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J. Transl. Med. Res 2017;22(2):77-83 DOI: 10.21614/jtmr-22-2-118
Journal of Translational Medicine and Research, 22 (2), 2017 77
ORIGINAL PAPER
Copyright © Celsius Publishing House
www.jtmr.ro
Received: 15.05.2017
Accepted: 09.06.2017
1Fundeni Clinical Institute, Department of Anaesthesia and Intensive Care, Bucharest, Romania
2University of Medicine and Pharmacy “Carol Davila “ Bucharest, Romania
ABSTRACT
Introduction: Prophylactic antifibrinolytics are recommended for patients at risk to develop
significant hyperfibrinolysis during liver transplantation, identified by the preoperative
thromboelastometry. Even with this approach, postreperfusion hyperfibrinolysis is frequent,
often leading to increased bleeding and transfusion requirements.The aim of this study was
to assess hyperfibrinolysis and to predict postreperfusion hyperfibrinolysis based on pre-
operative standard coagulation tests (SCTs) and thromboelastometry in liver transplant
patients without an indication for antifibrinolytic prophylaxis and/or therapy until graft
reperfusion.
Methods: The study group included cirrhotic patients undergoing orthotopic liver transplantation.
Preoperative and at 10 minutes after graft reperfusion, the following data were recorded for each
patient: SCTs, complete blood counts and rotation thromboelastometry (ROTEM®, TEM
International GmbH, Munich, Germany). From ROTEM measurements we used standard parame-
ters and indices calculated from the first derivative of the clot firmness curve.Hyperfibrinolysis was
defined as maximum lysis >15% in EXTEM or by an increase in MCF in APTEM compared to
EXTEM (DMCF) more than 7% of EXTEM MCF.
Results: Using ML>15% preoperative and postreperfusion hyperfibrinolysis were identified
in 20% and 22 % of the patients and were not correlated with SCTs, fibrinogen levels, platelet
number, with clot amplitude or thrombus formation on ROTEM.Using DMCF criteria, pre-
operative hyperfibrinolysis was present in 34% of the patients and was associated with
decreased thrombus formation (AUC, p=0.021) and decreased clot elasticity in EXTEM
(p=0.01). When DMCF criteria was used postreperfusion, hyperfibrinolysis was present in
42% of the patients, could not be correlated with preoperative ROTEM standard or derived
parameters and was associated with decreased MCF in EXTEM and FIBTEM (p= 0.04 and
0.006) and delayed and decreased thrombus formation.
Conclusions: The reported incidence of hyperfibrinolysis in cirrhotic patients before and
during liver transplantation depends on the ROTEM-based definition used. The difference
between APTEM and EXTEM identifies more patients with hyperfibrinolysis than ML>15%
criteria and was associated with a decrease in thrombus formation and elasticity both pre-
operative and post graft reperfusion.
Key words: liver transplant, hyperfibrinolysis, bleeding
Corresponding author:
Ecaterina Scarlatescu, MD
Dept of Anaesthesia and Intensive
Care, Fundeni Clinical Institute
258 Fundeni Street, 022328
Bucharest, Romania
E-mail: katyscarlatescu@yahoo.com
Assessment of Hyperfibrinolysis in Cirrhotic Patients
Undergoing Orthotopic Liver Transplantation. A Retrospective
Observational Study
Ecaterina Scarlatescu1, Ana M Buruiana1, Gabriela Droc1,2, Dana R Tomescu1,2
78 Journal of Translational Medicine and Research, 22 (2), 2017
Ecaterina Scarlatescu et al
INTRODUCTION
INTRODUCTION
Hyperfibrinolysis has been described in liver cirrhosis
patients, but the timing, the severity and the role in
bleeding complications are still a matter of debate (1-3).
Hyperfibrinolysis often occurs during liver transplant
procedures during the anhepatic and neohepatic
phases. In the anhepatic phase, the tendency towards
increased fibrinolysis is due to the reduced clearance of
tissue plasminogen activator (t-PA) with relatively stable
concentrations of PAI-1, while in the neohepatic phase it
is due to the increased release of t-PA from endothelial
surfaces (4,5).
During liver transplant procedures hyperfibrinolysis
is often associated with coagulopathic bleeding and
increased transfusion requirements (6,7). It is well
established that antifibrinolytic drugs (aprotinin and
tranexamic acid) can reduce perioperative bleeding and
blood product transfusions in patients undergoing
liver transplantation (8,9). However, the use of anti-
fibrinolytics in the liver transplant setting is not
standardised. Following the withdrawal of aprotinin in
2012, most transplant centers now use tranexamic acid.
