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The Year in Coagulation: Selected Highlights from 2020

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 ARTICLE IN PRESS
Journal of Cardiothoracic and Vascular Anesthesia 000 (2021) 113

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Special Article
The Year in Coagulation: Selected Highlights from
2020
Prakash A. Patel, MD, FASE*, , Reney A. Henderson JrMDy,
1

Daniel Bolliger, MDz, Gabor Erdoes, MD, PhDx,

Michael A. Mazzeffi, MD, MPH, MScy,{
*
Department of Anesthesiology, Cardiothoracic Division, Yale University School of Medicine, New Haven, CT
y
Department of Anesthesiology, Division of Cardiothoracic Anesthesia, University of Maryland School of
Medicine, Baltimore, MD
z
Department of Anesthesiology, Prehospital Emergency Medicine and Pain Therapy, University Hospital
Basel, Basel, Switzerland
x
Department of Anesthesiology and Pain Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland
{
Department of Anesthesiology, Division of Critical Care Medicine, University of Maryland School of Medi-
cine, Baltimore, MD

This is the second annual review in the Journal of Cardiothoracic and Vascular Anesthesia to cover highlights in coagulation for cardiac surgery.
The goal of this article is to provide readers with a focused summary from the literature of the prior year’s most important coagulation topics. In
2020, this included a discussion covering allogeneic transfusion, antiplatelet and anticoagulant therapy, factor concentrates, coagulation testing,
mechanical circulatory support, and the effects of coronavirus disease 2019.
Ó 2021 Elsevier Inc. All rights reserved.

Key Words: coagulation; transfusion; antiplatelet; anticoagulants; factor concentrates; viscoelastic testing; extracorporeal membrane oxygenation; ECMO; coro-
navirus disease 2019; COVID-19

The Year in Coagulation: Selected Highlights from 2020
THE AIM of this article is to provide a focused review of
the literature on the most relevant topics in coagulation as they
apply to cardiothoracic anesthesiology and surgery. The
authors thank the Journal leadership for the opportunity to
continue this series of annual highlights in coagulation.1 In
this second annual review, highlights from 2020 included the
effect of allogeneic blood transfusion on patient outcomes;
updates on the management of antiplatelet and anticoagulant
therapy; the expanding use of factor concentrates; the contin-
ued role for viscoelastic testing (VET), bleeding and
1 namically unstable patients, actively bleeding patients, or
Address correspondence to Prakash A. Patel, MD, FASE, Department of
Anesthesiology, Yale University School of Medicine, 333 Cedar St, PO Box
208051, New Haven, CT 06520-8051.
E-mail address: Prakash.Patel@yale.edu (P.A. Patel).
thrombosis in mechanical circulatory support; and the effects
of coronavirus disease 2019 (COVID-19).
Effect of Blood Transfusions on Clinical Outcomes
There are several indications for the transfusion of blood
products in cardiac surgery, including but not limited to vol-
ume resuscitation as a result of blood loss and for the manage-
ment of coagulopathy. The benefits and risks of allogeneic
blood component therapy have been extensively investigated
over the years, with greater emphasis currently being placed
on the associated risks. Even though the argument for the use
of red blood cell (RBC) transfusion can be made in hemody-
symptomatic patients, the majority of transfusions do not occur
in these settings. Rather, they often are given to patients whose
condition is stable and often given “prophylactically.”2 With

https://doi.org/10.1053/j.jvca.2021.02.057
1053-0770/Ó 2021 Elsevier Inc. All rights reserved.
 ARTICLE IN PRESS
2 P.A. Patel et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2021) 113
the risks of transfusion, such as hemolytic transfusion reac-
tions, acute lung injury, and circulatory overload, it is not sur-
prising that methods to limit unnecessary transfusion continue
to be explored.3 Multiple studies have compared the use of lib-
eral versus restrictive transfusion strategies, with a greater
focus on the effect of transfusion on clinical outcomes.4,5 This
focus on patient outcomes again was observed in 2020, with
several analyses not only looking at RBC transfusion, but also
the effect of plasma and platelet transfusion in the cardiac sur-
gery population. This becomes a critical topic given the role of
these blood component therapies in coagulation management.
The negative effect of exposure to allogeneic RBC transfu-
sion during cardiac surgery has been well-described. The
incremental risk of adverse outcomes with each RBC unit
includes a greater risk of mortality.6-8 The effect that fresh fro-
zen plasma (FFP) and platelet transfusion may have on clinical
outcomes has been investigated previously, but their direct
role on outcomes often was confounded by cotransfusion of
RBCs.9 During 2020, cardiac anesthesiologists gained a better
understanding of the outcomes associated with FFP or platelet
transfusion. In a large retrospective review (n = 8,238 patients)
at two cardiac surgery centers, mortality was observed in 1.3%
of patients.9 Transfusion of any blood component therapy
(RBC, FFP, and/or platelets) was associated with a higher rate
of mortality (2.0% v 0.18%; p < 0.01). Using propensity
score-matched pairs, the authors further analyzed the risks
when looking individually at each of the three blood compo-
nent therapies. Again, they reported an increased risk of mor-
tality with each transfused unit of RBCs (odds ratio [OR] 1.18,
95% confidence interval [CI] 1.14-1.22), FFP (OR 1.24, 95%
CI 1.18-1.30), or platelets (OR 1.12, 95% CI 1.07-1.18). The
same investigation also found an independent association
between the transfusion of RBCs, FFP, or platelets (>2 U) and
postoperative infection after cardiac surgery.9 Interestingly, a
smaller analysis of 197 patients from a single-center study also
looked at the relationship between blood transfusion in cardiac
surgery and postoperative infection.10 Infection included pneu-
monia, sepsis, colitis, mediastinitis, deep surgical site infec-
tion, myocarditis, pericarditis, and endocarditis. The results
demonstrated no difference in rates of infection (p = 0.902) for
those who did and did not receive blood transfusions, which
included RBCs, FFP, and/or platelets. The authors suggested
that transfusion should not be withheld based on a concern for
infection.10 Although the authors acknowledged the small
sample size of their study, a major concern with their analysis
was the high rate of transfusion in general (93.4% of patients
transfused), which made for a small number of control patients
(no transfusion).
