Transfusion and Apheresis Science xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Transfusion and Apheresis Science

journal homepage: www.elsevier.com/locate/transci

Patient blood management in the cardiac surgical setting: An updated

overview
L.E. Terwindta,b, A.A. Karlasa,b, S. Eberla,b, M. Wijnbergea,b, A.H.G. Driessena,b, D.P. Veeloa,b,
B.F. Geertsa,b, M.W. Hollmanna,b, A.P.J. Vlaara,b,
⁎

a
Dept. of Anesthesiology, Academic Medical Center, University of Amsterdam, the Netherlands
b
Dept. of Intensive Care, Academic Medical Center, University of Amsterdam, the Netherlands

ARTICLE INFO ABSTRACT

Keywords: In cardiac surgical patients it is a complex challenge to find the ideal balance between anticoagulation and
Anticoagulation hemostasis. Preoperative anemia and perioperative higher transfusion rates are related to increased morbidity
Blood transfusion and mortality. Patient blood management (PBM) is an evidence based patient specific individualized protocol
Cardiac surgery used in the perioperative setting in order to reduce perioperative bleeding and transfusion rates and to improve
Coagulation factors
patient outcomes. The three pillars of PBM in cardiac surgery consist of optimization of preoperative ery-
Fibrinogen
thropoiesis and hemostasis, minimizing blood loss, and improving patient specific physiological reserves. This
Hemostasis
Point of care tests narrative review focuses on the challenges with special emphasis on PBM in the preoperative phase and in-
Prothrombin complex concentrates traoperative transfusion management and hemostasis in cardiac surgery patients. It is a “must” that PBM is a
Transfusion thresholds collaborative effort between anesthesiologists, surgeons, perfusionists, intensivists and transfusion laboratory
teams. This review represents an up to date overview over “PBM in cardiac surgery patients”.

1. Introduction
Cardiac surgery procedures are associated with a high risk of peri-
operative blood loss and coagulation disorders. Patients in an instable
coronary situation are very often treated with platelet aggregation in-
hibitors before surgical intervention. The residual effects of this treat-
ment combined with the effects of extracorporeal circulation on platelet
number and function, coagulation factor activity and dilution anemia
are important reasons for the increased need for perioperative trans-
fusion.
More than 30% of this patient group receives blood products in the
perioperative phase [1–5]. Therefore, a significant percentage (34% UK
data) of all blood products used perioperatively are used in cardiac
surgery patients with a wide variation between different hospitals [6].
Perioperative anemia and the need for transfusion in cardiac sur-
gery patients are associated with an increased risk of developing
transfusion-related acute lung injury (TRALI) or transfusion associated
circulatory overload (TACO) [7,8]. Therefore, it is comprehensible that
transfusions are also linked with an increase in mortality and morbidity
and are independent risk factors of perioperative adverse events
(stroke, renal failure, myocardial dysfunction) [9–11].
The Society for Advancement of Blood Management defined Patient
Blood Management (PBM) as “The scientific use of safe and effective
medical and surgical techniques designed to prevent anemia and decrease
bleeding in an effort to improve patient outcome” [12]. PBM in adult
cardiac surgery stands for an individualized multidisciplinary approach
to optimize patient’s own conditions. Especially in the perioperative
period, optimal PBM is necessary to minimize blood transfusion pro-
ducts resulting in cost reduction, optimize hemostasis, manage anemia,
and reduce complications due to blood transfusions.
A systematic PBM approach requires an optimal interaction between
all team members during an operation and should be standardized. The
three pillars of PBM are preoperative optimization of erythropoiesis
(red blood cell mass and iron stores), minimization of surgical and
coagulopathic blood loss, and improvement of patient-specific physio-
logical reserves (e.g. anemia) [4,13]. PBM takes place in the

Abbreviations: ACT, activated clotting time; ASA, acetylsalicylic acid; AUC, receiver operating characteristic curve; COX1, cyclooxygenase-1; CPB, cardiopulmonary
bypass; DAPT, dual antiplatelet therapy; DOAC’s, direct oral anticoagulant drugs; Hb, hemoglobin; HRE, human recombinant EPO; LVBT, large volume blood
transfusion; PBM, patient blood management; PCC, prothrombin complex concentrates; POCT, point of care tests; rFVIIa, recombinant factor VIIa; ROTEM,
thromboelastometry; TACO, transfusion associated circulatory overload; TEG, thromboelastography; TRALI, transfusion-related acute lung injury; TXA2, throm-
boxane A2; TXa, tranexamic acid; VKA, vitamin K antagonists
⁎
Corresponding author at: Dept. of Intensive Care, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
E-mail address: a.p.vlaar@amc.uva.nl (A.P.J. Vlaar).

