Coagulation and Liver
Transplantation
Yoogoo Kang, MD
Paul Audu, MD
Liver transplantation is frequently complicated by hemostatic defects
associated with end-stage liver disease, surgical bleeding, and the grafted
organ recovering from ischemia and reperfusion injury. Management
of hemostatic defects in patients undergoing liver transplantation,
therefore, requires a thorough understanding of pathophysiology of
coagulation, clinically relevant assessment of coagulation, and the
selection of rational treatment modes.
’
Pathophysiology of Coagulation in End-state
Liver Disease
Hemostasis, a vital homeostatic function, is the process by which
blood in a liquid state is transformed into a solid state, then back to a
liquid state. The vascular endothelium, platelets, and coagulation
proteins participate, simultaneously and interdependently, in 5 equally
important phases, namely the vascular phase, the platelet phase, the fibrin
formation phase, the fibrin polymerization phase, and the fibrinolysis phase. Liver
disease affects all 5 phases of coagulation.1 The vascular phase of
coagulation is impaired by peripheral vasodilation, development of
numerous collateral vessels, reduced vascular constrictive response and
elasticity, and decreased interaction between vessel walls and platelets,
and is seen as prolonged bleeding time.2 The platelet phase is also
significantly affected in most patients. Thrombocytopenia is observed in
up to 70%,3 and is caused by splenomegaly, shortened platelet survival,
platelet consumption, sequestration of platelets in the regenerating liver,
the folic acid deficiency in alcoholic liver disease, and toxic effects of
alcohol on megakaryocytes. Platelet dysfunction is also revealed by the
prolonged bleeding time in the presence of adequate platelet count and
diminished clot retraction.4 The coagulation cascade is affected at all
levels, because production of most proteins involved in coagulation is
17
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Kang and Audu
impaired. They are coagulation factors (I, II, V, VII, VIII, IX, X, XI,
XII, XIII, Fletcher, Fitzgerald, prekallikrein, plasminogen, and highmolecular-weight kininogen), inhibitors (AT-III and a1-antitrypsin), and
regulatory proteins (C1 inhibitor and a2-macroglobulin). The fibrinogen level is generally normal or increased. An excessive sialic acid
content in the fibrinogen molecule, however, results in dysfibrinogenemia and prolongs thrombin time (TT) by interfering with polymerization of fibrin.5,6 The level of factor VIII is frequently increased owing
to its enhanced production at the enlarged vascular bed and to the
increased level of von Willebrand factor (vWF) antigen.7 On the
contrary, low levels of proteinases with antithrombin activity (AT-III
and a1-antitrypsin) and regulatory proteins (C1 inhibitor and a2macroglobulin) may result in thrombosis. Fibrin polymerization is
impaired by low levels of factor XIII and dysfibrinogenemia. The
fibrinolytic system is also affected either by reduced levels of proteases
involved in fibrinolysis (plasminogen, protein C, protein S, and a2antiplasmin) or by increased level of tissue plasminogen activator (tPA)
released from the enlarged vascular bed.
Consequently, all forms of coagulopathy may develop depending on
the net balance between procoagulants and their inhibitors and
prolysins and their inhibitors. The hypocoagulable state is caused by
impaired hepatic synthesis of procoagulants and quantitative and
qualitative defects of platelets. Fibrinolysis may develop when a large
quantity of tPA is produced from the enlarged vascular bed, production
of fibrinolysis inhibitors (a2-antiplasmin and histidine glycoprotein) is
insufficient, or the hepatic clearance of tPA is reduced.8 On the other
hand, decreased activity of coagulation inhibitors or fibrinolysins may
cause thrombotic condition. Excessive activation of coagulation or
impaired hepatic clearance of activated coagulation factors may lead to
thrombosis or disseminated intravascular coagulation.
’
Coagulation During Liver Transplantation
The complex, dynamic nature of coagulation during liver transplantation was well described in the early experience of liver
transplantation in the 1960s: ‘‘There was an intraoperative bleeding
diathesis, and at the same time fibrinolysis and hypofibrinogenemia
developed. In 4 of the cases, the hemorrhage was eventually controlled
after the administration of e-aminocaproic acid (EACA), fibrinogen, and
fresh blood. Subsequently, 3 of 4 survivors formed thrombi at or near
femoral venotomy sites which had been used for the insertion of
external bypass catheters; in all 3, the eventual result was multiple
pulmonary embolization.’’9 They concluded that liver transplantation
‘‘can cause hyperfibrinolysis, thrombocytopenia, and depression of
Coagulation and Liver Transplantation
’
19
various clotting factors; that the extent of these changes are prognostic
inasmuch as they are proportional to the magnitude of liver injury; and
that the depression of clotting is not necessarily succeeded by
hypercoagulability if thrombogenic agents are not administered.’’10
This observation has been confirmed by more recent clinical investigations and summarized in Table 1.3,11,12
During the dissection stage, preexisting coagulopathy is compounded by dilutional coagulopathy as surgical bleeding depletes
coagulation proteins and platelets. Bleeding complication is more
common and severe in patients with hepatocellular disease, portal
hypertension, previous upper abdominal surgery, and chronic steroid
therapy. Vascular injury together with impaired clearance of activated
coagulation factors caused by decreased hepatic blood flow may result in
excessive activation of coagulation and consumptive coagulopathy.
