CME/SAM. Cold Antibodies in Cardiovascular Surgery Is Preoperative Screening Necessary? Suneeti Sapatnekar, MD, PhD, and Priscilla I.

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1 Cold Antibodies in Cardiovascular Surgery Is Preoperative Screening Necessary? Suneeti Sapatnekar, MD, PhD, and Priscilla I. Figueroa, MD From the Section of Transfusion Medicine, Department of Laboratory Medicine, Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH. Key Words: Cold antibodies; Cardiovascular surgery; Transfusion practice Am J Clin Pathol June 2016;145: DOI: /AJCP/AQW054 CME/SAM ABSTRACT Objectives: Cold antibodies (CAs) are rarely significant for transfusion, but they can cause complications under the hypothermic conditions of cardiovascular surgery. The purpose of this study was to determine the incidence of such complications. Methods: Patients with CAs who underwent cardiovascular surgery were identified, and their records were reviewed for intraoperative complications attributable to CAs. Results: Over 14.5 years, of the 47,373 patients who underwent cardiovascular surgery, 99 had CAs before or within 30 days after surgery. Ninety-seven patients had hypothermic surgery, and intraoperative agglutination was noted in four; two of these cases were never reported to the transfusion service. Conclusions: The incidence of intraoperative complications among our patients with CAs was only 4%; therefore, the use of special testing protocols for the preoperative identification of CAs is neither necessary nor justified. Patient risk is best managed by preoperative clinical evaluation for potentially pathogenic CAs and intraoperative vigilance for agglutination. Upon completion of this activity you will be able to: explain why preoperative testing for cold antibodies is not routinely performed. apply the suggested guidelines to reduce the risk of complications caused by cold antibodies during cardiovascular surgery. discuss the rationale for timely reporting of perioperative complications associated with cold antibodies. The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit TM per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Exam is located at Cold antibodies (CAs) react more strongly at 4 C than at higher temperatures but may have a wide thermal range. CAs with anti-i specificity are frequently detectable in healthy individuals, but CAs may also be transiently associated with disease (eg, mycoplasma infection) and generally have a benign course. Benign CAs in healthy individuals typically have saline titers no higher than 64 and are reactive up to 10 Cto15 C. Pathogenic CAs are reactive at or close to physiologic temperature and associated with hemolytic anemia and/or microvascular occlusion on exposure to cold. 1 Most CAs are benign and are significant for the patient only in that they interfere with laboratory testing. due to room temperature reactive CAs may not be dispersed upon warming to 37 C, resulting in falsepositive reactivity at pretransfusion testing, thus complicating American Society for Clinical Pathology, All rights reserved. Downloaded For from permissions, please journals.permissions@oup.com on 19 August Am J Clin Pathol 2016;145:

2 Sapatnekar and Figueroa /COLD ANTIBODIES IN CARDIAC SURGERY the process of excluding clinically significant RBC antibodies. Protocols for routine pretransfusion testing are, therefore, deliberately designed to avoid detecting CAs unless they react at physiologic temperature (eg, by eliminating tests performed at room temperature). 2,3 Whether CAs are benign or pathogenic, they have the potential to cause complications if the individual is exposed to hypothermic conditions. Induced hypothermia is often used during cardiovascular surgery and is intended to reduce oxygen demand of the myocardium and avoid ischemic damage. Hypothermia is induced by formulations that are typically crystalloid mixed with autologous blood from the extracorporeal circuit and delivered as cold solutions for induction and intermittently for maintenance. The usual temperature range for hypothermic perfusion is 32 Cto34 C, 4 but at initial contact with cold solutions, blood may transiently cool to a temperature as low as 4 C. Numerous case reports of perioperative complications have been attributed to CAs that are activated by induced hypothermia, including RBC agglutination, hemolysis, and thrombosis. 