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Chapter 36 

Kenichi Tanaka

Packed Red Blood Cells
Blood Substitutes
Fresh Frozen Plasma The observation that blood circulates in a closed vascular
Albumin system by Harvey in 1628 was pivotal in the practice of blood
Synthetic Colloids transfusion.1 Because blood was recognized as vital to sustain-
Cryoprecipitate ing life, Denis in Paris and Lower in Oxford attempted xeno-
Recombinant Factor VIIa transfusion (animal blood to humans) with little success in the
Prothrombin Complex Concentrate 17th century. The first documented transfusion of human
Antithrombin Concentrate blood was made in 1818 by Blundell, an obstetrician in
Protein C Concentrate London, who recognized the need for transfusion in women
PHARMACOLOGIC AND TOPICAL AGENTS suffering from postpartum hemorrhage. His results were not
Lysine Analogues reproducible due to the lack of knowledge of blood types and
Desmopressin anticoagulants.
Topical Hemostatic Agents Major advances were made in the beginning of 20th
SPECIAL CONSIDERATIONS century when Landsteiner identified blood groups A, B, and
Liver Failure C (later renamed group O). Storage and distribution of
Jehovah’s Witnesses donated blood became possible after sodium citrate was added
EMERGING DEVELOPMENTS as an anticoagulant during World War I. The infrastructure
of the modern blood banking system was established by
World War II, and use of fresh whole blood transfusion saved
many wounded soldiers, although hepatitis transmission was
not uncommon. During World War II, Cohn and colleagues
developed the cold ethanol method to separate albumin,
γ-globulin, and fibrinogen from plasma, which became the
basic principle for commercial plasma fractionation.
In the late 1970s and early 1980s, pooling of random donor
plasma to manufacture factor (F) VIII concentrates without
effective donor screening or virus inactivation steps led to
transfusion-related transmission of viruses, particularly human
immunodeficiency virus (HIV) and hepatitis C to a large
number of hemophiliac patients worldwide. Since the mid-
1980s, many precautions for bloodborne pathogens have been
implemented, including vapor heat treatment and nanofiltra-
tion, and recombinant coagulation factors became available in
the 1990s. The risk of infectious transmission also fueled
efforts to develop synthetic oxygen carriers.2,3 Over the years,
clinicians have recognized the importance and potential
harms of blood component therapies. The rational and cost-
effective uses of blood components are now the subject of
published transfusion guidelines.4-7

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Chapter 36  Transfusion and Coagulation Therapy

ABO and Rh blood group–specific packed RBCs should be

administered whenever possible (Figure 36-2). In case of life-
threatening hemorrhage without time for formal cross-
matching, either Rh-positive or Rh-negative group O RBCs
Packed Red Blood Cells
can be transfused in principle. In Rh-negative women of
Circulating red blood cells (RBCs) are anuclear, hemoglobin-
carrying cells of about 7 to 8 µm in diameter. The biconcave
and discoid shape of RBCs confers advantages in increasing
surface area for gas exchange and flexibility in passing through Normal artery
capillaries. On average, RBCs remain in circulation for 120 100
days. Senescent or abnormal RBCs are eliminated by the
spleen. The synthesis of RBCs (erythropoiesis) is regulated by Normal
erythropoietin, which is elevated in anemia and hypoxia.
Erythropoiesis is also affected by the availability of iron, an 75
integral component of hemoglobin.

SO2 (%)
Packed RBCs are prepared by separating most plasma
components of donated whole blood by centrifugation. One
unit of RBCs collected in anticoagulant-preservative solution 50
is about 300 mL with a hematocrit of 50% to 70%. Dextrose
is added to maintain glucose metabolism, and adenine and
phosphate allow synthesis of adenosine triphosphate. Additive 25
solutions (adenine, glucose, mannitol, sodium chloride) are
also used to extend shelf life up to 42 days (Table 36-1).8
Depending on the storage solution, RBCs have a shelf life of
28 to 42 days at 1°C to 6°C. During storage, intracellular 0
0 20 40 60 80 100
2,3-DPG is reduced to less than 10% of normal at 5 weeks
such that release of oxygen from hemoglobin is significantly
impaired (Figure 36-1). PO2 (mm Hg)
Normal dissociation ↓ pH ↑ 2,3-DPG
CLINICAL USES curve ↑ temperature
Transfusion of RBCs is indicated to restore the oxygen-
Figure 36-1  Oxygen-dissociation curve of hemoglobin at normal pH is
carrying capacity in patients with severe anemia or major shown in blue. The dissociation of oxygen from hemoglobin can be increased
blood loss. There is no absolute level of hemoglobin that (in purple) by acidosis, elevated 2,3-DPG (diphosphoglycerate), or higher
indicates a threshold for transfusion (“transfusion trigger”); temperature. Conversely, the curve can be shifted to left by alkalosis, low
underlying clinical conditions and laboratory data for each 2,3-DPG, or hypothermia. The P50, or partial pressure of oxygen (PO2) when
hemoglobin saturation (SO2) is 50%, is about 26.6 mmHg.
patient should be considered. Acute anemia is less well toler-
ated compared to chronic anemia in which peripheral oxygen
delivery is compensated by elevated 2,3-DPG levels in RBCs
and higher cardiac output (see Figure 36-1). In patients with RBC compatibility Plasma compatibility
moderate to severe cardiovascular dysfunction, anemia might
not be well tolerated. The extent and duration of clinical
bleeding are also important criteria for transfusion in major O AB
trauma and surgery. According to the American Society of
Anesthesiologists (ASA) guidelines for blood component
therapy, transfusion of RBCs is almost always indicated for Y Y
hemoglobin less than 6 g/dL, whereas it is rarely indicated for A B YA Y YB Y
hemoglobin greater than 10 g/dL. For hemoglobin between Y Y

6 g/dL and 10 g/dL, transfusion should be considered if com-

plications due to inadequate oxygenation are anticipated.4
Table 36-1.  Blood Component Volumes and Stability
Figure 36-2  ABO compatibility. For RBC transfusion, the recipient can
STORAGE receive the same blood type or blood group(s) specified by the arrow(s).
COMPONENT VOLUME SHELF LIFE TEMPERATURE Blood group O recipients can be only transfused with group O blood whereas
group AB recipients can be transfused with either O, A, B, or AB group RBCs.
Red blood cells 220-340 mL 42 days 1°C-6°C Rh-positive or Rh-negative RBCs can be transfused in an Rh-positive recipi-
Apheresis platelets 250-300 mL 5 days 20°C-24°C ent, and Rh-negative RBCs should be given to an Rh-negative recipient. For
Random donor platelets 50-70 mL 5 days 20°C-24°C plasma product transfusion, the recipient can receive the same plasma type
Plasma* 200-250 mL 1 year <−18°C or plasma group(s) specified by the arrow(s). Blood group AB recipient can
Cryoprecipitate 10-15 mL 1 year <−18°C be only transfused with group AB plasma whereas type O recipient can be
transfused with either O, A, B, or AB group plasma. Rh types are not con-
*Plasma frozen within 8 hours is called FFP, and plasma frozen between 8 and 24 sidered for plasma product transfusion. Orange symbol, anti-B antibody;
hours of collection is called FP24. green symbol, anti-A antibody.

