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Perioper Med (Lond)
v.4; 2015
PMC4589068
Perioper Med (Lond). 2015; 4: 9.

Published online 2015 Sep 29. doi: 10.1186/s13741-015-0019-7
PMCID: PMC4589068
Effects of different colloid infusions on

ROTEM and Multiplate during elective brain
tumour neurosurgery
N. Li, S. Statkevicius, B. Asgeirsson, and U. Schtt
Author information Article notes Copyright and License information
Abstract
Go to:
Background
In brain tumour neurosurgery, intra- and post-operative
bleeding in brain tumour resection can be linked to the
vascularity of the tumours, tumour size and localization (Goh
et al. 1997). Most of the losses will be surgical, and as the
field is open, direct haemostasis with cautery or topical
coagulants is more relevant. Post-operative hematomas are
rare but may be more related to a coagulopathy than a
surgical bleed. During surgery, different fluids are used to
replace blood loss and maintain arterial pressure, including
crystalloids and blood products, and during the last few
decades, synthetic colloids as well. However, all of these
fluids are associated with adverse effects, and an ideal fluid
for haemodynamic stabilisation and resuscitation has yet to
be found.
Hydroxyethyl starches (HESs) are synthetic colloids with
different molecular weights and substitutions that are used
for their plasma-expanding effects. In recent years, several
studies have highlighted the adverse effects of this colloid,
particularly the risk of acute renal failure (Zarychanski et
al. 2013), allergic skin manifestations and hypocoagulability
following infusion. HES has been shown to impair clot
strength, platelet function and increase fibrinolysis to an
extent that cannot be explained by haemodilution alone (Levi
& Jonge 2007). HES infusions decrease plasma levels of
fibrinogen and several coagulation factors, leading to weaker
and smaller clots (Fenger-Eriksen et al. 2009). It can also
decrease circulating levels of von Willebrands factor (F),
thus impairing platelet function (de Jonge et al. 2001).
In Europe, market authorisations for HES have been
suspended due to these findings (Agency EM. PRAC
recommends suspending marketing authorisations for
infusion solutions containing hydroxyethyl starch: European
Medicines Agency & [cited 2013Jun 14]). However, the
clinical perioperative implications of these findings are still
uncertain for stable patients undergoing elective surgery
(Moral et al. 2013). Human albumin (HA) is an alternative
fluid that has recently been replacing HES in neurosurgery at
Lund University Hospital. Albumin is used by us in
accordance with the Lund concept of brain injury
resuscitation (Grande 2011), and for us, it was natural to
replace HES with HA. However, in large meta-analyses on
the effectiveness of HA on patient mortality and morbidity,
no significant benefits have been shown when comparing HA
to synthetic colloids or crystalloids (Perel et al. 2013;
Roberts et al.2011). HA may have lesser impact on
coagulation compared to synthetic colloids (Niemi et
al. 2006), which is a desirable quality for perioperative use.
The coagulopathy caused by HA also seems to be easily
reversed by fibrinogen and FXIII concentrate (Winstedt et
al. 2013), making it a potentially better fluid for patients that
might already suffer from a coagulopathy or risk of
developing one.
Routine clinical laboratory analyses of coagulation, such as
activated partial thromboplastin time (aPTT) and
prothrombin time (PT), are plasma-based and might not
correctly predict a clinical coagulopathy. Whole blood
viscoelastic methods, such as thromboelastometry (e.g.
ROTEM) and whole blood-aggregometry (e.g.
Multiplate), have gained recognition as alternative
methods. Thromboelastometry is able to assess global
haemostatic functions, and platelet aggregometry assesses
platelet function in response to different reagents. These
systems have already been introduced clinically as point-of-
care methods for quickly determining bleeding risk and
helping to guide transfusions (Shore-Lesserson et al. 1999).
They have also been used to study haemostasis in different
critical care situations, such as trauma (Solomon et al. 2011)
and sepsis (Brenner et al. 2012). ROTEM is known to detect
colloid-induced coagulopathy (Fenger-Eriksen et al. 2009),
even at low levels of dilution (Tynngrd et al. 2014).
The purpose of this study was to compare the effects on
coagulation of 5 % HA and HES 130/0.42 in elective brain
tumour neurosurgical patients. Our aim was to investigate
whether HA had a more favourable effect on coagulation and
platelet function, assessed by a viscoelastic method and a
platelet aggregometry method (ROTEM and Multiplate,
respectively). Our hypothesis was that HA infusions would
induce less hypocoagulability than HES, as seen on ROTEM
and Multiplate.
Go to:
Methods
This study was performed as a prospective unblinded
observational cohort study with two colloid fluid regimens.
During 2013 and 2014, our fluid regimen for haemodynamic
stabilisation and initial blood-loss substitution during
elective brain tumour resection was changed from HES to
5 % HA. We had studied 18 consecutive patients with HES
according to a protocol, and our initial aim was to include
more patients with HES and the combined testing with
ROTEM and Multiplate when the department replaced HES
with HA.
We therefore decided to continue the protocol with HA and
compare its effects on ROTEM and Multiplate with the data
from the previous HES-patients. According to a power
analysis from an in vitro study (Winstedt et al. 2013), >15
patients in each group would give a statistical power of 0.8 at
a significance level of p<0.05, defined by detected
differences in FIBTEM-MCF (see below), as this is the best
predictive ROTEM parameter for dilutive coagulopathy,
correlating with fibrinogen; the first coagulation factor to
reach critical low levels during haemodilution (Winstedt et
al.2013).
General ethical approval was obtained from the Regional
Ethical Review Board (Lund, Protocol DNR 2012/482) for
monitoring neurosurgery patients with ROTEM and
Multiplate. Signed consent was received from all patients in
the two test groups. All patients were over 18 years.
No patients with a known haemostatic disturbance,
anticoagulants, antiplatelet drugs (also including
aspirin/nonsteroidal anti-inflammatory drugs), abnormal
preoperative coagulation analysis (aPTT/PT, platelet count),
known renal impairment or increased plasma-creatinine level
were included.
Anaesthesia was induced and maintained with propofol
(Diprivan; AstraZeneca, Sweden) and remifentanil
(Ultiva, GlaxoSmithKline, Sweden). Intubation was
facilitated with rocuronium (Esmeron; MSD, USA) (0.5
0.8 mg/kg), and ventilation was maintained with positive
pressure ventilation in a circle system. Minute ventilation
was adjusted to maintain normocapnia (PaCO2 of 4.55.5
kPa).
After induction, a radial arterial catheter was inserted for
continuous measurement of blood pressure and for collection
of blood samples, and a bladder catheter was inserted for
hourly measurement of diuresis.
All patients received thromboprophylaxis with mechanical
calf compression (Kendall SCD Express Sleeves;
Covidien, USA) during surgery and postoperatively for 24 h.
Normothermia during the surgery was maintained with a
Bair Hugger (3 M, St. Paul, USA) and oesophageal
temperature monitoring.
During this study, there was no intervention on our part in
the transfusion/infusion protocols. The crystalloid/colloid
infusions and transfusion of blood components were solely
determined by the anaesthetist in charge, based on a standard
protocol from the anaesthesia department (see below) and
were not affected by the study protocol or the
ROTEM/Multiplate test results.
Standard Lund departmental protocol for perioperative fluids
during neurosurgery: After the induction of anaesthesia, a
basal infusion of 1.52.0 ml/kg/h of saline (NaCl 0.9 %; B.
Braun Medical AB) was started. Initial bleeding up to 200
300 ml was substituted with saline (23 ml per 1 ml of
bleeding). The HES group received hydroxyethyl starch
130/0.42 in sodium chloride for maintaining mean arterial
pressure of >6065 mm Hg, systolic blood pressure
>90 mmHg, pulse pressure variation (PPV) <12 mmHg and
replacing bleeding of >200300 ml (see above) (12 ml HES
per 1 ml of bleeding) (HES; Venofundin 60 mg/ml
hydroxyethyl starch; MW 130 kDa; substitution 0.42; B.
Braun Medical AG, Germany). HES was thus also used to
compensate for the haemodynamic effects of anaesthesia.
HES was restricted to 1000 ml by the departmental protocol.
The HA group was given 5 % human albumin (Albumin;
CSL Behring, Germany) at 12 ml HA per 1 ml of bleeding
of >200300 ml (see above). HA was also used to
compensate for the haemodynamic effects of anaesthesia as
for HES. Albumin was restricted to 500 ml by the
departmental protocol.
According to departmental protocol, packed red blood cells
(PRBCs) are to be administered when the concentration of
haemoglobin reaches <95100 gram/L, and blood loss of
more than 30 % of the calculated blood volume is substituted
with PRBCs, fresh-frozen plasma (FFP) and platelet
concentrates (PC).
Arterial blood was sampled from radial arterial catheters
with a continuous sodium chloride flush system with no
heparin. The blood samples were collected in 2.7-ml citrated
plastic vacuum tubes (3.2 % citrate; BD Vacutainer systems,
UK) for ROTEM and in 3.0-ml hirudin tubes (Dynabyte
GmbH, Germany) for Multiplate analysis. Blood sampling
was performed before surgical incision, after every colloid
unit (i.e. after every 250 ml HA or 500 ml HES infusion) and
at the end of surgery; altogether, three or four samples were
collected per patient. Blood loss during surgery was
evaluated from suction reservoir and swabs.
Arterial blood gases with haemoglobin, electrolyte, lactate
and glucose levels were analysed before the beginning of
surgery and during surgery every 12 h (Radiometer
ABL800 FLEX; Radiometer, Denmark).
Rotational thromboelastometry (ROTEM; TEM
Innovations GmbH, Germany) measures the coagulation
initiation, amplification and propagation kinetics of whole
blood. It uses a cup with a rotating pin, whose movement is
impeded as blood coagulates inside the cup. The impedance
reflects clot firmness and is plotted graphically against time.
Analysis was carried out within 1 h from blood sampling,
during which time the samples were kept at 37 C. The
following two assays were run on each sample: EXTEM and
FIBTEM. EXTEM measures coagulation activated by tissue
factor (extrinsic pathway), while the FIBTEM assay includes
a platelet inhibitor (cytochalasin D), thus measuring only
fibrinogen activity. For EXTEM, the following parameters
are assessed for each analysis (normal range within
brackets): clotting time/CT (4274 s), clot formation
time/CFT (46148 s), alpha-angle/AA (6381) and
maximum clot firmness/MCF (6381 mm). For FIBTEM,
only MCF (925 mm) was analysed. The normal ranges used
were established in a multi-centre study (Lang et al. 2005).
Multiple electrode aggregometry (Multiplate; Roche
Diagnostics, Basel, Switzerland) measures platelet
aggregation in whole blood using electrical resistance
between two electrodes. As aggregation occurs, the
increasing impedance is plotted against time, and the area
under the curve (AUC) is a measure of platelet function. The
blood samples were kept at room temperature for 3040 min
before analysis, which was done at 37 C. The following two
test assays were performed for each sample: platelet
aggregation in response to adenosine diphosphate (ADP-test,
AUC reference range 57113) and thrombin receptor-
activating peptide (TRAP-test, AUC reference range 84
128). For statistical analysis of the data, both inter- and intra-
group comparisons were made. Normal distribution was not
assumed (non-parametric data). Samples after first colloid
infusion, after second colloid infusion and at the end of
surgery were tested against the preoperative sample using the
Wilcoxon signed-rank test for paired samples. All ROTEM
and Multiplate values in one test group were also compared
to the corresponding values in the other test group, using the
Mann-Whitney U test for unpaired samples. The level of
significance was set to p<0.017 after correction in
accordance to Bonferroni, in order to decrease the risk of
type I errors due to multiple comparisons. Results are
presented as boxplots showing median and interquartile
range, with min-max whiskers and+signs identifying mean
values.
Go to:
Results
In total, 18 patients were included in the HES group and 21
patients in the HA group during a 5-month period. The
demographic, bleeding and transfusion/infusion data for
these patients are shown in Table 1. Six patients received
erythrocyte transfusions, one patient received platelet
transfusions and one patient received plasma transfusions
intra-operatively. There were no differences in median
haemoglobin concentration at the end of surgery between the
groups (Table 1). The decrease in haemoglobin preoperative-
postoperative was the same in both groups.
Table 1
Demographic and bleeding data for patients receiving 5 %
human albumin (HA) or hydroxyethyl starch 130/0.4 (HES)
during elective neurosurgery up to the end of surgery (eos)
Intra-group comparisons
Results from each sampling occasion were compared to the
preoperative results. In the HA group, the most significant
differences were detected after the second HA infusion, as
well as at the end of surgery (Tables 2 and and33 and
Figs. 1, ,22 and and3).3). After 250 ml HA, ROTEM only
showed a significant decrease in FIBTEM-MCF. After
500 ml HA, CFT, AA and EXTEM-MCF also differed as
compared to pre-surgery levels. At the end of surgery,
changes were detected in all ROTEM parameters except for
CT. Multiplate detected changes in the ADP parameter only
after 500 ml HA. No other significant changes could be
shown in ADP or TRAP parameters. In the HES group,
significant differences could be detected already after the
first infusion (Table 2 and and33 and Figs. 1, ,22and
and3).3). After 500 ml HES, CFT was markedly prolonged,
as seen in Fig. 1. AA and EXTEM-MCF both decreased
(Fig. 2 (AA not shown)). Only after 1000 ml HES was CT
prolonged (Tables 2 and and33 and Fig. 1). Additionally,
changes could be seen in the CFT, AA and FIBTEM-MCF
parameters after 1000 ml HES, as well as after surgery
(Tables 2 and and3).3). Multiplate did not detect any
significant differences within the HES group (Fig. 3).
Table 2
ROTEM and Multiplate parameters (median values, first and
third quartiles within brackets) of patients receiving
hydroxyethyl starch 130/0.4 (HES) during brain tumour
neurosurgery (n=18), blood samples taken at different times
during ...
Table 3
The p values when comparing ROTEM and Multiplate
parameters of brain tumour neurosurgery patients after
colloid infusions before surgery. Results after each colloid
infusion (250 ml for HA and 500 ml for HES) as well as at
the end of surgery ...
Fig. 1
ROTEM CT and CFT values of patients undergoing elective
brain tumour neurosurgery. Blood samples were taken before
