Activation of the Hemostatic System During Cardiopulmonary Bypass

REVIEW ARTICLE

Activation of the Hemostatic System DuringCardiopulmonary BypassRoman M. Sniecinski, MD,* and Wayne L. Chandler, MD†

Cardiopulmonary bypass (CPB) is a unique clinical scenario that results in widespreadactivation of the hemostatic system. However, surgery also results in normal increases incoagulation activation, platelet activation, and fibrinolysis that are associated with normalwound hemostasis. Conventional CPB interferes with normal hemostasis by diluting hemo-static cells and proteins, through reinfusion of shed blood, and through activation on thebypass circuit surface of multiple systems including platelets, the kallikrein-kinin system, andfibrinolysis. CPB activation of the kallikrein-kinin system increases activated factor XIIa,kallikrein, bradykinin, and tissue plasminogen activator levels, but has little effect onthrombin generation. Increased tissue plasminogen activator and circulating fibrin result inincreased plasmin generation, which removes hemostatic fibrin. The nonendothelial surface ofthe 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 highlightthe major mechanisms responsible for CPB-induced activation of the hemostatic system andexamine some of the markers described in the literature. Additionally, strategies used toreduce this activation are discussed, including limiting cardiotomy suction, increasing circuitbiocompatibility, antithrombin supplementation, and antifibrinolytic use. Determining whichpatients will most benefit from specific therapies will ultimately require investigation intogenetic phenotypes of coagulation protein expression. Until that time, however, a combinationof approaches to reduce the hemostatic activation from CPB seems warranted. (Anesth Analg2011;113:1319–33)

The hemostatic system consists of 4 integrated com-ponents: the coagulation system, endothelium andregulatory proteins, platelets, and fibrinolysis. These

elements work together to prevent blood loss from injuredvasculature without occluding the entire vessel. In certainsituations, however, this activation inappropriately spreadssystemically, creating both coagulopathy and thromboticcomplications. Cardiac surgery with the use of cardiopul-monary bypass (CPB) is one such scenario that results inwidespread activation of the hemostatic system. This canresult in micro thrombi during CPB, coagulation defectsafter its termination, and even hypercoagulability leadingto thrombotic complications in the postoperative period. Inthis review, we examine the current concepts thought to beinvolved with CPB-induced activation of the hemostaticsystem, as well as some of the potential interventions tominimize clinical sequelae.

THE IMPORTANCE OF THROMBIN ANDITS MEASUREMENTAt the site of a wound (Fig. 1), platelets bind to collagenthrough von Willebrand factor, activate and aggregate

forming an initial hemostatic plug. Active factor VII (FVIIa)in blood binds wound tissue factor (TF) leading to activa-tion of factor IX (FIXa) and factor X (FXa), which in turnactivate prothrombin to thrombin.1,2 Once thrombin isformed, it becomes the key regulatory protein, activatingplatelets and factors V, VIII, and XI, which acceleratescoagulation, while activation of fibrinogen and factor XIIIstabilizes the hemostatic clot. Thrombin formed at the siteof a wound we term “hemostatic” thrombin because it isparticipating in normal hemostasis.

Under some conditions, thrombin and fibrin may begenerated without wounds. This can occur locally as indeep venous thrombosis or systemically because of wide-spread organ damage (shock, sepsis) or systemic release ofprocoagulants such as TF and anionic phospholipids (braininjury). Excessive local or systemic thrombin and fibrinformation are not being made in response to a wound sitebut represent dysregulation of the coagulation system andmay result in consumptive coagulopathy and in some casesdisseminated intravascular coagulation, bleeding, andthrombosis. This is termed “nonhemostatic” thrombin andfibrin.

The average amount of thrombin produced in vivothroughout the vascular system can be estimated by mea-suring levels of the thrombin activation markers prothrom-bin fragment F1.2 or thrombin-antithrombin complex(TAT).3–6 The rate of thrombin production is not the sameas the average level of thrombin activity in blood. Theaverage amount of thrombin activity in vivo can be esti-mated by measuring fibrinopeptide A (FPA) levels, ameasure of fibrinogen activation to fibrin by thrombin (Fig.2). To interpret activation markers, it is important tounderstand how changes in production of the marker affectmarker levels. If the marker has a short half-life and rapidclearance such as FPA (t1/2 4 minutes) or TAT (t1/2 10

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

Accepted for publication August 22, 2011.

The authors declare no conflicts of interest.

Wayne L. Chandler, MD, is currently affiliated with the Department ofPathology 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 Hos-pital, Methodist Pathology Associates, 6565 Fannin St., Suite B-490, Houston,TX 77030. Address e-mail to [email protected].

