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Activation of the Hemostatic System During Cardiopulmonary Bypass

Sniecinski, Roman M. MD*; Chandler, Wayne L. MD

doi: 10.1213/ANE.0b013e3182354b7e
Cardiovascular Anesthesiology: Review Articles
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Cardiopulmonary bypass (CPB) is a unique clinical scenario that results in widespread activation of the hemostatic system. However, surgery also results in normal increases in coagulation activation, platelet activation, and fibrinolysis that are associated with normal wound hemostasis. Conventional CPB interferes with normal hemostasis by diluting hemostatic cells and proteins, through reinfusion of shed blood, and through activation on the bypass circuit surface of multiple systems including platelets, the kallikrein-kinin system, and fibrinolysis. CPB activation of the kallikrein-kinin system increases activated factor XIIa, kallikrein, bradykinin, and tissue plasminogen activator levels, but has little effect on thrombin generation. Increased tissue plasminogen activator and circulating fibrin result in increased plasmin generation, which removes hemostatic fibrin. The nonendothelial surface of the bypass circuit, along with circulating thrombin and plasmin, lead to platelet activation, platelet receptor loss, and reduced platelet response to wounds. In this review, we highlight the major mechanisms responsible for CPB-induced activation of the hemostatic system and examine some of the markers described in the literature. Additionally, strategies used to reduce this activation are discussed, including limiting cardiotomy suction, increasing circuit biocompatibility, antithrombin supplementation, and antifibrinolytic use. Determining which patients will most benefit from specific therapies will ultimately require investigation into genetic phenotypes of coagulation protein expression. Until that time, however, a combination of approaches to reduce the hemostatic activation from CPB seems warranted.

Published ahead of print October 14, 2011 Supplemental Digital Content is available in the text.

From the *Department of Anesthesiology, Division of Cardiothoracic Anesthesia, Emory University School of Medicine, Atlanta, Georgia; and Department of Laboratory Medicine, University of Washington, Seattle, Washington.

The authors declare no conflicts of interest.

Wayne L. Chandler, MD, is currently affiliated with the Department of Pathology and Genomic Medicine, The Methodist Hospital, Houston, TX.

Reprints will not be available from the authors.

Address correspondence to Wayne L. Chandler, MD, The Methodist Hospital, Methodist Pathology Associates, 6565 Fannin St., Suite B-490, Houston, TX 77030. Address e-mail to wlchandler@tmhs.org.

Accepted August 22, 2011

Published ahead of print October 14, 2011

The hemostatic system consists of 4 integrated components: the coagulation system, endothelium and regulatory proteins, platelets, and fibrinolysis. These elements work together to prevent blood loss from injured vasculature without occluding the entire vessel. In certain situations, however, this activation inappropriately spreads systemically, creating both coagulopathy and thrombotic complications. Cardiac surgery with the use of cardiopulmonary bypass (CPB) is one such scenario that results in widespread activation of the hemostatic system. This can result in micro thrombi during CPB, coagulation defects after its termination, and even hypercoagulability leading to thrombotic complications in the postoperative period. In this review, we examine the current concepts thought to be involved with CPB-induced activation of the hemostatic system, as well as some of the potential interventions to minimize clinical sequelae.

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THE IMPORTANCE OF THROMBIN AND ITS MEASUREMENT

At the site of a wound (Fig. 1), platelets bind to collagen through von Willebrand factor, activate and aggregate forming an initial hemostatic plug. Active factor VII (FVIIa) in blood binds wound tissue factor (TF) leading to activation of factor IX (FIXa) and factor X (FXa), which in turn activate prothrombin to thrombin.1,2 Once thrombin is formed, it becomes the key regulatory protein, activating platelets and factors V, VIII, and XI, which accelerates coagulation, while activation of fibrinogen and factor XIII stabilizes the hemostatic clot. Thrombin formed at the site of a wound we term “hemostatic” thrombin because it is participating in normal hemostasis.

Figure 1

Figure 1

Under some conditions, thrombin and fibrin may be generated without wounds. This can occur locally as in deep venous thrombosis or systemically because of widespread organ damage (shock, sepsis) or systemic release of procoagulants such as TF and anionic phospholipids (brain injury). Excessive local or systemic thrombin and fibrin formation are not being made in response to a wound site but represent dysregulation of the coagulation system and may result in consumptive coagulopathy and in some cases disseminated intravascular coagulation, bleeding, and thrombosis. This is termed “nonhemostatic” thrombin and fibrin.

The average amount of thrombin produced in vivo throughout the vascular system can be estimated by measuring levels of the thrombin activation markers prothrombin fragment F1.2 or thrombin-antithrombin complex (TAT).36 The rate of thrombin production is not the same as the average level of thrombin activity in blood. The average amount of thrombin activity in vivo can be estimated by measuring fibrinopeptide A (FPA) levels, a measure of fibrinogen activation to fibrin by thrombin (Fig. 2). To interpret activation markers, it is important to understand how changes in production of the marker affect marker levels. If the marker has a short half-life and rapid clearance such as FPA (t1/2 4 minutes) or TAT (t1/2 10 minutes), the concentration of the marker in blood will change in parallel with the formation rate and is essentially a direct measure of the formation rate of the marker.710 If the marker has a longer half-life and slower clearance such as prothrombin activation peptide F1.2 (t1/2 90 minutes) or D-dimer (t1/2 8 hours), the concentration of the marker during CPB is cumulative, thus the change or slope of the concentration versus time curve is proportional to the formation rate, not the concentration itself.11,12 Most activation markers are proteins or protein fragments that are cleared by the liver. The clearance rate remains the same even when marker production is increased.8 In most patients, liver blood flow is well maintained during CPB and marker clearance seems to be similar to preoperative values.13

Figure 2

Figure 2

The surgical wound produces increased hemostatic thrombin and fibrin at the wound site, but has little systemic effect.6,7,14,15 Immediately after going on CPB, hemodilution by the priming fluid in the bypass circuit reduces all factors in blood including coagulation factors, inhibitors, and activation markers, by approximately 30% to 40% (Fig. 3).1623 Changes during CPB in stable factor levels with long half-lives, such as albumin, coagulation proteins, and antithrombin (AT), primarily reflect hemodilution, blood loss, and transfusion with consumption having only a minor role.16,18,21,23

Figure 3

Figure 3

Hemodilution tends to obscure the underlying changes occurring in the hemostatic system during CPB.24,25 Because all proteins in the blood are diluted equally at the start of CPB, any factor that does not decrease must be undergoing a rapid increase in formation to maintain its concentration at preoperative levels. Most studies present activation data as marker level versus sample number with no reference to time or hemodilution effects (Fig. 4). With this kind of data, it is difficult to gauge what the underlying rate of activation is. One approach is correction for hemodilution, that is, dividing results by the average percent change in stable factor levels to give an indication of what the marker level would be if hemodilution had not occurred.26 If hemodilution-corrected results are plotted versus sample time, it is possible to get a sense of the magnitude and rate of change in the system (Fig. 4). The problem with correction for hemodilution is that it produces a set of values that are not the actual measured values from the patient, but adjusted values based on a simple dilution model.

Figure 4

Figure 4

Another approach to the analysis of hemostatic data is to use a computer to account for changes in marker levels caused by alternations of patient blood volume, hemodilution, blood loss, blood transfusion, timing of samples, and clearance of proteins. In most studies, none of these factors is accounted for when presenting raw measurements of marker levels in blood, yet conclusions are drawn from changes in the marker levels as if these effects were known. Computer analysis or modeling allows the reader to know the specific assumptions made in analyzing the data, what was accounted for, and what was not. As new information is developed, the model can be updated to improve the analysis. When all of the factors affecting marker levels are accounted for, it is possible to estimate the formation rate in vivo of thrombin or other factors. It is further possible to validate the estimate of formation rate by comparing rates based on different markers that measure the same process but have different clearance rates and thus marker patterns for raw data. Figure 4 shows the estimated in vivo thrombin generation rate in one patient during CPB based on measured levels of both F1.2 and TAT, which showed different patterns for the measured data but produced similar estimates of the in vivo thrombin formation rate. The overall best estimate can be determined based on the average or best fit data using both markers.7 Computer modeling is not the same as de novo simulation; modeling is essentially a more complete method for correcting hemodilution and other processes that affect marker levels.

Conventional CPB leads to substantial increases in thrombin activation markers, unrelated to the surgical wound itself. Figure 5 shows the estimated rate of thrombin generation, total fibrin generation, and soluble fibrin generation using computer analysis of data from one study of conventional CPB.7 After thoracotomy, there was only a small increase in the total amount of thrombin and fibrin generated.6,7,14,15 However, within 5 minutes of starting CPB, thrombin generation and soluble fibrin formation both increased approximately 20-fold, but because the patient was heparinized, thrombin activity and total fibrin generation actually decreased.7,11,14,27 Normally, fibrin does not circulate in blood; it is present only at the site of the wound. Soluble fibrin is nonhemostatic fibrin formed in circulating blood due to dysregulation of hemostasis in some way. Under normal circumstances, only approximately 1% of the fibrin formed circulates as soluble fibrin, and the remainder stays in the wound.7 Soon after CPB is started, total fibrin formation is reduced because of heparinization whereas soluble fibrin formation is increased to approximately 35% of the total. This indicates that much of the thrombin being formed during CPB is nonhemostatic thrombin, in turn producing soluble fibrin. Non–wound-related thrombin generation and soluble fibrin formation continue to be 5- to 10-fold increased throughout the remainder of CPB. Soluble and circuit-bound fibrin provide binding sites for non–wound-related thrombin that protects this thrombin from inhibition by AT, necessitating high-dose heparin as an anticoagulant.