https://doi.org/10.1016/j.transci.2019.06.015

1473-0502/ © 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: L.E. Terwindt, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.06.015
L.E. Terwindt, et al.
preoperative, intraoperative and postoperative management phases.
This narrative review will focus on PBM in the preoperative phase and
on transfusion and hemostasis during the procedure in cardiac surgery
patients.
2. Method
For this narrative, non-systematic review, we performed a literature
search (dated 19.11.2018) focusing on the clinical importance of PBM
in cardiac surgery resulting in a description of the best approach to
optimize hemostasis in this category of patients. Our search strategy in
Pub Med included systematic reviews, meta-analyses, guidelines, and
randomized controlled trials conducted in the last ten years. Search
terms were a combination of (1) “Cardiac Surgical Procedures” or
“Thoracic surgery” or “cardiac surgery”, (2) “blood management” or
“bleeding management” and (3) “blood transfusion” (see Appendix A).
Furthermore, we applied references checks to find additional relevant
articles.
All articles were independently screened and selected on title and
abstract by two different reviewers. Disagreements on selection of ar-
ticles were resolved between the reviewers (LT, AK). If necessary, a
third reviewer was consulted (AV). Duplicate and irrelevant articles
were excluded from further analysis. Studies were included if available
in English and full text, if elective cardiothoracic surgery and if non-
pediatric (see Chart 1). After reading the full text, a selection was made
for the narrative review resulting in 74 articles.
3. Patient blood management in the preoperative setting
3.1. Optimizing erythropoiesis
Anemia is an independent risk factor for morbidity and mortality in
cardiac surgery patients [14]. 50% of these patients show preexisting
anemia compared with 33% in non-cardiac surgery patients [14,15]. A
possible explanation could be found in preoperative medication, co-
morbidity such as renal failure or cardiovascular disease like arthro-
sclerosis, valve dysfunction, or cardiac decompensation. Timing of
surgery with hemoglobin optimization is an important factor to
Chart 1. Flowchart of selecting articles.
2
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
improve patient outcomes and reduce transfusion risks [16].
3.1.1. Iron therapy
There are multiple ways to restore anemia depending on the cause
of anemia. Transfusion of red blood cells is a simple option but contains
the risk of infection or induction of an immunological response and is
associated with increased morbidity and mortality. The most common
cause of anemia is iron deficiency, which results in a decrease of he-
moglobin (Hb) formation. Garrido-Martin et al. compared preoperative
iron supplementation (intravenous or oral iron) against placebo [17].
They found no difference in perioperative transfusion requirement.
Probably, the moment of iron treatment (5–6 days preoperatively) was
too short to produce a significant effect [17]. Padmanabhan et al.
performed a pilot RCT in a selected group of patients scheduled for
elective cardiac surgery with an existing anemia (Hb < 120 g/l for fe-
males and < 130 g/l for men) [18]. Patients were randomly allocated
to oral iron or Ferinject™ treatment for 3–8 weeks preoperatively. There
was no significant increase in Hb level (in both groups) compared to
baseline. Unfortunately, they did not include a placebo group. These
two studies do not support standard iron supplementation pre-opera-
tively in cardiac surgery patients (see Table 1).
3.1.2. Erythropoietin
Erythropoietin (EPO) is a hormone that increases formation of er-
ythrocytes. EPO is produced in the endothelial cells of the peri-tubular
capillaries of the kidneys. Production of EPO is stimulated by a low
paO2 tension. Weltert et al. [19,20] studied the effect of preoperatively
administered human recombinant EPO (HRE) on the outcome in car-
diac surgery patients. In 2010, Welter et al. performed a RCT with a
treatment group (HRE 14000IU 2 days pre-op, 14000IU 1 day pre-op,
8000IU at the morning of surgery, 8000IU 1 day post-op and 8000IU 2
days post-op) and a control group (no treatment) [19]. Results are
summarized in Table 1. Transfusion rates were significantly less in the
HRE group compared to the control group, and postoperative Hb levels
on day 4 postoperative were significantly higher. Nevertheless, there
was no significant effect on mortality rate. In 2015, the same group
conduct another RCT with a simplified dosage of HRE (one bolus of
80000 IU 2 days preoperatively) in patients with a preoperative Hb
 Table 1
Summary of studies reporting clinical outcomes of patient blood management in the preoperative setting.
Subject Author + Year Type N Results (%)

Pre-operative iron suppletion Garrido-Martin et al. RCT N = 159 No difference in transfusion requirements when treated preoperatively with iron compared to placebo (P = 0.70)
L.E. Terwindt, et al.

2012 [17] Pilot RCT N = 44 Mean Hb increased from 118.8 (8.9) g/l to 120.1(9.8) g/l in the ferinject group (P = 0.44) and from 113.9(11.1) g/l to
Padmanabhan et al. 118.3 (12.0) g/l in the oral group (P = 0.06)
2018 [18] Transfusion rates of packed red blood cells (PRBC) did not differ between the 2 groups [intravenous 2.0 units (interquartile
range 1.0–4.8), oral 1.5 units (interquartile range 0–2.0);P = 0.16]
Pre -operatively EPO Weltert et al. 2010 [19] RCT N = 320 Transfusions of PRBC per group: HRE 0.32 units of RBC, control 0.76 units of RBC (P = 0.008)
Weltert et al. 2015 [20] RCT N = 600 Hb on postoperative day 4: HRE 10.70 +/- 0.72 g/dL, control 9.26 +/- 0.71 g/dl (P = 0.03)
Transfusion incidence of allogeneic blood was 17% in the HRE group compared to 39% in the control group (P < 0.0005)
Patients with Hb baseline levels of 13.0 g/dl or more showed no difference in transfusion rates (P = 0.26)
Groups with Hb < 13.0 g/dl showed a significant lower transfusion rate in the HRE groep (P < 000.5)
ASA Aboul-Hassan et al. 2017 meta- analysis 12 RCT’s Any type of cardiac surgery
[24] of RCT and observational studies (N = 3922) Aspirin up until surgery, discontinuing aspirin less than 7 days before surgery, discontinuing aspirin more than 7 days
(OS) 28 OS before surgery, no aspirin or placebo.
(N = 30893) Mortality
No significant impact on 30-day postoperative mortality (OR 1.15; 95%CI 0.65-2.04;P = 0.62;I2 = 0%; P
heterogeneity = 0.95) Based on 7 RCT’s (N = 3362)
A 32% reduction in mortality was found in the group using preoperative ASA (OR 0.68; 95%CI
0.55-0.85;P = 0.0004;I2 = 23%; P heterogeneity = 0.19) Based on 16 OS (N = 27944)
Perioperative myocardial infarction
No significant effect was found on perioperative myocardial infarction (OR 0.83; 95%CI 0.66-1.04;P = 0.1;I2 = 0%;P
heterogeneity = 0.97) Based on 8 RCT’s (N = 3420)
No association was found between use of ASA and a reduction of myocardial infarction. (OR 0.95; 95%CI
0.71-1.27;P = 0.72;I2 = 21%;P heterogeneity = 0.2) Based on 5 OS (N = 20038)
Packed red blood cell transfusions
Increase in rate of PRBC transfusion in the group using preoperative ASA, but groups scored significant in heterogeneity.