Copyright © 2011 International Anesthesia Research SocietyDOI: 10.1213/ANE.0b013e3182354b7e

December 2011 • Volume 113 • Number 6 www.anesthesia-analgesia.org 1319

minutes), the concentration of the marker in blood willchange in parallel with the formation rate and is essentiallya direct measure of the formation rate of the marker.7–10 Ifthe marker has a longer half-life and slower clearance suchas prothrombin activation peptide F1.2 (t1/2 90 minutes) ord-dimer (t1/2 8 hours), the concentration of the markerduring CPB is cumulative, thus the change or slope of theconcentration versus time curve is proportional to theformation rate, not the concentration itself.11,12 Mostactivation markers are proteins or protein fragments thatare cleared by the liver. The clearance rate remains thesame even when marker production is increased.8 Inmost patients, liver blood flow is well maintained duringCPB and marker clearance seems to be similar to preop-erative values.13

The surgical wound produces increased hemostaticthrombin and fibrin at the wound site, but has littlesystemic effect.6,7,14,15 Immediately after going on CPB,hemodilution by the priming fluid in the bypass circuitreduces all factors in blood including coagulation factors,inhibitors, and activation markers, by approximately 30%to 40% (Fig. 3).16–23 Changes during CPB in stable factorlevels with long half-lives, such as albumin, coagulationproteins, and antithrombin (AT), primarily reflect hemodi-lution, blood loss, and transfusion with consumption hav-ing only a minor role.16,18,21,23

Hemodilution tends to obscure the underlying changesoccurring in the hemostatic system during CPB.24,25 Be-cause all proteins in the blood are diluted equally at thestart of CPB, any factor that does not decrease must beundergoing a rapid increase in formation to maintain itsconcentration at preoperative levels. Most studies present

activation data as marker level versus sample number withno reference to time or hemodilution effects (Fig. 4). Withthis kind of data, it is difficult to gauge what the underlyingrate of activation is. One approach is correction for hemodi-lution, that is, dividing results by the average percentchange in stable factor levels to give an indication of whatthe marker level would be if hemodilution had not oc-curred.26 If hemodilution-corrected results are plotted ver-sus sample time, it is possible to get a sense of themagnitude and rate of change in the system (Fig. 4). Theproblem with correction for hemodilution is that it pro-duces a set of values that are not the actual measuredvalues from the patient, but adjusted values based on asimple dilution model.

Another approach to the analysis of hemostatic data is touse a computer to account for changes in marker levelscaused by alternations of patient blood volume, hemodilu-tion, blood loss, blood transfusion, timing of samples, andclearance of proteins. In most studies, none of these factorsis accounted for when presenting raw measurements ofmarker levels in blood, yet conclusions are drawn fromchanges in the marker levels as if these effects were known.Computer analysis or modeling allows the reader to knowthe specific assumptions made in analyzing the data, whatwas accounted for, and what was not. As new informationis developed, the model can be updated to improve theanalysis. When all of the factors affecting marker levels areaccounted for, it is possible to estimate the formation rate invivo of thrombin or other factors. It is further possible tovalidate the estimate of formation rate by comparing ratesbased on different markers that measure the same processbut have different clearance rates and thus marker patterns

Figure 1. Normal hemostasis. 1, Initial plug formation begins with von Willebrand factor (VWF) binding to collagen in the wound and platelets(plt) adhering to VWF. 2, Coagulation is initiated by small amounts of active factor VII (FVIIa) in blood binding to the exposed tissue factor (TF)in the wound, leading to activation of factor IX (FIXa) and factor X (FXa), which in turn initiates the conversion of prothrombin to thrombin.Thrombin creates a positive feedback loop by activating factors VIII (FVIIIa) and V (FVa), which increases FIXa and FXa’s conversion ofprothrombin to thrombin. This local burst of thrombin production at the wound site converts soluble fibrinogen into a fibrin mesh that stabilizesthe initial plug. 3, Clot formation away from the site of injury is prevented by antithrombin (AT), which destroys thrombin and FXa, FIXa, andFXIa, activated protein C (APC), which destroys FVIIIa and FVa, and tissue factor pathway inhibitor (TFPI), which destroys TF-VIIa complexes.4, Additionally, the endothelium (endo) secretes tissue plasminogen activator (tPA), which binds to fibrin and converts plasminogen to plasmin,which in turn lyses the fibrin. Once a stable clot is formed and the wounded tissue is no longer exposed, the regulatory proteins and fibrinolyticproteins prevent further thrombus formation.

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1320 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

for raw data. Figure 4 shows the estimated in vivo throm-bin generation rate in one patient during CPB based onmeasured levels of both F1.2 and TAT, which showeddifferent 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 theaverage or best fit data using both markers.7 Computermodeling is not the same as de novo simulation; model-ing is essentially a more complete method for correctinghemodilution and other processes that affect markerlevels.

