Perioperative blood management:

GOALS OF PATIENT BLOOD MANAGEMENT

Patient blood management (PBM) is the timely application of evidence-based

medical and surgical concepts designed to maintain hemoglobin concentration (red
blood cell [RBC] mass), minimize blood loss, and ensure optimal physiologic
tolerance of anemia in an effort to improve patient outcome 1-3.
These principles are used to manage anemia and reduce the risk of anemia, with
the goal of improving patient outcomes. With their implementation, transfusions of
RBCs and other blood products may also be reduced, along with the risks of
reactions and other potential complications of transfusion [1,4,5]. As such, this
patient-centered multimodality and multidisciplinary approach focuses on clinical
outcomes rather than use of blood products [3].
Techniques and strategies for optimal PBM can be implemented in concert,
spanning the entire perioperative period from preoperative assessment until
discharge from the hospital ].
For major or complex surgical procedures with a known high risk of significant
blood loss (eg, >500 to 1000 mL), advanced discussions with the surgical team, a
hemostasis expert, and/or the patient's primary clinician may identify opportunities
to implement preoperative or intraoperative measures to avoid transfusion, such as
delay of an elective procedure to treat certain causes of anemia, preoperative
autologous blood donation, or intraoperative blood salvage, acute normovolemic
hemodilution (ANH), or use of antifibrinolytics or other hemostatic products

PATIENT BLOOD MANAGEMENT DURING THE COVID-19

PANDEMIC Since the novel coronavirus disease 2019 (COVID-19)

pandemic has resulted in blood shortages due to decreased donations, perioperative

patient blood management (PBM) is critically important to aid in balancing supply
and demand for blood components [1,8-11]. As discussed below, specific strategies
include implementation of preoperative anemia management :
 use of appropriate transfusion thresholds and evidence-based protocols,
 maintenance of normothermia throughout the perioperative period, and,
  when feasible, use of minimally invasive surgical techniques,
 intraoperative cell salvage,
 acute normovolemic hemodilution,
 antifibrinolytic therapy, and
 point-of-care coagulation testing.

PREOPERATIVE STRATEGIES The preanesthetic consultation provides

an opportunity to assess and address risks for bleeding and to evaluate possible
interventions to minimize the need for transfusions . Certain disorders (eg,
anemia), surgical procedures (eg, cardiac surgery, liver transplantation), and
medications that affect hemostasis are associated with increased potential for
bleeding and transfusion.
Elective surgical procedures — It may be appropriate to postpone an elective
procedure when there is a reversible cause of anemia or coagulopathy that can
be corrected in a reasonable period of time.