3
P2Y12 inhibitors (DAPT)
P2Y12 inhibitors (DAPT)
(MD 0.45 unit; 95%CI 0.24-0.67;P < 0.000; I2 = 54%; P heterogeneity = 0.02) based on 10 RCT’s (N = 3878)
No significant difference on PRBC transfusion was found, again groups scored significant heterogeneity (MD 0.08 unit;
95%CI − 0.05 to 0.21;P = 0.24; I2 = 61%;P heterogeneity = 0.00) based on 19 OS (N = 19392)
Reoperation for bleeding
No difference was found for incidence of reoperation for bleeding after cardiac surgery. (OR 1.31; 95%CI 0.90-1.93;
P = 0.16; I2 = 0%; P heterogeneity = 0.66) based on 10 RCT’s (N = 3828)
No difference in reexploration between patients using ASA up until surgery or patients withdrawing their ASA before
surgery. (OR 0.96; 95%CI 0.80-1.16; P = 0.7; I2 = 0%; P heterogeneity = 0.85) based on 17 OS (N = 22318)
Hansson et al. Retrospective observational study N = 2244 Cardiac surgical CABG patients on ASA + Ticagrelor (n = 1266) OR clopidogrel (n = 978)
2016 [25] Overall, three out of four definitions for bleeding showed significantly reduced risk for ticagrelor vs. clopidogrel. BARC-
CABG 12.9 vs. 17.6%
(P ¼ 0.0024), BART major bleeding 8.8 vs. 11.6% (P ¼ 0.041), and
PLATO life-threatening major bleeding 46.8 vs. 54.0% (P ¼ 0.0008). PLATO major bleeding did not show a significant
difference (89.9 vs. 92.1%; P ¼ 0.076)
For ticagrelor, discontinuation 0-72 h before surgery was associated with a significant higher rate of bleeding compared to
both 72-120 h [unadjusted OR 5.17 (95% CI 2.89–9.27), P, 0.0001], and > 120 h [unadjusted OR 4.81 (95% CI 3.34–6.95),
P, 0.0001].
For clopidogrel a higher incidence of major bleeding occurred when stopped 72-120 h before surgery compared to > 120 h
[unadjusted OR 1.71 (95% CI 1.04–2.79), P ¼ 0.033].
Tomsic Retrospective observational N = 626 cardiac surgical CABG patients with either ASA (n = 404), ASA + clopidogrel (N = 138) and ASA + ticagrelor (N = 84)
et al. cohort study Compared to ASA, DAPT showed higher volume chest drainage in first 12 h postoperative [605.0 ml (IQR 423.8–932.5) vs
2016 [26] 572.5 ml (IQR 390.0–750.0), (P = 0.005] and higher transfusion rates (65.3 vs 41.3%, P < 0.001). DAPT did not show
significant difference in surgical re-exploration (9.5 vs 5.4%, P = 0.057), postoperative MI (2.3 vs 2.0%, P = 0.82) or in-
hospital mortality (1.8 vs 1.0%, P = 0.39)
Group Ticagrelor (T < 72 hr) presurgery had higher transfusion needs compared to ASA alone (72.1 vs 41.3%, P < 0.001)
and higher in-hospital mortality (4.9 vs 1.0%, P = 0.019). Group clopidogrel (C < 120 hr) presurgery also had higher
transfusion needs (71.2 vs 41.3%, P < 0.001), increased massive chest drainage > 1000 ml in the first 12 hr (26.4 vs
12.6%, P < 0.001). T72-120 hr and C120-168hr did not show significant difference in bleeding related complications
compared to the ASA group.
(continued on next page)
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L.E. Terwindt, et al. Transfusion and Apheresis Science xxx (xxxx) xxx–xxx

level of less than 14.5 g/dl [20]. Overall transfusion rates were reduced

because of relevant bleeding (6.2%), 4 after apixaban (11.4%) and 1 after rivaroxaban therapy (2.7%). Intensive care unit
stay was 2 days after DOAC withdrawal of 10 days, compared with 4.2 days without termination. Thirty-day mortality was
Surgery was performed at a median 4 days (IQR: 3 to 6) after DOAC withdrawal. Reduced renal function was predictive for
in treatment group [20]. However, there was no effect on reduction of

length of stay (p < 0.0001) and administration of red blood cells p = 0.0291). Five patients needed re-thoracotomy
transfusion rate when patients had a Hb level of 13 g/dl or more. The
reduction in transfusion rate without significant adverse effects makes
HRE treatment a recommended preoperative intervention strategy for
cardiac surgical patients with preoperative low Hb levels (< 13 g/dl).
The downside of EPO are safety concerns based on the increased risk for
cardiovascular events and thromboembolism. Therefore, balancing risk,
benefit and optimization, the optimal Hb target for treating anemia is
important and preoperative EPO treatment must be weighed against the
risks. Literature varies regarding the optimal Hb target, but most
guidelines recommend a level of 11 g/dl to consider EPO administration
[21].

3.2. Risk scores

A risk assessment of bleeding during the surgery pre-operative may

help in providing a patient tailored PBM approach. In 2015, Goudi et al.
developed a risk model for perioperative bleeding during cardiac sur-
gery based on prospectively collected multicenter data (26 hospitals)
among cardiac surgery patients. Risk models for “any transfusion” and
“large volume blood transfusion” (LVBT) (≥4 RBC units) were devel-
oped and showed excellent discrimination on the area under the re-
ceiver operating characteristic curve (AUC 0.80 (0.79-0.80)) [22] (See
Table 1). Characteristics in both risk models were a combination of
patient characteristics (sex, height, weight age), medical history (dia-
betic on medication, previous neurological accident, previous cardiac
Cardiac surgery patients

surgery, etc.), medical status (ejection fraction, serum creatinine, he-

moglobin levels, etc.) and type of procedure (CABG, valve replacement,
etc.). These risk models could be the first step in the early pre-operative
phase to identify patients that are at high risk for transfusion. The risk
Results (%)

scores are available as on-line calculators (http://

cardiacsurgeryleicester.com). In this “high risk” patient category a
3.7%.

POCT guided algorithm to correct coagulopathy’s is recommend. These

predictive models may guide cardiac surgery PBM, however further
randomized trials are needed to evaluate their effect on outcome.
N = 81

3.3. Minimize blood loss

N

3.3.1. Acetylsalicylic acid

The degree of perioperative coagulation disorders is often a com-
Single center retrospective

bination of preoperative used medication, patient characteristics, kind

of surgical procedure, and clinical experience of the anesthesiologist. In
an optimal PBM policy knowledge of preoperative anticoagulation is
necessary to minimize blood loss and improve individual patient coa-
gulation.
Thromboxane A2 (TXA2) is a highly potent platelet-aggregating
Type

activating agent. It is formed in platelets from arachidonic acid by cy-

clooxygenase-1 (COX1). Acetylsalicylic acid (ASA) irreversibly inhibits
COX-1 by acetylation and causes a reduced platelet aggregation for the
rest of the lifespan of the platelet, which is 8 to 10 days in circulation.
ASA has shown its importance in primary and secondary prevention of
ischemic cardiovascular events like stroke or myocardial infarction,
Author + Year

however, with the increased risk of bleeding incidents [10]. Current

2018 [28]

guidelines based on a meta-analysis in 2015 regarding urgent and

Hassan

elective surgery suggest to stop ASA 5 days before surgery in high risk
et al.

patients (complex surgery, hematological disorders, renal insufficiency

and hereditary platelet function deficiencies) [23]. Among patients
with normal risk for bleeding, ASA can be continued until surgery. A
recent meta-analysis by Aboul-Hassan et al. studied efficacy and safety
Table 1 (continued)

of ASA if used up until surgery [24]. Outcomes are summarized in

Table 1. The pooled results of the randomized controlled trials suggest
that there is no increase in mortality, perioperative myocardial infarc-
tion, and rate of reoperations in patients using ASA. Transfusion rates
DOAC’s
Subject

and postoperative chest drainage were significantly higher using ASA.