Figure 5

Figure 5

Another burst of nonhemostatic thrombin and soluble fibrin generation occurs after reperfusion of the heart and lungs.7,11,15,2831 Thrombin generation after reperfusion may be involved in myocardial ischemia-reperfusion injury and impaired hemodynamic recovery, but the increase in thrombin generation after reperfusion is reduced or eliminated if shed blood is not reinfused.12,3236 After protamine reversal, there is another peak in thrombin generation as more thrombin and fibrin are produced at the site of the wound.7,27 The increase in postoperative thrombin generation lasts hours to days and then begins to decrease toward baseline levels.

An in vitro thrombin generation test, also called calibrated automated thrombography, measures the ability of plasma to generate thrombin when stimulated, termed the “endogenous thrombin potential” (ETP).37,38 Briefly, the method adds TF and phospholipids to the patient's platelet-poor plasma and monitors the cleavage of a fluorogenic substrate, producing a curve, the area under which represents ETP. Low ETP, such as can occur after CPB, may indicate a hypocoagulable state and bleeding risk,22,39 whereas high ETP may predict possible thrombotic risk.40 Two limitations of the ETP are that it measures the ability of plasma to produce thrombin in vitro, which is not the same as thrombin generation in vivo, hence the term thrombin “potential,” and that the test cannot be run in the presence of heparin or direct thrombin inhibitors (DTIs).

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MECHANISMS OF ACTIVATION

Hemostatic system activation occurs via several mechanisms including the contact system, fibrinolysis, inflammation, and platelets. This is summarized in Figure 6 and detailed in the sections below.

Figure 6

Figure 6

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The Contact System

Kinins are a diverse set of proteins involved in vascular tone, patency, and tissue repair.41 The best studied member of this family is bradykinin, which may have a role in attenuating cardiac ischemia and hypertension.42 Kinins are synthesized as kininogens, of either high molecular weight (HMWK) or low molecular weight, and are inactive until cleaved by proteins known as kallikreins. In plasma, kallikrein circulates in an inactive form known as prekallikrein, or Fletcher factor, until activated by factor XIIa, also known as Hageman factor. The “contact system” refers to factor XII, factor XI, HMWK, and prekallikrein, which are associated proteins that travel together in the plasma. There is normally a low level of kallikrein activity on endothelial cell surfaces producing kinins, including bradykinin, that are rapidly degraded by kininases, which are enzymes found in plasma and in high concentrations in kidney and lung tissue.43,44

Once CPB is initiated, there is a dramatic increase in contact system activity as blood touches the artificial material comprising the CPB circuit.45,46 Factor XII auto-cleaves itself upon contact with a variety of anionic surfaces including glass, polyethylene, and silicone rubber, and produces FXIIa, which converts prekallikrein to active kallikrein. Plasma kallikrein creates a positive feedback loop by cleaving more FXII, as well as producing bradykinin from HMWK. Prekallikrein and HMWK levels decrease not only because of hemodilution, but also because of consumption and binding to the CPB circuit.47 Bradykinin levels increase 10-fold due to increased HMWK cleavage as well as reduced lung clearance because pulmonary blood flow is minimal.46,48 This has important implications for fibrinolysis because elevated bradykinin levels induce secretion of tissue plasminogen activator (tPA) (see below).49,50

The role of FXIIa in activation of the hemostatic system remains unclear.51 Besides producing kallikrein, FXIIa has been shown to convert FXI to FXIa in vitro, thus initiating the intrinsic pathway of coagulation. However, FXII-deficient patients do not have hemostatic defects, indicating that FXIIa does not normally have a role in hemostasis.52 Indeed, FXII deficiency does not stop the increase in thrombin generation during CPB.53,54 However, FXIIa has been shown to activate plasminogen to plasmin in vitro, suggesting its possible role in inducing fibrinolysis during CPB.55,56 Additionally, FXIIa and other fragments of FXII activate the classic complement cascade, accounting for some of the “crosstalk” between coagulation and inflammation.

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The Fibrinolytic System

Endothelial cell release of tPA is a major activator of plasminogen, turning it into fibrin-degrading plasmin. On average, CPB stimulates a 5-fold increase in tPA secretion and active tPA levels,15,57,58 although there is some variability and approximately one-third of patients may show no change.59 Although active thrombin has been shown to release tPA in vitro,60 human in vivo studies are lacking and it is more likely that bradykinin is the main stimulus. Indeed, tPA release has been shown to be reduced by blocking bradykinin receptors or reducing its production by inhibiting kallikrein.61,62

Increased tPA alone does not increase fibrinolytic activity if no fibrin is present. D-dimer levels, an indicator of fibrin degradation, do not change under normal conditions, even when tPA levels are transiently increased 10-fold.63 In the setting of CPB, however, soluble and circuit-bound fibrin provide a huge surface for plasminogen activation to occur.56,64,65 There is a 10- to 100-fold increase in plasmin generation shortly after the commencement of CPB, and plasmin generation, along with fibrin degradation, remain increased 10- to 20-fold throughout the duration of CPB.66 Normally only 1% of fibrin is degraded by the fibrinolytic system, with the remainder being removed by cells during wound healing. During CPB, however, fibrin formation and degradation rates are nearly equal, indicating that much of the fibrin degradation is not at the sites of vascular injury. This hyperfibrinolytic state consumes fibrinogen, leaving less available for coagulation postoperatively. Additionally, large amounts of plasmin can damage platelets through cleavage of their glycoprotein (GP)Ib receptor,67,68 and partially activate them (see below), making them less responsive to further activation with agonists such as adenosine diphosphate and arachidonic acid.6971

It is important to recognize that a hypofibrinolytic state can also occur postoperatively. Plasminogen activator inhibitor 1 (PAI-1) prevents the formation of plasmin. Although levels on CPB are initially much less than tPA, PAI-1 is an acute phase reactant and, by 2 hours after surgery, its secretion is increased 15-fold.66,7274 This increase may continue into the first postoperative day, which is associated with an increased risk of coronary graft occlusion.75 Similar to tPA levels, there is some variability with approximately one-third of patients showing no postoperative PAI-1 increase.59 This individual variability is one of the reasons it is difficult to predict which patients are at risk for bleeding versus thrombosis.

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Inflammation

The coagulation and immune responses are linked; a break in the vasculature not only must be fixed, but also any foreign invaders neutralized. Inflammation has multiple mediators that can create profound amplification, sometimes resulting in an out-of-proportion response to the stimulating event and causing pathologic conditions in the host. A sepsis-like clinical picture that often results from CPB, termed the systemic inflammatory response syndrome, can be linked to “crosstalk” with the coagulation system and has been extensively reviewed elsewhere.7680 A few key points will be emphasized here.

Leukocytes, including neutrophils and monocytes, bind to and are activated by the surface of the bypass circuit,64,8188 which leads to an increase in TF expression, procoagulant activation, and thrombin generation on these cells.8385,89 Shed blood contains increased numbers of activated leukocytes and levels of TF bound to cells and microparticles, as well as soluble TF.81,82,9092 CPB also alters the protein C system. Protein C is activated by the binding of thrombin to thrombomodulin expressed on endothelial cells. This normally functions to suppress further thrombin formation away from the wound by destroying FVIIIa and FVa. Activated protein C also binds with endothelial protein C receptors to downregulate cytokine production and decrease vascular permeability.93,94 In addition to hemodilution, CPB further decreases protein C levels by downregulating thrombomodulin and endothelial protein C receptor expression of the endothelium. Overall, systemic inflammatory response syndrome caused by CPB increases TF expression while simultaneously depressing protein C activation, thereby favoring the production of thrombin.

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Platelets

Fibrinogen bound to the CPB circuit provides a large binding site for platelets through their GPIIb/IIIa receptors. Once platelets bound to either the vascular system or to the circuit are activated, they spread pseudopods, express receptors, release granules and microparticles, and support thrombin formation.64,95101 Additionally, there is some evidence that leukocytes may stimulate TF release directly from platelets.102 CPB increases platelet activation markers including β-thromboglobulin, platelet factor 4, soluble and platelet P-selectin, and platelet GMP140 (granule membrane protein 140).16,30,32,34,69,103108 Shed blood shows evidence of platelet activation including reduced platelet levels, increased platelet activation markers, increased microparticles, and decreased platelet responsiveness.32,108110 When shed blood is reinfused, part, but not all, of the increase in systemic platelet activation markers can be accounted for by markers in the shed blood. However, platelet activation still occurs during CPB even when shed blood is not reinfused.32,34,111113

During CPB, platelets are activated, platelet thrombin receptor responsiveness is reduced, and platelet protease-activated receptor 1 (PAR1) cleavage is increased. This suggests that thrombin generated during CPB is activating platelets through PAR1.114,115 Plasmin formed by activation of the fibrinolytic system can damage and directly activate platelets through PAR4, causing them to aggregate and release α and dense granule contents.116119 Use of tranexamic acid (TXA) during CPB preserves platelet adenosine diphosphate levels, and use of aprotinin during CPB reduces platelet activation, preserves PAR1 function, and reduces platelet GPIb cleavage.67,104,115,120122

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REDUCING ACTIVATION

Ideally, hemostatic activation should be minimized during CPB and then quickly maximized after its termination. Placing the system in a sort of “hibernation” until needed would not only maintain required fluidity and reduce thrombotic risk, but also prevent the unproductive consumption of coagulation factors, fibrinogen, and platelets. Efforts to achieve this goal have focused both on modifying the conduct of CPB and its circuit, as well as pharmacologic methods to reduce the patient's response to these insults.

