CLINICAL PRACTICE GUIDELINES The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology: Clinical Practice Guidelines* Anticoagulation During Cardiopulmonary Bypass Linda Shore-Lesserson, MD, Robert A. Baker, PhD, CCP, Victor A. Ferraris, MD, PhD, Philip E. Greilich, MD, David Fitzgerald, MPH, CCP, Philip Roman, MD, MPH, and John W. Hammon, MD Department of Anesthesiology, Zucker School of Medicine at Hofstra Northwell, Hempstead, New York; Cardiac Surgery Research and Perfusion, Flinders University and Flinders Medical Center, Adelaide, South Australia, Australia; Division of Cardiovascular and Thoracic Surgery, University of Kentucky, Lexington, Kentucky; Department of Anesthesiology and Pain Management, University of Texas-Southwestern Medical Center, Dallas, Texas; Division of Cardiovascular Perfusion, Medical University of South Carolina, Charleston, South Carolina; Department of Anesthesiology, Saint Anthony Hospital, Lakewood, Colorado; and Department of Cardiothoracic Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina Despite more than a half century of safe cardiopulmo- nary bypass (CPB), the evidence base surrounding the conduct of anticoagulation therapy for CPB has not been organized into a succinct guideline. For this and other reasons, there is enormous practice variability relating to the use and dosing of heparin, monitoring heparin anti- coagulation, reversal of anticoagulation, and the use of alternative anticoagulants. To address this and other gaps, The Society of Thoracic Surgeons, the Society of Cardio- vascular Anesthesiologists, and the American Society of Extracorporeal Technology developed an Evidence Based Workgroup. This was a group of interdisciplinary pro- fessionals gathered to summarize the evidence and create practice recommendations for various aspects of CPB. To date, anticoagulation practices in CPB have not been standardized in accordance with the evidence base. This clinical practice guideline was written with the intent to ll the evidence gap and to establish best practices in anti- coagulation therapy for CPB using the available evidence. To identify relevant evidence, a systematic review was outlined and literature searches were conducted in PubMed using standardized medical subject heading (MeSH) terms from the National Library of Medicine list of search terms. Search dates were inclusive of January 2000 to December 2015. The search yielded 833 abstracts, which were reviewed by two independent reviewers. Once accepted into the full manuscript review stage, two members of the writing group evaluated each of 286 full papers for inclusion eligibility into the guideline docu- ment. Ninety-six manuscripts were included in the nal review. In addition, 17 manuscripts published before 2000 were included to provide method, context, or addi- tional supporting evidence for the recommendations as these papers were considered sentinel publications. Members of the writing group wrote and developed recommendations based on review of the articles ob- tained and achieved more than two thirds agreement on each recommendation. The quality of information for a given recommendation allowed assessment of the level of evidence as recommended by the American College of Cardiology Foundation/American Heart Association Task *These clinical practice guidelines (CPGs) were developed prior to the publication of The American Association for Thoracic Surgery/Society of Thoracic Surgeons Position Statement on Developing Clinical Practice Documents (Bakaeen, et al. Ann Thorac Surg 2017;103:1350 6), and thus their development did not strictly adhere to the process for CPGs outlined in that document. Nevertheless, these CPGs were the product of a lengthy and rigorous review by a multidisciplinary panel of experts, and approved by all three participating societies. All future STS CPGs appearing in The Annals of Thoracic Surgery will be developed in accordance to the aforementioned Position Statement. This article is copublished in The Annals of Thoracic Surgery, Anesthesia & Analgesia, and the Journal of ExtraCorporeal Technology. The Society of Thoracic Surgeons requests that this document be cited as follows: Shore-Lesserson L, Baker RA, Ferraris VA, Greilich PE, Fitzgerald D, Roman P, Hammon JW. The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of Extra- Corporeal Technology: clinical practice guidelines anticoagulation dur- ing cardiopulmonary bypass. Ann Thorac Surg 2018;105:650 62. Address correspondence to Dr Shore-Lesserson, Department of Anes- thesiology, Northshore University Hospital, 300 Community Dr, Man- hasset, NY 11030; email: lshoreless@northwell.edu. The Appendix and Supplemental Tables can be viewed in the online version of this article [https://doi.org/10. 1016/j.athoracsur.2017.09.061] on http://www.annals thoracicsurgery.org. 2018 by The Society of Thoracic Surgeons, International Anesthesia Research Society, and the American Society of ExtraCorporeal Technology 0003-4975/$36.00 Published by Elsevier Inc. https://doi.org/10.1016/j.athoracsur.2017.09.061 REPORT Force on Practice Guidelines. Recommendations were written in the three following areas: (1) heparin dosing and monitoring for initiation and maintenance of CPB; (2) heparin contraindications and heparin alternatives; and (3) reversal of anticoagulation during cardiac operations. It is hoped that this guideline will serve as a resource and will stimulate investigators to conduct more research and to expand on the evidence base on the topic of anti- coagulation therapy for CPB. (Ann Thorac Surg 2018;105:650 62) 2018 by The Society of Thoracic Surgeons, International Anesthesia Research Society, and the American Society of ExtraCorporeal Technology The development of cardiopulmonary bypass (CPB) in the 1960s so successfully enabled open heart surgery that rigorous evidence-based clinical trials did not play a part in the initial phases of development [1]. After World War II, clinicians were faced with more and more treatment choices, to the point that uncertainty existed about the best options. Indeed, Archie Cochrane recognized the need for a more rigorousapproachtogivecliniciansanswerstokeyquestions about patient treatments. Cochrane s efforts eventually led to the formation of the Cochrane Collaboration as a re- pository of evidence-based summaries to answer important indeed requires, evidence to support surgeons in- terventions, preferably in the form of randomized controlled trials (RCTs). During the last 60-plus years since the intro- duction of clinical CPB as the foundation for performance of cardiac operations, surgeon investigators developed a safe, ef cient, and reproducible method of performing highly complex cardiac procedures using CPB. Many advances in CPB are the result of evidence-based RCTs. Others derive from prospective cohort studies and still others, from anec- dotal practice or consensus. Recognizing this large scope of practice and the varied nature of the evidence base to support the use of CPB, the Evidence Based Workforce of The Society of Thoracic Surgeons (STS) undertook a project to develop a series of practice guidelines that re ect the evidence base for the use of CPB in the current era. This effort included a collaboration with the Society of Cardiovas- cular Anesthesiologists (SCA) and the American Society of ExtraCorporeal Technology (AmSECT) to summarize available evidence in various areas of CPB. A critically important part of CPB is the use of anticoagulation therapy. To date, there are no evidence-based practice guidelines that de ne the optimal management of anti- coagulation during the conduct of CPB. As a result, practice in this area is highly variable and not stan- dardized in accordance with the evidence base to date. Therefore, the STS recognized this de cit and undertook a collaboration with the SCA and AmSECT to address the evidence gap regarding the use of anticoagulation treatment during CPB. This article reviews relevant published information about the use of anticoagulation for the conduct of CPB and provides a synthesis of the available evidence to create a clinical practice guideline. This guideline represents the initial evidence-based approach to the use of anticoagulation in CPB and is the only available comprehensive guideline of its kind. It is the hope of the