Selective laboratory testing

●Hemoglobin or complete blood count – A baseline hemoglobin
measurement (typically a component of a complete blood count [CBC]) is
obtained in patients undergoing selected major surgery surgical procedures
that have significant expected blood loss (eg, procedures with >10 percent
chance of needing a transfusion or >500 mL blood loss), and in individuals
likely to have preoperative anemia (eg, due to a known underlying condition)
unless the scheduled procedure is minor. Anemia should be addressed and
should alert clinicians to perform an evaluation and appropriately manage the
patient.
For patients with known or suspected medical conditions who will undergo
intermediate- to high-risk surgical procedures, additional preoperative
laboratory testing may be necessary
Ideally, a baseline CBC is obtained approximately four weeks prior to a
scheduled elective procedure. This allows adequate time for appropriate
treatment of conditions, such as replacement of iron stores in individuals with
iron deficiency [16]. In some cases, elective surgery may need to be delayed.
By contrast, a CBC or hemoglobin measurement is not necessary for patients
undergoing minor surgery unless the history suggests anemia .
●Screening tests for bleeding disorders – For patients with a personal
history, family history, or physical examination suggesting the presence of a
bleeding disorder, appropriate screening tests should be obtained. These often
 include, but are not limited to, a platelet count and screening tests of
coagulation (prothrombin time [PT] with international normalized ratio [INR]
and activated partial thromboplastin time [aPTT]).
If indicated, such screening should be done early enough to allow time for
diagnosis and treatment of causes of hemostatic abnormalities. A hematology
consultation is typically necessary. In selected cases (eg, patients with
significant prior bleeding episodes or recent decrease in hemoglobin level or
need for transfusion), it is appropriate to obtain a consultation even if
screening tests are normal. However, we do not obtain screening tests of
coagulation unless a bleeding disorder is suspected, in accord with the
recommendations of the American Society of Anesthesiologists [19], the
British Committee for Standards in Hematology [20], and the European
Society of Anaesthesia [21].
●Testing for individuals receiving anticoagulants – Individuals receiving
anticoagulants typically have recent laboratory testing available that should be
reviewed (eg, PT/INR for those on warfarin, creatinine for those on
a dabigatran or a direct factor Xa inhibitor). This information may factor into
decisions regarding the preoperative timing of anticoagulant discontinuation.
●Typing and crossmatching tests – Typing and crossmatching tests to ensure
availability of appropriate blood products are necessary before procedures with
large expected blood loss; the blood bank should be notified of the
approximate number of units that are likely to be required based on known
blood loss associated with the specific procedure as well as the potential for
greater than average blood loss that may occur or may be poorly tolerated in
certain patients (eg, those with comorbidities).
Treatment of anemia — Anemia is a highly prevalent risk factor for morbidity
and mortality in surgical patients and is independently associated with increased
risk of transfusion ]. Chronic anemia can be a marker for other comorbidities in
addition to being a direct cause of morbidity and mortality [25]. .)
Depending on the cause and degree of anemia, the urgency of the procedure, and
the expected amount of blood loss and other risk factors, surgery may be
postponed to diagnose the cause and correct anemia when feasible, in order to
avoid perioperative transfusion of red blood cells (RBCs)
While many patients with preoperative anemia have iron deficiency anemia or
anemia of chronic disease/anemia of inflammation, other causes of anemia include
folate and vitamin B12 deficiencies [24]. For patients who have unknown or
complex causes of anemia, input is sought from a consultant with expertise in
anemia management.
Iron deficiency anemia — Iron deficiency anemia is a surprisingly common
condition across various surgical and other patient populations. Even among
patients whose anemia is attributed to other causes (eg, chronic kidney disease or
inflammation), some degree of iron deficiency may be present. Individuals with
iron deficiency should be treated with iron rather than transfusion, unless the
anemia is extremely severe and there is risk of organ ischemia, as discussed
separately. If iron is administered, sufficient time should be allowed for effective
treatment of anemia before surgery (typically two to four weeks for partial
correction and six to eight weeks for full correction). In individuals with
unexplained iron deficiency, determination of the underlying cause is an essential
part of management.
Oral iron replacement can be initiated in an iron-deficient patient if at least four to
six weeks of time is available before planned surgery. Intravenous (IV) iron is an
option if there is less than four to six weeks until semi-elective surgery, and for
patients who cannot tolerate oral iron or do not have a response (eg, due to poor
absorption) ]. In this setting, IV iron can replenish body iron stores more rapidly
and effectively than oral iron therapy; however, time is still required for the iron to
be incorporated into developing RBCs and for the hemoglobin level to increase,
and available trials have not been adequately powered to determine whether rates
of transfusion are lower.
Use of erythropoietin — Erythropoietin (EPO) can increase the red cell mass and
therefore the hemoglobin level, potentially reducing patients' exposures to
allogeneic transfusion in certain patient-specific and surgery-specific settings [24].
Administration of EPO typically should include supplemental iron to avoid
functional iron deficiency which may occur in face of increased erythropoiesis.
EPO for treatment of anemia can be used in the following settings:
●For patients with anemia of chronic disease/inflammation undergoing any
surgical procedure with expected blood loss >500 mL, if their hemoglobin
level is <12 g/dL. Clinical judgment is used for patients with hemoglobin
levels between 12 and 13 g/dL.
●For patients with anemia of chronic disease/inflammation undergoing cardiac
surgery, if their hemoglobin is <13 g/dL. Our approach is consistent with
guidelines from the European Association for Cardio-Thoracic Surgery
(EACTS), the European Association of Cardiothoracic Anaesthesiology
(EACTA), and the Society of Cardiovascular Anesthesiologists, which
recommend consideration of preoperative EPO administration for anemic
cardiac surgical patients, even if iron deficiency is not present  
●For patients with anemia of chronic disease/inflammation undergoing major
orthopedic surgery, if their hemoglobin is <12 g/dL. Our approach is largely
consistent with recommendations from the 2018 Frankfurt consensus
 conference, although we generally do not use preoperative EPO in orthopedic
surgical patients who have iron deficiency alone; rather, we reserve EPO
therapy for those with anemia of chronic disease/inflammation
●For patients for whom blood transfusion is not an option, as described
separately.
Our general approach does not take the place of the judgment of the surgeon,
anesthesiologist, internist, or hematologist regarding likelihood of avoiding
transfusion and the risks and benefits of EPO administration for an individual
patient. We typically begin EPO therapy three weeks before an elective procedure
and provide three injections of 40,000 units or 300 to 600 units/kg of epoetin
alfa once weekly, together with supplemental iron to avoid functional iron
deficiency. If less than three weeks is available, we still administer EPO prior to