However, both results scored positive for heterogeneity, which makes

4
L.E. Terwindt, et al.
the results unreliable. Observational studies showed different results for
transfusion rates and chest drainage volume, but also a reduction of up
to 32% in mortality for patients using ASA up until surgery [24]. Un-
fortunately, results were highly heterogeneous and could not be used
for analysis. Nevertheless, based on the existing data it is recommended
continuing ASA until cardiothoracic surgery.
3.3.2. P2Y12 inhibitors
P2Y12 inhibitors are ADP receptor antagonists and inhibit binding
of ADP to the platelets P2Y12 surface receptor. Activation of P2Y12 by
ADP causes expression of GPIIb/IIIa on the platelets surface and am-
plifies platelet activation by other agonists. The GPIIb/IIIa receptors on
the surface of platelets are cross-linked by fibrinogen in plasma, re-
sulting in platelet aggregation. Combination with ASA (dual antiplatelet
therapy (DAPT)) is used in patients suffering from an acute coronary
syndrome to avoid thrombotic complications. Different P2Y12 in-
hibitors require different approaches regarding withdrawing prior sur-
gery considering the optimal timing to reduce risk of bleeding during
elective cardiac surgery and balancing the increased thrombosis risk.
Platelet function tests have widely been used to shorten discontinuation
time before surgery, but there are no data considering the incidence of
perioperative bleeding, and clear cut-off values are not available. Two
retrospective observational trials studied the risk for excessive bleeding
in patients using DAPT (ASA combined with either ticagrelor or clopi-
dogrel) scheduled for elective cardiac surgery [25,26]. Both described
an increased risk for bleeding with ticagrelor when used preoperatively
within 72 h until surgery and with clopidogrel within 120 h until sur-
gery (see Table 1). This supports the current guidelines regarding dis-
continuation of P2Y12 inhibitors preoperatively whereby ticagrelor
should be stopped 3, clopidogrel 5, and prasugrel 7 days before surgery.
3.3.3. Vitamin K antagonists
Vitamin K is an essential cofactor in the synthesis of coagulation
factors II, VII, IX and X. Vitamin K antagonists inhibit vitamin K epoxide
reductase from converting vitamin K1 epoxide (inactive) to vitamin K1
hydroquinone (active). Vitamin K1 hydroquinone is necessary for car-
boxylizing clotting factors in plasma. Inhibition of Vitamin K formation
inhibits activation of coagulation factors. Indications for the use of vi-
tamin K antagonists (VKA) are atrial fibrillation, mechanical heart
valves, and passed venous thromboembolic events. VKA’s must be
stopped 3–5 days before surgery to achieve an INR target of < 1.5. In
case of emergent surgery, prothrombin complex concentrate can be
given to reverse the effect of VKA completely. Furthermore, studies in
non-cardiac surgery patients showed that bridging with LMWH caused
increased bleeding after surgery and did not reduce the amount of
thrombotic events [27]. Bridging VKA with LMWH before surgery is
only indicated when patients are at high risk for thrombotic events (e.g.
those with pulmonary embolism less than 4 weeks before surgery, atrial
fibrillation with a CHA2DS2-VASc > 4, or mechanical valve replace-
ment).
3.3.4. Direct oral anticoagulant drugs
Direct oral anticoagulant drugs (DOAC’s), an alternative to VKA’s,
inhibit clotting factors IIa (dabigatran) or Xa (rivaroxaban, apixaban,
edoxaban) directly. Traditional anticoagulants, such as acenocoumarol
and phenprocoumon, inhibit the production of clotting proteins in the
liver and they work indirectly. This clotting process, influenced by diet
and other medication use, is not constant or predictable. Thereby it is
important to check the INR on a regular basis. DOAC’s work differently
and they directly affect one of the coagulation proteins themselves
(thrombin and Xa). Therefore there is no need to monitor the effect.
Since DOAC’s entered the market in 2010, data are available only from
a few case reports in cardiac surgery and one single-center retrospective
analysis (n = 81 patients) [28]. Length of DOAC withdrawal period
before cardiac surgery (mainly CABG and valve surgery) is essential for
patients with reduced renal function. It was significant predictive for
5
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
length of hospital stay and RBC transfusion (see Table 1) [28]. The
relation between withdrawal time and blood loss was shown to follow a
logarithmic curve [28]. Current guidelines recommend preoperative
discontinuation of 48 h based on five elimination half-life times and a
longer interval necessary for patients with impaired kidney function
[10]. Randomized controlled trials with foresight on longterm outcome
are needed to define the best breakpoint for DOAC’s preoperatively.
3.3.5. Low molecular weight heparin
Low molecular weight heparin (LMWH), mainly inhibitors of acti-
vated clotting factor X (Xa) (fondaparinux, enoxaparin) are mainly used
in bridging VKA before and after surgery to prevent thrombotic events
or in patients with known malignancy’s. Kincaid et al. found that pa-
tients scheduled for cardiac surgery are more at risk to suffer from a
bleeding when administered enoxaparin within 12 h before surgery
[29]. Medallion et al. in contrast found no relation with increased
postoperative bleeding or RBC transfusion [30]. Unfortunately, there is
limited data concerning preoperative LMWH in cardiac surgery and
therefore current guidelines suggest to stop LMWH depending on the
half-life and kidney function of the patient more than 12 h before sur-
gery [10].
Key points for patient blood management in the preoperative setting (see Fig. 2)
• There is insufficient evidence for standard iron treatment in PBM.
• Human recombinant EPO treatment should be considered in patients with a low
pre-operative Hb (< 13g/dL) and non-iron deficiency.
• Risk scores should be implemented in the early perioperative phase to identify
patients that are at high risk for transfusion.
• ASA can be continued up until surgery without an increased risk of mortality and
bleeding.
• Clopidogrel should be stopped > 5 days and ticagrelor > 3 days before cardiac
surgery.
• VKA should be stopped 3-5 day before surgery, bridging is only indicated in a
limited patient category with increased thrombotic risk.
• DOAC’s should be stopped 48 hours (5 elimination half-life times) before surgery
depending on kidney function this may be longer.
• LMWH should be stopped > 12 hours before surgery depending on the half-life
and kidney function.
4. Intraoperative transfusion management and hemostasis
To reduce perioperative costs and complications by reduction of
blood transfusion products, it is important to have a multidisciplinary
and multimodal approach for a cardiac surgery blood management
