CASE STUDY

Massive Transfusion Protocol in a 69 Year Old Woman

with Alloantibodies
Jesse Qiao, MD,1 Jude M. Abadie, PhD, DABCC, FAACC, DABMGG, FACMG1,*

  O whole blood. Because the compatibility of non-ABO is not immedi-

1
Department of Pathology, Paul L. Foster School of Medicine, Texas Tech ately prioritized in acute hemorrhage, the aforementioned is considered
University Health Sciences Center, El Paso, Texas, United States; *To whom cor-
standard-of-care until the ABO group is confirmed using 2 separate

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respondence should be addressed. jude.abadie@ttuhsc.edu
specimens.

Keywords: transfusion, incompatible, uncrossmatched, RBC antibodies,

transfusion, blood banking
Case Report
Abbreviations: RBC, red blood cell; MHP, massive hemorrhage protocol; A 69 year old female patient with a past medical history of obesity, un-
TXA, tranexamic acid; DAT, direct antiglobulin test; LDH, lactate dehydrogenase. controlled diabetes mellitus type II, hypertension, and hypothyroidism
presented to the emergency department with multiple episodes of nau-
Laboratory Medicine 2022;53:e30–e32; https://doi.org/10.1093/labmed/ sea and acute-onset hematemesis. On arrival, she had a hemoglobin level
lmab066 of 8.1 g/dL, an international normalized ratio within normal limits, and
platelets of 87,000/μL. Additional laboratory values and correspond-
ing reference ranges are summarized in TABLE 1. Her blood type was
assessed as group O, Rh positive. Subsequently, 3 units of emergency-
ABSTRACT release, uncrossmatched O positive RBCs were administered. The patient
was rapidly decompensating because of hemorrhagic shock secondary to
Unlike routine blood transfusions that are managed by attending severe bleeding in her upper gastrointestinal tract. During that time, the
providers and rely on compatibility testing, massive transfusions attending physician activated a massive hemorrhage protocol (MHP),
are managed by the trauma team members, who usually do not the rapid administration of large amounts of blood products (at least 6
have immediate access to compatibility testing. Incompatible C or units of packed RBCs) in fixed 1:1:1 ratios (plasma:platelets:RBCs) for
E antigens, when present in uncrossmatched O  positive blood, re- the management of hemorrhagic shock. This procedure is significant,
quire transfusion support so that health care professionals can considering that up to 20% of deaths are potentially preventable with
manage potential causes for extravascular hemolysis. Herein, better control of bleeding.2
we describe a massive transfusion situation in which immedi-
TABLE 1.  Laboratory Results After Transfusion of the 3
ate patient management was required to mitigate potentially fa-
O Positive, Uncrossmatched Blood Units
tal clinical consequences of transfused red blood cell antibodies. In
addition, this case study shows how the utility of chemistry and he- Analyte Result

matology laboratory results can illustrate the complexities of massive White blood count 9.13 × 103/mm3  (4.50–11.00)
transfusion management in the context of incompatible C or E Hemoglobin 8.1 g/dL      
(12.0–15.0)     L
antigens. Hematocrit 25.2%      (36.0–47.0)     L
Platelets 87 × 103/mm3    
(150–450)     L
Potassium 4.2 mmol/L     
(3.5–5.1)
The characterization of massive transfusion has been historically
Creatinine 0.6 mg/dL      
(0.52–1.04)
described as the transfusion replacement of 10 red blood cell (RBC)
Bilirubin total 0.90 mg/dL     
(0.2–1.3)
units within 24 hours in response to massive and uncontrolled bleed-
INR (0.9 – 1.1)     H
1.4         
ing.1 Through the development of more rapid and effective therapy,
updated criteria have been proposed to identify patients requiring rapid Partial thromboplastin time 30.8 sec     (23.3–33.6)
products for serious injuries related to uncontrolled bleeding.1 Newer Fibrinogen level 118 mg/dL      L
(234–500)      
criteria include administering 3 units of RBCs during 1 hour or any 4 DAT Weakly positive, polyspecific
blood components within 30 minutes, and universal ABO products are
DAT, direct antiglobulin test; H, high; INR, international normalized
used for resuscitation. This usually includes group O packed RBCs, with ­ratio; L, low. 
group AB or low-titer group A plasma, or, less commonly, low-titer group Reference ranges included in parentheses.