A retrospective study on the association of blood product
transfusion and postoperative acute kidney injury (AKI) also
was conducted in 2020. Again, RBC transfusion as a risk fac-
tor for AKI after cardiac surgery has been more widely
accepted, but the association between FFP and platelets
remains less clear.11 In an analysis of 1,960 patients undergo-
ing cardiac surgery with cardiopulmonary bypass (CPB),
transfusion data were collected intraoperatively and until the
first postoperative day.12 With an AKI incidence of 27.7%, the
authors found that transfusion of RBCs, FFP, and platelets all
were independently associated with Kidney Disease: Improv-
ing Global Outcomes stages 2 and 3. However, when adjusting
for AKI risk factors and the use of complementary products
(confounding effect), only RBC administration was associated
with the development of AKI.12
To further investigate the effect of intraoperative plasma
transfusion on outcomes in cardiac surgery, a single-center,
retrospective study examined the influence of plasma volume
on postoperative parameters such as need for additional trans-
fusion, redo surgery for bleeding, and intensive care unit
(ICU) and hospital lengths of stay.13 In the 1,794 patients
included, an international normalized ratio (INR) was mea-
sured before plasma transfusion and was required to be >1.1
to be included in the analysis. The results suggested that intra-
operative plasma dose (per unit) was associated with multiple
negative outcomes. For each additional unit of plasma, there
was an association with an increased odds of RBC transfusion
in the first 24 hours after surgery (OR 1.12, 95% CI 1.04-1.20)
and a decrease in hospital-free days (p = 0.04). In addition,
higher pre-transfusion INR values were associated with an
increased OR for RBC transfusion and redo surgery and with
fewer ICU- and hospital-free days. For a given plasma volume,
patients in whom a greater correction in the pre-INR-to-post-
INR value was achieved were noted to have more favorable
outcomes. Interestingly, changes in pre-transfusion and post-
transfusion R-times, as measured by thromboelastography
(TEG) (Haemonetics, Boston, MA), were not significantly
associated with these outcomes. The authors concluded that
higher plasma transfusion volumes can lead to worse clinical
outcomes in this patient population, but additional studies are
needed to determine optimal transfusion volumes.13
The association of platelet transfusion on outcomes after
cardiac surgery also remains unclear.14 As previously men-
tioned, there is a recent concern for mortality and postopera-
tive infection.9 To examine the effect of platelet transfusion in
a large-scale fashion, Yanagawa et al. performed a systematic
review and meta-analysis that included nine observational
studies and more than 100,000 patients.15 When comparing
patients who received platelet transfusions with those who did
not, those who received platelets were older and had more
comorbidities. They also were more likely to have more com-
plex and nonelective surgery and were more likely to be on
preoperative clopidogrel. When comparing the two groups
without adjusting for these differences in baseline characteris-
tics, the authors reported that perioperative morbidity was
greater in the group that received platelet transfusions. How-
ever, when analyzing only matched/adjusted data, there were
no significant differences between those who did and did not
receive platelets. There was no increased risk in mortality (risk
ratio [RR] 1.26, 95% CI 0.69-2.32), stroke (RR 0.94, 95% CI
0.62-1.45), myocardial infarction (RR 1.29, 95% CI 0.95-
1.77), redo surgery for bleeding (RR 1.20, 95% CI 0.46-3.18),
infection (RR 1.02, 95% CI 0.86-1.20), and dialysis (RR 0.91,
95% CI 0.63-1.32).15 Although the authors concluded that
administering platelets in cardiac surgery may not be unrea-
sonable for patients with thrombocytopenia or presumed
 ARTICLE IN PRESS
P.A. Patel et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2021) 113
platelet dysfunction, they acknowledged that their findings
should be hypothesis-generating and should be confirmed with
ongoing investigation. Future studies should aim to include the
number of platelet units being given to determine whether
there is a dose-dependent association with outcomes, and an
examination of the indications for platelet transfusion.
Although results vary regarding the effect of allogeneic
blood transfusion on outcomes after cardiac surgery, it is well-
accepted that transfusion does carry some inherent risks.
Regardless of the association with mortality, AKI, infection,
or redo surgery, efforts to reduce unnecessary blood product
use continue. The emphasis on the use of transfusion algo-
rithms and point-of-care testing to help guide treatment contin-
ued during 2020.16 Similarly, prediction models to identify
patients at risk for transfusion are gaining interest, as was dem-
onstrated in the recently released Australian Cardiac Surgery
Platelet Transfusion risk tool.17 Finally, the implementation of
patient blood management (PBM) guidelines also has resulted
in a measurable reduction in blood transfusion, including
RBCs, FFP, and platelets, with an associated reduction in hos-
pital stay.18 In the upcoming year, it is expected that ongoing
investigation into plasma and platelet transfusion, with an
emphasis on clinical outcomes, will continue to provide more
conclusive results.
Antiplatelet and Anticoagulant Therapy
Antiplatelet Therapy in Cerebrovascular and Coronary
Disease
Dual-antiplatelet therapy (DAPT), including aspirin and
P2Y12 receptor inhibitors, can reduce the risk of platelet-medi-
ated thrombosis in not only coronary but also cerebral and
peripheral vascular diseases. However, DAPT with potent
P2Y12 receptor inhibitors, such as prasugrel and ticagrelor,
also might be associated with increased risk of major and even
fatal bleeding. The balance between ischemic benefit and
bleeding risk remains a clinical challenge. Conclusive evi-
dence is limited because of various definitions of ischemic
benefit and relevant bleeding events.19,20 Potentially, individ-
ual endpoint definitions might specifically change the interpre-
tation of the findings and hamper the comparison among
different studies. Accordingly, the use of DAPT, including
aspirin and ticagrelor, was associated with a mortality benefit
in the large Platelet Inhibition and Patient Outcomes (PLATO)
trial,21 but follow-up studies could not prove such a mortality
benefit.19 In contrast, a recent large, retrospective analysis,
including more than 62,500 propensity-matched patients with
acute coronary syndrome who underwent percutaneous coro-
nary intervention (PCI), compared the use of ticagrelor with
clopidogrel. In that analysis, net clinical adverse events,
defined as recurrent myocardial infarction, revascularization,
ischemic stroke, hemorrhagic stroke, and gastrointestinal
bleeding at 12 months in patients treated with ticagrelor, was
questioned.22 Importantly, the endpoints in the study by You
et al. were not totally comparable with those of the PLATO
3
study,21 with the prior resulting in variable benefits with inten-
sified antiplatelet therapy including ticagrelor.
In another recent randomized controlled trial (RCT) includ-
ing more than 11,000 patients with acute non-cardioembolic
ischemic stroke, the combined therapy of ticagrelor and aspirin
was advantageous in respect to recurrent stroke within 30 days
compared with therapy with aspirin alone.23 However, bleed-
ing events were significantly more frequent in the group with
ticagrelor and aspirin. Again, this study might question the net
clinical benefit of intensified antiplatelet therapy.
Interestingly, a recent case series published in the Journal of
Cardiothoracic and Vascular Anesthesia suggested the use of
bridging therapy with cangrelor as an alternative to longer-act-
ing systemic antithrombotic therapy in patients who undergo
endovascular aortic repair with lumbar drain placement.24
Despite no bleeding or neurologic complications reported, the
supposed procedure certainly needs further evaluation regard-
ing efficacy and safety of bridging therapy shortly after endo-
vascular procedures with lumbar drain placement. Bleeding
events might be rare but catastrophic.
In summary, more potent platelet inhibitors regularly reduce
the risk of ischemic thromboembolic adverse events, but they
commonly are associated with increased bleeding risk.
Although it might be questionable to combine safety and effi-
cacy endpoints in antithrombotic trials because of the previ-
ously described challenges in definition and variable severity
of events,20 the net clinical effects are important for the
patient, and physicians should include the patient-specific
thrombotic and bleeding risk in decision-making.
