J Thromb Thrombolysis DOI 10.1007/s11239-013-1045-2
ABO blood group influences transfusion and survival after cardiac surgery Ian J. Welsby • Barbara Phillips-Bute • Joseph P. Mathew • Mark F. Newman Richard Becker • Sunil Rao • Carmelo A. Milano • Mark Stafford-Smith
Ó Springer Science+Business Media New York 2014
Abstract ABO dependent variation in von Willebrand factor (vWf) and procoagulant factor VIII (FVIII) is a plausible mechanism for modulating perioperative hemostasis and bleeding. Group AB has the highest and group O the lowest vWf and FVIII levels. Therefore, we tested the hypothesis that ABO blood group is associated with perioperative transfusion and subsequent survival after coronary revascularization. This retrospective study combined demographic, operative, and transfusion data, including follow-up for a median of 2,096 days, for consecutive aortocoronary bypass (CABG) and CABG/valve procedures from 1996–2009 at a tertiary referral University Heart Center. Between group differences were compared by a Kruskall Wallis test, and hazard ratios [95 % confidence intervals] are reported for mortality risk-adjusted Cox proportional hazards regression analysis. From 15,454 patients, follow-up records were available for 13,627
patients: 6,413 group O, 5,248 group A, 1,454 group B, and 435 group AB. Packed red blood cells were the most commonly transfused blood product (3 [0–5] units), while group AB received 2 [0–5] units (Kruskall Wallis Chi squared value for between group differences = 8.2; p = 0.04). Group AB favored improved long-term, postoperative survival (Hazard ratio = 0.82 [95 %CI 0.68–0.98]; p = 0.03), which became evident approximately a year after surgery. In conclusion, the procoagulant phenotype of blood group AB is associated with fewer transfusions and improved late survival after cardiac surgery. Whether this finding is related to fewer perioperative transfusions, a reduction in later bleeding or other mechanisms remains speculative. Keywords ABO blood group Transfusion Surgery Risk factors Mortality Von Willebrand factor
Introduction For members of the Cardiothoracic Anesthesiology Research Endeavors (CARE), Department of Anesthesiology see Appendix 1. A guest editor was appointed for this manuscript. I. J. Welsby (&) B. Phillips-Bute J. P. Mathew M. F. Newman M. Stafford-Smith Department of Anesthesiology, Duke University Medical Center DUMC, Box 3094, Durham, NC 27710, USA e-mail: [email protected]
; [email protected]
R. Becker S. Rao Duke Clinical Research Institute, Duke University Medical Center DUMC, Box 3094, Durham, NC 27710, USA C. A. Milano Department of Thoracic Surgery, Duke University Medical Center DUMC, Box 3094, Durham, NC 27710, USA
Risk stratification for cardiac surgery focuses primarily on 30-day perioperative mortality [1–3], whereas identifying risk factors for common morbidities, such as those associated with transfusion [4, 5], may lead to strategies that improve longer-term outcome. Furthermore, understanding factors that impact longer-term survival will inform individualized planning for surgical interventions. Practically applicable preoperative risk factor testing should be readily available and inexpensive. Our group previously reported that, after adjusting for known clinical covariates and risk scores, genetic factors may be predictive of adverse outcomes after cardiac surgery [6, 7]. ABO blood type is the most commonly tested phenotype of a genetic variation, and is routinely determined before any
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surgical procedure. It may add to existing risk stratification, because it is biologically plausible that ABO-dependent variation in von Willebrand factor (vWf) and procoagulant factor VIII (FVIII) [8–12] can alter primary hemostasis [13, 14]. Mechanistically, therefore, ABO blood type may be linked to perioperative bleeding, hemostasis, or thrombosis by modulating the prohemostatic effect of vWf and/ or FVIII. We hypothesized that ABO blood group is a determinant of perioperative transfusion and subsequent survival after coronary revascularization. To test this hypothesis, we compared perioperative transfusions by ABO group and survival by greater versus lesser transfused ABO groups.
