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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e

Chapter 238: Chapter 238: Transfusion TherapyTransfusion Therapy Clinton J. Coil; Sally A. Santen

INTRODUCTIONINTRODUCTION

Modern transfusion practice uses blood that has been separated into specific components (Table 238-1Table 238-1).Coagulation factors, either derived from human plasma or manufactured with recombinant technology, areused treat hemorrhage associated with a deficiency of one or more factors (Table 238-2Table 238-2). Transfusion in theED typically is done for acute blood loss and/or circulatory shock. As medical care is moved to outpatientsettings, emergency physicians may be responsible for transfusion therapy or complications previously

relegated to inpatient settings.1

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TABLE 238-1

Characteristics of Blood ProductsCharacteristics of Blood Products

ComponentComponentShelfShelf

LifeLife

Volume/UnitVolume/Unit

(mL)(mL)

ApproximateApproximate

Content/UnitContent/Unit**

InitialInitial

DoseDoseDosage E�ectDosage E�ect

Packed red blood

cells (PRBCs)

21–42 d 250–350 Red cells

65%–80%

Plasma 10–20

mL

Adult: 2

units

Pediatrics:

10–15

mL/kg

Raises hemoglobin

concentration

approximately 2

grams/dL (20 grams/L) or

hematocrit by 6% in

adults (2–3 grams/dL [20–

30 grams/L] or 7%–9% in

children)

Platelets

(apheresis-

collected single-

donor platelet

concentrate)

5 d 250–300 Platelets 3–6

× 1011

1 unit or 5

mL/kg

Raises platelet count by

up to 50,000/mm3 (50 ×

109/L), but less in many

cases

Platelets (pooled

donor platelet

concentrate, rarely

used in the United

States)

5 d 50–60 Platelets 8–9

× 1010

6 units or

5 mL/kg

Raises platelet count by

up to 50,000/mm3 (50 ×

109/L), but less in many

cases

Fresh frozen

plasma (FFP)

1 y

frozen

and up

to 5 d

a�er

thawing

200–250 Each

coagulation

factor about

200–250 units

Fibrinogen

400–500

milligrams

Four units

or 15

mL/kg

Raises most coagulation

factors levels

approximately 20%;

volume issues may make

factor correction di�icult;

benefits are transient

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*Unless specifically prepared, most blood-derived products contain some small amount of WBCs, red blood cells,

platelets, and plasma in addition to the specific component.

ComponentComponentShelfShelf

LifeLife

Volume/UnitVolume/Unit

(mL)(mL)

ApproximateApproximate

Content/UnitContent/Unit**

InitialInitial

DoseDoseDosage E�ectDosage E�ect

Cryoprecipitate 1 y

frozen

and 4 h

thawed

20–50 Factor VIII 80–

140 units

Fibrinogen

225–420

milligrams

von

Willebrand

factor in

variable

amounts

Factor XIII

and

fibronectin in

some

amounts

0.2

units/kg

or 10–15

units in an

adult

Increases fibrinogen 50–

100 milligrams/dL (0.5–

1.0 grams/L)

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TABLE 238-2

Coagulation Factor ProductsCoagulation Factor Products

Type of ProductType of Product** Initial DoseInitial Dose Comments and Approved IndicationsComments and Approved Indications

Fibrinogen

concentrate

(human)

RiaSTAP® (CSL

Behring)

Dosed to increase fibrinogen

level from baseline to over 150

milligrams/dL (1.5 grams/L)

If baseline fibrinogen level

unknown, administer 70

milligrams/kg

Each vial contains 900–1300 milligrams of

fibrinogen

Acute bleeding episodes in patients with

congenital fibrinogen deficiency

Three-factor

prothrombin

complex

concentrate

(human)

Profilnine SD®

(Grifols Biologicals)

Bebulin VH® (Baxter

Healthcare

Corporation)

Dosed according to desired

factor IX increase

Contains factors II, IX, and X

Treat hemophilia B (factor IX deficiency)

Four-factor

prothrombin

complex

concentrate

(human)

Kcentra® or

Beriplex® P/N (CSL

Behring)

Octaplex®

(Octapharma)

Dosed in factor IX units

according to pretreatment INR

Contains factors II, VII, IX, and X

Urgent reversal of bleeding due to vitamin K

antagonist (e.g., warfarin)–induced coagulation

factor deficiency in adult patients

Anti-inhibitor

coagulant complex

FEIBA NF® (Baxter)

50–100 units/kg Contains factors II, IX, and X, mainly

nonactivated, and factor VII mainly in activated

form

Bleeding in patients with hemophilia A or B with

inhibitors

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*Commercial trade names provided for ease of specific identification.

