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Limiting the extent of a delayed hemolytic transfusion reaction with automated red blood cell exchange.

Delayed hemolytic transfusion reactions (DHTRs) are caused by anamnestic responses of previously produced blood group alloantibodies. (1) Because many DHTRs are well tolerated, their clinical significance is frequently underestimated. In fact, according to the 2009 Serious Hazards of Transfusion reports, nearly 20% of DHTRs in the United Kingdom were associated with severe morbidity. (2) In addition, US Food and Drug Administration data (3) showed that non-ABO antibodies were the second most common cause of transfusion-related mortality from 2005-2011. Furthermore, numerous additional fatalities and severe reactions associated with DHTRs have been reported. (4-7) Unlike other adverse effects of transfusion, DHTRs remain difficult to prevent, because (1) there is no test to identify patients with evanescent antibodies, (2) sharing of antibody results between facilities is either not widely available or practiced, and (3) systematic follow-up testing after transfusion in order to detect newly formed antibodies is rare. Moreover, treatment options are limited, consisting primarily of supportive care and replacing cleared red blood cells (RBCs) via simple transfusion. One therapeutic option is automated RBC exchange (ARE) during which incompatible RBCs are removed and replaced with RBCs lacking the implicated antigen(s). However, there are few published cases of its use for the treatment, and none for the prophylaxis, of DHTRs. We report a case in which ARE was used in a prophylactic fashion to prevent a symptomatic reaction (eg, fever, hypotension, and chest pain) and progression to major morbidity (eg, renal failure, disseminated intravascular coagulation, and shock).


A 77-year-old man with a history of coronary artery disease, coronary artery bypass grafting, repaired abdominal aortic aneurysm, chronic obstructive pulmonary disease, psoriasis, and stage III hepatic fibrosis secondary to methotrexate was admitted for mental status changes. Of note, the patient typically received care in another state and, as such, had no medical records at our facility. Admission blood cultures grew group G Streptococcus and the patient's mental status gradually improved after antibiotic treatment.

On day 7 of admission, the patient experienced hematochezia and a drop in hematocrit (Hct) from 35.9% to 28.9% (reference range, 40%-52%; Figure) secondary to a duodenal ulcer. The gastrointestinal hemorrhage was confirmed by endoscopy and was treated with cautery, injection of epinephrine into the lesion, and RBC transfusion. The patient typed as group O, D+ with a negative antibody screen result in an EDTA-anticoagulated specimen. The tube method was used with low-ionic-strength solution enhancement. Four units of RBCs, which were crossmatch-compatible at immediate spin, were transfused and well tolerated. On days 8 through 11 the patient passed multiple melanotic stools associated with a fall in Hct to 18%. He received 8 more crossmatchcompatible RBC units through day 11 for a total of 12 units in 4 days.

On day 12 a family member indicated that the patient had received "special" blood products at another hospital. Communication with the other facility revealed that the patient had a history of 4 blood group alloantibodies (anti-E, anti-c, anti-[Fy.sup.a], and anti-M) last detected about 2.5 years ago. Testing of segments from the infused RBCs revealed that each unit possessed at least 1 incompatible antigen (Table 1). A day-12 blood specimen demonstrated a negative direct antiglobulin test (DAT) result. A 3-cell screen, including cells that were homozygous for the implicated antigens, also yielded a negative result. Repeated testing on earlier specimens from days 7 and 11 confirmed the previously negative antibody screen results (Table 2). The patient had normal vital signs and urine output.

Because of the risk for an anamnestic response, twice-daily antibody screens and DATs were initiated, along with testing of the Hct and bilirubin every 6 to 8 hours (Figure). This increased frequency of testing over the 3-day interval, required by the AABB standards, was done so that we could detect an anamnestic response as soon as it occurred. (8) Vital signs and urine output were closely monitored. At this point, the transfusion service recommended ARE to the medical team as a means to reduce the potential for hemolysis in anticipation of an anamnestic response. A consensus to proceed with ARE, however, was not reached.

