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TRANSFUSION AND
COAGULATION THERAPY
Kenichi Tanaka
HISTORICAL CONSIDERATIONS
HEMOGLOBIN AND PLATELET REPLACEMENT
Packed Red Blood Cells
Erythropoietin
Blood Substitutes
Platelet Concentrates HISTORICAL CONSIDERATIONS
PLASMA AND COAGULATION FACTORS
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
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
P50
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
629
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Section V FLUID, ELECTROLYTE, AND HEMATOLOGIC HOMEOSTASIS
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
Erythropoietin
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).
CLINICAL USES
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
TXA2
Platelet
F activation
Fibrinogen
PAR1 Platelet GPIb/IX
activation ADP
IIa F Activated
GPIb/IX platelet
Xa
GPVI GPIb/IX
vWF GPIIb/IIIa
EC VIIa α2β1 IIa
vWF
TF EC
α2β1
Pericytes
and Collagen
fibroblasts Collagen
Injury site Injury site
A B
IIa
XIa
F
F
IXa
Activated VIIIa
F platelet Activated
platelet
Va
Fibrinogen
vWF Xa
F Activated
platelet
GPIb/IX IIa
GPIIb/IIIa
IIa
vWF
EC α2β1
XIIIa Fibrin
Collagen
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
631
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Section V FLUID, ELECTROLYTE, AND HEMATOLOGIC HOMEOSTASIS
PRINCIPLE
TRACES
Rotating pin
4.75°
Fibrinolysis
Light ray
EXTEM-MCF
Mirror
Stationary cup
XIIIa
Microvascular bleeding
A Heating block
EXTEM
MCF 10 mm 10 mm
or or
fibrinogen 150 mg/dL platelet 100 x 109/L
Tranexamic acid
or
Plasma Cryoprecipitate Platelets Aminocaproic acid
C
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
PLASMA AND COAGULATION FACTORS
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
632
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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
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.
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).
633
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Section V FLUID, ELECTROLYTE, AND HEMATOLOGIC HOMEOSTASIS
R1 R1 1
O O OR
6
4
5 α-Amylase
O O O
( RO R O
RO
1 O RO 1 O RO
3 2 R
O O O RO O
O R O
R R O
O O )n
O 4
O O R1
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.)
634
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Chapter 36 Transfusion and Coagulation Therapy
635
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Section V FLUID, ELECTROLYTE, AND HEMATOLOGIC HOMEOSTASIS
8
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
INR
2 SIDE EFFECTS
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
0
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,
150
heat-resistant viruses (e.g., parvovirus B19), but these risks are
considered to be low.81
100
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 (%)
75
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
200
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 (%)
636
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Chapter 36 Transfusion and Coagulation Therapy
IIa
Fibrin Lysine analogues
AT Heparin IIa Thrombomodulin
Xa
Xa PC Plgn Fibrin
Va
APC VIIIa
tPA Plasmin
IIa PAR
Free FXa, thrombin IIa
IIa
Heparin
AT
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.
2010;24:96-106.)
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
effect.89
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
SIDE EFFECTS
Systemic thrombosis is uncommon with EACA or TXA,
PHARMACOLOGIC AND TOPICAL AGENTS
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
637
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Section V FLUID, ELECTROLYTE, AND HEMATOLOGIC HOMEOSTASIS
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
Desmopressin
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-
SPECIAL CONSIDERATIONS
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
638
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Chapter 36 Transfusion and Coagulation Therapy
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Section V FLUID, ELECTROLYTE, AND HEMATOLOGIC HOMEOSTASIS
640
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Chapter 36 Transfusion and Coagulation Therapy
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