Type of ProductType of Product** Initial DoseInitial Dose Comments and Approved IndicationsComments and Approved Indications

Coagulation factor

VIIa (recombinant)

NovoSeven® RT

(Novo Nordisk)

90 micrograms/kg Bleeding episodes and perioperative

management in adults and children with

hemophilia A or B with inhibitors

Congenital factor VII deficiency

Glanzmann's thrombasthenia with

refractoriness to platelet transfusions

Bleeding episodes and perioperative

management in adults with acquired hemophilia

Blood products are provided using standardized preparations as "units" (Table 238-1). Provide information topatients about the risks, benefits, and alternatives to transfusion prior to the initial infusion of red blood

cells, plasma, or platelets.2,3 Obtain informed consent or document that the patient was unable to consent if

a medical emergency exists.2 Use great care to assure that the correct blood product is delivered to thecorrect patient because of the consequences of transfusing the wrong unit; use two individuals to verify theidentification of the patient and the unit before transfusion. Bar-code identification along with verification by

one individual is an alternative to two-person verification.4

TRANSFUSION OF BLOOD PRODUCTSTRANSFUSION OF BLOOD PRODUCTS

PACKED RED BLOOD CELLSPACKED RED BLOOD CELLS

Adult total blood volume is approximately 2.5 L/m2, 75 mL/kg, or about 5 L in a 70-kg person. Whole bloodtransfusion would seem ideal to replace acute blood loss; however, storage of whole blood inactivatesplatelets and other factors. Therefore, whole blood is fractionated to its components for storage andtransfusion. Packed red blood cells (PRBCs) are prepared by the centrifugation of whole blood to removeapproximately 80% of the plasma; then a preservative solution is added (most commonly, citrate-phosphate-dextrose) with the additional nutrients adenosine, and mannitol (Table 238-1).

The primary reason for PRBC transfusion is to increase oxygen-carrying capacity.1,4 Emergency PRBCtransfusion is usually performed for acute blood loss or, occasionally, profound anemia with impairedoxygen delivery. Transfusion thresholds assist the physician in assessing whether PRBC transfusion willbenefit the patient. Current evidence is substantial that a restrictive threshold for PRBC transfusion is

appropriate for most patients.5,6,7,8,9 In previously healthy adults, transfusion should be considered athemoglobin concentrations less than 7 grams/dL (70 grams/L), and for patients with sepsis or ischemic heartor brain injury, transfusion should be considered at a hemoglobin concentration less than 8 to 9 grams/dL (80

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to 90 grams/L).10,11,12,13 Transfusion threshold values for children may be higher and depend on the etiology

of their anemia.14 Some patients with severe sepsis receiving early, goal-directed therapy may benefit fromtransfusion up to a hemoglobin of 10 grams/dL (100 grams/L) when the central venous oxygen saturation is

less than 70%.15

For actively bleeding patients, transfusion is based on clinically estimated blood loss rather than hemoglobinlevels, because the fall in measured hemoglobin will lag behind the clinical impact of acute blood loss. A lossof about 30% blood volume (1500 mL in an adult) generally produces symptoms and signs, but young,healthy patients can tolerate this degree of loss when treated with crystalloid. However, patients with chronicillness such as underlying anemia, cardiac diseases, or pacemakers or those on β-blockers or similarmedications may not tolerate blood loss. Consider emergency PRBC transfusion for unstable trauma patientsbased on an inadequate response to an initial 2-L bolus of IV crystalloid or 40 mL/kg in children. Theanticipated clinical course also guides the decision to transfuse the patient with acute hemorrhage; thetransfusion threshold is lower if the source of bleeding cannot be controlled immediately compared to apatient whose acute hemorrhage has stopped.

Use the minimum amount of PRBCs to accomplish the desired clinical outcome.7,12 A single PRBC unit willA single PRBC unit willraise the hemoglobin by 1 gram/dL (10 grams/L) and hematocrit by 3% in adults. In children, 10 to 15 mL/kgraise the hemoglobin by 1 gram/dL (10 grams/L) and hematocrit by 3% in adults. In children, 10 to 15 mL/kgof PRBCs will raise the hematocrit by 6% to 9% and the hemoglobin level by approximately 2 to 3 grams/dLof PRBCs will raise the hematocrit by 6% to 9% and the hemoglobin level by approximately 2 to 3 grams/dL

(20 to 30 grams/L).(20 to 30 grams/L).14

One unit of PRBCs, approximately 250 mL in volume, is generally transfused over 1 to 2 hours. PRBCs shouldbe transfused more rapidly in patients with hemodynamic instability. Single-unit PRBC transfusions shouldnot exceed 4 hours to prevent contamination. If a slow transfusion is desired (e.g., in a patient at risk forvolume overload), the blood bank should be asked to split a unit so that the first half can be transfused over4 hours while the second half waits in the blood bank refrigerator. During standard transfusions, the initialinfusion rate is slower over the first 30 minutes so that if there is a transfusion reaction, the infusion may bestopped.

Type and Cross-MatchType and Cross-Match

PRBC transfusion requires matching the recipient's and donor's red blood cells according to blood type (ABOand Rh) and screening the recipient's plasma for antibodies to the minor red blood cell antigens. Screening isdone using a mixture of commercially available red blood cells that have all of the important minor

antigens.12 If the screen is positive, then the recipient's plasma is cross-matched against the specific PRBCunit intended for transfusion. Blood type can be determined in approximately 15 minutes, whereas it takesabout 45 to 60 minutes to perform a serologic cross-match. If an anti–red blood cell antibody is found in therecipient's plasma, cross-matching may take longer and require additional blood specimens from thepatient. For most patients with no antibodies detected on the screen, serologic cross-matching can beforegone and ABO-Rh–compatible PRBC units can be released by the blood bank using a process termedelectronic (or computerized) cross-match. This process has computer-based verifications to ensure the

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patient receives ABO-Rh–compatible blood.12 Electronic cross-matching typically takes 5 minutes or less toperform.