authors that this guideline will stim- ulate investigators to amplify and elaborate on the evi- dence available on this topic. Search Methods To identify relevant evidence, a systematic review was outlined and literature searches were conducted in PubMed using standardized medical subject heading (MeSH) terms from the National Library of Medicine list of search terms and were inclusive of the dates January 2000 to December 2015. The following terms comprised the standard baseline search terms for topics and were connected with the logical OR connector:  Extracorporeal circulation (MeSH number E04.292 includes extracorporeal membrane oxygenation, left heart bypass, hemo ltration, hemoperfusion, and cardiopulmonary bypass)  Cardiovascular surgical procedures (MeSH number E04.100 includes off-pump coronary artery bypass graft surgery, coronary artery bypass graft surgery, myocardial revascularization, all valve operations, and all other operations on the heart)  Pharmacologic actions of anticoagulant drugs (MeSH number D27.505 includes molecular mecha- nisms, physiologic effects, and therapeutic use of drugs)  Anticoagulation reversal (MeSH number D12.776 includes protamine sulfate and other protamines and nuclear proteins) These broad search terms allowed speci c topics to be added to the search with the logical AND connector and Abbreviations and Acronyms ACT = activated clotting time AmSECT = The American Society of Extracorporeal Technology CPB = cardiopulmonary bypass ECT = ecarin clotting time ELISA = enzyme-linked immunosorbent assay HIPA = heparin-induced platelet activation HIT = heparin-induced thrombocytopenia MeSH = medical subject heading PF4 = platelet factor 4 RCT = randomized controlled trial SCA = The Society of Cardiovascular Anesthesiologists SRA = serotonin release assay STS = The Society of Thoracic Surgeons Ann Thorac Surg 2018;105:650 62 ANTICOAGULATION DURING CARDIOPULMONARY BYPASS REPORT publication types and groups to be excluded (Appendix). This search methodology provided a broad list of generated references speci c for the search topic. The searches yielded 833 abstracts. Abstracts were reviewed by two independent reviewers for acceptance into the paper review stage. Ab- stracts with at least one acceptance were sent to full manu- script review. In all, 286 full papers were reviewed by at least two members of the writing group for inclusion eligibility in the guideline. To be included, a paper had to report data on both of the following: (1) anticoagulant used for cardiopul- monary bypass; and (2) the monitoring techniques used to measure that anticoagulation. After passing mandatory in- clusion criteria, it was preferable that included papers have a prospective study design and also report on the frequency of anticoagulation monitoring, bleeding outcomes, and transfusion outcomes. Ninety-six manuscripts were included in the nal review. In addition, 17 manuscripts published before 2000 that were referenced within a manuscript and considered to be sentinel papers were included to provide method, context, or additional sup- porting evidence for the recommendations. Individual members of the writing group read the retrieved references for their assigned topics and formu- lated recommendations based on assessment of the relevant literature. Only English language articles contributed to the nal recommendations. For almost all topics reviewed, only evidence relating to adult patients entered into the nal recommendations, primarily because of limited availability of high-quality evidence relating to pediatric patients hav- ing cardiac procedures. Evidence tables were constructed to ensure that selected studies conformed to minimum re- quirements in terms of study design and reporting of out- comes. (A representative evidence table evaluating the anticoagulation studies is shown in Supplemental Table 1; study appraisals of randomized controlled trials and meta- analyses are shown in Supplemental Table 2; and the Newcastle-Ottawa appraisal for nonrandomized studies is depicted in Supplemental Table 3). Duties of the Writing Group Members of the writing group wrote and developed rec- ommendations based on review of the articles obtained us- ing the search technique described above. The quality of information for a given recommendation allowed assess- ment of the level of evidence as recommended by the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines (avail- able at: http://www.americanheart.org/downloadable/ writing_committees.pdf). The Appendix contains a summary of recommendations put forth in this guideline as a result of the evidence base. Heparin Dosing for Initiation and Maintenance of CPB Class I Recommendation  A functional whole blood test of anticoagulation, in the form of a clotting time, should be measured and should demonstrate adequate anticoagulation before initiating and at regular intervals during CPB. (Level of Evidence C) Class IIa Recommendations  Bolus administration of unfractionated heparin based on weight is reasonable for achieving adequate anticoagulation, but individual response to heparin is heterogeneous and requires a therapeutic functional test of clot inhibition before initiation of CPB, independent of the bolus dose used. (Level of Evidence C)  It is reasonable to use activated clotting time (ACT) tests that produce maximally activated clotting times as these tests mitigate ACT variability, are less susceptible to hypothermia, and correlate more closely with factor Xa activity compared with tests that use a single activator. (Level of Evidence B)  It is reasonable to maintain activated clotting time above 480 seconds during CPB. However, this min- imum threshold value is an approximation and may vary based on the bias of the instrument being used. For instruments using maximal activation of whole blood or microcuvette technology, values above 400 seconds are frequently considered therapeutic. (Level of Evidence C) Class IIb Recommendations  Use of a heparin dose-response formula may iden- tify reduced sensitivity to heparin, but has not been shown to be more useful than weight-based heparin dosing in determining the heparin dose required to achieve an adequate ACT for initiation of CPB. (Level of Evidence B)  Use of heparin concentration monitoring in addition to ACT might be considered for the maintenance of CPB, as this strategy has been associated with a signi cant reduction in thrombin generation, bri- nolysis, and neutrophil activation. However, its ef- fects on postoperative bleeding and blood transfusion are inconsistent. (Level of Evidence B)  During CPB, routine administration of unfractio- nated heparin at xed intervals, with ACT moni- toring, might be considered and offers a safe alternative to heparin concentration monitoring. (Level of Evidence C) Activated clotting time is considered the gold standard in monitoring anticoagulation for CPB. The establishment of a safe or optimal range for ACT dates back to data published in the 1970s when Bull and colleagues [3] showed no development of clot in the oxygenator or cir- cuit when ACT was maintained above 300 seconds. However, Young and coauthors [4] challenged this threshold when they demonstrated brin formation in the circuits of rhesus monkeys maintained on CPB with a minimum ACT value of 300 seconds, and they recom- mended that this threshold value be increased to 400 seconds by showing it was safe in 5 pediatric patients on 652 Ann Thorac Surg ANTICOAGULATION DURING CARDIOPULMONARY BYPASS 2018;105:650 62 REPORT CPB. To maintain a margin of safety above 400 seconds, the minimum acceptable ACT value of approximately 480 seconds became a standard of care that was used in numerous future studies and in clinical practice, but was based on limited evidence. Despite this widely accepted level of anticoagulation, there is no clear consensus on the accurate calculation of this initial dose of unfractionated heparin. Options for calculating the initial heparin bolus include a xed, weight-based dose, (eg, 300 IU/kg), or use of point-of-care tests that measure the whole blood sensitivity to heparin using an associated dose response. In addition to the heterogeneity of heparin formula- tions themselves, individual responsiveness to heparin is variable. The pharmacodynamics of unfractionated hep- arin are highly