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childbearing age, Rh-negative group O RBCs should be pre- oxygen carriers (HBOC) and perfluorocarbon (PFC) emul-
ferred for reducing the risk of alloantibody (anti-D) develop- sions. Bovine-derived hemoglobin glutamer-200 (Oxyglobin)
ment, which can cause anemia in an Rh-positive fetus. is currently approved for canine anemia in the United States.
Transfusion of mismatched RBCs, typically related to ABO, In South Africa, bovine hemoglobin glutamer-250 (Hemo-
can induce IgM antibody-mediated acute hemolysis, but in pure) is approved for the treatment of human anemia. Free
less serious mismatches of minor antigens such as Rh, Kell, hemoglobin solutions have a higher affinity for oxygen than
and Duffy, survival of transfused RBCs is shortened. RBCs (P50 of 12-14 mmHg for HBOC vs. 27 mmHg for
RBCs).12,13 The modification of hemoglobin by pyridoxal
SIDE EFFECTS phosphate increases P50 to 32 mmHg, improving release of
Acute hemolytic transfusion reactions are usually caused by oxygen.3 Potential benefits of HBOCs include sparing alloge-
ABO incompatibility. This potentially fatal complication neic RBC transfusion in anemia, trauma, and major surgery,
occurs in about 1 in 30,000 transfusions. As little as 20 to and reduction of transfusion-related infection and other com-
30 mL of incompatible RBCs can cause agitation, nausea and plications. However, the vasoconstrictive property of HBOC,
vomiting, dyspnea, fever, flushing, hypotension, tachycardia, due to scavenging of nitric oxide, remains a major concern.2,3
and hemoglobinuria. Two major complications of intravascu- PFC emulsions consist of halogen-substituted hydrocar-
lar hemolysis include renal failure from acute tubular necrosis bons that enhance plasma oxygen solubility. Hydrophobic
and disseminated intravascular coagulation (DIC). PFC molecules are dissolved in plasma using emulsifiers.
Febrile nonhemolytic transfusion reaction is relatively Unlike hemoglobin, the oxygen-carrying capacity of PFC is
common (0.1%-1% of RBC transfusions). Other immuno- directly proportional to oxygen partial pressure.2 Febrile reac-
logic complications of transfusion include HLA alloimmuni- tions or flulike symptoms can occur in that PFC emulsion is
zation, graft-versus-host disease, and immunosuppression taken up by the reticuloendothelial system. PFC is not clini-
triggered by donor leukocytes.9 The risk of these complica- cally available at present, but potential perioperative uses
tions can be partially reduced by use of leukocyte adsorption include acute lung injury, and acute normovolemic hemodilu-
(leukoreduction) filters at blood collection, and γ-irradiation tion to spare RBCs from extracorporeal circuits.
after collection to prevent lymphocyte proliferation. The leu-
koreduction process presumably reduces virologic risks asso-
Platelet Concentrates
ciated with leukocytes including cytomegalovirus, Epstein-Barr
virus, and human T-cell leukemia virus I and II. Although Platelets are anuclear, granulated cells about 2 to 4 µm in
transfusion-related variant Creutzfeldt-Jakob diseases (vCJD diameter derived from bone marrow megakaryocytes. Normal
and bovine spongiform encephalopathy) are rare, there is a half-life of platelets is 7 to 10 days. There are 150 to 350 ×
theoretical advantage in leukodepletion to prevent prion 109/L platelets in circulation, but their concentration near
transmission.10 arterial vessel walls is significantly higher due to the margin-
ation of platelets by larger RBCs.14 Platelets rapidly respond
to disruption of normal endothelium, contributing to the
initial arrest of bleeding (primary hemostasis), and the support
Erythropoietin is a hormone produced in the kidney in of localized thrombin generation and fibrin formation (sec-
response to hypoxemia as seen in chronic pulmonary disease ondary hemostasis or coagulation) (Figure 36-3).15 Procoagu-
and at high altitudes. The primary indication for recombinant lant activity of platelets can increase the risk of vascular
erythropoietin is anemia associated with chronic renal insuf- occlusion of atheromatous lesions (see Chapter 37).
ficiency. Other indications for erythropoietin include treat- Since the first platelet transfusion in the 1950s, platelet
ment of anemia related to the antiviral zidovudine in concentrate remains the mainstay therapy for thrombocyto-
HIV-infected patients, and of chemotherapy-induced anemia penia.16 Platelet concentrates are prepared by centrifugation
in patients with metastatic, nonmyeloid malignancies. Preop- of citrated whole blood within 8 hours of collection. After
erative erythropoietin treatment of anemia has been shown to separating RBCs from platelet-rich plasma, further centrifu-
reduce allogeneic RBC transfusion.11 gation yields one unit of platelet concentrate and plasma.
Each unit of platelets, referred to as “random-donor plate-
SIDE EFFECTS lets,” contains 5.5 × 1010 platelets in 50 to 70 mL of plasma.
Erythropoietin therapy induces a marked expansion of ery- Four to eight random-donor units are pooled to increase
throid cells, which can result in iron deficiency, so iron should platelet count by 15 to 30 × 109/L in the adult. In order to
be supplemented as appropriate. Target hemoglobin levels decrease multiple donor exposures, single donor platelet
should not be set above 13 g/dL because the risk for cardio- apheresis is increasingly used. During the apheresis proce-
vascular events and stroke is increased. Hypertension can be dure, donor blood is placed in the extracorporeal circuit and
worsened by erythropoietin, especially in patients with centrifuged to separate platelets. One platelet apheresis unit
chronic renal failure. Erythropoietin therapy can adversely contains 30 to 50 × 1010 platelets in 250 to 300 mL of plasma.
affect the survival of cancer patients, and progression or Platelet concentrates are agitated and stored at room tem-
recurrence of certain tumors. perature (20°C to 24°C) for up to 5 days (see Table 36-1).