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Limiting Use of Cardiotomy Suction

During conventional CPB, blood in the surgical field is typically removed using cardiotomy suction (“pump suckers”) and returned to the venous reservoir where it can be oxygenated and reinfused into the patient via arterial inflow. Advantages include returning red cells and coagulation factors back to the patient. However, shed blood that has been exposed to wounded tissue surfaces has already started to activate hemostatic proteins, albeit appropriately. Pericardial blood in particular shows increased levels of F1.2, TAT, fibrin degradation products, and elevated levels of TF.81,82,92,123125 From a purely research perspective, reinfusing the already activated blood complicates data analysis by increasing the measured level of activation markers in the patient, although it may not represent “new” formation of the markers.26,32 From a clinical standpoint, shed blood contains fibrin and fibrin degradation products that can stimulate increased activity of tPA and contribute to platelet dysfunction.33,117 Thus, use of the cardiotomy suction may contribute to both “true” and “false” increases in nonhemostatic thrombin formation.

Small observational studies showed a reduction in hemostatic activation if shed blood was not reinfused, or if the cells were washed (i.e., “cell saver” was used in lieu of cardiotomy suction). Four recent studies ranging from 29 to 75 on-CPB coronary artery bypass graft (CABG) patients have shown lower markers of inflammation and platelet activation in patients in whom cardiotomy suction blood was not retransfused.112,126128 de Haan et al.,33 who conducted a study with 40 on-CPB CABG patients, demonstrated decreased blood loss and lower blood product consumption in patients who were not retransfused cardiotomy suctioned blood. Likewise, in the latest meta-analysis of cell-saver use during cardiac surgery from 1982 to 2008, the authors concluded that cell-saver use, versus retransfusion of cardiotomy suction blood, reduces exposure to allogeneic blood products when used throughout the entire surgical procedure.129 The results of all of these studies must be interpreted with the caveat that study populations were almost exclusively first-time CABG patients with CPB runs in the 2-hour range and blood volumes of approximately 1000 mL being processed through the cell saver. More-complex operations result in higher hemostatic activation,113 and longer CPB exposure resulting in higher cell-saver use would likely result in more coagulation factors and platelets being washed out.

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Increasing Circuit Biocompatibility

As mentioned above, the large foreign surface of the CPB circuit provides ample space for the deposition of fibrin and other proteins that activate platelets and leukocytes. Efforts to increase the biocompatibility of these circuits have focused on either incorporating heparin into the tubing or modifying the surface polymers to decrease protein adsorption.130 Heparin-bonded circuits have been around the longest and are the best studied. One randomized trial with high-risk patients, including those with preexisting lung or kidney impairment, showed a decreased incidence of postoperative renal dysfunction and fewer days of mechanical ventilation.131 In a meta-analysis of heparin-bonded circuits versus conventional tubing, the authors showed a modest decrease in bleeding and red cell transfusion with heparin circuits.132 Other than heparin, circuits have been coated with polymethoxyethylacrylate, phosphorylcholine, and siloxane in an attempt to make the tubing less favorable for cell binding.133136 None of the coatings, however, has demonstrated in vivo reductions in hemostatic activation.137 A more recent systematic review of biocompatible CPB circuits concluded that although they may offer some benefit in reducing red cell transfusions, a decreased incidence of atrial fibrillation, and shorter intensive care unit (ICU) stays, high-quality studies are limited and the surfaces alone do little to contain hemostatic activation without implementing additional measures.138

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Decreasing CPB Circuit Size

So-called “miniaturized” CPB has been developed with the idea of reducing blood contact with foreign material and air by using low prime-volume tubing and eliminating the venous reservoir and cardiotomy suction. In general, priming volume for miniaturized CPB systems is on the order of 500 mL versus the 1500 to 2000 mL in conventional circuits, and virtually all systems use some type of heparin-bonded tubing. Lower levels of thrombin activation have been reported with the use of miniaturized CPB.139,140 Two recent meta-analyses of randomized trials confirmed a reduced need for blood-product transfusions using the smaller circuits.141,142 However, this would be expected given the significant reduction in hemodilution using lower prime volumes. Additionally, because reinfusion of shed blood alone has been shown to increase hemostatic activation, it is not clear whether miniaturized CPB systems offer any benefit regarding hemostatic activation other than simply eliminating the cardiotomy suctions. It is likely that any combined approach using heparin-bonded circuits, adequate antifibrinolytic therapy, and removal of cardiotomy suction will reduce hemostatic activation.35

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Off-Pump Coronary Artery Bypass

Of course, the ultimate reduction in CPB circuit size is to eliminate CPB entirely. Although not practical for many cardiac operations, off-pump coronary artery bypass (OPCAB) currently comprises about 20% of coronary bypass graft procedures, and has been shown to be a viable technique with regard to graft patency.143 Although the patient still undergoes thoracotomy, heparinization, and grafting, there is no blood contact with foreign material and blood in the surgical field is generally cleared using a cell-saver device because there is no cardiotomy suction. The time course for hemostatic activation is somewhat different for OPCAB. In general, there is no early peak of thrombin generation, presumably because of the lack of contact activation, and activation of the fibrinolytic system is less.106 However, there is equal activation of the TF pathway, and thrombin generation and fibrinolytic activity are actually equal to CPB patients within 24 hours postoperatively.144 In general, studies have shown less platelet activation and dysfunction with OPCAB, leading to the potential concern of a greater prothrombotic state in the early postoperative period.145,146 Increased prothrombotic states may last as long as 1 month after surgery for both OPCAB and standard CABG on CPB, and there does not seem to be a greater risk of graft thrombosis at experienced OPCAB centers.147

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Heparin Versus DTIs

Unfractionated heparin (UFH) has been, and continues to be, the mainstay anticoagulant used for CPB, primarily because of its rapid effect and availability of a neutralizing agent (protamine). It is not a direct inhibitor of thrombin, but instead enhances the effects of AT. It is this dependency on AT that partially accounts for the drug's variable anticoagulation efficacy in individual patients and in various situations.25 However, AT levels alone cannot predict UFH's ability to achieve a desired activated clotting time (ACT) value.148 Other factors, such as the heterogeneity of UFH's chain lengths and its variable binding to endothelial cells, macrophages, and plasma proteins, affect its bioavailability.149 It is this variability that makes frequent monitoring necessary while on CPB, most commonly using the ACT. Yet, the ACT itself has significant limitations, beginning with a lack of consensus as to what ACT value reflects adequate anticoagulation for CPB.150 ACT values do not correlate well with actual heparin plasma concentrations,151 and thrombin is still activated despite values >480.5,152 Efforts to dose UFH more effectively have centered on measuring heparin plasma levels and maintaining a constant concentration. Although some studies have shown decreased hemostatic activation using this strategy,153,154 others have shown no difference than ACT-based dosing.155

Aside from dosing problems, there are other issues that prevent UFH from being an ideal anticoagulant. Heparin itself is known to cause platelet activation and stimulate fibrinolysis.156 Heparin-induced release of TF pathway inhibitor occurs as well, potentially exhausting TF pathway inhibitor stores from the endothelium.157,158 Heparin-induced thrombocytopenia (HIT), which has been extensively reviewed elsewhere,159162 is a result of antibodies formed to the complex of heparin and platelet factor 4. Approximately 25% to 50% of patients will develop the antibodies 5 to 10 days after surgery, which can lead to thrombotic complications if heparin therapy is continued in the postoperative period.163

The above limitations of heparin have helped drive the development of DTIs. A major advantage of DTIs is that AT is not required and their smaller molecular size enables greater inhibition of thrombin bound to fibrin (i.e., clot-bound versus free thrombin).164 More effective thrombin inhibition with less platelet activation would obviously be desirable for decreasing hemostatic activation. Bivalirudin, a DTI with a half-life of 25 minutes, has been shown to adequately suppress hemostatic activation on CPB when cardiotomy suction is not used.165 Interestingly, when cardiotomy suction was used, markers of activation such as D-dimer, TAT, and FPA levels were significantly increased. This is likely attributable to the fact that stagnant blood causes a tremendous amount of thrombin generation, which may locally overwhelm the reversible inhibition of the DTI. Multicenter trials using bivalirudin for CABG patients both on and off CPB have demonstrated the same safety and procedural efficacy as heparin anticoagulation, although in the United States it is currently only approved for patients with HIT undergoing percutaneous coronary interventions.166,167 Argatroban is another DTI that has been used in the setting of HIT, although the development of intraoperative thrombi has been reported when used for CPB anticoagulation.168170 Use of DTIs in the setting of CPB is also currently limited by lack of a neutralizing agent. Oral DTIs, such as dabigatran etexilate, have been developed as potential replacements for coumadin therapy, and may pose a bleeding risk when patients present to surgery. It is recommended that dabigatran therapy be discontinued 2 to 4 days before cardiac surgery, and longer in patients with impaired renal function.171

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AT Supplementation

AT levels show a 30% to 50% decrease from baseline after initiation of CPB, a consequence of both acute hemodilution and typical heparin administration, then recover, although not fully, several hours postoperatively.23,172,173 However, after prolonged CPB use, especially that associated with deep hypothermic circulatory arrest, AT levels can decrease even further and can take days to return to baseline levels.174 This can contribute to inadequate thrombin suppression with heparin, as well as potential thrombotic complications.175,176 Indeed, studies have shown that post-CPB patients with AT levels <60% of normal have a greater risk of adverse neurologic and cardiac events in the ICU.177,178 Most studies of low-dose AT supplementation during CPB have failed to show a decrease in thrombin generation, plasmin generation, or platelet activation.175,179182 Although clinical trials have shown that AT supplementation corrects heparin resistance in patients with low AT activity and reduces the need for fresh frozen plasma, outcomes have been similar to patients simply receiving additional heparin.183185