The prophylactic use of antifibrinolytics has been
restricted in many transplant centers to the patients that
will probably develop significant bleeding due to hyper-
fibrinolysis during the surgery and will benefit most
from the administration of an antifibrinolytic drug (8).
Recent data shows that preoperative thrombo-
elastometry can identify the patients at a high risk to
develop hyperfibrinolysis during liver transplantation
and prophylactic antifibrinolytics may be used in these
cases (10). Even with this approach, postreperfusion
hyperfibrinolysis develops frequently, being considered
as one of the criteria of the postreperfusion syndrome
(6).
The aim of this study was to assess the incidence of
hyperfibrinolysis and to predict postreperfusion hyper-
fibrinolysis based on preoperative standard coagulation
tests (SCTs) and rotational thromboelastometry
(ROTEM®, TEM International GmbH, Munich, Germany)
in liver transplant patients without prophylactic or thera-
peutic antifibrinolytic therapy until graft reperfusion.
MATERIAL AND METHODS
MATERIAL AND METHODS
Patient selection
This is a single-center, retrospective, observational
study of coagulation profiles in cirrhotic patients under-
going orthotopic liver transplantation. After the
approval of the institutional ethics committee, adult
patients with liver cirrhosis undergoing orthotopic liver
transplantation with grafts from brain dead donors in a
2 year period were included in the study group.
Informed consent was waived by the IRB due to the
observational retrospective nature of the study.
Exclusion criteria were: chronic kidney failure, hemato-
logic diseases, pregnancy, chronic anticoagulant and
antiplatelet therapy, recent therapy with blood
derivates or procoagulant treatments within the last 7
days prior to enrollment. Patients with preoperative
criteria for the administration of prophylactic anti-
fibrinolytic therapy (A10 in EXTEM<25 mm, flat line in
FIBTEM or CT+CFT in EXTEM longer than 280 sec) (10) or
receiving intraoperative antifibrinolytic therapy before
graft reperfusion were excluded from the study. Patients
with incomplete data were also excluded from the study.
Laboratory analysis
Preoperative and at 10 minutes after graft reperfu-
sion, the following data were recorded for each patient:
SCTs, complete blood count and rotation thrombo-
elastometry (ROTEM®, Pentapharm, Germany).
Standard coagulation tests
Blood samples for laboratory analysis and rotational
thromboelastometry were drawn simultaneously,
assuring minimal venous stasis preoperatively. After
graft reperfusion, blood samples were drawn from an
indwelling arterial catheter after removing 3 dead
space volumes of blood from the pressure tubing. In
each patient 3 blood samples were drawn: one EDTA
tube for complete blood count and 2 citrate tubes (for
the ROTEM assay and for conventional coagulation
tests). Conventional coagulation tests included pro-
thrombin time (PT), International normalized ratio
(INR), activated partial thromboplastin time (aPTT) and
fibrinogen level (Clauss method).
Rotational Thromboelastometry
Whole blood coagulation was assessed using
ROTEM (TEM International GmbH, Munich, Germany).
Standard citrated blood samples (1:9 ratio of citrate to
blood by volume) were kept at room temperature until
analysis within 60 minutes after collection. The tests
were performed using standard reagents, cups, and
pins from the manufacturer (TEM International GmbH,
Munich, Germany).
Thromboelastometric assays use citrated whole blood
(300 μL per assay), which is recalcified and activated using
different activators: tissue factor (extrinsic pathway),
ellagic acid (intrinsic pathway) or ecarin (11). In EXTEM
assay, the extrinsic pathway of coagulation is revealed by
recalcification and addition of tissue thromboplastin. The
Journal of Translational Medicine and Research, 22 (2), 2017 79
Assessment of Hyperfibrinolysis in Cirrhotic Patients Undergoing Orthotopic Liver Transplantation. A Retrospective Observational Study
FIBTEM assay is obtained by the addition of a potent
platelet inhibitor (cytochalasin D) to the EXTEM assay,
blocking platelet activation; in this way platelet contribu-
tion to clot formation and clot strength is eliminated in
FIBTEM(11, 12). APTEM is a modified EXTEM assay where
the activation is realised also with tissue factor, but hyper-
fibrinolysis is blocked by adding tranexamic acid (11).
INTEM assays are activated by recalcification and addition
of ellagic acid and phospholipids, revealing the intrinsec
pathway of coagulation (11).
Each ROTEM assay reports the following information
regarding clot formation: CT (clotting time, in seconds),
CFT (clot formation time, in seconds), MCF (maximum
clot firmness, in millimeters). From ROTEM measure-
ments we used standard parameters and indices calcu-
lated from the first derivative of the clot firmness curve:
Maximum Velocity (MaxVel), Time to Maximum Velocity
of clot formation (t- MaxVel) and area under the curve
(AUC) as surrogate markers of thrombin generation (13).
