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MOH 260606

REVIEW

CURRENT
OPINION Transfusion support and alternatives for Jehovah’s
Witness patients
Elizabeth P. Crowe and Robert A. DeSimone

Purpose of review
Jehovah’s Witness patients with critical anemia or undergoing major surgery are challenging for healthcare
providers to manage, as most will decline transfusion of whole blood and its main components. Recent
advances in our understanding of hemostatic agents, alternative hemoglobin-based oxygen carriers, and
patient blood management have culminated in a complex array of options to manage critical anemia and
bleeding in this patient population.
Recent findings
Refusal of blood products in the setting of critical anemia is associated with significant risk of morbidity and
mortality. With implementation of patient blood management measures, targeted treatment of anemia and
coagulopathy has reduced the need for transfusions. Likewise, increased clinical experience with
hemoglobin-based oxygen carriers in Jehovah’s Witnesses with critical anemia has provided new insights
into their potential benefits and pitfalls.

Summary
Options and alternatives to manage the Jehovah’s Witness patient in the perioperative setting or in the
setting of critical anemia will be reviewed.

Keywords
anemia, coagulopathy, Jehovah’s Witness, transfusion

INTRODUCTION platelets, and white blood cells, even in life-threat-

Patients who decline blood component therapy on
the basis of religious objection, such as Jehovah’s
Witnesses, pose unique and challenging opportuni-
ties for bleeding management in the perioperative
setting and in cases of critical anemia. As the arma-
mentarium of blood component therapy, derivatives,
blood substitutes, and techniques to reduce blood
loss continues to expand, the approach to Jehovah’s
Witness patients should entail an individualized dis-
cussion of permitted and prohibited products and
procedures. Morbidity and mortality associated with
critical anemia as well as management strategies
(including experimental use of hemoglobin-based
oxygen carriers if obtainable) as well as perioperative
considerations will be reviewed.
BACKGROUND
There are over 8.5 million practicing Jehovah’s
Witnesses worldwide, with approximately 1.2 mil-
lion residing in the United States [1]. In general,
most will decline transfusion of whole blood and its
main components – red blood cells (RBCs), plasma,
ening situations (Table 1) [2,3]. This decision is
based on the religion’s interpretation of several
Bible passages, and transfusions are considered a
disassociating offense by the majority of Jehovah’s
Witness followers [4].
Despite this, several anonymous surveys of Jeho-
vah’s Witnesses in life-threatening situations have
revealed that 10–12% of patients are willing to
accept blood products [5–7]. Obtaining informed
consent without pressure of family or religious eld-
ers present may reveal a willingness to receive trans-
fusions in a minority but significant number of
cases. Therefore, the consent process for blood
Department of Pathology and Laboratory Medicine, New York-Presbyte-
rian Hospital, Weill Cornell Medicine, New York, New York, USA
Correspondence to Robert A. DeSimone, MD, Transfusion Medicine and
Cellular Therapy, Department of Pathology and Laboratory Medicine,
Weill Cornell Medicine, 525 East 68th Street, Room M-09, New York, NY
10065, USA. Tel: +1 212 746 6768; fax: +1 212 746 8435;
e-mail: rod9096@med.cornell.edu
Curr Opin Hematol 2019, 26:000–000
DOI:10.1097/MOH.0000000000000535

