18/4/23, 15:55 Intraoperative transfusion and administration of clotting factors - UpToDate

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Intraoperative transfusion and administration of

clotting factors
Authors: Thomas J Graetz, MD, Gregory Nuttall, MD
Section Editors: Michael F O'Connor, MD, FCCM, Steven Kleinman, MD
Deputy Editors: Nancy A Nussmeier, MD, FAHA, Jennifer S Tirnauer, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2023. | This topic last updated: Jan 20, 2023.

INTRODUCTION

This topic will review general principles guiding intraoperative decisions to transfuse blood
products, and the indications and risks for administration of specific components.

Strategies employed to avoid or minimize perioperative transfusion are discussed

separately. (See "Perioperative blood management: Strategies to minimize transfusions".)

The following intraoperative circumstances are discussed separately:

● Cardiac surgery following cardiopulmonary bypass – (See "Achieving hemostasis after

cardiac surgery with cardiopulmonary bypass", section on 'Transfusion of red blood
cells'.)

● Need for massive transfusion during surgery – (See "Massive blood transfusion".)

Indications for and general risks associated with transfusion of specific blood products in
any setting are addressed in separate topics:

● Red blood cells (adults) (see "Indications and hemoglobin thresholds for red blood cell
transfusion in the adult")
● Red blood cells (children) (see "Red blood cell transfusion in infants and children:
Indications")
● Plasma (see "Clinical use of plasma components")
● Platelets (see "Platelet transfusion: Indications, ordering, and associated risks")
● Cryoprecipitate (see "Clinical use of Cryoprecipitate")

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PREPARATIONS FOR LARGE EXPECTED BLOOD LOSSES

Elective surgery with risk for significant blood loss

● Estimate expected blood loss – For elective procedures associated with clinically
significant bleeding, the patient's total blood volume and the overall amount and rate
of expected blood loss are estimated in the preoperative period in consultation with
the surgeon. (See 'Estimating blood loss' below.)

● Type and crossmatch – Pretransfusion testing (typing and crossmatching) for red
blood cells (RBCs) is routinely performed in the preoperative period for selected
procedures with known risk for significant blood loss. For cases with the potential for
sudden significant blood loss (eg, open repair of abdominal aortic aneurysm, hepatic
resection), RBC units should be available in the operating room (OR) before surgical
incision. If large volume blood loss is possible, preoperative communication between
the anesthesiologist and the transfusion service is necessary to ensure that additional
RBC units and other blood products will be readily available during the surgical
procedure, and that there are no risk factors affecting access to additional cross-
matched units (eg, rare blood type or known RBC alloantibodies). (See "Pretransfusion
testing for red blood cell transfusion".)

In addition to procedure-specific factors, the likelihood of transfusion is also influenced

by preoperative laboratory evidence of coagulopathy and by anemia [1,2]. In a large
retrospective study of 672,075 patients who had a coagulation profile obtained before
common elective noncardiac and cardiac surgical procedures, abnormal findings in the
preoperative international normalized ratio (INR) or platelet count were associated with
risk of bleeding requiring transfusion during both the intraoperative and postoperative
periods [3]. Preoperative anemia should be addressed before any elective surgical
procedure if possible (ie, the underlying cause determined and optimal treatment
provided). Details are discussed separately. (See "Perioperative blood management:
Strategies to minimize transfusions", section on 'Treatment of anemia'.)

● Prepare for blood conservation techniques if appropriate – In some cases,

management includes planning for blood conservation techniques such as
preoperative autologous blood donation (PAD), intraoperative acute normovolemic
hemodilution (ANH), and/or intraoperative blood salvage to avoid or minimize the need
for allogeneic transfusions. Indications, candidate selection, and technical aspects of
these surgical blood conservation techniques are discussed separately:

• PAD – (See "Surgical blood conservation: Preoperative autologous blood donation".)

• ANH – (See "Surgical blood conservation: Acute normovolemic hemodilution".)

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• Blood salvage – (See "Surgical blood conservation: Blood salvage".)

Emergency surgery with possibility of massive blood transfusion — For patients with
hemorrhage who will undergo emergency surgery and may require massive transfusion,
early communication with the institutional blood bank or transfusion medicine service is
necessary to activate a massive transfusion protocol to order appropriate amounts and
types of blood components. Details are discussed in a separate topic. (See "Massive blood
transfusion".)

Typically, RBCs, plasma products such as Fresh Frozen Plasma (FFP), and platelets are
ordered and transfused in approximately equal (1:1:1) ratios as soon as these blood products
are available (either before and/or during surgery). If RBC units have not been made
available and blood is urgently needed, the transfusion service can provide "immediate
release" blood without pretransfusion testing.

Examples of surgical cases that may require early activation of a massive transfusion
protocol include:

● Trauma surgery – (See "Massive blood transfusion", section on 'Trauma' and "Initial
management of moderate to severe hemorrhage in the adult trauma patient".)

● Aortic rupture – (See "Surgical and endovascular repair of ruptured abdominal aortic
aneurysm", section on 'Preparation'.)

● Obstetric catastrophes – (See "Postpartum hemorrhage: Management approaches

requiring laparotomy" and "Postpartum hemorrhage: Medical and minimally invasive
management".)

TECHNICAL ASPECTS OF BLOOD TRANSFUSION

Establishing intravenous access — If significant blood loss is anticipated, adequate

intravenous (IV) access is necessary for possible blood product transfusion(s). If rapid fluid
and blood product administration is anticipated, large-bore catheters with short lumens
should be employed for optimal flow, in addition to the use of rapid infusion systems that
will allow administration of large volumes more quickly [4,5]. If patient positioning for the
planned surgical procedure will create challenges for obtaining additional access, all IV
catheters should be inserted prior to final positioning, with confirmation of patency and flow
after final patient positioning.

Either peripheral or central routes of access may be selected:

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● Peripheral venous access – Large-bore (eg, 14 or 16 gauge) peripheral IV catheters (or

a short 7 French rapid infusion catheter inserted using a modified Seldinger technique)
may be selected [6,7]. Peripheral catheters are typically placed in the upper extremities.
Compared with a central venous catheter (CVC), peripheral catheters are generally
associated with fewer complications. However, large-bore peripheral venous access is
not feasible in some patients due to body habitus, vein fragility, or prior use of multiple
peripheral veins. (See "Peripheral venous access in adults".)

● Central venous access – A single-lumen, large-bore central venous introducer sheath

or other CVC with large lumen(s) provides reliable access for blood and fluid
administration, as well as central venous access for infusion of vasoactive agents.
Either a multilumen CVC or a large, single-lumen introducer sheath (typically, 8.5
French) may be used. Multilumen catheters have limited flow properties due to long
length and smaller lumens, while an introducer sheath allows rapid flow through its
single lumen (and may be used for later placement of a pulmonary artery catheter
[PAC] if necessary) [8,9]. (See "Central venous access in adults: General principles".)

Avoiding transfusion errors — Practices to ensure that the intended transfusion is given to
the intended recipient are critical for preventing serious transfusion reactions. It is more
likely that individuals will bypass manual system checks that are in place to avoid errors
during urgent surgical cases compared with other settings. Safety improvements such as
barcode scanners installed in operating rooms increase adherence to protocols and may
decrease likelihood of transfusion errors [10,11]. (See "Practical aspects of red blood cell
transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-
transfusion considerations'.)

Use of filters — All red blood cell (RBC) units, plasma products, and platelets must be
transfused through a standard 170 to 260 micron filter (contained as an integral part of a
standard infusion set), which is designed to remove clots and aggregates.

In the United States, most blood product units released for transfusion are leukoreduced at
the time of collection. If pre-storage leukoreduction was not performed, an add-on filter for
leukoreduction may be used. (See "Practical aspects of red blood cell transfusion in adults:
Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction'.)

Thawing and warming products, use of blood warmers — Frozen blood products are not
thawed unless it is likely that they will be needed. Refrigerated products such as RBCs should
be kept cold until a decision has been made to transfuse each one.

● RBCs and plasma – When possible, cold and previously thawed blood products (RBC
units and plasma products) should be administered via a blood warmer to avoid

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causing systemic hypothermia with resultant coagulopathy and other adverse effects
[12-19].

● Cryoprecipitate and platelets – Cryoprecipitate units are thawed to room

temperature and should be administered within four to six hours of thawing; use of a
blood warmer is unnecessary. Platelets are stored at room temperature and are
typically infused via separate intravenous tubing that is not connected to a blood
warmer. However, if the patient is hypothermic, use of a blood warmer to administer
cryoprecipitate or platelets is not prohibited [20]. (See "Practical aspects of red blood
cell transfusion in adults: Storage, processing, modifications, and infusion", section on
'Administering the transfusion'.)

Administration with compatible fluids — Only compatible fluids are coadministered with
RBCs through the IV tubing (see "Practical aspects of red blood cell transfusion in adults:
Storage, processing, modifications, and infusion", section on 'Compatible fluids'):

● If dilution of packed RBCs is necessary (such as during rapid intraoperative

transfusion), the blood banking community recommends 0.9 percent saline (normal
saline).