Combined Antiplatelet and Anticoagulant Therapy
Concurrent indications for multiple antithrombotic therapies
are a common clinical scenario. It is estimated that atrial fibril-
lation (AF) occurs in about one-fourth of all individuals during
their lifespan. Because of multiple shared risk factors, one-
fourth-to-one-third of these patients also have coronary artery
disease.25-29 Oral anticoagulation is advantageous in situations
of low shear stress conditions for clot formation, such as in the
left atrial appendage during AF, and antiplatelet therapy is
mandatory for prevention of thrombotic complications after
PCI. Each drug helps to reduce thrombotic complications in
the specific setting, but their combined use might be indicated
in certain situations, as previously described. However, com-
bined anticoagulant and antiplatelet therapy significantly
increases the risk of major bleeding events, which can be life-
or organ-threating.27 The recent American College of Cardiol-
ogy (ACC) “Expert Consensus Decision Pathway” tried to pro-
vide “actionable knowledge” regarding clinical decision-
making and treatment plans in patients with an indication for
both anticoagulation and antiplatelet therapy, rather than a sin-
gle correct answer for all patients and each situation.27 In order
to choose the ideal antithrombotic drug in the optimal dosage
or a combined therapy, the individual patient’s thrombotic and
bleeding risk must be evaluated using established scores
including CHA2DS2-VASc or HAS-BLED.29 Recent evidence
suggests that direct oral anticoagulant (DOAC) therapy might
 ARTICLE IN PRESS
4 P.A. Patel et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2021) 113
be preferred over vitamin K antagonists (VKA) when a com-
bined therapy with antiplatelet drugs is required. Furthermore,
clopidogrel might be the preferred P2Y12 inhibitor after PCI
when combined anticoagulant and antiplatelet therapy is
required. In addition, the overall duration of combined therapy
should be kept as short as possible, and additional measures,
such as the use of proton pump inhibitors or non-pharmaco-
logic alternatives, such as closure devices, for the left atrial
appendage must be evaluated.25-28
Anticoagulant and Antiplatelet Therapy After Transcatheter
Aortic Valve Replacement
Patients undergoing transcatheter aortic valve replacement
(TAVR) are another group with potential for combined antith-
rombotic therapy (either as a combination of oral anticoagu-
lants and P2Y12 receptor antagonists or as DAPT). Two recent
European randomized multicenter studies investigated the role
of anticoagulation and antiplatelet therapy in patients undergo-
ing TAVR. Nijenhuis et al. randomly assigned 313 patients
undergoing TAVR, who were receiving long-term oral antico-
agulation for an appropriate indication, to receive either clopi-
dogrel or not receive the drug for three months after valve
implantation.30 Bleeding events, most of them within the first
month after intervention, were more common in the group that
received oral anticoagulants plus clopidogrel than in patients
on oral anticoagulants alone (34.6% v 21.7%; p = 0.01). In
contrast, thromboembolic events, including stroke and myo-
cardial infarction, were similar in both groups. The group with
oral anticoagulation alone therefore showed a net clinical ben-
efit compared with the combined therapy including clopidog-
rel.30 Of note, that study also included patients receiving either
VKA (73% of patients) or a DOAC (23%). The use of a
DOAC rather than VKA might be associated with fewer bleed-
ing events27; however, that trial was not powered to assess dif-
ferences between patients on VKA or DOAC.
The same group of investigators also studied patients without
an indication for long-term oral anticoagulation. In 665 patients
undergoing TAVR, the authors compared the clinical benefit of
combining aspirin with clopidogrel for three months after TAVR
compared with aspirin alone.31 Again, bleeding events occurred
more commonly in patients with aspirin plus clopidogrel than in
patients with aspirin alone (26.6% v 15.1%; p = 0.001). How-
ever, there was no difference between the groups in respect to
thromboembolic events at one year. Therefore, the therapy with
aspirin alone resulted in a net clinical benefit compared with
patients on DAPT with aspirin and clopidogrel.
In summary, these two RCTs suggested that antithrombotic
therapy after TAVR can be reduced safely to aspirin or oral
anticoagulants alone, compared with a combined antithrom-
botic therapy, to minimize the bleeding risk without increasing
the ischemic or thromboembolic risk.
Management of Bleeding Patients on DOAC Therapy
With a continuously aging population, the number of
patients with indications for anticoagulation is increasing.
Among these indications, AF is the most common indication.
Recent surveys show a steadily increasing use of DOACs in
patients with AF or venous thromboembolism.32 In parallel
with the increased use of oral anticoagulants, including use
beyond established and approved indications,33 acute bleeding
complications might occur. Whereas it commonly is recom-
mended to use prothrombin complex concentrates (PCCs) to
treat bleeding patients on a VKA,32 optimal therapeutic
options in bleeding patients treated with DOACs are less evi-
dent.34 Recently, the ACC updated its “Expert Consensus
Decision Pathway” regarding therapeutic approaches in bleed-
ing patients on oral anticoagulants. The use of specific reversal
agents was proposed as first-line therapy for life-threating
bleeding in patients on DOACs.35 Whereas the use of idaruci-
zumab for urgent/emergency before procedural reversal of
dabigatran has been studied and is rather well-established and
supported by the 2020 ACC “Expert Consensus Decision
Pathway,” the use of andexanet alfa for oral factor Xa inhibi-
tors is less clear for several reasons.35 First, it is not ubiqui-
tously available. Second, andexanet alfa is not selectively
specific for Xa antagonists and can interact with several
endogenous substances. Recently, heparin resistance has been
suspected with the administration of andexanet alfa in patients
undergoing emergency cardiovascular surgeries requiring
higher doses of heparin.36-38 Finally, andexanet alfa is very
expensive.29 In emergency cardiovascular procedures with
planned heparinization, the administration of andexanet alfa
potentially should be considered only after protamine adminis-
tration. Instead, PCC at a dose of about 2,000 U might be con-
sidered. The latter is also the second-choice treatment in
bleeding patients on factor Xa inhibitors when no specific
reversal is available.32,34,35
Antiplatelet and Anticoagulant Therapy in COVID-19
Severe acute respiratory syndrome coronavirus-2, the virus
that causes COVID-19, frequently is associated with hypercoa-
gulopathy. COVID-19 coagulopathy has some common fea-
tures with disseminated intravascular coagulation (DIC) or
pre-DIC secondary to an increased inflammatory state. In con-
trast to bacterial infectioninduced DIC, COVID-19 coagul-
opathy commonly is associated with relatively minimal
changes in thrombocyte count, antithrombin levels, or labora-
tory coagulation tests such as prothrombin time or activated
partial thromboplastin time (aPTT). Even though COVID-19
coagulopathy could involve microangiopathy, local thrombus
formation, large-vessel thrombosis, or pulmonary embolism,
the common lack of thrombocytopenia indicates that it is a
prothrombotic but not consumptive coagulopathy typical for
DIC.39,40 Often, these patients are treated with heparin agents.