protocol [9]. Recent literature shows implementation of a PBM protocol
in daily cardiac surgery is effective, decreases mortality and improves
patient outcome (see Fig. 1) [9,31]. Successful components thereby are
a skilled project manager, tools for PBM workflow, an algorithm based
on ROTEM, a strong clinical multidisciplinary leader, and a permanent
clinical project leader [31]. Using this structured PBM algorithm,
transfusion related costs can be reduced [32].
4.1. Red blood cells and the optimal transfusion threshold
In cardiac surgery patients anemia is common due to hemodilution
caused by the extracorporeal circulation [33,34]. Anemia worsens the
quality of coagulation, is an independent risk factor of perioperative
adverse events (stroke, renal failure, and myocardial dysfunction), and
is associated with an increased morbidity and mortality
[11,35].Therefore, anemia is an important trigger for blood transfu-
sions in the perioperative period during cardiac surgery.
On the other hand, in the group of Jehovah's Witnesses mortality is
not increased despite very low Hb levels (minimal hemoglobin level
was 8.4 g/dl), compared to patients treated with PBM protocols [36].
The optimal hemoglobin level in cardiac surgery patients is therefore an
important point of further discussion and a balance between treatment
of anemia and the potential downside of blood transfusion.
L.E. Terwindt, et al.
Fig. 1. Successful components to improve PBM in cardiac surgery using a multidisciplinary approach.
To treat anemia successfully, it is important to optimize cardiac
output, maximize oxygen delivery, minimize oxygen consumption by
reducing stress, and to use evidence based blood transfusion strategies.
During an anemic period, there must be compensation mechanisms that
ensure that tissue supply with oxygen is guaranteed. Mechanisms that
could be used include increasing blood flow and cardiac output, and
inducing peripheral vasodilatation. The optimal transfusion threshold
(critical hematocrit/Hb value) is a balance act of preventing tissue from
hypoxia and optimizing oxygen delivery (even by red blood cell
transfusion) on one hand and other hand dealing with the downsides of
transfusion.
Based on current literature, a restrictive transfusion is re-
commended (see Table 2) [34,37–40]. The idea of restrictive transfu-
sion thresholds are based on studies of non-cardiac surgery patients
which report an increased risk of morbidity and mortality in liberal
transfusion policy [34,40]. Murphy et al. compared a restrictive (75 g/l)
versus a liberal Hb threshold (90 g/l) after cardiac surgery. As result,
the restrictive group showed a lower transfusion percentage and was
non-inferior regarding the composite primary endpoint compared to the
liberal group [40]. The TRICS III trial confirmed that a restrictive
transfusion policy has no advantage with regard to outcome compared
with a liberal transfusion threshold [1]. Compared to observational
analysis in cardiac surgery patients, adverse outcomes were found
within the liberal group [41]. These results were in line with findings
investigated in surgical and intensive care patients [42].
4.2. Transfusion reduction strategies; cell salvage and hemodilution
To avoid transfusion, cell salvage is a frequently used and re-
commended technique. A cell saver is a device that recycles blood lost
during operation by separating plasma and cellular debris from red
blood cells by centrifugal washing. This 'erythrocyte concentrate like’
product, can be re-infused as autologous blood transfusion. Current
evidence recommended the use of a cell saver to reduce blood trans-
fusions during cardiac surgery. However, mortality is not reduced [43].
The use of intra-operative cell salvage system in high risk-bleeding
cardiac surgery patients does not necessarily benefit blood coagulation
[44]. Using cell salvage during CPB period may result in an increased
risk of FFP transfusion (see Table 2) [10,43].
Hemodilution during CPB is another method to reduce allogenic
blood transfusions. However, hemodilution induces coagulation
6
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
disorders due to dilution of coagulation factors and excessive dilution is
associated with increased morbidity and mortality [10,45]. The dif-
ferent RCT’s we included in our search varied in method and quality
[46]. Most recent literature (systematic review) showed that acute
normovolemic hemodilution reduces allogeneic RBC and overall
transfusions of allogeneic blood with a significant reduction of post-
operative blood loss [5]. However, despite the size of the population in
this meta-analysis, there is still a lack of data and standard use of in-
traoperative hemodilution is not recommended. Judgment should be
made on individual basis and patients with a high Hb level pre-
operatively might benefit most.
4.3. Individualized and goal-directed coagulation therapy with point of care
tests
Compared with conventional standard laboratory tests (APTT, PT,
INR, platelet count, plasma-fibrinogen) point of care tests (POCT) are
much faster in providing useable results. Viscoelastic coagulation tests
include thromboelastography (TEG) and thromboelastometry
(ROTEM). POCTs can be used in a goal-directed algorithm to optimize
coagulation therapy and are essential in emergency situations and/or
with massively blood loss [47,48]. According to recent literature, POCT
guided correction of coagulation can improve outcome in cardiac sur-
gical patients [49,50].
A recent meta-analysis of Deppe et al. showed that the number of
transfusions and re-explorations decreased by using POCT based cor-
rection of coagulation [51] whereas the use of factor concentrates in-
creased [52]. Furthermore, a reduction in mortality, using POCT guided
algorithm, is described compared to coagulation management guided
by other methods (see Table 3) [51].
Although significant research has been done (retrospective trials) to
study the effect of implementation of transfusion algorithms and POCT
monitoring on the outcome, large randomized trials are lacking.
Current evidence recommends an individualized and goal-directed
coagulation therapy by using a POCT guided algorithm.
4.4. Optimizing coagulation
Optimizing coagulation is an important part of the cardiac PBM
algorithm to reduce bleeding, blood transfusions, and reoperations.
Coagulation disorders are often caused by a deficiency of specific
L.E. Terwindt, et al. Transfusion and Apheresis Science xxx (xxxx) xxx–xxx

clotting factors and adequate administration of the deficient factors is

The primary outcome (composite outcome) occurred in 35.1% of the patients in the restrictive-threshold group and 33.0% of

endpoint: more deaths in the restrictive-threshold group than in the liberal-threshold group (4.2% vs. 2.6%; hazard ratio, 1.64;