● Normal saline, albumin, or plasma can be administered through the same tubing as
RBCs. Modern rapid infusion devices have reservoirs into which practitioners can add
RBCs and fresh frozen plasma (FFP) in their desired combination (typically one FFP unit
for each RBC unit).

● In practice, anesthesiologists often coadminister other isotonic crystalloid solutions

that have sodium and other electrolyte composition similar to plasma (eg, lactated
Ringer's solution, Plasmalyte, Normosol) without adverse events.

● Dextrose (5 percent in water) or hypotonic solutions (eg, 0.45 percent saline) should
never be coadministered with RBCs, because RBCs will take up glucose and/or free
water and lyse. Hypertonic solutions (eg, 3 percent saline) are also avoided.

Other blood products (eg, platelets, cryoprecipitate) should be administered alone via
separate tubing, or in tubing containing 0.9 percent sodium chloride. Importantly,
cryoprecipitate may clot in IV tubing if that tubing still contains active thrombin from
previously transfused blood products such as platelets [21,22].

Returning unused products — Unused blood products are returned to the blood bank for
possible use in another patient or appropriate disposal.

To avoid wastage, RBCs should be removed from refrigerated storage immediately before
use and should never be left to warm up at room temperature for long periods. RBC units

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that were not transfused should be returned to the blood bank with notation regarding the
duration they were out of refrigeration. This helps with record-keeping and patient contact
should a lookback be required. The blood bank will not transfuse RBCs to another person if
they were out of refrigeration for 30 to 60 minutes [23]. (See "Practical aspects of red blood
cell transfusion in adults: Storage, processing, modifications, and infusion", section on
'Storage/transport temperature'.)

Blood products that are not needed are never transfused to avoid wastage, because this
exposes the patient to unnecessary risks.

GENERAL PRINCIPLES FOR TRANSFUSION DECISIONS

When to transfuse — Major factors influencing intraoperative decisions to transfuse red

blood cells (RBCs) and other blood components include estimates of the amount of current
and expected ongoing blood loss, evidence of intractable microvascular bleeding indicating
abnormal hemostasis, and clinical signs of anemia (eg, tachycardia, hypotension, dilute-
appearing blood in the surgical field, pallor) and/or coagulopathy (eg, persistent
microvascular bleeding). Ideally, confirmation with diagnostic testing for anemia and
hemostatic function is obtained before transfusion.

For individuals without rapid bleeding, further administration of RBCs is avoided if the
hemoglobin concentration is >7 to 8 g/dL for a young healthy patient (or <9 g/dL for older
patients with high risk or evidence of ischemia). Supporting evidence for using a restrictive
transfusion threshold and possible exceptions are discussed separately and below. (See 'Red
blood cells' below and "Indications and hemoglobin thresholds for red blood cell transfusion
in the adult".)

Also, further administration of other blood products is avoided if active microvascular and
surgical bleeding have ceased. However, individuals with active ongoing bleeding may
require additional transfusions. When bleeding is too rapid to be monitored with
measurements of hemoglobin concentration, the number of transfused units is
individualized according to estimated ongoing blood loss.

Estimating blood loss — There is no clear consensus regarding optimal methods for
assessing blood loss. The following methods are used but are subject to inaccuracies [24-31]:

● Subjective estimates of blood loss, typically based on periodic visual assessment of the
surgical field and communication with the surgeon regarding excessive microvascular
bleeding at surgical dissection or wound sites and perceived volume and persistence of
blood loss.

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● Estimates based on standard quantitative methods including monitoring blood suction

canister volumes, the number and degree of saturation of surgical sponges and
drapes, as well as serial laboratory measurements.

● Trends in hemoglobin concentration.

Intraoperative diagnostic testing — Estimates of blood loss may prompt testing for
anemia and hemostatic function to determine if administration of RBCs or other blood
products is indicated (plasma, platelets, cryoprecipitate). These decisions are based in part
on results of these tests, but the context of the intraoperative clinical situation is always
considered. (See 'Indications and risks for specific blood products' below.)

Standard tests — Standard laboratory tests include hemoglobin concentration and/or

hematocrit. In intraoperative settings, results of these tests may be available within a few
minutes depending on local laboratory resources.

Standard coagulation tests (prothrombin time [PT], international normalized ratio [INR], and
activated partial thromboplastin time [aPTT]), fibrinogen level, and platelet count are
obtained if coagulopathy is suspected. The time required for processing and reporting
standard coagulation tests, platelet count, and fibrinogen concentration is typically 45 to 90
minutes and may be longer. Thus, the utility of these standard tests for assessing cause(s) of
bleeding and coagulopathy is limited in rapidly changing intraoperative situations.

Point-of-care tests — When available, rapid point-of-care (POC) tests can provide more
timely information compared with standard tests, allowing more rapid decision-making
regarding the need for targeted transfusion of blood products.

Hemoglobin or hematocrit measurements — In many institutions, rapid estimates

of hemoglobin or hematocrit are obtained using arterial blood gas machines located in or
near the operating room. We also use an automated analyzer for POC complete blood
counts.

Although POC instruments to measure hemoglobin are available, these are not as accurate
as standard laboratory measurements [32-37]. Accuracy can be altered by sample source
(hemoglobin measurements are highest in capillary > venous > arterial blood samples), use
of a tourniquet which falsely lowers hemoglobin levels, and administration of intravenous
fluids which may acutely hemodilute the blood sample and decrease the hemoglobin level
[36,37].

Tests of hemostatic function — POC tests of hemostatic function allow rapid

assessment of coagulopathy and responses to blood product transfusion. We agree with
professional society recommendations regarding use of viscoelastic POC methods, if
available (eg, thromboelastography [TEG] or an adaptation of TEG known as rotational
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thromboelastometry [ROTEM]), to test overall hemostatic function during selected surgical

procedures such as cardiac surgery or liver transplant [38-48]. The role of viscoelastic POC
methods continues to develop in other patient populations with significant bleeding,
including obstetrics and orthopedic surgery [49].

With TEG or ROTEM tests, a tracing result provides information regarding clot initiation,
kinetics of clot formation, clot strength, and fibrinolysis ( figure 1 and figure 2 and
table 1):

● Primary fibrinolysis ( figure 3A-B)

● Secondary hyperfibrinolysis ( figure 3A, 3C)
● Thrombocytopenia ( figure 3A, 3D)
● Clotting factor consumption ( figure 3A, 3E)
● Hypercoagulability ( figure 3A, 3F)

In general, randomized trials and observational studies in surgical patients have noted that
use of viscoelastic testing (in conjunction with a transfusion algorithm) reduces RBC and
possibly FFP and platelet transfusions, compared with standard care based on standard
laboratory coagulation tests and/or clinical judgment, although results are inconsistent,
particularly in noncardiac surgical procedures [43,48,50-86]. Evidence presented in meta-
analyses has been limited by heterogeneity among studies since the TEG or ROTEM
parameters used for a transfusion algorithm or protocol were institution-specific for each
study, as well as high risk of bias, imprecision, and/or indirectness [50-55,74,76,77].

TEG-based transfusion of blood products is also commonly used to manage the acute
coagulopathy associated with trauma. Viscoelastic testing can be performed rapidly;
however, patients requiring resuscitation using a rapid transfuser device are less likely to
benefit from such testing compared with patients with lower transfusion requirements. (See
"Clinical use of coagulation tests", section on 'Point-of-care testing' and 'Use of a transfusion
algorithm or guideline' below and "Coagulopathy in trauma patients", section on
'Thromboelastography' and "Coagulopathy in trauma patients", section on
'Thromboelastography-based transfusion'.) .

However, POC viscoelastic tests are not available in every institution [87]. Even in institutions
that do use these POC tests, standard laboratory coagulation tests are also recommended to
provide additional information [42].

POC aggregometry, which tests platelet function, may be performed if available and if
platelet dysfunction is suspected. Detecting a residual effect of P2Y12 inhibitors may be
helpful in the setting of mild to moderate bleeding. However, testing for platelet dysfunction
may not be useful in an actively bleeding patient if results are not immediately available, and
the accuracy of most tests depends on a relatively normal platelet count. Also, these tests

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are not accurate after cardiopulmonary bypass due to dilutional changes and platelet
activation [88]. (See "Coagulopathy in trauma patients", section on 'Platelet dysfunction' and
"Clinical use of coagulation tests" and "Platelet function testing".)

Use of a transfusion algorithm or guideline — Similar to recommendations in the practice

guidelines of several professional societies, we use a goal-directed protocol or algorithm to
guide transfusion decisions based on measurement of hemoglobin or hematocrit and
assessment of specific abnormalities of hemostasis, either obtained from standard
laboratory tests or POC viscoelastic coagulation tests (eg, TEG ( table 1 and table 2) or
ROTEM) [38-47,86].

Overall, use of an algorithm reduces unnecessary transfusions of RBCs, plasma products,

platelets, and cryoprecipitate while allowing optimal treatment of coagulopathy during
major surgical procedures. However, no trials have prospectively compared different
algorithms. (See 'Standard tests' above and 'Point-of-care tests' above.)

For patients with severe and ongoing or massive hemorrhage, transfusion decisions are not
based exclusively on the most recent hemoglobin value and tests of hemostasis. In such
patients, more aggressive transfusion may be necessary to compensate for ongoing blood
loss, as discussed separately. (See "Massive blood transfusion", section on 'Approach to
volume and blood replacement'.)