First derivative parameters of whole blood clot formation
using thromboelastometry indirectly reflect the course
of thrombin generation, can provide extensive informa-
tion on hemostasis and are useful especially in patients
with severe hemostasis problems (14).
Hyperfibrinolysis was defined as maximum lysis
>15% in EXTEM within 60 minutes after clotting time
(the manufacturer’s definition) or by an increase in
MCF in APTEM compared to EXTEM (DMCF criteria)
more than 7% of EXTEM MCF(15).
Statistical analysis
Continuous variables were tested for normality
using the Shapiro-Wilks test and if normally-distributed,
data were expressed as mean and standard deviation
(SD). If significantly skewed, median and interquartile
range were used as appropriate. Continuous variables
were compared between the groups using a Student's
t-test or Mann-Whitney U test. Statistical tests were
assumed to have reached significance at the conven-
tional level of 0.05. Statistical analyses were performed
using SPSS Statistics v 23.0 (IBM).
RESULTS
RESULTS
Between 2014 and 2016 were included in the study
group 50 patients with liver cirrhosis with a mean
age (±SD) of 47.73 (±14.34) years. The patient’s charac-
teristics are shown in table 1.
Using as hyperfibrinolysis criteria the maximum
lysis higher than 15%(ML>15% criteria), preoperative
hyperfibrinolysis was identified in 20% of the patients
(n=10) and was not correlated with preoperative SCTs
(p=0.91 for PT and p=0.16 for aPTT), fibrinogen levels
(p=0.71) or platelet number (p=0.51). The presence of
preoperative ML>15% was not correlated with pre-
operative clot amplitude in EXTEM or FIBTEM (p= 0.608
and respectively 0.513).
Postreperfusion hyperfibrinolysis using ML >15%
criteria was found in 22 % (n=11) of the patients and
was associated with preoperative hyperfibrinolysis
(p=0.03). Postreperfusion hyperfibrinolysis was not
correlated with SCTs or ROTEM standard or derived
parameters both preoperative or post graft reperfusion
(data shown in table 2).
Using DMCF criteria (DMCF higher than 7% of MCF
in EXTEM), preoperative hyperfibrinolysis was present in
34% (n=17) of the patients and could not be correlated
with preoperative fibrinogen levels (p=0.4), platelet
number (p=0.314), prothrombin time (p=0.92), MCF in
EXTEM or FIBTEM (p= 0.058 and respectively 0.069).
However, it was associated with decreased preoperative
thrombus formation (AUC, p=0.021) and decreased pre-
operative clot elasticity in EXTEM (p=0.01).
When DMCF criteria was used, postreperfusion hyper-
fibrinolysis was present in 42% (n=21) of the patients
(fig. 1). Postreperfusion hyperfibrinolysis could not be
correlated with preoperative SCTs, ROTEM standard or
derived parameters, but showed statistically significant
correlations with parameters of postreperfusion thrombus
formation- decreased clot firmness, increased t-MaxVel,
decreased AUC and clot elasticity (table 3).
Table 1 - Characteristics of the Study Population (n=50)
Total study subjects (n=50)
Mean Age 47.73 (±14.34) years
Mean MELD score 15.43 (±6.36)
Gender
Male 23 (46%)
Female 27 (54%)
Diagnosis
HVB cirrhosis 2 (4%)
HVC cirrhosis 6 (12%)
HVB+HVD cirrhosis 13 (26%)
Alcoholic cirrhosis 11(22%)
HVB cirrhosis+ hepatocarcinoma 4 (8%)
HVC cirrhosis+ hepatocarcinoma 3(6%)
Wilson’s disease 4(8%)
Cryptogenic cirrhosis 7 (14%)
HVB = Hepatitis virus B; HVC = Hepatitis virus C;
HVD= Hepatitis virus D
Data are expressed as mean (and standard deviation, SD) or n (%)
*p statistically significant
80 Journal of Translational Medicine and Research, 22 (2), 2017