Conventional CPB leads to substantial increases inthrombin activation markers, unrelated to the surgicalwound itself. Figure 5 shows the estimated rate of thrombingeneration, total fibrin generation, and soluble fibrin gen-eration using computer analysis of data from one study ofconventional CPB.7 After thoracotomy, there was only asmall increase in the total amount of thrombin and fibringenerated.6,7,14,15 However, within 5 minutes of startingCPB, thrombin generation and soluble fibrin formationboth increased approximately 20-fold, but because thepatient was heparinized, thrombin activity and total fibringeneration actually decreased.7,11,14,27 Normally, fibrindoes not circulate in blood; it is present only at the site ofthe wound. Soluble fibrin is nonhemostatic fibrin formed incirculating blood due to dysregulation of hemostasis insome way. Under normal circumstances, only approxi-mately 1% of the fibrin formed circulates as soluble fibrin,and the remainder stays in the wound.7 Soon after CPB isstarted, total fibrin formation is reduced because of hepa-rinization whereas soluble fibrin formation is increased toapproximately 35% of the total. This indicates that much ofthe thrombin being formed during CPB is nonhemostaticthrombin, in turn producing soluble fibrin. Non–wound-related thrombin generation and soluble fibrin formationcontinue to be 5- to 10-fold increased throughout theremainder of CPB. Soluble and circuit-bound fibrin providebinding sites for non–wound-related thrombin that pro-tects this thrombin from inhibition by AT, necessitatinghigh-dose heparin as an anticoagulant.

Another burst of nonhemostatic thrombin and solublefibrin generation occurs after reperfusion of the heart andlungs.7,11,15,28–31 Thrombin generation after reperfusionmay be involved in myocardial ischemia-reperfusion injuryand impaired hemodynamic recovery, but the increase inthrombin generation after reperfusion is reduced or elimi-nated if shed blood is not reinfused.12,32–36 After protaminereversal, there is another peak in thrombin generation asmore thrombin and fibrin are produced at the site of thewound.7,27 The increase in postoperative thrombin genera-tion lasts hours to days and then begins to decrease towardbaseline levels.

An in vitro thrombin generation test, also calledcalibrated automated thrombography, measures the abil-ity of plasma to generate thrombin when stimulated,termed the “endogenous thrombin potential” (ETP).37,38

Briefly, the method adds TF and phospholipids to thepatient’s platelet-poor plasma and monitors the cleavageof a fluorogenic substrate, producing a curve, the areaunder which represents ETP. Low ETP, such as can occurafter CPB, may indicate a hypocoagulable state andbleeding risk,22,39 whereas high ETP may predict pos-sible thrombotic risk.40 Two limitations of the ETP are

Figure 2. Thrombin production versus activity on cardiopulmonarybypass (CPB). Sample times are 1 � baseline (BL), 2 � aftersternotomy, 3 � after heparinization, 4 to 6 � 5, 15, and 30minutes on CPB, 7 � before removal of aortic cross-clamp, 8 � afterremoval of cross-clamp, 9 � after protamine administration, 10 � 2hours postoperatively. (Adapted from Eisses et al.35)

Figure 3. Effect of hemodilution on stable factor levels. Hemodilutionduring cardiopulmonary bypass (CPB) has a similar effect on thelevel of all stable factors in blood as shown for antiplasmin,plasminogen, fibrinogen, antithrombin, and prothrombin. (Adaptedfrom Chandler.23)

Hemostasis and Cardiopulmonary Bypass


CPBCPB

CPB CPB

CPB

Original Thrombin Marker Data

Hemodilution Corrected vs Time

Estimated In Vivo Thrombin Generation

Figure 4. Computer model of in vivo thrombin production. This figure shows 2 approaches used to analyze in vivo thrombin production duringcardiopulmonary bypass (CPB). The top row of graphs shows the original measured levels of thrombin activation markers. The second row showshemodilution corrected marker levels versus sampling time, a better indicator of the magnitude and rate of marker changes. Using both F1.2 andthrombin-antithrombin complex data, the bottom graph shows the estimated in vivo thrombin generation rate in the patient based on analysis of thedata using a computer model of the patient’s vascular system that accounted for hemodilution, blood loss, transfusion, and marker clearance. The2 peaks correlate with commencement of CPB and release of the aortic cross-clamp. (This research was originally published in Blood. Chandler WL,Velan T. Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass. Blood 2003;101:4355–4362. © the AmericanSociety of Hematology.)

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that it measures the ability of plasma to produce throm-bin in vitro, which is not the same as thrombin genera-tion in vivo, hence the term thrombin “potential,” and

that the test cannot be run in the presence of heparin ordirect thrombin inhibitors (DTIs).

MECHANISMS OF ACTIVATIONHemostatic system activation occurs via several mecha-nisms including the contact system, fibrinolysis, inflamma-tion, and platelets. This is summarized in Figure 6 anddetailed in the sections below.

