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doi: 10.1093/bja/aew023
Advance Access Publication Date: 1 March 2016
Clinical Practice
Abstract
Background: Hyperbrinolysis is one of the main causes of non-surgical bleeding during liver transplantation (LT).
Viscoelastic haemostatic assays, including thromboelastometry (ROTEM) and thrombelastography (TEG), can detect
hyperbrinolysis at the bedside. No study has yet demonstrated which device or assay is more suitable for detecting
hyperbrinolysis.
Methods: This prospective observational study compared ROTEM and TEG in isolated adult LT. ROTEM (EXTEM [tissue
factor activation], FIBTEM [tissue factor activation with platelet inhibition], and APTEM [tissue factor activation with
tranexamic acid/aprotinin]) and TEG (kaolin-TEG) were simultaneously performed using arterial blood samples at eight time-
points during LT: induction of general anaesthesia, 60 min after skin incision, 10 and 45 min after portal vein clamp, 15 min
before graft reperfusion, and ve, 30, and 90 min after graft reperfusion. Hyperbrinolysis was identied per the manufacturers
denitions (maximum lysis >15% in ROTEM or Lysis30>8% in TEG) and conrmed with APTEM; incidence was compared
between assays McNemars test.
Results: Among 296 possible measurement points from 376 consecutive LT recipients, 250 underwent nal analysis: 46
measurement points were excluded because of missing assays or at line. Hyperbrinolysis was conrmed at 89 (36%) of 250
measurement points: FIBTEM, EXTEM, and kaolin-TEG detected 84 (94%), 41 (46%), and 21 (24%) hyperbrinolysis,
respectively. These hyperbrinolysis detection rates signicantly differed from each other (P<0.001).
Conclusions: Tissue factor-triggered ROTEM tests were more sensitive than contact-activated k-TEG in identifying
hyperbrinolysis in LT patients. Inhibition of platelet-brin interaction in FIBTEM enhanced sensitivity to hyperbrinolysis
detection compared with EXTEM.
507
508 | Abuelkasem et al.
Results was 14, that of FIBTEM was 10, and that of APTEM was 12).
These measurement points were not considered as conrmed
Patient characteristics
hyperbrinolysis.
Thirty-seven subjects were enrolled and completed the study Hyperbrinolysis was observed at all eight measurement
protocol. (Table 1). Average age was 57 yr; 76% were male. The points. Hyperbrinolysis incidence was highest at ve min after
median Model for End-Stage Liver Disease (MELD) score was 18. graft reperfusion (58%), followed by 45 min after portal vein
The most common aetiology of end-stage liver failure was post- clamp (54%). At baseline, hyperbrinolysis was detected and
necrotic cirrhosis (76%). Eight subjects (22%) received live donor conrmed (23%); this was only detected by ROTEM assays.
grafts. -amino caproic acid was administered in 7 subjects who
showed both bleeding in the surgical eld and a hyperbrinolysis Comparison between k-TEG, EXTEM, and FIBTEM
pattern in k-TEG, especially based on the result of k-TEG at
30 min after graft reperfusion. Of 296 possible measurement Among 89 hyperbrinolysis measurement points, FIBTEM
points, 46 (16%) were excluded because of missing measure- showed a sensitivity of 94% and a specicity of 99%; EXTEM
ments of any one of the assays (27 measurement points) or at showed a 46% sensitivity and a 100% specicity, respectively;
line (19 measurement points) as detected in Table 2. k-TEG showed 23% and 99%, respectively (Table 3). A statistical
difference (P<0.001) was found in the sensitivities of one assay to
the others between FIBTEM, EXTEM, and k-TEG. The specici-
Hyperbrinolysis
Table 2 Incidence of hyperbrinolysis during liver transplantation. *Two reasons for exclusion from the analysis. One measurement was
not included because of lack of conrmation of detected hyperbrinolysis pattern. One of each category was not included because of lack of
APTEM conrmation of detected hyperbrinolysis. Baseline, at induction of general anaesthesia
brin binding to platelet glycoprotein IIb/IIIa. Platelet-induced k-TEG uses kaolin, which is a contact pathway (or intrinsic path-
clot retraction is often misinterpreted as hyperbrinolysis on way) activator. Use of the intrinsic pathway activator in k-TEG
VHA, but platelet activation and clot retraction are well known explains, at least in part, the lesser sensitivity of k-TEG in identi-
to inhibit brinolysis. Kunitada and colleagues14 demonstrated fying hyperbrinolysis. Of note, other than the activators or the
that inactivation of platelets by pre-treatment with cytochalasin additives in each assay, the mechanical feature of each VHA
D abolished platelet-induced inhibition of lysis and increased tPA could also contribute to the difference found in the study, which
binding to brin clot. Katori and colleagues15 also demonstrated could be checked performing the k-TEG assay in the ROTEM
in a TEG experiment that abciximab, a glycoprotein IIb/IIIa re- system and EXTEM assay in the TEG system.