By late morning of day 13 the patient's antibody screen and DAT results both turned positive (Table 2). The Hct dropped from 31.2% to 23.1%, indirect bilirubin concentration increased to 4.9 mg/dL from 0.95 mg/dL, and lactate dehydrogenase level increased slightly to 268 U/L from a baseline of 229 U/L (reference range, 125-243 U/L) in association with new-onset jaundice. There was no new-onset hematochezia or other changes in clinical status to suggest a repeated gastrointestinal bleed. The patient remained afebrile with all vital signs within normal limits; renal function was unchanged from baseline (creatinine, 1.1 mg/dL; reference range, 0.5-1.5 mg/dL). As such, the patient was demonstrating asymptomatic hemolysis. Coagulation results (prothrombin time, 21.0 seconds [reference range, 10. (4-12).7 seconds] and activated partial thromboplastin time, 30.8 seconds [reference range, 23.6-37.6 seconds]) and platelet count (65 000/u.L; reference range, 130 000-450 000/[micro]L) were unchanged from admission values. Given this evidence of an anamnestic response and the likelihood that most of the RBC mass now consisted of incompatible RBCs, the decision to proceed with ARE was made.

Approximately 10 hours after the initial positive DAT and antibody screen results, the patient underwent ARE through a double-lumen catheter in his right femoral vein with a COBE Spectra TerumoBCT, Lakewood, CO). Replacement RBCs were group O, c-, [Fy.sup.a]-, E-, and M-negative; and crossmatch-compatible by tube method at antiglobulin phase. Before the start of the procedure, a specimen was sent to a blood center reference laboratory for antibody identification. We chose not to wait for the serologic results before proceeding with ARE. We reasoned that if hemolysis of the remaining incompatible RBCs resulted in a severe reaction, then ensuing vascular instability might have complicated the ARE. To achieve 1 RBC exchange, the instrument calculated an RBC replacement volume of 2643 mL RBCs, or about 8 units. The apheresis procedure lasted 3 hours without incident and resulted in a postexchange Hct of 23.5%, which was slightly less than the target of 25%.

The reference laboratory called with preliminary results while the ARE was in progress. Anti-c and anti-[Fy.sup.a] reactive at 37[degrees]C and antihuman globulin (AHG) phases were detected in the plasma, while anti-c, anti-[Fy.sup.a], and anti-M were detected in an RBC eluate. AntiM was reactive at 37[degrees]C and AHG phases. As such, all antibodies were regarded as potentially clinically significant. Several hours after the completion of ARE, the reference laboratory verbally reported the presence of anti-S in the eluate, reactive at AHG phase. On retrospective testing, 2 of the 8 units used for ARE were S positive. In all likelihood, these units were crossmatch compatible because anti-S was present only in the eluate.

The patient's indirect bilirubin level peaked at 8.5 mg/dL early in the morning of day 14. Subsequent bilirubin levels progressively decreased to baseline (Figure). A DAT performed approximately 12 hours after the ARE, and all subsequent DATs, yielded negative results (Table 2). Extended serologic phenotyping of the patient (C+ E- c- M- N+ S- s+ [P.sub.1] + K- [Fy.sup.a] - [Fy.sup.b] + [Jk.sub.a] + [Jk.sup.b]+), performed on a pretransfusion specimen and reported on day 14, revealed that the K antigen was the only remaining clinically significant antigen against which the patient could form a new antibody. Therefore, we provided K-negative RBCs for future transfusions in case he had been previously sensitized to the K antigen. As such, all subsequent units, beginning with 2 units transfused on days 16 and 18, were negative for the c, E, [Fy.sup.a], M, S, and K antigens.

A second upper gastrointestinal bleed occurred on day 25, resulting in the transfusion of 5 additional RBC units. The posttransfusion course was uneventful with no evidence of hemolysis. Anti-E was detected for the first time on day 25, associated with a negative DAT result. After 34 days of admission, the patient was discharged to a rehabilitation facility in his home state. At that time, the laboratory values were as follows: Hct, 27.5%; total bilirubin, 1.1 mg/dL (reference range, 0.2-1.2 mg/dL); and creatinine, 0.9 mg/dL.


