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DITORIAL COMMENT

here Will Be Blood*

rendan Doyle, MD

ochester, Minnesota

leeding in patients with coronary artery disease has at-racted increasing interest because it has been found to haveajor implications. Outcomes following acute coronary

yndromes and percutaneous coronary intervention areuch worse among those patients who experience major

leeding (1,2). What continues to be unclear is whetherleeding identifies a high-risk group by virtue of theemorrhage itself, by virtue of comorbid illness, or by somether mechanism. Recently, suspicion has focused on po-entially harmful effects of red blood transfusion.

See page 46

In this issue of JACC: Cardiovascular Interventions,hishehbor et al. (3) have compared the outcomes ofatients who did or did not require blood transfusion duringospitalization with ST-segment elevation myocardial in-arction (STEMI). The patient cohort is derived from the

USTO (Global Use of Strategies to Open Occludedoronary Arteries) IIb trial that compared hirudin witheparin in patients with acute coronary syndromes. A totalf 3,575 patients who had presented with ST-segmentlevation were eligible for analysis, of whom 307 (8.6%)equired a blood transfusion. The investigators found thatlood transfusion was associated with increased short- andong-term mortality in the setting of STEMI.

Patients who needed a blood transfusion were older andicker than those who did not require transfusion. The studyesign was nonrandomized. In an attempt to overcomehese limitations, the investigators used multiple statisticalethods including use of Cox proportional hazards survivalodels with transfusion as a time-dependent covariate forhole and propensity-matched groups and sensitivity anal-ses to assess the magnitude of potential hidden bias. Thenvestigators are to be commended for this probing analysisf the data, wherein blood transfusion remained a strongredictor of death in the setting of STEMI even after suchdjustment. Although not proof of a cause-and-effect rela-

Editorials published in JACC: Cardiovascular Interventions reflect the views of theuthors and do not necessarily represent the views of JACC: Cardiovascular Interven-ions or the American College of Cardiology.

pFrom the Division of Cardiovascular Diseases, Mayo Clinic College of Medicine,

ochester, Minnesota.

ionship, the findings are in agreement with recent dataighlighting potentially significant risk associated withlood transfusion among patients with non–STEMI andatients undergoing percutaneous or surgical revascularization.What does this mean? Could blood transfusions really be

illing patients? The hypothesis that transfusion may inertain circumstances do more harm than good is neitherew nor surprising. Growing concern, however, reacheseyond the familiar hazards of microbial transmission andcute antigen-antibody reactions, with particular focus onhe potential for transfused blood to impair tissue oxygen-tion. It is well established that stored red blood cells areow in 2,3-diphosphoglyceric acid resulting in high oxygenffinity (i.e., the hemoglobin will tend not to release oxygeno the tissues). However, experimental studies now indicatehat the physiologic impact of 2,3-diphosphoglyceric acidepletion may have been overstated and that other structuralnd biochemical changes that occur in blood during storageay have greater impact on their function in vivo—and may

xplain the paradox whereby increasing hemoglobin byransfusion may raise calculated oxygen delivery but measuresf tissue oxygenation either decrease or do not change (4).

Normally, erythrocytes have a flexible membrane and caneversibly alter their biconcave, discoid shape, thus allowinghem to pass through capillaries smaller in diameter (2 to 6m) than red blood cells (�8 �m). During storage, there issignificant decrease in the deformability of red blood cells.ther hemorheologic alterations have also been docu-ented, such as changes in red blood cell shape, decreased

urface/volume ratio, increased mean hemoglobin concen-ration and osmotic fragility, increased aggregability andntracellular viscosity (5). Together, these factors may pre-ispose to “plugging” of transfused cells at the microvascular

evel, leading to tissue ischemia. It is reasonable to assumehat vascular beds already compromised by microvascularysfunction or obstruction (such as acutely infarcted myo-ardium) may be particularly vulnerable in this respect.

Attention has also focused on the transport of nitricxide (NO) by red blood cells. Nitric oxide produced byascular endothelium may be bound by erythrocytes inrotected form as an S-nitrosothiol. Upon release of oxygen,-nitrosothiol hemoglobin may dispense NO bioactivity toicrovascular cells, physiologically coupling hemoglobin

eoxygenation to vasodilation (6). This elegant mechanismacilitates increases in regional blood flow in zones ofypoxia and, intriguingly, may enable NO-bioactivity to be

mported from a healthy vascular bed to one that isompromised by endothelial dysfunction (as would pertainn the coronary circulation of patients with STEMI).ecent data indicate that this biochemical function is

ignificantly disrupted by storage of erythrocytes (7). Otherdverse effects of red blood cell transfusion may include

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Editorial Comment

55

ressive effects of cytokines and other infused bioactiveubstances that accumulate in stored blood.