the start of surgery, after receiving colloid infusions (human
albumin (HA) or hydroxyethyl starch (HES) 130/0.4 and at
the end of surgery. ...
Fig. 2
ROTEM EXTEM-MCF and FIBTEM-MCF values of
patients undergoing elective brain tumour neurosurgery.
Blood samples were taken before the start of surgery, after
receiving colloid infusions (human albumin (HA) or
hydroxyethyl starch (HES) 130/0.4 and at the ...
Fig. 3
Multiplate ADP and TRAP AUC values of patients
undergoing elective brain tumour neurosurgery. Blood
samples were taken before the start of surgery, after receiving
colloid infusions (human albumin (HA) or hydroxyethyl
starch (HES) 130/0.4 and at the end ...
Inter-group comparisons
When comparing the two test groups against each other, each
parameter was compared to the corresponding one in the
other test group. Most of the changes occurred after the first
dose of colloid. Before the start of surgery, only the CT
parameter differed between the groups (p=0.0001), with a
lower median CT in the HES group. After the first colloid
infusion, CT was still significantly shorter in the HES group
(p=0.0014), while CFT was longer (p=0.0002). EXTEM-
MCF were lower (p=0.001 and p=0.0107, respectively) in
the HES group as compared to the HA group. After the
second dose of colloid infusion, no further changes between
the groups were detected. At the end of surgery, the
following two parameters differed between the groups: CT
(p=0.0068) and FIBTEM-MCF (p=0.0117), which
registered significantly lower values in the HES test group.
For Multiplate analysis, no parameters were found to be
different between the two test groups.
There were no differences in the median arterial blood gas
parameters nor were there any differences in median systolic,
diastolic or mean arterial blood pressures, heart rate or pulse
pressure variation (only measured during anaesthesia, with
muscle relaxation and tidal volumes of >10 ml/kg body
weight and no arrhytmias) or in intra- and post-operative
median hourly diuresis between the groups. Post-operatively,
there was no increase in plasma creatinine in either group
(controlled 38 weeks postoperatively).
Go to:
Discussion
Our results indicate that the two types of colloid infusions
induce coagulation defects in elective brain tumour
neurosurgical patients, most notably seen with ROTEM
parameters and after HES infusion. There are dose-response
effects with both HA and HES. At the end of surgery, the
HES group had more deranged ROTEM values than the HA
group, but had been infused at a much higher volume ratio to
assessed bleeding. Multiplate showed only one significant
intra-group deterioration in the ADP parameter, detected after
500 ml HA, as compared to pre-surgery, and normalised
already at the end of surgery. No significant Multiplate
changes could be seen in the HES group.
Using viscoelastic or aggregometric techniques as point-of-
care methods for assessing perioperative bleeding risks is a
desirable option, since they provide faster results than
traditional laboratory-based tests. ROTEM has already been
used for this purpose and is able to detect colloid-induced
coagulopathies (Fenger-Eriksen et al. 2009; Hartog et
al.2011); Multiplate has not been studied as thoroughly in
this aspect. One study used Multiplate to detect impaired
platelet function after 60 % colloid dilution in vitro (Kind et
al. 2013), but the clinical implications are uncertain as this
represents an extreme dilution seldom observed in clinical
practice. In our study with colloid dilutions of 1020 %,
Multiplate indicated a statistically significant lowered ADP
aggregation as compared to the preoperative result only after
500 ml HA. However, at all sampling points, median levels
were within normal ranges for both the ADP and TRAP
reagents for both fluids. It is possible that Multiplate is not
sensitive enough to detect changes in platelet function at low
degrees of colloid dilution in vivo. Multiplate is also affected
by platelet count, especially at levels beneath 100109/L
(Hanke et al. 2010).
Only one of our patients had a low borderline platelet count
due to radiation therapy prior to surgery, and received one
unit of platelet transfusion at the beginning of the surgery
due to increased wound bleeding, and additionally, 250 ml
HA and three units of platelets intra-operatively. This
patients Multiplate values for TRAP/ADP were 67/30
preoperatively, 59/18 after 250 ml HA and 128/34 at the end
of surgery (after the three units of platelet transfusions;
patients data is not included in the Multiplate data statistical
evaluation). This might indicate a colloid-induced effect on a
low-platelet function/count that is restored after additional
platelet transfusions.
In this study, blood samples were taken before the start of
surgery to determine a baseline value. Some of these
preoperative values fell outside of the normal ROTEM
ranges, possibly induced by the tumour itself or stress due to
anaesthesia (Hahnenkamp et al. 2002). After the first volume
of colloid infusion, there were significant changes in several
ROTEM parameters in the HES test group but almost none
in the HA group. As seen in Fig. 1 and Table 2, CFT
increased, and AA decreased with successive colloid
infusions, which probably reflects a dilution effect on
coagulation factors.
The difference in CFT and AA between test groups could be
due to the different volumes of colloids given. Patients
receiving HA were given an infusion of 500 ml in total,
while those receiving HES had >double the volume, thus
probably leading to a greater extent of initial dilution.
Haemodilution could also explain why the CT parameter
only changed after 1000 ml HES. The efficacy of volume
replacement therapy depends on the initial plasma volume-
expanding effect of the colloid and the duration of its effect.
At the start of the present study, when HES data were
collected, all patients received consecutive doses of 500 ml
HES intra-operatively. However, with the new 5 % HA fluid
regimen at our centre, very few patients received more than
500 ml for haemodynamic stabilisation and initial blood-loss
replacement, probably due to a greater and enduring volume-
expanding effect of HA as compared to HES (Dubniks et
al.2009). However, the fluid therapy used in this study is
only empiric-based. Future studies should involve
blood/plasma volume measurements or cardiac output
measurements to better evaluate the colloid insult on
haemostasis.
MCF measures the amplification and propagation of the clot,
dependent on fibrin polymerisation and platelet function.
EXTEM- and FIBTEM-MCF are the most widely used
parameters in clinical settings for assessing coagulation since
they correlate strongly with traditional tests, most notably
plasma fibrinogen (Theusinger et al. 2013; Haas et al.2012).
In our study, EXTEM-MCF decreased after the second
volume infusion of HA, but already after the first volume of
HES.
With FIBTEM-MCF, we observe a similar decrease,
although it was now present after the first volume of HA.
This is in accordance with previous studies, since colloids
are known to affect coagulation through dilution as well as
interaction with coagulation factors and fibrin
polymerisation. HES has been especially well-documented to
exert its effects on coagulation by interacting with FXIII and
fibrin polymerisation (Nielsen2005). Fenger-Eriksen et al.
showed that HES decreases coagulation factors (e.g.
fibrinogen, FII, FX, FXIII) more than can be expected from
haemodilution alone, suggesting that the resulting
coagulopathy could be due to an acquired fibrinogen
deficiency (Fenger-Eriksen et al. 2009).
The specific effects of HA on coagulation in vivo are not as
well documented. Some studies imply that HA affects
coagulation by decreasing platelet aggregation (Jorgensen &
Stoffersen 1980; Kim et al. 1999). Another study showed that
HA infusions are linked to decreased fibrinogen levels
(Johnson et al. 1979); although, it is unclear whether this is
merely an effect of haemodilution. Niemi et al. observed a
hypercoagulative effect of HA haemodilution (Niemi &
Kuitunen 1998), but this effect could not be reproduced in
clinical settings (Niemi et al. 2005). In our study, the
difference in volume required for MCF to be affected by
each colloid might be accounted for by the different
biochemical properties of HES and HA. In clinical bleeding
situations, FIBTEM-MCF of <10 mm can indicate plasma
fibrinogen deficiency and prompts the use of fibrinogen
concentrate or fresh-frozen plasma (Bolliger et al. 2012). The
minimum values were especially low in the HES group
where it registered as low as 4 mm.
However, we found no correlation between lower FIBTEM-
MCF values and increased perioperative bleeding in our data,
as blood losses were similar in both test groups.
For inter-group comparisons, several parameters differed
between the test groups after the first colloid infusion.
However, after the second infusion, no further changes could
be seen. Furthermore, CT and FIBTEM-MCF both differed
between groups at the end of surgery. The difference in CT
was already present preoperatively, but the change in
FIBTEM-MCF is possibly due to the more prominent effects
of HES on clot stability; as discussed earlier, HES is known
to weaken clot structure (Mittermayr et al. 2007). Previous
studies have found hypercoagulative ROTEM tracings at
lower haemoglobin levels (Nagler et al. 2013; Solomon et
al. 2013), but no such effect could be observed with certainty
in our study.
At Lund University Hospital, 5 % HA is the preferred colloid
for neurosurgery right now due to its ability to maintain
plasma oncotic pressure. With a 20 % HA alleviation of
cerebral oedema is possible (Jungner et al. 2010). However,
it is hard to foresee changes in blood brain barrier that might
contribute to oedema during elective brain tumour resection,
so control of oncotic pressure with albumin for these types of
patients is controversial.
In neurosurgery, haemostatic control poses a significant
problem, as the balance between coagulation and bleeding
must be maintained. If HA is to be preferred over HES, there
might be a limitation to the appropriate volume of HA
infusion. Either from haemodilution or another mechanism,
HA seems to have an impact on coagulation. At Lund
University Hospital, the upper limit of HA infusions is
usually 500 ml for neurosurgical patients, with only a few
receiving 750 ml. With regard to our data, infusions of these
volumes might require monitoring with ROTEM or
laboratory-based methods in order to detect coagulopathy
and the need for fibrinogen or other transfusions. HA might
be preferable in this regard since HA-induced coagulopathy
is more easily reversed with fibrinogen concentrate than
coagulopathy induced by HES, at least in vitro (Winstedt et
al. 2013; Schlimp et al. 2013).
There are several limitations to this study. This study is not
double-blinded or randomised. Initially, the aim was to study
the safety of HES, as HES was our routine for
haemodynamic stabilisation and initial blood-loss
replacement in elective neurosurgery. This routine was later
replaced by HA. It is underpowered to detect a correlation
between our findings and clinical bleeding/postoperative
complications. In ROTEM/Multiplate systems, results might
not always correlate with clinical bleeding as there is no
blood flow or endothelial interactions that affect coagulation
in vivo.
We did not use the same amount of HA and HES. The
patients received a mean of 375 ml HA but a mean of 861 ml
HES, which is 230 % more fluid. From our very basic
haemodynamic monitoring, there was an impression that the
need for HA volume was much less than that of the HES
volume. However, to measure this in an optimal way, we
should have used blood-volume measurements or at least
cardiac output monitoring. The volumes of HA and HES
were not controlled by us, but by the anaesthetist in charge,
trying to optimise MAP, systolic blood pressure, systolic
blood pressure and PPV on top of replacing initial blood loss
with 12 ml of the respective colloid for every millilitre of
blood loss.
Dubnics M et al. have published two works on HES versus
Albumin [Dubnics et al.2007; Dubnics et al. 2009]. In short,
one can say that they showed that 3 h after rescucitation with
HES and HA (20 ml/kg) after bleeding in guinea pigs,
plasma volume (PV) increased by 27 ml/kg in the HA group
and 18 ml/kg in the HES group, equal to 1.5 times more HES
needed to get the same PV-expanding effect. Corresponding
PV expansion in a rat with increased permeability was
17 mL/kg for HA and 7 ml/kg of HES equal to 2.4 times as
much HES albumin that needs to be given for the same PV
expansion. Since the surgery, and bleeding is not likely to
give the same greater permeability increase, it is more
probable that the ratio for the conditions prevailing at
neurosurgery are closer to 1.5 than 2.4, maybe 2.
The Saline protocol used by department may not be optimal,
although we did not find any signs of hyperchloremic
acidosis, hypernatremia or renal failure in our patients.
Balanced crystalloids may be better [van Haren et al. 2014]
from these aspects. Also, balanced crystalloids may be better
than saline (and albumin) to maintain coagulation (Smith et
al. 2015; Pathirana et al. 2015).
Finally, as this is a pilot study carried out during a limited
period of time, the sample sizes are small, and conclusions
must therefore be drawn with care regarding the preference
of HA over HES as a neurosurgical fluid therapy.
Nevertheless, as this study investigates clinically used fluid-
therapy routines as opposed to fluid regimes designed a
priori, the results are easier to apply to real-life clinical
settings.
Go to:
Conclusions
There were no clinically relevant differences concerning
kidney function, bleeding or coagulation; although, ROTEM
and Multiplate measurements indicated both inter- and intra-
group statistical differences. Albumin had a certain impact on
coagulation; especially after 500 ml infusion, the ROTEM
changes are close to those induced by 1000 ml hydroxyethyl
starch. Clot structure measured by ROTEM FIBTEM-MCF
was significantly lower with HES at the end of surgery, but
HES had been infused at higher volumes to maintain intra-
operative haemodynamics. Unlike previous studies that
focused on thromboelastography, we also used Multiplate to
assess coagulation, but no significant changes could be
detected other than after 500 ml HA infusion, and those
changes were normalised by the end of surgery. HA seems to
be a more favourable fluid for volume replacement in
neurosurgical patients at restricted volumes of infusion;
however, larger studies need to be carried out for more
conclusive results and preferably with plasma volume
measurements. Irrespective of the type of fluid regimen,
intra-operative monitoring of coagulation during
neurosurgery is recommended.
Go to:
Acknowledgements
The study was funded by Lund University ISEX/ALF funds
for Ulf Schtt.
Go to:
Abbreviations
AA alpha angle
ADP adenosine diphosphate
aPTT activated thromboplastin time