dependent on the level and function of plasma antithrombin III. In patients with preoperative hypercoagulability or reduced antithrombin III respon- siveness, increased levels of circulating heparin are necessary to achieve a therapeutic ACT value before CPB [5]. Na and coauthors [5] reported signi cant variations to heparin responsiveness in an observational study of pa- tients with known, stabilized infectious endocarditis. Garvin and associates [6] also reported observed varia- tions in heparin response in patients having CPB. In a retrospective institutional database review of 3,880 pa- tients, these investigators found wide variation in the heparin bolus dose required to obtain a target ACT. The initial unfractionated heparin bolus dose did not correlate well with the rst post-heparin ACT (r2 0.03). The route and timing of the initial administration of unfractionated heparin has a direct impact on the ability to obtain a therapeutic ACT. A small randomized trial done by Grima and colleagues [7] found that intermittent doses of unfractionated heparin administered before CPB (100 IU/kg for 3 doses) maintained adequate levels of anticoagulation during CPB better than a single bolus dose of 300 IU/kg. Intermittent pre-CPB heparin treat- ment resulted in lower mean decreases in factor VIII, brinogen, antithrombin III, and platelet count than if a large bolus dose were administered. In a prospective nonrandomized trial performed by Neema and col- leagues [8], 6 of the 100 patients who received 300 IU/kg of unfractionated heparin before CPB had a resultant post-heparin ACT less than 350 seconds. Other patho- logic disturbances such as thrombocytosis may limit the effectiveness of weight-based heparin bolus administration. Owing to the heterogeneity of the pharmacodynamic response to unfractionated heparin, the utilization of ex vivo heparin dose-response technologies was studied as a more accurate prediction of initial heparin dosing. Although ex vivo heparin dose-response technologies may identify patients who have a reduced sensitivity to conventional doses of heparin, these tests have limited ability to calculate correctly an optimal initial unfractio- nated heparin bolus dose. The observational study by Garvin and colleagues [6] demonstrated poor correlation of the calculated in vitro heparin dose response curve compared with the actual patient heparin dose response, resulting in a failure to reach therapeutic ACT values in nearly 17% of patients. During CPB, an overestimation of heparin concentration may occur when using the ACT assay alone. Falsely elevated ACT values may be observed under conditions of hypothermia, reduced he- moglobin concentration, hypo brinogenemia, and phar- macologic agents that are not associated with a concomitant increase in heparin concentration [9]. In a controlled, nonrandomized study of 42 patients, Machin and colleagues [10] demonstrated prolongation of ACT values during hypothermic CPB when compared with normothermic CPB. Leyvi and colleagues [11] reported similar ACT prolongation under conditions of both hy- pothermia and hemodilution using a number of ACT technologies while plasma antifactor Xa heparin level activity remained constant. Maintaining ACT values during CPB without heparin concentration monitoring may result in lower doses of heparin. These known sensitivity limitations in ACT monitoring may result in subclinical plasma coagulation occurring during CPB. Whole blood heparin concentration assays are statisti- cally more closely correlated with plasma anti-Xa levels than the ACT [12]. Clinically, heparin concentration tests are performed alongside a functional test of clotting, such as an ACT, because a therapeutic functional con rmation of anticoagulation provides important safety data. In a randomized controlled trial of 200 patients, Koster and colleagues [13] found that adhering to a heparin con- centration maintenance protocol led to a signi cant reduction in thrombin generation, brinolysis, and neutrophil activation, when compared with ACT moni- toring alone (480 seconds). Despotis and associates [14] randomized patients to ACT-based (using 5,000 units unfractionated heparin doses to maintain ACT values >480 seconds) versus heparin concentration-based man- agement (with minimum ACT >480 seconds), and re- ported a higher heparin total dose in patients in the heparin concentration group (612  147 U/kg versus 462  114 U/kg, p < 0.0001). Patients in the heparin concen- tration group also had lower protamine to heparin ratios and required signi cantly fewer blood product trans- fusions (platelets, plasma, and cryoprecipitate) than the ACT-based control group. Another randomized trial of 31 patients scheduled for reoperation resulted in signi cant reductions in perioperative blood loss and blood product usage when maintaining higher patient-speci c heparin dosing during CPB [15]. Another study found reduced platelet activation and evidence of reduced thrombin generation with heparin concentration monitoring compared with routine ACT monitoring [16]. Together, these studies suggest that whole blood heparin concen- tration monitoring results in larger doses of unfractio- nated heparin during CPB and improved hemostatic suppression compared with ACT monitoring alone. However, these results did not translate into improved clinical outcomes and have not been wholly reproducible in the literature. A retrospective analysis involving 686 patients favored ACT-based monitoring compared with heparin concentration monitoring because of less post- operative bleeding and transfusion requirements associ- ated with ACT-based monitoring [17]. Ann Thorac Surg 2018;105:650 62 ANTICOAGULATION DURING CARDIOPULMONARY BYPASS REPORT Traditionally, the gold standard for measuring the anticoagulant effects of heparin is inhibition of factor Xa (anti-Xa) activity. Factor Xa is a major target for unfrac- tionated heparin and can be readily measured in plasma using laboratory assays. The various studies that seek to validate a new measure of heparin activity, or a clotting time assay, use anti-Xa activity as the gold standard comparison. However, plasma assays for anti-Xa activity are not ideally suited for point-of-care testing. Anti-Xa measurement serves as a validating test for novel point- of-care assays that re ect anti-Xa activity. Hansen and associates [18] studied a whole blood modi ed ACT test and found it to be highly correlated to laboratory anti-Xa measurement. Helstern and associates [19] reported another one-step clotting assay that correlates well with anti-Xa tests and is not in uenced by hemodilution, but clinical studies are lacking. Routine redosing of unfractionated heparin at xed intervals during CPB, despite a therapeutic ACT, is commonly used when heparin concentration assays are not available to simulate the practice of higher heparin dosing. This practice prescribes additional xed doses of unfractionated heparin at speci c timepoints, even though ACT may be above target. In a prospective trial of 100 patients presenting for cardiac surgery, one third of the initial heparin bolus was administered at the 90- minute point of CPB, with repeat doses every 60 mi- nutes thereafter [8]. This strategy maintained adequate anticoagulation during the entire period of hypothermic CPB; bleeding variables were not reported. Despite the reported bene ts of higher heparin dosing, other studies seemingly contradict these results. In a small prospective trial of 21 patients, Gravlee and colleagues [20] concluded that subclinical plasma coag- ulation occurs during CPB despite heparin concentra- tions greater than 4.1 IU/mL. Furthermore, postoperative mediastinal chest tube drainage correlates with increased heparin concentration, especially if hep- arin rebound is not carefully monitored. A subsequent, prospective study of 63 patients by Gravlee and col- leagues [21] showed that subjects who received an unfractionated heparin bolus of 400 IU/kg and had heparin concentration maintained greater than 4 IU/mL did not differ in mediastinal drainage or transfusion products from a control group of patients receiving a bolus dose of 200 IU/kg plus additional heparin for ACT values less than 400 seconds. A prospective trial in 31 patients undergoing cardiac surgery revealed that all patients had a residual