Restrictive vs liberal transfusion in patients moderate to high risk for death and with an EuroSCORE 1-6. Restrictive was non

Use of intraoperative cell saver reduced rate of exposure to any allogeneic blood product by 37% (95% CI; 0.43-0.94, P = 0.02)

Cell salvage was associated with a significantly increase in the relative risk ratios for heparin residual and excessive bleeding.

transfused cell salvage blood volume has poor discrimination in predicting perioperative platelet and plasma transfusion.(AUC
the patients in the liberal-threshold group (odds ratio, 1.11; 95% confidence interval [CI], 0.91 to 1.34; P = 0.30). Secondary
Pooled fixed effects mortality odds ratios comparing liberal versus restrictive transfusion thresholds was 0.70 (95% CI 0.49-
necessary. We will discuss the most important and frequently used

inferior to a liberal strategy (outcome, myocardial infarction, stroke, new onset renal failure) Mortality of 3.0% vs 3.6% in
products and strategies (see Fig. 2).

Less postoperative blood loss in ANH group (388 ml versus 450 ml; MD=-0.64; 95% CI -0.97 to -0.31; P= < 0.001
4.4.1. Tranexamic acid
Antifibrinolytic agents are widely used in cardiac surgery [53–55].

ANH group (n = 1252) fewer allogeneic RBC transfusions (MD -0.79; 95% CI, -1.25 to -0.34; P = < 0.001)
Tranexamic acid (TXa), an antifibrinolytic agent, is a competitive in-
hibitor of plasminogen and inhibits its conversion to plasmin in the

and red blood cells by 40% (95% CI: 0.39–0.92, P0.02). No difference in mortality between groups
fibrinolytic system. It is necessary to find a balance between fibrinolysis
and coagulation or in other words between the positive effect of re-
ducing blood loss and against the negative effect of inducing throm-
bosis. A recent RCT by Myles et al. showed a significant reduction in
reoperation rate and the need for transfusions in the TXa group. Com-
restrictive group (OR 0.41; 95% CI, 0.37-0.47). No significant secondary outcomes

pared with placebo, a higher percentage of seizures were found in the

TXa group, but there was no higher risk of death or complications [53].
For this trial, a dose of 100 mg/kg TXa (initially) and 50 mg/kg (later)
was used without a different number of seizures between both doses
(see Table 3). The doses used in daily practice are lower and never-

0.642 and 0.613 respectively) CAGB (65%) value surgery (17%)

Cardiac surgical patients; Acute Normovolemic Hemodilution
theless several studies confirm their positive effect on reduction of
blood transfusions (see Table 3) [56]. TXa might reduce transfusions
and reoperations and based on literature it is recommended to use it at
a low dose (15 mg/kg) in cardiac surgery.
Cardiac surgical patients with cell saver support
Cardiac surgical patients-high risk bleeding
1.02; p = 0.060) for cardiac surgical trials.

4.4.2. Fresh frozen plasma versus prothrombin complex concentrates

Non-emergency cardiac surgical patients
Summary of relevant studies of PBM in cardiac surgery reporting red blood cell transfusion (RBC) thresholds, salvage and hemodilution.

In recent years there is a gaining interest in factor concentrates for

the treatment of coagulation disorders and bleeding in the periopera-
95% CI, 1.00 to 2.67; P = 0.045).

(p = 0.034, 0.049, respectively)

tive setting during cardiac surgery. Factor concentrates can be divided

into active versus non-active or in single (recombinant activated factor
Cardiac surgical patients

Cardiac surgical patients

Cardiac surgical patients

VII, Fibrinogen) or multiple coagulation factors (PCC). Prothrombin

complex concentrate (PCC) is virus-inactivated human plasma and
contains four vitamin K-dependent coagulation factors (II,VII,IX, X).
Fresh frozen plasma (FFP) obtained from whole donor blood, contains
Results (%)

all of the labile and stable humoral components of the blood clotting,
fibrinolysis and complement system, as well as all immunoglobulins
and albumin needed to maintain colloid-osmotic pressure. FFP is
sometimes used in cardiac surgery to reduce (therapeutic) and prevent
N = 2007

N = 5243

N = 2282
N=3352

N=2439
29 RCTs
N = 110

N = 395
6 RCT’s

(prophylaxis) bleeding. A Cochrane systematic review concluded that

there was no evidence for the use of FFP for preventive purposes to
N

reduce blood loss (< 24 h) and reduce 30 days mortality [57]. These
findings are confirmed by Yang et al. [58,59]. If used prophylactically,
Multicenter, parallel group TITRe2

FFP can reduce the effect of oral anticoagulation, but for ther-
Systematic review and meta-

apeutically indications prothrombin complex concentrates (PCC) ap-

pears to be more effective (see Table 3) [58,59].
Multicenter, Open label,

A recent meta-analysis reported a reduced all-cause mortality, a

Systematic review

better INR correction or higher rate of INR normalization, no significant

Prospective RCT

difference of thromboembolic complications and a decrease of post-

Meta-analysis

Retrospective

transfusion overload with the use of PCC compared to FFP(see Table 3)

TRICS III

analysis

[60]. Part of this meta-analysis were 2 RCTs that included cardiac

Type

RCT
trial

surgical patients and reported both that PCC effectively reverses an-
ticoagulation [59,61]. Tang et al. confirmed recently in a prospective
Al-Khabori et al. 2015 [76]

trial that factor concentrates are more effective in treatment of coagu-

Murphy et al. 2015 [40]

Wang et al. 2009 [43]

lopathy [62]. Also Fariborz Farsad et al. confirmed (in a small number
Patel et al. 2015 [34]

Mazer et al. 2017 [1]

Shen et al. 2016 [44]

Barile et al. 2017 [5]

of patients) that PCC is safe and effective in patients with mechanical

heart valves and recommended PCC for rapid and effective correction of
Author + Year

Warfarin [61]. Retrospective cohort studies showed an association with

a reduction of postoperative bleeding after CPB and major cardiac
surgery, when using PCC compared with FFP [63,64]. In addition, a
decrease was seen from RBC transfusion requirements in cardiac sur-
RBC Transfusion Threshold

gery setting [65]. Despite heterogeneity of all included studies with

Transfusion Threshold

Transfusion Threshold

regards to study design, population and reversal protocols, recent

guidelines recommend that PCC administration should be used in car-
diac surgery patients for the correction of coagulation factors. [10].
Hemodilution
Cell salvage

Cell salvage

Cell salvage

4.4.3. Fibrinogen
Subject
Table 2

Fibrinogen is a pharmaceutically separated coagulation factor.