Type O Rh-negative (universal donor) blood may be used in critical circumstances because these transfusedred cells do not contain major blood group antigens (A or B). Type O Rh-positive blood may be used if type ORh-negative is not available, but should be avoided in girls and women of childbearing potential.Approximately 20% of Rh-negative patients transfused with 1 unit of Rh-positive PRBCs will develop anti-Rh(D) antibodies, creating the risk for hemolytic disease of the newborn with subsequent pregnancies. Thisis usually clinically inconsequential for men or postmenopausal women.

Treated Red Blood CellsTreated Red Blood Cells

PRBCs may be further treated for specific clinical applications: leukocyte-reduced PRBCs, irradiated PRBCs,

washed PRBCs, and frozen PRBCs.16 Leukocyte-reduced PRBCs have 70% to 85% of the white cells removed.Leukocyte-reduced PRBCs are used (1) to decrease the occurrence of nonhemolytic febrile reactions due tocytokines from transfused white cells, (2) to prevent sensitization to human leukocyte antigen antibodiesfound on white cells in patients who may be eligible for bone marrow transplantation, and (3) to minimizethe risk of intracellular virus transmission, such as cytomegalovirus. Leukocytes can be reduced by filtrationor other methods before storage of the PRBCs or during transfusion. Irradiation of PRBCs eliminates thecapacity of T lymphocytes to proliferate, thereby preventing the donor's T lymphocytes from reacting to therecipient's cells and causing gra�-versus-host disease. Irradiated cells are used in transplant patients,neonates, and immunocompromised patients, and with directed donations from relatives of the patient.Washed PRBCs are indicated in patients who have a hypersensitivity to plasma, such as immunoglobulin Adeficiency or persistent febrile reactions. For rare blood types, red cells may be frozen and saved for up to 10years for later use. Freezing red blood cells is more expensive than normal storage, and once thawed, theblood must be washed and transfused within 24 hours.

MASSIVE TRANSFUSIONMASSIVE TRANSFUSION

Massive transfusionMassive transfusion is the replacement of one blood volume or approximately 10 units of PRBCs in an adultwithin a 24-hour period. If only PRBCs are used, platelets and coagulation factors lost or consumed will notbe replaced, potentially producing increased bleeding. The military medical experience during the past

decade finding good results with using fresh whole blood transfusion for trauma patients17 has led to theconcept of incorporating the platelets and plasma in addition to PRBCs to closer mimic whole blood during a

massive transfusion.18,19 Studies routinely using platelets and fresh frozen plasma (FFP) with PRBCs during

massive transfusion have yielded mixed results on reducing mortality.20,21

Institution-specific massive transfusion protocol is recommended to guide the clinician in correct ordering of

the individual products and facilitate release from the blood bank.22 The best ratio of PRBCs to platelets to

FFP during a massive transfusion is controversial.23 Some experts advocate a 1:1:1 ratioSome experts advocate a 1:1:1 ratio, although lower

ratios of platelets and FFP have been used without clear evidence of inferiority.24 Including

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cryoprecipitate,20 fibrinogen concentrate,24 or coagulation factor VIIa (recombinant)20,24 during a massivetransfusion has produced mixed results, depending on the outcome measured.

If fixed ratios of platelets or FFP are not used, suggested indications for their administration during massive

transfusion include the following: (1) when the platelet count is <50,000/mm3(<50 × 109/L), a platelettransfusion is warranted; (2) if the INR is >1.5, FFP may be given; and (3) if the fibrinogen level is <100milligrams/dL (<1 g/L), it may be replaced with cryoprecipitate or fibrinogen concentrate.

Draw su�icient specimens early in the course from massive transfusion patients because once the patienthas received close to one blood volume of transfused products, new blood specimens will contain so muchdonor blood that it will confuse further cross-matching of subsequent units. Hypothermia is a risk duringmassive transfusion, so blood and crystalloid should be warmed, in addition to instituting warmingmeasures for the patient. Hypocalcemia from the preservative citrate chelating calcium may occur with a

massive transfusion.22

PLATELET TRANSFUSIONPLATELET TRANSFUSION

Platelet transfusions are used either prophylactically to prevent bleeding in thrombocytopenia or

therapeutically when patients with thrombocytopenia are actively bleeding.25,26 One apheresis-collected,single-donor platelet concentrate is the standard product in developed countries (Table 238-1). Plateletscollected from six di�erent donors (a "six pack") can be combined for transfusion but are not recommendedbecause this increases the risk of disease transmission and transfusion reaction.

One apheresis single-donor platelet unit will increase the platelet count by up to 50,000/mmOne apheresis single-donor platelet unit will increase the platelet count by up to 50,000/mm33 (50 × 109/L), anamount su�icient to stop most spontaneous and minor traumatic bleeding. Check platelet levels at 1 and 24hours a�er transfusion completion because the response is variable. Failure of platelets to rise appropriatelymay be due to increased consumption of platelets from an underlying process, active thrombosis due toongoing hemorrhage, destruction due to platelet antibodies, or sequestration due to hypersplenism.Transfused platelets should survive 3 to 5 days unless there is a platelet-consumptive process.