AUS area under curve
CFT clot formation time
CT clotting time
F factor
HA human albumin
HES hydroxyethyl starch
MCF maximal clot formation
PT prothrombin time
ROTEM rotational thromboelastometry
TRAP thrombin receptor-activating peptide
Go to:
Footnotes
Competing interests
The authors declare that they have no competing interests.
Authors contributions
NL performed the ROTEM and Multiplate analyses, compiled the
statistics and prepared the tables and figures and took part in
drafting the manuscript. SS collected clinical and other laboratory
data from ROTEM/Multiplate and took part in drafting the final
manuscript. BA is the director of neurosurgical anaesthesia,
collected signed consent and took part in drafting the final
manuscript. US planned, financed, prepared ethical committee
application, informed patients and collected signed consents and
took part in drafting the final manuscript. All authors have read and
approved the final version of the manuscript.
Go to:
Contributor Information
N. Li, Email: es.grebonork@il.aron.
S. Statkevicius, Email: es.enaks@suicivektatS.sanujavS.
B. Asgeirsson, Email: es.enaks@nossriegsA.igoB.
U. Schtt, Email: es.enaks@ttohcs.flu.
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Salchner C, Klingler A, et al. Hemostatic changes
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25. Niemi TT, Kuitunen AH. Hydroxyethyl starch
impairs in vitro coagulation. Acta Anaesthesiol
Scand. 1998;42:11041109. doi: 10.1111/j.1399-
6576.1998.tb05385.x. [PubMed] [Cross Ref]
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27. Niemi TT, Suojaranta-Ylinen RT, Kukkonen SI,
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not albumin, impair hemostasis after cardiac
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10.1213/01.ane.0000200285.20510.b6.[PubMed]
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28. Pathirana S, Wong G, Williams P, Yang K, Kershaw
G, Dunkley S, et al. The effects of haemodilution
with albumin on coagulation in vitro as assessed by
rotational thromboelastometry. Anaesth Intensive
Care. 2015;43:187192.[PubMed]
29. Perel P, Roberts I, Ker K. Colloids versus
crystalloids for fluid resuscitation in critically ill
patients. Cochrane Database Syst
Rev. 2013;2:CD000567. [PubMed]
30. Roberts I, Blackhall K, Alderson P, Bunn F,
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31. Schlimp CJ, Cadamuro J, Solomon C, Redl H,
Schchl H. The effect of fibrinogen concentrate and
factor XIII on thromboelastometry in 33 % diluted
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saline in vitro. Blood Transfus. 2013;11:510
517. [PMC free article] [PubMed]
32. Shore-Lesserson L, Manspeizer HE, DePerio M,
Francis S, Vela-Cantos F, Ergin MA.
Thromboelastography-guided transfusion algorithm
reduces transfusions in complex cardiac
surgery. Anesth Analg. 1999;88:312319. [PubMed]
33. Smith CA, Gosselin RC, Utter GH, Galante JM,
Young JB, Scherer LA, et al. Does saline resuscitation
affect mechanisms of coagulopathy in critically ill
trauma patients? An exploratory analysis. Blood
Coagul Fibrinolysis. 2015;26:250254. doi:
10.1097/MBC.0000000000000154. [PubMed] [Cross
Ref]
34. Solomon C, Traintinger S, Ziegler B, Hanke A,
Rahe-Meyer N, Voelckel W, et al. Platelet function
following trauma. A multiple electrode aggregometry
study.Thromb Haemost. 2011;106:322330. doi:
10.1160/TH11-03-0175. [PubMed][Cross Ref]
35. Solomon C, Rahe-Meyer N, Schchl H, Ranucci
M, Grlinger K. Effect of haematocrit on fibrin-based
clot firmness in the FIBTEM test. Blood
Transfus.2013;11:412418. [PMC free
article] [PubMed]
36. Theusinger OM, Schrder CM, Eismon J, Emmert
MY, Seifert B, Spahn DR, et al. The influence of
laboratory coagulation tests and clotting factor levels
on Rotation Thromboelastometry (ROTEM(R))
during major surgery with hemorrhage. Anesth
Analg. 2013;117:314321. doi:
10.1213/ANE.0b013e31829569ac. [PubMed] [Cross
Ref]
37. Tynngrd N, Berlin G, Samuelsson A, Berg S. Low
dose of hydroxyethyl starch impairs clot formation as
assessed by viscoelastic devices. Scand J Clin Lab
Invest. 2014;74:344350. doi:
10.3109/00365513.2014.891259. [PubMed][Cross
Ref]
38. van Haren F, Zacharowski K. Whats new in
volume therapy in the intensive care unit? Best Pract
Res Clin Anaesthesiol. 2014;28:275283. doi:
10.1016/j.bpa.2014.06.004. [PubMed] [Cross Ref]
39. Winstedt D, Hanna J, Schott U. Albumin-induced
coagulopathy is less severe and more effectively
reversed with fibrinogen concentrate than is synthetic
colloid-induced coagulopathy. Scand J Clin Lab
Invest. 2013;73:161169. doi:
10.3109/00365513.2012.762114. [PubMed] [Cross
Ref]
40. Zarychanski R, Abou-Setta AM, Turgeon AF,
Houston BL, McIntyre L, Marshall JC, et al.
Association of hydroxyethyl starch administration
with mortality and acute kidney injury in critically ill
patients requiring volume resuscitation: a systematic
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doi: 10.1001/jama.2013.430. [PubMed] [Cross Ref]
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Effects of different colloid infusions on ROTEM and Multiplate during elective b...
Effects of different colloid infusions on ROTEM and Multiplate during elective brain tumour neurosurgery
Perioperative Medicine. 2015; 4()
Haemostatic changes during surgery for primary brain tumours
Journal of Neurology, Neurosurgery, and Psychiatry. 1997 Sep; 63(3)334
Abnormal coagulation profile in brain tumor patients during surgery.
Neurosurgery. 1994 Mar ;34(3):389-94; discussion 394-5.
PubMed
See more...
Haemostatic changes during surgery for primary brain