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Antifibrinolytics

As previously noted, tPA and plasmin production are increased during CPB. The lysine analogs, ε-aminocaproic acid (EACA) and TXA, are frequently used to mitigate this potentially hyperfibrinolytic state. Both agents competitively inhibit the fibrin binding site on plasminogen, thus reducing the rate of fibrinolysis, although plasmin production is unaffected.12,186 TXA is more potent than EACA, has a longer elimination half-life, and is the better studied agent in cardiac surgery.187 Its prophylactic use has been the subject of 2 large meta-analyses, with one demonstrating a reduced need for blood transfusions,188 and the other showing no benefit compared with placebo.189 Additionally, TXA may increase the risk of seizures during open heart procedures.190 By decreasing fibrinolysis without reducing thrombin generation, there is the potential for thrombotic complications. Although studies have not demonstrated increased risk of myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism from TXA or EACA use in cardiac surgery, there are case reports of retinal artery and glomerular capillary thrombosis, and the agents should probably be used with caution in patients with other risk factors for hypercoagulability.191

Aprotinin is a nonspecific serine protease inhibitor that also inhibits plasmin. Aprotinin therapy has been shown to increase the rate of plasmin inhibition 10-fold during CPB, which in turn reduced the rate of fibrin degradation a similar amount.192 Unlike the lysine analogs, however, aprotinin inhibits a broad spectrum of other proteins involved in coagulation including kallikrein, activated protein C, and thrombin.193 Platelet activation is also reduced with aprotinin therapy, possibly by protecting PAR4 receptors and by blocking thrombin activation of platelet PAR1 receptors.67,115 As such, it has both pro- and anticoagulation effects as well as antiinflammatory effects. Multiple studies have shown its efficacy at decreasing markers of hemostatic activation and preserving platelet function post-CPB.29,30,62,67,194196 Additionally, multiple clinical trials have demonstrated its efficacy at reducing transfusion of blood products during cardiac surgery.186,197 However, marketing of the drugs was suspended in November 2007 after preliminary results of the BART trial, which showed an increasing mortality trend relative to the lysine analogues.198 The underlying cause of the increased mortality is unclear, but it has been suggested that aprotinin's risk-benefit profile is more suited to patients undergoing cardiac surgical procedures at high risk for massive blood loss.199

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GENOMICS AND FUTURE DIRECTIONS

CPB-induced hemostatic activation leads to both pro- and anticoagulant activity. Despite an improved understanding of these mechanisms, it is difficult to predict whether any single patient is at greater risk for bleeding or thrombosis. There is a strong heritability of coagulation protein levels such as PAI-1, FVII, fibrinogen, and tPA.200 Although some experts have argued for routine testing of certain inherited thrombophilias such as factor V Leiden,201 the answer is not quite so simple. The dilemma has its roots in our DNA, because gene polymorphisms can significantly affect susceptibility to adverse postoperative events.202 Genetic variability is certainly present in the modulation of thrombin production, and genetic factors have been identified that contribute to bleeding after cardiac surgery.203 However, expression of certain proteins, particularly those associated with adrenergic sensitivity and cardiac myofilament structure, changes between the initiation of CPB and its termination.204 Therefore, it is not sufficient to know that a gene polymorphism is present, but the knowledge of how it is expressed under CPB conditions is also needed. Future directions will need to concentrate not only on risk stratification, but also on trying to discern how individual patients will react to CPB and who will benefit most from certain therapies such as antifibrinolytics or factor replacement therapy.

Until genetically tailored therapy becomes available, however, it is probably best to take a combined approach in reducing hemostatic activation. Adequate thrombin suppression while on CPB should be the goal, either by ensuring adequate heparin and AT levels or by using DTIs in cases of HIT. During procedures in which blood loss is not expected to be massive, specialized circuits to minimize hemodilution and avoiding reinfusion of cardiotomy blood are probably appropriate adjuvants, and may further reduce hemostatic activation. Finally, antifibrinolytic therapy should be used when hyperfibrinolysis occurs, either in the operating room or in the ICU. CPB shares many characteristics with disseminated intravascular coagulation, and suppressing hemostatic activation while it is occurring is probably the best way to avoid a massive consumptive coagulopathy or devastating thrombotic complications.

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DISCLOSURES

Name: Roman M. Sniecinski, MD.

Contribution: This author helped write the manuscript.

Attestation: Roman M. Sniecinski approved the final manuscript.

Name: Wayne L. Chandler, MD.

Contribution: This author helped write the manuscript.

Attestation: Wayne L. Chandler approved the final manuscript.

This manuscript was handled by: Jerrold H. Levy, MD, FAHA.