The Contact SystemKinins are a diverse set of proteins involved in vasculartone, patency, and tissue repair.41 The best studied memberof this family is bradykinin, which may have a role inattenuating cardiac ischemia and hypertension.42 Kininsare synthesized as kininogens, of either high molecularweight (HMWK) or low molecular weight, and are inactiveuntil cleaved by proteins known as kallikreins. In plasma,kallikrein circulates in an inactive form known as prekalli-krein, or Fletcher factor, until activated by factor XIIa, alsoknown as Hageman factor. The “contact system” refers tofactor XII, factor XI, HMWK, and prekallikrein, which areassociated proteins that travel together in the plasma. Thereis normally a low level of kallikrein activity on endothelialcell surfaces producing kinins, including bradykinin, thatare rapidly degraded by kininases, which are enzymesfound in plasma and in high concentrations in kidney andlung tissue.43,44

Once CPB is initiated, there is a dramatic increase incontact system activity as blood touches the artificial ma-terial comprising the CPB circuit.45,46 Factor XII auto-cleaves itself upon contact with a variety of anionic surfacesincluding glass, polyethylene, and silicone rubber, andproduces FXIIa, which converts prekallikrein to activekallikrein. Plasma kallikrein creates a positive feedbackloop by cleaving more FXII, as well as producing brady-kinin from HMWK. Prekallikrein and HMWK levels de-crease not only because of hemodilution, but also because

Figure 5. Estimated thrombin, total fibrin, and soluble fibrin genera-tion rates during conventional cardiopulmonary bypass (CPB). Errorbars indicate the standard error. White squares indicate a significantdifference (P � 0.05) from baseline. Values based on computermodeling. (Adapted from Chandler and Velan7 and Eisses et al.12)

Figure 6. Summary of hemostatic activa-tion mechanisms on cardiopulmonary by-pass (CPB). BK � bradykinin; FXIIa �activated factor XII; TF � tissue factor;TPA � tissue plasminogen activator; Plt �platelets; Fib � fibrin degradation prod-ucts; Endo � endothelium. Details pro-vided in text.



of consumption and binding to the CPB circuit.47 Brady-kinin levels increase 10-fold due to increased HMWKcleavage as well as reduced lung clearance because pulmo-nary blood flow is minimal.46,48 This has important impli-cations for fibrinolysis because elevated bradykinin levelsinduce secretion of tissue plasminogen activator (tPA) (seebelow).49,50

The role of FXIIa in activation of the hemostatic systemremains unclear.51 Besides producing kallikrein, FXIIa hasbeen shown to convert FXI to FXIa in vitro, thus initiating theintrinsic pathway of coagulation. However, FXII-deficientpatients do not have hemostatic defects, indicating that FXIIadoes not normally have a role in hemostasis.52 Indeed, FXIIdeficiency does not stop the increase in thrombin generationduring CPB.53,54 However, FXIIa has been shown to activateplasminogen to plasmin in vitro, suggesting its possible rolein inducing fibrinolysis during CPB.55,56 Additionally, FXIIaand other fragments of FXII activate the classic complementcascade, accounting for some of the “crosstalk” betweencoagulation and inflammation.

The Fibrinolytic SystemEndothelial cell release of tPA is a major activator ofplasminogen, turning it into fibrin-degrading plasmin. Onaverage, CPB stimulates a 5-fold increase in tPA secretionand active tPA levels,15,57,58 although there is some vari-ability and approximately one-third of patients may showno change.59 Although active thrombin has been shown torelease tPA in vitro,60 human in vivo studies are lackingand it is more likely that bradykinin is the main stimulus.Indeed, tPA release has been shown to be reduced byblocking bradykinin receptors or reducing its productionby inhibiting kallikrein.61,62

Increased tPA alone does not increase fibrinolytic activ-ity if no fibrin is present. d-dimer levels, an indicator offibrin degradation, do not change under normal conditions,even when tPA levels are transiently increased 10-fold.63 Inthe setting of CPB, however, soluble and circuit-boundfibrin provide a huge surface for plasminogen activation tooccur.56,64,65 There is a 10- to 100-fold increase in plasmingeneration shortly after the commencement of CPB, andplasmin generation, along with fibrin degradation, remainincreased 10- to 20-fold throughout the duration of CPB.66

Normally only 1% of fibrin is degraded by the fibrinolyticsystem, with the remainder being removed by cells duringwound healing. During CPB, however, fibrin formationand degradation rates are nearly equal, indicating thatmuch of the fibrin degradation is not at the sites of vascularinjury. This hyperfibrinolytic state consumes fibrinogen,leaving less available for coagulation postoperatively. Ad-ditionally, large amounts of plasmin can damage plateletsthrough cleavage of their glycoprotein (GP)Ib receptor,67,68

and partially activate them (see below), making them lessresponsive to further activation with agonists such asadenosine diphosphate and arachidonic acid.69–71

It is important to recognize that a hypofibrinolytic statecan also occur postoperatively. Plasminogen activator in-hibitor 1 (PAI-1) prevents the formation of plasmin. Al-though 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.66,72–74 This in-crease may continue into the first postoperative day, whichis associated with an increased risk of coronary graftocclusion.75 Similar to tPA levels, there is some variabilitywith approximately one-third of patients showing no post-operative PAI-1 increase.59 This individual variability isone of the reasons it is difficult to predict which patients areat risk for bleeding versus thrombosis.