INDICATIONS AND RISKS FOR SPECIFIC BLOOD PRODUCTS

Red blood cells

● Use of a restrictive transfusion strategy – We transfuse autologous, salvaged, or

allogeneic red blood cell (RBC) units when hemoglobin is <7 to 8 g/dL (approximately
equivalent to a hematocrit ≤21 to 24 percent) in most cardiac and noncardiac surgical
patients without significant ongoing bleeding. These threshold values are similar to the
guidelines of several professional societies for use of a restrictive transfusion strategy
[38-40,42,44-47,89,90]. (See "Indications and hemoglobin thresholds for red blood cell
transfusion in the adult", section on 'Overview of our approach'.)

Trials in surgical patients have compared restrictive transfusion strategies (typically

defined as Hgb <7 or <8 g/dL) versus more liberal transfusion strategies (typically
defined as Hgb <9 or <10 g/dL). Most have noted decreases in the number of RBC units
transfused in patients managed with a restrictive strategy, without higher incidences of
adverse events (eg, mortality, myocardial infarction, stroke, renal failure, infection) with
either strategy [39,42,44-47,91-107]. However, data are inconsistent; some studies have
noted associations of a restrictive strategy with increased risk of mortality or other

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adverse outcomes [108,109]. Important limitations of trials comparing restrictive

versus liberal transfusion strategies include variability in post-transfusion hemoglobin
targets, difficulties in precisely maintaining a selected target, differences in endpoints
(eg, percentage of patients transfused versus number of units transfused per patient),
and differences in the time periods studied (eg, intraoperative, postoperative, or both
periods) [110]. These trials are summarized in a separate topic. (See "Indications and
hemoglobin thresholds for red blood cell transfusion in the adult", section on
'Thresholds for specific patient populations'.)

However, decisions to transfuse RBC units are carefully considered and individualized.
For example, if a patient is known to tolerate a hemoglobin concentration <8 g/dL, then
it may be possible to avoid transfusion. Conversely, we typically use a hemoglobin
threshold of <9 g/dL (approximately equivalent to a hematocrit ≤27 percent) in patients
with known acute coronary syndrome or signs of myocardial or other organ ischemia
[91,92,108,111-117]. Myocardial ischemia may be diagnosed by changes noted on the
electrocardiogram (ECG), pulmonary artery catheter (PAC), or with transesophageal
echocardiography (TEE), while poor perfusion and ischemia of other organs may
manifest as increased lactate levels or decreased mixed venous oxygen saturation, or
urine output. Also, in cases with rapid blood loss or significant ongoing bleeding,
immediate transfusion may be life-saving and necessary before quantitative laboratory
assessment of hemoglobin can be obtained, based on the rate of bleeding, expected
volume of ongoing bleeding, and the preoperative red cell mass. However, there is
general consensus that transfusion of packed RBC units is indicated if Hgb <6 g/dL, and
that transfusion is rarely indicated if Hgb >10 g/dL. (See "Indications and hemoglobin
thresholds for red blood cell transfusion in the adult", section on 'Thresholds for
specific patient populations'.)

We reassess hemoglobin levels after transfusion to inform decisions regarding whether

additional RBC units are needed. Accurate assessment of a post-transfusion
hemoglobin level can be performed as early as 15 minutes following RBC
administration (in the absence of ongoing active bleeding) [118,119]. However, when
blood loss is rapid and significant, immediate life-saving transfusion may be necessary
before quantitative laboratory assessment of hemoglobin can be obtained, based on
the rate of bleeding and expected total volume of blood [39,40]. Although noninvasive
hemoglobin measurements are still obtained in such situations, these will not
accurately reflect the degree of reduced red cell mass [37].

● Risks of transfusion – There are inherent risks associated with either perioperative
transfusion of RBCs or severe anemia [120].

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Adverse events occur in individuals receiving transfusions; however, these are likely to
be related to the severity of comorbidities rather than actual complications of
transfusion. Cause and effect has not been demonstrated for any of them:

• Infection [121-124]
• Cardiovascular complications [120,125]
• Mortality [108,109,119-121,124,126]
• Acute kidney injury [103,104,120,127]

General risks associated with transfusion of RBCs are noted below (see 'Risks of blood
product transfusion' below).

Massive transfusion can be associated with metabolic complications [128,129]. (See

"Massive blood transfusion", section on 'Complications' and "Early noncardiac
complications of coronary artery bypass graft surgery", section on 'Blood transfusion'.)

● Risks of severe anemia – Severe anemia has been associated with higher mortality in
surgical patients [130-132]. In one study of patients who refused perioperative
transfusion, mortality was 21 percent in those with a hemoglobin nadir of 6.1 to 7 g/dL,
but increased to 41 percent in those with a lower hemoglobin nadir of 5.1 to 6 g/dL
[130]. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the
adult", section on 'Rationale for transfusion'.)

Platelets

● Indications – Similar to recommendations in the practice guidelines of several

professional societies, we transfuse platelets to maintain adequate platelet count in
surgical patients, typically >50,000/microL or >100,000/microL when central nervous
system bleeding is present or likely [38-47,86,133]. Platelet transfusions are also a
component of massive transfusion protocols. (See "Platelet transfusion: Indications,
ordering, and associated risks", section on 'Indications for platelet transfusion'.)

Abnormalities of platelet function affect hemostasis even if platelet count is adequate.

Thus, if ongoing bleeding is suspected to be due to qualitative platelet defects, platelet
transfusion may be used [133]. Examples include emergency surgery in patients with
qualitative platelet defects caused by chronic use of antiplatelet agents that inhibit
cyclooxygenase, glycoprotein IIb/IIIa, and/or adenosine diphosphate (ADP), or uremic
platelet dysfunction when there is insufficient time for dialysis. (See "Uremic platelet
dysfunction", section on 'Invasive procedures'.)

Platelet dysfunction due to aspirin, dipyridamole, P2Y12 receptor antagonists, or

reversible GP IIbIIIa antagonists (eg, eptifibatide) may not be detected by point-of-care

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(POC) viscoelastic tests such as thromboelastography (TEG) or rotational

thromboelastometry (ROTEM) [48,134]. (See 'Tests of hemostatic function' above.)

Further information regarding the utility of POC tests of coagulation for diagnosis of
platelet-dependent bleeding is available in separate topics:

• (See "Platelet transfusion: Indications, ordering, and associated risks", section on

'Specific clinical scenarios'.)
• (See "Clinical use of coagulation tests", section on 'Point-of-care testing'.)
• (See "Coagulopathy in trauma patients", section on 'Thromboelastography-based
transfusion'.)

We typically avoid prophylactic intraoperative platelet transfusions in patients who are

not bleeding, especially if the platelet count is >50,000/microL [135]. Exceptions may be
made if consequences of even minor bleeding would be severe (eg, ophthalmic
procedures or neurosurgery), or if a surgical procedure is likely to cause significant
bleeding. (See "Platelet transfusion: Indications, ordering, and associated risks", section
on 'Actively bleeding patient'.)

● Preparations – Platelets can be obtained by apheresis from a single donor or as

pooled units of whole blood derived platelets (typically derived from whole blood
donations from four to six different donors) ( table 3). One apheresis unit is
equivalent to four to six pooled platelet units. Although exact platelet quantities vary,
each platelet dose (one apheresis unit or a pool of whole blood derived platelets)
contains approximately 3 to 4 x 1011 platelets suspended in 200 to 300 mL of plasma
and will increase the platelet count by approximately 30,000/microL to 50,000/microL in
a non-bleeding adult ( table 3). (See "Platelet transfusion: Indications, ordering, and
associated risks", section on 'Whole blood derived (WBD) versus apheresis platelets'.)

● Risks – General risks of platelet transfusion are the same as other blood products, as
noted below (see 'Risks of blood product transfusion' below).

Historically, the risk of bacterial infection is higher with platelet transfusion compared
with other blood products due to storage at room temperature; this increased risk has
been substantially mitigated by the addition of risk reduction methods (eg, bacterial
culture and pathogen inactivation). Rarely, post-transfusion purpura may occur. (See
"Transfusion-transmitted bacterial infection".)

Plasma

● Indications – The main indication for plasma products such as Fresh Frozen Plasma
(FFP) or Plasma Frozen within 24 Hours of Collection (PF24) is reversal of warfarin in
preparation for urgent surgery when a prothrombin complex concentrate (PCC) is not
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available ( table 4). (See "Perioperative management of patients receiving

anticoagulants", section on 'Urgent/emergency invasive procedure' and "Management
of warfarin-associated bleeding or supratherapeutic INR", section on 'Urgent
surgery/procedure'.)

Similar to recommendations in the practice guidelines of several professional societies,

other intraoperative uses of plasma include ( table 3) [38-47]:

• As a component of massive transfusion protocols. (See "Massive blood transfusion",

section on 'Approach to volume and blood replacement'.)