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REFERENCES

1. Nomura S, Ozaki Y, Ikeda Y. Function and role of microparticles in various clinical settings. Thromb Res 2008;123:8–23
2. Roberts HR, Hoffman M, Monroe DM. A cell-based model of thrombin generation. Semin Thromb Hemost 2006;32:32–8
3. Boisclair MD, Lane DA, Philippou H, Sheikh S, Hunt B. Thrombin production, inactivation and expression during open heart surgery measured by assays for activation fragments including a new ELISA for prothrombin fragment F1 + 2. Thromb Haemost 1993;70:253–8
4. Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheifh S, Hunt B, Smith KJ. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993;82:3350–7
5. Slaughter TF, LeBleu TH, Douglas JM, Leslie JB, Parker JK, Greenberg CS. Characterization of prothrombin activation during cardiac surgery by hemostatic molecular markers. Anesthesiology 1994;80:520–6
6. Philippou H, Adami A, Boisclair MD, Lane DA. An ELISA for factor X activation peptide: application to the investigation of thrombogenesis in cardiopulmonary bypass. Br J Haematol 1995;90:432–7
7. Chandler WL, Velan T. Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass. Blood 2003;101:4355–62
8. Bauer KA, Goodman TL, Kass BL, Rosenberg RD. Elevated factor Xa activity in the blood of asymptomatic patients with congenital antithrombin deficiency. J Clin Invest 1985;76:826–36
9. Shifman M, Pizzo S. The in vivo metabolism of antithrombin III and antithrombin III complexes. J Biol Chem 1982;257:3243–8
10. Leonard B, Bies R, Carlson T, Reeve EB. Further studies of the turnover of dog antithrombin III: study of 131I-labelled antithrombin protease complexes. Thromb Res 1983;30:165–77
11. Knudsen L, Hasenkam JM, Kure HH, Hughes P, Bellaiche L, Ahlburg P, Djurhuus C. Monitoring thrombin generation with prothrombin fragment 1.2 assay during cardiopulmonary bypass surgery. Thromb Res 1996;84:45–54
12. Eisses MJ, Velan T, Aldea GS, Chandler WL. Strategies to reduce hemostatic activation during cardiopulmonary bypass. Thromb Res 2006;117:689–703
13. Hampton WW, Townsend MC, Schirmer WJ, Haybron DM, Fry DE. Effective hepatic blood flow during cardiopulmonary bypass. Arch Surg 1989;124:458–9
14. Hunt BJ, Parratt RN, Segal HC, Sheikh S, Kallis P, Yacoub M. Activation of coagulation and fibrinolysis during cardiothoracic operations. Ann Thorac Surg 1998;65:712–8
15. Valen G, Eriksson E, Risberg B, Vaage J. Fibrinolysis during cardiac surgery: release of tissue plasminogen activator in arterial and coronary sinus blood. Eur J Cardiothorac Surg 1994;8:324–30
16. Harker LA, Malpass TW, Branson HE, Hessel EA II, Slichter SJ. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: acquired transient platelet dysfunction associated with selective alpha-granule release. Blood 1980;56:824–34
17. Pickering NJ, Brody JI, Fink GB, Finnegan JO, Ablaza S. The behavior of antithrombin III, alpha 2 macroglobulin, and alpha 1 antitrypsin during cardiopulmonary bypass. Am J Clin Pathol 1983;80:459–64
18. Gelb AB, Roth RI, Levin J, London MJ, Noall RA, Hauck WW, Cloutier M, Verrier E, Mangano DT. Changes in blood coagulation during and following cardiopulmonary bypass: lack of correlation with clinical bleeding. Am J Clin Pathol 1996;106:87–99
19. Mammen EF, Koets MH, Washington BC, Wolk LW, Brown JM, Burdick M, Selik NR, Wilson RF. Hemostasis changes during cardiopulmonary bypass surgery. Semin Thromb Hemost 1985;11:281–92
20. Welters I, Menges T, Ballesteros M, Knothe C, Ruwoldt R, Gorlach G, Hempelmann G. Thrombin generation and activation of the thrombomodulin protein C system in open heart surgery depend on the underlying cardiac disease. Thromb Res 1998;92:1–9
21. Chandler WL, Patel MA, Gravelle L, Soltow LO, Lewis K, Bishop PD, Spiess BD. Factor XIIIA and clot strength after cardiopulmonary bypass. Blood Coagul Fibrinolysis 2001;12:101–8
22. Davidson SJ, Burman JF, Philips SM, Onis SJ, Kelleher AA, De Souza AC, Pepper JR. Correlation between thrombin potential and bleeding after cardiac surgery in adults. Blood Coagul Fibrinolysis 2003;14:175–9
23. Chandler WL. Effects of hemodilution, blood loss, and consumption on hemostatic factor levels during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2005;19:459–67
24. Moor E, Hamsten A, Blomback M, Herzfeld I, Wiman B, Ryden L. Haemostatic factors and inhibitors and coronary artery bypass grafting: preoperative alterations and relations to graft occlusion. Thromb Haemost 1994;72:335–42
25. Yavari M, Becker RC. Coagulation and fibrinolytic protein kinetics in cardiopulmonary bypass. J Thromb Thrombolysis 2009;27:95–104
26. van den Goor JM, Nieuwland R, Rutten PM, Tijssen JG, Hau C, Sturk A, Eijsman L, de Mol BA. Retransfusion of pericardial blood does not trigger systemic coagulation during cardiopulmonary bypass. Eur J Cardiothorac Surg 2007;31:1029–36
27. Velan T, Chandler WL. Effects of surgical trauma and cardiopulmonary bypass on active thrombin concentrations and the rate of thrombin inhibition in vivo. Pathophysiol Haemost Thromb 2004;33:144–56
28. Kalweit G, Bach J, Huwer H, Winning J, Hellstern P. The impact of cardiac ischemia and reperfusion on markers of activated haemostasis and fibrinolysis during cardiopulmonary bypass: comparison of plasma levels in arterial and coronary venous blood. Thromb Res 2005;116:33–9
29. Teufelsbauer H, Proidl S, Havel M, Vukovich T. Early activation of hemostasis during cardiopulmonary bypass: evidence for thrombin mediated hyperfibrinolysis. Thromb Haemost 1992;68:250–2
30. Marx G, Pokar H, Reuter H, Doering V, Tilsner V. The effects of aprotinin on hemostatic function during cardiac surgery. J Cardiothorac Vasc Anesth 1991;5:467–74
31. Raivio P, Kuitunen A, Suojaranta-Ylinen R, Lassila R, Petaja J. Thrombin generation during reperfusion after coronary artery bypass surgery associates with postoperative myocardial damage. J Thromb Haemost 2006;4:1523–9
32. de Haan J, Boonstra PW, Tabuchi N, van Oeveren W, Ebels T. Retransfusion of thoracic wound blood during heart surgery obscures biocompatibility of the extracorporeal circuit. J Thorac Cardiovasc Surg 1996;111:272–5
33. de Haan J, Boonstra PW, Monnink SH, Ebels T, van Oeveren W. Retransfusion of suctioned blood during cardiopulmonary bypass impairs hemostasis. Ann Thorac Surg 1995;59:901–7
34. De Somer F, Van Belleghem Y, Caes F, Francois K, Van Overbeke H, Arnout J, Taeymans Y, Van Nooten G. Tissue factor as the main activator of the coagulation system during cardiopulmonary bypass. J Thorac Cardiovasc Surg 2002;123:951–8
35. Eisses MJ, Seidel K, Aldea GS, Chandler WL. Reducing hemostatic activation during cardiopulmonary bypass: a combined approach. Anesth Analg 2004;98:1208–16
36. Raivio P, Lassila R, Petaja J. Thrombin in myocardial ischemia-reperfusion during cardiac surgery. Ann Thorac Surg 2009;88:318–25
37. Hemker HC, Beguin S. Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost 1995;74:134–8
38. Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt E, Wagenvoord R, Lecompte T, Beguin S. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003;33:4–15
39. Coakley M, Hall JE, Evans C, Duff E, Billing V, Yang L, McPherson D, Stephens E, Macartney N, Wilkes AR, Collins PW. Assessment of thrombin generation measured before and after cardiopulmonary bypass surgery and its association with post-operative bleeding. J Thromb Haemost 2010;9:282–92
40. Eichinger S, Hron G, Kollars M, Kyrle PA. Prediction of recurrent venous thromboembolism by endogenous thrombin potential and D-dimer. Clin Chem 2008;54:2042–8
41. Campbell DJ. The kallikrein-kinin system in humans. Clin Exp Pharmacol Physiol 2001;28:1060–5
42. Sharma JN. Role of tissue kallikrein-kininogen-kinin pathways in the cardiovascular system. Arch Med Res 2006;37:299–306
43. Sharma JN. Involvement of the kinin-forming system in the physiopathology of rheumatoid inflammation. Agents Actions Suppl 1992;38:343–61
44. Schmaier AH, McCrae KR. The plasma kallikrein-kinin system: its evolution from contact activation. J Thromb Haemost 2007;5:2323–9
45. Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE. Studies on components of the plasma kallikrein-kinin system in patients undergoing cardiopulmonary bypass. Adv Exp Med Biol 1986;198:385–91
46. Campbell DJ, Dixon B, Kladis A, Kemme M, Santamaria JD. Activation of the kallikrein-kinin system by cardiopulmonary bypass in humans. Am J Physiol Regul Integr Comp Physiol 2001;281:R1059–70
47. Gallimore MJ, Jones DW, Winter M, Wendel HP. Changes in high molecular weight kininogen levels during and after cardiopulmonary bypass surgery measured using a chromogenic peptide substrate assay. Blood Coagul Fibrinolysis 2002;13:561–8
48. Cugno M, Nussberger J, Biglioli P, Alamanni F, Coppola R, Agostoni A. Increase of bradykinin in plasma of patients undergoing cardiopulmonary bypass: the importance of lung exclusion. Chest 2001;120:1776–82
49. Brown NJ, Gainer JV, Stein CM, Vaughan DE. Bradykinin stimulates tissue plasminogen activator release in human vasculature. Hypertension 1999;33:1431–5
50. Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost 1997;77:522–5
51. Agostoni A, Cugno M. Influence of contact system deficiencies during cardiopulmonary bypass. Thromb Haemost 2001;85:191–2
52. Stavrou E, Schmaier AH. Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis? Thromb Res 2010;125:210–5
53. Burman J, Chung H, Lane D, Philippou H, Adami A, Lincoln J. Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass. Lancet 1994;344:1192–3
54. Chung HI, Burman JF, Balogun BA, Lincoln JCR, Pepper JR. Elevated fibrinolysis in cardiopulmonary bypass is factor XII dependent. Fibrinolysis 1994;8:84–5
55. Braat EA, Dooijewaard G, Rijken DC. Fibrinolytic properties of activated FXII. Eur J Biochem 1999;263:904–11
56. Zhao X, Courtney JM, Yin HQ, West RH, Lowe GD. Blood interactions with plasticised poly (vinyl chloride): influence of surface modification. J Mater Sci Mater Med 2008;19:713–9