tumours.[J Neurol Neurosurg Psychiatry. 1997]
Review Association of hydroxyethyl starch administration with

mortality and acute kidney injury in critically ill patients requiring
volume resuscitation: a systematic review and meta-analysis.
[JAMA. 2013]
Review Clinical relevance of the effects of plasma expanders

on coagulation.[Semin Thromb Hemost. 2007]
Mechanisms of hydroxyethyl starch-induced dilutional

coagulopathy.[J Thromb Haemost. 2009]
Decreased circulating levels of von Willebrand factor after

intravenous administration of a rapidly degradable hydroxyethyl
starch (HES 200/0.5/6) in healthy human subjects.[Intensive
Care Med. 2001]
Tetrastarch solutions: are they definitely dead?[Br J Anaesth.
2013]
Review The Lund concept for the treatment of patients with

severe traumatic brain injury.[J Neurosurg Anesthesiol. 2011]
Review Colloids versus crystalloids for fluid resuscitation in

critically ill patients.[Cochrane Database Syst Rev. 2013]
Review Human albumin solution for resuscitation and volume

expansion in critically ill patients.[Cochrane Database Syst Rev.
2011]
Gelatin and hydroxyethyl starch, but not albumin, impair

hemostasis after cardiac surgery.[Anesth Analg. 2006]
Albumin-induced coagulopathy is less severe and more

effectively reversed with fibrinogen concentrate than is synthetic
colloid-induced coagulopathy.[Scand J Clin Lab Invest. 2013]
Thromboelastography-guided transfusion algorithm reduces

transfusions in complex cardiac surgery.[Anesth Analg. 1999]
Platelet function following trauma. A multiple electrode

aggregometry study.[Thromb Haemost. 2011]
Viscoelastic and aggregometric point-of-care testing in patients

with septic shock - cross-links between inflammation and
haemostasis.[Acta Anaesthesiol Scand. 2012]