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MOH 260606
Transfusion medicine and immunohematology
KEY POINTS
 Heterogeneity exists among Jehovah’s Witness patients
with regard to acceptable blood components,
derivatives, and procedures; therefore, it is essential to
conduct an individualized discussion regarding the risks
and benefits of each as part of informed consent.
 Patient blood management measures, newer hemostatic
agents, and advances in surgical techniques have
facilitated the targeted treatment of perioperative
anemia and coagulopathy while avoiding transfusions.
 Prompt administration of artificial oxygen carriers
should be considered as a temporizing measure in
patients with critical anemia who refuse transfusion.
 Alternative pro-coagulant measures including early
supplementation of fibrinogen in patients with acquired
hypofibrinogenemia and administration of
antifibrinolytics in the perioperative setting reduces
blood loss.
products must be confidential and take place
independent of family and elder members to avoid
coercion.
Jehovah’s Witnesses are often unsure, which
specific blood products, derivatives, and procedures
they are willing and not willing to accept, and little
advice exists regarding this issue from their national
organization – the Watch Tower Bible and Tract
Society of Pennsylvania. The decision to accept
autologous, salvaged blood, and blood derivatives
including albumin, globulins, thrombin, clotting
Table 1. Generally prohibited and permitted products and procedures in Jehovah’s Witness patients
Generally prohibited
Whole blood
Red blood cells (allogeneic and autologous)
White blood cells (e.g. granulocytes)
Plasma
Platelets
2 www.co-hematology.com
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
factors, and so forth is a personal choice and subject
to individual variation (Table 1) [8].
It is best practice for transfusion services and
hospitals to develop an informed consent form list-
ing various categories of blood products, derivatives,
and procedures to have Jehovah’s Witnesses sign at
the start of hospitalization or before major surgery.
Categories of therapy discussed on such a consent
form may include RBCs, platelets, plasma, cryopre-
cipitate, plasma-derived derivatives, recombinant
derivatives, and cell salvage, for example. This
approach can organize an educational discussion
between care providers and patients and also serve
as a legal document, especially should they become
incapacitated. Once the patient has decided which
products, derivatives, and procedures he or she will
and will not accept, both the hospital Transfusion
Service/Blood Bank and pharmacy must be notified
to prevent release and subsequent accidental trans-
fusion or infusion.
MORTALITY WHEN TRANSFUSION IS NOT
AN OPTION
Although recent studies in Patient Blood Manage-
ment (PBM) have investigated ‘restrictive’ transfu-
sion thresholds often in the 7.0–8.0 g/dl range,
Jehovah’s Witnesses more often reach lower nadir
hemoglobin levels because of this denial. Multiple
studies have investigated the association of lower
nadir hemoglobin levels with mortality in such
patients. In one study of 300 Jehovah’s Witness
surgical patients declining blood products, overall
Generally permitted
Plasma-derived fractions
Albumin
Globulins
Cryoprecipitate
Cryoprecipitate-poor plasma
Clotting factors
Recombinant derivatives and clotting factors
White blood cell fractions (interferons, interleukins)
Therapeutic plasma exchange (plasma cannot be used as replacement fluid)
Red blood cell labeling and tagging studies
Epidural blood patches
Hemodialysis (must maintain continuous circuit)
Cardiopulmonary bypass (must maintain continuous circuit)
Intraoperative red blood cell salvage (must maintain continuous circuit)
Acute normovolemic hemodilution (ANH)
Hemoglobin-based oxygen carriers (experimental, obtained with FDA approval)
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MOH 260606
Jehovah’s Witness transfusion management Crowe and DeSimone
mortality was 16% with odds of death increasing 2.4
times for each 1.0 g/dl decrease in nadir hemoglobin
[9]. A similar study of 293 surgical Jehovah’s Witness
patients confirmed these findings with odds of
death increasing 2.04 times for each 1.0 g/dl
decrease in nadir hemoglobin [10]. A more recent
study of 1306 medical and surgical patients who
declined blood products showed a 55% increased
risk of mortality for each 1.0 g/dl decrease in nadir
&
hemoglobin [11 ]. This study also revealed a 42%
increase in risk of myocardial ischemia for each
1.0 g/dl risk in nadir hemoglobin.
Taken together, these studies reveal that refus-
ing blood products in the setting of critical anemia is
associated with significant risk of morbidity and