57. Chandler WL, Velan T. Secretion of tissue plasminogen activator and plasminogen activator inhibitor 1 during cardiopulmonary bypass. Thromb Res 2003;112:185–92
58. Tanaka K, Takao M, Yada I, Yuasa H, Kusagawa M, Deguchi K. Alterations in coagulation and fibrinolysis associated with cardiopulmonary bypass during open heart surgery. J Cardiothorac Anesth 1989;3:181–8
59. Chandler WL, Fitch JCK, Wall MH, Verrier ED, Cochran RP, Soltow LO, Spiess BD. Individual variations in the fibrinolytic response during and after cardiopulmonary bypass. Thromb Haemost 1995;74:1293–7
60. Booyse FM, Bruce R, Dolenak D, Grover M, Casey LC. Rapid release and deactivation of plasminogen activators in human endothelial cell cultures in the presence of thrombin and ionophore A23187. Semin Thromb Hemost 1986;12:228–30
61. Pretorius M, Scholl FG, McFarlane JA, Murphey LJ, Brown NJ. A pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass. Clin Pharmacol Ther 2005;78:477–85
62. Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE. Aprotinin in cardiopulmonary bypass: effects on the Hageman factor (FXII)–kallikrein system and blood loss. Blood Coagul Fibrinolysis 1992;3:99–104
63. Chandler WL, Alessi MC, Aillaud MF, Vague P, Juhan-Vague I. Formation, inhibition and clearance of plasmin in vivo. Haemostasis 2000;30:204–18
64. van den Goor JM, van Oeveren W, Rutten PM, Tijssen JG, Eijsman L. Adhesion of thrombotic components to the surface of a clinically used oxygenator is not affected by trillium coating. Perfusion 2006;21:165–72
65. Nishida H, Aomi S, Tomizawa Y, Endo M, Koyanagi H, Nojiri C, Oshiyama H, Kido T, Yokoyama K. Comparative study of biocompatibility between the open circuit and closed circuit in cardiopulmonary bypass. Artif Organs 1999;23:547–51
66. Chandler WL, Velan T. Plasmin generation and D-dimer formation during cardiopulmonary bypass. Blood Coagul Fibrinolysis 2004;15:583–91
67. de Haan J, van Oeveren W. Platelets and soluble fibrin promote plasminogen activation causing downregulation of platelet glycoprotein Ib/IX complexes: protection by aprotinin. Thromb Res 1998;92:171–9
68. Michelson AD, Barnard MR. Plasmin-induced redistribution of platelet glycoprotein Ib. Blood 1990;76:2005–10
69. Rinder CS, Bohnert J, Rinder HM, Mitchell J, Ault K, Hillman R. Platelet activation and aggregation during cardiopulmonary bypass. Anesthesiology 1991;75:388–93
70. Slaughter TF, Sreeram G, Sharma AD, El-Moalem H, East CJ, Greenberg CS. Reversible shear-mediated platelet dysfunction during cardiac surgery as assessed by the PFA-100 platelet function analyzer. Blood Coagul Fibrinolysis 2001;12:85–93
71. Velik-Salchner C, Maier S, Innerhofer P, Kolbitsch C, Streif W, Mittermayr M, Praxmarer M, Fries D. An assessment of cardiopulmonary bypass-induced changes in platelet function using whole blood and classical light transmission aggregometry: the results of a pilot study. Anesth Analg 2009;108:1747–54
72. Ray MJ, Marsh NA, Hawson GAT. Relationship of fibrinolysis and platelet function to bleeding after cardiopulmonary bypass. Blood Coagul Fibrinolysis 1994;5:679–85
73. Freyburger G, Janvier G, Dief S, Boisseau MR. Fibrinolytic and hemorheologic alterations during and after elective aortic graft surgery: implications for postoperative management. Anesth Analg 1993;76:504–12
74. Lu H, Du Buit C, Soria J, Touchot B, Chollet B, Commin PL, Conseiller C, Echter E, Soria C. Postoperative hemostasis and fibrinolysis in patients undergoing cardiopulmonary bypass with and without aprotinin therapy. Thromb Haemost 1994;72:438–43
75. Rifon J, Paramo JA, Panizo C, Montes R, Rocha E. The increase of plasminogen activator inhibitor activity is associated with graft occlusion in patients undergoing aorto-coronary bypass surgery. Br J Haematol 1997;99:262–7
76. Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 2003;75:S715–20
77. Warren OJ, Smith AJ, Alexiou C, Rogers PL, Jawad N, Vincent C, Darzi AW, Athanasiou T. The inflammatory response to cardiopulmonary bypass. Part 1. Mechanisms of pathogenesis. J Cardiothorac Vasc Anesth 2009;23:223–31
78. Warren OJ, Watret AL, de Wit KL, Alexiou C, Vincent C, Darzi AW, Athanasiou T. The inflammatory response to cardiopulmonary bypass. Part 2. Anti-inflammatory therapeutic strategies. J Cardiothorac Vasc Anesth 2009;23:384–93
79. Levy JH. Anti-inflammatory strategies and hemostatic agents: old drugs, new ideas. Hematol Oncol Clin North Am 2007;21:89–101
80. Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology 2002;97:215–52
81. Shibamiya A, Tabuchi N, Chung J, Sunamori M, Koyama T. Formation of tissue factor-bearing leukocytes during and after cardiopulmonary bypass. Thromb Haemost 2004;92:124–31
82. Chung J, Suzuki H, Tabuchi N, Sato K, Shibamiya A, Koyama T. Identification of tissue factor and platelet-derived particles on leukocytes during cardiopulmonary bypass by flow cytometry and immunoelectron microscopy. Thromb Haemost 2007;98:368–74
83. Johnell M, Elgue G, Thelin S, Larsson R, Siegbahn A. Cell adhesion and tissue factor upregulation in oxygenators used during coronary artery bypass grafting are modified by the Corline Heparin Surface. Scand Cardiovasc J 2002;36:351–7
84. Barstad RM, Ovrum E, Ringdal MA, Oystese R, Hamers MJ, Veiby OP, Rolfsen T, Stephens RW, Sakariassen KS. Induction of monocyte tissue factor procoagulant activity during coronary artery bypass surgery is reduced with heparin-coated extracorporeal circuit. Br J Haematol 1996;94:517–25
85. Tabuchi N, Shibamiya A, Koyama T, Fukuda T, van Oeveren W, Sunamori M. Activated leukocytes adsorbed on the surface of an extracorporeal circuit. Artif Organs 2003;27:591–4
86. el Habbal MH, Carter H, Smith LJ, Elliott MJ, Strobel S. Neutrophil activation in paediatric extracorporeal circuits: effect of circulation and temperature variation. Cardiovasc Res 1995;29:102–7
87. Gillinov AM, Bator JM, Zehr KJ, Redmond JM, Burch RM, Ko C, Winkelstein JA, Stuart RS, Baumgartner WA, Cameron DE. Neutrophil adhesion molecule expression during cardiopulmonary bypass with bubble and membrane oxygenators. Ann Thorac Surg 1993;56:847–53
88. Shen M, Horbett TA. The effects of surface chemistry and adsorbed proteins on monocyte/macrophage adhesion to chemically modified polystyrene surfaces. J Biomed Mater Res 2001;57:336–45
89. Parratt R, Hunt BJ. Direct activation of factor X by monocytes occurs during cardiopulmonary bypass. Br J Haematol 1998;101:40–6
90. Hattori T, Khan MM, Colman RW, Edmunds LH Jr. Plasma tissue factor plus activated peripheral mononuclear cells activate factors VII and X in cardiac surgical wounds. J Am Coll Cardiol 2005;46:707–13
91. Sturk-Maquelin KN, Nieuwland R, Romijn FP, Eijsman L, Hack CE, Sturk A. Pro- and non-coagulant forms of non-cell-bound tissue factor in vivo. J Thromb Haemost 2003;1:1920–6
92. Philippou H, Adami A, Davidson SJ, Pepper JR, Burman JF, Lane DA. Tissue factor is rapidly elevated in plasma collected from the pericardial cavity during cardiopulmonary bypass. Thromb Haemost 2000;84:124–8
93. Weiler H. Regulation of inflammation by the protein C system. Crit Care Med 2010;38:S18–25
94. Danese S, Vetrano S, Zhang L, Poplis VA, Castellino FJ. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 2010;115:1121–30
95. Musial J, Niewiarowski S, Rucinski B, Stewart GJ, Cook JJ, Williams JA, Edmunds LH Jr. Inhibition of platelet adhesion to surfaces of extracorporeal circuits by disintegrins: RGD-containing peptides from viper venoms. Circulation 1990;82:261–73
96. Tsai WB, Grunkemeier JM, McFarland CD, Horbett TA. Platelet adhesion to polystyrene-based surfaces preadsorbed with plasmas selectively depleted in fibrinogen, fibronectin, vitronectin, or von Willebrand's factor. J Biomed Mater Res 2002;60:348–59
97. Niimi Y, Ichinose F, Ishiguro Y, Terui K, Uezono S, Morita S, Yamane S. The effects of heparin coating of oxygenator fibers on platelet adhesion and protein adsorption. Anesth Analg 1999;89:573–9
98. Gorbet MB, Sefton MV. Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes. Biomaterials 2004;25:5681–703
99. Gemmell CH, Ramirez SM, Yeo EL, Sefton MV. Platelet activation in whole blood by artificial surfaces: identification of platelet-derived microparticles and activated platelet binding to leukocytes as material-induced activation events. J Lab Clin Med 1995;125:276–87
100. Grunkemeier JM, Tsai WB, Horbett TA. Hemocompatibility of treated polystyrene substrates: contact activation, platelet adhesion, and procoagulant activity of adherent platelets. J Biomed Mater Res 1998;41:657–70
101. Gemmell CH. Assessment of material-induced procoagulant activity by a modified Russell viper venom coagulation time test. J Biomed Mater Res 1998;42:611–6
102. Zillmann A, Luther T, Muller I, Kotzsch M, Spannagl M, Kauke T, Oelschlagel U, Zahler S, Engelmann B. Platelet-associated tissue factor contributes to the collagen-triggered activation of blood coagulation. Biochem Biophys Res Commun 2001;281:603–9
103. Khuri S, Wolfe J, Josa M, Axford TC, Szymanski I, Assousa S, Ragno G, Patel M, Silverman A, Park M, Valeri CR. Hematologic changes during and after cardiopulmonary bypass and their relationship to the bleeding time and nonsurgical blood loss. J Thorac Cardiovasc Surg 1992;104:94–107
104. Shigeta O, Kojima H, Jikuya T, Terada Y, Atsumi N, Sakakibara Y, Nagasawa T, Mitsui T. Aprotinin inhibits plasmin-induced platelet activation during cardiopulmonary bypass. Circulation 1997;96:569–74
105. Diago MC, Garcia-Unzueta MT, Marcano G, Merino J, Salas E, Amado JA. Serum soluble selectins in patients undergoing cardiopulmonary bypass: relationship with circulating blood cells and inflammation-related cytokines. Acta Anaesthesiol Scand 1997;41:725–30
106. Vallely MP, Bannon PG, Bayfield MS, Hughes CF, Kritharides L. Quantitative and temporal differences in coagulation, fibrinolysis and platelet activation after on-pump and off-pump coronary artery bypass surgery. Heart Lung Circ 2009;18:123–30