The decision to transfuse platelets depends on the severity of thrombocytopenia and clinical circumstances

(Table 238-3Table 238-3).13,25,26,27 Patients with comorbid conditions, such as infection, fever, medications, and CNSinvolvement, may be more likely to bleed or be at higher risk if they bleed; therefore, the threshold for

platelet transfusion is more liberal.13,28

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TABLE 238-3

General Indications for Platelet TransfusionGeneral Indications for Platelet Transfusion

Platelet count <5000/mm3 (<5 × 109/L)

Platelet count <20,000/mm3 (<20 × 109/L) with a coagulation disorder, low-risk procedure, or during

outpatient treatment

Platelet count <50,000/mm3 (<50 × 109/L) with active bleeding or invasive procedure within 4 h

Platelet count <100,000/mm3 (<100 × 109/L) with neurologic or cardiac surgery

As part of a massive transfusion protocol

There are no clear recommendations concerning platelet transfusions in patients with nonfunctioningplatelets (antiplatelet medications, uremia, von Willebrand's disease, or hyperglobulinemia) and activebleeding. In von Willebrand's disease, normal platelets may help deliver von Willebrand factor to thebleeding site. Conversely, in uremic patients, the transfused platelets may not function any better than nativeplatelets. In these complex cases, consult with a hematologist or transfusion medicine specialist forrecommendations.

Relative contraindications to the transfusion of platelets are disorders associated with platelet activation,such as thrombotic thrombocytopenic purpura or heparin-induced thrombocytopenia, in which transfusionmay worsen thrombosis. In these conditions, ongoing bleeding or the need to perform procedures maynecessitate platelet transfusion in consultation with the appropriate specialist.

Platelet transfusions are usually ABO-type specific because the platelets are bathed in plasma, although aserologic cross-match is usually not done. As a result, patients receiving platelets are subject to many of thesame complications described for plasma transfusion. Depending on availability, non–type-specific plateletsmay sometimes be transfused. This practice is usually avoided in children or patients receiving multipletransfusions because they are at higher risk for complications. Transfusing non–type-specific platelets mayalso shorten the half-life of the transfused platelets.

As with PRBCs, platelets can be leukocyte reduced or washed. Patients who have had repeated transfusionsmay become alloimmunized and refractory to platelet transfusion, noted by the lack of expected rise inplatelet count a�er transfusion. Such patients need human leukocyte antigen–matched or cross-matchedplatelets. Other factors may a�ect the e�icacy of platelet transfusion, including bacterial sepsis in therecipient, antibiotics forming an antigen complex epitope with the platelet, disseminated intravascularcoagulation, and splenomegaly.

FRESH FROZEN PLASMA TRANSFUSIONFRESH FROZEN PLASMA TRANSFUSION

FFP is plasma obtained a�er the separation of whole blood from erythrocytes and platelets and then frozen

within 8 hours of collection.29 FFP takes approximately 20 to 40 minutes to thaw, and this process cannot be

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sped up through artificial heating. Once thawed, FFP can be transfused up to 5 days later. Trauma centersand other specialty hospitals may keep prethawed units of FFP available.

Transfused FFP should be ABO-type compatible, and Rh compatibility is unnecessary. A commonmisconception is that type O plasma is the universal FFP donor, as it is for PRBCs. This is not the case,because type O plasma contains antibodies to A and B blood group antigens. Type AB is the universal donorType AB is the universal donorfor FFP, and in emergencies, universal donor FFP can be given minutes a�er thawing.for FFP, and in emergencies, universal donor FFP can be given minutes a�er thawing. Each unit of FFP has avolume of 200 to 250 mL and contains approximately 1 unit of each coagulation factor and 2 milligrams offibrinogen per milliliter (Table 238-1). FFP is used for replacement of multiple coagulation deficiencies incases such as liver failure, warfarin-induced overanticoagulation, disseminated intravascular coagulation,

and massive transfusion in bleeding patients, although evidence of benefit is weak (Table 238-4Table 238-4).30 FFP isalso used with bleeding due to an individual coagulation factor deficiency when a specific replacement factoris not available. FFP is unlikely to reverse anticoagulation from oral anticoagulants such as dabigatran andrivaroxaban, which are specific inhibitors of thrombin and factor Xa, respectively (see chapter 239,

"Thrombotics and Antithrombotics" and the "Prothrombin Complex Concentrate" section, below).31

TABLE 238-4

General Indications for Fresh Frozen Plasma TransfusionGeneral Indications for Fresh Frozen Plasma Transfusion

Reversal of warfarin overanticoagulation (not the primary agent)

Bleeding with multiple coagulation defects

Correction of coagulation defects for which no specific factor is available

As a component of a massive transfusion protocol

As part of plasma exchange when treating thrombotic microangiopathies or neurologic disorders

Response to FFP treatment is monitored by tests of the coagulation system: the prothrombin time, INR, andactivated partial thromboplastin time. Using fresh frozen plasma to achieve complete normalization ofcoagulation studies is neither necessary nor realistic in most circumstances. Clinically adequate hemostasisis generally present with functional coagulation factor levels of 30% to 40% of normal, which corresponds toan INR of about 1.7. Although it is common to administer FFP before a procedure when the INR exceeds

1.5,13,27 there is little evidence to support this practice,32 and it will likely have little e�ect on patients with

an INR less than 1.85.33 If rapid reversal of a vitamin K antagonist coagulopathy is needed, prothrombin

complex concentrate or coagulation factor VIIa (recombinant) is faster and more reliable.34

Administering FFP prophylactically to nonbleeding patients is not indicated, and prophylaxis is not needed

before procedures in patients with a coagulopathy.32 Procedures such as abdominal paracentesis35 or

endoscopy with variceal banding36 can be performed safely with a coagulopathy. If correction is desired, thee�ect of FFP is transient, dose dependent, and may subject the patient to volume overload.