Consequently, generalized coagulopathy may be observed, even in the
presence of continuous infusion of coagulation factors-rich blood
products (Fig. 1). Inadvertent hypothermia and ionized hypocalcemia
may also impair coagulation. Fibrinolysis may begin to develop in
patients with severe hepatocellular disease or requiring a massive blood
transfusion. More significant changes occur during the anhepatic stage.
The heparin effect may be observed when heparin solution (2000 to
5000 units of heparin) is used in the venovenous bypass system, and
Table 1.
Coagulopathy During Orthotopic Liver Transplantation
Stage
Coagulopathy
Dissection
Preexisting coagulopathy
Dilution
Fibrinolysis (mild)
Ionized hypocalcemia
Dilution
Anhepatic
Heparin effect (with venovenous bypass)
Fibrinolysis (moderate)
Intravascular coagulation
Hypothermia
Ionized hypocalcemia
Fibrinolysis (severe)
Early Neohepatic
Heparin effect
Intravascular coagulation
Dilution
Hypothermia
Ionized hypocalcemia
Late Neohepatic
Gradual recovery
20
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Kang and Audu
U/mL
1.5
Anhepatic Stage
2.0
1.0
VIII
XII
0.5
I
VII
V
0
Time
Figure 1. Intraoperative changes in coagulation factors. The levels of coagulation factors decrease
during the anhepatic stage and reaches nadir immediately reperfusion even with the administration
of coagulation factors-rich blood (RBC:FFP:crystalloids = 300:200:250 mL). Normal baseline
factor VIII level decreases rapidly during the same period, most likely from activation of fibrinolytic
system. Modified with permission from Hepatology. 1989;9:710–714.
dissipates within 30 to 60 minutes. Surgical bleeding and the absence of
the hepatic synthetic and clearance function further deplete platelets
and coagulation factors. The release of tissue thromboplastin and the
absence of the hepatic clearance of activated coagulation factors may
cause excessive activation of coagulation, and this is observed by gradual
increases in thrombin-antithrombin-III complex (TAT) and fibrin
degradation products (FDPs).13 However, clinically significant intravascular coagulation or thrombosis is uncommon during this period.
Fibrinolysis, caused by the release of tPA and the absence of its hepatic
clearance, is seen in about 20% of patients (Fig. 2).
Severe coagulopathy, a component of the postreperfusion syndrome, occurs on reperfusion of the grafted liver, and it is observed as
prolonged prothrombin time (PT), activated partial thromboplastin
time (aPTT), reptilase time (RT), and TT, thrombocytopenia, a decrease
in coagulation factor levels including factors I, V, VII, and VIII, a
Coagulation and Liver Transplantation
’
21
70
tPA
activity
(IU/mL)
60
50
40
Anhepatic stage
80
30
20
10
0
Minimal fibrinolysis (n=7)
Severe fibrinolysis (n=13)
Figure 2. Intraoperative changes in tPA level of patients with and without fibrinolysis.
Intraoperative levels of tPA activity (mean + SEM) is much higher in patients with severe
fibrinolysis (solid circles, n = 13) compared to those with minimal fibrinolysis (open circles, n = 7).
Modified with permission from Transplantation. 1989;47:978–984.
sudden increase in tPA, a shortened euglobulin lysis time, and a
moderate increase in FDP and TAT.13–15 The cause of the postreperfusion coagulopathy is multifactorial. The release of endogenous
heparin from the grafted liver results in moderate to severe heparin
effect and may last for 60 to 120 minutes. Other coagulation inhibitors
or heparin-like substance may also play a role.16 Fibrinolysis occurs in
approximately 80% of patients, although clinically significant fibrinolysis and bleeding are observed in about 40% of patients.14 It is caused
by the massive release of tPA from the grafted liver, congested viscera
and lower extremities together with the reduced plasminogen activator
inhibitor activity,17 contact activation of fibrinolysis, and activation of
protein C or urokinase-type plasminogen activator.18 Fibrinolysis is most
likely primary in origin because of its association with high tPA level, a
relatively steady level of AT-III,19 only moderate increases in FDP and
D-dimers,14 a selective decrease in factors I, V, and VIII,12 the
effectiveness of EACA without complications,14 and no known microembolization. Fibrinolysis is seen as shortened euglobulin lysis time
(as short as 0 to 15 min), a very high level of tPA, a prolonged reaction
time, and short fibrinolysis time in thromboelastography (TEG).