5-9 Large studies have observed such complications only infrequently, but their incidence is unknown, leading to inconsistency in practices for pretransfusion testing, result reporting, and surgical management of patients undergoing cardiovascular surgery. The purpose of our study was to determine the type and frequency of intraoperative complications attributable to CAs among cardiovascular surgery patients and to develop guidelines for the pretransfusion testing and perioperative management of these patients. Index Case A 73-year-old woman with coronary artery disease was scheduled for aortic valve replacement with coronary artery bypass surgery. Anti-M antibody, nonreactive when plasma and reagent cells were prewarmed to 37 C, was reported on the preoperative sample. RBC units that were compatible on the antiglobulin crossmatch were allocated for transfusion. The transfusion service offered no recommendation on the management of. Cold blood was initiated during surgery, using a 4:1 ratio of blood and crystalloid, and almost immediately, RBC agglutination was observed in the proximal line. Cardioplegia was stopped immediately, and the patient was warmed. The RBC agglutinates were intercepted before they reached the patient, and no clinical adverse reaction was noted. The blood bank was immediately notified of the event. Surgery was continued with warm and completed over a period of approximately 7 hours without further incident. Laboratory evaluation of the post-event patient sample demonstrated no hemolysis and negative direct antiglobulin test. Record review revealed a patient history of giant cell arteritis and immunoglobulin M monoclonal gammopathy of undetermined significance, conditions that may be associated with CAs, but no suggestion of cold agglutinin disease or hemolytic anemia. Testing at a reference laboratory against M-negative RBCs demonstrated pan-reactive CA with a titer of 512 at 4 C, explaining the observation of macroscopic agglutination at initiation of cold, when the patient s blood in the line was probably close to 4 C. The sample was nonreactive at 30 C with all test cells, consistent with a nonpathogenic CA. This case motivated us to investigate the occurrence of similar intraoperative events. Materials and Methods Following Cleveland Clinic Institutional Review Board approval, a report of all patients identified with CAs was generated from the laboratory information system (Sunquest Information Systems, Tucson, AZ) for July 1, 1998, through December 31, For most of the study period, the primary method was gel testing, but solid-phase RBC adherence technology and polyethylene glycol tube method were also sometimes used. Evaluation of antibodies reactive at room temperature was limited to specific circumstances (eg, investigation of a blood typing discrepancy). Because of the retrospective nature of this study, we cannot definitively identify the testing method used for each case over the 14.5 years of the study. Each patient with a CA was checked against our institution s Cardiovascular Information Registry, a prospectively collected database of clinical, laboratory, and follow-up data on adult patients undergoing cardiac surgery. Patients with a history of a CA who were listed in the registry were further studied to identify those who had preexisting antibodies or antibodies detected within 30 days after surgery. For each such patient, the operative and discharge notes were reviewed for any indication of intraoperative agglutination or hemolysis. Available reports of transfusion reactions over the study period were reviewed for any instances of intraoperative complications that were potentially attributable to CAs. Results Over the 14.5 years of the study, 47,373 patients were enrolled in the Cardiovascular Information Registry. Ninety-nine (0.21%) of these patients had CAs identified 790 Am J Clin Pathol 2016;145: American Society for Clinical Pathology 790 Downloaded from

3 before surgery or within 30 days after surgery. The patients ranged in age from 26 to 87 years (mean 6 SD, years), and the male-to-female ratio was 1.2:1. The most common antibody specificity was anti-m Table 1. Two of the 49 patients with anti-m were M-positive by serologic RBC typing. Among the 99 patients with CAs, there were two patients for whom the surgical team elected to operate under normothermic conditions. One of these patients had a history of hemolytic anemia. The other patient had a nonspecific CA reported reactive at 4 C, room temperature, 33 C, and 37 C, but it is not clear from the available records what led to the extensive testing performed in this case. The remaining 97 patients underwent hypothermic surgery, and intraoperative agglutination was reported in four cases (including the index case), for an incidence of 4.1%. The presentation, test results, and surgical outcomes for these cases are described in Table 2. There were no reports of intraoperative hemolysis. No other reports of intraoperative agglutination or hemolysis during cardiovascular surgery were found in the transfusion reaction reports for the study period. Records of systemic temperature achieved during surgery were available for 57 patients; seven patients had a temperature at or below 25 C, but no agglutination was reported. Discussion Our institution is a major referral center for cardiovascular surgery. During the final year of our study (July 2010 