ceptor antagonist, abolished the platelet-induced masking effect In clinical practice, k-TEG and EXTEM have been used as
of hyperbrinolysis. They suggested that the contractility force the standard hyperbrinolysis detection assays of each VHA. In
transmitted via platelet glycoprotein IIb/IIIa receptors, which comparing these assays, EXTEM was superior to k-TEG, with
bind the polymerized brin network to the platelets actin cyto- a two-fold higher sensitivity. This result indicates that the choice
skeleton, is the major contributor to clot strength. Therefore, of VHA (TEG vs. ROTEM) matters in reporting the incidence
a glycoprotein IIb/IIIa receptor antagonist (e.g., abciximab) of hyperbrinolysis and/or interpreting reported incidences of
prevents platelets from exerting contractile force on the brin hyperbrinolysis. We also applied a manufacturers denition
network, which allows tPA, along with plasminogen, to bind to of hyperbrinolysis to FIBTEM, which provided sensitivity
the brin surface and convert plasminogen to plasmin, leading more than two-fold superior to EXTEM. In clinical LT manage-
to brinolysis. Since platelets are the source of continuous ment, using ROTEM (especially FIBTEM) would allow detection
production of large amounts of active plasminogen activator of hyperbrinolysis more often than k-TEG (or EXTEM only),
inhibitor 1 (PAI-1), which stabilizes the blood clot,16 inhibition which could lead to an increased opportunity for pharmacologic
of platelets might reduce the release of PAI-1. intervention with anti-brinolytic agents when facing clinically
The lower sensitivity of k-TEG to EXTEM is noteworthy. signicant bleeding.5 However, all clinicians should be aware
Thrombin activatable brinolysis inhibitor (TAFI) is activated by that the manufacturers reference values used in denition of
thrombin; activated TAFI (TAFIa) protects the brin clot by hyperbrinolysis are based on results derived from healthy
inhibition of tPA-mediated brinolysis. Conversion to TAFIa is volunteers. As such, the diagnostic characteristics of each assay
greatly enhanced by high concentrations of thrombin. Nielsen observed might not necessarily be translated into a clinical
and colleagues17 demonstrated that TAFI primarily contributed impact in management of LT, in which most hyperbrinolysis
to contact pathway protein-mediated attenuation of brinolysis, is self-limited without warranting therapeutic interventions.18
although they used plasma rather than whole blood. Unlike This study has several limitations. First, no clinical manage-
EXTEM, which uses tissue factor and phospholipids as activators, ment was altered based on the results of ROTEM, as this device
TEG Vs. ROTEM in hyperbrinolysis | 511
was used only for observational research purposes during the International provided the ROTEM device and reagents; how-
study period. Therefore, no clinical correlation between hyper- ever, it was not involved in any part of study planning or manu-
brinolysis and clinical bleeding was examined. Second, because script preparation.
of limited funding, we were not able to perform extrinsically ac-
tivated TEG assays at all eight measurement points: functional
brinogen TEG as the counterpart of FIBTEM, and rapid-TEG
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