Blood Substitutes
Platelet transfusion is used to prevent or treat bleeding due
The limited availability of blood and infection risks are the to platelet dysfunction or thrombocytopenia. Hereditary
driving forces in developing oxygen-carrying blood substi- platelet dysfunction is rare, but adhesion defects in Bernard-
tutes. Two major classes of substitutes are hemoglobin-based Soulier syndrome (GPIb/IX deficiency), aggregation defects

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Chapter 36  Transfusion and Coagulation Therapy

F activation

PAR1 Platelet GPIb/IX
activation ADP
IIa F Activated
GPIb/IX platelet
EC VIIa α2β1 IIa
and Collagen
fibroblasts Collagen
Injury site Injury site


Activated VIIIa
F platelet Activated
vWF Xa

F Activated
EC α2β1
XIIIa Fibrin

C Injury site D Polymerized fibrin
Figure 36-3  Clot formation at vascular injury site. At the injury site, platelets adhere to subendothelial collagen via interactions between von Willebrand
factor (vWF) and the platelet-surface glycoprotein (GP) receptor GPIb/IX. Platelet integrin receptor α2β1 reinforces binding to collagen. Trace amounts of
thrombin are generated during the initiation phase of coagulation by factor Xa (FXa) via interactions between circulating FVIIa and tissue factor (TF)
expressed on subendothelial pericytes and fibroblasts (A). Platelets activated by collagen and thrombin release adenosine-5′-diphosphate (ADP) and throm-
boxane A2 (TXA2), which activate platelets in the vicinity (B). Activated platelets express GPIIb/IIIa and capture fibrinogen (F) (C). On the activated platelet
surface, thrombin-mediated feedback activation of FXI, FVIII, and FV results in the propagation phase of thrombin generation. Sustained activation of
prothrombin is feasible via formation of tenase (IXa-VIIIa) and prothrombinase (Xa-Va). Polymerization of fibrin is achieved by thrombin-activated FXIII
during the propagation phase (D). (Modified with permission from Bolliger D, Gorlinger K, Tanaka KA. Pathophysiology and treatment of coagulopathy in
massive hemorrhage and hemodilution. Anesthesiology. 2010;113:1205-1219.)

in Glanzmann’s thrombasthenia (GPIIb/IIIa deficiency), and count remains to be established.4-7 A platelet count of 50 ×
a secretion defect in Hermansky-Pudlak syndrome (lack of 109/L is reached after loss of twice the blood volume in an
dense granules) are prototypical hemorrhagic conditions average sized adult.19 Although a fixed ratio (1 : 1 : 1) trans­
resulting from decreased primary hemostasis.17 Platelet dys- fusion of RBC, fresh frozen plasma (FFP), and pooled plate-
function in the perioperative patient is usually due to anti- let units has been suggested to improve acute survival in
platelet therapy (see Chapter 38). Platelet transfusion may be severely injured patients with massive bleeding, hemostatic
required even with a normal platelet count if platelet dysfunc- efficacy of platelet transfusion is difficult to validate without
tion due to acetylsalicylic acid (aspirin), thienopyridines, or platelet function testing.20,21 The timing and amount of plate-
GPIIb/IIIa inhibitors is clinically suggested or identified by let transfusion can be individualized by point-of-care labora-
platelet aggregometry. For thrombocytopenia associated with tory tests (platelet count or thromboelastometry/graphy;
bone marrow disorders, the threshold for platelet transfusion Figure 36-4).22,23
is 10 × 109/L, which is usually sufficient to maintain vascular
integrity.18 In trauma or major surgery, platelet transfusion SIDE EFFECTS
is empirically administered to maintain platelet counts above The risk of bacterial contamination is higher with platelet
50 × 109/L, although the hemostatic threshold for platelet concentrates than with other blood components because they

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Rotating pin

Light ray

Clot firmness (mm)


Stationary cup

Plasma Platelet-fibrin interaction (inhibited in fibtem)

coagulation Fibrin polymerization

XIIIa Example of Hemostatic Management

Microvascular bleeding

A Heating block

CT 80 sec MCF 48 mm Fibrinolysis

PT 16.5 sec

MCF 10 mm 10 mm
or or
fibrinogen 150 mg/dL platelet 100 x 109/L

Tranexamic acid
Plasma Cryoprecipitate Platelets Aminocaproic acid
Figure 36-4  Principle of rotational thromboelastometry. A, The rotational thromboelastometry (ROTEM) instrument has a rotating pin immersed in the sample
blood. Viscoelastic changes due to fibrin polymerization are detected optically. B, Blood samples can be activated by tissue factor (EXTEM) or ellagic acid
(INTEM). The initial lagtime of coagulation (clotting time; CT) reflects procoagulant reactions to generate thrombin in plasma. Thrombin-mediated activation
of platelets (pink oval), FXIII (blue oval), and fibrin (blue line) result in increased linkage (viscoelasticity) between the pin and cup (A). When cytochalasin
D is added, platelet-fibrin interactions are inhibited, and fibrinogen levels can be estimated (FIBTEM). C, In the event of microvascular bleeding in surgery,
an algorithm such as this example can be used to standardize hemostatic therapy (see references 22 and 23).

are stored at room temperature. An immunoassay kit is avail- recipient.25 The incidence of severe hemolysis is estimated to
able to test for aerobic or anaerobic gram-positive and gram- be in the range of 1 in 6600 (apheresis platelet transfusion) to
negative bacteria (sensitivity, 103-105 colony formation 1 in 9000 (non–ABO-identical platelet transfusions).
units/mL). Alloimmunizations after platelet transfusion can Other potential complications of platelet transfusion in
result in antibodies against HLA class I antigens and platelet- surgical patients include transfusion-associated lung injury
specific antigens. Problems due to platelet alloimmunization (TRALI) and thrombotic complications.26
include refractoriness to platelet transfusion, and posttrans­
fusion purpura. For those who require frequent platelet
transfusions, the use of leukoreduced, HLA-matched, and
ABO-compatible platelet units should be considered to reduce
the risk of platelet alloimmunization.24 The hemolysis of
Fresh Frozen Plasma
RBCs can be caused by anti-A or anti-B antibody present in
the donor plasma of platelet concentrates. This typically FFP is a unit of plasma separated from whole blood (~500 mL)
occurs after group O platelet transfusion in non–group O or apheresis donations, and frozen at −18°C within 8 hours

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Chapter 36  Transfusion and Coagulation Therapy

of collection. FP24 is an FDA-approved plasma product greater than 1.5 times the upper limit of normal.30 The usual
frozen between 8 and 24 hours of collection. Each unit is dose is 5 to 8 mL/kg, but up to 10 to 30 mL/kg might be
approximately 200 to 250 mL and contains all components of necessary to keep coagulation factors above 50% of normal.31,32
donor plasma, including procoagulant and anticoagulant Plasma products need to be administered early rather than
factors, albumin, and immunoglobulins. The recovery of late to avoid fluid overload in cases of massive hemorrhage.33
coagulation factors after each plasma unit is about 2% to 3% Early plasma transfusions using a 1 : 1 ratio of FFP : RBC
in the adult, but can vary with donors, clinical hemorrhage, improved early survival in military and civilian trauma,34-37 but
and/or consumption. Plasma products can be stored frozen some retrospective data suggest no benefit of increased plasma
up to 12 months. Thawed plasma can be kept at 1°C to 6°C transfusion, and increased risk of multiorgan failure.38-40 The
and used within 5 days since coagulation factors including the guidelines of the American Association of Blood Banks and
most labile FV and FVIII remain adequate for this period.27 the European task force recommend early plasma transfusion
Donor plasma should be compatible with recipients’ ABO without a specific FFP : RBC ratio.7,30 The rational use of
types (see Figure 36-2), but Rh types do not need to be con- plasma is facilitated by rapid point-of-care coagulation moni-
sidered. Blood group AB plasma can be used as the universal tors (see Figure 36-4), and by adopting safer transfusion pro-
donor for emergency. tocols and products (e.g., lyophilized plasma-derived or
recombinant protein concentrates).41
CLINICAL USES For congenital factor deficiencies, plasma-derived or
Plasma transfusion is mainly indicated for the treatment of recombinant factor concentrates are often available, and are
complex coagulopathies in which multiple coagulation factors preferable to plasma transfusion in terms of safety and efficacy
and inhibitors are depleted. For congenital factor deficiency, (Table 36-3). Plasma can be used as a replacement fluid
plasma transfusion should be considered only if recombinant (plasma exchange) in patients undergoing a therapeutic apher-
or plasma-derived factor concentrate is not available (Table esis procedure.42 It is the first-line therapy to reduce mortality
36-2). Plasma products can be transfused prophylactically from thrombotic thrombocytopenia purpura by providing
before invasive procedures when risk of bleeding is high. metalloprotease (ADAMTS13) that cleaves high-molecular
When the international normalized ratio (INR) is less than von Willebrand factor (vWF).43 For acute reversal of vitamin
1.5, excessive bleeding is unlikely.28,29 Plasma transfusion is K antagonist (e.g., warfarin) therapy, FFP is used in conjunc-
used to treat bleeding conditions when prothrombin time tion with vitamin K. Plasma-derived, virus-inactivated pro-
(PT) is greater than 1.5 times the midpoint of the normal thrombin complex concentrate (PCC) is an alternative therapy
range, or activated partial thromboplastin time (aPTT) is for this indication as described below.6