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Other possible indications for FFP include hereditary angioedema if C1 esterase inhibitor is not available (see

chapter 14, "Anaphylaxis, Allergies, and Angioedema").37,38 FFP is used during plasma exchange for

treatment of diseases such as thrombotic thrombocytopenic purpura and Guillain-Barré syndrome.39,40

For isolated factor deficiencies, specific factor replacement is preferred over FFP for major bleeding, withfresh frozen plasma sometimes used for minor bleeding episodes (Table 238-5Table 238-5).

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Abbreviations: FFP = fresh frozen plasma; PCC = prothrombin complex concentrate.

TABLE 238-5

Replacement Therapy for Congenital Factor DeficienciesReplacement Therapy for Congenital Factor Deficiencies

CoagulationCoagulation

FactorFactorApproximate IncidenceApproximate Incidence** Replacement TherapyReplacement Therapy

Factor I

(fibrinogen)

1 per million Cryoprecipitate

Fibrinogen concentrate

Factor II

(prothrombin)

1 per 2 million 3- or 4-factor PCC for major bleeding

Factor V 1 per million FFP

Factor VII 1 per 500,000 4-factor PCC for major bleeding

Coagulation factor VIIa (recombinant)

Factor VIII† 1 per 5000–10,000 males Recombinant factor VIII

Desmopressin for mild hemophilia

Von Willebrand's

disease‡

Up to 1 per 100 persons Desmopressin or factor VIII concentrates (or

cryoprecipitate if either unavailable)

Factor IX† 1 per 30,000 males Recombinant factor IX

3- or 4-factor PCC

Factor X 1 per million FFP for minor bleeding episodes

3- or 4-factor PCC for major bleeding

Factor XI‡ 3 per 10,000 Ashkenazi

Jews

1 per million in general

population

FFP

Factor XII 25 per 1000 No bleeding manifestations, replacement not required

Factor XIII 1 per million FFP or cryoprecipitate

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*Source van Herrewegen F, Meijers JC, Peters M, van Ommen CH: Clinical practice: the bleeding child. Part II: disorders

of secondary hemostasis and fibrinolysis. Eur J Pediatr 171: 207, 2012.

†See chapter 235, "Hemophilias and von Willebrand's Disease."

‡Factor XI levels correlate poorly with bleeding complications; many patients have low levels but no bleeding

complications.

The increase in individual coagulation factors seen a�er FFP infusion varies depending on the specific factor.In general, 1 unit of FFP will increase most coagulation factors by 3% to 5% in a 70-kg adult. Administering 2units of FFP to an adult (approximately 7 to 8 mL/kg) will increase coagulation factors up to 10%, a clinicallyinconsequential benefit in most circumstances. For clinically relevant correction of coagulation factordeficiencies, a dose of 15 mL/kg (or 4 units in a 70-kg adult) is o�en required (Table 238-1). A�er transfusion,coagulation studies should be repeated and further FFP transfusion guided by the results.

CRYOPRECIPITATECRYOPRECIPITATE

Cryoprecipitate is the cold-insoluble protein fraction of fresh frozen plasma.34 With the development ofrecombinant factor VIII products for use in hemophilia, the current role for cryoprecipitate is as replacement

of fibrinogen.41 Cryoprecipitate may be used in bleeding patients with fibrinogen levels <100 milligrams/dL(< 1 g/L) due to severe liver disease, uremia, disseminated intravascular coagulation, and dilutional

coagulopathy, although there is controversy over dosing and e�icacy (Table 238-6Table 238-6).42,43 Five units ofcryoprecipitate are typically pooled for use, with adults receiving one to three pooled infusions.

Cryoprecipitate may also be included in some massive transfusion protocols.20,24

TABLE 238-6

General Indications for Cryoprecipitate TransfusionGeneral Indications for Cryoprecipitate Transfusion

Bleeding with a fibrinogen level of <100 milligrams/dL (< 1 g/L)

Dysfibrinogenemia

Bleeding in some subtypes of von Willebrand's disease that are unresponsive to desmopressin, and factor VIII

concentrates are unavailable

FIBRINOGEN CONCENTRATEFIBRINOGEN CONCENTRATE

Fibrinogen concentrate is derived from pooled human plasma and used to treat bleeding episodes in

patients with congenital fibrinogen deficiency.44 Fibrinogen has been investigated for benefit in otherhemorrhagic conditions with an observed ability to reduce bleeding and transfusion requirements, but

without a measurable e�ect on mortality.45 Four products are commercially available. The advantages over

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cryoprecipitate are minimal risk of disease transmission due to viral inactivation, accurate dosing becauseeach vial is assayed for fibrinogen content, a lower volume for infusion, no need for thawing, no requirementof ABO testing and compatibility, and a rapid reconstitution for infusion.

Fibrinogen is dosed according the patient's baseline fibrinogen level, the target level (in most circumstances

>150 milligrams/dL),46 volume of distribution, and body weight. If the baseline fibrinogen level is unknown,the initial dose is 70 milligrams/kg. The most common adverse reactions include allergic reactions, fever,chills, nausea, and vomiting.