Materials and methods Study design This is a retrospective, observational cohort study including consecutive patients. Following Institutional Review Board approval, we retrieved all available data for nonemergent, adult aorto-coronary bypass (CABG) surgeries and CABG valve procedures performed at Duke University Medical Center between January 1, 1996 and November 30, 2009. Patient demographics, operative details, and postoperative outcomes data were accessed from our institutional cardiac surgical database, which is housed in the Duke Databank for Cardiovascular Diseases and contributes to the Society of Thoracic Surgeons National Database. In-patient data for this study were collected from contemporaneous medical records, custom datasheets, and records of laboratory results. For quality assurance, random chart review was performed for data confirmation and assessment of data completeness; incomplete fields were updated on a chart review basis. Survival data were gathered from 6-month telephone follow-ups and/or from death records, and were provided by the Duke Clinical Research Institute Follow-up Group, as recently described . Medical record numbers were used to query Duke Blood Bank transfusion records to confirm numbers of blood product units transfused on the day of surgery through postoperative day 2. While previous studies on the effect of ABO groups on outcomes have compared two groups (O and non-O) [14, 16–18], we planned to compare group AB to non-AB as group AB is the only group not to express the H antigen that confers the biological effect of ABO on vWf and FVIII levels . For example, group A includes genotypic AA
and AO, the latter with heterozygous H antigen expression; an analogous consideration applies to group B. Patient management Patients received balanced, general anesthesia with invasive hemodynamic monitoring and standardized cardiopulmonary bypass (CPB). Briefly, non-pulsatile, hypothermic (28–34 °C) CPB was performed using a membrane oxygenator and porcine heparin to maintain an activated clotting time of[480 s. During CPB, temperature adjusted flow rates of 2.5 L/min/m2 were used, and mean arterial pressure was maintained between 50–60 mmHg, or between 60–70 mmHg if previous evidence of cerebrovascular disease was noted. Standard practice included intraoperative administration of an antifibrinolytic therapy. Most often this was epsilon aminocaproic acid, although, due to surgeon preference, a few patients did receive aprotinin. To avoid unnecessary use of blood products, cell-saver technology, which returns washed shed red blood cells to the patient, was routinely used. Hemostatic blood product transfusion decisions were based on local guidelines as well as activated clotting time, platelet count, fibrinogen level, thromboelastogram, prothrombin and partial thromboplastin time tests, and the presence of clinically apparent bleeding. A hematocrit [0.20 was considered acceptable during CPB. After separation from CPB, red blood cells were transfused depending on the patient’s preoperative condition, volume status, and hemoglobin concentration, as outlined in our transfusion protocol (Appendix 2). Outcome measures Perioperative transfusion was defined as blood products transfused on the day of surgery and on the first and second postoperative days. Packed red blood cells (PRBCs), transfusable plasma (fresh frozen, frozen within 24 h of collection, or thawed and refrigerated for up to 5 days), and adult doses of platelets and cryoprecipitate are all described as units. Postoperative survival was based on follow-up data extending to 11 years after the date of surgery. Statistical analysis Continuous variables were described as mean (±SD) or median [interquartile range], as appropriate. Categorical variables were described as a percentage, and odds ratios were presented as point estimates [95 % confidence
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intervals]. Transfusion of PRBCs over POD 0, 1, and 2 was compared by Kruskall Wallis rank tests for multiple groups (O, A, B and AB). Kaplan–Meier analysis was performed to evaluate the association between AB or non-AB blood groups and long-term survival, defined as the number of days between surgery and the date of death or last followup. A Cox proportional hazards regression analysis was adjusted for the Hannan score , a preoperative mortality risk estimate. Hazard ratios and 95 % confidence intervals (HR [95 % CI]) were reported for this Cox proportional hazards regression analysis of group AB vs non-AB for the outcome death or loss to follow-up. A p value of 0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.2 (SAS Inc, Cary, NC).