Fibrinolysis dissipates gradually within the next 2 hours if the grafted
liver begins to function.
Excessive activation of coagulation with secondary fibrinolysis may
also contribute to postreperfusion coagulopathy and is observed as high
22
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Kang and Audu
levels of TAT complex, FDP, and fibrin monomers, and low levels of
AT-III and plasminogen activator inhibitor. This phenomenon seems
to be caused by tPA-induced platelet activation20 or the release of
lysosomal proteinases from macrophages (cathepsin B) and granulocytes (elastase),21 and may induce consumption coagulopathy, venous
thrombosis, or pulmonary thromboembolism.22 In a clinical study,
transesophageal echocardiography revealed a significant pulmonary
thromboembolism (>0.5 cm in diameter) within 60 seconds of
reperfusion in 59% of patients without venovenous bypass and 11%
of patients with venovenous bypass.23 Gologorsky et al24 reported
6 patients who developed clinical signs or echocardiographically visible
intracardiac thrombi or pulmonary embolism and speculated that
the complication could have been associated with ischemic damage of
endothelium, release of lysosomal proteinases from activated macrophages and platelets, or low AT-III level. Fortunately, fatal pulmonary
embolism occurs rarely, possibly due to the simultaneous activation
of fibrinolysis. Platelet defects may play a significant role in most
patients. The transhepatic gradient of platelet count is as much as
55%, and may be caused by extravasation of platelets into Disse
spaces in the perisinusoidal region or phagocytosis by Kupffer cells.25
Platelet function can be impaired by the loss of granulation and
impaired platelet aggregation. Reperfusion hypothermia (by 1to 21C),
dilutional coagulopathy, unknown coagulation inhibitors released
from the grafted liver, and ionic hypocalcemia may also interfere with
coagulation.
Coagulopathy improves gradually as the grafted liver begins
to function. Fibrinolysis and the heparin effect dissipate gradually
within 2 hours, and the levels of coagulation factors and platelet
count increase toward baseline levels at the end of surgery.3 However,
bleeding or oozing may persist in some patients. Bleeding with
persistent coagulopathy may be caused by either insufficient replacement therapy or poorly functioning graft liver.22,26 Bleeding
with persistent low levels of factors I, V, and VIII is a complication
of fibrinolysis as plasminogen and plasmin selectively destroys
these factors.12 Delayed bleeding or oozing in the presence of
an acceptable coagulation profile and TEG may occur approximately
1 to 2 hours after reperfusion. This is frequently caused by the loss
of defective clots formed in the presence of dilutional coagulopathy
or gradual digestion of clots containing fibrin-plasmin complex.
No specific treatment is effective, and bleeding complication dissipates
within 60 to 90 minutes once new clots are formed at the injured
vessels.
Postoperatively, levels of coagulation factors and platelet count
increase steadily toward normal values. In patients with a poorfunctioning graft, however, severe coagulopathy may persist.
Coagulation and Liver Transplantation
’
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Assessment and Monitoring of Coagulation
Although a variety of conventional laboratory tests are performed to
identify the type and severity of the coagulation disorder, most tests have
limited application during liver transplantation. PT measures the time
to form the initial clot after tissue thromboplastin is added to the
recalcified, citrated blood specimen, and is an expression of the extrinsic
pathway. Clinical use of PT is limited during liver transplantation,
because it, being the most sensitive hepatic synthetic function test, is
prolonged in most patients during surgery. aPTT measures the time to
form the initial clot after phospholipid, calcium, and a contact activator
(kaolin or silica) are added to the recalcified, citrated specimen and
reflects the activity of the intrinsic and common pathways. Although it is
sensitive in monitoring heparin activity, its clinical application in liver
transplantation is limited as its intraoperative changes are similar to
those of PT. TT measures the time to form the initial clot after thrombin
is added to the recalcified, citrated specimen. It is prolonged in
hypofibrinogenemia, dysfibrinogenemia, and in the presence of
thrombin inhibitors, such as heparin and FDPs. The RT is a modification
of the TT. Reptilase, like thrombin, cleaves fibrinogen, but the cleavage
fragments can spontaneously polymerize even in the presence of FDPs.
Additionally, reptilase is unaffected by AT-III and heparin. An abnormal
TT with a normal RT suggests the presence of a thrombin inhibitor. The
Bleeding Time is a sensitive test of platelet dysfunction as long as platelet
count is greater than 100,000/mm3. Therefore, simultaneous determination of platelet count is important in interpretation of bleeding time.