Low dose of hydroxyethyl starch impairs clot formation as

assessed by viscoelastic devices.[Scand J Clin Lab Invest. 2014]
Multi-centre investigation on reference ranges for ROTEM

thromboelastometry.[Blood Coagul Fibrinolysis. 2005]

Review Influence of hydroxyethyl starch (HES) 130/0.4 on

hemostasis as measured by viscoelastic device analysis: a
systematic review.[Intensive Care Med. 2011]
Is dilutional coagulopathy induced by different colloids

reversible by replacement of fibrinogen and factor XIII
concentrates?[Anesth Analg. 2013]
Impact of platelet count on results obtained from multiple

electrode platelet aggregometry (Multiplate).[Eur J Med Res.
2010]
Review The effects of local anesthetics on perioperative

coagulation, inflammation, and microcirculation.[Anesth Analg.
2002]
Comparison of the plasma volume-expanding effects of 6%

dextran 70, 5% albumin, and 6% HES 130/0.4 after hemorrhage
in the guinea pig.[J Trauma. 2009]
The influence of laboratory coagulation tests and clotting factor

levels on Rotation Thromboelastometry (ROTEM(R)) during
major surgery with hemorrhage.[Anesth Analg. 2013]
Comparison of thromboelastometry (ROTEM) with standard
plasmatic coagulation testing in paediatric surgery.[Br J Anaesth.
2012]
Colloids decrease clot propagation and strength: role of factor

XIII-fibrin polymer and thrombin-fibrinogen interactions.[Acta
Anaesthesiol Scand. 2005]

On the inhibitory effect of albumin on platelet aggregation.

[Thromb Res. 1980]
Effect of increasing serum albumin on plasma D-dimer, von

Willebrand factor, and platelet aggregation in CAPD patients.[Am
J Kidney Dis. 1999]
Altered coagulation after albumin supplements for treatment of

oligemic shock.[Arch Surg. 1979]
Hydroxyethyl starch impairs in vitro coagulation.[Acta

Anaesthesiol Scand. 1998]
Albumin induced hypercoagulability does not reduce blood

loss in patients undergoing total hip arthroplasty.[Scand J Surg.
2005]
Review Principles and practice of thromboelastography in

clinical coagulation management and transfusion practice.
[Transfus Med Rev. 2012]
Hemostatic changes after crystalloid or colloid fluid

administration during major orthopedic surgery: the role of
fibrinogen administration.[Anesth Analg. 2007]
Impact of changes in haematocrit level and platelet count on
thromboelastometry parameters.[Thromb Res. 2013]
Effect of haematocrit on fibrin-based clot firmness in the

FIBTEM test.[Blood Transfus. 2013]
Effects on brain edema of crystalloid and albumin fluid

resuscitation after brain trauma and hemorrhage in the rat.
[Anesthesiology. 2010]

The effect of fibrinogen concentrate and factor XIII on

thromboelastometry in 33% diluted blood with albumin, gelatine,
hydroxyethyl starch or saline in vitro.[Blood Transfus. 2013]
Plasma volume expansion of 5% albumin, 4% gelatin, 6% HES

130/0.4, and normal saline under increased microvascular
permeability in the rat.[Intensive Care Med. 2007]
Comparison of the plasma volume-expanding effects of 6%

dextran 70, 5% albumin, and 6% HES 130/0.4 after hemorrhage
in the guinea pig.[J Trauma. 2009]
Review What's new in volume therapy in the intensive care

unit?[Best Pract Res Clin Anaesthesiol. 2014]
Does saline resuscitation affect mechanisms of coagulopathy

in critically ill trauma patients? An exploratory analysis.[Blood
Coagul Fibrinolysis. 2015]
See more ...
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J Res Med Sci
v.19(1); 2014 Jan
PMC3963329
J Res Med Sci. 2014 Jan; 19(1): 812.