• In patients with ongoing clinically significant bleeding, particularly if intracranial

hemorrhage is present, if there are suspected or documented severe abnormalities
of clotting (eg, international normalized ratio [INR] >2.0 or abnormalities of
viscoelastic testing due to vitamin K deficiency) ( figure 3A, 3E) [48]. (See 'Tests of
hemostatic function' above and 'Standard tests' above.)

However, plasma products are not administered to stable nonbleeding patients

solely to "correct" a mildly elevated INR (eg, INR up to 2) [136]. The rationale is
discussed separately. (See "Clinical use of plasma components", section on 'Settings
in which plasma is not appropriate'.)

• Other rare indications that may be relevant in the perioperative period are
discussed separately. (See "Clinical use of plasma components", section on
'Overview of indications'.)

● Risks – Risks of FFP transfusion are noted below (see 'Risks of blood product
transfusion' below).

Cryoprecipitate or fibrinogen concentrate — As stated in the practice guidelines of several

professional societies [38-47], Cryoprecipitate or fibrinogen concentrate is administered to
patients with clinically significant bleeding when the fibrinogen concentration is <150 mg/dL
or when hypofibrinogenemia is suspected and fibrinogen cannot be measured in a timely
fashion ( table 3) [85,137-140]. Abnormally low concentrations of fibrinogen can result in
impaired clot formation and increased bleeding.

Clinical use of Cryoprecipitate has become obsolete in some parts of Europe due to the
availability of fibrinogen concentrates [141-143]. In the United States and the United
Kingdom, Cryoprecipitate is still commonly used because of its wider availability and lower
cost compared with fibrinogen concentrate. (See "Disorders of fibrinogen", section on
'Fibrinogen concentrate: Dosing and monitoring'.)

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● Indications and uses – Fibrinogen concentrate or Cryoprecipitate has been used to

treat life-threatening intraoperative bleeding due to:

• Hypofibrinogenemia, with fibrinogen concentration <150 mg/dL [42,144]. (See

"Achieving hemostasis after cardiac surgery with cardiopulmonary bypass", section
on 'Cryoprecipitate versus fibrinogen concentrate' and "Disorders of fibrinogen",
section on 'Treatment/prevention of bleeding'.)

• Disseminated intravascular coagulation (DIC) with active bleeding and low

fibrinogen. (See "Evaluation and management of disseminated intravascular
coagulation (DIC) in adults", section on 'Prevention/treatment of bleeding'.)

• Uremic bleeding. (See "Clinical use of Cryoprecipitate", section on 'Uremic

bleeding'.)

• Hepatic insufficiency with active bleeding and low fibrinogen. (See "Hemostatic
abnormalities in patients with liver disease", section on 'Bleeding'.)

• Postpartum hemorrhage. (See "Overview of postpartum hemorrhage", section on

'Recognize alarm findings and intervene early' and "Disseminated intravascular
coagulation (DIC) during pregnancy: Management and prognosis", section on 'Blood
products'.)

• Treatment of excessive bleeding and coagulopathy during massive blood loss if

hypofibrinogenemia is strongly suspected and testing is not available or lags behind
[42,139,141-143,145-156]:

- (See "Clinical use of Cryoprecipitate", section on 'Massive blood loss (eg,

surgery, trauma)'.)
- (See "Disorders of fibrinogen", section on 'Acute bleeding'.)
- (See "Anesthesia for adult trauma patients", section on 'Treatment of
hemorrhagic shock'.)

Cryoprecipitate — Cryoprecipitate is preferred over FFP to treat documented

hypofibrinogenemia when there are not other clotting factor deficiencies and fibrinogen
concentrate is not available. (See "Clinical use of Cryoprecipitate".)

Differences between these blood products are summarized in the table ( table 5).

● Dosing – The typical Cryoprecipitate dose, as received from the blood bank, is a pooled
product that has been prepared by combining individual cryoprecipitate units derived
from 5 to 10 blood donors in a volume of 50 to 200 mL ( table 3). This typical dose
contains all of the fibrinogen present in one unit of whole blood (approximately 200 to
400 mg), as well as most of the factor VIII, factor XIII, von Willebrand factor (VWF), and
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fibronectin derived from one unit of FFP in a small volume of 10 to 20 mL (rather than
250 to 300) ( table 3 and table 5).

Dosing with a 5-unit bag of Cryoprecipitate will increase fibrinogen levels by

approximately 35 to 50 mg/dL in a 70 kg adult (each unit of Cryoprecipitate raises the
fibrinogen concentration by approximately 7 to 10 mg/dL), although this increase may
be less if the patient is actively hemorrhaging [157]. Similar to fibrinogen concentrate,
the plasma fibrinogen level is monitored after administration to determine if repeat
doses are necessary to maintain fibrinogen >150 mg/dL.

● Risks – Risks of Cryoprecipitate transfusion are similar to those for FFP (see 'Risks of
blood product transfusion' below). However, hemolytic transfusion reactions and
transfusion-associated circulatory overload (TACO) are less likely than with plasma since
the total transfused volume will be substantially less. Also, due to the low volume of
plasma in each unit, Cryoprecipitate does not need to be ABO matched in adults.
However, risk of infection per dose may be higher since the product is pooled from
multiple donors. Safety considerations are discussed is a separate topic. (See "Clinical
use of Cryoprecipitate", section on 'Risks and adverse events'.)

Fibrinogen concentrate — If available, we prefer a fibrinogen concentrate, rather than

cryoprecipitate or FFP, to treat hypofibrinogenemia. In continental Europe and Canada,
fibrinogen concentrate rather than cryoprecipitate is typically selected to treat
hypofibrinogenemia, in part because cryoprecipitate is not typically available in these
regions [141-143]. Also, fibrinogen concentrate has less risk of infection transmission and
immunological complications compared with transfusion of cryoprecipitate or other blood
products [140,141,158]. However, fibrinogen concentrate is more expensive than
cryoprecipitate [140,141].

Proponents of fibrinogen concentrate argue that the natural baseline concentration of

fibrinogen is relatively low, and there are no fibrinogen stores to be mobilized. Therefore,
fibrinogen is the first coagulation protein to become critically low during intraoperative
bleeding [145]. A 2020 meta-analysis included 13 trials with 900 patients who had author-
defined low fibrinogen level or clinically significant blood loss during any type of surgery
[159]. In this meta-analysis, blood loss was reduced in the first 12 postoperative hours in
patients who received fibrinogen concentrate compared with those who received placebo,
but the mean difference was only -135 mL (95% CI -183 to -87 mL), and results were
inconsistent for other clinically important outcomes such as survival.

However, guidelines do not suggest aiming for supranormal fibrinogen levels, and they do
not recommend prophylactic administration of fibrinogen concentrate in individuals with
normal fibrinogen levels [141,142,160,161].

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● Dosing – The dose of fibrinogen concentrate is calculated according to the target

fibrinogen concentration. (See "Disorders of fibrinogen", section on 'Fibrinogen
concentrate: Dosing and monitoring'.)

Dosing is typically monitored with POC testing and monitoring of plasma fibrinogen
level [151,152]. However, use of viscoelastic tests to determine when and how to
supplement fibrinogen in patients with intraoperative bleeding has been particularly
challenging [162]. (See 'Point-of-care tests' above.)

● Risks – Thromboembolic complications can occur, particularly in pregnant patients.

Overcorrection of fibrinogen deficiency should be avoided to minimize this risk. While
caution is warranted, most studies have not reported increased risk of thrombotic
events [149,153].

Risks of blood product transfusion — Potential complications of transfusion of blood

products include hemolytic transfusion reactions, febrile non-hemolytic transfusion
reactions (FNHTRs), transfusion-related acute lung injury (TRALI) [163], transfusion-related
circulatory overload (TACO), transfusion-transmissible infections (bacterial, viral, or parasitic
( table 6)), transfusion-associated graft-versus-host disease (TA-GVHD), and transfusion-
related immunomodulation that may lead to postoperative infection [121]. Not all
complications occur with all products.

The incidence of TRALI may be higher in perioperative patients compared with nonsurgical
patients [163].

These complications are discussed elsewhere:

● (See "Indications and hemoglobin thresholds for red blood cell transfusion in the
adult", section on 'Risks and complications of transfusion'.)
● (See "Platelet transfusion: Indications, ordering, and associated risks", section on
'Complications'.)
● (See "Clinical use of plasma components", section on 'Risks'.)
● (See "Clinical use of Cryoprecipitate", section on 'Risks and adverse events'.)

Massive transfusion may result in additional complications (eg, citrate toxicity with
hypocalcemia, hyperkalemia, acidosis, hypothermia), which are discussed separately. (See
"Massive blood transfusion".)

The approach to a patient with an acute transfusion reaction is discussed separately

[164,165]. (See "Approach to the patient with a suspected acute transfusion reaction".)

Evaluation of specific complications is discussed in separate topics:

● (See "Immunologic transfusion reactions".)

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● (See "Transfusion-related acute lung injury (TRALI)".)

● (See "Transfusion-associated circulatory overload (TACO)".)
● (See "Transfusion-transmitted bacterial infection".)
● (See "Blood donor screening: Laboratory testing", section on 'Viruses'.)
● (See "Transfusion-associated graft-versus-host disease".)