InflammationThe coagulation and immune responses are linked; a breakin the vasculature not only must be fixed, but also anyforeign invaders neutralized. Inflammation has multiplemediators that can create profound amplification, some-times resulting in an out-of-proportion response to thestimulating event and causing pathologic conditions in thehost. A sepsis-like clinical picture that often results fromCPB, termed the systemic inflammatory response syn-drome, can be linked to “crosstalk” with the coagulationsystem and has been extensively reviewed elsewhere.76–80

A few key points will be emphasized here.Leukocytes, including neutrophils and monocytes, bind

to and are activated by the surface of the bypass cir-cuit,64,81–88 which leads to an increase in TF expression,procoagulant activation, and thrombin generation on thesecells.83–85,89 Shed blood contains increased numbers ofactivated leukocytes and levels of TF bound to cells andmicroparticles, as well as soluble TF.81,82,90–92 CPB alsoalters the protein C system. Protein C is activated by thebinding of thrombin to thrombomodulin expressed onendothelial cells. This normally functions to suppress fur-ther thrombin formation away from the wound by destroy-ing FVIIIa and FVa. Activated protein C also binds withendothelial protein C receptors to downregulate cytokineproduction and decrease vascular permeability.93,94 In ad-dition to hemodilution, CPB further decreases protein Clevels by downregulating thrombomodulin and endothelialprotein C receptor expression of the endothelium. Overall,systemic inflammatory response syndrome caused by CPBincreases TF expression while simultaneously depressingprotein C activation, thereby favoring the production ofthrombin.

PlateletsFibrinogen bound to the CPB circuit provides a largebinding site for platelets through their GPIIb/IIIa receptors.Once platelets bound to either the vascular system or to thecircuit are activated, they spread pseudopods, expressreceptors, release granules and microparticles, and supportthrombin formation.64,95–101 Additionally, there is someevidence that leukocytes may stimulate TF release directlyfrom platelets.102 CPB increases platelet activation markersincluding �-thromboglobulin, platelet factor 4, soluble andplatelet P-selectin, and platelet GMP140 (granule mem-brane protein 140).16,30,32,34,69,103–108 Shed blood showsevidence of platelet activation including reduced plateletlevels, increased platelet activation markers, increased mi-croparticles, and decreased platelet responsiveness.32,108–110

When shed blood is reinfused, part, but not all, of theincrease in systemic platelet activation markers can beaccounted for by markers in the shed blood. However,

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platelet activation still occurs during CPB even when shedblood is not reinfused.32,34,111–113

During CPB, platelets are activated, platelet thrombinreceptor responsiveness is reduced, and platelet protease-activated receptor 1 (PAR1) cleavage is increased. Thissuggests that thrombin generated during CPB is activatingplatelets through PAR1.114,115 Plasmin formed by activa-tion of the fibrinolytic system can damage and directlyactivate platelets through PAR4, causing them to aggregateand release � and dense granule contents.116–119 Use oftranexamic acid (TXA) during CPB preserves platelet aden-osine diphosphate levels, and use of aprotinin during CPBreduces platelet activation, preserves PAR1 function, andreduces platelet GPIb cleavage.67,104,115,120–122

REDUCING ACTIVATIONIdeally, hemostatic activation should be minimized duringCPB and then quickly maximized after its termination.Placing the system in a sort of “hibernation” until neededwould not only maintain required fluidity and reducethrombotic risk, but also prevent the unproductive con-sumption of coagulation factors, fibrinogen, and platelets.Efforts to achieve this goal have focused both on modifyingthe conduct of CPB and its circuit, as well as pharmacologicmethods to reduce the patient’s response to these insults.

Limiting Use of Cardiotomy SuctionDuring conventional CPB, blood in the surgical field istypically removed using cardiotomy suction (“pump suck-ers”) and returned to the venous reservoir where it can beoxygenated and reinfused into the patient via arterialinflow. Advantages include returning red cells and coagu-lation factors back to the patient. However, shed blood thathas been exposed to wounded tissue surfaces has alreadystarted to activate hemostatic proteins, albeit appropriately.Pericardial blood in particular shows increased levels ofF1.2, TAT, fibrin degradation products, and elevated levelsof TF.81,82,92,123–125 From a purely research perspective,reinfusing the already activated blood complicates dataanalysis by increasing the measured level of activationmarkers in the patient, although it may not represent“new” formation of the markers.26,32 From a clinical stand-point, shed blood contains fibrin and fibrin degradationproducts that can stimulate increased activity of tPA andcontribute to platelet dysfunction.33,117 Thus, use of thecardiotomy suction may contribute to both “true” and“false” increases in nonhemostatic thrombin formation.