the surgical procedure as it may still provide benefit.
Potential adverse effects of EPO include:
●Venous thromboembolism – However, patients receiving perioperative
deep vein thrombosis (DVT) prophylaxis are usually protected from such
events.
●Hypertension – We generally avoid EPO in patients with severe,
uncontrolled hypertension. However, for those with well-controlled
hypertension, we do not consider the risk of hypertension or ischemic events to
be prohibitive, consistent with the advice of other experts41,42.
●Cancer progression – Decisions regarding preoperative EPO administration
in patients with cancer are discussed separately.
There is significant heterogeneity among published studies with respect to dosing
and timing of preoperative EPO administration, the presence, cause, and severity
of preoperative anemia and/or iron deficiency, whether iron therapy was
concomitantly administered, and the types of surgical procedures studied [24].
Data regarding benefits and risks of preoperative EPO administration are
summarized as follows:
●A 2020 meta-analysis of randomized trials that included 1880 anemic
patients (hemoglobin <13 g/dL for males or <12 g/dL for nonpregnant
females) undergoing noncardiac surgery (primarily orthopedic,
gastrointestinal, and gynecological surgery) compared administration of
preoperative EPO plus iron therapy with placebo or standard of care (with or
without iron) [43]. Preoperative EPO plus iron reduced the need for RBC
transfusion.
●A 2019 meta-analysis of randomized trials comparing preoperative
administration of EPO versus placebo (32 trials; 4750 patients, mostly
 orthopedic and cardiac surgery) found reduced blood transfusions in the EPO
groups. Decreased blood transfusions were seen in the entire population (RR
0.59, 95% CI 0.47-0.73; 28 trials), as well as the subgroups undergoing cardiac
surgery (RR 0.55, 95% CI 0.47-0.73; nine trials) and major orthopedic surgery
(RR 0.36, 95% CI 0.28-0.46; five trials). In addition, the EPO group had
increased hemoglobin levels. There was no increase in the incidence of
thromboembolic events with EPO.
●Another 2019 randomized trial in elective cardiac surgical patients with
preoperative anemia or isolated iron deficiency noted reduced RBC
transfusions from a median of one to zero units in those who received
preoperative subcutaneous EPO administered together with IV iron,
subcutaneous vitamin B12, and oral folic acid on the day before surgery,
compared with those receiving placebo drugs ●A 2018 randomized trial in
orthopedic surgical patients with mild anemia (hemoglobin 10 to 13 g/dL)
before hip or knee arthroplasty reported greater iron stores and improved
erythropoiesis after treatment with weekly EPO plus concomitant
administration of IV iron for three weeks before surgery, compared with
treatment with EPO plus oral iron for the same period .
Anemia associated with chronic kidney disease — Management of patients with
chronic kidney disease (CKD; with or without hemodialysis) may include iron
and/or EPO.
Details of therapy should be discussed with the patient's primary nephrologist. In
particular, we try to avoid transfusion when possible in any patient on a transplant
waiting list, as transfusion-induced sensitization may increase antibody levels and
reduce the likelihood of eventual successful renal transplantation. However,
transfusion should not be withheld from an individual awaiting a kidney transplant
if indicated to treat more severe symptomatic anemia. .)
Preoperative autologous blood donation — In some institutions, preoperative
autologous donation (PAD) is offered as a blood conservation option for
candidates in relatively good health who are not anemic and are undergoing
surgical procedures with significant expected blood loss. The exact threshold may
differ slightly at different institutions; an approximate range is expected loss of
>500 mL or >1000 mL [47]. Recombinant human EPO may be used as an adjunct
Use of PAD with planned reinfusion during or shortly after the surgical procedure
has been declining. There is a high risk of wastage of unused PAD units, and most
patients will be made anemic by the series of donations, thereby increasing the risk
of transfusion. Additional drawbacks are expense and inconvenience, including the
need for planning weeks before the proposed surgical procedure [47].
Management of thrombocytopenia or platelet dysfunction
●Thrombocytopenia – For individuals with known thrombocytopenia, a
discussion with the consulting hematologist or the patient's primary clinician
should focus on determining a safe platelet count for the proposed procedure
and appropriate interventions to raise the platelet count to a safe level if
needed.
For patients who are found to have a low platelet count, causes of
thrombocytopenia are evaluated prior to elective surgery. Depending on the
type and urgency of the surgical procedure and the cause and degree of
thrombocytopenia, surgery may be postponed and/or therapy may be given to
increase the platelet count before the procedure.
•Immune thrombocytopenia – For some elective procedures in patients
with immune thrombocytopenia (ITP), properly-timed glucocorticoids
and/or intravenous immune globulin (IVIG) can be used to raise the
platelet count before surgery. The table shows the expected time to first
response for various ITP treatments (table 3). If time is not an issue, we
generally use the agent that has previously been effective for the
individual patient. Data are limited for the use of other approaches such as
administration of a thrombopoietin receptor agonist (TPO-RA) prior to
surgery in individuals with ITP .
•Liver disease – In contrast with ITP, there is evidence that individuals
with liver disease who have significant thrombocytopenia and are
undergoing an elective procedure with a high bleeding risk can be treated
with a properly-timed TPO-RA prior to the procedure.
●Platelet dysfunction – The functional status of platelets is also important in
decisions regarding platelet transfusion before or during surgery. Some studies
suggest that results of platelet function tests better predict surgical bleeding
than the platelet count [49,50]. However, there is insufficient evidence to
incorporate these tests as part of routine preoperative assessment.
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Management of medications affecting hemostasis — Some patients undergoing
surgery are taking medications intended to reduce the risk of thrombosis
(eg, warfarin or another anticoagulant, aspirin or a P2Y12inhibitor such
as clopidogrel). In some cases, medications taken for other indications may alter
hemostasis (eg, nonsteroidal antiinflammatory drugs [NSAIDs], herbal
medications).
Appropriate perioperative management of a patient taking a specific medication
depends on the indication for which the agent was prescribed, the underlying
thrombotic risk, the planned surgical procedure, and other factors that affect
bleeding risk. Discontinuation of antithrombotic medications is often appropriate,
with the details of timing typically determined using institutional or other
guidelines as well as consultation with the surgeon and the prescribing clinician.
Management of specific hemostatic disorders —
●Liver disease – Patients with liver disease may have abnormalities in routine
laboratory tests of coagulation, especially when liver synthetic function is
significantly impaired and portal pressures are increased. These include
prolongation of the PT, INR, and aPTT, as well as mild thrombocytopenia and
elevated D-dimer. Furthermore, both quantitative and qualitative platelet
disorders are a consequence of not only chronic, but also acute liver damage.
However, individuals with hepatic insufficiency also have abnormalities that
may increase the risk of thrombosis. Consequently, laboratory abnormalities
are poor predictors of bleeding risk.