It is also prolonged in patients with anemia, severe hypofibrinogenemia,
and vascular defects. It is labor intensive, and results may vary
depending on the test site, technical expertise, and age and sex of the
patient. Platelet Aggregometry measures platelet aggregation induced by
adenosine diphosphate, thrombin, and collagen. Flow Cytometry uses
monoclonal antibodies to determine platelet surface receptor density.
The Platelet Function Analyzer evaluates primary hemostasis by measuring
the time required for whole blood to occlude an aperture in the test
cartridge membrane that is coated with platelet agonist. It is reported to
be a simple, reliable, and reproducible platelet function test.27 The
Activated Clotting Time measures the time to form the initial clot after an
activator (kaolin or diatomaceous earth) is added to whole blood at
371C. It monitors clot formation by the intrinsic pathway and is reliable,
even when a large dose of heparin is given during cardiopulmonary
bypass.
The conventional coagulation profile described above, however, has
several drawbacks to be used for clinical coagulation monitoring. It does
not assess blood coagulability, has poor correlation with clinical bleeding,
and requires laboratory facility. Common perioperative coagulation tests
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Kang and Audu
(PT, aPTT, fibrinogen level, and platelet count) are poor screening tools
for surgical population and do not per se predict the risk of
bleeding.28,29 In patients undergoing liver transplantation, PT does
not have significant relationship with the fresh frozen plasma (FFP) use,
and aPTT does not predict the perioperative RBC requirement.30
TEG
TEG, developed in the 1950s, was introduced to the clinical arena
only recently.3 It continuously measures the shear elasticity of fibrins
formed in the fresh whole blood, including the interaction of all cellular
and noncellular elements involved in coagulation, and has been shown
to be effective in monitoring clinical coagulation during liver transplantation,3 cardiac surgery, and other major surgical procedures.31 Its
technical aspects have been extensively reviewed.32,33 Briefly, a small
quantity of fresh whole blood (0.36 mL) is placed into a cuvette (371C)
and a central pin suspended by a torsion wire is lowered into the blood
specimen (Fig. 3). The cuvette rotates with a 4.5 angle in either direction
at every 4.5 seconds with a 1 second midcycle oscillatory pause. When
the blood remains in a fluid state, the pin is stationary. As clot begins to
form, elastic force of fibrin strands attached to the pin and the cuvette
couples them, and oscillatory movement of the cuvette is subsequently
transmitted to the pin. The torque applied to the pin is plotted against
time and displayed graphically or, digitally on a computer screen
(Hemoscope, Skokie, IL). Most commonly, the recording should begin
4.5o
37oC
Figure 3. Schematic diagram of thromboelastography.
Coagulation and Liver Transplantation
’
25
α
r
MA
A60
20 min
60 min
r+k
4 min
T
F
Figure 4. Typical thromboelastographic variables and normal values. r indicates reaction time —6
to 8 minutes; r + k, coagulation time —10 to 12 minutes; a, clot formation rate —>50 degrees;
MA, maximum amplitude —50 to 70 mm; A60, amplitude at 60 minutes after MA; A60/MA100,
fibrinolysis index —>85%; F, fibrinolysis time —>300 minutes. With permission from Hepatic
Transplantation: Anesthetic and Perioperative Management. New York: Praeger; 1986:154.
exactly 4 minutes after blood sampling when done at the bedside, or
4 minutes after recalcification when the sample is collected in a citrated
tube for TEG testing in a remote laboratory facility. The reaction time (r)
is the latency period between the initiation of the recording and
measurable fibrin formation (amplitude of 2 mm) (Fig. 4). The clot
formation time (k) begins from the initiation of clot formation
(amplitude of 2 mm) to the point where shear elasticity reaches the
amplitude of 20 mm. r and k are prolonged in patients with coagulation
factor deficiency, in the presence of anticoagulants, hypothermia and
hypocalcemia. The alpha angle (a) measures the rate of clot formation
and is a function of coagulation proteins and/or platelets. Maximum
amplitude (MA) is affected by platelet function and fibrinogen
concentration. The time interval between the MA and subsequent zero
amplitude is the fibrinolysis time (F). The amplitude 60 minutes after
MA (A60) is used to determine the fibrinolysis index (A60/MA. 100).
A fibrinolysis index of less than 85% indicates fibrinolysis. Attempts have
been made to compare TEG variables with conventional coagulation
tests.34 r and k times correlate with aPTT, and amplitude (A) with the
clot strength or shear elastic modulus, G [G (dynes/cm – 2) = (5000A)/
(100 – A)]. A positive relation between MA and platelets and fibrinogen
has been demonstrated.35 However, a strong positive relation between
conventional coagulation tests and TEG variables is unlikely, because
TEG variables are determined by combined effects of proteases, cellular
components, and other chemical elements.