The study by Shishehbor et al. (3) has a number ofimitations. No information was available regarding associ-ted transfusions that may have been administered inddition to the packed red cell units (such as fresh frozenlasma or platelets). Such data would be important to helpetermine the specific role of red blood cell transfusionersus the effects of severe hemorrhage and/or associatedoagulopathy. The age of stored units was not included inhe GUSTO IIb database but is another important variablehat may influence the risk associated with transfusion.lder units exhibit progressive decline in erythrocyte func-

ion and higher levels of potentially harmful cytokines andellular breakdown products. The clinical significance ofhese in vitro findings are uncertain, although recent datarom patients undergoing cardiac surgery suggest that trans-usion of older rather than fresh blood may indeed bessociated with increased risk of adverse events, includingxcess mortality (8). In this context, data regarding thergency of transfusion in the study by Shishehbor et al. (3)ould also have been of interest as O-negative units used in

n emergency setting tend to be older than cross-matchednits used in an elective setting, and theoretically may carryxcess risk as a result.

Shishehbor et al. (3) suggest a randomized trial should beerformed to define the optimal use of blood transfusion inatients with STEMI. Designing such a trial would beifficult. Many would consider it unethical to withholdransfusion from an anemic patient who (despite successfulevascularization) exhibits clear evidence of ongoing cardiacschemia, although a study of fresh versus older blood in thisetting would certainly appear reasonable. A study of bloodransfusion versus no blood transfusion for asymptomaticnemia following STEMI would also be of tremendousnterest, although perhaps more as a means to confirm theutative adverse effects of transfusion. It is difficult toelieve that a beneficial effect of transfusion would bebserved in anemic patients with STEMI who have alreadyeceived prompt revascularization and who have no evidencef ongoing ischemia, although this remains an open ques-ion. Asymptomatic patients who have received incompleteevascularization might conceivably benefit in the presencef silent ischemia, particularly in watershed areas of acutenfarction. Such factors would need to be considered in theesign and analysis of any future randomized trial.It is important to emphasize that concerns about possible

dverse effects of transfusion should not lead doctors to a

ithhold blood when it is clearly indicated. Patients whohow symptoms or signs of ischemia are most likely toerive a net benefit from transfusion, particularly those whoxhibit evidence of oxygen-supply dependency. For asymp-omatic patients, it would seem prudent to avoid the use ofrbitrary cutoffs (such as a hemoglobin �8 g/dl) to triggerransfusion. With minimal potential gain to offset anydverse effects, transfusion could in theory be more likely toause harm in these circumstances. One exception may beransfusion of an asymptomatic patient who has anemiaaused by major bleeding and who remains at high risk forurther bleeding. Greater reserve of red cell mass mightessen the chance that such a re-bleed would be a fatal event.or the majority of asymptomatic patients, however, this

mportant study by Shishehbor et al. (3) adds to a growingiterature that prompts us to think twice before decidingthere will be blood.”

eprint requests and correspondence: Dr. Brendan Doyle, Mayolinic, 200 First Street SW, Rochester, Minnesota 55902. E-mail:oyle.brendan@mayo.edu.

EFERENCES

. Rao SV, Eikelboom JA, Granger CB, Harrington RA, Califf RM,Bassand JP. Bleeding and blood transfusion issues in patients withnon–ST-segment elevation acute coronary syndromes. Eur Heart J2007;28:1193–204.

. Doyle BJ, Ting HH, Bell MR, et al. Major femoral bleeding compli-cations after percutaneous coronary intervention: incidence, predictors,and impact on long-term survival among 17,901 patients treated at theMayo Clinic from 1994 to 2005. J Am Coll Cardiol Intv 2008;1:202–9.

. Shishehbor MH, Madhwal S, Rajagopal V, et al. Impact of bloodtransfusion on short- and long-term mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol Intv2009;2:46–53.

. Tsai AG, Cabrales P, Intaglietta M. Microvascular perfusion uponexchange transfusion with stored red blood cells in normovolemicanemic conditions. Transfusion 2004;44:1626–34.

. Almac E, Ince C. The impact of storage on red cell function in bloodtransfusion. Best Pract Res Clin Anaesthesiol 2007;21:195–208.

. Crawford JH, Isbell TS, Huang Z, et al. Hypoxia, red blood cells, andnitrite regulate NO-dependent hypoxic vasodilation. Blood 2006;107:566–74.

. Reynolds JD, Ahearn GS, Angelo M, Zhang J, Cobb F, Stamler JS.S-nitrosohemoglobin deficiency: a mechanism for loss of physio-logical activity in banked blood. Proc Natl Acad Sci U S A 2007;104:17058–62.

. Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage andcomplications after cardiac surgery. N Engl J Med 2008;358:1229–39.

ey Words: blood transfusion � ST-segment elevationyocardial infarction � long-term outcome � propensity

nalysis.