through June 2011), there were 551 coronary artery bypass graft procedures, 2,141 heart valve surgeries, and 767 valve surgeries with coronary artery bypass grafting. Our transfusion service does not modify pretransfusion testing for these patients, and the rarity of adverse events in our study supports this approach of testing cardiovascular surgery patients in the same manner as other patients. In a large study of nearly 15,000 patients who underwent cardiopulmonary bypass, Jain et al 12 found 47 patients Table 1 Specificities of Cold Antibodies Identified in Cardiovascular Surgery Patients Antibody Specificity No. of Patients Anti-M alone 42 Cold panagglutinin alone 18 Lewis group antibodies 16 Anti-A1 12 a Anti-M with cold panagglutinin 7 Anti-P1 4 a More than 60% of the patients typed A or AB. with a positive CA screen (agglutination of reagent cells after incubation at C for 30 minutes). However, on further testing, more than half of the screen-positive patients were determined to be falsely positive (rouleaux, fibrin, or over-call), emphasizing that routine screening adds less value than expected due to a high proportion of false-positive results. For CAs that are identified before cardiovascular surgery, their behavior under the conditions of hypothermia cannot be accurately predicted. Most CAs have low thermal amplitude (maximum temperature of reactivity) and/or low titer, and they only rarely cause complications during induced hypothermia. Even for CAs with a relatively high thermal amplitude on laboratory testing, an intraoperative complication may not occur despite cooling the patient below the thermal amplitude Moreover, the causative role of CAs in an intra- or perioperative complication may not always be clear, as illustrated by some case reports of hemolysis in patients with CAs. 9,11,14 In our study, the frequency of intraoperative agglutination was 4% among patients with CAs. There were no reports of hemolysis, but the possibility of transient, unrecognized hemolysis cannot be ruled out. The population that we selected for detailed review represents only 0.2% of patients who underwent cardiovascular surgery during the study period, and significantly, even the few cases of intraoperative agglutination that we found were not all reported to the transfusion service. As we did not perform a detailed records review for more than 47,000 patients without CAs, our calculated frequency of 4% probably underestimates the occurrence of intraoperative agglutination due to CAs. The absence of reporting may also indicate that if a complication occurred, it did not significantly alter the outcome of the procedure. The study results have been helpful for developing guidelines for pretransfusion testing and perioperative management of patients scheduled for cardiovascular surgery Figure 1. In keeping with recent recommendations, 11,12 these guidelines are based on the premise that the optimal approach to risk management is not preoperative testing for CAs but, rather, a strategy to minimize the likelihood of complications due to CAs under conditions of induced hypothermia. Preoperative Evaluation The wide prevalence of CAs; the poor specificity of testing for CAs; the labor, time, and cost of testing (including additional testing to rule out clinically significant alloantibodies); and the low likelihood of perioperative clinical complications due to CAs all argue against routine testing of cardiovascular surgery patients for CAs. Moreover, American Society for Clinical Pathology Am J Clin Pathol 2016;145: Downloaded 791 from

4 Sapatnekar and Figueroa /COLD ANTIBODIES IN CARDIAC SURGERY Table 2 Summary of Cardiovascular Surgery Patients With Intraoperative Complications Due to Cold Antibodies or Recognized as Being at Risk for Such Complications Case No. Age, y/ Sex Clinical History 1 80/M Recurrent aortic stenosis and insufficiency, psoriasis, migraine, benign prostatic hyperplasia, history of transient ischemic attack 2 70/M Coronary artery disease, aortic stenosis, mitral valve regurgitation, CLL with hemolytic anemia Preoperative Blood Bank Testing Type of Surgery Intraoperative Complication Outcome 3 64/M Aortic aneurysm, hypertension, chronic obstructive pulmonary disease 4 66/F Coronary artery disease, diabetes, hypertension, chronic obstructive pulmonary disease, peripheral arterial disease, chronic kidney disease 5 65/M Coronary artery disease, hyperlipidemia, hypertension, reflux disease, chronic occupational lung disease Index case 73/F Coronary artery disease, giant cell arteritis, IgM monoclonal gammopathy of undetermined significance Yes, cold agglutinins at 4 C, room temperature, 30 C, and 37 C; DAT: C3þ, IgG 0; recommended avoiding hypothermia Cold agglutinins; DAT: C3þ, IgG 0; also anti- E; no recommendation to avoid hypothermia Anti-M, prewarm nonreactive, patient Mþ; no recommendation to avoid hypothermia Cold