© The Author(s) 2021. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions,
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e30 www.labmedicine.com
 The blood bank initiated a plasma thaw in anticipation of an emer- hemorrhage. Much of the preparation time includes the thawing of fresh
gent need for massive transfusion. During this time, blood bank testing frozen plasma (up to 20 minutes) and the continued preparation and
revealed that the patient had a positive antibody screen indicating the thawing of products that are directed by the clinical team managing the
presence of an anti-C and anti-E antibody. This testing was performed massive hemorrhage protocol.
using solid-phase (Immucor Echo) antibody panel detection, with In retrospect, the immediate clinical management of our pa-
strong (3+ to 4+) reactivity against panel cells with C and E antigen pos- tient could have been approached differently to meet transfusion
itivity. Based on these results and the patient’s presentation, the clinical requirements. Instead of waiting for C and E antigen negative units from
team decided to forego the use of additional uncrossmatched O positive the blood supplier, uncrossmatched universal donor products (O posi-
blood and wait for the arrival of antigen-compatible O positive blood. tive RBCs and AB fresh frozen plasma) could have been accepted. Given
There was an approximately 1-hour average time for this product to ar- the patient’s low fibrinogen levels, units of cryoprecipitate that are rou-
rive via delivery from the local blood supplier. However, during that tinely administered during our massive transfusion protocol could have
time, the patient’s hypotension worsened, which, combined in the set- been an appropriate course. Tranexamic acid (TXA) was not considered
ting of hemorrhagic shock, led to her death approximately 90 minutes by the clinical team as a course of treatment units. Accepting universal
after the initial transfusion. donor products initially could save lives, and waiting for crossmatch-

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Just before the patient’s death, a final hematocrit result was 9.0 g/ compatible units during massive transfusions could lead to poor
dL and did not show evidence of gross hemolysis. Additional specimens, outcomes. Based on the CRASH-2 and WOMAN trials,3 early adminis-
including urine, were not available for evaluation before the time of tration of TXA in this patient with hemorrhage could have resulted in a
death and posttransfusion. Phenotyping of the 3 emergently transfused more favorable outcome.
blood showed 2 units positive for the C and E antigens (crossmatch- Research has shown that 15% to 20% of the White  donor popula-
incompatible). Because a transfusion reaction workup was not ordered, tion and 50% to 60% of Black populations are negative for both the C
there was concern that transfusion of the incompatible units may have and E antigens.4 Given this prevalence, it can be difficult to address the
led to the death of the patient. presence of anti-C and anti-E RBC antibodies in the context of massive
transfusions. It follows that if any given patient receives several rounds
of O positive universal donor RBCs, then it would be likely that more
Questions for Consideration than half of those units would be incompatible because they would con-
tain either the C or the E antigens.
1. How are massive transfusions different from routine blood Anti-C and anti-E are present usually from exposure to C and E anti-
transfusions? gen positive RBCs, respectively, and they are typically acquired from prior
2. What should have been done differently in the immediate clinical transfusion(s) or pregnancies.5 Hemolysis caused by anti-C and anti-E is usu-
course of this patient, to better meet transfusion requirements? ally of delayed onset, meaning that these antigens are IgG in nature and do
3. How are anti-C and anti-E RBC antibodies addressed in the con- not usually cause immediate clinical consequences. Furthermore, during a
text of massive transfusion? mass hemorrhage event, a patient’s blood volume will undergo rapid turno-
4. What additional laboratory workup could include or exclude he- ver because of exsanguination and replacement. Therefore, during such rapid
molysis? turnover and transfusion, delayed hemolysis is not an immediate clinical
5. Should there be concern for a hemolytic transfusion reaction as concern. Hemolysis secondary to anti-C and anti-E may arise after acute re-
the cause of death? suscitation, in which routine transfusions of C and E antigen negative units
would then be appropriate to boost endogenous RBC production. This factor
becomes critical in the management of a patient’s subsequent anemia.
Discussion After a massive transfusion in the setting of known anti-C and anti-E,
When managing transfusions, it is critical to understand how massive the blood bank usually requests C and E antigen negative units from the
transfusions differ from routine transfusions. Both are regulated through supplier and ensures crossmatch compatibility with the patient. During
hospital transfusion services that are governed by the US Food & Drug the next few days, the clinical team monitors serial hemoglobin and he-
Administration and either the College of American Pathologists, as in this matocrit, along with other signs of extravascular hemolysis. Transfusion
case study, the American Association of Blood Banks (AABB), or both or- support is subsequently provided on a routine and as-needed basis with
ganizations. During routine, nonemergent circumstances, laboratory test- the C and E antigen negative units received from the blood supplier.
ing is performed on all patients before they receive blood products. This Because the prevalence of C and E antigen  negative units in the
practice ensures compatibility and supports proper identification of the O-positive donor population is low, an additional consideration would
patient’s ABO blood type. At a minimum, approximately 1 to 1.5 hours be to administer O negative RBC units as an alternative to antigen neg-
are usually required for a patient to receive crossmatch-compatible blood, ative RBC units, when there is insufficient time to perform antigen typ-
including time to receive and perform the ABO/Rh type, antibody screen, ing. Furthermore, D-negative donors are likely to be C and E negative
and an immediate spin or electronic crossmatch (assuming a negative an- because of the r haplotype (dce) being the most common D  negative
tibody screen result). Any blood products emergently required before the haplotype. However, in the case of our patient, we had only 4 units of
completion of testing would be uncrossmatched, universal donor products O negative blood at the time, and those units are reserved for women
(O positive RBCs and AB plasma). aged ≤45 years (childbearing age) with unknown blood type. In addition,
However, during a massive transfusion, compatibility testing is not the timing of this patient’s case coincidentally occurred during peak
routinely performed, mainly because of time constraints in the blood COVID-19 events that drastically reduced blood donations.
bank in the preparation of blood products to be used for emergency TABLE 2 lists different types of RBC antibodies that can cause he-
transfusion and resuscitation of patients with acute and active mass molysis and that clinicians can use to help identify additional labora-