•Vitamin K deficiency – Vitamin K deficiency may develop in

individuals with reduced oral intake or decreased absorption due to
conditions such as cystic fibrosis, biliary atresia, sclerosing cholangitis,
cholestasis, or intestinal diseases with malabsorption. Significant vitamin
K deficiency will prolong the PT. Vitamin K deficiency can be treated
with vitamin K, which may take one or more days to be effective, or with
an unactivated prothrombin complex concentrate (PCC) if needed for
emergency surgery with a significant bleeding risk.
•Disseminated intravascular coagulation – .)
•Acquired coagulation factor inhibitors (eg, autoantibodies against
factors II, V, VII, VIII [acquired hemophilia A], IX, XI, or XIII) –
●Inherited conditions affecting hemostasis
•Hemophilia –
•Other congenital coagulation factor deficiencies (eg, factors XIII, XI,
X, VII, V, II [prothrombin], fibrinogen) –
•Von Willebrand disease (VWD) – .)
•Other congenital platelet disorders that cause platelet dysfunction or
thrombocytopenia – .)
Consents and advanced directives — Patient preferences and acceptance or
declining various blood components and/or blood conservation modalities should
be discussed in the preoperative period. Related consents and advanced directives
should be obtained and documented in the preoperative period to ensure that
acceptable options for optimal care are provided ].
Certain patients may decline transfusions, or appropriate blood products may be
limited or unavailable for other reasons (eg, previously transfused patients with
multiple alloantibodies or incompatible cross-matching for other reasons, wounded
soldiers on the battlefield, surgical procedure performed in areas of limited blood
supply). These situations pose additional challenges for treatment of severe
anemia, and for cases in which significant blood loss is likely [52,53].
There may be substantial variability in acceptance of various components and
factors, necessitating discussion of specific transfusion decisions on an individual
basis before invasive interventions [52,54]. As an example, acute normovolemic
hemodilution (ANH) may be a good option for some Jehovah Witnesses who will
usually consent to ANH if the blood is maintained in a closed circuit continuous
flow.
Specific arrangements regarding acceptable alternatives should be made in advance
to allow provision of the most effective care while respecting the patient's
preferences, values, and their right of self-determination. Strategies to optimize
preoperative red cell mass and minimize blood loss in patients who decline blood
transfusions are presented separately.
Urgent and emergency surgical procedures — For urgent or emergency surgery,
it may be impossible to correct all factors adversely affecting baseline hemoglobin,
coagulation, bleeding, and the potential need for transfusion of blood products. For
example, it is not possible to correct iron deficiency anemia before emergency
surgery [56], because iron must be incorporated into developing blood cells.
Specific issues may include the following:
●Hemorrhage – When blood loss is rapid or extensive, or when the
hemoglobin level drops below a defined threshold, RBC transfusion may be
necessary in the preoperative period. Perioperative indications for transfusion
of RBCs are discussed in detail separately.
In patients with major bleeding and coagulopathy (eg, due to trauma), goal-
directed replacement of blood components and coagulation factors is
recommended [57,58]. For those requiring massive transfusion of blood
components (RBCs, plasma products, platelets), administration of crystalloid
solutions should be monitored and minimized as much as possible throughout
the perioperative period to avoid dilutional coagulopathy.
●Anticoagulants – Anticoagulant reversal may be necessary before an
emergency procedure. However, not all individuals and surgical settings
require reversal, especially if thrombotic risk from an underlying condition is
high and bleeding risk of the surgery is low.

A 4-component PCC product is the preferred therapy for a patient who is

receiving a vitamin K antagonist and requires immediate reversal of
 anticoagulation for urgent surgery, including in the setting of intracranial
hemorrhage [63]. In comparative studies with plasma in this setting, PCC
has been associated with a more rapid correction of the INR and reversal
of anticoagulation. Concomitant vitamin K also needs to be administered
to prevent further effects of vitamin K antagonists.

•Direct oral anticoagulants (DOACs;

•Heparin –
●Thrombocytopenia – Platelet transfusions may be required for emergency
major surgery in which there is insufficient time to raise the platelet count by
treating the underlying condition responsible for thrombocytopenia (eg, use of
IVIG in an individual with ITP). In such cases, platelets are often transfused if
the count is <50,000/microL, although a higher transfusion threshold may be
used in selected cases (eg, <100,000/microL for neurosurgical or ocular
procedures). Platelet transfusion is usually not necessary for minor invasive
procedures such as placement of a central venous catheter unless the platelet
count is <20,000/microL

INTRAOPERATIVE STRATEGIES

Minimally invasive surgical techniques have been developed; these may decrease
blood loss and need for transfusion compared with conventional open surgical
procedures [1]. Other intraoperative strategies involving surgical and anesthetic
care are discussed below.
Fluid management — We typically administer a balanced electrolyte crystalloid
solution for routine perioperative fluid repletion in order to maintain
normovolemia and/or to replace lost blood on a 1.5:1 basis (1.5 volumes of
crystalloid for every 1 volume of lost blood). If the hemoglobin level drops below
a certain threshold or there is bleeding at such a rate that hemoglobin levels do not
accurately reflect the patient's clinical status, transfusions may be initiated. In a
bleeding patient, some clinicians select a colloid solution to be administered on a
1:1 basis (equal volume of colloid to volume of lost blood) basis until a transfusion
threshold is met.
Maintenance of normovolemia throughout the perioperative period is ideal.
Administration of large volumes of crystalloid solution (eg, a fixed volume or
traditional liberal approach to fluid therapy) should be avoided since this is
associated with dilutional anemia and coagulopathy, which may lead to
transfusions and tissue edema-related adverse outcomes.
Maintenance of normothermia — Hypothermia is avoided throughout the
perioperative period in noncardiac surgical patients. Hypothermia causes
coagulopathy due to impairment of platelet aggregation and reduced activity of
enzymes in the coagulation cascade. This combination of platelet and enzyme
impairment typically reduces clot formation and increases perioperative blood loss
and the need for transfusion. In one meta-analysis, even mild (eg, 1°C)
hypothermia increased blood loss by approximately 20 percent.
A blood warmer should be used for transfusion of all thawed or refrigerator-
temperature blood products (eg, red blood cell [RBC] units, plasma products,
cryoprecipitate) to avoid hypothermia <36°C, which can lead to coagulopathy,
bleeding, and additional transfusions ]. If necessary, other fluid and patient
warming devices are routinely employed to maintain perioperative normothermia.
These may include warming all intravenous fluids with a commercially available
blood warming device and application of upper- and lower-body forced-air
warming devices and blankets.

