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American Journal of Therapeutics 19, e90–e94 (2012)
Acute Hypotensive Transfusion Reaction With
Concomitant Use of Angiotensin-Converting
Enzyme Inhibitors: A Case Report and Review of
the Literature
Ankur Kalra, MD,1 Chandrasekar Palaniswamy, MD,2* Ritesh Patel, MD,1
Ankit Kalra, MBBS,3 and Dhana R. Selvaraj, MD2
Hypotension can be a manifestation of transfusion reactions, including acute hemolysis, bacterial
contamination, transfusion-related acute lung injury, and anaphylaxis. In addition to hypotension,
these reactions usually present with other characteristic symptoms and signs. In rare cases,
hypotension is the only manifestation of a transfusion reaction. This reaction, characterized by early
and abrupt onset of hypotension that resolves quickly once the transfusion is stopped, is referred to
as acute hypotensive transfusion reaction (AHTR). We report a case of AHTR observed in a patient
on angiotensin-converting enzyme inhibitor therapy. The Naranjo adverse drug reaction probability
scale score indicated that the association between angiotensin-converting enzyme inhibitor therapy
and AHTR was probable. If a patient on angiotensin-converting enzyme inhibitor therapy develops
AHTR, it is important to recognize the need to switch to another class of antihypertensive
medication, at least while the patient continues to require transfusion.
Keywords: hypotension, transfusion, angiotensin-converting enzyme inhibitors, bradykinin, acute
hypotensive transfusion reaction
INTRODUCTION
CASE REPORT
Acute hypotensive transfusion reaction is characterized
by early and abrupt onset of hypotension, which is
often severe, other than signs or symptoms that are
attributed directly to the drop in systolic blood
pressure. Once the transfusion is stopped, the hypotension rapidly resolves without specific therapy.1
An 81-year-old man presented to emergency department with lethargy of 3 days’ duration. This was
insidious in onset and not associated with headache,
fever, loss of consciousness, bladder or bowel dysfunction, seizures, or focal neurologic deficit. The patient’s
medical history was significant for diabetes mellitus,
chronic kidney disease, coronary artery disease, atrial
fibrillation, gout, and recurrent staphylococcal spinal
osteomyelitis. Medications included allopurinol, celecoxib, furosemide, spironolactone, insulin, and warfarin. Physical examination revealed an elderly man,
lethargic and slow to respond but oriented to time,
place, and person with no focal neurologic deficit.
Pertinent laboratory data included hemoglobin of
14.6 g/dL, white blood cell count of 16,000/mm3,
and serum creatinine of 2.6 mg/dL. Furosemide
and spironolactone were held secondary to renal
1
Department of Medicine, Cooper University Hospital, UMDNJRobert Wood Johnson Medical School, Camden, NJ; 2Department
of Medicine, New York Medical College and Westchester Medical
Center, Valhalla, NY; and 3Department of Medicine, Kalra
Hospital & SRCNC, New Delhi, India.
The authors have no conflicts of interest to declare.
*Address for correspondence: New York Medical College, Westchester Medical Center, 95 Grasslands Road PMB 503, Valhalla,
NY 10595. E-mail: [email protected]
1075-2765 Ó 2012 Lippincott Williams & Wilkins
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AHTR
insufficiency. The patient was started on empiric
antibiotics for sepsis. A nontender left clavicular mass,
3 3 4 cm, was also noted, the biopsy of which revealed
osteomyelitis. The patient improved while being
treated with empiric antibiotics, vancomycin and
aztreonam. Blood cultures subsequently grew methicillin-resistant Staphylococcus aureus; a total of 6 weeks
of therapy was planned. The hospital course was
complicated by acute blood loss anemia, presumably
secondary to a gastrointestinal bleed that required
blood transfusion. Meanwhile, renal function had
showed a steady improvement and lisinopril was
added to the existing regimen. The patient continued to
remain anemic and needed to be transfused further.
Within 15 minutes of initiation of the second blood
transfusion, the patient developed lightheadedness.
The heart rate was 82 beats/minute, and the blood
pressure had abruptly dropped from his baseline of
110/74 mmHg to 67/37 mmHg that was confirmed by
repeat automatic and manual measurements. Oxygen
saturation by pulse oximetry was 97%. The rest of the
physical examination was unremarkable. Transfusion
was immediately stopped, and intravenous fluid bolus
was initiated. After this, blood pressure rapidly
normalized to his baseline values. Analysis of the
blood products revealed no crossreacting antibodies or
bacterial contamination. Workup for hemolysis was
negative. It is notable that the second set of blood
transfusions was ordered after initiation of angiotensin-converting enzyme (ACE) inhibitor therapy. The
onset of hypotension was abrupt with the start of blood
transfusion with rapid resolution of hypotension once
the transfusion was stopped. This phenomenon is
referred to as acute hypotensive transfusion reaction
(AHTR) and ACE inhibitors are known to play a key
role in the pathogenesis of this phenomenon.