TEGs of various clinical conditions are shown in Figure 5.36
A normal TEG pattern is characterized by an initial latency period,
followed by a gradual increase in fibrin shear elasticity or amplitude
that reaches MA within 30 to 60 minutes. The fibrinolysis index remains
above 85%. Deficiency of coagulation factors (eg, hemophilia),
26
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Kang and Audu
Hemophilia
Normal
Thrombocytopenia
Fibrinolysis
Hypercoagulation
Figure 5. Thromboelastographic patterns of normal and disease states. With permission from
Hepatic Transplantation: Anesthetic and Perioperative Management. New York: Praeger;
1986:155–173.
hypocalcemia, hypothermia, and heparin effect are seen as a prolonged
reaction time and slow clot formation rate. MA, however, is within the
normal range, because normal clot formation occurs once greater than
the critical level of factor X is activated. Thrombocytopenia is seen as
small MA. In addition, reaction time is prolonged and clot formation
rate is reduced because platelet surface receptors are essential to the
progression of the coagulation cascade. In patients with fibrinolysis,
amplitude decreases gradually to zero amplitude. More importantly,
active digestion of fibrin decreases the number of fibrin strands as the
clot is being formed and results in prolonged reaction time and reduced
clot formation rate and amplitude. Excessive activation of coagulation is
seen as a very short reaction time and rapid clot formation rate. Once
disseminated intravascular coagulation develops, all TEG variables
deteriorate, and a straight line is observed.
TEG has several advantages over standard methods in clinical
coagulation monitoring. Results can be obtained fairly quickly; the onset
of clot formation within a few minutes and platelet function within 45
minutes. Although most conventional coagulation tests end their
observation when clots begin to form, TEG assesses dynamic changes
of the complete coagulation process, from the onset of coagulation to
complete clot formation, and to fibrinolysis. Further, definitive differential diagnosis of coagulopathy can be made by comparing multiple
channels of TEG, allowing a selective replacement or pharmacologic
therapy. For example, a comparison between TEG of untreated blood
(0.36 mL) and that of blood treated with FFP (0.03 mL of FFP in
Coagulation and Liver Transplantation
’
27
5 min before reperfusion
5 min after reperfusion
Untreated blood
EACA-treated blood
Protamine-treated blood
Figure 6. Fibrinolysis and the heparin effect on reperfusion. The first TEG is taken 5 minutes
before reperfusion. The next 3 TEGs are taken 5 minutes after reperfusion with untreated blood,
blood treated with EACA (0.3 mg), and blood treated with protamine sulfate (3 mg). Fibrinolysis and
potential heparin effect are seen in the untreated blood, and their presence is confirmed by inhibition
of fibrinolysis in the blood treated with EACA and shortened reaction time in the blood treated with
protamine sulfate, respectively. With permission from Hepatic Transplantation: Anesthetic and
Perioperative Management. New York: Praeger; 1986:151–173.
0.33 mL of whole blood) identifies the presence of coagulation factor
deficiency and beneficial effects of FFP administration. Other types of
coagulation defects can be diagnosed by comparing TEGs with blood
treated with other blood products (platelets and cryoprecipitate) or
pharmacologic agents (EACA, protamine sulfate, aprotinin, and
DDAVP).14,36,37,38 Differential diagnosis of pathologic coagulation
during liver transplantation is shown in Figure 6. A dramatic
reperfusion coagulopathy is shown as a prolonged reaction time, small
amplitude, and severe fibrinolysis. A blood specimen treated with EACA
improved coagulation by a shortened reaction time, increased amplitude and disappearance of fibrinolysis, suggesting active fibrinolysis.
The same blood specimen treated with protamine sulfate normalized
the reaction time and increased amplitude with persistent fibrinolysis,
indicating the heparin effect. The most important contribution of TEG
to the clinical coagulation, however, may be that it helps clinicians
understand the global coagulation process.
Some clinicians may implicate several drawbacks in TEG monitoring. The test results may not be reliable at times, but most of them are
operator-related quality control issue. The test is best performed using
fresh whole blood sample, not with citrated blood sample, which may be
inconvenient in the laboratory setting. It cannot differentiate coagulopathy associated with a specific coagulation factor deficiency (eg, factor
VIII vs. IX). This difficulty, however, is not a drawback of TEG, because
28
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Kang and Audu
it is a global monitoring tool, not a diagnostic test for an individual
coagulation defect. TEG results may not correlate with surgical bleeding
or field. Unfortunately, TEG, like all other tests, does not measure
vascular phase of coagulation including the severity of vascular injury.