PMCID: PMC3963329
Comparative evaluation of the effects of

hydroxyethyl starch on coagulation state of
patients during brain tumor surgeries in
comparison to crystalloids by
thromboelastography
Mohammad Golparvar, Mahmood Saghaei, Hossein Hamidi, Parvin
Sajedi, Parviz Kashefi, Omid Aghadavoudi, and Saeed Abbasi
Author information Article notes Copyright and License information
Abstract
Go to:
INTRODUCTION
Hypercoagulability is a well-known state in primary brain
tumors.[1,2] Inadvertent clot formation or disseminated
intravascular coagulation (DIC) has been reported during
brain tumor surgeries.[2] Thrombotic complications [deep
vein thrombosis and/or pulmonary embolization (DVT/PE)]
occur in 18 to 50% of the patients harboring brain tumors
who undergo neurosurgical procedures.[3] Clinical risk
factors associated with venous thromboembolic (VTE)
events are paresis, prior thrombotic disease, chemotherapy,
location, and histology of tumor.[4] Studies involving brain
tumor tissue cell cultures have implicated factors released by
the tumor or surrounding neural tissues that activate the
coagulation system or inhibit fibrinolysis.[4]
During surgeries, crystalloid and colloid solutions are used as
volume expanders or for the replacement of blood loss. One
of the most frequently used colloid volume expanders is
hydroxyethyl starch (hetastarch).[5]
Hetastarch is a synthetic colloid solution. It produces
dilutional effects similar to other volume expanders and
reduces the levels of factor VIIIc and von Willebrand factor
(vWF) by 50 to 80% in a dose of 1 to 1.5 L, with
prolongation of the partial thromboplastin time. Hetastarch
also can interfere with platelet adhesion and clot formation
by reduction in glycoprotein IIb/IlIa availability and direct
movement of the hetastarch molecules into the fibrin clot.[6]
Adverse effects of hetastarch on blood coagulation have been
confirmed by multiple studies.[7,8,9,10,11,12]
Goh and colleagues evaluated the coagulation profile of
patients with brain tumors undergoing surgery by using
thromboelastography (TEG) and concluded that TEG is
useful in the perioperative assessment of hemostatic profile
of patients with large brain tumors.[1]
TEG evaluates the elastic properties of whole blood and
provides a global assessment of hemostatic function.[13]
The aim of this study was evaluation of the effects of the use
of hetastarch during brain tumor surgeries on coagulation
and reduction of the hypercoagulable state in these patients
with the intention of decreasing complications such as VTE
and DIC.
Go to:
MATERIALS AND METHODS
After approval of the ethical committee, approximately 90
patients who suffered from brain tumors and were candidates
for craniotomy at Al-Zahra Medical Center presented for
eligibility and 74 of them agreed to participate in this double-
blinded clinical trial study; they also provided written
informed consent.
Inclusion criteria were age between 18 and 65 years, health
status classification (ASA) I and II of the American Society
of Anesthesiologists, no coagulation abnormality, hepatic,
renal, or endocrine disease, and no use of nonsteroidal
inflammatory dugs (NSAIDs), aspirin, or anticoagulant drugs
in the previous week.
Nine participants could not participate in the study after
screening on the basis of the exclusion criteria (uncontrolled
hypertension, usage of NSAIDs or unknown drugs in the past
week, abnormal creatinine level, and opium addiction). The
participants were randomly allocated into crystalloid (normal
saline) and colloid (hetastarch) study groups.
Two patients in the crystalloid group and three in the colloid
group were excluded because of change in plan of surgery
and technical problems in sampling and process of TEG.
Finally, 30 patients remained in each group of the study
[Figure 1] [for 80% power (Z2 = 0.84), 0.05 significance
level (Z1 = 1.96), equal number of cases in both groups (r =
1), and considering S1 and S2, respectively, 0.35 and 0.45 and
d = 0.3 according to a previous partly similar study,[14] we
calculated a minimum sample size of 29 patients in each
group for our study].
Figure 1
CONSORT flowchart of study
All patients were given 2 mL/kg/hour of normal saline
during the eight-hour fast before the surgery. In the operating
room, routine monitoring [pulse oxymeter, noninvasive
blood pressure (NIBP), electrocardiography (EKG), and
temperature] was started and readings were recorded every
five minutes during surgery. After induction of anesthesia
(fentanyl: 3-4 g/kg, sodium thiopental: 5-7 mg/kg,
cisatracurium: 0.15 mg/kg, lidocaine: 1.5 mg/kg), central
venous and arterial lines were inserted and blood sampling
for TEG was done by atraumatic withdrawing of 2 mL of
blood via antecubital vein from the hand that did not have the
fluid infusion line.
After the first blood sample was taken, the patients were
given 10 mL/kg of fluids in 30 minutes from covered coded
boxters prepared by coworkers for the purpose of double
blinding according to a randomized list created by Random
Allocation Software.[15]
Sixty minutes (three time constants) after infusion of fluids,
the second blood sampling was done. All blood samples were
immediately sent to the operating room laboratory for TEG.
After the second blood sampling, the participants (in both
groups) had similar fluid and blood component therapy
during and after surgery.
The patients were given propofol (0.15-0.20 mg/kg/min),
remifentanil (0.1 g/kg/min), and cisatracurium (2
g/kg/min) for maintenance of anesthesia.
At the end of surgery, cisatracurium was discontinued and
the infusion of propofolremifentanil reduced to 50%; 10
minutes later, the muscle relaxant was reversed by the
administration of prostigmine (45 g/kg) plus atropine (20
g/kg).
The patients were extubated after resumption of spontaneous
ventilation and transferred to the postanesthesia care unit
(PACU) and then to the intensive care unit (ICU) for
postoperative care.
The primary end point of this study was evaluating
differences in bleeding during surgery and TEG criteria
before and after infusion of colloids in comparison to
crystalloids; so, the volume of bleeding during surgery and
TEG data (R, K, angle, MA, and Ly30)* were measured
and compared within and between groups.
* R: Time to initiate fibrin formation; K: Measure of the
speed taken to reach a specific level of clot strength; angle:
Measure of the speed of fibrin buildup and cross-linking,
MA: Ultimate strength of clot and measure of platelet
function, Ly30: Percent of fibrin distraction after 30 minutes
of clot formation.
The major morbidity end points were defined as any signs
and symptoms of bleeding tendency (ecchymosis, blood
oozing, or abnormal bleeding in the surgical site), DVT
(swelling, redness, and pain in legs), or thromboembolic
events (dyspnea, chest pain, hemoptysis).
All data were expressed as the number of patients or mean
standard deviation (SD). Data were examined for a normal
distribution of variance with analysis of variance (ANOVA)
and expressed as the mean SD. Discrete variables between
the groups were compared using a chi-square test or Fisher's
exact test and P < 0.05 was considered to be statistically
significant. Statistical analyses were performed using SPSS
18.0 for Windows.
Go to:
RESULTS
There were no significant differences in the demographic
data, duration of surgery, and duration of recovery care
between the two groups. Volume of bleeding, urine output,
and total volume of fluids infused during surgery were a little
more in the crystalloid group but they were not statistically
significant [Table 1].
Table 1
Demographic, duration of surgery, duration of care in
postanesthesia care unit (PACU), fluids balance, and
hemodynamic data
The mean of heart rate, mean of arterial blood pressure, end-
tidal carbon dioxide, peripheral oxygen saturation (SpO2),
and temperature were similar between the groups during
surgery [Table 1].
Based on the analysis of TEG variables, there were
significant differences in R and K between measurements
before and after crystalloid infusion, but , MA, and Ly30
did not show any significant differences in this comparison
[Table 2].
Table 2
TEG data in crystalloid group
The TEG variable analysis in the colloid group showed
significant differences in all variables (R, K, , MA, and
Ly30) [Table 3].
Table 3
TEG data in colloid group
Statistical analysis of mean of changes in TEG variables by
fluid infusion in the two groups clarified significant
differences in R, K, and Ly30 between them [Table 4].
Table 4
Comparison of percentage of changes in
thromboelastography variables between the two groups
The length of stay in the ICU (1.56 0.5 and 1.46 0.5 days,
respectively, in the crystalloid and colloid groups; (P =
0.447) postoperatively was not different between the two
groups.
There was only one patient who had transient (for less than 2
hours) tachypnea and dyspnea in the crystalloid group which
was suspicious of a thromboembolic event (P = 0.313).
Go to:
DISCUSSION
This study was a prospective randomized double-blinded
trial addressing the effects of 10 mL/kg hetastarch compared
to crystalloid solution (normal saline) in patients undergoing
brain tumor surgeries who are in a hypercoagulable state and
the complications of this condition.
No differences were observed in terms of volume of
bleeding, duration of surgery, and duration of ICU care after
surgery. TEG parameters showed delay in clot formation
(increased R and K) and increase in fibrinolysis (increased
Ly30) in the hetastarch group in comparison to the
crystalloid group (t > 1.699).
Hetastarch has been reported to induce a type I von
Willebrand-like syndrome with decreased factor VIII activity
and decreased von Willebrand factor antigen and VIII-related
cofactor level.[16]
These effects manifest as an increase in R and K and a
decrease in MA and angle on TEG that are associated with
an actual decrease in coagulability of blood and in maximum
(33 mL/kg) increase in bleeding during surgeries.
[17,18,19,20] In a study, dose-dependent alterations in
coagulation without an actual increase in blood loss were
observed.[21]
There is a hypercoagulable state in patients suffering from
brain tumors, and DVT and thromboembolic events are more
common in them. This state can worsen by the patient lying
on the operating table (or ICU bed) for a long time during
craniotomy and ICU care.
The pharmacokinetic properties of hetastarch produce some
degree of disturbances in hemostasis; hemodilution per
se causes lower platelet availability which may pose to clot
formation in response to venous stasis in the lower limbs
during craniotomy and ICU care, and pharmacodynamic
effects of these may increase this suitable side effect.
In this study, 10 mL/kg of hetastarch 200 which was infused
early in the craniotomy surgeries did not increase the amount
of perioperative blood loss compared to crystalloids.
Indeed, based on TEG parameters, hetastarch decreased the
speed of clot formation and clot strength and increased lysis
of the produced clot, but these changes did not deteriorate the
levels of hemostasis which are needed during craniotomy.
This study had some ethical and budget limitations in
confirming the clinical diagnosis of thromboembolic events
by highly specific methods.
Go to:
CONCLUSION
Infusion of 10 mL/kg hetastarch in brain tumor resection
surgeries decreases coagulability while preserving
hemostasis, and it can probably decrease susceptibility of
these patients to DVT and thromboembolic events.
Go to:
ACKNOWLEDGMENT
The authors would like to acknowledge the Anesthesia and
Critical Care Research Center which helped in all processes
of this study.
Go to:
Footnotes
Source of Support: This study was supported under project
number 388365 by the Research Department, Faculty of Medicine,
Isfahan University of Medical Sciences, Isfahan, Iran
Conflict of Interest: None declared
Go to:
REFERENCES
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2. Hsieh V, Molnar I, Ramadan A, Safran AB, Bouvier CA,
Berney J. Hypercoagulability syndrome associated with
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cases) Neurochirurgie.1986;32:4049. [PubMed]
3. Rodas RA, Fenstermaker RA, McKeever PE, Blaivas M,
Dickinson LD, Papadopoulos SM, et al. Correlation of
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report. J Neurosurg.1998;89:2005. [PubMed]
4. Jubelirer SJ. Venous thromboembolism and malignant
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Safety of modern starches used during surgery. Anesth
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6. Kaye AD, Ropelle JM. Intravascular fluid and electrolyte
physiology. In: Miller RD, editor. Miller's Anesthesia. 7th ed.
Philadelphia: Churchill Livingstone; 2010. p. 1727.
7. Casutt M, Kristoffy A, Schuepfer G, Spahn DR, Konrad C.
Effects on coagulation of balanced (130/0.42) and non-
balanced (130/0.4) hydroxyethyl starch or gelatin compared
with balanced Ringer's solution: An in vitro study using two
different viscoelastic coagulation tests ROTEMTM and
SONOCLOTTM. Br J Anaesth.2010;105:27381. [PubMed]
8. Lindroos AC, Schramko A, Tanskanen P, Niemi T. Effect
of the combination of mannitol and ringer acetate or
hydroxyethyl starch on whole blood coagulation in vitro. J
Neurosurg Anesthesiol. 2010;22:1620. [PubMed]
9. Kuitunen AH. Artificial colloids impair haemostasis. An in
vitro study using thromboelastometry coagulation
analysis. Acta Anaesthesiol Scand. 2005;49:3738.[PubMed]
10. Blanloeil Y, Trossart M, Rigal JC, Rozec B. Effects of
plasma substitutes on hemostasis. Ann Fr Anesth
Reanim. 2002;21:64867. [PubMed]
11. De Jonge E, Levi M. Effects of Plasma Substitutes on
Coagulation. Yearbook of Intensive Care and Emergency
Medicine. 2006:27986.
12. Nikkar R, Golparvar M. Is Hydroxyethyl starch 130
preferred over hydroxyethyl starch 200 in terms of effects on
the coagulation system? J Isfahan Med School.2012;29:171
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13. Chitlur M. Challenges in the laboratory analyses of
bleeding disorders. Thromb Res.2012;130:16. [PubMed]
14. Jamnicki M, Zollinger A, Seifert B, Popovic D, Pasch T,
Spahn DR. Compromised blood coagulation: An in
vitro comparison of hydroxyethyl starch 130/0.4 and
hydroxyethyl starch 200/0.5 using
thrombelastography. Anesth Analg. 1998;87:98993.
[PubMed]
15. Saghaei M. Random allocation software for parallel
group randomized trials. BMC Med Res
Methodol. 2004;4:26. [PMC free article] [PubMed]
16. Jonge E, Levi M. Effects of different plasma substitutes
on blood coagulation: A comparative review. Crit Care
Med. 2001;29:12617. [PubMed]
17. Kuitunen AH, Hynynen MJ, Vahtera E, Salmenper MT.
Hydroxyethyl starch as a priming solution for
cardiopulmonary bypass impairs hemostasis after cardiac
surgery.Anesth Analg. 2004;98:2917. [PubMed]
18. Httner I, Boldt J, Haisch G, Suttner S, Kumle B, Schulz
H. Influence of different colloids on molecular markers of
hemostasis and platelet function in patients undergoing major
abdominal surgery. Br J Anesth. 2000;85:41723. [PubMed]
19. Gallandat Huet RC, Siemons AW, Baus D, van Rooyen-
Butijn WT, Haagenaars JA, van Oeveren W, et al. A novel
hydroxyethyl starch for effective perioperative plasma
volume substitution in cardiac surgery. Can J
Anesth. 2000;47:120715.[PubMed]
20. Innerhofer P, Fries D, Margreiter J, Klingler A,
Khbacher G, Wachter B, et al. The effects of perioperatively
administered colloids and crystalloidson primary platelet-
mediated hemostasis clot formation. Anesth
Analg. 2000;;95:85865. [PubMed]
21. Deusch E, Thaler U, Kozek-Langenecker SA. The effects
of high molecular weight hydroxyethyl starch solutions on
platelets. Anesth Analg. 2004;99:6658. [PubMed]
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Comparative evaluation of the effects of hydroxyethyl starch on coagulation state of patients during brain
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[Hypercoagulability syndrome associated with cerebral lesions.