107. Lo B, Fijnheer R, Castigliego D, Borst C, Kalkman CJ, Nierich AP. Activation of hemostasis after coronary artery bypass grafting with or without cardiopulmonary bypass. Anesth Analg 2004;99:634–40
108. Johnell M, Elgue G, Larsson R, Larsson A, Thelin S, Siegbahn A. Coagulation, fibrinolysis, and cell activation in patients and shed mediastinal blood during coronary artery bypass grafting with a new heparin-coated surface. J Thorac Cardiovasc Surg 2002;124:321–32
109. Kongsgaard UE, Hovig T, Brosstad F, Geiran O. Platelets in shed mediastinal blood used for postoperative autotransfusion. Acta Anaesthesiol Scand 1993;37:265–8
110. Fabre O, Vincentelli A, Corseaux D, Juthier F, Susen S, Bauters A, Van Belle E, Mouquet F, Le Tourneau T, Decoene C, Crepin F, Prat A, Jude B. Comparison of blood activation in the wound, active vent, and cardiopulmonary bypass circuit. Ann Thorac Surg 2008;86:537–41
111. Koster A, Bottcher W, Merkel F, Hetzer R, Kuppe H. The more closed the bypass system the better: a pilot study on the effects of reduction of cardiotomy suction and passive venting on hemostatic activation during on-pump coronary artery bypass grafting. Perfusion 2005;20:285–8
112. Skrabal CA, Khosravi A, Choi YH, Kaminski A, Westphal B, Steinhoff G, Liebold A. Pericardial suction blood separation attenuates inflammatory response and hemolysis after cardiopulmonary bypass. Scand Cardiovasc J 2006;40:219–23
113. Takayama H, Soltow LO, Chandler WL, Vocelka CR, Aldea GS. Does the type of surgery effect systemic response following cardiopulmonary bypass? J Card Surg 2007;22:307–13
114. Ferraris VA, Ferraris SP, Singh A, Fuhr W, Koppel D, McKenna D, Rodriguez E, Reich H. The platelet thrombin receptor and postoperative bleeding. Ann Thorac Surg 1998;65:352–8
115. Day JR, Punjabi PP, Randi AM, Haskard DO, Landis RC, Taylor KM. Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery. Circulation 2004;110:2597–600
116. Niewiarowski S, Senyi AF, Gillies P. Plasmin-induced platelet aggregation and platelet release reaction: effects on hemostasis. J Clin Invest 1973;52:1647–59
117. de Haan J, Schonberger J, Haan J, van Oeveren W, Eijgelaar A. Tissue-type plasminogen activator and fibrin monomers synergistically cause platelet dysfunction during retransfusion of shed blood after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;106:1017–23
118. Mao Y, Jin J, Daniel JL, Kunapuli SP. Regulation of plasmin-induced protease-activated receptor 4 activation in platelets. Platelets 2009;20:191–8
119. Quinton TM, Kim S, Derian CK, Jin J, Kunapuli SP. Plasmin-mediated activation of platelets occurs by cleavage of protease-activated receptor 4. J Biol Chem 2004;279:18434–9
120. van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur CR. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:788–96
121. Huang H, Ding W, Su Z, Zhang W. Mechanism of the preserving effect of aprotinin on platelet function and its use in cardiac surgery. J Thorac Cardiovasc Surg 1993;106:11–8
122. Soslau G, Horrow J, Brodsky I. Effect of tranexamic acid on platelet ADP during extracorporeal circulation. Am J Hematol 1991;38:113–9
123. Khan MM, Hattori T, Niewiarowski S, Edmunds LH Jr, Colman RW. Truncated and microparticle-free soluble tissue factor bound to peripheral monocytes preferentially activate factor VII. Thromb Haemost 2006;95:462–8
124. Weerwind PW, Lindhout T, Caberg NE, De Jong DS. Thrombin generation during cardiopulmonary bypass: the possible role of retransfusion of blood aspirated from the surgical field. Thromb J 2003;1:3
125. Chung JH, Gikakis N, Rao AK, Drake TA, Colman RW, Edmunds LH. Pericardial blood activates the extrinsic coagulation pathway during clinical cardiopulmonary bypass. Circulation 1996;93:2014–8
126. Aldea GS, Soltow LO, Chandler WL, Triggs CM, Vocelka CR, Crockett GI, Shin YT, Curtis WE, Verrier ED. Limitation of thrombin generation, platelet activation, and inflammation by elimination of cardiotomy suction in patients undergoing coronary artery bypass grafting treated with heparin-bonded circuits. J Thorac Cardiovasc Surg 2002;123:742–55
127. Westerberg M, Bengtsson A, Jeppsson A. Coronary surgery without cardiotomy suction and autotransfusion reduces the postoperative systemic inflammatory response. Ann Thorac Surg 2004;78:54–9
128. Nakahira A, Sasaki Y, Hirai H, Matsuo M, Morisaki A, Suehiro S, Shibata T. Cardiotomy suction, but not open venous reservoirs, activates coagulofibrinolysis in coronary artery surgery. J Thorac Cardiovasc Surg 2011;141:1289–97
129. Wang G, Bainbridge D, Martin J, Cheng D. The efficacy of an intraoperative cell saver during cardiac surgery: a meta-analysis of randomized trials. Anesth Analg 2009;109:320–30
130. Belway D, Rubens FD. Currently available biomaterials for use in cardiopulmonary bypass. Expert Rev Med Devices 2006;3:345–55
131. Ranucci M, Mazzucco A, Pessotto R, Grillone G, Casati V, Porreca L, Maugeri R, Meli M, Magagna P, Cirri S, Giomarelli P, Lorusso R, de Jong A. Heparin-coated circuits for high-risk patients: a multicenter, prospective, randomized trial. Ann Thorac Surg 1999;67:994–1000
132. Mangoush O, Purkayastha S, Haj-Yahia S, Kinross J, Hayward M, Bartolozzi F, Darzi A, Athanasiou T. Heparin-bonded circuits versus nonheparin-bonded circuits: an evaluation of their effect on clinical outcomes. Eur J Cardiothorac Surg 2007;31:1058–69
133. Gunaydin S. Emerging technologies in biocompatible surface modifying additives: quest for physiologic cardiopulmonary bypass. Curr Med Chem Cardiovasc Hematol Agents 2004;2:295–302
134. De Somer F, Francois K, van Oeveren W, Poelaert J, De Wolf D, Ebels T, Van Nooten G. Phosphorylcholine coating of extracorporeal circuits provides natural protection against blood activation by the material surface. Eur J Cardiothorac Surg 2000;18:602–6
135. Ereth MH, Nuttall GA. Biocompatibility of Trillium Biopassive Surface-coated oxygenator versus uncoated oxygenator during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2001;15:545–50
136. Pappalardo F, Della Valle P, Crescenzi G, Corno C, Franco A, Torracca L, Alfieri O, Galli L, Zangrillo A, D'Angelo A. Phosphorylcholine coating may limit thrombin formation during high-risk cardiac surgery: a randomized controlled trial. Ann Thorac Surg 2006;81:886–91
137. Zimmermann AK, Weber N, Aebert H, Ziemer G, Wendel HP. Effect of biopassive and bioactive surface-coatings on the hemocompatibility of membrane oxygenators. J Biomed Mater Res B Appl Biomater 2007;80:433–9
138. Ranucci M, Balduini A, Ditta A, Boncilli A, Brozzi S. A systematic review of biocompatible cardiopulmonary bypass circuits and clinical outcome. Ann Thorac Surg 2009;87:1311–9
139. Fromes Y, Gaillard D, Ponzio O, Chauffert M, Gerhardt MF, Deleuze P, Bical OM. Reduction of the inflammatory response following coronary bypass grafting with total minimal extracorporeal circulation. Eur J Cardiothorac Surg 2002;22:527–33
140. Rahe-Meyer N, Solomon C, Tokuno ML, Winterhalter M, Shrestha M, Hahn A, Tanaka K. Comparative assessment of coagulation changes induced by two different types of heart-lung machine. Artif Organs 2010;34:3–12
141. Biancari F, Rimpilainen R. Meta-analysis of randomised trials comparing the effectiveness of miniaturised versus conventional cardiopulmonary bypass in adult cardiac surgery. Heart 2009;95:964–9
142. Zangrillo A, Garozzo FA, Biondi-Zoccai G, Pappalardo F, Monaco F, Crivellari M, Bignami E, Nuzzi M, Landoni G. Miniaturized cardiopulmonary bypass improves short-term outcome in cardiac surgery: a meta-analysis of randomized controlled studies. J Thorac Cardiovasc Surg 2010;139:1162–9
143. Halkos ME, Puskas JD. Off-pump coronary surgery: where do we stand in 2010? Curr Opin Cardiol 2010;25:583–8
144. Casati V, Gerli C, Franco A, Della Valle P, Benussi S, Alfieri O, Torri G, D'Angelo A. Activation of coagulation and fibrinolysis during coronary surgery: on-pump versus off-pump techniques. Anesthesiology 2001;95:1103–9
145. Untch BR, Jeske WP, Schwartz J, Botkin S, Prechel M, Walenga JM, Bakhos M. Inflammatory and hemostatic activation in patients undergoing off-pump coronary artery bypass grafting. Clin Appl Thromb Hemost 2008;14:141–8
146. Ballotta A, Saleh HZ, El Baghdady HW, Gomaa M, Belloli F, Kandil H, Balbaa Y, Bettini F, Bossone E, Menicanti L, Frigiola A, Bellucci C, Mehta RH. Comparison of early platelet activation in patients undergoing on-pump versus off-pump coronary artery bypass surgery. J Thorac Cardiovasc Surg 2007;134:132–8
147. Puskas JD, Williams WH, Mahoney EM, Huber PR, Block PC, Duke PG, Staples JR, Glas KE, Marshall JJ, Leimbach ME, McCall SA, Petersen RJ, Bailey DE, Weintraub WS, Guyton RA. Off-pump vs conventional coronary artery bypass grafting: early and 1-year graft patency, cost, and quality-of-life outcomes—a randomized trial. JAMA 2004;291:1841–9
148. Garvin S, Fitzgerald D, Muehlschlegel JD, Perry TE, Fox AA, Shernan SK, Collard CD, Aranki S, Body SC. Heparin dose response is independent of preoperative antithrombin activity in patients undergoing coronary artery bypass graft surgery using low heparin concentrations. Anesth Analg 2010;111:856–61
149. Hirsh J. Current anticoagulant therapy: unmet clinical needs. Thromb Res 2003;109:S1–8
150. Lobato RL, Despotis GJ, Levy JH, Shore-Lesserson LJ, Carlson MO, Bennett-Guerrero E. Anticoagulation management during cardiopulmonary bypass: a survey of 54 North American institutions. J Thorac Cardiovasc Surg 2010;139:1665–6
151. Fitzgerald DJ, Patel A, Body SC, Garvin S. The relationship between heparin level and activated clotting time in the adult cardiac surgery population. Perfusion 2009;24:93–6
152. Brister SJ, Ofosu FA, Buchanan MR. Thrombin generation during cardiac surgery: is heparin the ideal anticoagulant? Thromb Haemost 1993;70:259–62
