is recommended for high doses. Lepirudin (Hoechst, Marion, Roussel) has a half-life in plasma of approximately 80 minutes in healthy individuals and hours longer in patients with renal dysfunction [81]. Bivalirudin (Medicines Company) has a half-life of 25 to 36 minutes, is essentially non-antigenic, and is largely cleared by proteolysis and secondarily by the kidney. Lepirudin and bivalirudin are analogs of leech hirudin.

For CPD and OHS bivalirudin and lepirudin are preferably monitored by ecarin clotting times [84] but have been successfully monitored by activated clotting times or aPTT. These drugs have the potential to completely suppress thrombin generation during OHS and CPB (Table 2) [80], but the longer half-life and renal clearance of lepirudin favor bivalirudin and Argatroban. In the absence of an effective, fast antidote, restoration of normal coagulation requires rapid clearance of the anticoagulant. Thus bivalirudin, which has a half-life of 30 minutes, has the most potential [84].


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  		Table 2. Bivalirudin for Coronary Artery Bypass Grafting With Cardiopulmonary Bypass a
 
Conclusions
Since the discovery and commercial production of heparin and protamine made OHS and CPB possible, many secrets controlling the fluid and gel states of blood during extracorporeal circulation have been learned. It is now clear that the production of thrombin by mechanisms initiated in the surgical wound and perfusion circuit is fundamental for suppressing fibrin formation, fibrinolysis, and perhaps the severity of platelet numerical and functional losses during CPB, OHS, and other applications of extracorporeal perfusion technology. Both temporary and long-term applications of extracorporeal perfusion broaden with each incremental gain in control of the defense reaction. Unfortunately, after a half century of effort, the complexity of biomaterial surface chemistry and physics, when exposed to blood, remains daunting; thus, no biomaterial or coating yet discovered reduces thrombin generation in extracorporeal perfusion systems [61]. Our prospects are better by controlling the blood side of the interface.

The routine use of a cell saver for all wound blood and a direct thrombin inhibitor for anticoagulation [80] amounts to "proof of principle" and highlights the pathway to completely suppress thrombin generation during OHS and CPB. Introduction of direct thrombin inhibitors into daily practice, however, probably must await discovery of an effective and rapid-onset antidote, reductions in costs, new operational protocols, and improved real-time monitoring of the anticoagulant effect. Progress begets great expectations, but it now appears that the thrombotic component of the defense reaction can be controlled. This control encourages far wider applications of extracorporeal perfusion technology for patients with cardiovascular disease, but also may improve therapy for a wide range of other diseases that may benefit from regional perfusion of organs and tissues.


   Acknowledgments
Top
 Abstract
 Introduction
 Methods
 Heparin
 Thrombin
 Fibrinolysis
 Platelets
 Clinical Consequences
 Control of the Thrombotic...
 Acknowledgments
References
 
The editor thanks Dr Richard J. Novick for managing the blinded review of this article.


   References
Top
 Abstract
 Introduction
 Methods
 Heparin
 Thrombin
 Fibrinolysis
 Platelets
 Clinical Consequences
 Control of the Thrombotic...
 Acknowledgments
 References
 

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