However, the use of antiplatelet therapy also might be benefi-
cial. Although no clinical trials have shown protective or thera-
peutic effects of antiplatelet therapy in COVID-19 until now,
some studies have suggested improved patient outcomes with
aspirin.41,42 Despite the advantages of safety and low costs of
aspirin, randomized trials are necessary before the use of aspi-
rin in COVID-19 patients can be generally recommended. In
 ARTICLE IN PRESS
P.A. Patel et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2021) 113
the meantime, it seems advisable that hospitalized patients
with COVID-19 who are taking anticoagulant or antiplatelet
therapy should continue their treatment unless significant
bleeding develops or other contraindications interfere with
their administration.
Factor Concentrates in Cardiac Surgery
Modern hemostatic therapy in cardiac surgery optimally is
guided by point-of-care VET.16 When implemented in an insti-
tutional transfusion algorithm, VET allows for the identifica-
tion of the cause of coagulopathic bleeding and helps to guide
targeted treatment with factor concentrates. Unlike transfusion
of allogeneic blood products, the administration of recombi-
nant or purified factor concentrates has clear advantages,
among them immediate availability, low administration vol-
ume, and high degree of viral safety.43 During 2020, a number
of new articles addressed the topic of factor concentrates and
their use in cardiac surgery.
Diagnosis of Hypofibrinogenemia With VET
In a diagnostic test accuracy study with systematic literature
review,44 nine journal articles met the eligibility criteria of
reporting sensitivity and specificity of a point-of-care VET
device for the detection of hypofibrinogenemia in patients
undergoing cardiac surgery. Overall, the results indicated that
identification of hypofibrinogenemia with VET was associated
with a high false positive rate (30%-58%) and a low false neg-
ative rate (2%-26%) for detecting FIBTEM A10 <7.5-to-
8 mm compared with the gold standard of laboratory fibrino-
gen measurement. The authors of the diagnostic test accuracy
study supported the use of VET and acknowledged its impor-
tant role as a point-of-care test for hypofibrinogenemia in car-
diac surgery. The fast turn-around time and associated rapid
availability of results in the bleeding patient are reasons for
preferring the assay over standard laboratory fibrinogen test-
ing, which is associated with processing times of up to 45
minutes. Moreover, the low false negative rate and the high
negative predictive value (96%-98%) for FIBTEM >8 mm
support withholding the administration of fibrinogen concen-
trates when the FIBTEM amplitude is not decreased. In this
case, other causes of bleeding should be evaluated.
Prophylactic and Preoperative Administration of Fibrinogen
Concentrate
A normal plasma fibrinogen level (200-450 mg/dL) is a pre-
requisite for adequate perioperative hemostasis. Under severe
bleeding conditions, fibrinogen levels decrease rapidly, and
fibrinogen reaches, as the first coagulation factor, a critically
low plasma level. According to European guidelines, plasma
fibrinogen levels in a bleeding patient should be kept >150-to-
200 mg/dL, corresponding with a FIBTEM A10 of >8-to-
10 mm.43,45,46
The prophylactic administration of fibrinogen concentrate
appears to be an interesting option in this context. Followingup
5
on related publications in previous years,47,48 a 2020 study,
with a prospective, randomized, and double-blinded design,
investigated prophylactic fibrinogen administration in 58
patients undergoing elective high-risk cardiac surgery.49
Patients were given either fibrinogen concentrate or placebo
after weaning off CPB and protamine administration. The
study medication was administered independent of the clinical
assessment of bleeding and solely based on VET results. These
were obtained toward the end of CPB, and they were used to
calculate the dose of fibrinogen concentrate for a target FIB-
TEM maximum clot firmness (MCF) of >15 mm. The primary
outcome was the cumulative number of any blood products
given within the first 24 hours. Although VET parameters
were improved in the treatment group, the authors could not
demonstrate a significant difference in the primary and second-
ary outcomes. Because of limitations in the study design and
statistical analysis, it is advisable to interpret the results with
caution.
More information on the preoperative plasma fibrinogen
level and its association with bleeding and transfusion rate was
provided by two recent single-center, retrospective studies in
elective cardiac surgery patients.50,51 Both studies concluded
that high preoperative plasma fibrinogen levels represent a risk
factor for severe perioperative bleeding and increased transfu-
sion requirements. The correlation in this respect is U-shaped,
indicating that both a low level and a very high level (>580
mg/dL) of plasma fibrinogen promote bleeding. The latter can-
not yet be fully explained, but presumably is associated with
systemic inflammation, hyperfibrinolysis, and dysfibrinogene-
mia, with the appearance of alternate fibrinogen forms having
antithrombotic activity.
Effect of Cell Salvage on Postoperative Plasma Fibrinogen
Levels
Intraoperative cell salvage, when used as a PBM strategy, is
ubiquitous in cardiac surgery.45,52-54 In this respect, any mea-
sure to avoid exposure to allogeneic red blood cells clearly is
recommended and contributes to improved patient outcomes.
A recent ex vivo study investigated the effect of different
amounts of salvaged blood on postoperative coagulation, spe-
cifically on FIBTEM values in cardiac surgery.55 The authors
concluded that retransfusion of a high amount of salvaged
blood (corresponding to >18.5% of a patient’s blood volume)
may impair fibrinogen contribution to the clot, especially in
individuals with a low preoperative fibrinogen level. This also
may decrease FIBTEM MCF <8 mm and trigger administra-
tion of fibrinogen concentrate. A related editorial put the study
findings into perspective and pointed out limitations that had
not been discussed by the authors.56 In conclusion, intraopera-
tive cell salvage should not be abandoned because of the
changes in the coagulation profile that are taken for granted
after processing the patient’s blood. Rather, a better under-
standing of coagulation processes and close monitoring of
coagulation are necessary, especially in complex surgeries
with a high amount of volume turnover through the cell saver.
 ARTICLE IN PRESS
6 P.A. Patel et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2021) 113
Risk of Thromboembolic Events With Fibrinogen Concentrate
In a retrospective, single-center cohort study of more than
5,000 patients undergoing elective cardiac surgery, the inci-
dence of a composite endpoint of thromboembolic events and
death within one year after surgery was investigated.57 The
authors demonstrated that administration of fibrinogen did not
increase the incidence of the composite endpoint at 30 days
(occurrence 3.5%) or at one year (10.5%) after surgery. Con-
sistent with previous studies,17,18 this large-scale study con-
tributed knowledge of the safety of fibrinogen concentrate.58,59
In this regard, however, the following two points must be con-
sidered: (1) adjusting statistical analyses for perioperative vari-
ables, such as transfusion rate, is important because the authors
were able to identify excessive bleeding as a factor promoting
thromboembolic complications and (2) monitoring of throm-
boembolic events should be continued in the late postoperative
phase and afterwards. Thus, attention should be paid not only
to evident thromboembolic complications, such as venous
thromboembolism and ischemic stroke, but also to other possi-
bly associated clinical (eg, myocardial infarction) and subclin-
ical events.