We present this case to highlight the availability of ARE as an option for the prevention or treatment of DHTRs. Automated RBC exchange is not currently an accepted therapy for DHTRs as reflected by its absence from American Society for Apheresis guidelines. (9) Our literature review revealed only 2 reports (10,11) in which ARE was used to treat severe DHTRs, and ARE was not the focus of either report. In those cases, ARE was performed after the reactions had already progressed to renal failure and hemodynamic instability. Our goal was to prevent that degree of DHTR progression. This case and the 2 earlier reports suggest possible benefit of ARE in the setting of a DHTR. Therefore, ARE might be considered when incompatible RBCs constitute a substantial portion of the RBC mass and when the involved antibodies are known to cause hemolysis.

This case is notable in that it represented an opportunity to intervene before the development of a DHTR. We discovered that the patient was primed for an anamnestic response while still in a lag phase after antigen reexposure. Given this forecasting of a DHTR, we considered 2 options: (1) watchful waiting until his antibodies reemerged or (2) a more aggressive approach to reduce the large volume of incompatible RBCs by ARE. We weighed the pros and cons of each approach. On one hand, perhaps no action would be necessary since some patients only experience clinically benign serologic reactions following an anamnestic response. (12) On the other hand, if anyone was at risk of a serious reaction, it was this patient. He had received a large volume of RBCs that would be incompatible in the event of an anamnestic response and all of his antibodies could potentially mediate hemolysis. (4-7) In addition, the patient's age and comorbid conditions could have compromised his ability to tolerate a DHTR. Overall, we concluded that the benefit of ARE outweighed its risks. Our decision was reinforced by the relative rate of adverse reactions to apheresis in comparison to the morbidity of DHTRs. Adverse events during apheresis are typically mild and reported in less than 5% of procedures, whereas more than 60% of DHTRs are associated with mild to severe morbidity. (1,2,13-17) In fact, major morbidity has been observed in greater than 10% of DHTRs. (2,12-16) Because the patient was likely to clear more of the incompatible RBCs even in the absence of a reaction, ARE had the added benefit of isovolemic RBC replacement.

Our initial intent was to perform ARE entirely prophylactically. However, hemolysis was already underway by the start of the ARE, based on the decline in the patient's Hct from 31.2% to 23.1%, which represents loss of 30% of the RBC mass. Because a major fraction of the patient's remaining RBCs were most likely also incompatible, and because the antibody titers may still have been increasing, we believed the patient was at risk for further hemolysis. For this reason, and because our goal was also to prevent a symptomatic reaction and major morbidity, we consider the ARE to still have been prophylactic.

The extent to which ARE avoided a reaction or further hemolysis cannot truly be judged, since there is no way to predict the severity of a DHTR a priori. On theoretical grounds, the ARE should have at least limited the maximum extent of the hemolysis. Moreover, interruption of the DHTR by ARE is supported by the following: (1) the DAT results were repeatedly negative in all postprocedure testing, (2) the bilirubin level began decreasing shortly after ARE, and (3) the drop in Hct was less than expected if all incompatible RBCs had been hemolyzed.

Our decision to proceed with ARE before obtaining the final serologic report from the reference laboratory was a calculated risk. We assumed that the probability of an additional unknown antibody was low, especially since the RBC units intended for the ARE were crossmatch compatible. Because waiting incurred the risk of deterioration of the patient's condition, we proceeded without delay. Unexpectedly, a previously unknown anti-S was detected post procedure by the reference laboratory. Fortunately, only 2 of the 8 units used for the ARE were S positive and their administration had no significant clinical impact.