mortality. However, such patients have led to criti-
cal developments in the fields of surgery and trans-
fusion medicine through promotion of bloodless
surgery techniques and minimally invasive surgery,
which have improved outcomes and recovery, even
in those who accept blood product transfusions [12].
MANAGEMENT OF CRITICAL ANEMIA
Severe anemia is defined as a hemoglobin less than
7 g/dl and critical anemia is defined as a hemoglobin
less than 5 g/dl and/or an elevated lactate with base
deficit, hypoperfusion, shock, hemodynamic stabil-
ity, or active hemorrhage. A multifaceted approach
to the treatment of severe anemia in Jehovah’s
Witness patients has been previously published
[13]. Briefly, the authors recommend epoetin alfa
at a dose of 40 000 units intravenous or subcutane-
ous daily until hemoglobin recovers to greater than
7 g/dl to promote erythropoiesis. By contrast, treat-
ment with low-dose epoetin beta (<600 IU/kg/week)
was not effective in reducing duration of severe
&
anemia or mortality in Jehovah’s Witnesses [14 ].
Other supportive therapies should include iron
(100 mg iron sucrose formulation intravenous daily),
vitamin C (500 mg oral three times daily), folate (1 mg
oral or intravenous daily), and vitamin B12 (1 mg oral
daily). Once critical anemia is identified, experimental
hemoglobin-based oxygen carrier (HBOC) therapy
and subsequent monitoring for adverse effects can
also be considered. Finally, attempts must be made
to reduce iatrogenic anemia. Laboratory testing
should be limited as much as possible, with utilization
of pediatric-sized specimen tubes and point-of-care
&&
instruments whenever possible and necessary [15 ].
ALTERNATIVES TO BLOOD COMPONENT
THERAPY
Researchers have pursued the development of blood
substitutes for more than a century [16]. Numerous
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artificial oxygen carriers have been developed and
&&
clinically tested to date [17 ]. Despite the exhaustive
pursuit of a suitable alternative to RBC transfusions,
the current artificial oxygen carriers in the form of
HBOCs remain inferior to erythrocytes with signifi-
cant adverse effects. In extenuating clinical circum-
stances, when transfusion is not an option (i.e.
religious/personal objection, inability to find cross-
match-compatible blood because of autoimmune
hemolytic anemia, alloimmunization, remote loca-
tion, etc.), current evidence suggests that artificial
oxygen carriers may provide a mortality benefit for
&&
patients with severe, life-threatening anemia [17 ].
In Phase II and III clinical trials of several
HBOCs, concerns arose regarding hypertension, cor-
onary artery vasoconstriction, myocardial infarc-
tion, and increased mortality [13]. A meta-analysis
of 16 trials involving 3711 adult patients who were
treated with five different HBOCs demonstrated a
significant increase in the risk of death and myocar-
dial infarction [18]. However, these findings have
been the subject of scrutiny and dispute over lack of
uniformity [19]. A review of clinical studies involv-
ing only HBOC-201 (Hemopure, HbO2 Therapeu-
tics, Souderton, Pennsylvania, USA) administered to
over 1700 patients in clinical trials and as part of
expanded access protocols showed that HBOC-201
was well tolerated, protective against cardiac ische-
mia, and did not demonstrate an increase in mor-
&
tality [20 ].
Despite the known risks and lack of Food and
Drug Administration (FDA) approval at this time,
HBOCs can serve as a temporizing measure to pro-
mote tissue oxygenation in the setting of critical
anemia until the patient recovers. In the setting of
severe, life-threatening anemia, therapy with an
HBOC on an experimental basis, if available, can
be considered as many Jehovah’s Witness patients
will accept them. Several recent case reports have
highlighted their successful, albeit investigational
use in Jehovah’s Witness patients [21,22]. A recent
review of artificial oxygen carriers summarized 62
clinical cases of compassionate use of HBOC-201 in
patients for whom blood transfusion was not an
&&
option, including Jehovah’s Witnesses [17 ]. Time
to initiation of infusion was significantly shorter in
&
survivors, thus emphasizing the need for access [20 ].
The FDA has not approved any HBOCs for clinical
use to date, and only HBOC-201 and PEGylated car-
boxyhemoglobin bovine (SANGUINATE, Prolong
Pharmaceuticals, South Plainfield, New Jersey, USA)
remain under FDA discussion. The current mecha-
nism to obtain either product remains arduous. They
are both potentially available for emergency single-
patient Investigational New Drug (IND) compassion-
ate use through the FDA’s expanded access program.
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Transfusion medicine and immunohematology