Prospective study of coagulation during surgery of primary brain
tumors (17 cases)].[Neurochirurgie. 1986]
Correlation of intraluminal thrombosis in brain tumor vessels

with postoperative thrombotic complications: a preliminary report.
[J Neurosurg. 1998]
Review Safety of modern starches used during surgery.
[Anesth Analg. 2013]
Effects on coagulation of balanced (130/0.42) and non-

balanced (130/0.4) hydroxyethyl starch or gelatin compared with
balanced Ringer's solution: an in vitro study using two different
viscoelastic coagulation tests ROTEMTM and SONOCLOTTM.
[Br J Anaesth. 2010]
Effect of the combination of mannitol and ringer acetate or

hydroxyethyl starch on whole blood coagulation in vitro.[J
Neurosurg Anesthesiol. 2010]
Artificial colloids impair haemostasis. An in vitro study using

thromboelastometry coagulation analysis.[Acta Anaesthesiol
Scand. 2005]
See more ...

Review Challenges in the laboratory analyses of bleeding

disorders.[Thromb Res. 2012]
Compromised blood coagulation: an in vitro comparison of

hydroxyethyl starch 130/0.4 and hydroxyethyl starch 200/0.5
using thrombelastography.[Anesth Analg. 1998]
Random allocation software for parallel group randomized

trials.[BMC Med Res Methodol. 2004]
Review Effects of different plasma substitutes on blood

coagulation: a comparative review.[Crit Care Med. 2001]
Hydroxyethyl starch as a priming solution for cardiopulmonary
bypass impairs hemostasis after cardiac surgery.[Anesth Analg.
2004]
Influence of different colloids on molecular markers of

haemostasis and platelet function in patients undergoing major
abdominal surgery.[Br J Anaesth. 2000]
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Cancer, Coagulation, and Anticoagulation

1. Anthony Letaia,b and
2. David J. Kutera
+ Author Affiliations
1. aHematology-Oncology Department, Massachusetts General Hospital Cancer
Center, Boston, Massachusetts, USA;
2. bDana-Farber Cancer Institute, Boston, Massachusetts, USA
1. Anthony Letai, M.D., Ph.D., Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA
02115, USA. Telephone: 617-632-6077; Fax: 617-632-5822; e-mail: aletai@partners.org
Accepted October 31, 1999.
Next Section
ABSTRACT
Thromboembolic disease affects about 15% of cancer patients and presents a challenge to the
oncologist for both prophylaxis and treatment. Although long known to be associated with
malignancy, the underlying biochemical mechanisms are poorly understood. Both low-dose
warfarin and low molecular weight heparin are effective strategies for prophylaxis of venous
thromboembolism, including those involving venous access devices. Current treatment options
for venous thromboembolism include heparin (unfractionated and low molecular weight),
warfarin, and internal vena cava filters. The appropriate use of these therapeutic options in
cancer patients is reviewed herein. There is suggestive evidence that heparin may be superior to
warfarin in the long-term treatment of venous thromboembolism. Whether anticoagulants might
also improve cancer survival rates independent of their effect on thromboembolism deserves
further investigation.
Cancer
Heparin
Warfarin
Coagulation
Thrombosis
Pulmonary embolism
Small-cell
Chemotherapy
Breast
Previous SectionNext Section
INTRODUCTION
One of the most frequent hematological complications encountered by the practicing oncologist
is disordered coagulation. Thromboembolic disease affects approximately 15% of all cancer
patients [1]. This includes superficial and deep venous thrombosis, pulmonary emboli, thrombosis
of venous access devices, as well as arterial thrombosis and embolism. It is the second leading
cause of death for cancer patients [2], although obviously in many of these patients,
thromboembolic disease represents only one of many complications of the end-stage patient.
In this paper we will focus on the hypercoagulable states associated with cancer and the role of
chemotherapy in inducing thrombosis. We will review the problem of central venous catheters
and their associated thrombotic risk in cancer patients. We will describe aspects of treatment of
thromboembolic disease which are peculiar to cancer patients and focus on the relative roles of
coumadin, heparin, and low molecular weight heparin (LMWH) in this treatment. Finally, we will
summarize the data concerning the use of anticoagulants as antineoplastic agents.
THROMBOPHILIA OF MALIGNANCY
Cancer and its treatment can affect all three arms of Virchow's classical triad of causation of
thromboembolic disease: alteration in blood flow, damage of endothelial cells, and elaboration of
procoagulants. Cancer can affect blood flow by mechanical effects on blood vessels near a tumor.
Also, the angiogenesis induced by many tumors causes the creation of complexes of blood
vessels that are aberrant in appearance and have very disordered flow. In fact, flow in these
vessels can vary not only in magnitude, but also in direction. Endothelial cells can also be
damaged directly by tumors or chemotherapy.
Procoagulants can be increased on the surface of cancer cells, and may also be secreted into the
blood stream by cancer cells [3]. Examples of molecules elaborated by cancer cells that can
predispose to disordered coagulation include tissue factor, a Vitamin K-dependent cysteine
protease that activates factor X, and a mucin procoagulant that activates prothrombin.
Furthermore, chemotherapy treatment can cause a reduction in levels of the anticoagulant
proteins C and S. Indwelling venous access devices may also predispose to thrombosis by altering
blood flow, damaging endothelial cells, and serving as a surface upon which procoagulants can
promote thrombosis.
In addition, other factors can cause dysregulation of the normal mechanisms of thrombosis and
hemostasis. Certain tumors cause thromboembolism by direct extension and blockage of
neighboring vessels. The best-known example is probably renal cell carcinoma, which can be
associated with internal vena cava (IVC) thrombus by direct extension of tumor into this vessel.
Long-term survival of patients with this disorder has been reported after complete resections of
the tumor and thrombosed vessel, sometimes even including the right ventricle.
Other tumors are associated with a secondary thrombocytosis [4]. However, there is not an
association of this thrombocytosis with activation of the clotting cascade or clinical
thromboembolism. Tumor cells may activate platelets in yet other cases. It is hypothesized that
the resulting platelet aggregation may assist in the implantation of metastases, and perhaps
even in protection from the host immune system.
CHEMOTHERAPY AND THROMBOSIS