autoagglutinins at RT and 30 C; recommended avoiding hypothermia None; antibody screen negative Anti-M, prewarm nonreactive Redo aortic valve replacement Redo coronary artery bypass grafting, replacement of aortic and mitral valves Ascending aorta and arch replacement; elephant trunk procedure Coronary artery bypass grafting three times, over 6 h 20 min Coronary artery bypass grafting three times, over 5 h 45 min Coronary artery bypass grafting two times, aortic valve replacement, performed over 7 h NA; used warm NA; used warm only; not reported to blood bank only; not reported to blood bank only; reported to blood bank a only; reported to blood bank a Surgery performed Surgery performed, but scope of surgery redefined CLL, chronic lympohocytic leukemia; DAT, direct antiglobulin test; IgG, immunoglobulin G; IgM, immunoglobulin M; NA, not applicable; RT, room temperature. a On retrospective testing of the preoperative sample, cold panagglutinin demonstrable in low ionic strength saline at RT. as found in our study and reported by others, intraoperative RBC agglutination under induced hypothermia can occur in patients with unrecognized CAs, 5,8,9,11 and therefore, efforts at risk reduction should be focused on early detection of agglutination and quick intervention to avoid clinical harm. Patients with pathogenic CAs are at high risk of perioperative complications; therefore, preoperative probing for evidence of cold agglutinin disease is recommended, including review of records for a history of hemolysis or acrocyanosis and investigation of anemia. Patients with a symptomatic or potentially symptomatic CA should be referred for hematology consultation, and further laboratory testing to characterize the antibody may be indicated. Surgery should be planned without the use of hypothermia or, at least, at a temperature above the thermal amplitude of the CA. Additional measures for perioperative management may be necessary if hypothermia is unavoidable (eg, immunosuppression or plasmapheresis to reduce the CA titer) 13,15 or perfusion protocols that avoid prolonged systemic hypothermia. 16 For patients with an incidental CA without hemolysis, standard pretransfusion testing should be performed to determine whether the antibody is an alloantibody, but further testing is generally not necessary. However, hemolysis in a cold-stored blood sample tube may indicate a potentially pathogenic CA and should be investigated. 792 Am J Clin Pathol 2016;145: American Society for Clinical Pathology 792 Downloaded from

5 Cold antibody detected, present or past Cold antibody not detected Symptomatic antibody, eg, cold agglutinin disease Incidental antibody Laboratory evaluation, as indicated; avoid hypothermia Alloantibody, eg, anti-m Autoantibody AHG XM incompatible AHG XM compatible 37 C nonreactive (settled reading) 37 C reactive (settled reading) Hypothermic procedure Hypothermic or normothermic procedure Hypothermic or normothermic procedure Use antigen-negative RBC units, as feasible Use antigennegative RBC units Use unselected RBC units Watch for agglutination during surgery. If agglutination occurs, warm patient quickly. Report incident to blood bank. Figure 1 Guideline for managing cardiovascular surgery patients with cold antibodies. The patient s preoperative visit must include evaluation for a history suggestive of a pathogenic cold antibody. AHG XM, antihuman globulin crossmatch. Transfusion Management If a CA is incidentally detected, the clinical team should be informed. Our practice is to convey this information via the pathologist s antibody interpretation report, which describes the expected behavior of any allo- or autoantibodies detected, or other potential impact of the serologic findings, and provides guidance with regard to expected blood availability. In the case of a patient scheduled for cardiovascular surgery, this report also includes a comment on the potential for complications under hypothermic conditions, an aspect that is discussed with the surgical team, when possible. The growing practice of patients presenting on the day of planned surgery without previous testing and the emergent nature of some procedures present challenges to timely communication; in such cases, we make every attempt to contact the anesthesiology team assigned to the case. The laboratory characteristics of the CA determine the selection of RBC units for intraoperative transfusion. If an alloantibody (eg, anti-m) is identified, antiglobulin crossmatch-compatible units should be prepared for surgery, regardless of whether the surgery is to be performed under hypothermia. If the standard antiglobulin crossmatch is incompatible, the antibody is tested to determine if it is reactive at the 37 C settled reading that is, reagent RBCs and the patient s plasma are separately warmed to 37 C, incubated at 37 C for 1 to 2 hours (allowed to settle ), and read without