PROTHROMBIN COMPLEX CONCENTRATEPROTHROMBIN COMPLEX CONCENTRATE

Prothrombin complex concentrates are blood-derived concentrations of three or four vitamin K–dependent

clotting factors: prothrombin and factors VII, IX, and X.47 Some prothrombin complex concentrateformulations may also contain the anticoagulant proteins C, S, and antithrombin, as well as heparin. Three-factor prothrombin complex concentrate is approved for treatment of hemophilia B (factor IX deficiency)(Table 238-2). Four-factor prothrombin complex concentrate is approved for urgent reversal of

overanticoagulation from vitamin K antagonists (such as warfarin),48,49 resulting in a more reliable reduction

in the elevated INR than three-factor prothrombin complex concentrate.50,51 The four-factor prothrombincomplex concentrate dose in this circumstance is administered using factor IX units and adjusted accordingto the pretreatment INR value. O�-label use of three- or four-factor prothrombin complex concentrateincludes bleeding in patients with congenital factor II, IX, or X deficiency.

Prothrombin complex concentrate does not require thawing, does not necessitate ABO-compatibility testing,and does not carry the risk of volume overload, all of which can hinder fresh frozen plasma use. Becauseprothrombin complex concentrate's e�ects are transient, vitamin K should usually be co-administered forsustained warfarin reversal. Prothrombin complex concentrate is part of some protocols for reversal ofrivaroxaban and dabigatran in the setting of life-threatening bleeding, despite limited evidence for their

e�ectiveness.31,52,53 Thrombosis is the major complication of prothrombin complex concentrate, observedin about 5% of treated patients, although this incidence is not much higher than in similar patients treatedwith fresh frozen plasma.

COAGULATION FACTOR VIIa (RECOMBINANT)COAGULATION FACTOR VIIa (RECOMBINANT)

Coagulation factor VIIa (recombinant) is primarily used for treatment of hemophilia A and B in patients whohave developed inhibitor antibodies to factors VIII or IX, respectively. Other uses for this agent have beeninvestigated, such as coagulation support in liver failure, multisystem trauma, intracranial hemorrhage, andpostpartum bleeding, but evidence for overall safety and e�icacy in these expanded indications is

lacking.54,55,56,57,58 The major drawbacks to this product are risk of thrombosis (up to 4% in patients withacquired hemophilia) and the high cost.

COMPLICATIONS OF BLOOD TRANSFUSIONSCOMPLICATIONS OF BLOOD TRANSFUSIONS

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Up to 20% of all transfusions may result in some type of adverse reaction.4,59 Most reactions are minor;

serious reactions are uncommon, and life-threatening ones are rare (Table 238-7Table 238-7).60 In critically ill patients,transfusion reactions may be di�icult to identify; therefore, watch for unexpected changes in patient statusduring a transfusion. Two important first steps in any confirmed or suspected transfusion reaction are to (1)Two important first steps in any confirmed or suspected transfusion reaction are to (1)

immediately stop the transfusion, and (2) contact the blood bank that issued the transfusion product.immediately stop the transfusion, and (2) contact the blood bank that issued the transfusion product.1212,,1616

The blood bank physician is an important resource for managing the suspected transfusion reaction.

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TABLE 238-7

Transfusion ReactionsTransfusion Reactions

ReactionReaction

TypeType

Signs andSigns and

SymptomsSymptomsManagementManagement EvaluationEvaluation

Acute

intravascular

hemolytic

reaction

Fever, chills, low

back pain, flushing,

dyspnea,

tachycardia, shock,

hemoglobinuria

Immediately stop transfusion.

IV hydration to maintain

diuresis; diuretics may be

necessary.

Cardiorespiratory support as

indicated.

Retype and repeat cross-match.

Direct and indirect Coombs test.

CBC, creatinine, prothrombin

time, activated partial

thromboplastin time.

Haptoglobin, indirect bilirubin,

lactate dehydrogenase, plasma

free hemoglobin.

Urine for hemoglobin.

Delayed

extravascular

hemolytic

reaction

O�en have low-

grade fever but may

be entirely

asymptomatic

Usually presents days to

weeks a�er transfusion.

Rarely causes clinical

instability.

Hemolytic workup as above to

investigate the possibility of

intravascular hemolysis.

Febrile

nonhemolytic

transfusion

reaction

Fever, chills Stop transfusion.

Initially manage as in

intravascular hemolytic

reaction (above) because one

cannot initially distinguish

between the two.

Can treat fever and chills with

acetaminophen.

Usually mild but can be life

threatening in patients with

tenuous cardiopulmonary

status.

Consider infectious workup.

Premedication with

acetaminophen can mask this

reaction.

Hemolytic workup as above

because may not be able to

initially distinguish febrile from

hemolytic transfusion reactions.

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ReactionReaction

TypeType

Signs andSigns and

SymptomsSymptomsManagementManagement EvaluationEvaluation

Allergic

reaction

Mild: urticaria,

pruritus

Severe: dyspnea,

bronchospasm,

hypotension,

tachycardia, shock

Stop transfusion.

If mild, reaction can be treated

with diphenhydramine; if

symptoms resolve, can restart

transfusion.

If severe, may require

cardiopulmonary support; do

not restart transfusion.

For mild symptoms that resolve

with diphenhydramine, no

further workup is necessary,

although blood bank should be

notified.

For severe reaction, do hemolytic

workup as above because

initially may be indistinguishable

from a hemolytic reaction.