153. Koster A, Fischer T, Praus M, Haberzettl H, Kuebler WM, Hetzer R, Kuppe H. Hemostatic activation and inflammatory response during cardiopulmonary bypass: impact of heparin management. Anesthesiology 2002;97:837–41
154. Despotis GJ, Joist JH, Hogue CWJ, Alsoufiev A, Kater K, Goodnough LT, Santoro SA, Spitznagel E, Rosenblum M, Lappas DG. The impact of heparin concentration and activated clotting time monitoring on blood conservation: a prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1995;110:46–54
155. Slight RD, Buell R, Nzewi OC, McClelland DB, Mankad PS. A comparison of activated coagulation time-based techniques for anticoagulation during cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2008;22:47–52
156. Khuri SF, Valeri CR, Loscalzo J, Weinstein MJ, Birjiniuk V, Healey NA, MacGregor H, Doursounian M, Zolkewitz MA. Heparin causes platelet dysfunction and induces fibrinolysis before cardiopulmonary bypass. Ann Thorac Surg 1995;60:1008–14
157. Kemme MJ, Burggraaf J, Schoemaker RC, Kluft C, Cohen AF. Quantification of heparin-induced TFPI release: a maximum release at low heparin dose. Br J Clin Pharmacol 2002;54:627–34
158. Sandset PM, Bendz B, Hansen JB. Physiological function of tissue factor pathway inhibitor and interaction with heparins. Haemostasis 2000;30:48–56
159. Levy JH, Tanaka KA, Hursting MJ. Reducing thrombotic complications in the perioperative setting: an update on heparin-induced thrombocytopenia. Anesth Analg 2007;105:570–82
160. Levy JH, Winkler AM. Heparin-induced thrombocytopenia and cardiac surgery. Curr Opin Anaesthesiol 2010;23:74–9
161. Sniecinski RM, Hursting MJ, Paidas MJ, Levy JH. Etiology and assessment of hypercoagulability with lessons from heparin-induced thrombocytopenia. Anesth Analg 2011;112:46–58
162. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg 2003;76:2121–31
163. Gluckman TJ, Segal JB, Schulman SP, Shapiro EP, Kickler TS, Prechel MM, Conte JV, Walenga JM, Shafique I, Rade JJ, Menicanti L, Frigiola A. Effect of anti-platelet factor-4/heparin antibody induction on early saphenous vein graft occlusion after coronary artery bypass surgery. J Thromb Haemost 2009;7:1457–64
164. Van De Car DA, Rao SV, Ohman EM. Bivalirudin: a review of the pharmacology and clinical application. Expert Rev Cardiovasc Ther 2010;8:1673–81
165. Koster A, Yeter R, Buz S, Kuppe H, Hetzer R, Lincoff AM, Dyke CM, Smedira NG, Spiess B, Menicanti L, Frigiola A. Assessment of hemostatic activation during cardiopulmonary bypass for coronary artery bypass grafting with bivalirudin: results of a pilot study. J Thorac Cardiovasc Surg 2005;129:1391–4
166. Smedira NG, Dyke CM, Koster A, Jurmann M, Bhatia DS, Hu T, McCarthy HL II, Lincoff AM, Spiess BD, Aronson S. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg 2006;131:686–92
167. Dyke CM, Smedira NG, Koster A, Aronson S, McCarthy HL II, Kirshner R, Lincoff AM, Spiess BD. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006;131:533–9
168. Martin ME, Kloecker GH, Laber DA. Argatroban for anticoagulation during cardiac surgery. Eur J Haematol 2007;78:161–6
169. Smith AI, Stroud R, Damiani P, Vaynblat M. Use of argatroban for anticoagulation during cardiopulmonary bypass in a patient with heparin allergy. Eur J Cardiothorac Surg 2008;34:1113–4
170. Follis F, Filippone G, Montalbano G, Floriano M, Lobianco E, D'Ancona G, Follis M. Argatroban as a substitute of heparin during cardiopulmonary bypass: a safe alternative? Interact Cardiovasc Thorac Surg 2010;10:592–6
171. Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 2011;123:1436–50
172. Zaidan JR, Johnson S, Brynes R, Monroe S, Guffin AV. Rate of protamine administration: its effect on heparin reversal and antithrombin recovery after coronary artery surgery. Anesth Analg 1986;65:377–80
173. Ranucci M, Ditta A, Boncilli A, Cotza M, Carboni G, Brozzi S, Bonifazi C, Tiezzi A. Determinants of antithrombin consumption in cardiac operations requiring cardiopulmonary bypass. Perfusion 2004;19:47–52
174. Okita Y, Takamoto S, Ando M, Morota T, Yamaki F, Matsukawa R, Kawashima Y. Coagulation and fibrinolytic system in aortic surgery under deep hypothermic circulatory arrest with aprotinin: importance of adequate heparinization. Circulation 1997;96:II-376–81
175. Slaughter TF, Mark JB, El-Moalem H, Hayward KA, Hilton AK, Hodgins LP, Greenberg CS. Hemostatic effects of antithrombin III supplementation during cardiac surgery: results of a prospective randomized investigation. Blood Coagul Fibrinolysis 2001;12:25–31
176. Sniecinski R, Szlam F, Chen EP, Bader SO, Levy JH, Tanaka KA. Antithrombin deficiency increases thrombin activity after prolonged cardiopulmonary bypass. Anesth Analg 2008;106:713–8
177. Ranucci M, Frigiola A, Menicanti L, Ditta A, Boncilli A, Brozzi S. Postoperative antithrombin levels and outcome in cardiac operations. Crit Care Med 2005;33:355–60
178. Garvin S, Muehlschlegel JD, Perry TE, Chen J, Liu KY, Fox AA, Collard CD, Aranki SF, Shernan SK, Body SC. Postoperative activity, but not preoperative activity, of antithrombin is associated with major adverse cardiac events after coronary artery bypass graft surgery. Anesth Analg 2010;111:862–9
179. Koster A, Fischer T, Gruendel M, Mappes A, Kuebler WM, Bauer M, Kuppe H. Management of heparin resistance during cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation. J Cardiothorac Vasc Anesth 2003;17:171–5
180. Avidan MS, Levy JH, van Aken H, Feneck RO, Latimer RD, Ott E, Martin E, Birnbaum DE, Bonfiglio LJ, Kajdasz DK, Despotis GJ. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg 2005;130:107–13
181. Levy JH, Despotis GJ, Szlam F, Olson P, Meeker D, Weisinger A, Menicanti L, Frigiola A. Recombinant human transgenic antithrombin in cardiac surgery: a dose-finding study. Anesthesiology 2002;96:1095–102
182. Rossi M, Martinelli L, Storti S, Corrado M, Marra R, Varano C, Schiavello R, Menicanti L, Frigiola A. The role of antithrombin III in the perioperative management of the patient with unstable angina. Ann Thorac Surg 1999;68:2231–6
183. Williams MR, D'Ambra AB, Beck JR, Spanier TB, Morales DL, Helman DN, Oz MC. A randomized trial of antithrombin concentrate for treatment of heparin resistance. Ann Thorac Surg 2000;70:873–7
184. Avidan MS, Levy JH, Scholz J, Delphin E, Rosseel PM, Howie MB, Gratz I, Bush CR, Skubas N, Aldea GS, Licina M, Bonfiglio LJ, Kajdasz DK, Ott E, Despotis GJ. A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass. Anesthesiology 2005;102:276–84
185. Conley JC, Plunkett PF, Menicanti L, Frigiola A. Antithrombin III in cardiac surgery: an outcome study. J Extra Corpor Technol 1998;30:178–83
186. Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007;356:2301–11
187. Ozier Y, Bellamy L. Pharmacological agents: antifibrinolytics and desmopressin. Best Pract Res Clin Anaesthesiol 2010;24:107–19
188. Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, McClelland B, Laupacis A, Fergusson D. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007;4:CD001886
189. Brown JR, Birkmeyer NJ, O'Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007;115:2801–13
190. Martin K, Wiesner G, Breuer T, Lange R, Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients. Anesth Analg 2008;107:1783–90
191. Ide M, Bolliger D, Taketomi T, Tanaka KA. Lessons from the aprotinin saga: current perspective on antifibrinolytic therapy in cardiac surgery. J Anesth 2010;24:96–106
192. Kang HM, Kalnoski MH, Frederick M, Chandler WL, Menicanti L, Frigiola A. The kinetics of plasmin inhibition by aprotinin in vivo. Thromb Res 2005;115:327–40
193. Levy JH, Sypniewski E. Aprotinin: a pharmacologic overview. Orthopedics 2004;27:s653–8
194. Segal H, Sheikh S, Kallis P, Cottam S, Beard C, Potter D, Townsend E, Bidstrup BP, Yacoub M, Hunt BJ. Complement activation during major surgery: the effect of extracorporeal circuits and high-dose aprotinin therapy. J Cardiothorac Vasc Anesth 1998;12:542–7
195. Longstaff C. Studies on the mechanisms of action of aprotinin and tranexamic acid as plasmin inhibitors and antifibrinolytic agents. Blood Coagul Fibrinolysis 1994;5:537–42
196. Rossi M, Storti S, Martinelli L, Varano C, Marra R, Zamparelli R, Possati G, Schiavello R. A pump-prime aprotinin dose in cardiac surgery: appraisal of its effects on the hemostatic system. J Cardiothorac Vasc Anesth 1997;11:835–9
197. Ray MJ, Marsh NA. Aprotinin reduces blood loss after cardiopulmonary bypass by direct inhibition of plasmin. Thromb Haemost 1997;78:1021–6
198. Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussieres JS, Cote D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319–31
199. Karkouti K, Wijeysundera DN, Yau TM, McCluskey SA, Tait G, Beattie WS. The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery. Anesth Analg 2010;110:21–9
200. Perry TE, Muehlschlegel JD, Body SC. Genomics: risk and outcomes in cardiac surgery. Anesthesiol Clin 2008;26:399–417
201. Shore-Lesserson L, Reich DL. A case of severe diffuse venous thromboembolism associated with aprotinin and hypothermic circulatory arrest in a cardiac surgical patient with factor V Leiden. Anesthesiology 2006;105:219–21
202. Podgoreanu MV, Schwinn DA. New paradigms in cardiovascular medicine: emerging technologies and practices—perioperative genomics. J Am Coll Cardiol 2005;46:1965–77
203. Welsby IJ, Podgoreanu MV, Phillips-Bute B, Mathew JP, Smith PK, Newman MF, Schwinn DA, Stafford-Smith M. Genetic factors contribute to bleeding after cardiac surgery. J Thromb Haemost 2005;3:1206–12
204. Clements RT, Smejkal G, Sodha NR, Ivanov AR, Asara JM, Feng J, Lazarev A, Gautam S, Senthilnathan V, Khabbaz KR, Bianchi C, Sellke FW. Pilot proteomic profile of differentially regulated proteins in right atrial appendage before and after cardiac surgery using cardioplegia and cardiopulmonary bypass. Circulation 2008;118:S24–31
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