USE OF CLOTTING FACTORS

Clotting factors have been administered to selected patients with persistent or severe
intraoperative (or preoperative or postoperative) bleeding due to various causes of impaired
hemostasis. Ideally, any products administered should treat the specific deficiency. For
example, fibrinogen concentrate may be administered to treat an isolated fibrinogen
deficiency with fibrinogen concentration <150 mg/dL in a patient with clinically significant
bleeding, as noted above. (See 'Fibrinogen concentrate' above.).

Intraoperative use of other clotting factors such as unactivated or activated prothrombin

complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) is discussed below.
(See 'Prothrombin complex concentrates (PCCs)' below and 'Recombinant activated factor VII
(rFVIIa)' below.)

Intraoperative uses of hemostatic agents such as antifibrinolytics or desmopressin (DDAVP)

are discussed in a separate topic. (See "Perioperative blood management: Strategies to
minimize transfusions", section on 'Systemic hemostatic agents'.)

Prothrombin complex concentrates (PCCs)

Unactivated PCCs

● Indications and uses — The main indication for unactivated PCC is reversal of warfarin
for emergency surgery. Advantages of using a PCC product rather than fresh frozen
plasma (FFP) include rapid administration and small volume; volume overload and
transfusion reactions are avoided [42,145,146,166-177]. (See "Management of warfarin-
associated bleeding or supratherapeutic INR", section on 'Urgent surgery/procedure'
and "Plasma derivatives and recombinant DNA-produced coagulation factors", section
on 'PCCs'.)

• Reversal of vitamin K antagonists – A four-factor PCC should be used; this

contains factors II, VII, IX and X, ( table 7). PCCs are typically used to treat
intraoperative bleeding associated with warfarin or another vitamin K antagonist, in
combination with vitamin K [166]. (See "Management of warfarin-associated
bleeding or supratherapeutic INR", section on 'PCC products' and "Reversal of
anticoagulation in intracranial hemorrhage", section on 'Warfarin'.)
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• Reversal of factor Xa inhibitors – A four-factor PCC can be used to treat life-

threatening bleeding in a patient actively anticoagulated with a factor Xa inhibitor
(apixaban, rivaroxaban, edoxaban). Assessment of active anticoagulation and
discussion of PCC versus andexanet alpha is presented separately. (See
"Management of bleeding in patients receiving direct oral anticoagulants", section
on 'Factor Xa inhibitors'.)

• Treatment of intractable bleeding in selected surgical procedures – A PCC

product may be reasonable in selected surgical patients with intractable
coagulopathy and diffuse bleeding (eg, cardiac surgery with cardiopulmonary
bypass [CPB], liver transplantation, trauma surgery), particularly if intolerance of
high FFP transfusion volume is a factor. These uses of PCC and fibrinogen
concentrate are off label in the United States.

- Cardiac surgery – Off-label intraoperative use of PCCs has been reported for
treatment of patients with intractable coagulopathic bleeding after cardiac
surgery with CPB [42,44,82,145,146,167-183]. Randomized trials and
observational studies in cardiac surgical patients have noted reductions in
blood transfusions in patients with excessive bleeding and coagulopathy after
CPB who received unactivated four-factor or three-factor PCC products
compared with those receiving FFP [82,173,174,176,177,183]. However,
prospective data regarding the safety, efficacy, and dosing of PCCs in this
setting are limited. Other sources of coagulopathy (eg, surgical sources,
thrombocytopenia, hypofibrinogenemia, platelet dysfunction, disseminated
intravascular coagulation [DIC]) should be sought and treated. (See "Achieving
hemostasis after cardiac surgery with cardiopulmonary bypass", section on
'Prothrombin complex concentrate (PCC) products'.)

- Liver transplantation – In a propensity score-matched retrospective study of

60 pairs of patients undergoing liver transplantation, PCC use was associated
with significantly decreased red blood cell (RBC) and FFP transfusion
requirements compared with no PCC use, and no thromboembolic events were
noted [184]. However, causality is challenging to demonstrate.

- Trauma surgery – In trauma patients with findings of trauma-induced

coagulopathy, limited data (mostly observational) suggest that administration
of four-factor PCC, alone or in combination with fibrinogen concentrate or FFP,
can reduce transfusion of RBCs and other blood components [185-189]. (See
"Coagulopathy in trauma patients", section on 'Treatment'.)

● Dosing – The dose of a PCC product is tailored to the individual patient's needs based
on clinical indications and laboratory testing, but typically 1000 to 2000 units is
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administered. (See "Management of warfarin-associated bleeding or supratherapeutic

INR", section on 'PCC products'.)

Ideally, point-of-care (POC) laboratory tests such as thromboelastography (TEG) are

obtained to monitor overall hemostatic function and supplement information provided
by standard laboratory tests (eg, prothrombin time [PT], international normalized ratio
[INR], activated partial thromboplastin time [aPTT], fibrinogen level). (See
"Coagulopathy in trauma patients", section on 'Diagnosis' and 'Point-of-care tests'
above.)

● Risks – Data for intraoperative safety of PCC are limited [56,142,167,173,178,183,190].

Risk for thromboembolic events may be more likely with repeat or excessive dosing of
either four-factor and three-factor PCC products, a risk that may extend well into the
postoperative period [191]. Also, some PCC products contain heparin and should not
be used in an individual with a history of heparin-induced thrombocytopenia. (See
"Plasma derivatives and recombinant DNA-produced coagulation factors", section on
'PCCs' and "Management of warfarin-associated bleeding or supratherapeutic INR",
section on 'PCC risks'.)

Activated PCC — In contrast with standard three- or four-component PCCs, an activated

PCC product (aPCC; FEIBA) contains activated factor VII ( table 7). Due to the greater
prothrombotic risk compared with unactivated PCC, aPCC is rarely used in the intraoperative
setting [167,190]. However, FEIBA may be administered in selected individuals such as those
with bleeding due to a factor VIII inhibitor, or bleeding associated with fondaparinux or
dabigatran when a specific reversal agent is not available. (See "Plasma derivatives and
recombinant DNA-produced coagulation factors", section on 'Recombinant factor VIIa' and
"Management of bleeding in patients receiving direct oral anticoagulants", section on
'Dabigatran reversal' and "Fondaparinux: Dosing and adverse effects", section on
'Bleeding/emergency surgery'.)

Recombinant activated factor VII (rFVIIa)

● Indications and uses

• Factor inhibitors – Recombinant activated factor VII (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'.)

• Treatment of life-threatening bleeding in selected surgical procedures - In rare

instances when intractable bleeding that is life-threatening persists after cardiac or

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other major surgery, off-label administration of rFVIIa has been reported in

attempts to achieve hemostasis and reduce transfusion requirements [42,192-195].
Similar to off-label use of PCCs, primary causes of coagulopathy should always be
sought and treated before considering administration of rFVIIa. Failure to treat the
primary coagulation disorder increases the likelihood of inadequate response to the
initial dose of rFVIIa [196-198], and may encourage use of higher doses and greater
risk of thrombosis [199,200]. (See "Recombinant factor VIIa: Administration and
adverse effects", section on 'General approach to administration'.)

Information regarding efficacy of rFVIIa in this setting is largely anecdotal.

Systematic reviews have not found a great impact on morbidity and mortality,
although transfusion requirements may be reduced [199,201-203]. In cardiac
surgical patients, one study reported that a median dose of 13.3 mcg/kg resulted in
low overall blood transfusions in cardiac surgical patients [194]. Administration of
rFVIIa earlier in the postbypass period when intractable bleeding was identified
after transfusion of one or fewer units of RBCs resulted in a relatively lower total
dose of rFVIIa (12.2 [9.7-16.4] mcg/kg), whereas higher doses were necessary (18.0
[11.8 to 29.0] mcg/kg) after five or more units of RBCs had been transfused [204].
However, a median of two additional blood products were necessary after
administration of rFVIIa regardless of the total dose. (See "Recombinant factor VIIa:
Administration and adverse effects", section on 'Off-label uses'.)

● Dosing – Dosing practices vary widely because data are lacking regarding optimal
dosing and there are no laboratory tests to monitor drug effect or efficacy. We dose
rFVIIa cautiously in small incremental doses of 10 mcg/kg up to a total dose of up to 90
mcg/kg. Stocking the smaller 1 mg vials of rFVIIa facilitates this incremental approach.
(See "Recombinant factor VIIa: Administration and adverse effects", section on 'General
approach to administration'.)

● Risks – High thromboembolism rates >20 percent have been reported in retrospective
evaluations of registries for refractory bleeding cases [197-199]. Arterial
thromboembolic events have been noted in some trials, particularly in patients with
intracranial hemorrhage and those undergoing cardiac surgery [199,201-203].
Thromboembolic complications are more likely with dose escalation, or in the presence
of stagnant flow or devices such as extracorporeal membrane oxygenation (ECMO)
[42]. Conversely, risk of thrombotic complications may be reduced when lower doses
(eg, 10 to 30 mcg/kg) are administered [199,205]. Off-label intraoperative use of rFVIIa
is also associated with increased mortality and morbidity (eg, renal failure), especially
with administration of higher doses or in older patients [145,192,199,206,207].

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SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Transfusion and
patient blood management".)