Effectiveness of PCC
To investigate the effectiveness of PCC in the treatment of
bleeding, a case series involving nine patients and a systematic
review with meta-analysis of 17 observational studies were
published in 2020.60,61 In the case series, a fixed dose of up to
2,000 U (median 14 U/kg) of a four-factor PCC was used to
treat bleeding in complex cardiac surgery patients who refused
allogeneic blood transfusion. Acceptable hemostasis could be
achieved in the majority of patients receiving PCC. However,
other concentrates (factor VIIa, fibrinogen concentrate, antifi-
brinolytics) and blood conservation measures (intraoperative
cell salvage, retrograde autologous circuit priming) also were
used in the PCC group according to PBM recommendations.
Interestingly, three of nini patients developed thrombotic com-
plications (ischemic stroke or deep venous thrombosis) and
were investigated further with regard to risk factors. Unfortu-
nately, because of the small sample size, the combination of
PCC with other prothrombotic agents, the lack of a control
group, and the lack of a predefined transfusion protocol, the
validity of the results remains limited. In contrast, the afore-
mentioned systematic review could not demonstrate an
increase in thromboembolic events (p = 0.38, I2 = 0%) with
PCC usage, either in the overall population or in a subgroup of
cardiac surgery patients. Moreover, the authors demonstrated a
reduction in blood loss (p = 0.02, I2 = 86%), and especially in
cardiac surgery, a decreased need for red blood cell transfusion
by 2 U with PCC usage (p = 0.003, I2 =81%). A weakness of
that study was the inclusion of only observational studies with
considerable heterogeneity in the study population.
Another RCT compared the effectiveness and safety of PCC
(intervention arm, 15 U/kg) versus FFP (standard arm, 15 mL/
kg) in 50 adults who experienced bleeding within 24 hours
after cardiac surgery.62 Although the study was a pilot trial
aiming to determine the recruitment rate for an upcoming
larger trial, the results are valid and can be interpreted inde-
pendently because of the clear and comprehensible methodol-
ogy and study design. Similar to prior studies, the study did
not indicate an increase in thromboembolic complications
with PCC, and there wawere no differences in all-cause mor-
tality or stroke between the PCC and FFP groups. Likewise,
transfusion requirements were similar for the intervention and
the standard arms. At one hour, levels of fibrinogen; factors V,
VII, and XIII; alpha2-antiplasmin; and antithrombin signifi-
cantly were increased in the FFP group compared with base-
line but not in the PCC group. In contrast, the PCC group
demonstrated significant increases in factors II and X at the
same timepoint. At 24 hours, no differences in the clotting fac-
tors were detectable between the two groups.
The First European Consensus on PCC
Because of the large variability in dosing strategies and
associated lack of evidence, a systematic literature review was
needed to reach agreement among experts with regard to dos-
ing, efficacy, safety, and monitoring of PCC.32 The Writing
Committee agreed on an initial PCC bolus of 25 IU/kg for
massively bleeding cardiac or non-cardiac patients whose
coagulation is affected by the preoperative intake of VKA
therapy. In individuals at risk for thromboembolic events,
especially those undergoing cardiac surgery without prior
VKA therapy, an initial half-dose bolus with 12.5 IU/kg was
recommended to treat severe bleeding. It further was agreed
that 25 IU/kg PCC is suitable to reverse the effect of DOACs
when no other antidotes are available. Despite consensus on
additional areas (eg, monitoring of PCC effect and therapy
guided by tissue-factor-activated, factor VII-dependent, and
heparin insensitive assays), the experts emphasized the urgent
need for large international registries to improve current
knowledge of PCC.
Coagulation Testing in Cardiac Surgery
Clinical Effect of VET (Transfusion Algorithms)
The COVID-19 pandemic has had a major effect on health-
care systems around the world, causing more emphasis on
techniques to address shortages within the supply chain.
Global quarantines and closure of many blood donation cen-
ters, which typically support 80% of the national blood supply,
have forced hospitals to adapt to more stringent blood adminis-
tration guidelines and splitting of platelet units into two
doses.63 Approximately 40%-to-50% of cardiac surgical
patients will require a blood transfusion during their index hos-
pitalization, enhancing the spread of PBM efforts.64 VET has
become a mainstay in many institutional transfusion algo-
rithms for cardiac surgery, but there has been a paucity of evi-
dence of improved morbidity, mortality, and outcomes. The
meta-analysis by Serraino et al. on the routine use of VET
(rotational thromboelastometry [ROTEM; Instrumentation
Laboratory, Bedford, MA] and TEG) in cardiac surgery,
 ARTICLE IN PRESS
P.A. Patel et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2021) 113
showed no reductions in mortality (RR 0.55, 95% CI 0.28-
1.10), major bleeding, ventilation time, or hospital length of
stay.65 There were a reduced frequencies of RBC transfusion
(RR 0.88, 95% CI 0.79-0.97) and platelet transfusion (RR
0.78, 95% CI 0.66-0.93). These authors concluded that VET is
not useful in reducing mortality in cardiac surgery and that no
additional controlled trial should be performed. Recently, San-
tos et al. reevaluated the results of this meta-analysis with their
own systematic review and found significant reductions in the
risk of death (7.3% v 12.1%, RR 0.64, 95% CI 0.43-0.96;
p = 0.03) and risk of acute renal failure (10.5% v 17.6%, RR
0.53, 95% CI 0.34-0.83; p = 0.005) with the use of VET.66
There was a greater reduction in the risk of death in patients
who were coagulopathic or massively bleeding (14.8% v
26.8%, RR 0.58, 95% CI 0.32-1.07; p = 0.08). This finding
was non-significant, most likely secondary to its small sample
size. In similar opposition, a meta-analysis by Meco et al. of
VTE use compared seven studies encompassing 1,035 patients,
in which a transfusion algorithm with ROTEM or TEG was
used in 522 patients.67 Not only were there reductions in RBC
(OR 0.61, 95% CI 0.37-0.99; p = 0.04) and FFP (risk differ-
ence 0.22, 95% CI 0.37-0.99; p < 0.0001) transfusions, but
also a reduction in 12- and 24-hour chest tube drainage (mean
difference [MD] 178.7, 95% CI 308.9 to 48.4; p = 0.007
and MD 175.4, 95% CI 305.78 to 40.9; p = 0.01), respec-
tively. Reductions also were seen with redo surgery for bleed-
ing (OR 0.51, 95% CI 0.28-0.94; p = 0.03) and ICU length of
stay (OR 4.03, 95% CI 6.28 to 1.78; p = 0.005).67 Similar
to the meta-analysis by Serraino et al, a significant difference
in mortality was not found, nor was a reduction in platelet
transfusion. One main cause in variability in outcome meas-
ures could be secondary to the lack of standardized transfusion
algorithms across institutions. Therefore, randomized studies
are warranted to further clarify the true value of VET.
VET (Blood Conservation)
Additional components of PBM include blood conservation
techniques such as cell salvaging, acute normovolemic hemo-
dilution (ANH), and factor concentrate administration.68-70
Recently VET has been used to improve guidance on imple-
mentation and clarification of mechanistic advantages of these
techniques. Since 1996, it had been believed that large
amounts of cell saver transfusion could cause increased bleed-
ing and blood transfusion.71-73 Cell salvaging also has been
shown to reduce the risk of allogeneic blood transfusion by
33% in cardiac surgery.53 How much cell salvaging is too
much to require supplementation of non-RBC transfusions?