This case is also notable for the disappearance of 5 antibodies during a period of about 2.5 years between the patient's last test at another hospital and his first antibody screen at our facility, without any intervening RBC transfusions. This observation is consistent with a previous study (18) that demonstrated that blood group antibodies in multiply alloimmunized patients tend to share a common fate--either persistent or evanescent. It is not known whether an anamnestic response always occurs after antigen reexposure and whether the timing of the response is identical for all antigens. In our case, 5 antigens of varying immunogenicities all caused antibody reinduction. Four of the antibodies were apparently reinduced simultaneously. We were initially perplexed as to why the anti-E was not reinduced at the same time. This might be explained by the fact that the patient's first exposure to antigen E did not occur until 4 days after the other antigens.

Our report reflects several fundamental and widespread deficiencies in antibody recordkeeping. First, records are not typically shared between institutions for patients undergoing transfusion at more than 1 facility. Second, alloimmunization may go undetected owing to a lack of routine follow-up testing after transfusion. Moreover, even if testing is done, it may not be at the optimal time, that is, the antibodies may not yet have been induced or may have already evanesced. (19) To overcome these deficiencies, the transfusion medicine community could make better use of existing mechanisms, such as (1) issuance of wallet cards and/or medical alert bracelets to alloimmunized patients, (2) regular, routine follow-up testing of patients with recent transfusions, and (3) increased participation in antibody registries. Shared electronic databases, either Web based or achieved by regional computer networking, have yielded encouraging results on a limited basis. (20)


In summary, we present the case of a 77-year-old man with 5 anamnestic alloantibodies who was prophylactically treated with ARE after transfusion of incompatible RBCs. This case illustrates the use of ARE as an option to limit hemolysis during an evolving DHTR. However, prevention of such cases through increased portability of antibody information and improved detection should be the eventual goal of the transfusion medicine community.

Caption: Hematocrit and total bilirubin trends before and after red blood cell (RBC) exchange.


(1.) Davenport RD. Hemolytic transfusion reactions. In: Popovsky MA, ed. Transfusion Reactions. 3rd ed. Bethesda, MD: AABB Press;2007:1-56.

(2.) Taylor C, Cohen H, Mold D, et al; on behalf of the Serious Hazards of Transfusion (SHOT) Steering Group. The 2009 Annual SHOT Report. Manchester, United Kingdom; 2010.

(3.) US Food and Drug Administration (FDA). Fatalities reported to FDA following blood collection and transfusion. SafetyAvailability/ReportaProblem/TransfusionDonationFatalities/ucm302847.htm. Accessed August 21, 2012.

(4.) Freiesleben E. Fatal hemolytic transfusion reaction due to anti-[Fy.sup.a]. Acta Pathol Microbiol Scand. 1951;29(3):283-286.

(5.) Hillman NM. Fatal delayed hemolytic transfusion reaction due to anti-c + E. Transfusion. 1979;19(5):548-551.

(6.) Schorn TF, Knospe WH. Fatal delayed hemolytic transfusion reaction without previous blood transfusion. Ann Intern Med. 1989;110(3):241-242.

(7.) Sancho JM, Pujol M, Fernandez F, Soler M, Manzano P, Feliu E. Delayed haemolytic transfusion reaction due to anti-M antibody. Br J Haematol. 1998; 103(1):268-269.

(8.) Carson TH, ed. Standards for Blood Banks and Transfusion Services. 27th ed. Bethesda, MD: AABB Press; 2011.

(9.) Szczepiorkowski ZM, Winters JL, Bandarenko N, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher. 2010;25(3):83-177.

(10.) von Zabern I, Ehlers M, Grunwald U, Mauermann K, Greinacher A. Release of mediators of systemic inflammatory response syndrome in the course of a severe delayed hemolytic transfusion reaction caused by anti-D. Transfusion. 1998;38(5):459-468.

(11.) Kalyanaraman M, Heidemann SM, Sarnaik AP, MeertKL, Sarnaik SA. Antis antibody-associated delayed hemolytic transfusion reaction in patients with sickle cell anemia. J Pediatr Hematol Oncol. 1999;21(1):70-73.

(12.) Tormey CA, Stack G. Estimation of combat-related blood group alloimmunization and delayed serologic transfusion reactions in U.S. military veterans. Mil Med. 2009;174(5):503-507.