Surgical blood conservation techniques

Electrosurgery devices — Adequate hemostasis during surgical dissection can be
achieved by employing electrocautery to control bleeding from small vessels in
most cases, as well as standard suturing techniques for larger vessels.
Topical hemostatic agents and tissue adhesives — In selected cases, topical
hemostatic agents, tissue adhesives, fibrin sealants, and autologous platelet gels are
used as adjuncts to standard techniques and electrocautery to control bleeding.
Topical application of agents that enhance coagulation allows dosing at the
application site without systemic exposure.
Intraoperative blood salvage — Unlike preoperative autologous donation (PAD)
and acute normovolemic hemodilution (ANH), in which patient's blood is collected
prior to occurrence of surgical blood loss, intraoperative blood salvage (also
known as blood recovery) focuses on retrieving and salvaging blood that has
already been shed and is otherwise lost. The collected blood is washed or filtered
and returned back to the patient as transfusion is needed. Blood salvage is
generally safe and associated with a very low incidence of adverse events [80]. The
technique can be used during surgery to retrieve post-surgical blood loss. Benefits
are most significant in procedures with high blood losses (≥1000 mL) [81,82]. In
cardiac surgery, reinfusion of mediastinal blood after washing may be considered
as part of a multimodal blood conservation strategy, particularly for patients who
will not accept allogeneic blood products.
Acute normovolemic hemodilution — ANH is a blood conservation technique
appropriate for selected patients with normal initial hemoglobin levels who are
expected to lose two or more units of blood (≥1000 mL) during surgery. The
technique involves removal of blood from a patient shortly after induction of
anesthesia, with maintenance of normovolemia using crystalloid and/or colloid
replacement fluid.
The ANH technique is safest when used in healthy, young adults but can be used in
other populations. ANH may also be a good option for Jehovah Witnesses if they
accept the procedure (Jehovah Witnesses will often consent to ANH if the blood is
maintained in a closed circuit continuous flow); the patient's wishes must be
determined prior to the procedure
Use of hemostatic agents
Overview of indications for hemostatic agents — Hemostatic agents may be
used to reduce the risk of bleeding or to treat excessive bleeding due to an
anticoagulant or other cause of impaired hemostasis. In most cases, use is guided
by clinical experience rather than high-quality clinical trials.
●Cardiac surgery with cardiopulmonary bypass and other surgical
procedures with significant blood loss – The most commonly used
intraoperative agents are antifibrinolytic agents, which have multiple
mechanisms of action. These are routinely used in cardiac surgery with
cardiopulmonary bypass (CPB), orthopedic surgery, and other surgical
procedures associated with significant blood loss.
●Significant blood loss and/or consumptive coagulopathy – In surgical
patients with significant blood loss or consumptive coagulopathy (eg,
disseminated intravascular coagulation), plasma and/or fibrinogen
concentrate may be used to replace lost or consumed clotting factors.
●Specific clotting factor deficiencies, uremia, or anticoagulants –
Individual clotting factors, prothrombin complex concentrates (PCCs),
and/or desmopressin (DDAVP) are generally reserved for those with specific
factor deficiencies, uremic platelet dysfunction, or those receiving
anticoagulants that require immediate reversal for urgent or emergency
surgery. When needed, these agents are typically initiated preoperatively rather
than intraoperatively, although additional doses may be used intraoperatively
in emergency cases and for longer procedures.
●Refractory bleeding – In rare cases with unexplained persistent bleeding, an
activated PCC such as factor eight inhibitor bypassing activity (FEIBA) or
recombinant activated factor VII (rFVIIa) may be used to treat life-threatening
coagulopathy, with the understanding that there are no high quality data to
support this practice, and these agents have potentially devastating thrombotic
risks.
Many of these conditions can coexist (eg, cardiac surgery with low fibrinogen). In
such cases, the products administered ideally should treat the specific deficiency. If
a large blood volume is lost, then plasma (or whole blood) may be the most
appropriate choice. If there is isolated fibrinogen deficiency, then a source of
fibrinogen (cryoprecipitate or a fibrinogen concentrate) can be used and is likely to
carry a lower risk of adverse events.
Antifibrinolytic agents — Antifibrinolytic agents have multiple effects that
prevent fibrinolysis by plasmin, thereby supporting hemostasis. These agents
include epsilon-aminocaproic acid (EACA) and tranexamic acid(TXA). They are
increasingly being used prophylactically to reduce surgical blood loss and
transfusion, with many studies supporting their efficacy [ ]. Most experience in
surgical populations is with intravenous use; oral and topical administration of
TXA have also been reported in orthopedic surgery [91,92].
Availability of these agents varies across institutions and regions. In the United
States, EACA is more commonly used during cardiac surgery due to the higher
cost of TXA and the reported association of TXA with postoperative seizures at
higher doses ]. However, TXA is commonly used in most other countries for
cardiac and other surgical procedures ]. Although aprotinin was effective in
reducing surgical bleeding and transfusion rates, it was associated with increased
mortality in cardiac surgery patients in a large trial, leading to its withdrawal and
suspension. Subsequent studies have noted increased bleeding and transfusions
following worldwide withdrawal of aprotinin [100]. A reevaluation of the prior
reports has led to its reintroduction in Europe for use in selected patients ].
●Indications and uses – Antifibrinolytic agents are routinely used in cardiac
surgical procedures that include CPB ]. Antifibrinolytic agents have also been
used in major noncardiac surgical procedures that are likely to incur clinically
significant blood loss (eg, liver transplantation or resection, major orthopedic
procedures such as hip or knee arthroplasty or spine surgery, prostate surgery,