Adam et al. performed a prospective, observational study on
the effect of intraoperative cell salvaging in cardiac surgical
patients. Pre-processed (reservoir blood) and post-processed
(cell saver bag) autologous blood samples were gathered, and
coagulation factor levels were tested. All coagulation factor
levels were found to be reduced when comparing pre-proc-
essed versus post-processed autologous blood.74 Specifically
fibrinogen; antithrombin; von Willebrand factor (vWF); and
factors II, VII, X, and XII were measured. A greater than 50%
7
reduction was found in each factor, with the greatest reduction
of 93% in vWF activity.74 Autologous blood from cell saver
has been found to be devoid of a meaningful level of coagula-
tion factors, risking hemodilution with increased volume trans-
fused. The recent study by Son et al. was summarized earlier in
this review to demonstrate the effect of cell salvage on fibrino-
gen levels.55 Along with a reduction in the FIBTEM MCF
with a high volume of cell salvage, the authors also noted an
increase in the INTEM clotting time (CT)/HEPTEM CT ratio
from 1.07 (1.03-1.12) to 1.16 (1.11-1.20) (p
0.001) with
18.5% of salvaged blood added to postoperative samples. This
indicates the effect of residual heparin, similar to findings in
other studies regarding cell salvaged blood.56,75 Clinicians
should understand that although the effect of cell salvaged
blood may reduce transfusions, the greater volume used
increases the risk of heparin rebound and dilutional coagulop-
athy. Additional prospective studies are needed to add clinical
correlation to the replacement of 18.5% of blood volume with
cell salvaged blood and when factor replacement should be
considered.
ANH is another blood conservation technique in which the
clinical effect and volume needed for optimal effects are
unclear. A meta-analysis by Barile et al. showed a reduction of
12% in overall allogeneic transfusions in patients undergoing
cardiac surgery with a minimal volume of 650 mL of ANH.76
Other studies have suggested that a greater volume of ANH
results in increased reduction of RBC transfusion and non-
RBC transfusion.77,78 Recently Smith et al. performed a pro-
spective study to assess changes in coagulation after reinfusion
of ANH versus control patients. Eighty patients undergoing
cardiac surgery requiring CPB (40 ANH and 40 control) were
enrolled. A median of 890 mL (794-909 mL) of autologous
blood was removed from the ANH group and 0 mL from the
control group. Blood samples were drawn at the following 2
timepoints: (1) 5 minutes before protamine and (2) 30 minutes
after the first blood draw. Blood samples were analyzed for
fibrinogen, aPTT, hemoglobin, platelet count, and TEG (R-
time, maximum amplitude (MA), a-angle, and LY-30/60). A
statistical significance was found at timepoint 2 with increased
hemoglobin (11.3 [9.8-12.8] v 11.5 [10.5-12.5], 95% CI 0.1-
0.8; p = 0.024) and fibrinogen levels (236 mg/dL [199-283] v
221 mg/dL [167-275], 95% CI 1-26; p = 0.04) in the ANH
group after inverse probability treatment weighting and con-
trolling for the value of timepoint 1.79 The aPPT level (29.7
[24.8-34.6] v 27.7 [24.2-31.2], 95% CI 2.7 to 0; p = 0.044)
also was reduced in the ANH group at timepoint 2 when con-
trolling for timepoint 1. No significant difference was found
with evaluation of TEG measurements. Markers of hemostasis
were improved in the ANH group compared with the control
group, although not apparent on TEG. This could have been
secondary to short bypass times, unknown patient selection
process, and a low overall transfusion rate of approximately
8%. Henderson et al. recently performed a prospective, obser-
vational study using ROTEM to assess the ANH effect on
coagulation in cardiac surgical patients.80 Fifty patients were
enrolled (25 ANH and 25 control) with a median of 1,200 mL
(1,116-1,280) autologous blood removed from the ANH group
 ARTICLE IN PRESS
8 P.A. Patel et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2021) 113
and a median of 0 mL (0-328) from the control group. Blood
samples were drawn at the following 3 timepoints: T1, base-
line; T2, on CPB after aortic cross-clamp removal; and T3, 30
to 60 minutes after protamine administration. ROTEM param-
eters showed a significant shortening at T3 in EXTEM CT
(MD 11.4 s [21.4 to 1.4]; p = 0.3) and a significant per-
centage increase in EXTEM A10 (MD 7.8% [95% CI 1.1%-
14.5%]; p = 0.02) from T2 to T3 in the ANH group compared
with the control group.80 Other coagulation proteins were
tested without any significant variance. Clinically, there was a
decrease in the overall transfusion during the index hospitali-
zation by 44% in the ANH group. Only 9 U of allogeneic prod-
ucts were used in the ANH group versus 50 U in the control
group. In addition, increased hematocrit levels in the ANH
group at 24 hours and discharge were similar to those in other
studies.78,81 When calculating the amount of coagulation fac-
tors in the autologous blood bags, Henderson et al. found 2.5 g
(2.0-2.9) of fibrinogen and 2.6 (2.1-2.9) £ 1011 of platelets.
With 2.5 g of fibrinogen reinfused, the authors expected a
change in FIBTEM A10 parameters, which was not found to be
significant. This study concluded that ANH may improve
hemostasis, although the mechanism should be investigated
further.
Factor concentrateguided therapy is an evolving field in
cardiac anesthesia. VET has been studied as a guide to admin-
ister factor concentrate. Fibrinogen concentrate has been stud-
ied extensively recently on its effect on bleeding in cardiac
surgery.82 Fibrinogen is an integral component of stable clot
formation and is one of the first proteins lost in massive bleed-
ing or hemodilution. Guidelines have been created to use
ROTEM FIBTEM for fibrinogen administration because the
prophylactic use of fibrinogen concentrate has not improved
clinical outcomes.49,83 ROTEM FIBTEM MCF measurements
can be affected by hematocrit levels, although the correlation
is acceptable when compared with Clauss fibrinogen levels at
a hematocrit <25% (r = 0.88).84 The Quantra QPlus (Hemo-
Sonics, Charlottesville, VA) is a fully automated, cartridge-
based VET that uses sonorheometry (acoustic deformation) to
measure clot formation. Quantra QPlus, similar to ROTEM, is
able to isolate fibrinogen clot formation to assist fibrinogen
replacement algorithms. Recently, Naik et al. observed
patients undergoing cardiac and orthopedic surgery comparing
Quantra QPlus threshold values for fibrinogen contribution to
clot stiffness (FCS) and platelet contribution to clot stiffness
(PCS) to fibrinogen level and platelet count. FCS <1.9 corre-
lated with a fibrinogen level of <200 mg/dL with a sensitivity
of 87.9% and negative predictive value of 95.2%. PCS <14.1
correlated with a platelet count <100,000 with a sensitivity of
89.5% and negative predictive value of 98.5%.85 Using sug-
gested threshold values for FCS and PCS, Quantra QPlus could
be a reliable VET to guide fibrinogen and platelet replacement.