’
Perioperative Management of Coagulation
Preoperative Management
Preoperative optimization of coagulation determined by the
conventional coagulation profile is frequently unsuccessful owing to
insufficient hepatic synthesis of coagulation factors and ongoing
excessive activation of coagulation. Preoperative management of
coagulation, therefore, should be tailored to meet specific clinical needs
based on the type and severity of coagulation defects, the type of
invasive procedure, and the nature and location of bleeding.
Vitamin K, absorbed directly from the GI tract with the assistance of
bile salts or produced by intestinal flora, is required for hepatic synthesis
of coagulation factors II, VII, IX, and X. For mild vitamin K deficiency,
oral administration of vitamin K together with bile salts, or injection of
vitamin K1 (IM or IV, 5 mg/d) is effective in correcting PTwithin 24 to 48
hours. Repeated administration of vitamin K1 and coagulation factors
may be necessary to treat bleeding tendency. Vitamin K, however, may
not be effective in patients with severe hepatocellular disease.39 FFP,
containing most coagulation elements and their inhibitors, is commonly
administered to correct coagulopathy. It is generally accepted that FFP is
given to patients with a prolonged PT (>1.5 INR) before liver needle
biopsy. Improvement of coagulation, however, is only transient, and a
large volume of FFP required to treat coagulopathy may cause fluid
overloading. Platelet transfusion is used to treat severe thrombocytopenia. Its therapeutic effect is short lived, as platelets are removed by
splenic sequestration and ongoing activation of coagulation. Clinical
bleeding is rare with platelet count of greater than 75,000/mm3,
although satisfactory hemostasis can be obtained with lesser platelet
counts (>40,000/mm3). Cryoprecipitate, containing fibrinogen and factors
VIII and XIII, is indicated, when hypofibrinogenemia or fibrinolysis is
present. One unit of cryoprecipitate contains 300 mg of fibrinogen and
the transfusion of 1 unit of cryoprecipitate increases the fibrinogen level
approximately 10 mg/dL in a patient weighing 60 kg. The half-life of the
fibrinogen is about 3 to 4 days and repeated transfusion of cryoprecipitate is necessary to supplement the loss. Anticoagulation therapy is rarely
indicated in liver disease, although a subcutaneous injection of a small
dose of heparin (<5000 units) seems to be acceptable in patients with
thrombotic tendency. Oral anticoagulant therapy requires a close
monitoring owing to unpredictable response. Antifibrinolytic agents may
Coagulation and Liver Transplantation
’
29
reduce bleeding even without signs of fibrinolysis by stabilizing fragile
hemostatic plugs formed at the gastric mucosal ulcer or esophageal
varices. However, EACA has been shown not to improve coagulation
in patients with liver disease.40 Plasmapheresis (30 to 40 mL/kg), in
combination with replacement therapy, may improve coagulation by
removing filterable coagulation inhibitors, particularly in patients with
fulminant hepatic failure. Plasmapheresis is shown to decrease PT from
28.3 to 17.7 seconds and aPTT from 64.8 to 43.3 seconds in liver
transplantation candidates.39
Intraoperative Management
The goal of medical coagulation therapy is to maintain close to
normal blood coagulability by frequent monitoring and specific
replacement and/or pharmacologic therapy while avoiding thrombosis.
It consists of physiologic therapy, replacement therapy, and pharmacologic Therapy.
Physiologic Therapy Hypothermia inhibits coagulation by interfering with the activity of proteases involved in coagulation, and is
shown to prolong reaction time and decrease clot formation rate on
TEG operated on patient’s temperature. Hypothermia-induced delayed
coagulation, however, may be beneficial to patients with hypothermiainduced venous stasis by preventing thrombosis. A similar delayed
coagulation is observed in patients with ionized hypocalcemia, because
calcium ion is a cofactor in the coagulation cascade. Acidosis and altered
electrolyte balance may alter coagulation, directly by triggering
inflammatory process or indirectly by impairing tissue perfusion.41
Therefore, body temperature, tissue perfusion, gas exchange, acid-base
state, and fluid-electrolyte balance should be optimized to maintain
normal blood coagulability.
Replacement Therapy Replacement therapy is guided by the
conventional coagulation profile or TEG variables. Replacement guidelines based on conventional coagulation vary widely from institution to
institution, ranging from specific guideline [PT (INR) <1.5, hematocrit
>30%, platelet count >30,000/mm3, and AT-III level >70%)]42 to
general guideline (hemoglobin >9 g%, FFP to correct coagulopathy,
and platelet count >100,000/mm3).43 Most transplantation centers
administer coagulation factors-rich blood (RBC:FFP = 1:1) to maintain
the sufficient coagulation factor level above 30% of normal value and/or
PT (INR) <1.5 to 2.0. The critical level of platelet count is considered to
be in the range of 40,000 to 50,000/mm3.