selected trauma patients), as well as for postpartum hemorrhage. A growing
number of studies, including several randomized trials, have found that
prophylactic administration of EACA or TXA is associated with reduced
blood loss and reduced transfusion in the perioperative periods .
●Dosing – Dosing and timing of EACA or TXA administration is procedure-
specific and institution-specific since dose regimens have not been
standardized for intraoperative uses of either agent [ . TXA dosing should be
reduced in patients with end-stage renal disease or moderate to severe renal
insufficiency ].
●Risks
•Prothrombotic effects – In general, data do not support increased risk of
thrombotic events associated with use EACA or TXA. Some evidence
 suggests reduced risk of such events [85]. These agents appear to be safe
even in cancer patients who are generally at increased risk of
thromboembolic events [113]. Nonetheless, individual patient-specific and
procedure-specific risks for bleeding and transfusion are considered [85].
•Seizures – TXA has been associated with postoperative seizures after
cardiac surgery, and this risk may be dose-related.
•Hypotension or arrhythmias with rapid injection – Rapid intravenous
administration of EACA should be avoided since this may induce
hypotension, as well as bradycardia or other arrhythmias [116].
Fibrinogen concentrate (versus cryoprecipitate) — Virally-inactivated human
fibrinogen concentrates have been developed from human pooled plasma for use in
individuals with fibrinogen deficiency and/or dysfunction (eg, RiaSTAP, Fibryga,
Haemocomplettan). Fibrinogen concentrate is expected to have a lower risk of
infectious complications compared with cryoprecipitate
●Indications and uses – In a patient with a low plasma fibrinogen level
(typically, below 150 to 200 mg/dL) or a fibrinogen disorder, treatment with
a fibrinogen concentrate is appropriate to treat or prevent bleeding during
surgery. It may also be reasonable to administer fibrinogen concentrate to treat
excessive bleeding and coagulopathy if a low fibrinogen concentration (eg,
<150 to 200 mg/dL, with higher fibrinogen thresholds during pregnancy) is
documented or strongly suspected in certain surgical settings (eg, cardiac
surgery with CPB, thoracic aortic surgery, liver transplantation, severe
postpartum hemorrhage with disseminated intravascular coagulation, trauma
surgery). Studies in these settings have found that administration of fibrinogen
concentrate can reduce transfusions of blood components, but have reached
different conclusions regarding more clinically important outcomes such as
survival.  
Administration of fibrinogen concentrate is more common in European
countries where cryoprecipitate is not available, compared with the United
States [130]. The European Society of Anesthesia guidelines suggest use of
fibrinogen concentrate to maintain a target fibrinogen concentration >150 to
200 mg/dL in patients with significant bleeding [90]. Similarly, the
Hemostasis and Transfusion Scientific subcommittee of the European
Association of Cardiothoracic Anaesthesiology (EACTA) recommends
consideration of administration of fibrinogen concentrate in cardiac surgical
patients with microvascular bleeding after CPB to maintain physiologic
fibrinogen activity based on viscoelastic coagulation testing ]. Proponents
argue that the baseline concentration of fibrinogen is relatively low, and there
are no fibrinogen stores to be mobilized; thus, fibrinogen is the first
coagulation protein to become critically low during intraoperative bleeding .
 ●Dosing – The dose of fibrinogen concentrate is calculated according to the
target fibrinogen concentration.
●Risks – Thromboembolic complications can occur, particularly in pregnant
patients or in those with a thrombotic fibrinogen variant. Overcorrection of
fibrinogen deficiency should be avoided to minimize this risk.
Prothrombin complex concentrate (PCC) — Different PCCs vary in their factor
contents. All PCCs contain factors II, IX and X. Those that do not contain
therapeutic levels of factor VII are known as 3-factor PCCs, while those containing
factor VII are labeled as 4-factor PCCs (table 8). If the only available PCC is a 3-
factor product, then supplemental factor VII may be administered. Most PCC
preparations contain low doses of heparin as well as variable amounts of protein C
and protein S. Advantages of PCCs over fresh frozen plasma (FFP) include rapid
administration in a small volume, resulting in more rapid reversal of the
anticoagulant effect and avoidance of volume overload and transfusion reactions.
In contrast with standard 4-component PCCs, activated PCC (aPCC; eg, FEIBA)
contain activated factor VII (table 8) [133]. aPCC have a greater prothrombotic
risk than unactivated PCC and are only rarely used.
●Indications and uses
•Reversing warfarin – As noted above, an unactivated PCC is typically
used to treat patients who have bleeding associated with warfarin or
another vitamin K antagonist and/or who require emergency surgery,
particularly those presenting with intracranial hemorrhage.
•Intractable bleeding in cardiac, hepatic, and trauma surgery – Off-
label intraoperative use of PCCs has been reported for treatment of
patients with intractable coagulopathic bleeding after cardiac surgery with
CPB [29]. However, prospective data are limited regarding the safety,
efficacy, and dosing of PCCs for this use. Other sources of coagulopathy,
such as hypofibrinogenemia, thrombocytopenia, platelet disorders, or
surgical sources of bleeding are treated before considering use of a PCC
product.
Limited data from observational studies of off-label use of unactivated 4-
factor or 3-factor PCC products in patients with excessive bleeding and
coagulopathy after cardiac surgery show that these products may decrease
risk for further RBC transfusions;
In a propensity score-matched retrospective study of 60 pairs of patients
undergoing liver transplantation, PCC use was associated with
significantly decreased RBC and FFP transfusion requirements, and no
thromboembolic events were noted [139].
In trauma patients with findings of trauma-induced coagulopathy, limited
data (mostly observational) suggest that administration of 4-factor PCC,
 alone or in combination with fibrinogen concentrate or FFP, can reduce
transfusion of RBCs and other blood components [140-144].