SUMMARY AND RECOMMENDATIONS

● Prepare for large surgical blood loss

• Elective surgery – We obtain preoperative typing and crossmatching and

determine whether blood products should be available in the operating room
before incision. (See 'Elective surgery with risk for significant blood loss' above.)

• Emergency surgery with possible massive transfusion – Early communication is

necessary to activate a massive transfusion protocol. We transfuse red blood cells
(RBCs), plasma, and platelets in approximately equal ratios (1:1:1). (See 'Emergency
surgery with possibility of massive blood transfusion' above.)

● Technical considerations – Establish intravenous access. Adhere to protocols for

patient identification. Use compatible fluids. Use a blood warmer for cold and
previously thawed products. (See 'Technical aspects of blood transfusion' above.)

● Assess blood loss and bleeding risk – Blood loss is assessed visually and quantified
from blood suction canisters, surgical sponges, and drapes. (See 'Estimating blood loss'
above and 'Intraoperative diagnostic testing' above.)

• Standard tests – Includes hemoglobin, prothrombin time (PT), international

normalized ratio (INR), activated partial thromboplastin time (aPTT), platelet count,
and fibrinogen concentration. (See 'Standard tests' above.)

• Point-of-care (POC) tests – POC hemostatic tests (thromboelastography [TEG] or

rotational thromboelastometry [ROTEM]) may be used for rapid assessment of
causes of coagulopathy and responses to interventions ( figure 1 and figure 2
and table 1 and table 2). POC platelet aggregometry is rarely used. (See 'Tests
of hemostatic function' above.)

● Transfusion decisions – We use protocols or algorithms to guide transfusion decisions

( table 3). For patients with significant coagulopathic bleeding, we use TEG or ROTEM
(if available) rather than standard coagulation tests. Estimates of blood loss, signs of
anemia, and intractable microvascular bleeding are also considered. (See 'General
principles for transfusion decisions' above.)
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• Restrictive strategy for RBCs – For most surgical patients without significant
ongoing bleeding, we suggest a restrictive strategy, transfusing for hemoglobin <7
to 8 g/dL rather than higher levels (Grade 2C). This includes autologous, salvaged,
or allogeneic RBCs. However, decisions are individualized; a hemoglobin threshold
of <9 g/dL may be used in selected patients with signs of myocardial or other organ
ischemia. (See 'Red blood cells' above.)

• Platelets – We typically maintain a platelet count >50,000/microL (>100,000/microL

when ocular central nervous system bleeding is present or likely). Each dose (one
apheresis unit or one pool of whole blood-derived platelets) increases the platelet
count by 30,000/microL to 50,000/microL ( table 3). (See 'Platelets' above.)

• Plasma – Plasma can be used for emergency surgery with severe bleeding and
deficiency of multiple coagulation factors, particularly if intracranial hemorrhage is
present ( table 3 and table 4). (See 'Plasma' above.)

• Cryoprecipitate or fibrinogen concentrate – We aggressively correct

hypofibrinogenemia (<150 mg/dL) if there is active and ongoing bleeding.
Cryoprecipitate is more commonly used in the United States and United Kingdom;
fibrinogen concentrate is more often available in continental Europe and Canada.
Risks are lower with fibrinogen concentrate ( table 5). (See 'Cryoprecipitate or
fibrinogen concentrate' above.)

● Transfusion risks – (See 'Risks of blood product transfusion' above and "Approach to
the patient with a suspected acute transfusion reaction".)

● Clotting factors

• Prothrombin complex concentrates (PCCs) – Unactivated PCCs are used for

emergency reversal of warfarin, along with vitamin K ( table 7). PCC or andexanet
alfa can be used for emergency reversal of factor Xa inhibitors. Off-label uses such
as intractable coagulopathy and diffuse bleeding after CPB may be reasonable
( table 7). Other causes of intractable microvascular bleeding should be treated
before considering a PCC. (See 'Unactivated PCCs' above.)

Activated PCC (aPCC; FEIBA) contains activated factor VII and is rarely used
intraoperatively due to greater prothrombotic risk than unactivated PCC. (See
'Activated PCC' above.)

• Recombinant activated factor VII (rFVIIa) – May be used off-label for intractable
life-threatening coagulopathic bleeding after CPB. (See "Achieving hemostasis after
cardiac surgery with cardiopulmonary bypass", section on 'Recombinant activated
factor VII (rFVIIa)'.)
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160. Bilecen S, de Groot JA, Kalkman CJ, et al. Effect of Fibrinogen Concentrate on
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174. Karkouti K, Bartoszko J, Grewal D, et al. Comparison of 4-Factor Prothrombin Complex

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plasma-based therapy. Crit Care 2011; 15:R83.

187. Innerhofer P, Westermann I, Tauber H, et al. The exclusive use of coagulation factor
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188. Innerhofer P, Fries D, Mittermayr M, et al. Reversal of trauma-induced coagulopathy

using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-
centre, parallel-group, open-label, randomised trial. Lancet Haematol 2017; 4:e258.

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Coagulopathy of Trauma: Four is Better Than Three. Shock 2019; 52:23.

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195. Hessel EA 2nd. What's New in Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth
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use of recombinant activated factor VII in cardiac surgery. Circulation 2008; 118:331.
198. Lee AI, Campigotto F, Rawn JD, et al. Clinical significance of coagulation studies in
predicting response to activated recombinant Factor VII in cardiac surgery patients. Br J
Haematol 2012; 157:397.

199. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in
randomized clinical trials. N Engl J Med 2010; 363:1791.
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201. Yank V, Tuohy CV, Logan AC, et al. Systematic review: benefits and harms of in-hospital
use of recombinant factor VIIa for off-label indications. Ann Intern Med 2011; 154:529.
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treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev
2012; :CD005011.
204. Sutherland L, Houchin A, Wang T, et al. Impact of Early, Low-Dose Factor VIIa on
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survival in complex cardiac surgical patients. Ann Thorac Surg 2014; 98:618.
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GRAPHICS

Thromboelastography (TEG) tracing interpretation

TEG: thromboelastograph.

%: percent.

TEG® Hemostasis Analyzer Tracing Image and TEG® LY30 Clot Breakdown Diagram reproduced with permission of
Haemonetics Corporation. TEG® and Thromboelastograph® are registered trademarks of Haemonetics
Corporation in the US, other countries, or both.

Graphic 80241 Version 5.0

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Thromboelastography (TEG) tracing parameters

"R" is the reaction time (the time it takes the coagulation cascade to
generate thrombin and fibrin). "K" is the clot firmness. "α" (alpha) is the
angle (describes the kinetics of clot formation). MA is the maximum
amplitude (describes the maximum clot strength). Ly30 is the percent clot
lysis 30 minutes after the MA is reached. Refer to UpToDate topics on
platelet function testing and trauma management for details of the use
and interpretation of thromboelastography.

TEG® Hemostasis Analyzer Tracing Image reproduced with permission of Haemonetics

Corporation. TEG® and Thrombelastograph® are registered trademarks of Haemonetics
Corporation in the US, other countries or both.

Graphic 100078 Version 2.0

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Thromboelastography definitions

Clot TEG ROTEM Enzymatic

Parameter Measurement
phase abbreviation abbreviation stage

Clot Clotting time Time from start Reaction time Clot time (CT) Early P
initiation of sample to 2 (R) activation of c
mm clot clotting d
amplitude cascade a
resulting in h
initial S
thrombin h
burst s

Clot Clot Time from 2 to Clot formation Clot formation Clot P

kinetics formation 20 mm clot time (K) time (CFT) potentiation c
time amplitude by activation d
of platelets h
and t
thrombin- a
mediated d
cleavage of
Angle Angle of tangent Alpha angle Alpha angle A
soluble
line from 2 to 20 c
fibrinogen
mm clot d
formation h
t
a
d

Clot Maximal clot Amplitude Maximal Maximal clot Maximal clot A

strength strength measured at amplitude (MA) firmness (MCF) strength h
peak clot achieved via t
strength GP IIb/IIIa- o
mediated d
platelet-
Clot Calculated from G Maximal clot A
fibrin
viscoelasticity maximal elasticity (MCE) p
interactions
amplitude h

Clot lysis Clot lysis Percentage of Lysis at 30 Lysis index at Activation of A

loss of amplitude minutes (LY30), 30 minutes fibrinolytic e
at fixed time estimated (LI30), maximal system m
after maximal percentage of lysis (ML) h
amplitude lysis (EPL)

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Normal thromboelastography and parameters

Normal citrated rapid thromboelastography study (rapid-TEG) tracing with normal ACT, R
time, K time, alpha angle, MA, G, and LY30.

R (reaction time): time from sample placement or activation until the tracing amplitude
reaches 2 mm; K (clot formation time): time elapsed between the R-time and the point
where the tracing amplitude reaches 20 mm; alpha angle: angle between the middle line
of the tracing and a tangential line to the developing "body" of the tracing; MA (maximal
amplitude): the maximal amplitude reached after clot initiation; G: a calculated measure
of total clot strength based on amplitude; LY30: the amount of clot lysis detected 30
minutes after the maximal amplitude (MA) is reached; SP (split point): time from sample
placement (or activation with an exogenous procoagulant) until the earliest detectable
resistance.