circulating heparin level after protamine administration (mean 0.18 IU/mL), detected by a chromogenic anti-Xa assay. This residual heparin concentration did not correlate with ACT or whole blood heparin concentration nor did it correlate with post- operative mediastinal tube drainage volume [22]. Although the studies supporting higher unfractionated heparin doses are greater in size and number, the impact of using higher doses of heparin on postoperative bleeding appears to be unclear, especially if residual effects of heparin are not detected or treated. Documented therapeutic anticoagulation treatment of patients having CPB is necessary and is routinely per- formed using an ACT. However, ACT devices vary considerably in their measurement platforms, activators, sample volumes, and sensitivities to external elements such as hemodilution, hypothermia, and concomitant drug therapies [23, 24]. It appears that arterial versus venous blood sampling and a wait period as long as 15 minutes do not signi cantly affect the ACT result [25, 26]. Currently there are many instruments and platforms available that purport to measure ACT values. To ratio- nally utilize an ACT device for patients undergoing CPB, it is important to understand how the testing platform works, the therapeutic target that corresponds to a his- torical ACT of 480 seconds, and how well the results correlate with anti-Xa activity. In an early study of hep- arin monitoring and ACT threshold values, it was noted that the two most commonly used ACT devices correlated with each other, yet there was signi cant bias with one of the instruments [27]. Another observational study showed that many ACT tests correlated poorly with heparin level as assessed by anti-Xa plasma activity [28]. Patteril and associates [29] demonstrated that after switching their cohort population to a newer ACT device, the new instrument yielded a lower mean ACT value compared with temporal controls (557 versus 618 sec- onds, p < 0.05), and a higher dose of unfractionated heparin was needed to achieve a minimum ACT of 480 seconds [29]. A certain level of validation has been per- formed for other ACT instruments as well [30]. Tests that use a maximal degree of activation of the blood sample by using multiple or more potent activators produce shorter clotting times relative to the standard ACT with a single activator [11]. The tests that utilize a maximally activated sample also report less variability in clotting times and are less susceptible to prolongation by hypothermia and artifacts [10]. The maximal activation removes the variability induced by hemodilution of clot- ting factors. Maximal activation is also accomplished in the microcuvette ACT technology owing to the small sample volume and minimization of sample dilution. A plasma supplemented ACT accomplishes a similar result. This test has been shown to mitigate the ACT variability to more closely mirror anti-Xa levels; however, it is cumbersome and dif cult to perform at the point of care [19]. The viscoelastic tests have been modi ed for point-of- care measurement of the ACT and in a small ex vivo analysis in CPB patients, the two tests performed simi- larly to standard ACT tests with respect to heparinization and hemodilution [30, 31]. Another observational study involving 50 CPB patients demonstrated that a visco- elastic measurement of ACT activity mirrored the activity of both standard ACT tests and anti-Xa levels [32]. It remains uncertain what the threshold minimum safe values are for the viscoelastic clotting times in CPB and how they correspond with the historical 480 second target. Further clinical and outcome studies are war- ranted before switching patient management to a visco- elastic ACT test. 654 Ann Thorac Surg ANTICOAGULATION DURING CARDIOPULMONARY BYPASS 2018;105:650 62 REPORT Heparin Contraindications and Heparin Alternatives Class IIa Recommendations  Clinical scoring estimates that use a fall in platelet count greater than 50% or a thrombotic event be- tween 5 and 14 days after a heparin exposure can be used to determine whether a heparin platelet anti- body test should be performed to diagnose heparin- induced thrombocytopenia (HIT). (Level of Evidence B)  Serum tests that include functional testing with se- rotonin release assay (SRA) or heparin-induced platelet activation (HIPA) can be bene cial in iden- tifying patients with HIT who have a history of thrombocytopenia, and elevated clinical HIT risk scores, when platelet factor 4 (PF4) heparin antibody testing is inconclusive (weakly positive) for HIT. (Level of Evidence C)  For patients who are seropositive for heparin- platelet antibodies or have a recent history of HIT, it is reasonable to delay elective cardiac operations requiring CPB until a patient s functional test or antigenic (antibody) assay are negative, with the expectation that heparin anticoagulation therapy for CPB is likely to be safe and effective. (Level of Evi- dence C)  For patients with a diagnosis of HIT and in need of an urgent operation requiring CPB, anticoagulation with bivalirudin is a reasonable option. (Level of Evidence B) Class IIb Recommendation  In patients with signi cant renal dysfunction who are seropositive for HIT and require urgent opera- tion requiring CPB, use of plasmapheresis, arga- troban, or heparin with antiplatelet agents (such as tiro ban, ilioprost) may be considered, understand- ing that there are increased risks of bleeding with these interventions. (Level of Evidence C) The chief contraindications to the use of heparin for CPB are a history of HIT and known hypersensitivity to heparin. Whereas HIT is characterized by the develop- ment of immunoglobulin G antibodies recognizing PF4- heparin complexes [33, 34], hypersensitivity reactions to heparin can be type I, II, or IV [35, 36]. Heparin-induced thrombocytopenia with or without thrombosis occurs in patients who form PF4-heparin immune complexes capable of activating platelets [37, 38]. These anti PF4- heparin antibodies form the basis for the clinical anti- genic assay (enzyme-linked immunosorbent assay [ELISA]) for HIT [37]. Although PF4-heparin complexes after heparin exposure can be quite high (greater than 30% among surgical patients), the incidence of HIT is much lower (1% to 2%) [39 43]. Patients who test positive (antigen assay) for anti PF4-heparin antibodies preoper- atively appear to have a higher overall risk for complications and increased mortality after cardiac sur- gery [44 46]. Given the 60- to 90-day amnestic period for HIT antibodies, postponing elective cardiac surgery in patients with elevated PF4-heparin antibodies could potentially mitigate this avoidable risk [47 50]. Platelet count monitoring is currently recommended for patients with heparin exposure before cardiac surgery (eg, cardiac catheterization or deep vein thrombosis prophylaxis) to determine whether further testing is indicated [43]. Detection of PF4-heparin antibodies that activate platelets and trigger serotonin release requires a highly speci c and sensitive functional test for HIT [51]. Func- tional testing with SRA or HIPA detect only those immunoglobulin G antibodies capable of activating platelets [43]. Thrombocytopenia or thrombosis are much more likely when platelet activation occurs. Speci c tests of platelet serotonin release can be particularly helpful when low levels of positivity are detected using HIT antibody (antigen) assays, which are sensitive but not speci c to platelet activation [37, 51]. Heparin-induced thrombocytopenia is a clinicopatho- logic diagnosis [52]. The spectrum ranges from formation of anti PF4-heparin antibodies to increasing degrees of thrombocytopenia due to platelet activation, and in its most severe form, diffuse deposition of platelet-related thrombi into microcirculation and extreme depletion of circulating platelets. In a single-center observational study of 1,722 patients undergoing cardiac surgery, HIT was suspected in 63 (3.6%) and con rmed in 24 (1.4%) [53]. Validated clinical scoring systems can guide initial decision-making and laboratory testing [37, 53 57]. These scoring methods take into consideration the characteristic temporal relationship of the onset of thrombocytopenia (with or without thrombotic event) to heparin exposure (5 to 14 days) [58], the percent decrease in