Results We evaluated 15,454 consecutive, non-emergent on-pump aorto-coronary bypass graft (CABG) and CABG/valve surgeries at Duke Heart Center from January 1996 through November 2009. Complete follow-up records were available for 13,627 patients: 6,413 group O (47 %), 5,248 group A (39 %), 1,454 group B (11 %) and 435 group AB (3 %). The patient and procedural characteristics are detailed in Table 1. The median follow-up period was 2,096 [797–2,930] days. Perioperative (30-day) mortality was 2.91 %, and overall mortality during the follow-up period was 30.4 %. Total perioperative blood product transfusion included PRBCs 3[0–5] units, plasma 0[0–2] units, platelets 0[0–1] adult doses, or cryoprecipitate units 0[0-0] adult doses. As illustrated in Fig. 1, there was a difference between blood groups in terms of PRBC usage (Kruskall Wallis Chi squared value for between-group differences 8.2; p = 0.04), which supported our approach to compare group AB to non-AB for the survival analysis below. The median number of RBC units transfused to group AB patients was one fewer than the other groups (2 vs 3 units). Post hoc intergroup comparisons for RBC, or the other less frequently used blood products, were not statistically significant between groups. As illustrated in Fig. 1, an unadjusted Kaplan–Meier plot showed better long-term survival (Log-rank Chi square 4.14; p = 0.04) for blood group AB (n = 435) compared to non-AB patients (n = 13,192). The percentage of CABG/valve surgeries performed was similar across groups (11.3 % AB vs 11.5 % non-AB; p = 0.90), and the average age of AB patients was similar to non-AB patients
Table 1 Patient and procedural characteristics of coronary revascularization patients Patient demographic
Age, mean (SD), y
Gender, no. (% female) Height, mean (SD), cm
32.7 170.24 (13.13)
34 170.59 (13.82)
Weight, mean (SD), kg
Ethnicity (% non-Caucasian)
Diabetes, no. (%)
Hypertension, no. (%)
Smoking history, no. (%) Previous CHF, no. (%)
Previous stroke, no. (%)
Previous MI, No. (%)
Baseline serum creatinine (mean (SD), mg/dL)
Valve procedure Number of bypass grafts, mean (SD)
11.5 1.07 (0.29)
11.3 1.08 (0.31)
CPB duration, mean (SD), minutes
CHF history of congestive heart failure, MI myocardial infarction, CPB cardiopulmonary bypass, SD standard deviation, F/M female/ male
Fig. 1 Red blood cell transfusion by ABO blood group
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at the time of surgery (64.47 ± 10.78 vs 64.32 ± 11.41 years, respectively; p = 0.78). After adjusting for the Hannan score, group AB still favored improved postoperative survival (Hazard ratio = 0.82 [95 %CI 0.68–0.98]; p = 0.03).
Discussion We observed ABO blood group dependent differences in transfusion and long-term survival after coronary revascularization surgery. Group AB demonstrated improved long-term survival compared to other groups. ABO blood type is determined by a single gene on chromosome 9 (9q34.1–34.2). The consensus coding sequence is the AlOl allele and all polymorphisms that affect the specificity and efficacy of the glycosyl transferase are considered mutations of AlOl. For example, a single base deletion in the A allele distinguishes the A2 allele which results in greatly reduced glycosyl transferase A enzyme activtity. Two alleles, A and B, encode glycosyl transferase A or B respectively that add immunodominant, N-acetylgalactosamine or D-galactose residues, respectively, to the H-antigen fucose moiety attached to precursor oligosaccharide chains, to form the A and B antigens. The O allele does not encode a functional enzyme and unmodified H antigen characterizes blood group O. The ABH antigenic structures are expressed on the Nlinked oligosaccharide chains of vWf, and glycosylation of the H antigen is thought to reduce plasma vWf clearance; thus, O carriers, with unmodified H antigen, have the lowest levels of FVIII and its carrier protein vWf . While the amount of glycosylation of the H antigen may explain variation in vWf in non-surgical patients, this relationship has not been confirmed in a surgical setting. ABO blood group is a major determinant of vWf and FVIII levels, which have been identified as important risk factors for thrombosis in the arterial and venous circulation [16, 17, 20, 21]. These studies found an increased risk for thrombosis, as well as higher plasma levels of FVIII and vWf, for all non-O blood groups. Type O individuals seem to show reduced coagulability compared to A, B, or AB individuals . Classification of ABO type can be refined by considering the genotype rather than the phenotype. There is a graded genotype effect on FVIII and vWf levels, which can be divided into markers of low (O, A2O, A2A2), intermediate (A1O, BB, BO), high (A1A1, A1B) and highest (A2B) levels . The A and B alleles have been associated with clinical thrombotic episodes  and a higher
Fig. 2 Postoperative survival for AB and non-AB blood groups