At the Thomas Jefferson University Hospital, coagulation therapy is
guided by TEG variables and platelet count. In general, continuous
30
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Kang and Audu
replacement of coagulation factors is required to compensate for their
loss from dilution, excessive coagulation, and fibrinolysis. This is
achieved by the administration of a mixture of blood products
(RBC:FFP:crystalloids = 300:200:250 mL) containing 30% to 50% of
normal levels of coagulation factors. Additional blood products may
be administered based on TEG variables and platelet count. Platelets
(10 units) are administered when MA is less than 40 mm to improve MA
as well as reaction time. Cryoprecipitate (6 units) may be given when clot
formation rate is persistently less than 40 degrees even after platelet
transfusion, particularly in patients with fibrinolysis-induced hypofibrinogenemia. Additional FFP (2 units) may be administered when
reaction time is persistently longer than 15 minutes even after the
administration of platelets and cryoprecipitate.44
During the anhepatic stage, administration of platelets and
cryoprecipitate is discouraged to prevent potential thromboembolism.
An aggressive replacement therapy may be needed during the
neohepatic stage when surgical bleeding persists, or fibrinolysis or the
heparin effect remains untreated. Untreated fibrinolysis may require
replacement of a large quantity of factors I, V, and VIII by
administration of FFP and cryoprecipitate. Additional platelet transfusion may be required in patients with poorly functioning graft livers.
In addition, alloimmunization to specific class-1 human lymphocyte
antigens in highly sensitized patients may result in refractoriness to
platelet transfusion, and they may benefit from transfusion of typespecific single-donor platelets.45
Administration of AT-III was suggested to minimize excessive
activation of coagulation during the anhepatic and early neohepatic
stages. However, its level remains above 30% to 50% of normal with
FFP administration alone,19 and additional AT-III preparation neither
improved the coagulation profile nor reduced blood loss and fibrinolytic
activity.46 Therefore, AT-III is reserved for patients with excessively low
AT-III levels.
The TEG patterns and coagulation profile of a patient with
fulminant hepatic failure are shown in Figure 7.3,46 The baseline TEG
pattern (I+ 5) showed a prolonged reaction time and decreased MA and
clot formation rate indicating a generalized decrease in coagulation
factors and platelets. Administration of 2 units of FFP (I+ 30) improved
reaction time. The administration of 10 units of platelets (I+ 120)
improved MA, but mild fibrinolysis began to develop. Transfusion of 6
units of cryoprecipitate (I+ 180) did not improve clot formation rate
owing to continuous deterioration of coagulation and worsening
fibrinolysis. Severe fibrinolysis was observed during the anhepatic stage
(II+ 30). On reperfusion (III+ 5), severe coagulopathy was noted with a
prolonged reaction time, decreased clot formation rate and MA, and
signs of fibrinolysis, and improved gradually in the following 2 hours.
Cryo 6u
’
31
End
Plat 10u
III + 120’
III + 30’
III + 5’
II + 30’
Cryo 6u
I + 180’
Plat 10u
I + 120’
Baseline
FFP 2 U
I + 30’
Coagulation and Liver Transplantation
Figure 7. Thromboelastographic patterns and coagulation profile of a patient with fulminant
hepatic failure during liver transplantation. I = dissection phase; II = anhepatic phase; III =
reperfusion to end of surgery phase. Numbers refer to number of minutes after start of phase.
Modified with permission from Anesth Analg. 1985;64:888–896.
The administration of platelets and cryoprecipitate normalized the TEG
by the end of surgery. The majority of coagulation tests were moderately
or severely abnormal at the beginning of surgery. The coagulation
profile gradually improved at the end of surgery, although it was still in
the moderately abnormal range.
Pharmacologic Therapy Although any pharmacologic intervention that promotes hemostasis and reduces the need for blood
transfusion is of obvious benefit, the benefit should be weighted against
the potential thrombotic complications.
Synthetic antifibrinolytic therapy uses lysine analogs, EACA, and
tranexamic acid, They accelerate the conversion of plasminogen to
plasmin by inducing conformational changes, but inhibit fibrinolysis by
blocking the lysine-binding site of plasmin. EACA was used in the 1960s
to treat generalized oozing caused by fibrinolysis, but all 3 patients
developed fatal bleeding or pulmonary embolism.9 Although this
unfortunate experience discouraged the use of the antifibrinolytic
therapy, recent clinical studies have shown positive results. In a study of
79 patients, EACA (1 g) was administered to 20 patients who developed
severe fibrinolysis (fibrinolysis time <120 min), and fibrinolysis was
corrected in all without thrombotic, hemorrhagic, or renal complications.14 The use of a small dose of EACA was one of the important
findings of this study compared to the conventional priming dose of 4 to
5 g followed by 1 g/h to achieve a plasma level of 13 mg/dL.47 It seems
that a single, small dose of EACA is sufficient to treat severe, but
32
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Kang and Audu
transient fibrinolysis, although its short half-life may necessitate a second
dose in patients with an extremely high tPA level or massive transfusion.