platelet count (greater than 30% to 50%), and absolute level of platelets (20 to 100,000/uL), in addition to duration of CPB and other potential contributory causes of thrombocytopenia [55, 57]. The negative predictive value (for HIT) for pa- tients with a low clinical scores is 98% (range, 97% to 100%) [56, 57]. Therefore, additional serologic testing and delays in heparin anticoagulation or complications asso- ciated with heparin alternatives in these patients can be avoided. The positive predictive value of the anti PF4-heparin assay (ELISA) for HIT is very low (2% to 15%) [59, 60]. As such, this assay should be limited to patients with higher pretest probabilities (for HIT) found in those with intermediate (positive predictive value 10% to 20%) or high (positive predictive value 40% to 80%) clinical scores. That usually occurs when the fall in platelet count ex- ceeds 50% or a thrombotic event occurs between post- operative days 5 and 14. Patients with low antibody titers (optical density less than 0.4) would be candidates for heparin anticoagulation without further intervention given the high sensitivity (90% to 98%) of this clinical assay [43, 51]. Postoperatively, close monitoring of platelet counts are recommended and screening for HIT anti- bodies considered if clinical scores indicate further sero- logic testing is warranted. Patients with mild elevations in anti heparin-PF4 titers (optical density 0.4 to 1.0) should have further serologic Ann Thorac Surg 2018;105:650 62 ANTICOAGULATION DURING CARDIOPULMONARY BYPASS REPORT testing using a functional assay especially if their clinical scores are in the intermediate or high ranges [37]. The high sensitivity (90% to 98%) and speci city (80% to 97%) of the functional assays (SRA, HIPA) make them the gold standard for diagnosing HIT [61]. Negative SRA and HIPA frequently occurs in patients with elevated anti- body titers using the clinical antigen assays (ELISA) owing to PF4-heparin antibodies that do not activate platelets or cause thrombocytopenia or thrombosis [33]. Patients with high clinical scores and high antibody titers (optical density greater than 1.0) are candidates for hep- arin alternatives when urgent operations preclude the use a functional assay (SRA, HIPA). True hypersensitivity to heparin is rare, yet can occur in patients allergic to heparin or the sources of heparin (eg, porcine or bovine sources of heparin) [35, 36, 62 64]. Pa- tients clinically suspected of having hypersensitivity to heparin should undergo testing to con rm the diagnosis as soon as possible, given the often urgent need for heparin anticoagulation in a variety of clinical settings [35]. The decision to utilize an alternative anticoagulant agent during CPB is based on the urgency of the cardiac procedure and on heparin antibodies capable of acti- vating platelets. The American College of Chest Physi- cians recommends delaying nonurgent cardiac procedures until heparin antibodies are no longer detectable [43]. The single most cumbersome aspect of heparin alternatives is inability to rapidly reverse anti- coagulation after weaning from CPB. For nearly all hep- arin alternatives, there is no reversal agent equivalent to protamine. Other negative side effects include prolonged operative times and the risk of increased blood loss and transfusion. Although several agents have been used as alternates to heparin [45, 52], there is only suf cient data on bivalirudin to make recommendations in this clinical setting. Bivalirudin Bivalirudin, a recombinant direct thrombin inhibitor, is not currently approved by the Food and Drug Adminis- tration for use during CPB (albeit approved for this use outside the United States). Bivalirudin effectively inhibits the coagulation cascade and has a short 25-minute half- life in patients with normal renal function. Monitoring of anticoagulation with bivalirudin is more challenging than with heparin. The ecarin clotting time (ECT) corre- lates strongly (R2 0.91) with therapeutic bivalirudin concentrations but is not commonly available as a point- of-care test [65]. In a comparative analysis study of 10 patients undergoing cardiopulmonary bypass, three different methods of the ACT test were compared with ECT [66]. Although not as accurate as the ECT, the more commonly available celite-ACT was found to have an acceptable correlation with ECT-determined bivalirudin 0.93). Bivalirudin has the broadest experience in patients undergoing cardiac surgery (with and without CPB) and in patients with HIT and patients with HIT with throm- bosis requiring CPB [67]. This includes procedures requiring deep hypothermic circulatory arrest [68]. Controlled trials suggest that bivalirudin provides adequate anticoagulation in all patients [69, 70]. In these trials, secondary endpoints including mortality, 24-hour blood loss, overall incidence of transfusions, and dura- tion of surgery were similar for bivalirudin-treated pa- tients and for patients having CPB with heparin anticoagulation and protamine reversal. Several studies for example, the Evaluation of Patients During Coronary Artery Bypass Graft Operation: Linking Utilization of Bivalirudin to Improved Outcomes and New Anticoagu- lant Strategies (EVOLUTION-ON) and the Coronary Artery Bypass Grafting Heparin-Induced Thrombocyto- penia Thrombosis Syndrome On- and Off-Pump Safety and Ef cacy (CHOOSE-ON) trials propose a reliable therapeutic protocol for bivalirudin [69, 70]. Bivalirudin dosing in the CHOOSE-ON and EVOLUTION-ON trials included a loading dose of 1.0 mg/kg, infusion of 2.5 mg $ , and pump prime of 50 mg. The adequacy of anticoagulation was monitored using 2.5 times the base- line ACT. In many centers, target ACT levels were ach- ieved with lower loading dose and infusion rates. In the EVOLUTION-ON multicenter, open label trial, 101 patients were randomly assigned to either bivalirudin or heparin with protamine reversal. Both groups were successfully anticoagulated, and there were no signi cant differences in morbidity or mortality between groups at 7 days, 30 days, or 12 weeks. Postoperative blood loss was statistically higher at 2 hours (238 mL versus 160 mL, p 0.0009), but not at 24 hours (793 mL versus 668 mL, p 0.15). Postoperative reexploration occurred in 6.1% versus 1.9%, but was not statistically signi cant [70]. Anti- coagulation with the direct thrombin inhibitor bivalirudin appears to provide a safe and effective alternative to heparin and protamine reversal, even though it may in- crease the risk of excessive bleeding. In extreme cases, a combination of modi ed ultra ltration, hemodialysis, and administration of recombinant factor VIIa in addition to balanced hemostatic resuscitation with fresh frozen plasma, cryoprecipitate and platelets may be required until the anticoagulant effects of bivalirudin are reversed [68, 71, 72]. Other Alternatives to Heparin Other strategies for anticoagulation treatment of patients with HIT consist of reintroduction of heparin after either the removal of PF4-heparin antibodies (plasmapheresis), administration of intravenous antiplatelet therapy, or use of argatroban. The use of plasmapheresis is generally limited to patients with weakly positive ELISA results requiring urgent cardiac procedures [73 75]. Although each approach appears to be safe and effective, there is insuf cient evidence for a recommendation in the setting of CPB. In a small case series by Welsby and colleagues [74], 11 patients with recent (less than 2 months) diagnosis of HIT received therapeutic plasma volume exchange after in- duction of anesthesia. All patients had a reduction in antibody titers (range of reduction, 50% to 84%). Of these 11 patients, 2 patients had positive HIT antibodies at the 656 Ann Thorac Surg ANTICOAGULATION DURING CARDIOPULMONARY BYPASS 2018;105:650 62 REPORT time of operation. One patient had an ischemic foot, likely related to an intraaortic balloon pump. Three patients (27%) died during the postoperative period (range, 3 months to 1 year) although none of the deaths was attributed to HIT thrombosis. Other case reports and smaller series are summarized in a practice guideline by the American Society for Apheresis, although recom- mendations regarding CPB are limited [52, 73]. Iloprost (prostacyclin analogue) was used in several studies of HIT patients to inhibit