Table 36-2.  Plasma Concentrations and Half-Lives of Coagulation Factors


Fibrinogen 7.6 72-120 pd-fibrinogen, cryoprecipitate

Prothrombin 1.4 72 PCC, FEIBA
Factor V 0.03 36 None
Factor VII 0.01 3-6 pd-FVII, r-FVIIa, PCC*, FEIBA
Factor VIII 0.00003 12 pd-FVIII, r-FVIII
Factor IX 0.09 24 pd-FIX, r-FIX, FEIBA
FX 0.17 40 pd-FX, PCC, FEIBA
Factor XI 0.03 80 pd-FXI
Factor XIII 0.03 120-200 pd-FXIII, r-FXIII, cryoprecipitate
vWF 0.03 10-24 pd-vWF, r-vWF, cryoprecipitate
Protein C 0.08 10 pd-Protein C, PCC*
Protein S 0.14 42.5 PCC*
Antithrombin 2.6 48-72 pd-antithrombin, r-antithrombin

Adapted with permission from Bolliger D, Gorlinger K, Tanaka KA. Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution.
Anesthesiology. 2010;113:1205-1219.
FEIBA, Factor eight inhibitor bypassing activity; PCC, prothrombin complex concentrate (*some PCC products contain minimal levels of FVII, protein C and S; see
Table 36-3); pd, plasma-derived; r, recombinant; vWF, von Willebrand factor.

Table 36-3.  Contents of Commercial Prothrombin Complex Concentrates in North America



Bebulin Baxter 120 13 100 139 Present Present Not on label <0.15 U per IU of FIX
Beriplex CSL Behring 111 57 100 150 15-45 13-26 0.2-1.5 0.4-2.0
Octaplex Octapharma 98 66 100 96 7-32 7-32 Not on label Not on label
Profilnine Grifols 148 11 100 64 Not on label Not on label Not on label Not contained

Each PCC vial is labeled according to the FIX content in international units (IU). The contents of other procoagulant factors are shown relative to FIX (e.g., one
500-IU vial of Bebulin contains 65 IU of FVII and 600 IU of FII).

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SIDE EFFECTS hydroxyethyl units at C2 relative to C6. HES with higher

Allergic reactions to plasma are the most common complica- molar replacement and C2/C6 ratios is retained longer due
tions occurring in 1% to 3% of all transfusions. The risk of to slower metabolism (Table 36-4). HES is excreted by the
fluid overload due to a large volume of plasma transfusion kidney after degradation.
should be considered in patients with a limited cardiovascular Differences between albumin and HES in efficacy and
reserve. Hypocalcemia can result from citrate accumulation safety are controversial. HES products are available in iso-
after plasma transfusion, and is treated with calcium chloride. oncotic (6%) or hyperoncotic (10%) solutions. The 6% HES
Risk of viral transmission has been significantly reduced since solutions with the average molecular weight of 600 to 670 kDa
the 1990s by implementing nucleic acid testing for human (Hespan, Hextend) are most commonly used, but low molecu-
immunodeficiency virus and hepatitis C virus. Use of lar weight HES (130 kDa, Voluven) has recently become
pathogen-inactivated plasma (solvent-detergent or methylene available in the United States.46 HES products are as effective
blue-treated plasma) might further reduce viral transmission as albumin as fluid replacements, but large doses of HES
risks.44 (particularly Hespan) can adversely affect coagulation (fibrin
TRALI is a serious complication of plasma transfusion. It polymerization) and exacerbate renal dysfunction in sepsis.47,48
is causally associated with anti-HLA antibodies. Multiparous Excess HES can falsely elevate turbidimetric fibrinogen
females are often sensitized to HLA antigens, and thus the measurements.49
incidence of TRALI has gone down after many blood centers
started to produce the majority of plasma products from male
Cryoprecipitate is prepared from thawing FFP at 1°C to 6°C.
The cold-insoluble precipitate contains FVIII, vWF, FXIII,
fibrinogen, and fibronectin. The precipitate is resuspended in
Albumin is a 69-kDa protein synthesized in the liver and a small amount of plasma (~15 mL) and is stored at −18°C up
present in plasma at 3 to 5 g/dL (~60% of plasma protein). to 12 months. Cryoprecipitate was the first concentrated
Plasma-derived pasteurized (60°C for 10 hours) fractions are source of FVIII and used to be called cryoprecipitated anti-
available in iso-oncotic (5%) or hyperoncotic (25%) solutions. hemophilic factor. Plasma-derived or recombinant factor con-
Albumin exerts oncotic activity (colloid osmotic pressure) to centrate has largely replaced the use of cryoprecipitate in
retain intravascular water. The oncotic pressure of 5% congenital deficiency of FVIII, vWF, FXIII, or fibrinogen.50
albumin is equivalent to plasma. Albumin also serves to carry
poorly water-soluble molecules (e.g., apoprotein, bilirudin,
transferrin). Indications for albumin use include fluid replace-
ment for hypovolemic shock, priming for extracorporeal cir-
cuits, and plasma exchange therapy. In acute liver failure,
albumin can be used to restore oncotic pressure. The intra- Table 36-4.  Synthetic Hydroxyethyl Starch Colloid Solutions
vascular retention of albumin is affected by increased vascular
permeability (e.g., first 24 hours of thermal injury) and excre- TYPE OF HES 600/0.7 670/0.75 260/0.45 130/0.4
tion (e.g., nephrotic syndrome). Albumin does not affect Product name Hespan Hextend Pentaspan Voluven
hepatic or renal function. Concentration 6% 6% 10% 6%
Solvent Saline LR Saline Saline
Oncotic pressure 25-30 25-30 55-60 36
Synthetic Colloids (mmHg)
Mean molecular mass 600 670 260 130
Synthetic colloid solutions include hydroxyethyl starches (kDa)
(HES) in which rapid degradation by α-amylase is prevented Molar substitution 0.7 0.75 0.45 0.4
by hydroxyethylation of glucose subunits (Figure 36-5). The C2/C6 ratio 5 4.5 6 9
molar replacement ratio indicates the proportion of glucose Maximum daily dose 20 20 20 33
molecules replaced with hydroxyethyl units (e.g., 0.4 = 40%
replacement). The C2/C6 ratio indicates the number of LR, Lactated Ringer’s.