Recently, even a smaller dose of EACA (250 to 500 mg) was found to be
effective in treating most types of fibrinolysis.48,49 Early diagnosis and
treatment of fibrinolysis seems to be beneficial, It reduces bleeding and
blood transfusion, conserves factors I, V, and VIII by inhibiting plasmin,
and minimizes warm ischemia by reducing surgical hemostasis time.
Fibrinolysis can be diagnosed in its early stage by observing a significant
improvement in TEG variables (reaction time and clot formation rate) in
blood treated with EACA compared with untreated blood in the first 10
to 15 minutes of recordings. The prophylactic use of EACA is not
recommended, however, to avoid any potential thrombotic complications.24,50 Carlier et al50 reported that the use of tranexamic acid was
safe in pediatric patients undergoing liver transplantation, and similar
positive results were reported in prospective randomized clinical trials of
tranexamic acid.51,52
Aprotinin is a nonspecific inhibitor of serine protease and inactivates
a large number of serine proteases including trypsin, chymotrypsin,
plasmin, kallikrein, Hageman factor, and most coagulation factors. It
also prevents platelet activation during cardiopulmonary bypass and has
been shown to preserve platelet GPIb receptors. The beneficial effects of
aprotinin seem to be related to reduced production of tPA and plasmin
through inhibition of kallikrein and fibrinolysis.53 This antifibrinolytic
effect is observed indirectly by the similar blood product requirement
between patients receiving aprotinin and tranexamic acid.54 Interestingly, aprotinin also inhibits coagulation cascade, and this has been well
demonstrated in the TEG of blood treated with aprotinin.37 Therefore,
the clinical benefit of aprotinin may be associated with the inhibition of
excessive activation of coagulation and fibrinolysis. The dosage of
aprotinin ranges from a high dose (2 million KIU followed by 0.5
million KIU/h) to a continuous infusion of low dose (0.2 to 0.4 million
KIU/h). Early clinical trials showed that aprotinin decreased blood loss,
operative time, and length of stay in the intensive care unit in patients
undergoing liver transplantation.53,55,56 However, recent literature
questions the clinical benefit of aprotinin,57–59 and its use has been
reduced in many centers. Aprotinin is not without potential complications, and anaphylactic reaction, renal injury, and fatal pulmonary
embolism have been reported.60
Protamine sulfate (25 to 50 mg) is used to reverse the heparin effect
during the anhepatic or neohepatic stage. In clinical trials, the
administration of protamine sulfate or heparinase has shown to shorten
the reaction time of TEG and aPTT.
Desmopressin acetate (DDAVP, 1-deamino 8-D-arginine vasopressin) is
a synthetic analog of the naturally occurring posterior pituitary
hormone, vasopressin (antidiuretic hormone). It stimulates endothelial
Coagulation and Liver Transplantation
’
33
cells to release factor VIII and subtypes of vWF within 1 hour.
Desmopressin improves hemostasis in patients with hemophilia A and
von Willebrand disease61 and shortens bleeding time in patients with
uremia,62 congenital platelet defects, end-stage liver disease,63 and
possibly those undergoing cardiac surgery.64 The recommended dosage
of desmopressin is 0.3 mg/kg intravenously or subcutaneously; or 300 mg
(150 mg in children) intranasally, and it may be repeated 12 to 24 hours
after the initial dose.
DDAVP improves blood coagulability of patients undergoing liver
transplantation in vitro, possibly by activating coagulation factors and
platelets.38 However, its benefit in clinical liver transplantation has not
been established.
Recombinant factor VIIa (rVIIa) is the most recently introduced
pharmacologic agent in liver transplantation. Factor VII, in high
concentrations, binds to the surface of activated platelets and directly
activates factor X, resulting in platelet surface thrombin generation
without factors VIIIa and IXa.65 It has been shown to improve
coagulation in factor VII deficiency, factor X deficiency, factor XI
deficiency, von Willebrand disease with inhibitors to vWF, platelet
function defects, and thrombocytopenia. It has been shown to reduce
PT in patients with liver disease and reduce blood loss during liver
transplantation. However, further clinical studies are required to
identify its benefit and potential complications.
Fully borrowed (permission necessary) with permission from Am J Gastroenterol
1989;28:475–480.
Modified or adapted (permission necessary) adapted with permission from Blood.
1990;125:615–623.
Created using data from other sources (no permission is necessary). Data from Arch Surg
1988;89:339–345.
Hepatic Transplantation: Anesthetic and Perioperative Management. New York: Praeger;
1986:135–141.
’
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