platelet activation dur- ing cardiac surgery [76]. In a large retrospective analysis of 1,518 consecutive cardiac surgery patients, Palatianos and associates [77] identi ed 10 patients with clinical symptoms of HIT with PF4-heparin antibodies and compared them with 10 randomly selected control sub- jects. Patients presenting with HIT received a protocol of iloprost infusion, supplemented with norepinephrine as needed, in conjunction with heparin. The postoperative reduction in platelet count was less in the iloprost group (12.5%  8.7%) versus the control group (38.1%  15.2%), and no thrombotic complications were detected. In another small study (n 10) by Koster and associates [78], heparin was used in conjunction with a tiro ban infusion during CPB. There was no clinical or laboratory (D- dimer) evidence of thrombosis or excessive bleeding. The use of argatroban has been reported with patients requiring renal replacement therapy. Given that renal clearance is an important means of bivalirudin excretion and inactivation, argatroban should be limited to these exceptional circumstances, given that excessive bleeding is the norm [79 83]. Patients who are seropositive for heparin antibodies are at increased risk of both thrombosis and bleeding (asso- ciated with heparin alternatives). Given the potentially catastrophic thrombotic complication associated with rapid-onset HIT in patients with a recent history of HIT, a very high level of vigilance is recommended in patients reexposed to heparin. These patients warrant careful surveillance, thromboprophylaxis, and possibly other special treatments to manage the increased risk. Reversal of Anticoagulation During Cardiac Operations Class IIa Recommendation  Protamine dosing for heparin reversal: It can be bene cial to calculate the protamine reversal dose based on a titration to existing heparin in the blood as this technique has been associated with reduced bleeding and blood transfusion. (Level of Evidence B) Heparin is by far the most commonly used anticoagu- lant during the conduct of cardiac operations, whether done with or without CPB. The preeminent bene t of heparin as compared with other anticoagulants is the ability to reverse its effect with protamine in a safe and expeditious manner. The goals of successful anticoagulation during CPB include limiting clotting and safely reversing the anticoagulation effect during and at the conclusion of operation, respectively. For the vast majority of opera- tions performed using CPB, heparin is the anticoagulant used and protamine is the reversal agent. An important part of the operation is to adequately remove all of the heparin effect at the end of operation. There are at least three methods commonly used to detect residual heparin effect after protamine reversal: (1) ACT measurement; (2) point-of-care testing using protamine titration of hepa- rinized blood samples; and (3) thromboelastography with or without heparinase. Comparisons of these three methods suggest that ACT-based measurements of re- sidual heparin effect are the least accurate means of detecting residual heparin effect [84, 85]. Methods of heparin reversal are several and contro- versy exists regarding the optimal strategy. Traditional methods administer heparin based on body weight and protamine based on the amount of heparin administered. Certain methods of protamine administration depend on titration of protamine to neutralize heparin in blood samples at the end of CPB. The literature comparisons of these methods are mixed, with most reports [86 88] but not all [89, 90] favoring titration methods. A meta-analysis of standard weight-based versus titrated protamine dosing favors titrated dose protamine for heparin reversal because of less postoperative blood loss and decreased packed red blood cell transfusion [91]. Two studies suggest that viscoelastic measurements are useful indicators of adequate titrated heparin reversal [92, 93]. These studies found that individualized heparin-protamine titration decreased the protamine- to-heparin ratio, improved post-CPB thromboelasto- metric hemostatic factors, and reduced the incidence of severe blood loss compared with an ACT-based strat- egy. In addition, evidence supports the use of sequential heparin and protamine titrations after CPB to further limit blood loss and to provide adequate protamine reversal [86]. Class IIa Recommendation  Protamine overdose: It is reasonable to limit the ratio of protamine/heparin to less than 2.6 mg protamine per 100 units heparin because total doses above this ratio inhibit platelet function, prolong ACT, and in- crease the risk of bleeding. (Level of Evidence C) It is possible to overdose patients with protamine. Excess protamine inhibits platelet function and prolongs the ACT after CPB. Two studies provide convincing evi- dence that when the ratio of protamine to heparin (protamine mg per 100 units heparin) is above 5:1, platelet aggregation and function are impaired [94, 95]. In addi- tion, Mochizuki and associates [94] demonstrated that at ratios above 2.6:1, the ACT signi cantly increases. The European Association of Cardiothoracic Surgery identi- ed a ratio of 2.6:1 of protamine to heparin as risking excessive bleeding. Their guidelines recommend limiting protamine, preferably using a titration method, after the completion of CPB [96]. Ann Thorac Surg 2018;105:650 62 ANTICOAGULATION DURING CARDIOPULMONARY BYPASS REPORT Class IIb Recommendation  Heparin rebound: Because of the risk of heparin rebound in patients requiring high doses of heparin and with prolonged CPB times, low-dose protamine infusion (25 mg/h) for as long as 6 hours after the end of CPB may be considered as part of a multi- modality blood conservation program. (Level of Ev- idence C) Heparin rebound occurs when detectable heparin blood levels are present at some remote time after apparently adequate heparin reversal with protamine. That likely occurs because of the ability of large molecules of heparin to sequester in fat stores and plasma proteins, with eventual reappearance in the blood at some time after protamine neutralization. Heparin dosing in excess of 400 IU/kg can result in heparin rebound. High heparin dosing during CPB results in higher doses of protamine required for reversal. Randomized comparisons of high-dose and low-dose heparin for CPB suggest that heparin rebound increases with high-dose heparin [21]. One study suggests that 10% to 15% of patients receiving usual heparin doses for CPB will have detectable heparin levels 2 hours after prot- amine reversal [97]. Another study nds that detectable heparin levels, using both anti-Xa and viscoelastic mea- surements, are present immediately after, 2 hours after, and 4 hours after protamine administration [22]. Usual methods of monitoring heparin reversal and measuring postoperative coagulation (eg, ACT and acti- vated partial thromboplastin time) do not detect residual heparin levels [84, 98]. A randomized trial involving 300 patients showed that a continuous infusion of protamine after initial protamine reversal (25 mg/h for 6 hours) abolishes heparin rebound and results in modest, but signi cant, reductions in chest tube blood loss but not transfusion requirements [99]. Class I Recommendation  Complications associated with protamine reversal of heparin after CPB: For patients at high risk for anaphylactic response to protamine who have pul- monary hypertension and circulatory collapse shortly after protamine administration, discontinu- ation of protamine and implementation of resusci- tative measures including reinstitution of CPB with adequate anticoagulation may be lifesaving. (Level of Evidence C) As one might expect with any drug, there are side ef- fects and complications associated with the use of prot- amine to reverse the effects of heparin after CPB. A unique feature of these complications associated with CPB is that they occur at a crucial time of the operative procedure. Life-threatening complications associated with protamine include anaphylaxis, pulmonary edema, and pulmonary hypertension [100]. Life-threatening car- diovascular compromise after intravenous protamine can occur even in young infants [101]. These complications are associated with operative mortality and serious organ dysfunction [102, 103]. It is likely that protamine