Small observational studies showed a reduction in he-mostatic activation if shed blood was not reinfused, or if thecells were washed (i.e., “cell saver” was used in lieu ofcardiotomy suction). Four recent studies ranging from 29 to75 on-CPB coronary artery bypass graft (CABG) patientshave shown lower markers of inflammation and plateletactivation in patients in whom cardiotomy suction bloodwas not retransfused.112,126–128 de Haan et al.,33 who con-ducted a study with 40 on-CPB CABG patients, demon-strated decreased blood loss and lower blood productconsumption in patients who were not retransfused car-diotomy suctioned blood. Likewise, in the latest meta-analysis of cell-saver use during cardiac surgery from 1982to 2008, the authors concluded that cell-saver use, versus

retransfusion of cardiotomy suction blood, reduces expo-sure to allogeneic blood products when used throughoutthe entire surgical procedure.129 The results of all of thesestudies must be interpreted with the caveat that studypopulations were almost exclusively first-time CABG pa-tients with CPB runs in the 2-hour range and blood volumesof approximately 1000 mL being processed through the cellsaver. More-complex operations result in higher hemostaticactivation,113 and longer CPB exposure resulting in highercell-saver use would likely result in more coagulationfactors and platelets being washed out.

Increasing Circuit BiocompatibilityAs mentioned above, the large foreign surface of the CPBcircuit provides ample space for the deposition of fibrinand other proteins that activate platelets and leukocytes.Efforts to increase the biocompatibility of these circuitshave focused on either incorporating heparin into thetubing or modifying the surface polymers to decreaseprotein adsorption.130 Heparin-bonded circuits have beenaround the longest and are the best studied. One random-ized trial with high-risk patients, including those withpreexisting lung or kidney impairment, showed a de-creased incidence of postoperative renal dysfunction andfewer days of mechanical ventilation.131 In a meta-analysisof heparin-bonded circuits versus conventional tubing, theauthors showed a modest decrease in bleeding and red celltransfusion with heparin circuits.132 Other than heparin,circuits have been coated with polymethoxyethylacrylate,phosphorylcholine, and siloxane in an attempt to make thetubing less favorable for cell binding.133–136 None of thecoatings, however, has demonstrated in vivo reductions inhemostatic activation.137 A more recent systematic reviewof biocompatible CPB circuits concluded that although theymay offer some benefit in reducing red cell transfusions, adecreased incidence of atrial fibrillation, and shorter inten-sive care unit (ICU) stays, high-quality studies are limitedand the surfaces alone do little to contain hemostaticactivation without implementing additional measures.138

Decreasing CPB Circuit SizeSo-called “miniaturized” CPB has been developed with theidea of reducing blood contact with foreign material and airby using low prime-volume tubing and eliminating thevenous reservoir and cardiotomy suction. In general, prim-ing volume for miniaturized CPB systems is on the order of500 mL versus the 1500 to 2000 mL in conventional circuits,and virtually all systems use some type of heparin-bondedtubing. Lower levels of thrombin activation have beenreported with the use of miniaturized CPB.139,140 Tworecent meta-analyses of randomized trials confirmed areduced need for blood-product transfusions using thesmaller circuits.141,142 However, this would be expectedgiven the significant reduction in hemodilution using lowerprime volumes. Additionally, because reinfusion of shedblood alone has been shown to increase hemostatic activa-tion, it is not clear whether miniaturized CPB systems offerany benefit regarding hemostatic activation other thansimply eliminating the cardiotomy suctions. It is likely thatany combined approach using heparin-bonded circuits,



adequate antifibrinolytic therapy, and removal of car-diotomy suction will reduce hemostatic activation.35

Off-Pump Coronary Artery BypassOf course, the ultimate reduction in CPB circuit size is toeliminate CPB entirely. Although not practical for manycardiac operations, off-pump coronary artery bypass(OPCAB) currently comprises about 20% of coronary bypassgraft procedures, and has been shown to be a viabletechnique with regard to graft patency.143 Although thepatient still undergoes thoracotomy, heparinization, andgrafting, there is no blood contact with foreign material andblood in the surgical field is generally cleared using acell-saver device because there is no cardiotomy suction.The time course for hemostatic activation is somewhatdifferent for OPCAB. In general, there is no early peak ofthrombin generation, presumably because of the lack ofcontact activation, and activation of the fibrinolytic systemis less.106 However, there is equal activation of the TFpathway, and thrombin generation and fibrinolytic activityare actually equal to CPB patients within 24 hours postop-eratively.144 In general, studies have shown less plateletactivation and dysfunction with OPCAB, leading to thepotential concern of a greater prothrombotic state in theearly postoperative period.145,146 Increased prothromboticstates may last as long as 1 month after surgery for bothOPCAB and standard CABG on CPB, and there does notseem to be a greater risk of graft thrombosis at experiencedOPCAB centers.147