The association of ACE inhibitor use with AHTR
in our patient was not definitively proven, because
there could have been other plausible explanations. To
assess this probability, we used the Naranjo adverse
drug reaction probability scale.2 This scale aids in
systematically eliminating all other possible origins of
a reaction as well as correlating the onset of symptoms
with suspect drug administration. Using the Naranjo
adverse drug reaction probability scale, the patient’s
score indicated that the association of ACE inhibitor
therapy to AHTR was probable.
ETIOLOGY AND PATHOGENESIS
Reports of hypotensive reactions from plasma derivates date back to the 1970s, when plasma protein
fraction (PPF), a partially purified derivative of plasma
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fractionation, was used as colloid replacement. In 1978,
Alving and colleagues published a report linking
hypotensive reactions associated with the use of PPF
to the presence of factor XII in those plasma derivates.3
Later in 1982, another report linked the use of PPF and
bradykinin (BK) generation to the development of
hypotensive transfusion reactions. In an open-label,
nonrandomized study comparing PPF versus albumin
as colloid replacement during open heart surgery, PPF
was found to be associated with more episodes of rapid
onset of hypotension.4 This correlated with levels of
factor XII and BK in PPF; albumin lacked both factor
XII and BK, and its use did not cause hypotensive
reactions. Albumin became the colloid of preference
and the use PPF was abandoned. The use of leukocyte
reduction of cellular blood products by depth filtration
became widespread in the 1990s with the objectives of
decreasing the rates of febrile transfusion reactions,
alloimmunization, and the transmission of leukocyteborne infectious diseases. In 1993, the American
association of blood banks (AABB) reported 25 cases
of acute hypotensive reactions with the infusion of
platelet products.5 It was suggested that there might be
interactions with the medications the patients were
taking and the use of platelet product filters, but no
clear explanation for that phenomenon was available at
that time.
To further characterize these reactions, the AABB
transfusion practice committee sent questionnaires
to the institutions reporting severe and/or unusual
reactions to platelet transfusions and also to all AABB
institutional members. From those questionnaires, they
identified 17 reactions that were primarily characterized by hypotension.6 Of these hypotensive reactions,
88% occurred within 1 hour of the beginning of the
transfusion and 82% resolved rapidly after the
cessation of transfusion. Of note, 88% of the implicated
products had been leukoreduced, mainly with bedside
filters. A significantly increased levels of BK was
observed when platelet concentrates were filtered
through negatively charged depths filters but not
positively charged filters.7 Elevated venous blood
levels of BK were observed when platelet concentrates
were filtered through negatively charged filters and
transfused to patients with low ACE activity.8
The occurrence of hypotensive reactions related to
the use of ACE inhibitors in patients undergoing
apheresis procedures has been well documented, and
the medication is recommended to be discontinued at
least 24 hours before the patient undergoes apheresis.
Of 301 patients undergoing plasma exchange, all 15
patients taking ACE inhibitors experienced hypotension or flushing during a procedure, whereas only
a small fraction (11%) of the patients not taking the
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medication had similar problems.9 Hypotensive reactions have also been reported with the use of dextran
sulfate columns and staphylococcal protein A columns.10,11 The combination of ACE inhibitors and
negatively charged dialysis membranes has been
implicated in the development of hypotensive reactions, mainly through the mediation of des-Arg9-BK.12
An understanding of the pathophysiology of AHTR
depends on knowing BK function and metabolism13,14
(Fig. 1). BK is a vasoactive peptide that is produced by
the activation of the contact system. The starting point
of the activation process requires the interaction of
activated factor XII with negatively charged surfaces
such as glass, dialysis membranes, and blood filters.
Once activated, factor XIIa transforms prekallikrein,
a plasma glycoprotein that freely circulates bound to
high-molecular-weight kininogen into its active form
kallikrein that is responsible for generating BK from
high-molecular-weight kininogen. The carboxyterminal arginine residue of BK stimulates normally present
B2 receptors on the endothelium and mediates the
pharmacologic effects of BK, which include hemodynamic, analgesic, and proinflammatory actions.