R1 R1 1
5 α-Amylase
( RO R O
1 O RO 1 O RO
3 2 R
O O )n
O 4
O O R1
Figure 36-5  Hydroxyethyl substitution of hydroxyethyl starch (HES). The structural formula of HES poly(O-2-hydroxyethyl)starch. R, –H, –CH2CH2OH; R1, –H,
CH2CH2OH or glucose unit. Enzymatic cleavage site of α-amylase (yellow arrow) is at C1 and C4 atoms. Hydroxyethyl groups at position C2 inhibit the access
of α-amylase to the substrate more effectively than those at C6. HES products with high C2/C6 ratios are more slowly degraded. (Reprinted with permission
from Kozek-Langenecker SA. Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology. 2005;103:654-660.)

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Chapter 36  Transfusion and Coagulation Therapy


Cryoprecipitate is used to manage bleeding due to acquired The recommended initial dose of rFVIIa for hemophiliacs
hypofibrinogenemia (<100-150 mg/dL). Each unit contains with inhibitors is 90 to 120 µg/kg, but higher doses of 200 to
150 to 250 mg of fibrinogen; 5 to 10 units are thawed and 400 µg/kg have been used without major thrombosis. In
pooled before infusion. Each unit of cryoprecipitate increases refractory bleeding, combination therapy with factor eight
plasma fibrinogen by approximately 100 mg/dL per 5-kg inhibitor bypassing activity (FEIBA), an activated PCC, has
body weight. The volume of cryoprecipitate required to been suggested.64
increase fibrinogen levels is far less than that of FFP. However, In nonhemophiliacs, the initial dose of rFVIIa is lower
it takes longer to thaw and pool multiple units of cryoprecipi- (20-70 µg/kg).63 In randomized trauma trials, the efficacy of
tate, whereas thawed FFP is more readily available for trans- higher initial doses (200 µg/kg) was limited to a small reduc-
fusion. In many European countries, cryoprecipitate is no tion in RBC use with no effect on 30-day mortality.65,66 In a
longer available, and plasma-derived, pasteurized fibrinogen randomized trial in intracerebral hemorrhage, rFVIIa at
concentrate is used.51 It is feasible to rapidly treat hypofibri- 80 µg/kg reduced hematoma expansion but led to increased
nogenemia with the fibrinogen concentrate because no arterial thrombosis.67 Similarly, in a study of bleeding after
thawing and blood type matching are required, and it can be cardiac surgery there were fewer reoperations and decreased
infused at a low volume (1 g of fibrinogen per 50 mL after allogeneic blood use with rFVIIa at 40 µg/kg and 80 µg/kg,
reconstitution). but with increased adverse events including stroke.68
The minimal level of plasma fibrinogen to minimize
perioperative bleeding has not been well established.52 SIDE EFFECTS
International guidelines previously recommended a minimal Thrombotic complications after rFVIIa are infrequent in
fibrinogen of 80 to 100 mg/dL, similar to management of hemophilia, but these risks appear to be increased in nonhe-
congenital afibrinogenemia.5,31 More recently, higher fibrino- mophiliacs undergoing surgery.69 In an analysis of 35 pub-
gen levels (150-200 mg/dL) are recommended in European lished randomized clinical studies, the incidence of arterial
guidelines for perioperative transfusion based on clinical thromboembolic events, but not venous thrombosis, was
data supporting fibrinogen above 200 mg/dL in postpartum increased by 1.7-fold with rFVIIa therapy.70 Higher rFVIIa
hemorrhage, coronary bypass grafting, aortic replacement, dose (>80 µg/kg), age, and coronary artery disease were con-
and cystectomy.6,7,53-58 Plasma fibrinogen levels can be esti- tributing factors to thrombosis.
mated by the modified Clauss method or platelet-inhibited
thromboelastometry/graphy (see Figure 36-4).59,60
Prothrombin Complex Concentrate
SIDE EFFECTS PCC is a sterile, lyophilized concentrate of factors II, VII, IX,
The exposure to multiple donors from pooled cryoprecipitate and X and protein C and S. Before development of FIX con-
units is a major concern since no viral inactivation procedure centrates, PCC with low amounts of FVII (3-factor PCC) was
is clinically available.61 Use of pasteurized plasma-derived used to treat hemophilia B. The content of PCC is thus stan-
fibrinogen concentrates is strongly recommended for patients dardized to the amount of FIX in each vial (each vial contains
with congenital afibrinogenemia or dysfibrinogenemia. Cryo- at least 500 IU of FIX) (see Table 36-3). Advantages of PCC
precipitate contains some plasma, but the risk of TRALI include rapid availability, small volume of infusion, and avoid-
is unknown. Risk of thrombotic complications is unknown, ance of complications such as ABO incompatibility and
but is potentially of concern because cryoprecipitate rapidly TRALI associated with FFP. PCC containing clinically rele-
increases plasma fibrinogen, FVIII, FXIII, and vWF vant FVII levels (4-factor PCC) is available for acute reversal
(ADAMTS13 is minimal in cryoprecipitate units).62 of vitamin K antagonists in Europe and Canada (currently in
clinical trials in the United States).71 PCCs increase thrombin
generation by interacting with negatively charged phospho-
Recombinant Factor VIIa
lipids on activated platelets at the vascular injury site.72 Com-
Recombinant activated factor VIIa (rFVIIa) is an activated mercial PCCs are fractionated from pooled plasma and
form of human FVII produced in hamster kidney cells. Its undergo viral inactivation using vapor-heat or solvent/
hemostatic activity is mainly mediated by tissue factor- detergent-treatment and nanofiltration.
dependent activation of FX and subsequent thrombin genera-
tion. Use of rFVIIa is clinically indicated for prophylaxis or CLINICAL USES
treatment of bleeding in hemophiliacs who develop neutral- PCC can be rapidly reconstituted with sterile water (20 mL
izing antibodies to FVIII or FIX and with congenital FVII per 500 IU) without the need for thawing and blood type
deficiency. matching. Dosing depends on the extent of anticoagulation.
Off-label use of rFVIIa is common after major bleeding A high initial dose of 30 to 50 IU/kg (maximum, 5000 IU) is
in trauma and surgery, but efficacy and safety of rFVIIa used in life-threatening bleeding associated with anticoagula-
outside of congenital factor deficiency has not been estab- tion including intracranial hemorrhage and retroperitoneal
lished.63 It is not uncommon to observe multifactorial bleeding. A lower dose of 20 to 25 IU/kg is used for soft tissue
coagulopathy in addition to hypothermia and acidosis in bleeding, epistaxis, and hematuria. Subsequent doses are
nonhemophiliac patients who developed profuse bleeding based on PT/INR measurements. In acute bleeding, the
after trauma or surgery. The use of rFVIIa should be con- major advantage of PCC is that procoagulant FII, FVII, FIX,
sidered only after replenishing plasma proteins (particularly and FX can be rapidly (<30 minutes; Figure 36-6) increased
prothrombin and fibrinogen), and optimizing body tempera- by 40% to 80% without dilution of RBCs and platelets.73,74
ture and pH. The vicious cycle of hematoma formation, tissue edema, and