Table 2 - Correlations of postreperfusion hyperfibrinolysis using ML>15% criteria with preoperative and postreperfusion SCTs,
standard and derived ROTEM parameters
Parameters Patients with postreperfusion Patients with postreperfusion P value
(preoperative) ML>15% (n=11) ML<15% (n=39) (Mann Whitney U test)
PT sec 17.45 (11.9) 20.6 (7.1) 0.99
aPTT sec 46.2 (28.3) 46.3 (14.1) 0.198
Platelets (per μl) 92000 (60250) 70500 (50450) 0.154
Fibrinogen mg/dl 233.7 (117.3) 154 (59) 0.051
EXTEM MCF mm 45 (25) 43 (11) 0.816
FIBTEM MCF mm 13 (13) 9 (9) 0.87
MaxVel mm/sec 11.5 (12) 11 (10) 0.795
t-MaxVel sec 67 (86) 69 (74) 0.88
AUC 4517 (1801) 4235 (1207) 0.563
MCE 83 (85) 73 (36.5) 0.555
Parameters (postreperfusion)
PT sec 36.7 (22.9) 22.9 (23.5) 0.189
APTT sec 76.9 (73) 72.3 (70.4) 0.149
Fibrinogen mg/dl 100 (34.9) 99 (45.9) 0.09
Platelets (per μl) 65500 (16500) 61000 (44500) 0.664
EXTEM MCF mm 39.5 (4) 40 (13) 0.229
FIBTEM MCF 6 (3) 6 (8) 0.537
MaxVel mm/sec 6.5 (6) 7 (8) 0.337
t-MaxVel sec 130 (88) 107 (154) 0.291
AUC 3933 (370) 3817 (1291) 0.297
MCE 65.5 (13) 61 (38) 0.308
PT = prothrombin time; aPTT = activated partial thromboplastin time; MCF = Maximum Clot Firmness; MCE = Maximum clot elasticity;
MaxVel = Maximum velocity of clot formation; t-MaxVel = Time to Maximum velocity of clot formation; AUC = Area under the curve of clot formation
Data are expressed as median (and interquartile range); *p statistically significant
Figure 1: Different incidence of preoperative and postreperfusion hyperfibrinolysis using ML>15% criteria
compared to DMCF criteria
ML> 15% criteria= hyperfibrinolysis defined as maximum lysis higher than 15%
DMCF criteria= hyperfibrinolysis defined as difference in clot amplitude between APTEM and EXTEM higher
than 7% of EXTEM
Ecaterina Scarlatescu et al
Journal of Translational Medicine and Research, 22 (2), 2017 81
Table 3 - Correlations of postreperfusion hyperfibrinolysis using DMCF criteria with preoperative and postreperfusion SCTs,
standard and derived ROTEM parameters
Parameters Patients with postreperfusion Patients with postreperfusion P value
(preoperative) DMCF>7% of EX MCF (21) DMCF<7% of EX MCF (n=29) (Mann Whitney U test)
PT sec 20.7 (4.1) 16.2 (6.6) 0.07
aPTT sec 47.6 (14.4) 41.7 (20.7) 0.059
Platelets (per μl) 79000 (38000) 92500 (121750) 0.776
Fibrinogen mg/dl 153.5 (71.2) 188.25 (121) 0.363
EXTEM MCF mm 41.5 (11) 45 (15) 0.26
FIBTEM MCF mm 8 (5) 14.5 (19) 0.055
MaxVel mm/sec 10 (8) 12 (12) 0.278
t-MaxVel sec 81 (89) 68 (74) 0.516
AUC 4254 (1166) 4482 (1354) 0.453
MCE 74.5 (29.5) 82 (94) 0.387
Parameters (postreperfusion)
PT sec 25.6 (28.4) 21.95 (16.5) 0.194
aPTT sec 76.1 (71.5) 50.9 (48.8) 0.023*
Fibrinogen mg/dl 98.35 (59.8) 103 (43.4) 0.354
Platelets (per μl) 54500 (26750) 68500 (49500) 0.116
EXTEM MCF mm 39 (11) 39.5 (11) 0.04*
FIBTEM MCF 5 (4) 7.5 (7) 0.006*
MaxVel mm/sec 6 (6) 7.5 (6) 0.388
t-MaxVel sec 187.5 (157) 66.5 (81) 0.026*
AUC 3621 (1159) 3933 (967) 0.011*
MCE 57 (29) 65.5 (32) 0.01*
PT = prothrombin time; aPTT = activated partial thromboplastin time; MCF = Maximum Clot Firmness; MCE= Maximum clot elasticity;
MaxVel = Maximum velocity of clot formation; t-MaxVel = Time to Maximum velocity of clot formation; AUC = Area under the curve of clot formation
Data are expressed as median (and interquartile range); *p statistically significant
DISCUSSION
DISCUSSION
Similar to previous studies in patients with end-stage
liver disease, our results also show preoperative prolon-
gation of standard coagulation tests, low fibrinogen
levels and thrombocytopenia (16).