Although stopping the transfusion at the first sign of complications is an important step, a common error inmanagement of a confirmed or possible transfusion reaction is to abandon all transfusion. Typically,transfusion reactions, such as hemolytic reactions or transfusion-related acute lung injury, are due to theinteraction between a particular unit and a particular patient. Even patients with severe reactions can stillsafely receive future blood products if they are appropriately matched to the patient. In fact, a patient whohad clinical indications for transfusion may need that product even more if a transfusion reaction has causeddeterioration. One of the first steps in management of a transfusion reaction is to draw a new specimen to

retype and cross-match new units so that transfusion can resume as soon as possible.12,16

Premedication with diphenhydramine and acetaminophen is a widespread practice to prevent febrile and/or

allergic transfusion reactions61; however, the e�ects are limited,62,63 and routine prophylacticpremedication is not recommended. Premedication may be used for patients with previous febrile or allergictransfusion reactions.

HEMOLYTIC TRANSFUSION REACTIONSHEMOLYTIC TRANSFUSION REACTIONS

Hemolytic transfusion reactions occur when the recipient's antibodies recognize and induce hemolysis of the

donor's RBCs.1,12,16,64 The reaction is usually acute when antibodies already exist as anti-A or anti-Bimmunoglobulin M antibodies or immunoglobulin G antibodies in very high titer. Reactions can be delayedwhen there is an amnestic response to a transfused red blood cell antigen to which the recipient has been

previously sensitized.16,64,65 Immediate transfusion reactions are caused by ABO incompatibility and usuallyare the result of technical errors made during the collection of blood, in pretransfusion testing, or in patientidentification. The majority of transfusion fatalities are acute hemolytic reactions due to human error ofincorrect cross-matching or inadvertent administration of the wrong blood to the wrong patient. The risk ofacute hemolytic transfusion reaction due to incompatible blood is 1 to 4 per million units transfused.

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With acute hemolytic reaction, most of the transfused cells are destroyed, which may result in activation ofthe coagulation system, disseminated intravascular coagulation, and release of anaphylatoxins and othervasoactive amines. Clinical features of an acute hemolytic reaction include back pain, pain at the site of thetransfusion, headache, alteration of vital signs (fever, hypotension, dyspnea, tachycardia), chills,bronchospasm, pulmonary edema, bleeding due to developing coagulopathy, and evidence of new orworsening renal failure.

Ongoing transfusion should be stopped immediately on first indication of potential problemsOngoing transfusion should be stopped immediately on first indication of potential problems. Whilelaboratory confirmation is being performed, the sequelae of hemolysis are treated supportively. Check renalfunction, electrolytes, and coagulation status. Maintain renal blood flow and urine output with fluids,mannitol, and furosemide, as needed. Treat circulatory shock with intravenous infusions and vasopressors tosupport blood pressure.

The remaining donor blood should be sent, along with a posttransfusion blood specimen from the recipient,to the blood bank. Diagnosis is confirmed by evidence of hemolysis (hemoglobinuria or hemoglobinemia)and by blood incompatibility. In rechecking the blood type and cross-match, the patient's serum is tested forblood group alloantibodies, and the donor's plasma is tested for the presence of antibodies that react withthe patient's blood. In intravascular hemolytic transfusion reactions, serum haptoglobin will be decreased,serum lactate dehydrogenase will be elevated, and a direct antigen (Coombs) test usually will be positive.The blood bank will be able to test the blood, review records, confirm blood types, and determine if thepatient's syndrome is from a transfusion reaction.

Extravascular delayed hemolytic reactions occur in approximately 1 per 1000 to 6000 PRBC units

transfused.16 Hemolysis most commonly occurs in the spleen and occasionally in liver and bone marrow.This type of reaction is less serious and rarely fatal. It may be identified by a positive Coombs test, elevatedunconjugated (indirect) bilirubin level, and less than expected increase in hemoglobin from the transfusion.

FEBRILE TRANSFUSION REACTIONSFEBRILE TRANSFUSION REACTIONS

Febrile transfusion reactions are characterized by fever during or within a few hours of a blood

transfusion.1,12,16 A febrile reaction occurs in approximately 1 per 300 units of PRBCs infused. Febriletransfusion reactions are more common in patients who have been exposed to foreign blood antigens, suchas multiparous women or multiply transfused patients. Febrile transfusion reactions result from acombination of recipient antibody against donor leukocytes and the release of cytokines that are producedduring storage. Clinical presentation can range from a mild elevation in temperature to a high fever alongwith rigors, headache, myalgias, tachycardia, dyspnea, and chest pain. A febrile reaction may be di�icult toinitially di�erentiate from the more serious hemolytic transfusion reaction or sepsis.

For a febrile reaction during a patient's first-time transfusion, or in any severe reaction, the transfusionshould be stopped and the product returned to the blood bank for testing. Laboratory investigation similar tothat done for possible hemolytic transfusion is done and blood cultures should be obtained. The febriletransfusion reaction is usually self-limited and will respond to antipyretics. A mild fever in a patient who has

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been transfused before is usually not serious. In most cases, the transfusion can be restarted a�erconsultation with the blood bank physician. For patients with recurrent febrile reactions, the use ofleukocyte-reduced blood products may be helpful, as well as pretreatment with antipyretics.