●Dosing – The dose is tailored to the individual patient's needs based on

clinical indications and laboratory testing, but usually are 1000 to 2000 units.
(See "Management of warfarin-associated bleeding or supratherapeutic INR",
section on 'PCC products, efficacy, risks'.)
Ideally, point-of-care (POC) laboratory tests such as thromboelastography are
obtained to monitor overall hemostatic function, along with standard
laboratory testing that includes prothrombin time (PT), INR, activated partial
thromboplastin time (aPTT), and fibrinogen level. (See "Intraoperative
transfusion of blood products in adults", section on 'Point-of-care
tests' and "Coagulopathy in trauma patients", section on 'Diagnosis'.)
●Risks – Data for intraoperative safety of PCC are limited [90,133,145,146].
aPCC products such as FEIBA are thought to have a greater prothrombotic
risk because they contain activated factor VII.
Prothrombotic risk increases with repeat or excessive dosing. This risk extends
well into the postoperative period. (See "Management of warfarin-associated
bleeding or supratherapeutic INR", section on 'PCC products, efficacy, risks'.)
Special considerations in individuals with hemophilia and an inhibitor are
discussed separately. (See "Treatment of bleeding and perioperative
management in hemophilia A and B", section on 'Inhibitors'.)
Some PCC products contain heparin and should not be used in an individual
with a history of heparin-induced thrombocytopenia.
Recombinant activated factor VII (rFVIIa)
●Indications and uses – rFVIIa is licensed for prevention of surgical bleeding
in patients with hemophilia who have developed an inhibitor to factor VIII or
factor IX, as discussed separately. (See "Treatment of bleeding and
perioperative management in hemophilia A and B", section on 'Inhibitors'.)
rFVIIa has been used off-label in selected non-hemophilic patients with
bleeding related to trauma or as a hemostatic agent in patients with intractable
bleeding [29,147,148]. (See "Recombinant factor VIIa: Administration and
adverse effects", section on 'Off-label uses'.)
Information regarding efficacy of rFVIIa is largely anecdotal. Systematic
reviews have not found a great impact on morbidity and mortality, although
transfusion requirements may be reduced [149-152]. (See "Recombinant factor
VIIa: Administration and adverse effects", section on 'General evidence for
off-label use'.)
●Dosing – Cautious dosing of rFVIIa is advised since optimal dosing for off-
label use is unknown. Administration can be started with small incremental
 doses of 10 to 30 mcg/kg approximately every 15 minutes to a total dose of up
to 90 mcg/kg. Selected patients with massive coagulopathic bleeding may be
given an initial dose of 90 mcg/kg. Dosing practices vary widely because data
are lacking regarding optimal dosing and there are no laboratory tests to
monitor drug effect or efficacy. (See "Recombinant factor VIIa:
Administration and adverse effects", section on 'General approach to
administration'.)
●Risks – An increased risk of arterial thromboembolic events has been noted
in some trials, particularly in patients with intracranial hemorrhage and those
undergoing cardiac surgery [149-152]. Risk for thrombotic complications may
be less when a low dose (eg, 10 to 30 mcg/kg) is used [150,153]. Off-label use
of rFVIIa may be associated with increased mortality and morbidity (eg, renal
failure), especially in older patients and when higher doses are administered
[40,147,150,154,155].
Desmopressin (DDAVP) — DDAVP increases plasma levels of von Willebrand
factor, factor VIII, and tissue-type plasminogen activator (tPA) by causing these
factors to be released from platelets and endothelial cells.
●Indications and uses – In consultation with a hematologist, DDAVP is
administered prophylactically for minor surgery or treatment of mild bleeding
in selected patients with von Willebrand disease (vWD) or mild hemophilia A
for whom a positive response to the drug has been demonstrated previously
[156] (table 9). (See "Treatment of bleeding and perioperative management in
hemophilia A and B", section on 'DDAVP for mild hemophilia A' and "von
Willebrand disease (VWD): Treatment of minor bleeding and routine care",
section on 'DDAVP'.)
DDAVP has also been administered to treat clinically significant
intraoperative microvascular bleeding in patients with acquired platelet defects
due to uremia or acquired von Willebrand syndrome (eg, due to chronic aortic
stenosis or presence of a left ventricular assist device) [40,157].
(See "Acquired von Willebrand syndrome", section on 'Treatment of acute
bleeding' and "Platelet dysfunction in uremia".)
DDAVP may be beneficial in certain other settings (eg, intractable
microvascular bleeding due to hypothermia, acidosis, aspirin use, CPB), but
reduction in transfused RBC volume is small and unlikely to be clinically
significant compared with placebo [29,158,159]. Generalized perioperative use
is not warranted [13,29,40]. (See "Coagulopathy in trauma patients", section
on 'Pharmaceutical hemostatic agents' and "Reversal of anticoagulation and
management of bleeding after cardiopulmonary bypass", section on
'Desmopressin (DDAVP)'.)
 ●Dosing – The DDAVP dose is 0.3 mcg/kg, administered intravenously by
slow infusion over 30 minutes to minimize hypertension, hypotension, and
flushing (table 9). Tachyphylaxis typically develops after the second dose.
●Risks – In addition to hypertension, hypotension, and flushing, possible
adverse side effects include fluid overload, hyponatremia (which may cause
seizures if close attention to free water restriction is not used), and rare
thrombotic events (table 9). Monitoring of serum sodium is prudent in patients
receiving more than one or two doses.

POSTOPERATIVE STRATEGIES Restrictive transfusion thresholds and

individualized goal-directed treatment of coagulopathy with bleeding remain

important in the postoperative period [1,160].
Close monitoring for bleeding — During the first few hours following the
surgery, patients should be closely monitored to detect signs of persistent bleeding
of unacceptable quantity and tempo [1]. Medical causes of bleeding should be
investigated and treated.
Management of postoperative anemia — Postoperative anemia is common due
to exacerbation of pre-existing anemia, blood loss during surgery, and excessive
postoperative phlebotomies ]. Anemia may be further aggravated by reduced
erythropoietin (EPO) production due to inflammatory mediators, blunted bone
marrow response to EPO, and decreased iron availability, similar to patients with
critical illness.
Excessive diagnostic blood draws should be avoided since this can contribute
significantly to blood loss and development of hospital-acquired anemia
[1,28,166]. Perioperative blood sampling for laboratory tests should be minimized
(eg, by using smaller collection tubes when feasible). Standing orders for
laboratory tests are generally avoided; rather, tests are ordered if indicated.
When anemia is noted in the postoperative period, a diagnostic workup is
performed to determine its cause, as illustrated in the algorithm (algorithm 2),
incorporating information from the workup done in the preoperative period (eg,
iron studies) [161,167]. As with preoperative anemia, postoperative anemia should
not be overlooked or neglected [1,30,161]. Since postoperative anemia is usually
due to surgical blood loss, iron studies are usually appropriate, especially if anemia
and/or microcytosis persist for more than one to two weeks. Subcutaneous
erythropoietin has been administered in selected patients (eg, after major trauma
surgery).
Transfusion may be required if the postoperative hemoglobin is <7.0 g/dL or if
there are signs of tissue hypoxia.
Postoperative blood salvage — Postoperative blood salvage (also known as blood
recovery) is occasionally performed during recovery following selected surgical
procedures (eg, certain orthopedic procedures), with washing and filtering drained
blood followed by reinfusion into the patient.