Graphic 58281 Version 3.0

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Primary hyperfibrinolysis as assessed by thromboelastography

Citrated rapid thromboelastography study (rapid-TEG) showing primary hyperfibrinolysis.

The red tracing indicates a normal study.

This study has a normal ACT, normal R time, normal K time, and normal alpha angle; low
MA and G, reflecting significant fibrinolysis prior to achieving maximal clot strength; and
high LY30, reflecting hyperfibrinolysis.

R (reaction time): time from sample placement or activation until the tracing amplitude
reaches 2 mm; K (clot formation time): time elapsed between the R-time and the point
where the tracing amplitude reaches 20 mm; alpha angle: angle between the middle line
of the tracing and a tangential line to the developing "body" of the tracing; MA (maximal
amplitude): the maximal amplitude reached after clot initiation; G: a calculated measure
of total clot strength based on amplitude; LY30: the amount of clot lysis detected 30
minutes after the maximal amplitude (MA) is reached; SP (split point): time from sample
placement (or activation with an exogenous procoagulant) until the earliest detectable
resistance.

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Secondary hyperfibrinolysis

Citrated rapid thromboelastography study (rapid-TEG) showing secondary

hyperfibrinolysis. The red tracing indicates a normal study.

This study shows a normal ACT, R time, K time, and alpha angle; high LY30 reflecting
hyperfibrinolysis; and normal MA and G, reflecting onset of fibrinolysis after achieving
maximal clot strength.

R (reaction time): time from sample placement or activation until the tracing amplitude
reaches 2 mm; K (clot formation time): time elapsed between the R-time and the point
where the tracing amplitude reaches 20 mm; alpha angle: angle between the middle line
of the tracing and a tangential line to the developing "body" of the tracing; MA (maximal
amplitude): the maximal amplitude reached after clot initiation; G: a calculated measure
of total clot strength based on amplitude; LY30: the amount of clot lysis detected 30
minutes after the maximal amplitude (MA) is reached; SP (split point): time from sample
placement (or activation with an exogenous procoagulant) until the earliest detectable
resistance.

Graphic 70388 Version 4.0

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Thrombocytopenia

Citrated rapid thromboelastography study (rapid-TEG) reflecting thrombocytopenia.The

red line is a normal tracing.

This study shows a normal ACT, R time, K time, and LY30, and a low alpha angle, MA, and
G, reflecting platelet hypocoagulability.

R (reaction time): time from sample placement or activation until the tracing amplitude
reaches 2 mm; K (clot formation time): time elapsed between the R-time and the point
where the tracing amplitude reaches 20 mm; alpha angle: angle between the middle line
of the tracing and a tangential line to the developing "body" of the tracing; MA (maximal
amplitude): the maximal amplitude reached after clot initiation; G: a calculated measure
of total clot strength based on amplitude; LY30: the amount of clot lysis detected 30
minutes after the maximal amplitude (MA) is reached; SP (split point): time from sample
placement (or activation with an exogenous procoagulant) until the earliest detectable
resistance.

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Clotting factor consumption and hypofibrinogenemia

Citrated rapid thromboelastography study (rapid-TEG) reflecting clotting factor

consumption and hypofibrinogenemia. The red line indicates a normal study.

This study shows a prolonged ACT, R time, and K time, reflecting enzymatic
hypocoagulability; markedly low alpha angle, MA, and G, reflecting platelet
hypocoagulability and poor fibrin deposition; and normal LY30.

R (reaction time): time from sample placement or activation until the tracing amplitude
reaches 2 mm; K (clot formation time): time elapsed between the R-time and the point
where the tracing amplitude reaches 20 mm; alpha angle: angle between the middle line
of the tracing and a tangential line to the developing "body" of the tracing; MA (maximal
amplitude): the maximal amplitude reached after clot initiation; G: a calculated measure
of total clot strength based on amplitude; LY30: the amount of clot lysis detected 30
minutes after the maximal amplitude (MA) is reached; SP (split point): time from sample
placement (or activation with an exogenous procoagulant) until the earliest detectable
resistance.

Graphic 60690 Version 4.0

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Hypercoagulability

Citrated rapid thromboelastography study (rapid-TEG) reflecting hypercoagulability. The

red tracing indicates a normal study.

This study shows a shortened to normal ACT, R time, and K time, reflecting enzymatic
hypercoagulability; high alpha angle, MA, and G, reflecting platelet hypercoagulability
and/or excessive fibrin deposition; and normal LY30. To distinguish the relative
contribution of platelet hypercoagulability and excessive fibrin deposition, one would
need to perform TEG platelet mapping or rotation thromboelastometry (RoTEM) fibrin
function testing.

R (reaction time): time from sample placement or activation until the tracing amplitude
reaches 2 mm; K (clot formation time): time elapsed between the R-time and the point
where the tracing amplitude reaches 20 mm; alpha angle: angle between the middle line
of the tracing and a tangential line to the developing "body" of the tracing; MA (maximal
amplitude): the maximal amplitude reached after clot initiation; G: a calculated measure
of total clot strength based on amplitude; LY30: the amount of clot lysis detected 30
minutes after the maximal amplitute (MA) is reached; SP (split point): time from sample
placement (or activation with an exogenous procoagulant) until the earliest detectable
resistance.

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Thromboelastography-guided transfusion parameters

r-TEG parameter Normal range Transfusion trigger

TEG-ACT 78-110 seconds >128 seconds (FFP)

Alpha angle 66°-82° <65° (cryoprecipitate)

MA (maximum amplitude) 54-72 mm <54 mm (platelets)

LY-30 (lysis at 30 min) 0-7.5% >5% (tranexamic acid)

Values in the table are for citrated rapid TEG whole blood samples. Note: A study of critically
injured trauma patients identified an increase in risk of massive transfusion (91% versus 30%)
and death due to hemorrhage (46% versus 5%) at an LY30 of 3%, which is a much lower target
than the manufacturer-provided normal upper bound of 7.5%. [3]

TEG: thromboelastography; ACT: activated clotting time; FFP: fresh frozen plasma.

Adapted from:

1. Stahel PF, Moore EE, Schreier SL, et al. Transfusion strategies in postinjury coagulopathy. Curr Opin Anaesthesiol
2009; 22:289.
2. Einersen PM, Moore EE, Chapman MP, et al. Rapid thrombelastography thresholds for goal-directed resuscitation
of patients at risk for massive transfusion. J Trauma Acute Care Surg 2017; 82:114.
3. Chapman MP, Moore EE, Ramos CR, et al. Fibrinolysis greater than 3% is the critical value for initiation of
antifibrinolytic therapy. J Trauma Acute Care Surg 2013; 75:961.

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Blood components: Indications and dosing in adults

Component
Contents Indications and dose
(volume)

Whole blood (1 RBCs, platelets, Rarely required.

unit = 500 mL)* plasma May be appropriate when massive bleeding requires
transfusion of more than 5 to 7 units of RBCs
(increasingly used in early trauma management).

RBCs in additive RBCs Anemia, bleeding.

solution (1 unit = The increase in hemoglobin from 1 unit of RBCs will be
350 mL) approximately 1 g/dL; the increase in hematocrit will
be approximately 3 percentage points.

FFP or other All soluble Bleeding or expected bleeding (eg, emergency

plasma product ¶ plasma proteins surgery) in individuals with deficiencies of multiple
(1 unit = 200 to and clotting coagulation factors (eg, DIC, liver disease, massive
300 mL) factors transfusion, anticoagulation with warfarin or warfarin
overdose if not corrected by vitamin K and/or PCC,
depending on the clinical setting).
Bleeding in individuals with isolated factor deficiencies
(most often factor V) if a factor concentrate or
recombinant factor is not available.
Therapeutic plasma exchange in TTP (as a source of
ADAMTS13).
In the rare event that FFP is used to replace a clotting
factor, the dose is 10 to 20 mg/kg. This dose will raise
the level of any factor, including fibrinogen, by close to
30%, which is typically sufficient for hemostasis.

Cryoprecipitate, Fibrinogen; Bleeding patients with acquired hypofibrinogenemia,

also called "cryo" factors VIII and which may be due to cardiac surgery, liver transplant,
(1 unit = 10 to 20 XIII; VWF postpartum hemorrhage, or trauma with massive
mL) transfusion.
DIC.
Uremia if DDAVP (desmopressin) is ineffective.
The increase in plasma fibrinogen from 1 unit of
Cryoprecipitate per 10 kg body weight will be
approximately 50 mg/dL.
Cryoprecipitate is generally provided in pools
containing 5 units, and most patients receive 1 to 2
pools.

Platelets (derived Platelets The platelet count increase from 5 to 6 units of whole
from whole blood-derived platelets or 1 unit of apheresis platelets
blood or will be approximately 30,000/microL in an average-
apheresis) (1 unit sized adult.

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of apheresis
platelets or a 5 to
6 unit pool of
platelets from
whole blood =
200 to 300 mL)

Refer to UpToDate topics on these products and on specific conditions for details of use. Frozen
blood products (FFP, Cryoprecipitate) take 10 to 30 minutes to thaw. It may take the same
amount of time to perform an uncomplicated crossmatch.