The clinical correlation is inconclusive warranting further
examination. Quantra QPlus also was affected by hematocrit;
low levels generated higher stiffness. ROTEM-guided transfu-
sion protocols in cardiac surgery have been shown to reduce
patient cost by approximately $5,000.86 When compared with
ROTEM measurements in cardiac and orthopedic surgery,
Quantra QPlus had a correlation of r >0.8 for INTEM, HEP-
TEM, EXTEM, and FIBTEM values.87 Zghaibe et al. com-
pared Quantra QPlus with TEG measurements and standard
laboratory tests in cardiac surgical patients.88 Using different
threshold values than those of Niak et al., Quantra QPlus had a
very high negative predictive values for PCS <13.5 (97.4%),
FCS <2 (89.6%), and CT >159 seconds (70.5%) compared
with PLT <100,000, MA <50 mm, and R-time >10 seconds,
respectively.88 With poor positive predicative values, Quantra
QPlus was not able to predict the need for blood transfusion.89
In order to conclude a benefit, additional studies are needed to
apply threshold values to clinical treatment.
New Tools in VET
Limitations in the use of VET include the requirement of
individually trained operators and the complexity of interpreta-
tion. This is a challenge for expanded implementation of VET.
TEG and ROTEM are the most commonly used VET devices,
and both have become automated, with models TEG 6s and
ROTEM sigma using a ready-to-use cartridge. Quantra QPlus
also uses an automated system and has a user-friendly, color-
coded display to aid in interpretation. R€ossler et al. developed
Visual Clot as an alternative way to interpret ROTEM meas-
urements by creating a real-time visual representation of
ROTEM results. Sixty physicians were enrolled and randomly
assigned into 12 Visual Clot or standard ROTEM scenarios.
The Visual Clot had a median of 100% (interquartile range 83-
100) versus 44% (interquartile range 25-50) (p < 0.001) in the
ROTEM standard in correct therapeutic decision.90 A mixed
regression model showed an OR of 22.1 (95% CI 13.4-36.5; p
< 0.001) for the correct decision with Visual Clot compared
with standard ROTEM. Visual Clot may be able to improve
interpretations of ROTEM, making it easy to use throughout
the hospital and operating room. The application of Visual
Clot was limited to artificially created ROTEMs versus real
clinical situations; thus, additional clinical studies are needed
for validation in improved decision-making.
VET and COVID-19
Because of the emergency nature of cardiac surgery, it is
inevitable to encounter a patient with COVID-19. COVID-19
has been shown to cause abnormal coagulation profiles of ele-
vated D-dimers, elevated fibrinogen levels, lower antithrombin
levels, reduced thrombin time, and decreased fibrinolysis.91,92
Therefore, COVID-19 patients are hypercoagulable, which
may lead to difficulty in treating coagulopathy during cardiac
surgery. Currently there are no data regarding transfusion prac-
tices in COVID-19 patients, but the use of VET still is recom-
mended.93 This recommendation may be warranted because
Hranjec et al. used TEG with platelet mapping to guide antico-
agulation management of COVID-19 patients. Treatment
guided by TEG with platelet mapping resulted in an 82%
decrease in mortality (p = 0.0002). Non-algorithmguided
patients had an increased risk for ventilation (RR 10.9; p <
0.0001) and AKI (RR 2.3; p = 0.0017) and a 10.3-fold
 ARTICLE IN PRESS
P.A. Patel et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2021) 113
increased mortality risk (p = 0.0001).94 The limitations of that
study included its observational nature, non-randomized
design, and unequally matched cohorts. Given these limita-
tions, conclusions of beneficial effects were not verified,
requiring a need for additional investigation.
Coagulation in Mechanical Circulatory Support and
COVID-19 Considerations
Left Ventricular Assist DeviceRelated Bleeding, Thrombosis,
and Anticoagulation
Bleeding complications, particularly gastrointestinal (GI)
bleeding, continue to be a major morbidity in patients with
continuous-flow left ventricular assist devices (LVADs). In a
systematic review that included more than 1,000 LVAD
patients with GI bleeding, the mortality rate was 21% at a
mean follow-up of 14.6 months. Notably, the incidences of
stroke and LVAD thrombosis were high in patients with GI
bleeding, suggesting that when anticoagulation is held, there is
an increased risk for thrombotic complications.95 Another
study published in 2020 described the use of octreotide (30 mg
every 28 days) in patients with recurrent GI bleeding, and
found that it decreased the risk of recurrent GI bleeding, with
60% of patients having no recurrence.96
LVAD thrombosis is less common with contemporary cen-
trifugal-flow LVADs but still presents a difficult clinical chal-
lenge for some patients.97 In 2020, a study was published
suggesting that treatment with tirofiban (0.1 mg/kg/min £ 5 d)
may be an effective medical therapy.98 In a cohort of 12
patients, the authors found a 75% efficacy. Of note, seven
patients in that study also experienced bleeding complica-
tions.98 A second study described the use of alteplase (20 mg)
in 28 patients with LVAD thrombosis (HeartWare HVAD
[Medtronic, Dublin, Ireland] and HeartMate II [Abbott, Chi-
cago, IL]), for which the efficacy rate was 61%.99 The rate of
intracranial hemorrhage was 4.5% in that study.99
Although DOACs are not approved by the US Food and
Drug Administration for anticoagulation in patients with
LVADs, there are increasing reports of their use. In 2020, a
single-center cohort study was published describing seven
patients with an LVAD who were anticoagulated with apixa-
ban or rivaroxaban.100 Although the study was small, there
were no apparent differences in complication rates compared
with warfarin.100
Extracorporeal Membrane OxygenationRelated Bleeding,
Thrombosis, and Anticoagulation
Multiple prior studies have demonstrated an association
among bleeding, RBC transfusion, and morbidity and mortal-
ity in adult patients undergoing extracorporeal membrane oxy-
genation (ECMO). In 2020, several studies confirmed that
bleeding continues to be a major problem in adult ECMO
patients and affects survival.101,102 In a single-center cohort
study of 130 ECMO patients from Hong Kong, the authors
reported a bleeding incidence of 42%, and patients with
9
bleeding were slower to wean off ECMO.103 In a cohort study
of 27 ECMO patients, for whom the incidence of bleeding was
59%, the INR was 90% sensitive and 72% specific for identify-
ing patients who developed bleeding, whereas thromboelas-
tometry parameters had lower sensitivity.104 In a cohort study
of 243 ECMO patients in whom the incidence of major bleed-
ing was 46%, the authors identified several risk factors for
bleeding, including hypofibrinogenemia, hemoglobinemia,
and low body mass index.105
Over time there has been a trend toward using less anticoa-
gulation during ECMO. In a systematic review that was pub-
lished in 2020, the authors reported on 201 patients who were
on ECMO for at least 24 hours without systemic anticoagula-
tion. In that study, the pooled circuit thrombosis rate was
13.4%, and the pooled patient thrombosis rate was 9.5%. Inter-
estingly, even with no systemic anticoagulation, 27.9% of
patients had severe bleeding.106 Direct thrombin inhibitors
have been used as an alternative to heparin in some ECMO
centers. In 2020, one observational study that included 52
patients compared patients who were anticoagulated with biva-