Although not widely expressed in normal tissues, B1
receptors can be upregulated by injury and inflammation. Once hydrolyzed by carboxypeptidases N and M,
BK is transformed into des-Arg9-BK, a metabolite that
can also have vasoactive activity, chiefly binding to B1
receptors. Bradykinins are hydrolyzed by several
Kalra et al
metallopeptidases, which include kininase I enzymes
(carboxypeptidases N and M), kininase II enzymes
(ACE and neutral endopeptidase), and aminopeptidase
P. Under normal conditions, ACE is responsible for
75% of BK inactivation. Carboxypeptidases are
responsible for the metabolization of the remainder
of BK, removing the Arg9 from the carboxyterminal
end and producing des-Arg9-BK. In the presence of
ACE inhibition through antihypertensive medications,
or in the face of abnormal polymorphisms or low levels
of aminopeptidase P or ACE, larger amounts of desArg9-BK can form and a set up for the development of
hypotension and associated effects resulting from the
activation of B1 receptors.15–17
DIFFERENTIAL DIAGNOSIS
Acute hypotension can be a manifestation of other
transfusion reactions, including bacterial contamination of blood products, acute hemolysis, transfusionrelated acute lung injury, and anaphylaxis.
Bacterial contamination of blood products
Although hypotension can occur at the time of
transfusion of contaminated blood products by bacteria, other symptoms such as chills and fever are usually
present.
FIGURE 1. Bradykinin metabolism. Factor XII is activated by contact with negatively charged surfaces. This leads to the
activation of prekallikrein bound to high-molecular-weight kininogen (HMWK) into kallikrein (KK). Kallikrein cleaves the
HMWK to liberate bradykinin (BK), which is metabolized mainly by the angiotensin-converting enzyme (ACE) and also by
carboxypeptidases and aminopeptidase P (APP). Des-Arg9-BK is inactivated by ACE and APP.
American Journal of Therapeutics (2012) 19(2)
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AHTR
Acute hemolytic transfusion reactions
Hypotension is not the initial symptom and appears
later in the course of the reaction. Before hypotension
manifests, other symptoms such as nausea and
vomiting, back pain, fever, chills, hematuria, and other
signs of hemolysis are present.
Transfusion-related acute lung injury
This typically takes place within 1 to 6 hours after the
beginning of the transfusion. It chiefly manifests as
sudden onset of severe dyspnea, hypoxia, and the
development of diffuse pulmonary infiltrates. Fever
and hypotension, although they can be present, are
minor components of the reaction.
Anaphylactic transfusion reactions
These are characterized by an acute onset of hypotension early in the transfusion. Other symptoms that are
typical of an allergic reaction can also be present,
including urticaria and pruritus, laryngeal edema, and
respiratory tract obstruction leading to difficulty
breathing. Stopping the transfusion is not enough to
reverse the process and patients require antihistamines,
steroids, and epinephrine as part of the treatment to
prevent sometimes fatal progression.
Understanding the manifestations of other transfusion reactions that can present with hypotension
makes it easier to identify purely isolated AHTRs.
These reactions are characterized by the early and
abrupt onset of hypotension, which is often severe,
with a drop of the systolic blood pressure below 70 or
60 mmHg without many other signs or symptoms
aside from lightheadedness or anxiety attributed
directly to hypotension. Other symptoms that have
been occasionally reported include low-grade fever,
flushing, urticaria, dyspnea, and gastrointestinal symptoms. However, hypotension is always the predominant symptom and clearly overshadows all others.
Another typical characteristic of this type of reaction is
that once the transfusion is stopped, the hypotension
rapidly resolves without specific therapy.
MANAGEMENT
Once an episode of AHTR occurs, the most important
measure is to stop the transfusion immediately.
Symptoms usually subside quickly as the transfusion
is discontinued. The patient should not be rechallenged
with that same product, because symptoms are
expected to recur as a result of activation substances
presumed to be present in the product. In most
instances, no other treatment is required, although in
some cases when the hypotension does not
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immediately correct with the interruption of the
transfusion, the use of a bolus of intravenous fluids
may be helpful. Vasoactive drugs are rarely indicated.
Our patient responded to prompt interruption of the
transfusion alone, although a fluid bolus was also
started immediately. Because ACE inhibitors play
a major role in these reactions, once a patient who is
taking this type of drug develops an AHTR, it is
important to recognize the need to switch to another
class of antihypertensive medication, at least while the
patient continues to require transfusions or apheresis
procedures. Some experimental methods have been
suggested in the setting of repetitive AHTRs in patients
who need dialysis or pheresis. They include washing of
cellular blood products for removal of supernatant and
the use of kallikrein blockade with nafamostat
mesilate. In the absence of clinical validation, these
methods cannot be endorsed.
CONCLUSION
With increasing use of ACE inhibitors in clinical
practice, the incidence of AHTR is likely to increase
further. Physicians should be aware of this potentially
serious complication associated with the use of ACE
inhibitors. Understanding the implicated factors in the
etiology of AHTR and its clinical manifestations is the
key to providing care to patients who develop this
complication and for future prevention.
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