Once the decision to use an HBOC is made, the
manufacturer must be contacted to confirm that they
are willing to supply the HBOC free of charge, and the
manufacturer must supply the FDA with a letter of
authorization. After this confirmation, the patient’s
primary physician must apply to the FDA for
expanded access to an investigational drug under
single-patient IND using Form FDA 3926 (available
at: https://www.fda.gov/NewsEvents/PublicHealthFo-
cus/ExpandedAccessCompassionateUse/default.htm)
and in emergency settings should also call the FDA
Emergency Call Center at 1-866-300-4374. After FDA
approval, emergency Institutional Review Board
approval must be obtained, followed by written
informed consent from the patient or his or her
healthcare proxy [21]. In our experience in the United
States, the turnaround time from the clinical decision
to use an HBOC to its receipt in the hospital is approx-
imately 12–24 h.
PERIOPERATIVE CONSIDERATIONS
Initiation of PBM measures to minimize perioper-
ative anemia and coagulopathy should be consid-
ered to reduce the risk of bleeding and need
for transfusions.
Correction of anemia and coagulopathy
For elective cases, anemia should be diagnosed and
treated aggressively at least 4 weeks before the pro-
posed surgery date. Useful laboratory tests to help
determine the cause of anemia, and thus inform
treatment, include a complete blood count, iron
studies (iron level, total iron-binding capacity, fer-
ritin), a reticulocyte count, vitamin B12, and folate.
Nutritional anemia, in particular iron deficiency, is
common in surgical patients and can be readily
corrected leading up to elective cases [23]. Intrave-
nous iron is preferable to oral iron because of oral
iron’s poor absorption in inflammatory states, poor
patient compliance because of gastrointestinal side
effects, and overall delayed efficacy. The choice of
intravenous iron depends on various factors, includ-
ing insurance reimbursement, institutional avail-
ability, and the patient’s overall iron deficit. With
a single dose of 1000 mg intravenously, low-molec-
ular-weight dextran can provide iron repletion in
&&
one sitting [24 ].
In the setting of anemia of chronic disease,
erythropoiesis-stimulating agents can be used in
conjunction with iron based on the patient’s base-
line iron stores and timing before elective surgery
&&
(Table 2) [24 ]. A recent meta-analysis of 32 ran-
domized controlled trials evaluating preoperative
erythropoietin and iron supplementation in surgical
patients (N ¼ 2482) identified a significant reduc-
tion in blood transfusions and no difference in
thrombotic complications with erythropoietin
&
[25 ]. In addition, antiplatelet and anticoagulant
medications should be held in accordance with
the American Society of Regional Anesthesia and
Pain Medicine (ARSA) guidelines to prevent exces-
sive intraoperative and postoperative bleeding
&
(Table 3) [26 ].
Acute normovolemic hemodilution
Acute normovolemic hemodilution (ANH) involves
isovolemic exchange of whole blood with crystalloid
(3 : 1) or colloid (1 : 1) solution immediately prior to
surgery. As a result, any bleeding during surgery
results in loss of diluted whole blood with fewer
red cells and reduced factors. Whole blood is rein-
fused at the end of the case, providing an increase in
red cell mass, platelets, and clotting factors. Overall,
the procedure may result in reduced blood losses [27].
As many Jehovah’s Witnesses will not accept autolo-
gous blood products, such patients should be specifi-
cally consented for the ANH procedure prior to
surgery [28]. The benefits of ANH may be overesti-
mated and likely depend on a high preoperative
hematocrit, maximum tolerated volume of phlebot-
omy, and high blood loss surgery [29].