centrifugation. or hemolysis indicates an antibody that is truly reactive at 37 C, without overreading antibody reactivity. If the antibody is reactive at the 37 C settled reading, antigen-negative units should be prepared. These measures are consistent with our usual protocol for cold-reactive alloantibodies for all patients. If the antiglobulin crossmatch is incompatible, the alloantibody is nonreactive at 37 C (prewarmed, settled reading), and hypothermic surgery is planned, antigen-negative units may be prepared, as feasible, simply to avoid any risk of intraoperative agglutination that may interrupt the surgery. For an autoantibody, RBC units require no special preparation. Intraoperative Monitoring During surgery, the patient and circuit should be closely monitored for RBC agglutination and hemolysis (and hemoglobinuria), whether or not the patient American Society for Clinical Pathology Am J Clin Pathol 2016;145: Downloaded 793 from

6 Sapatnekar and Figueroa /COLD ANTIBODIES IN CARDIAC SURGERY is known to have a CA. If agglutination or hemolysis is noted, cold should be stopped immediately and the patient warmed rapidly. in the circuit can manifest as RBC separation, increased pressure in the line, or inadequate delivery of. Our cardiac perfusionists routinely inspect the heat exchanger and proximal line for agglutination before unclamping the line to deliver solution to the heart. Prompt detection of agglutination and quick corrective intervention can avoid clinical harm to the patient. In most cases, surgery can be continued with normothermic. Instances of agglutination or hemolysis that are potentially attributable to CAs should be immediately reported to the blood bank. We have applied these guidelines to several recent cases, including one with a pathogenic CA that was diagnosed before surgery only because an astute technologist noted severe hemolysis in the blood sample tube, stimulating follow-up review and investigation. We expect that adherence to these guidelines will ensure a uniform approach to the perioperative management of our cardiovascular surgery patients with CAs and less costly pretransfusion testing. Recently, we discovered a new case of agglutination during cold on an incidental review of a patient s intraoperative cell salvage record. The case was continued and never reported to the transfusion service. Such cases highlight the need for continuous improvement in communication between the surgical teams and the transfusion service. The increasing emphasis on adverse event reporting as part of patient safety monitoring may improve the reporting of intraoperative complications. Furthermore, by proactively engaging with the surgery or anesthesiology team, we believe that we are establishing the merits of consultation with the transfusion service team on the management of potentially problematic cases. We hope that this approach will encourage interaction over a wider variety of concerns and questions, as our clinical colleagues come to value the laboratory s integral role in the care team. Conclusion The risk of CA-associated complications in cardiovascular surgery is low and can be managed by preoperative assessment for clinical evidence of cold agglutinin disease and by careful monitoring of the cardiovascular circuit. There is no justification for routine preoperative screening for CAs. Ensuring timely reporting of intraoperative complications remains a challenge but should be pursued so that appropriate follow-up review and testing can be performed. A prospective study is needed to obtain complete and accurate data on complications due to CAs, so that evidence-based preventive or corrective actions may be instituted. Corresponding author: Suneeti Sapatnekar, MD, PhD, Dept of Laboratory Medicine, Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Mail Code Q6-200, 9500 Euclid Ave, Cleveland, OH 44195; sapatns@ccf.org. References 1. Klein HG, Anstee DJ. Red cell antibodies against self-antigens, bound antigens and induced antigens. In: Mollison s Blood Transfusion in Clinical Medicine. 11th ed. Oxford, UK: Blackwell; 2005: Issitt PD, Anstee DJ. Compatibility testing. In: Applied Blood Group Serology. 4th ed. Durham, NC: Montgomery Scientific Publications; 1998: Judd WJ. How I manage cold agglutinins. Transfusion. 2006;46: Engelman R, Baker RA, Likosky DS, et al. 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7 14. Wertlake PT, McGinniss MH, Schmidt PJ. Cold antibody and persistent intravascular hemolysis after surgery under hypothermia. Transfusion. 1969;9: Pesci SA, Almassi GH, Langenstroer P. Deep hypothermic circulatory arrest for a patient with known cold agglutinins. Ann Thorac Surg. 2009;88: Panos A, Murith N, Myers PO, et al. Aortic arch repair and cold-reactive agglutinins: what to do? Ann Thorac Surg. 2007;84: American Society for Clinical Pathology Am J Clin Pathol 2016;145: Downloaded 795 from