www.labmedicine.com e31
 TABLE 2.  Different Types of RBC Antibodies That Can Cause Hemolysis5
Antibody Type IgM (mainly ABO) IgG (most other blood groups)
Hemolysis type Intravascular Extravascular (reticuloendothelial system of the spleen)
Clinical severity Severe to fatal Mild to moderate
Onset of symptoms Immediate Delayeda
Patient complaints or Fever, back pain, chills, shortness of breath, an “impending sense of doom,” Mild to no symptoms, jaundice/itching within several days of trans-
presentation confusion, jaundice. fusion
Hyperkalemia Usually present Not present
Renal failure May be present Not present
Evidence of shock/DIC May be present Absent
Blood in urine Usually present May be present
Hemoglobin Decreased Decreased
Haptoglobin Decreased May be decreased

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LDH Increased May be increased
Serum bilirubin Increased Increased
DAT Positive, specific for C3 (may also show IgG positivity) Sometimes positive, specific for IgG only

DAT, direct antiglobulin test; DIC, disseminated intravascular coagulopathy; LDH, lactate dehydrogenase
a
Usually 3–14 days.

tory tests that could rule in or rule out hemolysis. In our case study, as fusion cases is to distinguish between acute and delayed hemolysis in roles
listed in TABLE 1, a comprehensive metabolic panel was ordered that for posttransfusion outcomes and assess whether the transfusion itself may
included potassium, bilirubin, and creatinine. All were within normal have been a contributing factor.
limits. A direct antiglobulin test (DAT) performed by the blood bank was
weakly positive with immunoglobulin polyspecificity. Additional tests Acknowledgments
that could have been ordered to better assess hemolysis include serial We thank Ms. Jennifer Davila, supervisor of blood bank and transfusion
hemoglobin and hematocrits, lactate dehydrogenase (LDH), haptoglo- services.
bin, urine hemoglobin, and RBC elution studies. A posttransfusion type
and screen and compatibility testing on returned units may have pro-
vided a better assessment of the clinical picture. Conflict of Interest
Based on the information presented in this case study, it is unlikely that The authors have no disclosures or conflicts of interest.
a hemolytic transfusion reaction was the cause of death. Hemolysis was
not identified in the posttransfusion specimen assayed for hemolysis and REFERENCES
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