Heparin Versus DTIsUnfractionated heparin (UFH) has been, and continues tobe, the mainstay anticoagulant used for CPB, primarilybecause of its rapid effect and availability of a neutralizingagent (protamine). It is not a direct inhibitor of thrombin,but instead enhances the effects of AT. It is this dependencyon AT that partially accounts for the drug’s variableanticoagulation efficacy in individual patients and in vari-ous situations.25 However, AT levels alone cannot predictUFH’s ability to achieve a desired activated clotting time(ACT) value.148 Other factors, such as the heterogeneity ofUFH’s chain lengths and its variable binding to endothelialcells, macrophages, and plasma proteins, affect its bioavail-ability.149 It is this variability that makes frequent monitor-ing necessary while on CPB, most commonly using theACT. Yet, the ACT itself has significant limitations, begin-ning with a lack of consensus as to what ACT value reflectsadequate anticoagulation for CPB.150 ACT values do notcorrelate well with actual heparin plasma concentra-tions,151 and thrombin is still activated despite values�480.5,152 Efforts to dose UFH more effectively have cen-tered on measuring heparin plasma levels and maintaininga constant concentration. Although some studies haveshown decreased hemostatic activation using this strat-egy,153,154 others have shown no difference than ACT-based dosing.155

Aside from dosing problems, there are other issues thatprevent UFH from being an ideal anticoagulant. Heparinitself is known to cause platelet activation and stimulatefibrinolysis.156 Heparin-induced release of TF pathwayinhibitor occurs as well, potentially exhausting TF pathway

inhibitor stores from the endothelium.157,158 Heparin-induced thrombocytopenia (HIT), which has been exten-sively reviewed elsewhere,159–162 is a result of antibodiesformed to the complex of heparin and platelet factor 4.Approximately 25% to 50% of patients will develop theantibodies 5 to 10 days after surgery, which can lead tothrombotic complications if heparin therapy is continued inthe postoperative period.163

The above limitations of heparin have helped drive thedevelopment of DTIs. A major advantage of DTIs is that ATis not required and their smaller molecular size enablesgreater inhibition of thrombin bound to fibrin (i.e., clot-bound versus free thrombin).164 More effective thrombininhibition with less platelet activation would obviously bedesirable for decreasing hemostatic activation. Bivalirudin,a DTI with a half-life of 25 minutes, has been shown toadequately suppress hemostatic activation on CPB whencardiotomy suction is not used.165 Interestingly, whencardiotomy suction was used, markers of activation such asd-dimer, TAT, and FPA levels were significantly increased.This is likely attributable to the fact that stagnant bloodcauses a tremendous amount of thrombin generation,which may locally overwhelm the reversible inhibition ofthe DTI. Multicenter trials using bivalirudin for CABGpatients both on and off CPB have demonstrated the samesafety and procedural efficacy as heparin anticoagulation,although in the United States it is currently only approvedfor patients with HIT undergoing percutaneous coronaryinterventions.166,167 Argatroban is another DTI that hasbeen used in the setting of HIT, although the developmentof intraoperative thrombi has been reported when used forCPB anticoagulation.168–170 Use of DTIs in the setting ofCPB is also currently limited by lack of a neutralizing agent.Oral DTIs, such as dabigatran etexilate, have been devel-oped as potential replacements for coumadin therapy, andmay pose a bleeding risk when patients present to surgery.It is recommended that dabigatran therapy be discontinued2 to 4 days before cardiac surgery, and longer in patientswith impaired renal function.171

AT SupplementationAT levels show a 30% to 50% decrease from baseline afterinitiation of CPB, a consequence of both acute hemodilutionand typical heparin administration, then recover, althoughnot fully, several hours postoperatively.23,172,173 However,after prolonged CPB use, especially that associated withdeep hypothermic circulatory arrest, AT levels can decreaseeven further and can take days to return to baselinelevels.174 This can contribute to inadequate thrombin sup-pression with heparin, as well as potential thromboticcomplications.175,176 Indeed, studies have shown that post-CPB patients with AT levels �60% of normal have a greaterrisk of adverse neurologic and cardiac events in the ICU.177,178

Most studies of low-dose AT supplementation during CPBhave failed to show a decrease in thrombin generation,plasmin generation, or platelet activation.175,179–182 Althoughclinical trials have shown that AT supplementation cor-rects heparin resistance in patients with low AT activityand reduces the need for fresh frozen plasma, outcomeshave been similar to patients simply receiving additionalheparin.183–185