ALLERGIC TRANSFUSION REACTIONSALLERGIC TRANSFUSION REACTIONS

Allergic transfusion reactions typically manifest with urticaria and pruritus during the infusion.1,12,16 A smallpercentage of patients will have more severe reactions, such as bronchospasm, wheezing, and anaphylaxis.These reactions are caused by an immune response to transfused plasma proteins. The incidence of allergic

transfusion reactions varies widely.66

Antihistamine therapy usually will control the symptoms. The transfusion should be stopped but can usuallybe restarted a�er evaluation. For severe symptoms, the transfusion should be stopped and treatment withepinephrine or bronchodilators initiated. Patients with immunoglobulin A deficiency may experience severeanaphylactic reactions in response to exposure from immunoglobulin A in donor products. Washing theplasma from the red blood cells minimizes this type of reaction.

INFECTIOUS COMPLICATIONS OF BLOOD TRANSFUSIONINFECTIOUS COMPLICATIONS OF BLOOD TRANSFUSION

Improved blood donor screening, serologic testing, safer handling of blood products, and viral inactivation of

blood products have reduced the risk of infection from transfusion.67,68,69,70 Despite screening donor bloodfor antibodies to most concerning viral agents, there is still a small risk of viral transmission (Table 238-8Table 238-8).Most cases of transmission are thought to occur during the window period between infection and antibodyproduction in the donor. This window can be reduced by antigen testing of donated blood for known viralantigens.

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Abbreviation: HIV = human immunodeficiency virus.

TABLE 238-8

Risk of Infections from Transfusion of Blood ProductsRisk of Infections from Transfusion of Blood Products

EtiologyEtiologyEstimated Frequency: One Infection per Number of UnitsEstimated Frequency: One Infection per Number of Units

TransfusedTransfused

HIV-1 1 per 6 million

HIV-2 Unknown, but extremely low

Human T-cell lymphotropic virus types 1

and 2

1 per 640,000

Hepatitis B 1 per million

Hepatitis C 1 per 100 million

Parvovirus B19 1 per 10,000

Prevalence for cytomegalovirus antibodies in the general population is between 50% and 80%; therefore, atransfusable unit is not tested routinely for cytomegalovirus unless the recipient is seronegative and eitherpregnant, a potential or present transplant candidate, immunocompromised, or a premature infant.Leukocyte-reduced blood components further decrease the risk of cytomegalovirus transmission to

susceptible populations because most of the virus resides in the leukocytes.68

Other infections transmitted by blood transfusion include West Nile virus, variant Creutzfeldt-Jakob,

babesiosis, and dengue.66,67,69 Additionally, blood can become contaminated with bacteria during storageor processing. Transfusion-associated bacterial infection was more commonly reported with plateletconcentrates than PRBC or fresh frozen plasma. Bacterial screening and inactivation procedures have

dramatically reduced the incidence of transfusion-associated bacterial sepsis.60 Response to a possibleseptic reaction involves immediate discontinuation of the transfusion, blood cultures from the patient,therapy with broad-spectrum antimicrobials, and examination of material from the blood container by Gram

stain with cultures of specimens from the container and the administration set.12,16

TRANSFUSION-RELATED ACUTE LUNG INJURYTRANSFUSION-RELATED ACUTE LUNG INJURY

Transfusion-related acute lung injury is an uncommon but complex process that is thought to be due to

granulocyte recruitment and degranulation within the lung.65,71,72 Transfusion-related acute lung injury is

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1. 

2. 

usually a complication of fresh frozen plasma or platelet transfusion and is rare a�er PRBC transfusion alone.This syndrome presents with respiratory distress and the appearance of bilateral pulmonary infiltrates due tononcardiogenic pulmonary edema, during or within 6 hours of transfusion. By itself, transfusion-relatedacute lung injury is self-limiting and generally resolves spontaneously with only supportive care, althoughsevere, fatal reactions can occur. Because the pulmonary edema is noncardiogenic, use care to distinguishthis situation from volume overload and avoid aggressive diuresis, which can cause rapid deterioration.

OTHER COMPLICATIONSOTHER COMPLICATIONS

HypervolemiaHypervolemia

Transfusion of blood products can cause rapid volume expansion when compared to similar volumes of

crystalloid fluids, leading to transfusion-associated cardiovascular overload.65 Patients with limitedcardiovascular reserve, such as infants, those with severe chronic compensated anemia, and the elderly, areat the highest risk. Clinical features include dyspnea, hypoxia, and pulmonary edema. Recognize thepotential for volume overload so that blood can be transfused slowly, the patient can be monitored carefully,and treatment with diuretics can be initiated when necessary. The usual rate of PRBC or fresh frozen plasmatransfusion is 2 to 4 mL/kg per h, but it can be slowed to 1 mL/kg per h in more delicate patients. Bloodproduct units may also be split, as described earlier.

Electrolyte ImbalanceElectrolyte Imbalance

Electrolyte imbalances of hypocalcemia, hypokalemia, or hyperkalemia due to large-volume transfusions oraltered elimination are uncommon. The anticoagulant citrate is a component of many blood preservativesand chelates calcium. The e�ect of infused citrate is clinically insignificant because patients with normalhepatic function metabolize the citrate to bicarbonate. Rarely with massive transfusions, hepatic metabolismis overwhelmed, and hypocalcemia can develop and/or the excess bicarbonate generated causes alkalemia,

driving potassium into the cells and causing hypokalemia.22 The potassium content in stored blood productsincreases during storage, and uncommonly, patients with renal insu�iciency or neonates can develophyperkalemia from transfusion.

Acknowledgment:Acknowledgment: We would like to acknowledge Holli Mason, MD, and William Robb, RN, BSN, for theirreview of the material in this chapter.

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