RBCs: red blood cells; FFP: Fresh Frozen Plasma; DIC: disseminated intravascular coagulation;
PCC: prothrombin complex concentrate; TTP: thrombotic thrombocytopenic purpura; VWF: von
Willebrand factor.

* 450 mL blood and 63 mL citrate-phosphate-dextrose (CPD) anticoagulant-preservative solution.

¶ Other plasma products include:

Plasma Frozen Within 24 Hours After Phlebotomy (PF24)
Thawed Plasma
PF24 may be used interchangeably with FFP for all of the indications listed above, with the
exceptions of factor VIII deficiency or protein C deficiency, which are treated with recombinant
products or plasma-derived factor concentrates. In the rare event that specific factor
concentrates are unavailable and these deficiencies must be treated with a plasma product, FFP
should be used.

Thawed Plasma may be used interchangeably with FFP for all of the indications listed above, with
the exception of factor VIII deficiency without access to factor VIII concentrates, in which FFP
should be used, or factor V deficiency, in which FFP or PF24 should be used.

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Reversing anticoagulation in warfarin-associated bleeding

Management Time to anticoagulation

Comments and cautions
option reversal

Discontinuing 5 to 14 days Five days is typical for patients with

warfarin therapy an INR in the therapeutic range

Vitamin K* 6 to 24 hours to correct the INR, Recovery of factors X and II

longer to fully reverse (prothrombin) takes longer than 24
anticoagulation hours

Risk of anaphylaxis with intravenous

injection

Impaired response to warfarin lasting

up to one week may occur after large
doses (ie, >5 mg)

Fresh frozen Depends on the time it takes to Effect is transient and concomitant
plasma complete the infusion; typically 12 to vitamin K must be administered
32 hours for complete reversal
Potential for volume overload (2 to 4
L to normalize INR)

Potential for TRALI

Potential for viral transmission

Prothrombin 15 minutes after 10-minute to 1-hour Effect is transient, and concomitant

complex infusion vitamin K must be administered;
concentrate limited availability

Cost

Variable factor VII content depending

on the product: a 4-factor PCC is
preferred

Potentially prothrombotic

Recombinant 15 minutes after bolus infusion Effect is transient, and concomitant

factor VIIa vitamin K must be administered

Cost

Potentially prothrombotic

Please refer to the UpToDate topic on warfarin reversal in intracerebral hemorrhage for further
details of management.

INR: international normalized ratio; TRALI: transfusion-related acute lung injury; PCC:
prothrombin complex concentrate.

* A total of 10 mg intravenously by slow infusion given over 10 minutes.

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Adapted with permission from: Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intercerebral
hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007; 82:82. Copyright © 2007 Dowden Health
Media.

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Comparison of Fresh Frozen Plasma and Cryoprecipitate

FFP Cryoprecipitate

Volume 250 to 300 mL 10 to 20 mL

Time to prepare 30 minutes 30 minutes

Fibrinogen 700 to 800 mg 150 to 250 mg

Other coagulation factors All, including factors II, VII, VIII, Factors VIII, XIII, and vWF
IX, X, XI, and vWF

Values for fibrinogen are approximate, per one unit of each component. FFP contains
coagulation factors at the same concentration present in plasma. Cryoprecipitate is a highly
concentrated source of fibrinogen. Cryoprecipitate also contains factor XIII, von Willebrand
factor (vWF), and factor VIII; however, it is not used to replace these factors because factor
concentrates and recombinant products with better safety profiles are available. The cost per
unit of fibrinogen is similar in FFP and Cryoprecipiate. In severe liver disease, pools of 8 to 10
units of Cryoprecipitate may be used so the total cost (and amount of fibrinogen given) may be
greater. Refer to UpToDate topics on plasma components and specific uses of these products for
indications and further details.

FFP: Fresh Frozen Plasma; Cryo: Cryoprecipitate.

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Risk of viral and bacterial infection following transfusion of blood

products

Components prepared from whole blood*

Hepatitis B virus [1,2] 1:1 million to 1:1.5 million

Hepatitis C virus [1,2] 1:2 million to 1:2.6 million

HTLV [3,4] 1:2.7 million

HIV [1,2] 1:1.6 million to 1:2.3 million

Solvent/detergent-treated plasma products

Hepatitis C virus Inactivated

Hepatitis B virus Inactivated

HIV Inactivated

Hepatitis A virus Not fully inactivated ¶

Parvovirus B19 Not fully inactivated ¶

Hepatitis E virus Not fully inactivated ¶

Platelets
With automated bacterial culturing methods in place, septic transfusion reactions are
estimated to occur at a rate of 1:50,000 to 1:80,000 transfused platelet apheresis units. This is
an underestimate since it relies on passive surveillance data [5] .

CMV infection
The risk of CMV infection is rare in recipients with selected conditions (eg, bone marrow or solid
organ transplants) who are at risk for severe morbidity from CMV infection and who receive
CMV reduced-risk products. Two methods to supply CMV reduced-risk products that appear to
have equal efficacy are CMV-seronegative cellular components (red blood cells, platelets) or
leukoreduced components.

These numbers are estimates; ranges are given for some viruses where different databases and
analyses have generated slightly different numbers. In the United States, blood is routinely
screened for syphilis, hepatitis B virus, hepatitis C virus, HIV-1, HIV-2, HTLV-I, HTLV-II, West Nile
virus, and Trypanosoma cruzi. Babesia microti testing is confined to states where community-
acquired babesisos is considered to be of high risk. CMV serology testing is not routine; instead,
enough products are tested to provide a sufficient inventory of CMV-negative products. Platelets
are tested for bacterial contamination. Refer to UpToDate topics on risks of blood transfusion for
further details.

HTLV: human T-lymphotropic virus; CMV: cytomegalovirus.

* These estimates apply to red blood cells, platelets, and plasma, with the exception of HTLV, for
which there is no risk from plasma.

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¶ Plasma products are tested for parvovirus B19, hepatitis A virus, and hepatitis E virus nucleic
acid before being used for further manufacturing into solvent/detergent-treated plasma.
Transmission of these agents should not occur (or should be extraordinarily rare) under these
conditions.

References:
1. Steele WR, Dodd RY, Notari EP, et al. HIV, HCV, and HBV incidence and residual risk in US blood donors before and
after implementation of the 12-month deferral policy for men who have sex with men. Transfusion 2021; 61:839.
2. Dodd RY, Crowder LA, Haynes JM, et al. Screening blood donors for HIV, HCV, and HBV at the American Red Cross:
10 year trends in prevalence, incidence, and residual risk, 2007 to 2016. Trans Med Rev 2020: 34(2):81.
3. Zou S, Stramer SL, Dodd RY. Donor testing and risk: Current prevalence, incidence, and residual risk of
transfusion-transmissible agents in US allogeneic donations. Transfus Med Rev 2012; 26:119.
4. Stramer SL, Notari EP, Zou S, et al. HTLV antibody screening of blood donors: Rates of false positive results and
evaluation of a potential donor re-entry algorithm. Transfusion 2011; 51:692.
5. Kleinman S, Reed W, Stassinopoulos A. A patient-oriented risk-benefit analysis of pathogen-inactivated blood
components: Application to apheresis platelets in the United States. Transfusion 2013; 53:1603.

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PCC products available in the United States*

Unactivated prothrombin complex concentrates (PCCs)

4 factor: Contains inactive forms of 4 factors: Factors II, VII, IX, and X
Kcentra Also contains heparin

3 factor: Contains inactive forms of 3 factors: Factors II, IX, and X

Profilnine Contains little or no factor VII

Does not contain heparin

Activated prothrombin complex concentrate (aPCC)

4 factor: Contains 4 factors: Factors II, VII, IX, and X. Of these, only factor VII is mostly
FEIBA the activated form ¶

Does not contain heparin

The table lists 4-factor and 3-factor PCC products available in the United States. Kcentra
is available as Beriplex in Canada. Bebulin (a 3-factor PCC) was discontinued in 2018 due to
decreased demand for the product. Potency is determined differently for different products;
refer to product information. All PCCs are plasma derived and contain other proteins, including
anticoagulant proteins (proteins C and S). Unactivated factors are proenzymes (inactive precursor
proteins). Activated factors have higher enzymatic activity. Refer to UpToDate topics for use of
these products.

US: United States; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing
activity.

* Other 4-factor PCCs available outside the US include Octaplex and Cofact Proplex.

¶ Single-factor recombinant activated factor VII (rFVIIa) products are also available.

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Contributor Disclosures
Thomas J Graetz, MD No relevant financial relationship(s) with ineligible companies to
disclose. Gregory Nuttall, MD Grant/Research/Clinical Trial Support: CSL Behring [Bleeding]. All of the
relevant financial relationships listed have been mitigated. Michael F O'Connor, MD,
FCCM Consultant/Advisory Boards: Intensix/CLEW [Predictive analytics in medicine]. All of the relevant
financial relationships listed have been mitigated. Steven Kleinman, MD No relevant financial
relationship(s) with ineligible companies to disclose. Nancy A Nussmeier, MD, FAHA No relevant
financial relationship(s) with ineligible companies to disclose. Jennifer S Tirnauer, MD No relevant
financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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