(13.) McLeod BC, Sniecinski I, Ciavarella D, et al. Frequency of immediate adverse effects associated with therapeutic apheresis. Transfusion. 1999; 39(3): 282-288.

(14.) Knowles S, Cohen H; on behalf of the Serious Hazards of Transfusion (SHOT) Steering Group. The 2010 Annual SHOT Report. Manchester, United Kingdom; 2011.

(15.) Taylor C, Cohen H, Mold D, et al; on behalf of the Serious Hazards of Transfusion (SHOT) Steering Group. The 2008 Annual SHOT Report. Manchester,

United Kingdom; 2009.

(16.) Taylor C, Cohen H, Stainsby D, et al; on behalf of the Serious Hazards of Transfusion (SHOT) Steering Group. The 2007 Annual SHOT Report. Manchester, United Kingdom; 2008.

(17.) Stainsby D, Jones H, Asher D, et al. Serious hazards of transfusion: a decade of hemovigilance in the UK. Transfus Med Rev. 2006;20(4):273-282.

(18.) Tormey CA, Stack G. The characterization and classification of concurrent blood group antibodies. Transfusion. 2009;49(12):2709-2718.

(19.) Tormey CA, Stack G. The persistence and evanescence of blood group alloantibodies in men. Transfusion. 2009;49(3):505-512.

(20.) Schwickerath V, Kowalski M, Menitove JE. Regional registry of patient alloantibodies: first-year experience. Transfusion. 2010;50(7):1465-1470.

Christopher A. Tormey, MD; Gary Stack, MD, PhD

Accepted for publication July 27, 2012.

From the Pathology and Laboratory Medicine Service, VA Connecticut Healthcare System, West Haven, Connecticut; and the Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Christopher A. Tormey, MD, Pathology and Laboratory Medicine Service/PLMS 113, VA Connecticut Healthcare System, West Haven, CT 06516 (e-mail:

Table 1. Phenotype of Incompatible Red Blood Cells
and Order of Transfusion (a)

Unit      Day of       c   E   Fy (a)   MS   S      Total
 No.   Admission When                             Incompatible
       Unit Infused                                Antigens

 1          7          +   -     +      +    +        4
 2          7          +   -     +      +    -        3
 3          7          +   -     -      +    -        2
 4          7          -   -     +      +    +        3
 5          9          +   -     +      +    -        3
 6          9          +   -     +      -    +        3
 7          11         -   -     +      -    +        2
 8          11         +   +     -      -    -        2
 9          11         -   -     -      +    -        1
10          11         -   -     +      -    -        1
11          11         +   +     +      +    -        4
12          11         +   +     -      -    -        2

(a) Presence of the antigen indicated by "+" and absence of the
antigen indicated by "-". Red blood cell units 1 through 12 are
presented in the order in which they were transfused.

Table 2. Summary of Immunohematologic Testing (a)

Day of      Antibody   Antibodies           Direct
Admission   Screen     Detected             Antiglobulin

7           -          None                 Not done
11          -          None                 -
12          -          None                 -
13 (b)      +          Anti-c,              + (Eluate: anti-c,
                         anti-[Fy.sup.a]      anti-[Fy.sup.a],
                                              anti-M, anti-S)

14          +          Not done             -
15          +          Not done             -
16          +          Not done             -
17          +          Not done             -
19          +          Not done             -
20          +          Not done             -
21          +          Not done             -
25          +          Anti-c,              -
                         anti-M, anti-S,

(a) Positive test result indicated by "+" and negative test result
indicated by "-".

(b) Indicates day of red blood cell (RBC) exchange. The direct
antiglobulin test was 2+ IgG, 1+ C3. Antibodies identified in the
RBC eluate were all reactive at anti-human globulin phase.


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Title Annotation:Case Report
Author:Tormey, Christopher A.; Stack, Gary
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Clinical report
Geographic Code:1USA
Date:Jun 1, 2013
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