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AntifibrinolyticsAs previously noted, tPA and plasmin production areincreased during CPB. The lysine analogs, �-aminocaproicacid (EACA) and TXA, are frequently used to mitigate thispotentially hyperfibrinolytic state. Both agents competi-tively inhibit the fibrin binding site on plasminogen, thusreducing the rate of fibrinolysis, although plasmin produc-tion is unaffected.12,186 TXA is more potent than EACA, hasa longer elimination half-life, and is the better studied agentin cardiac surgery.187 Its prophylactic use has been thesubject of 2 large meta-analyses, with one demonstrating areduced need for blood transfusions,188 and the othershowing no benefit compared with placebo.189 Addition-ally, TXA may increase the risk of seizures during openheart procedures.190 By decreasing fibrinolysis withoutreducing thrombin generation, there is the potential forthrombotic complications. Although studies have not dem-onstrated increased risk of myocardial infarction, stroke,deep vein thrombosis, or pulmonary embolism from TXAor EACA use in cardiac surgery, there are case reports ofretinal artery and glomerular capillary thrombosis, and theagents should probably be used with caution in patientswith other risk factors for hypercoagulability.191

Aprotinin is a nonspecific serine protease inhibitor thatalso inhibits plasmin. Aprotinin therapy has been shown toincrease the rate of plasmin inhibition 10-fold during CPB,which in turn reduced the rate of fibrin degradation asimilar amount.192 Unlike the lysine analogs, however,aprotinin inhibits a broad spectrum of other proteins in-volved in coagulation including kallikrein, activated pro-tein C, and thrombin.193 Platelet activation is also reducedwith aprotinin therapy, possibly by protecting PAR4 recep-tors and by blocking thrombin activation of platelet PAR1receptors.67,115 As such, it has both pro- and anticoagula-tion effects as well as antiinflammatory effects. Multiplestudies have shown its efficacy at decreasing markers ofhemostatic activation and preserving platelet function post-CPB.29,30,62,67,194–196 Additionally, multiple clinical trialshave demonstrated its efficacy at reducing transfusion ofblood products during cardiac surgery.186,197 However,marketing of the drugs was suspended in November 2007after preliminary results of the BART trial, which showedan increasing mortality trend relative to the lysine ana-logues.198 The underlying cause of the increased mortalityis unclear, but it has been suggested that aprotinin’srisk-benefit profile is more suited to patients undergoingcardiac surgical procedures at high risk for massive bloodloss.199

GENOMICS AND FUTURE DIRECTIONSCPB-induced hemostatic activation leads to both pro- andanticoagulant activity. Despite an improved understandingof these mechanisms, it is difficult to predict whether anysingle patient is at greater risk for bleeding or thrombosis.There is a strong heritability of coagulation protein levelssuch as PAI-1, FVII, fibrinogen, and tPA.200 Although someexperts have argued for routine testing of certain inheritedthrombophilias such as factor V Leiden,201 the answer isnot quite so simple. The dilemma has its roots in our DNA,

because gene polymorphisms can significantly affect sus-ceptibility to adverse postoperative events.202 Genetic vari-ability is certainly present in the modulation of thrombinproduction, and genetic factors have been identified thatcontribute to bleeding after cardiac surgery.203 However,expression of certain proteins, particularly those associatedwith adrenergic sensitivity and cardiac myofilament struc-ture, changes between the initiation of CPB and its termi-nation.204 Therefore, it is not sufficient to know that a genepolymorphism is present, but the knowledge of how it isexpressed under CPB conditions is also needed. Futuredirections will need to concentrate not only on risk strati-fication, but also on trying to discern how individualpatients will react to CPB and who will benefit most fromcertain therapies such as antifibrinolytics or factor replace-ment therapy.

Until genetically tailored therapy becomes available,however, it is probably best to take a combined approach inreducing hemostatic activation. Adequate thrombin sup-pression while on CPB should be the goal, either byensuring adequate heparin and AT levels or by using DTIsin cases of HIT. During procedures in which blood loss isnot expected to be massive, specialized circuits to minimizehemodilution and avoiding reinfusion of cardiotomy bloodare probably appropriate adjuvants, and may further re-duce hemostatic activation. Finally, antifibrinolytic therapyshould be used when hyperfibrinolysis occurs, either in theoperating room or in the ICU. CPB shares many character-istics with disseminated intravascular coagulation, andsuppressing hemostatic activation while it is occurring isprobably the best way to avoid a massive consumptivecoagulopathy or devastating thrombotic complications.

DISCLOSURESName: Roman M. Sniecinski, MD.Contribution: This author helped write the manuscript.Attestation: Roman M. Sniecinski approved the finalmanuscript.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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Activation of the Hemostatic System During Cardiopulmonary Bypass

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