RBC

RBC

Recent studies found a link between low fibrinogen level and bleeding

7
 L.E. Terwindt, et al.

Table 3
Summary of relevant studies of PBM in cardiac surgery reporting optimize coagulation and Individualized and goal-directed coagulation therapy with point of care tests.
Subject Author Year Type N Results (%)

POCT Deppe et al. 2016 [50] Meta- analysis 9 RCTs Cardiac surgical patients
8 OS POCT guided transfusion management decreased odds for patients to receive blood products (OR 0.63, 95% CI 0.56-0.71;
N = 8332 P < 0.00001) and re-exploration rate due to postoperative bleeding (OR 0.56, 95% CI 0.45-0.71; P < 0.00001).
No statistical differences in mortality, CVA, length of stay
POCT Wikkelso et al. 2016 [52] Cochrane systematic review 17 RCTs N = 1493 The majority of included participants undergoing cardiac surgery
Compared with transfusion by any method, ROTEM/TEG reduce overall mortality (7.4% versus 3.9%; risk ratio (RR) 0.52,
95% CI 0.28 to 0.95).
TXa Myles et al. 2017 [54] RCT N = 4662 Cardiac surgical patients
Major hemorrhage leading to reoperation was lower in TXa group (1.4% TXa vs 2.8% placebo(P = 0.001)).Dose of TXa
(100 mg/kg and 50 mg/kg).
Risk of death or thrombotic complications (< 30 days after surgery) of 16.7% in TXa group vs 18.1% placebo group (RR 0.92;
95% CI 0.81-1.05;p = 0.22
TXa was associated with a higher risk of postoperative seizures (0.7% TXa vs 0.1% placebo (P = 0.002))
TXa Ker et al. SR and cumulative meta- 129 RCTs Surgical patients
2012 [56] analysis N = 10488 Tranexamic acid reduced the probability of receiving a blood transfusion by a third (risk ratio 0.62, 95% confidence interval
0.58 to 0.65; P < 0.001).
FFP Desborough et al. 2015 [58] Cochrane N = 75515 Cardiac surgical patients
Transfusion Systematic review Prophylactic vs no FFP (14 trials). Administration in patients without coagulopathy. No difference in blood loss or transfusion
(adults n = 120) MD-12.0 ml(95% CI -101.16 to 77.16 ml). No difference reporting 30 days mortality (low evidence) No