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rebleeding can be prevented by prompt reestablishment of
hemostasis.75 Adjunctive vitamin K is recommended to sustain
Time (h) Median INR (IQR) PT/INR because plasma FVII falls quickly after a dose of
7 Baseline 3.2 (2.4-5.2) PCC due to its short half-life.73 The incidence of thrombotic
0.5 1.2 (1.0-1.3) complications after PCCs for acute reversal of anticoagulation
1 1.2 (1.1-1.3)
6 is about 0.9% to 2%.76
3 1.2 (1.1-1.4)
6 1.3 (1.1-1.4) There is a paucity of data on PCC for treatment of coagu-
12 1.3 (1.2-1.4) lopathy in trauma, major surgery, and hepatic dysfunction. In
5 24 1.2 (1.1-1.5) small retrospective studies, PCC was effective in achieving
48 1.2 (1.1-1.4) hemostasis in postcardiac surgical patients who were refrac-
4 tory to platelets, FFP, and cryoprecipitate.77,78 The use of

PCC after initial treatment with fibrinogen concentrate in

trauma patients reduced the need for FFP without affecting

Use of PCC is generally safe for acute reversal of anticoagula-
1 tion, but thrombogenicity is a concern in the setting of
massive hemorrhage and hemodilution. Prothrombotic risks
might be increased with anticoagulant deficiency associated
with hepatic cirrhosis or severe hemodilution.79,80 PCC should
Baseline 1 3 6 12 24 48 not be administered to patients with DIC.6
A Time (hr) Current antiviral protocols for factor concentrates are not
effective against prions (e.g., vCJD) or non–lipid-enveloped,
heat-resistant viruses (e.g., parvovirus B19), but these risks are
considered to be low.81
FIX (%)

50 Antithrombin Concentrate
Antithrombin (AT) is a serine protease inhibitor with a molec-
1 0
150 ular weight of 58 kDa. Normal plasma AT is about 150 µg/
mL (2.6 µM). Anticoagulant activity of AT is potentiated by
100 endothelial surface heparan sulfate or exogenously adminis-
FII (%)

tered heparin. In congenital AT deficiency, AT is 40% to 60%

of normal, resulting in prolonged half-life of FXa and throm-
2 0 bin (Figure 36-7).82 The incidence of venous thromboembo-
lism is increased in congenital AT deficiency during pregnancy
and after major trauma or surgery. Replacement of AT using
FVII (%)

plasma-derived (Thrombate III) and recombinant AT con-
50 centrate (Atryn) are indicated to prevent thrombotic compli-
25 cations in congenital deficiency. Recombinant AT is produced
3 0 in transgenic goats, and has different glycosylation and a
shorter half-life (11 hours vs. 2.5 days). Whether the cost of
150 higher doses is justified by the improved viral safety of recom-
FX (%)

100 binant AT is unknown.

Acquired AT deficiency is frequently observed following
treatment with intravenous heparin for more than 4 to 5 days.
4 0 In cardiac surgical patients with heparin insensitivity (acti-
Baseline 1 3 6 12 24 48 vated clotting time <400 seconds), plasma-derived or recom-
B Time (hr) binant AT concentrates restore plasma AT activity effectively
without the need for additional heparin or FFP.83,84 AT con-
Figure 36-6  Time course of international normalized ratio and vitamin centrates are less likely to decrease hematocrit and platelet
K–dependent procoagulant factors after reversal of oral anticoagulation with
PCC. A, The changes in international normalized ratio (INR) during acute
count compared to FFP. Both plasma-derived and recombi-
oral anticoagulant reversal with PCC are shown. B, Time course of plasma nant AT concentrates contain trace amounts of heparin, and
levels of (1) FIX, (2) FII, (3) FVII, and (4) FX after PCC therapy. Levels are so should not be used in patients with heparin-induced throm-
shown as a percent of normal. Boxes span the interquartile range (IQR). bocytopenia (HIT).6
Horizontal lines bisecting the boxes indicate median values and lower and
upper error bars the 10th and 90th percentiles, respectively. (Data from
Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate Protein C Concentrate
(Beriplex P/N) for emergency anticoagulation reversal: a prospective multina-
tional clinical trial. J Thromb Haemost. 2008;6:622-631.) Protein C is a vitamin K–dependent factor similar to pro-
thrombin, FVII, FIX, and FX. Protein C activation by throm-
bin is limited in the presence of fibrinogen, FV, FVIII, and

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Chapter 36  Transfusion and Coagulation Therapy

Vascular injury site

Fibrin Lysine analogues
AT Heparin IIa Thrombomodulin
Xa PC Plgn Fibrin
tPA Plasmin
Free FXa, thrombin IIa

Endothelial cells
Figure 36-7  Regulation of procoagulant responses. Local and systemic regulation of coagulation and fibrinolysis at a site of vascular injury is shown.
Hemostasis is established as fibrin is polymerized by thrombin (IIa) and activated FXIII. When thrombin or FXa is released (i.e., free thrombin) into the
systemic circulation during hemostatic activation, antithrombin (AT) and thrombomodulin of intact endothelium bind to thrombin and reduce its procoagulant
activity. Thrombomodulin-bound thrombin activates protein C (APC), which inactivates coagulation factors Va and VIIIa. Thrombin also causes the release
of tissue plasminogen activator (tPA) from endothelium, which promotes plasminogen (Plgn) conversion to plasmin on the fibrin surface. Broken lines
indicated inhibitory action of respective protease inhibitors. PAR, Protease-activated receptor (thrombin receptor on endothelium). (Adapted with permission
from Ide M, Bolliger D, Taketomi T, et al. Lessons from the aprotinin saga: current perspective on antifibrinolytic therapy in cardiac surgery. J Anesth.