lirudin with patients who were anticoagulated with intravenous
unfractionated heparin.107 The authors found comparable rates
of bleeding and thrombosis, but the study was underpowered
to detect small differences in outcomes.107 An RCT of anti-
thrombin supplementation in 48 venovenous (VV)-ECMO
patients was published in 2020. In that study, patients were
assigned randomly to receive antithrombin to maintain anti-
thrombin activity between 80% and 120%, or placebo.108 The
authors found no differences in bleeding or thrombosis
between the two groups despite there being higher antithrom-
bin activity in the treatment group. These findings suggested
that routine antithrombin supplementation is probably of little
value in VV-ECMO.108 In a systematic review and meta-anal-
ysis of studies that compared anti-Xa heparin monitoring with
time-based strategies (aPTT, activated clotting time [ACT],
VET), the authors concluded that the use of anti-Xa heparin
monitoring was associated with less bleeding and no difference
in thrombosis.109
The mechanisms that contribute to ECMO-induced coagul-
opathy continue to be elucidated. Although in vitro studies
have suggested that shear-induced blood trauma leads to plate-
let surface GP1ba shedding and increased adherence of plate-
lets to fibrinogen,110 a small cohort study that examined
platelet surface receptor density in ten patients with cardio-
genic shock on venoarterial (VA) ECMO showed reduced
platelet surface activated GPIIb/IIIa levels during ECMO (sug-
gesting impaired fibrinogen binding) and no difference in
platelet surface GP1ba levels during and after ECMO.111
Acquired von Willebrand syndrome is well-known to occur
during ECMO,112,113 but there have been few studies of how
to treat ECMO patients with acquired von Willebrand syn-
drome and bleeding. In 2020, one of the first reports of vWF
concentrate treatment for acquired von Willebrand syndrome
was published.114 In a small cohort of 1ten adult ECMO
patients treated with vWF concentrate, the authors demon-
strated that treatment increased both vWF ristocetin cofactor
activity and the ratio of vWF ristocetin cofactor activity-to-
 ARTICLE IN PRESS
10 P.A. Patel et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2021) 113
vWF antigen.114 In that study, there was one case of thrombo-
sis that was deemed likely to be related to treatment, so pru-
dence is important when using vWF concentrate.114
COVID-19 Considerations for ECMO
The COVID-19 pandemic has led to an increased use of
ECMO worldwide. As of January 5, 2021, there were almost
4,000 ECMO runs reported to the Extracorporeal Life Support
Organization for COVID-19 patients, and survival to hospital
discharge was 54%.115 COVID-19 is now well-described as a
multisystem disease that is associated with elevated factor
VIII activity; hyperfibrinogenemia; depleted endogenous anti-
coagulant levels (eg, antithrombin and protein C); and hyper-
coagulability in patients with severe disease.116-121 Several
studies have demonstrated that COVID-19 infects endothelial
cells causing endothelialitis.122,123
COVID-19 patients on ECMO require special consideration
for anticoagulation because they are at increased risk for
thrombosis compared with other ECMO patients. In a single-
center cohort study of 12 COVID-19 patients who were treated
with VV-ECMO, four patients developed thrombotic compli-
cations despite targeting an ACT of 150 to 220 seconds.124
Two patients died from thrombotic complications (one from
pulmonary embolism and the other from oxygenator thrombo-
sis).124 In a second single-center cohort study, seven of eight
COVID-19 patients on VV-ECMO developed oxygenator
thrombosis.125 Of note, in that study, a significant number of
patients also experienced major bleeding including tracheal
hemorrhage, oropharyngeal hemorrhage, and thoracic hemor-
rhage.125 The authors targeted an ACT of 180-to-200 sec-
onds.125 A retrospective cohort study that compared circuit
thrombosis rates in COVID-19 patients and non-COVID-19
patients on ECMO found a significantly higher rate of circuit
thrombosis in COVID-19 pateints.126 There also is a published
case report of massive life-threatening intracardiac thrombosis
in a COVID-19 patient on VV-ECMO.127
The concurrent risks of thrombosis and bleeding in COVID-
19 ECMO patients can be reconciled by the fact that severe
cases of severe acute respiratory distress syndrome coronavi-
rus 2 infection cause a release of procoagulant factors such as
factor VIII and fibrinogen, but at the same time ECMO leads
to derangements in primary hemostasis, mainly through loss of
large vWF multimers and platelet surface GP1ba
shedding.112,113,119,121,128,129 The result is that when low-flow
conditions occur, there is a predilection for thrombosis,
whereas when tissue injury occurs there is a predilection for
excessive bleeding. Although based on expert opinion, the
Extracorporeal Life Support Organization recommends con-
sidering a level of anticoagulation at the “high end of normal”
for COVID-19 patients.130 The most devastating bleeding
complication that has been reported in COVID-19 patients on
VV-ECMO is intracranial hemorrhage, which may occur in up
to 30%-to-40% of patients.131 It remains unclear whether intra-
cranial hemorrhage represents conversion of ischemic stroke
or is a primary hemorrhagic event in most patients.131 Tho-
racic hemorrhage also occurs at a high rate in COVID-19
patients on VV-ECMO because pulmonary ischemia causes
tissue necrosis and resultant hemorrhage.132
COVID-19 Considerations for Cardiac Surgery
There are few reports describing coagulation changes in
COVID-19 patients undergoing cardiac surgery. One cohort
study of 20 COVID-19 patients who underwent cardiac sur-
gery did not report increased bleeding or thrombosis.133
Patients in the cohort had elevated fibrinogen concentrations
(mean = 568 mg/dL) and low antithrombin activity (mean
activity = 74%), suggesting that hypercoagulability was pres-
ent.133 This may be of particular importance in patients under-
going coronary artery bypass grafting who could be at
increased risk for graft thrombosis.134 One study of critically
ill COVID-19 patients demonstrated that a very high percent-
age of patients (up to 80%) have heparin “resistance,” which is
an important consideration when heparinizing patients for
CPB.135 It seems likely that antithrombin replacement may be
needed more frequently in COVID-19 patients undergoing car-
diac surgery.
Conclusions
Coagulation and hemostasis add to the complexity of caring
both intra- and postoperatively for the cardiac surgical patient.
In 2020, new investigations continued to provide cardiotho-
racic anesthesiologists with insight into the management of
antiplatelet and anticoagulant agents, including reversal
options. Advances in blood management should limit unneces-
sary exposure to allogeneic blood therapy and its associated
risks. The expanding use of factor concentrates may see a
greater presence for managing post-CPB coagulopathy, which
also can be guided with the use of point-of-care tests. The role
of VET continues to grow in guiding existing blood conserva-
tion techniques. The balance between bleeding and thrombosis
in patients with LVAD and ECMO continues to warrant fur-
ther investigation. Finally, the effect of COVID-19 on all these
coagulation aspects certainly will be revisited in the coming
year.
Conflicts of Interest
None.
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