8
evidence to support prophylactic administration of FFP without coagulopathy
FFP Yang et al. 2012 [59] Systematic review 21 RCTs All surgical patients
Transfusion N = 36 No consistent evidence of benefits of FFP
1 RCT Cardiac adult surgical patients
No difference in bleeding and coagulation test between FFP and control group
FFP Demeyere et al. 2010 [60] Randomized study N = 40 Non-emergency cardiac surgical patients
Transfusion 2 units of FFP vs (1/2 of calculated dose) prothrombin complex concentrates (PPC). INR target ≤ 1.5
Blood loss through chest tube drainage in PPC group was 439.3 ml ( ± 247.3) vs 471.7 ml ( ± 294.4) in FFP group.
PCC reverses anticoagulation safely, faster and more effectively than FFP.
PCC Chai-Adisaksopha et al. 2016 Meta- analysis 5 RCTs Type of bleeding: intracranial surgery 2 RCTs, cardiac; 3 RCT’s
[61] 8 OS PCC use was associated with a significant reduction in all-cause mortality compared to FFP (OR = 0.56, 95 % CI; 0.37–0.84,
p = 0.006) and resulted in a shorter time to INR correction (mean difference –6.50 hours, 95 %CI; –9.75 to –3.24). Patients
receiving PCC had a lower risk of post-transfusion volume overload compared to FFP (OR 0.27, 95 % CI;0.13–0.58).
PCC Fariborz Farsad et al. 2015 RCT N = 50 Cardiac surgical patients;mechanical heart valves
[62] PCC reverses anticoagulation effectively and safely. 76% of PCC versus 20 % of FFP group reached the INR target.
Protamine Meesters et al. 2016 [77] multicentre, single-blinded, N = 96 Cardiac surgical patients
RCT The low protamine group (0.8) received less protamine (329 ± 95 vs 539 ± 117 mg; p < 0.001) versus high protamine
group (1.3), while post-protamine activated clotting times were similar among groups.
Postoperative blood loss was increased in the high dosing ratio group (615 ml; 95 % CI 500-830 ml vs 470 ml; 95 % CI 420-
530 ml; p = 0.021) when compared to the low dosing group
Platelet transfusions Spiess et al. 2004 [75] Retrospective analysis on RCT N=1720 CABG cardiac surgical patients
data 6 RCT’s < 30 day mortality (7.7%-1.4%, P = 0.003), stroke incidence(4.2%-1.3% P = 0.003) and mean thoracic drainage(cc)
1 pilot study (820+-22 vs 329+-13, P < 0.0001) were all significantly higher in platelet transfused patients compared to non-platelet
transfused patients.
Myocardial infarction (8.1% vs 4.1%) was not significantly different between groups.
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
L.E. Terwindt, et al.
Fig. 2. Overview of the three-pillars of patient blood management with the
most relevant key points of this narrative review. Based on the work of Hofman
A et al. (2012) and Isbister J.P. et al. (2013).
complications. Fibrinogen levels lower than 1.5 g/l are associated with
an increased percentage of postoperative bleeding. Therefore, an op-
timal strategy concerning the use and the necessary level of fibrinogen
is important [66]. Administration of low dose fibrinogen peri-opera-
tively in cardiac surgery seems not to be associated with an increase in
thromboembolic complications [67]. However, the ideal dosage of fi-
brinogen and the optimal target value in the context of blood loss re-
duction is still discussed in literature [66,68,69]. Fibrinogen can play
an important role in therapeutically optimization of coagulation but
should not be given as a standard prophylaxis.
4.4.4. Recombinant factor VIIa
Recombinant factor VIIa (rFVIIa) has been used clinically for the
treatment of hemophilia, for factor VII deficiency and in patient at risk
of major or uncontrolled bleeding (off label use) [70]. Data from a
Cochrane review, based on thirteen trials demonstrated no difference in
mortality, bleeding control or transfusion requirements in a therapeutic
setting compared to placebo [70]. However, a statistically significant
increase of arterial thrombotic events was observed (RR 1.45; 95% CI
1.02–2.05) [70,10]. There is no evidence for standard use of rFVIIa in
cardiac surgery and a lack of qualitative studies [70]. Therefore, the
recommendation is restricted on a POCT guided individual basis in case
of an ongoing uncontrolled blood loss without other therapeutic op-
tions.
4.4.5. Protamine
Before starting CPB, Heparin is administered to prevent hemostatic
activation and thrombosis. The level of anticoagulation of heparin is
monitored using activated clotting time (ACT). The CPB circuit can
induce fibrinolysis with risk of bleeding but also a massive activation of
coagulation with the risk of consumptive coagulopathy, thrombi for-
mation and (micro) infarction.
Protamine is used to antagonize the heparin effect by means of an
electrostatic binding. Protamine has different hemostatic effects e.g.
inhibition of coagulation (reducing of thrombin generation, clotting
activity of factor VIII, factor V and VII) and platelet function, and en-
hanced fibrinolysis [71]. Overdosing might be associated with an in-
creased need of transfusion and impaired function of coagulation.
Protamine is administered in a 0.8 to 1:1 ratio in relation to heparin. In
a retrospective case-control study, patient-directed protamine dosing
using a PK model was associated with a reduction in protamine dosing
and better hemostatic results compared to a fixed ratio [72]. A multi-
center single-blinded randomized controlled trial of Meesters et al.
found a relation between an increased postoperative blood loss and
higher transfusion rates in case of an overdose of protamine (see
Table 3) [73]. Patients were randomized into a low (0.8) or high (1.3)
protamine to heparin dose group. Based on low levels of evidence,
current guidelines recommend a 1:1 dose ratio correction of protamine
with a trend to 0.8:1 dose ratio [10,71].
9
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
4.4.6. Platelet transfusion
Platelet transfusion are administered either prophylactically to re-
duce the risk of bleeding or therapeutically to control active bleeding.
In cardiac surgery, most indications for platelet transfusions are
bleeding in the presence of TARs induced by thrombocytopathy.
Platelet function is affected by ASA and P2Y12 inhibitors. ASA binds
platelets irreversibly and causes dysfunction for the rest of a platelets
life span (8–10 days), this can be restored by platelet transfusion.
P2Y12 inhibitors have a longer half-life in blood plasma (T1/2 of tica-
grelor = 7–8.5 hours), which continuously effects aggregating func-
tions of platelets (also transfused). It is important to be aware of the
specific half life time and the active metabolites of P2Y12 inhibitors,
which effect platelets. Spiess et al. retrospectively analyzed the use of
platelet transfusions from data received of 6 RCT’s that primarily
looked at protamine dosing in CABG patients [74]. Overall results
showed that platelet transfusion was correlated to several adverse
outcome parameters (see Table 3). However, since many patients re-
ceived platelet transfusion and also FFP’s and PBC’s transfusion the real
cause remains unclear. Randomized trials are lacking to determine
when it is beneficial to transfuse platelets in cardiac surgery patients.
Current transfusion guidelines apply platelet transfusion triggers of <
50 × 109/L in bleeding cardiac surgery patients which are based on
expert level evidence.
Key points for intraoperative transfusion management and hemostasis (see
Fig. 2).
• A restrictive RBC transfusion policy is non-inferiory compared to a liberal
transfusion policy in cardiac surgery patients.
• The use of cell saver peri-operatively is recommended.
• Large cell saver blood volumes transfused are associated with coagulation disorders.
• Intraoperative hemodilution should only be used on an individually basis in
patients with a high Hb preoperatively.
• Coagulation therapy should be individualized and goal-directed by using a POCT
guided algorithm.
• Low dose TXa reduces transfusions and reoperations.
• Prothrombin complex concentrates and not FFP should be used to correct the effect
of oral anticoagulation.
•
Fibrinogen administration results in optimizing coagulation but should not be given
as a standard prophylaxis.
• Protamine should be used in a ratio of 1:1 (protamine: heparin) with a trend to
0.8:1.0
• There is no evidence for standard use of rFVIIa in cardiac surgery, only in
uncontrolled bleeding with no therapeutic options it may be considered.
5. Future directions and conclusion
Further directions in PBM in cardiac surgery patients should include
improved identification of high-risk patients by using big data. This
should lead to intervention trials including only patients with a high
risk of peri-operative bleeding resulting in trials with an increased
power. Furthermore, novel interventions to optimize coagulation are
essential in an era where more and more patients are on intensive an-
ticoagulant therapy prior surgery. A future application of new methods
to correct per-operative anticoagulant effects such as removal of ADP
receptor antagonists out of the systemic circulation while on the CPB
might be one of the directions. Finally, improvement and/or mod-
ification of conventional blood products such as cold stored platelets in
bleeding cardiac surgery patients will be topics of interest.
PBM is essential in cardiac surgery and is an ongoing process.
Implementation of PBM in cardiac surgery requires a skilled project
manager, tools for PBM workflow, a hemostasis algorithm based on
ROTEM, a strong clinical multidisciplinary leader and a permanent
clinical project leader.
Appendix A
("Cardiac Surgical Procedures"[Mesh] OR "Thoracic Surgery"[Mesh]
OR cardiac surger*[tiab]) AND (blood management[tiab] OR bleeding
L.E. Terwindt, et al.
management[tiab] OR "Blood Transfusion"[Mesh] OR blood transfusion
[tiab]) AND (therapy/narrow[filter] OR systematic[sb] OR guide-
line*[tiab])
AND ("2008"[Date - Publication]: "3000"[Date - Publication]).
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