CLINICAL VIGNETTES The following hypothetical clinical case

examples illustrate the principles discussed in this topic:

●A 40 year old woman presents to the emergency department following a
motor vehicle crash and requires emergency splenectomy. As she arrives in the
operating room, report comes from the emergency department that her
complete blood count (CBC) is abnormal with mild pancytopenia (white blood
count 3000/microL; hemoglobin 8 g/dL; platelet count 70,000/microL).
Surgery is performed, with point of care testing revealing a decrease in
hemoglobin to 6 g/dL; hemostasis is maintained. She receives a total of two
units of red blood cells intraoperatively, administered in one unit increments
with hemoglobin determination after the first unit showing a hemoglobin of
6.2 g/dl. Postoperatively she is evaluated by the consulting hematologist to
evaluate the cause of pancytopenia.
This case illustrates a setting in which the need for emergency surgery does
not allow sufficient time to perform a full evaluation of the cause of anemia;
clinical judgment determines that transfusion of one unit at a time may be
required in the short term; and specialist evaluation is required prior to
discharge from the hospital.
●A 52 year old man with no underlying medical conditions except for chronic
knee pain due to a prior sports injury is seen two weeks preoperatively for
knee replacement surgery. His report of recent fatigue and mild dyspnea on
exertion prompts testing of his hemoglobin level, which is found to be low at
10 g/dL. Review of his CBC reveals microcytosis (mean corpuscular volume
[MCV], 79 fL), and iron studies reveal iron deficiency with a ferritin level of
10 ng/mL, consistent with iron deficiency anemia. He is treated with iron and
undergoes colonoscopy, which identifies a large bleeding polyp that is
removed. Iron replacement is continued. Four weeks later, his hemoglobin has
risen to 14 g/dL with resolution of his fatigue and dyspnea.  
After treatment of iron deficiency anemia, he undergoes knee replacement,
with antifibrinolytic therapy administered during the procedure. Blood loss is
approximately 500 mL, and his postoperative hemoglobin level is 12 g/dL.
Transfusion is unnecessary and thus avoided. With the help of a new primary
care doctor, he continues iron to completely replete iron stores, and he
 undergoes regular screening colonoscopy. (See "Causes and diagnosis of iron
deficiency and iron deficiency anemia in adults" and "Treatment of iron
deficiency anemia in adults".)
This case illustrates the importance of treating correctable causes of anemia in
the preoperative period to minimize the likelihood of transfusion, the use of
intraoperative fibrinolytic therapy, and the need for postoperative follow-up.
Surgical blood loss may have been further reduced by implementing blood cell
salvage techniques.
●A 65 year old woman with type 2 diabetes mellitus has been highly adherent
with therapy and eats a well-balanced diet but continues to have mild anemia
due to her underlying diabetes and high body mass index (ie, anemia of
chronic inflammation). Her primary clinician has performed iron studies and
testing for vitamin B12 deficiency and found her levels to be adequate. She
has decided to pursue laparoscopic bariatric surgery and is seen two weeks
preoperatively. The preoperative evaluation includes review of her CBC
obtained one week earlier by her primary clinician, who documents a mild
anemia with a hemoglobin of 11.5 g/dL with normal red blood cell indices.
Discussion regarding possible postponement of surgery included the patient,
primary care clinician, surgeon, and anesthesiologist, resulting in a decision to
proceed as scheduled in order to help treat the underlying conditions that may
be contributing to her anemia. Appropriate intraoperative strategies are used to
avoid exacerbation of anemia (eg, fluid and temperature management,
fastidious hemostasis during surgical dissection). No transfusions are
administered.
This case illustrates the need for individual evaluation of patients with chronic
conditions that result in anemia, in order to exercise good clinical judgment
regarding decisions to proceed with a specific surgical procedure.
Importantly, the underlying cause of the anemia is addressed in each of these cases.
What differs is the decision regarding whether to proceed with surgery as planned
or to delay surgery to allow treatment of anemia.

ndications and hemoglobin thresholds for red blood cell transfusion in the
adult
Authors:
Jeffrey L Carson, MD
Steven Kleinman, MD
Section Editor:
Arthur J Silvergleid, MD
Deputy Editor:
Jennifer S Tirnauer, MD

INTRODUCTION

For many decades, the decision to transfuse red blood cells (RBCs) was based
upon the "10/30 rule": transfusion was used to maintain a blood hemoglobin
concentration above 10 g/dL (100 g/L) and a hematocrit above 30 percent [1].
However, concern regarding transmission of blood-borne pathogens and efforts at
cost containment caused a re-examination of transfusion practices in the 1980s.
The 1988 National Institutes of Health Consensus Conference on Perioperative
Red Blood Cell Transfusions suggested that no single criterion should be used as
an indication for red cell component therapy, and that multiple factors related to
the patient's clinical status and oxygen delivery needs should be considered [2].
During the subsequent 30 years, a large body of clinical evidence was generated,
resulting in the publication of many guidelines for RBC transfusion in different
settings (see 'Society guidelines' below). A common theme of these guidelines is
the need to balance the benefit of treating anemia with the desire to avoid
unnecessary transfusion, with its associated costs and potential harms. This
requires considerable diagnostic skill and acumen on the part of physicians
ordering transfusions.
As blood transfusion practices are evaluated in randomized trials, we are
increasingly able to emphasize clinical trial data, since these data provide the best
evidence to guide transfusion decisions.
The indications and thresholds for RBC transfusion in adults will be reviewed here.
Separate topics discuss indications and thresholds for newborns and children.
(See "Red blood cell transfusions in the newborn" and "Red blood cell transfusion
in infants and children: Indications".)
General aspects of RBC collection, storage, safety, and administration, as well as
practices for some special populations, are presented separately.