Hyperfibrinolysis is identified on rotational thrombo-
elastometry when the maximum clot lysis (ML) exceeds
15% of the maximumclot firmness according to the
manufacturer’s definition (17). Raza et al demonstrated
in a recent study on trauma patients that more than 90%
of fibrinolysis activation was not detected by this defini-
tion of hyperfibrinolysis (18). In their study, moderate
fibrinolysis activation not detected by ROTEM was
associated with increased transfusion requirements and
worse outcomes (18). Raza et al raised the suspicion that
ROTEM is simply insensitive until fibrinolysis activation
reaches a certain threshold (18). The lack of sensitivity of
ROTEM for detecting moderate hyperfibrinolysis with
clinical impact in critically ill patients was also described
by Durila (19). In a study using thrombelastography in
trauma patients, Chapman demonstrated that lower
thresholds than the accepted normal upper bound of
lysis index are associated with worse outcomes and
suggested that clinically relevant threshold for defining
hyperfibrinolysis might be lower than the actual
standard definition (20).
As hyperfibrinolysis during liver transplantation was
correlated with bleeding (7), valid diagnosis and rapid
treatment of hyperfibrinolysis are nesessary for
reducing allogenic blood transfusion and decreasing
perioperative morbidity and mortality (10). But the
issue of hyperfibrinolysis in cirrhotic patients remains
under debate, as the results of different studies
performed in this population are controversial(1-3).
One possible explanation for this discrepancy might be
the different methodology used to measure plasma
fibrinolytic activity used in different studies. Moreover,
the laboratory tests available for hiperfibrinolysis diag-
nosis (clot lysis time using whole blood or plasma,
Assessment of Hyperfibrinolysis in Cirrhotic Patients Undergoing Orthotopic Liver Transplantation. A Retrospective Observational Study
82 Journal of Translational Medicine and Research, 22 (2), 2017
Ecaterina Scarlatescu et al
euglobulin lysis time) are time- consuming and cannot
be used for guiding therapy in emergencies. Whole
blood viscoelatic tests are useful for detecting hyper-
fibrinolysis in different clinical situations, but their
sensitivity and thresholds for detecting moderate or
low fibrinolysis activations are still unknown. In a recent
study in liver transplant patients, Abuelkasem demon-
strated increased sensitivity of rotational thrombo-
elastometry compared to thromboelastography in
detecting hyperfibrinolysis; FIBTEM assay proved more
sensitive for hyperfibrinolysis diagnosis than EXTEM
(21). This results could also explain the different inci-
dence of hyperfibrinolysis during liver transplantation
reported in different studies(22). In our study, we found
different incidence of preoperative and postreperfu-
sion hyperfibrinolysis using two different definitions of
hyperfibrinolysis on ROTEM. This result stands in line
with the conclusion from the study by Abuelkasem et al
that hyperfibrinolysis is poorly defined using visco-
elastic tests, lacks standardisation and that a better
definition of hyperfibrinolysis is necessary for good
clinical practice.
This is the first study to apply the difference
between APTEM and EXTEM as a criteria for hyper-
fibrinolysis and to compare this criteria with the
standard definition of hyperfibrinolysis on ROTEM in a
population of cirrhotic patients undergoing liver trans-
plantation. The results of our study reveal that hyper-
fibrinolysis defined using DMCF criteria identifies
patients with decreased thrombus formation and
elasticity both preoperative and postreperfusion. This
definition seems to have a higher impact on clot forma-
tion than the standard definition and might be included
in the preoperative criteria for identifying patients at
high risk of developing hyperfibrinolysis during the
surgery, but more research about the clinical impact of
hyperfibrinolysis in the transplant setting is needed.
Study Limitations
This was a retrospective, observational study.
However, we have a standard management of liver
transplant procedures according to institutional proto-
cols, minimizing in this way the confounding variables.
Other limitations are the lack of laboratory tests
regarding fibrinolysis (other than ROTEM) and the fact
that clinical outcomes as bleeding or thrombosis were
not evaluated or correlated with the diagnosis of hyper-
fibrinolysis.
CONCLUSIONS
CONCLUSIONS
The reported incidence of hyperfibrinolysis in
cirrhotic patients before and during liver transplantation
depends on the ROTEM-based definition used. Our
results suggest that postreperfusion hyperfibrinolysis
could not be predicted from preoperative tests. The
difference between APTEM and EXTEM identifies more
patients with hyperfibrinolysis than ML>15% criteria
and was associated with a decrease in thrombus forma-
tion and elasticity both preoperative and post graft
reperfusion. In conclusion, this definition could be more
reliable for the identification of clinically significant
hyperfibrinolysis and of patients that might benefit from
antifibrinolytics during liver transplantation, but the
clinical implications of this result need more research.
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