platelets at a vascular injury site, but is more efficiently acti- to fibrin by occupying the plasminogen lysine-binding site
vated by thrombin bound to thrombomodulin expressed on (see Figure 36-7). By preventing colocalization of tissue plas-
the endothelium (see Figure 36-7). Elevated systemic throm- minogen activator and plasminogen on fibrin, plasmin activa-
bin activity thus increases protein C activation as observed in tion, and subsequent fibrin degradation are inhibited. Both
thrombophilia, sepsis, and traumatic injury.85-87 Activated EACA and TXA have a low molecular weight (131 Da and
protein C with protein S downregulates activated FV and 157 Da, respectively) in contrast to the bovine plasmin inhibi-
FVIII and exerts antiinflammatory and cytoprotective func- tor aprotinin (6512 Da). Reduced perioperative blood loss has
tions by modulating endothelial protein C receptor and been reported in cardiac, hepatic, and orthopedic surgeries,
protease-activated receptor-1 (PAR-1, thrombin receptor).88 although most studies are underpowered to demonstrate
Antiinflammatory effects of activated protein C (recombi- safety.92 The use of aprotinin has been on hold from the
nant) might be beneficial in patients with severe sepsis market after higher 30-day morbidity and mortality was
(APACHE score >25), but serious bleeding is the major side reported compared with lysine analogues.93,94
Homozygous protein C deficiency in newborns manifests CLINICAL USES
as purpura fulminans with thrombosis in small vessels causing The approved indication of lysine analogues is to reduce
skin necrosis.90 Incidence of venous thromboembolism is bleeding in hemophilia patients.95 EACA is administered
eightfold to 10-fold higher in individuals with heterozygous orally or intravenously for bleeding associated with fibrinoly-
protein C deficiency.91 sis with an initial dose of 5 g in adults. In hemophiliacs having
Lyophilized protein C concentrate (Ceprotin) is available dental extraction, TXA is given at a dose of 10 mg/kg three
for prevention and treatment of purpura fulminans and venous to four times a day.
thrombosis in the North America. The initial dose for acute In cardiac surgery with cardiopulmonary bypass, the
thrombosis is 100 to 120 IU/kg, followed by maintenance loading dose of intravenous EACA and TXA is 50 mg/kg and
doses of 45 to 60 IU/kg every 6 to 12 hours. The infectious 10-15 mg/kg, respectively, after systemic anticoagulation.
risk of plasma-derived protein C is low due to viral inactiva- Continuous infusion of EACA and TXA is commonly used at
tion steps, including polysorbate-80, vapor-heat, and ion 15 mg/kg/hr for EACA and 7.5 mg/kg/hr for TXA until the
exchange chromatography. Precautions for use include bleed- end of surgery. In trauma patients, TXA (1 g loading, fol-
ing, sodium overload, rare allergic reactions, and heparin- lowed by 1 g over 8 hours) improved mortality without
induced thrombocytopenia due to trace amounts of heparin. increasing cardiovascular complications.96

Systemic thrombosis is uncommon with EACA or TXA,
but they should not be used in patients with DIC.6 Lysine
analogues are mainly excreted by the kidney, and dosage
Lysine Analogues
should be reduced based on serum creatinine level. EACA and
The lysine analogues ε-aminocaproic acid (EACA) and TXA are eliminated by hemofiltration or dialysis. With renal
tranexamic acid (TXA) prevent plasminogen from binding or ureteral bleeding, lysine analogues can increase the risk

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of ureteral obstruction due to clot formation. Prolonged infu- surface bleeding. To prevent viral transmission from the
sion of TXA is associated with seizures. Presumably this is human plasma, fibrinogen and thrombin are treated with
due to TXA crossing the blood-brain barrier and antagoniz- solvent-detergent, nanofiltration, or vapor-heat. Recombi-
ing GABA receptors.97 nant aprotinin (Tisseel) and tranexamic acid (Crosseal) are
added for improved clot stability.
Gelatin forms (Gelfoam, Gelfilm, Surgiform) provide a
physical matrix for clot formation, and are effective in bleed-
Desmopressin (1-desamino-8-D-arginine vasopressin) is a ing from small capillaries and venules. Another gelatin-based
synthetic vasopressin analogue with antidiuretic activity. In sealant (FloSeal) is a mixture of human thrombin and bovine-
mild to moderate von Willebrand disease and hemophilia A, derived gelatin-based matrix. Thrombin generates fibrin from
intravenous desmopressin (0.3-0.4 µg/kg) increases plasma blood fibrinogen, and the gelatin particles expand to tampon-
vWF and FVIII by twofold to threefold within 60 to 90 ade bleeding. Gelatin matrix is reabsorbed after 6 to 8 weeks.
minutes. Increased vWF might improve platelet adhesion to These topical agents are generally safe and useful adjuncts
sites of vascular injury. Desmopressin is often administered to for hemostasis when used for appropriate indications and ana-
patients with preexisting platelet dysfunction related to anti- tomic sites.99
platelet drugs and uremia. Desmopressin appears to reduce
blood loss, but most studies failed to demonstrate reduced
RBC transfusion in nonhemophilic surgical patients.98 Incon-
sistent efficacy could be related to simultaneous release of tPA
and tachyphylaxis or exhaustion of stored vWF-FVIII in
Liver Failure
high-stress situations.
Patients with liver failure often develop abnormal hemostasis
SIDE EFFECTS because most coagulation factors and inhibitors are synthe-
Rapid intravenous administration of desmopressin causes sized by hepatocytes. Hemophilia A and B can be cured by
flushing and mild hypotension via vasopressin V2 receptor liver transplantation.101 The liver is also the major site for
stimulation. Vascular occlusion due to elevated vWF is rare clearance of activated coagulation factors and plasminogen
in von Willebrand disease and hemophilia A, but could be a activators. The extent of coagulopathy varies with the type
concern in surgical patients with preexisting cardiovascular and stage of liver and biliary tract disease.102,103 PT/INR has
disease.98 been used to estimate the outcome of liver disease because
decreased levels of prothrombin, FV, FVII, and FX reflect
severity of liver disease.104 Coagulopathy in end-stage liver
Topical Hemostatic Agents
disease is often viewed as a hemorrhagic condition, but
Topical hemostatic agents are useful in controlling minor recent clinical data indicate that the hypocoagulable state
bleeding from bone (bone wax, Ostene) or small capillaries coexists with a potentially prothrombotic state due to gener-
and venules (e.g., topical thrombin).99 Bovine thrombin has alized decreases in both procoagulant and anticoagulant
been clinically used for a long time, but is associated with proteins.102,103
major immunologic reactions including immunization against
endogenous prothrombin, thrombin, FV, and cardiolipin.
Jehovah’s Witnesses
Acquired FV deficiency due to bovine thrombin exposure
can result in serious bleeding.100 Plasma-derived thrombin Devout Jehovah’s Witnesses do not accept transfusion of
(Evithrom) or recombinant thrombin (Recothrom) are pre- “primary components” including red blood cells, white blood
ferred to bovine thrombin (Thrombin–JMI) as a topical agent. cells, platelets, and plasma. The use of immunoglobulins,
Oxidized cellulose (Surgicel) induces local hemolysis of albumin, and plasma-derived FVIII and FIX (“hemophiliac
RBCs by lowering pH, and provides a physical matrix for preparations” per religious leaders) have been allowed since
coagulation. Disadvantages include inactivation of natural 1978. The policy on blood transfusion was changed recently,
clotting enzymes such as thrombin and potential for inflam- and acceptance of fractionated products of “primary compo-
mation and delayed wound healing. Microfibrillar collagen nents” was left to the individual believer (Table 36-5). In
(Avitene) increases local platelet adhesion and activation,
leading to hemostasis within 5 minutes. The collagen particles
do not cause much swelling and are reabsorbed within 8
weeks. It should be cautioned that microfibrillar collagen can
Table 36-5.  Primary Components and Fractionated Products
pass through red blood cell salvage system filters. Platelet gel
for Jehovah’s Witnesses
(Vitagel) combines microfibrillar collagen and thrombin with
the patient’s own platelet and plasma (fibrinogen), but requires PRIMARY FRACTIONATED PRODUCTS OF
centrifugation for preparation. COMPONENTS PRIMARY COMPONENTS
Fibrin sealants (Tisseel, Crosseal, Evicel) are effective for
Not Acceptable Up to the Individual Believer
venous oozing from raw surfaces. They are supplied with Red blood cells Hemoglobin-based oxygen carrier
separate vials of fibrinogen, thrombin, and calcium chloride White blood cells Interleukins, Interferons
that are mixed at the wound by a dual-syringe applicator. Platelets Platelet gels
Hemostasis results from topical fibrin formation. A patch Plasma Albumin, immunoglobins, coagulation factor/
inhibitor concentrates, recombinant human
sponge (Tachosil) impregnated with lyophilized human
proteins, topical hemostatics
fibrinogen and thrombin is also available for treatment of raw