Table 2. Management of anemia of chronic disease before surgery

More than 3 weeks before elective surgery More than 3 weeks before elective surgery

Anemia of chronic disease,
normal iron stores
(ferritin >1000 ng/ml, iron
saturation >20%)
Anemia of chronic disease,
low iron stores (ferritin
<100 ng/ml, iron
saturation <20%)
EPO 600 units/kg s.c. weekly
starting 21 days prior, oral iron
EPO 600 units/kg s.c. with 125 mg
ferric gluconate i.v. weekly 21 days prior
EPO 300 units/kg s.c. daily, starting
10 days before surgery and up to
4 days postoperatively, oral iron
EPO 300 units/kg s.c. with 125 mg
ferric gluconate i.v. daily, starting
10 days before surgery and up to
4 days postoperatively

&&
Data from [24 ]. EPO, epoetin alfa; i.v., intravenously; s.c., subcutaneously.

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Jehovah’s Witness transfusion management Crowe and DeSimone
Table 3. Recommendations for holding antiplatelet and anticoagulant medications prior to elective surgery (2015 ASRA
Guidelines)
Drug Half-life
Aspirin 15–20 min, irreversible effect
Clopidogrel 7–8 h, irreversible effect
Prasugrel 2–15 h, irreversible effect
Ticagrelor 6–9 h
Dipyridamole 40 min alpha/10 h beta
Dabigatran 12–17 h (28 h renal disease)
Rivaroxaban 9–13 h
Apixaban 15–24 h
Warfarin Variable
&
Data from [26 ]. ARSA, American Society of Regional Anesthesia and Pain Medicine.
Intraoperative red cell salvage
Intraoperative red cell salvage consists of the collec-
tion, washing, and reinfusion of autologous blood
aspirated from the surgical field, and results in the
production of a packed RBC unit with a hematocrit
ranging from 60 to 70% [28]. Most Jehovah’s Witnesses
will accept intraoperative red cell salvage as long as
the circuit is established in a continuous fashion.
Surgical and anesthetic considerations
Surgical techniques that may reduce intraoperative
blood loss include use of minimally invasive meth-
ods, atraumatic tissue dissection, and the applica-
tion of local hemostatic agents (i.e. argon beam
coagulator, fibrin glue). Anesthetic considerations
include patient positioning of the surgical field at or
above heart level and maintenance of normother-
mia. Whenever possible, a bloodless surgical team
with extensive experience operating on Jehovah’s
Witness patients should be utilized.
Coagulation management
Dilutional coagulopathy may ensue during major sur-
gery in Jehovah’s Witness patients because of infusion
of fluids to maintain tissue perfusion without adequate
blood product replacement. In this setting, fibrinogen
is usually the first coagulation factor to fall below an
unacceptable level for hemostasis, less than 150 mg/dl.
Hypofibrinogenemia is associated with increased mor-
tality in patients with massive hemorrhage; therefore,
fibrinogen supplementation with either fibrinogen
concentrate or cryoprecipitate should be considered
& &
[30 ,31 ]. The relative safety and efficacy of fibrinogen
concentrate versus cryoprecipitate in bleeding patients
with acquired hypofibrinogenemia is the subject of
&
ongoing investigation [32,33 ]. In trauma patients,
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Stop before surgery
Continue for secondary prevention,
hold for 6 d if primary prevention
7 days
7–10 days
5 days
2 days
4–5 d (6 days if renal disease)
3 days
3–5 days
5 days and INR normalized
fibrinogen replacement guided by viscoelastic testing
reduced exposure to blood products [34]. Following
fibrinogen, other coagulation factors of the prothrom-
bin complex decline, followed finally by platelets.
Procoagulant drugs (Table 4) may be considered intra-
operativelyto manage dilutionalcoagulopathy,as long
as they are consistent with the patient’s wishes [28].
Prothrombin complex concentrates (PCCs) are
FDA-approved for reversal of Vitamin K antagonists
in the setting of life-threatening bleeding. Four-
factor PCC (Kcentra, CSL Behring GmbH, King of
Prussia, Pennsylvania, USA) is prepared from human
plasma and contains Factors II, VII, IX, X, as well as
Proteins C and S, Antithrombin III and human
albumin. The use of four-factor PCC in a Jehovah’s
Witness patient with life-threatening hemorrhage
for warfarin reversal has been reported and empha-
sizes the need for timely consideration of newer
hemostatic agents in this patient population [35].
Treatment with antifibrinolytic agents, such as
tranexamic acid (trans-4-aminomethyl cyclohexane-
1-carboxylic acid, TXA) and the less potent e-amino-
caproic acid in Jehovah’s Witness patients with
increased risk of hemorrhage can be considered. A
meta-analysis of over 10 000 surgical patients
revealed that administration of tranexamic acid
Table 4. Drugs for perioperative bleeding management
Fibrinogen concentrate, 2–4 g
Target plasma fibrinogen concentration >150 mg/dl
Prothrombin complex concentrate, 20–25 IU/kg
Target prothrombin time (PT) increase of 30–40%
Tranexamic acid, initial bolus 10–15 mg/kg followed by 1–5 mg/kg
Desmopressin, 0.3 mg/kg administered over 30 min
Factor XIII concentrate, 10–20 IU/kg
Recombinant factor VIIa, 90 mg/kg
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Transfusion medicine and immunohematology
reduces blood loss and the need for transfusions [36].
The benefits of antifibrinolytics are less understood
and are the subject of ongoing investigation in
patients with hematologic disorders [37].
PEDIATRIC CONSIDERATIONS
Pediatric patients belonging to a Jehovah’s Witness
family continue to present an ethical challenge in
healthcare. In the United States, a 1944 Supreme
Court case (Prince vs. Massachusetts) established that
government had the authority to regulate the
actions and treatment of children and that parental
authority can be limited if doing so is in the best
interest of the child’s welfare [38]. Providers should
make parents aware that although everything will be
done to prevent unacceptable transfusion of blood
products or use of procedures, they are legally obli-
gated to provide such life-saving interventions in
life-threatening circumstances.
Seven states, however, do allow older teenagers
autonomy to make their own healthcare decisions
by providing them ‘mature minor’ status. In these
circumstances, and in accordance with local laws,
the healthcare wishes of such capable minors must
&&
be respected and upheld [24 ].
CONCLUSION
Although Jehovah’s Witness patients may be chal-
lenging to manage in the setting of critical anemia
and surgery, they have inspired many advancements
in medicine, including the development of bloodless
surgery programs and minimally invasive surgery as
well as PBM. Continued multidisciplinary research is
necessary to develop safe and effective alternatives to
transfusion for this unique group of patients.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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