thrombus burden during percutaneous coronary intervention . There are few studies that address the effect of ABO group on postoperative complications and outcomes. The immediate postoperative period is complicated by the acute-phase reaction, which is an environmental determinant of vWf/FVIII levels  that has been noted to mask an ABO effect in trauma patients . We previously found that baseline primary hemostasis is reduced in group O patients undergoing CABG, consistent with reduced vWf/FVIII levels , while others reported equal impairment of immediate postoperative primary hemostasis in both O and non-O groups and no association between immediate postoperative bleeding and ABO group . This latter study, however, compared group O to the remainder (A, B, and AB), but was not powered to evaluate the least common AB group. Similar limitations apply to other studies designed to compare group O to non-O [16– 18]. Our study is significant in that it included over 400 AB patients, evaluating perioperative transfusion and longterm survival. However, our retrospective study design limits us to only describe associations, not causation. The associations we describe are between ABO phenotypes, rather than ABO genotypes, and evaluation of ABO genotypes would further refine the phenotypic association, as described above. With regards to outcome data, specific postoperative complications, such as ARDS or wound infections have been previously linked to transfusion [4, 27–30]. However, we did not include these complications in our evaluation because their incidence is too low to effectively compare 3 % of the population (group AB) to the remainder. Despite these limitations, our data did link ABO
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group to perioperative transfusion and postoperative survival. While the separation of the survival curves only began over 1 year after surgery (see Fig. 2), this is still consistent with a transfusion effect as each unit of red cells transfused has been associated with an incremental increase in the likelihood of adverse outcomes and reduced survival. Unfortunately, our long-term follow-up data did not provide a detailed cause of death to confirm this link. It would be interesting to evaluate whether group AB patients better tolerate anti-platelet agents, for example, thereby improving long-term outcome. While the need for fewer RBC transfusions in group AB supports that hemostasis/bleeding is mechanistically important for our findings, suggesting that higher vWf and VIII levels improves hemostasis and thereby survival is speculative, as levels of vWf and FVIII are inferred from the literature [10, 22, 31] and not measured. Survival differences may be linked to alternate ABO related mechanisms. For example, the unmodified H antigen (expressed only in the O genotype), has been associated with increased inflammation [31, 32], increased circulating E selectin levels [33–35], higher risk for type II diabetes , greater burden of atherosclerosis , and acute exacerbations of asthma . In contrast to genotype OO, AO, and BO individuals (phenotypically groups O, A, and B, respectively), group AB expresses no H antigen and may, therefore, be associated with less inflammation. This study, however, was not designed to evaluate modulation of inflammation related to the H antigen. On-going research relating vWf and FVIII levels to ABO genotype and clinical bleeding is targeting populations at higher risk for bleeding such as the LVAD recipients who have demonstrated an ABO phenotype dependent pattern of bleeding complications [ref]. Our data are valuable to the design of future research, as they emphasize the importance of considering AB as a distinct group rather than combined in a ‘‘non-O’’ category and describe alternate mechanisms (prothrombotic/pro-hemostatic and inflammatory) that could be explored to explain the important, novel association between group AB and reduced mortality following CABG surgery.
Conclusions In summary, group AB is uncommon (*3 % of our cardiac surgical population), but is associated with improved postoperative survival compared to non-AB patients. Defining the mechanisms of reduced mortality associated with blood group AB merits further, prospective study.
Appendix 1 Members of the Cardiothoracic Anesthesiology Research Endeavors (CARE), Department of Anesthesiology, Duke University Medical Center. Director: Joseph P. Mathew M.D. Anesthesiology: Solomon Aronson M.D., Katherine P. Grichnik M.D., Steven Hill M.D., G. Burkhard Mackensen M.D., PhD., Joseph P. Mathew M.D., Mark F. Newman M.D, Barbara Phillips-Bute Ph.D., Mihai V. Podgoreanu M.D., Andrew D. Shaw M.D., Mark Stafford-Smith M.D., Madhav Swaminathan M.D., Ian Welsby M.D., William D. White M.P.H., Lisa Anderson, Lauren Baker B.S., Bonita L. Funk R.N., Roger L. Hall A.A.S., Gladwell Mbochi A.A.S., Tiffany Bisanar R.N., Prometheus T. Solon M.D., Peter Waweru. Perfusion Services: Kevin Collins, B.S., C.C.P., Greg Smigla, B.S., C.C.P., Ian Shearer, B.S., C.C.P. Surgery: Thomas A. D’Amico M.D., R. Duane Davis M.D., Donald D. Glower M.D., R. David Harpole M.D., G. Chad Hughes M.D., James Jaggers M.D., Shu Lin M.D., Andrew Lodge M.D., James E. Lowe M.D., Carmelo Milano M.D., Peter K. Smith M.D., Jeffrey Gaca MD, Mark Onatis MD.
Appendix 2 Packed Red Blood Cell Transfusion Algorithm for cardiac surgical patients with chest tube output \400 mL/h and no ongoing ischemia.
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