compli- cations are underreported [100, 104]. A comprehensive review of the literature suggests true anaphylactic re- actions to protamine are rare (less than 1% of patients having CPB) [100], and approximately 60% occur before CPB, likely related to other drugs used in preoperative preparation of patients (eg, antibiotics or gelatin solution) [105]. The results from this limited database of anaphy- lactic reactions showed that cardiac surgery proceeded without complications after cardiovascular collapse caused by pre-CPB anaphylactic or anaphylactoid re- actions. Rapid institution of cardiopulmonary bypass may be lifesaving in this setting [106]. Catastrophic cardiovascular reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated. That suggests that methylene blue may be the treatment of choice in this setting but high level evidence to support this intervention is lacking [106]. Evidence to date suggests that the site of protamine administration does not in uence the incidence of protamine-induced pulmonary vasoconstriction, and aspirin ingestion within 1 week of surgery may decrease it [107]. Furthermore, acute right ventricular failure and pulmonary hypertension often precede catastrophic re- actions to protamine [103, 108, 109]. Prostacyclin and bradykinin B2 attenuate the acute pulmonary hyperten- sion in this setting but, again, no high level evidence supports the use of these agents to reverse the early stages of a reaction to protamine [108, 110]. What is known is that serious protamine reactions predispose to operative mortality, and discontinuation of protamine and reinstitution of CPB, if serious protamine reactions occur, may be lifesaving [103, 105]. Studies show that antibodies to the protamine/heparin complex occur commonly after CPB [111, 112]. These antibodies share a number of serologic features with HIT- derived antibodies, including platelet activation. In addition, these protamine/heparin antibodies cross react with protamine-containing insulin preparations [111]. Development of these antibodies predisposes to adverse outcomes after cardiac procedures and may pose risks of anamnestic response on reexposure to protamine [111, 112]. For example, a meta-analysis of the surgical litera- ture showed the risk of a protamine reaction in surgical patients to be 10 to 20 times higher for patients taking protamine-containing insulin compared with control pa- tients not taking insulin preparations [107, 113]. Alternate Agents Used to Reverse Heparin Anticoagulation Reversal of heparin with protamine affects platelet ag- gregation and whole blood clotting [94]. The over- whelming convenience of protamine reversal of heparin makes it the drug of choice for heparin neutralization despite potential adverse effects on platelet and clotting function. There are patients who are unable to receive protamine for various reasons. For this reason, PF4 has been investigated as a heparin reversal agent in ex vivo animal studies and occasional case reports [114 116]. The PF4 is released by activated platelets and has strong 658 Ann Thorac Surg ANTICOAGULATION DURING CARDIOPULMONARY BYPASS 2018;105:650 62 REPORT attraction for heparin. Studies show that recombinant PF4 provides adequate heparin neutralization. However, preformed antibodies against the PF4-heparin complex are important contributors to the pathophysiology of HIT. Patients previously exposed to heparin may have these preformed antibodies, and the addition of exogenous PF4 in the presence of heparin risks an anamnestic response and severe HIT or HIT with thrombosis. More clinical experience is required to validate the safety of PF4 for heparin reversal after CPB [116]. Reports document attempts at using other drugs for heparin neutralization. Methylene blue, hexadimethrine, vancomycin, and heparinase I are among drugs tested for heparin neutralization [115, 117, 118]. None of these drugs has proved equivalent to protamine in its safety pro le for reversal of heparin after CPB. One of these drugs, heparinase I, was compared with protamine in a multi- center, randomized, prospective trial; heparinase I had an inferior safety pro le after reversal of heparin at the end of CPB that was a result of increased transfusion and prolonged hospital stay in the heparinase group compared with the protamine group [118]. At this time, protamine is considered the gold standard for reversal of heparin anticoagulation. If protamine cannot be used, there are not enough data to make a recommendation regarding safety and ef cacy of any of the alternative heparin reversal agents. Class IIb Recommendation  Anticoagulation reversal when using heparin alter- natives and direct thrombin inhibitors: For patients requiring anticoagulation with bivalirudin who have excessive bleeding after CPB, a combination of modi ed ultra ltration, hemodialysis, and the administration of recombinant factor VIIa with blood product replacement may be considered to improve hemostasis in these extreme situations. (Level of Evidence C) Conclusion The ideal anticoagulation strategy for cardiac surgery with CPB in patients who cannot take heparin does not exist. Heparin and protamine remain the gold standard for anticoagulation therapy. A small subset of patients requires heparin alternatives for the conduct of CPB. Bivalirudin seems to offer the safest heparin alternative in this setting. This drug has a short half-life of approxi- mately 25 minutes. Nonetheless, coagulopathy occurs in bivalirudin-treated patients. There is no well-de ned reversal agent for bivalirudin, and patients with coagul- opathy and excessive bleeding require unusual in- terventions for hemorrhage control. Only anecdotal experience is available to address coagulopathy in cases of bivalirudin-related hemorrhage [68, 71]. Consensus suggests that a multifaceted approach offers the best chance of successful hemorrhage control for these pa- tients. Recombinant activated factor VII may be an important part of hemorrhage control but other in- terventions including modi ed ultra ltration, hemodialysis, and clotting factor replacement are also advocated [71]. References 1. Stoney WS. Evolution of cardiopulmonary bypass. Circu- lation 2009;119:2844 53. 2. Ferraris VA. Heroes and evidence. J Thorac Cardiovasc Surg 2002;124:11 3. 3. Bull BS, Korpman RA, Huse WM, Briggs BD. Heparin therapy during extracorporeal circulation. I. Problems inherent in existing heparin protocols. J Thorac Cardiovasc Surg 1975;69:674 84. 4. Young JA, Kisker CT, Doty DB. Adequate anticoagulation during cardiopulmonary bypass determined by activated clotting time and the appearance of brin monomer. Ann Thorac Surg 1978;26:231 40. 5. Na S. Stabilized infective endocarditis and altered heparin responsiveness during cardiopulmonary bypass. World J Surg 2009;33:1862 7. 6. Garvin S, FitzGerald DC, Despotis G, Shekar P, Body SC. Heparin concentration-based anticoagulation for cardiac surgery fails to reliably predict heparin bolus dose re- quirements. Anesth Analg 2010;111:849 55. 7. Grima C. The effects of intermittent prebypass heparin dosing in patients undergoing coronary artery bypass grafting. Perfusion 2003;18:283 9. 8. Neema P, Sinha P, Rathod R. Activated clotting time during cardiopulmonary bypass: is repetition necessary during open heart surgery? Asian Cardiovasc Thorac Ann 2004;12: 47 52. 9. Shore-Lesserson L. Evidence based coagulation monitors: heparin monitoring, thromboelastography, and platelet function. Semin Cardiothorac Vasc Anesth 2005;9:41 52. 10. Machin D, Devine P. The effect of temperature and apro- tinin during cardiopulmonary bypass on three different methods of activated clotting time measurement. J Extra Corpor Technol 2005;37:265 71. 11. Leyvi G, Shore-Lesserson L, Harrington D, Vela-Cantos F, Hossain S. An investigation of a new activated clotting time MAX-ACT in patients undergoing extracorporeal circula- tion. Anesth Analg 2001;92:578 83. 12. Koster A, Fischer T, Praus M, et al. Hemostatic activation and in ammatory response during cardiopulmonary bypass: impact of heparin management. Anesthesiology 2002;97:837 41. 13. Despotis GJ, Joist JH, Hogue CW, et al. The impact of heparin concentration and activated clotting time moni- toring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1995;110:46 54. 14. Despotis GJ, Joist JH, Hogue CW, et al. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost 1996;76:902 8. 15. Pappalardo F, Franco A, Crescenzi G, De Simone F, Torracca L, Zangrillo A. Anticoagulation management in patients undergoing open heart surgery by activated clot- ting time and whole blood heparin concentration. Perfusion 2006;21:285 90. 16. Hofmann B, Bushnaq H, Kraus FB, et al. Immediate effects of individualized heparin and protamine management on hemostatic activation and platelet function in adult patients undergoing cardiac surgery with tranexamic acid anti- brinolytic therapy. Perfusion 2013;28:412 8. 17. Newsome J, Stipanovich K, Flaherty S. Comparison of heparin administration using the Rapidpoint Coag and Hepcon HMS. J Extra Corpor Technol 2004;36:139 44. 18. Hansen R, Koster A, Kukucka M, Mertzlufft F, Kuppe H. A quick anti-Xa-activity-based whole blood coagulation assay for monitoring unfractionated heparin during Ann Thorac Surg 2018;105:650 62 ANTICOAGULATION DURING CARDIOPULMONARY BYPASS REPORT cardiopulmonary bypass: a pilot investigation. Anesth Analg 2000;91:533 8. 19. Hellstern P, Bach J, Simon M, Saggau W. Heparin moni- toring during cardiopulmonary bypass surgery using the one-step point-of-care whole blood anti-factor-Xa clotting assay Heptest-POC-Hi. J Extra Corpor Technol 2007;39: 81 6. 20. Gravlee GP, Haddon WS, Rothberger HK, et al. Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation. J Thorac Cardiovasc Surg 1990;99: 518 27. 21. Gravlee GP, Rogers AT, Dudas LM, et al. Heparin man- agement protocol for cardiopulmonary bypass in uences postoperative heparin rebound but not bleeding. Anesthe- siology 1992;76:393 401. 22. Ichikawa J, Kodaka M, Nishiyama K, Hirasaki Y, Ozaki M, Komori M. Reappearance of circulating heparin in whole blood heparin concentration-based management does not correlate with postoperative bleeding after cardiac surgery. J Cardiothorac Vasc Anesth 2014;28:1015 9. 23. Bosch YP, Ganushchak YM, de Jong DS. Comparison of ACT point-of-care measurements: repeatability and agree- ment. Perfusion 2006;21:27 31. 24. Wallock M, Jeske WP, Bakhos M, Walenga JM. Evaluation of a new point of care heparin test for cardiopulmonary bypass: the TAS heparin management test. Perfusion 2001;16:147 53. 25. Leyvi G, Zhuravlev I, Inyang A, et al. Arterial versus venous sampling for activated coagulation time measurements during cardiac surgery: a comparative study. J Cardiothorac Vasc Anesth 2004;18:573 80. 26. Searles B, Nasrallah F, Darling E, Yarcusko S. How does the age of a blood sample affect its activated clotting time? Comparison of eight different devices. J Extra Corpor Technol 2002;34:175 7. 27. Welsby IJ, McDonnell E, El-Moalem H, Stafford-Smith M, Toffaletti JG. Activated clotting time systems vary in pre- cision and bias and are not interchangeable when following heparin management protocols during cardiopulmonary bypass. J Clin Monit Comput 2002;17:287 92. 28. Raymond PD, Ray MJ, Callen SN, Marsh NA. Heparin monitoring during cardiac surgery. Part 2: calculating the overestimation of heparin by the activated clotting time. Perfusion 2003;18:277 81. 29. Patteril M, Stafford-Smith M, Toffaletti JG, Bute BP, Milano CA, Welsby IJ. Changing systems for measuring activated clotting times: impact on the clinical practice of heparin anticoagulation during cardiac surgery. Clin Chim Acta 2005;356:218 24. 30. Chavez JJ, Foley DE, Snider CC, et al. A novel thrombe- lastograph tissue factor/kaolin assay of activated clotting times for monitoring heparin anticoagulation during car- diopulmonary bypass. Anesth Analg 2004;99:1290 4. 31. Ganter MT, Monn A, Tavakoli R, et al. Monitoring activated clotting time for combined heparin and aprotinin applica- tion: in vivo evaluation of a new aprotinin-insensitive test using Sonoclot. Eur J Cardiothorac Surg 2006;30:278 84. 32. Ganter MT, Monn A, Tavakoli R, Klaghofer R, Zollinger A, Hofer CK. Kaolin-based activated coagulation time measured by Sonoclot in patients undergoing cardiopul- monary bypass. J Cardiothorac Vasc Anesth 2007;21:524 8. 33. Watson H, Davidson S, Keeling D, Haemostasis and Thrombosis Task Force of the British Committee for Stan- dards in Haematology. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: sec- ond edition. Br J Haematol 2012;159:528 40. 34. Prechel MM, Walenga JM. Emphasis on the role of PF4 in the incidence, pathophysiology and treatment of heparin induced thrombocytopenia. Thromb J 2013;11:7. 35. Bircher AJ, Harr T, Hohenstein L, Tsakiris DA. Hypersen- sitivity reactions to anticoagulant drugs: diagnosis and management options. Allergy 2006;61:1432 40. 36. Centers for Disease Control. Acute allergic-type reactions among patients undergoing hemodialysis multiple states, 2007 2008. MMWR Morb Mortal Wkly Rep 2008;57:124 5. 37. Greinacher A. Heparin-induced thrombocytopenia. N Engl J Med 2015;373:252 61. 38. Warkentin TE. Clinical picture of heparin-induced throm- bocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia. Thromb Haemost 2016;116:813 22. 39. Kerendi F, Thourani VH, Puskas JD, et al. Impact of heparin-induced thrombocytopenia on postoperative out- comes after cardiac surgery. Ann Thorac Surg 2007;84: 1548 55. 40. Bennett-Guerrero E, Slaughter TF, White WD, et al. Pre- operative anti-PF4/heparin antibody level predicts adverse outcome after cardiac surgery. J Thorac Cardiovasc Surg 2005;130:1567 72. 41. Kress DC, Aronson S, McDonald ML, et al. Positive heparin-platelet factor 4 antibody complex and cardiac surgical outcomes. Ann Thorac Surg 2007;83:1737 43. 42. Stribling WK, Slaughter TF, Houle TT, Sane DC. Beyond the platelet count: heparin antibodies as independent risk predictors. Am Heart J 2007;153:900 6. 43. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antith- rombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl):e495 530. 44. Selleng S, Haneya A, Hirt S, Selleng K, Schmid C, Greinacher A. Management of anticoagulation in patients with subacute heparin-induced thrombocytopenia sched- uled for heart transplantation. Blood 2008;112:4024 7. 45. Warkentin TE, Sheppard JA. Serological investigation of patients with a previous history of heparin-induced thrombocytopenia who are reexposed to heparin. Blood 2014;123:2485 93. 46. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocy- topenia: American College of Chest Physicians evidence- based clinical practice guidelines (8th edition). Chest 2008;133(Suppl):340 80. 47. Lubenow N, Kempf R, Eichner A, Eichler P, Carlsson LE, Greinacher A. Heparin-induced thrombocytopenia: tem- poral pattern of thrombocytopenia in relation to initial use or reexposure to heparin. Chest 2002;122:37 42. 48. Warkentin TE, Kelton JG. A 14-year study of heparin- induced thrombocytopenia. Am J Med 1996;101:502 7. 49. Nuttall GA, Oliver WC, Santrach PJ, et al. Patients with a history of type II heparin-induced thrombocytopenia with thrombosis requiring cardiac surgery with cardiopulmo- nary bypass: a prospective observational case series. Anesth Analg 2003;96:344 50. 50. Potzsch B, Klovekorn WP, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia. N Engl J Med 2000;343: 515. 51. Warkentin TE, Arnold DM, Nazi I, Kelton JG. The platelet serotonin-release assay. Am J Hematol 2015;90:564 72. 52. Warkentin TE. Heparin-induced thrombocytopenia in crit- ically ill patients. Semin Thromb Hemost 2015;41:49 60. 53. Piednoir P, Allou N, Provenchere S, et al. Heparin-induced thrombocytopenia after cardiac surgery: an observational study of 1,722 patients. J Cardiothorac Vasc Anesth 2012;26: 585 90. 54. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006;4:759 65. 55. Lillo-Le Louet A, Boutouyrie P, Alhenc-Gelas M, et al. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost 2004;2: 1882 8. 56. Cuker A, Arepally G, Crowther MA, et al. The HIT expert probability (HEP) score: a novel pre-test probability model 660 Ann Thorac Surg ANTICOAGULATION DURING CARDIOPULMONARY BYPASS 2018;105:650 62 REPORT for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost 2010;8:2642 50. 57. Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Pre- dictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 2012;120:4160 7. 58. Warkentin TE, Kelton JG. Temporal aspects of heparin- induced thrombocytopenia. N Engl J Med 2001;344:1286 92. 59. Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000;96:1703 8. 60. 