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Chapter 36  Transfusion and Coagulation Therapy

addition to recombinant proteins such as erythropoietin and

activity of thrombin, fibrinogen, and FXIII) can be
rFVIIa, plasma-derived factor concentrates (see Table 36-2)
can be acceptable to Jehovah’s Witnesses.105
• Early administration of FFP along with RBCs in major
hemorrhage has recently gained popularity at civilian
trauma centers. This approach theoretically prevents
excessive factor dilution, and can improve hemostasis
and early survival. Potential concerns regarding more
Improved pathogen detection in donors and pathogen reduc-
plasma use include increased acute lung injury,
tion treatments should allow increasingly safer supplies of
immunomodulation, and volume overload.
allogeneic blood products.106
• For certain hereditary deficiencies of coagulation factors
The duration and resources (e.g., culture medium) required
or inhibitors, plasma-derived or recombinant
for autologous cell production remain major hurdles in filling
concentrates are available, and are preferable for safety
clinical needs. Better understanding and technologies related
(e.g., reduced risk of viral transmission) and efficacy.
to hematopoietic progenitors, embryonic stem cells, and plu-
Use of factor concentrates in acquired factor deficiency
ripotent stem cells have recently enabled in vitro production
is generally considered as off-label, but there are some
of functional RBCs in terms of deformability, enzyme content,
supportive data available for certain indications (e.g.,
and oxygen-carrying capacity.107 In time, cultured autologous
PCCs for vitamin K antagonist reversal and fibrinogen for
RBCs and platelets could become valid transfusion resources
dilutional coagulopathy).
for those with rare antigens and multiple alloantibodies.
• Topical hemostatic agents are frequently used by
In addition to cellular components, human stem cell tech-
surgeons, and can be potentially useful to reduce blood
nology can be applied to produce structured tissue sheets
loss. The proper indications and sites should be
(e.g., hepatocytes).108 Deficient coagulation factors and inhibi-
considered to reduce untoward complications (e.g.,
tors can be replaced by implanted hepatocellular tissue
tissue swelling, necrosis, intravascular absorption).
Clinical application of nanoparticles (diameter <100 nm)
holds some promise. For example, biodegradable GPIb-
conjugated nanoparticles might be used to compensate for Key References
impaired platelet function.110
Novel recombinant coagulation proteins or synthetic Bolliger D, Gorlinger K, Tanaka KA. Pathophysiology and treat-
chemicals are being developed for bleeding disorders. Exam- ment of coagulopathy in massive hemorrhage and hemodilution.
ples of such molecules are modified recombinant FVIIa with Anesthesiology. 2010;113:1205-1219. Reviews the pathogenesis of
prolonged half-life and improved potency for hemophilia, and hemodilution-induced coagulopathy with a focus on component-
based hemostatic therapies. Significant consumption and loss of
a synthetic 700 Da plasmin inhibitor for perioperative antifi- fibrinogen is common in major trauma and surgical patients. The
brinolytic therapy.111,112 minimal fibrinogen level was previously set at 80 to 100 mg/dL,
similar to hereditary fibrinogen deficiency. However, recent clini-
cal data suggest improved hemostasis at higher fibrinogen levels,
KEY POINTS and many revised guidelines adopted 150 to 200 mg/dL as a
threshold fibrinogen level. Hemodilution also affects anticoagu-
• Transfusion of blood components can be life saving, but lant factors (e.g., antithrombin), and reduced thrombin inhibition
there are a number of potentially serious complications. can paradoxically increase thrombotic complications in bleeding
patients. (Ref. 52)
ABO incompatible transfusion and TRALI are two of the Goodnough LT, Brecher ME, Kanter MH, et al. First of two parts—
most common causes of death after blood transfusion. blood transfusion. N Engl J Med. 1999;340:438-447; Goodnough
The proper identifications of the donor unit and the LT, Brecher ME, Kanter MH, et al. Transfusion medicine.
patient and careful risk-benefit assessments are essential Second of two parts—blood conservation. N Engl J Med. 1999;
340:525-533. Reviews trends in transfusion medicine including
before each component transfusion. indications for therapy, immunomodulation, infectious risks, and
• Transfusion of RBC concentrates should be determined, the feasibility and efficacy of blood conservation techniques
not only by threshold hemoglobin values but also by the (autologous donation, erythropoietin, acute normovolemic
rate/extent of hemorrhage, clinical conditions (e.g., hemodilution) in a two-part article. (Refs. 12 and13)
reduced cardiovascular reserve), and the risk-benefit Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver
disease: evidence and clinical consequences. Blood. 2010;116:878-
ratio. 885. Coagulation abnormalities cannot be predicted by prolonged
• Hemodilution can be extensive in major trauma and PT values. The liver is the site for synthesis and degradation
surgery, and affects both procoagulant and anticoagulant of many procoagulant and anticoagulant as well as profibrino­
factors. Reduced plasma levels of fibrinogen and factor lytic and antifibrinolytic factors. The balance of hemostasis and
bleeding is delicate in patients with liver disease due to concomi-
XIII early during hemodilution result in fragile clot tant changes in both procoagulant and anticoagulant pathways.
formation, which is susceptible to fibrinolysis. Fibrinogen (Ref. 103)
can be replaced more efficiently by cryoprecipitate (or Nuttall GA, Oliver WC, Santrach PJ, et al. Efficacy of a simple
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2001;94:773-781. Investigates the algorithm for non-RBC trans-
evaluate coagulopathy, but are not predictive of fusion based on laboratory coagulation test during cardiac surgery.
perioperative bleeding risks. Thromboelastography/metry In this prospective randomized study, 92 patients (11%) devel-
is a useful adjunct to PT/aPTT and platelet count oped microvascular bleeding, and 51 of 92 were randomized
because the stability of fibrin polymerization (i.e., to receive empirical care. The algorithm-based therapy, which

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Chapter 36  Transfusion and Coagulation Therapy

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