Chemotherapy itself can increase the risk of thromboembolic disease. This has been best studied
in breast cancer where tamoxifen and cytotoxic chemotherapy both appear independently to
increase the risk for venous thrombosis [5-10]. The increase in risk appears to be greatest in
postmenopausal patients. An increased risk for arterial thrombosis has also been observed
[7, 11]. It should be noted, however, that many of the chemotherapy regimens in these studies
contained more drugs (up to seven) than are typically present in today's one, two, or three-drug
regimens.
It is reasonable to ask if there is an effective strategy to prevent thrombosis in breast cancer
patients receiving chemotherapy. Perhaps the best data are from a British study in 1994 [12].
Three hundred and eleven metastatic breast cancer patients receiving first or second-line
chemotherapy were enrolled within four weeks of initiating the chemotherapy. One hundred and
fifty-nine received a sham pill and sham internationalized normalized ratio (INR) in a double-
blinded fashion. One hundred and fifty-two received low-dose warfarin at 1 mg daily for six
weeks; after six weeks, the warfarin dose was adjusted to attain an INR between 1.3 and 1.9.
Patients were screened with an ultrasound if they had symptoms of venous thrombosis. A positive
ultrasound finding was confirmed by venography. There was a statistically significant difference in
thrombotic events between these groups. In the placebo arm, there were six deep venous
thromboses (DVTs) and one pulmonary embolus (PE); in the warfarin arm, there was one PE.
There was no difference in bleeding events between the arms; there were two major bleeding
events, one fatal, in the placebo arm and a single nonfatal bleeding event in the warfarin arm.
There was no difference in survival between the groups.
Because of concern that the benefit in preventing nonfatal thromboembolic events did not justify
the expense and labor involved in giving low-dose warfarin, a follow-up study in 1995 estimated
that low-dose warfarin would be not only cost-effective, but also cost-saving [13]. The amount
saved was estimated to be 2,443 Canadian dollars per 100 patients. Based on this study, low-
dose warfarin may be an option for patients who are receiving breast cancer chemotherapy and
do not have a contraindication. However, such a practice has not been widely adopted in the
USA. It is important to see if a simpler regimen of warfarin at 1 mg per day would also be
effective. Such a regimen would certainly be even cheaper and more convenient and could be
easily applied to patients receiving chemotherapy for other cancers.
Another drug that is commonly associated with derangement of coagulation is L-asparaginase,
used almost exclusively in the treatment of acute lymphoblastic leukemia. This drug effects the
depletion of L-asparagine, which in turn inhibits production of many plasma proteins, including
fibrinogen, plasminogen, antithrombin III, protein C and protein S. Thrombotic complications often
manifest as stroke or seizures, arise in 1%-14% of patients treated [14]. Unfortunately, since
hemorrhage is also a potential complication of this drug, prophylactic anticoagulation is not
employed. Adminstration of antithrombin III (AT III) has been shown to correct laboratory
abnormalities, but has not been shown to affect clinical outcomes. As depleted fibrinogen can
lead to bleeding, many physicians follow fibrinogen levels on patients treated with L-
asparaginase and transfuse cryoglobulin if levels fall too low. Recent evidence indicates that
patients with inherited defects in coagulation, such as Factor V Leiden AT III deficiency, are at
significantly increased risk of thrombosis due to L-asparaginase [15].
INDWELLING CENTRAL LINES AND VENOUS THROMBOSIS

Patients with cancer often receive central venous access catheters for administering
chemotherapy, blood products, fluids, medicines, and also for drawing blood for diagnostic tests.
There is good evidence that these create an increased risk for DVT of the ipsilateral upper
extremity. Although rates of symptomatic thrombosis are lower, clots have been venographically
documented in 38%-62% of venous access devices [16, 17]. Several factors have been identified
that may influence the risk of thrombosis. Left subclavian lines are at higher risk than the right
[18]. Polyvinyl chloride or polyethylene lines are more likely to lead to PE than are polyurethane
or siliconized lines [19]. A triple lumen catheter may be more thrombogenic than a double lumen.
A line requiring two punctures for insertion was more thrombogenic than those placed with a
single puncture. Finally, the type of fluid infused through the line may affect the thrombosis rate:
infusion of total parenteral nutrition fluid has been found to be more thrombogenic than infusion
of crystalloid fluid [20].
Upper extremity DVTs (UEDVT) can indeed give rise to PE. Asymptomatic cancer patients with
indwelling central lines were screened with ultrasound to look for UEDVTs. In those with positive
results, a nuclear ventilation/perfusion (V/Q) scan was then obtained regardless of whether the
patient had symptoms of PE. Of 86 patients with UEDVT, 13 (15%) were considered to have PE by
a high-probability V/Q scan [19]. Four of the 13 had signs or symptoms of PE. Of note, two of the
13 ultimately died of massive PE despite anticoagulation with heparin. In a study of patients (only
a minority of whom had cancer) presenting with symptomatic UEDVTs, PE was found in 36% (8 of
22), based either on a high-probability lung ventilation/perfusion scan or pulmonary angiography
[21]. Other investigators found that the relative risk was 3.4 when PE from catheter-related
UEDVT was compared with other causes of UEDVT [22].
UEDVTs associated with indwelling catheters are therefore common and carry with them a
significant risk for PE as well as the local morbidity associated with the thrombosis. Additionally,
such thrombosis may lead to other costly procedures to clear or replace the central line. Are
these DVTs preventable? In a randomized, prospective trial, Bern and coworkers demonstrated
that 1 mg per day of warfarin is a safe and effective prophylaxis against thrombosis in cancer
patients with central venous catheters [16]. Consecutive cancer patients receiving portacaths
placed by surgeons were enrolled. If they had no contraindications to anticoagulation, they were
randomized to receive either 1 mg per day of warfarin or no drug. Warfarin was initiated three
days prior to the placement of the portacath. The distribution of cancers in both arms was similar.
In those receiving warfarin, four out of 40 (9.5%) had thrombi; in the 40 patients who did not
receive warfarin, 15 out of 40 (37.5%) had thrombi (p < 0.001). Similar results have been
obtained in a study of British cancer patients receiving central venous lines [23]. A LMWH
(dalteparin, Fragmin) also demonstrated benefit in preventing central catheter-associated
thrombosis in cancer patients in a randomized, prospective trial [17].
Taken together, these studies show: A) UEDVT is common in cancer patients with indwelling lines;
B) pulmonary embolus is a significant risk of these DVTs, and C) 1 mg per day of warfarin is a
safe, cheap, and effective way to reduce the risk of UEDVT. Anticoagulation of indwelling central
lines should be considered in all cancer patients who do not have a specific contraindication.
TREATMENT OF THROMBOEMBOLIC DISEASE IN CANCER PATIENTS

Should the treatment of thromboembolic disease be any different for cancer patients than it is for
noncancer patients? One concern is that cancer patients who are anticoagulated might have an
increased risk of hemorrhage due to tumor, thrombocytopenia, or concurrent coagulation
disorders. Retrospective studies do not provide a clear answer. Some did not find coexistent
malignancy to be a risk factor for major hemorrhage during anticoagulation [24, 25] while some
did [26]. In a prospective cohort study, cancer patients who received warfarin for the treatment
of DVT and/or PE were no more likely than controls to have hemorrhage [27, 28]. A second
concern is that compared to patients with nonmalignant disease, cancer patients are more likely
to have a recurrence on warfarin or after warfarin is stopped [29-32]. Some authors suggest that
instead of anticoagulating for 6-24 weeks for a first DVT, cancer patients need to be
anticoagulated until there is no evidence of disease. Therefore, in treating a cancer patient with
thromboembolic disease, the oncologist faces a situation where there may be a slightly greater
risk of hemorrhage, but also a greater risk of recurrent thrombosis. In most nonmoribund cancer
patients, anticoagulation for thromboembolic disease is usually begun unless potential
contraindications exist.
Special conditions may be present which might present a relative or absolute contraindication to
anticoagulation. Oncologists are often confronted with a patient with a brain tumor who requires
anticoagulation for a DVT. There has been a long-standing reluctance to treat these patients with
therapeutic anticoagulation due to the fear of intracranial hemorrhage. An alternative therapy
that has been used is an IVC filter. There are no good prospective randomized studies to evaluate
the relative safety and efficacy of IVC filter placement versus anticoagulation in this setting. A
retrospective series can give us only rough estimates of efficacy and complication rates. The
chance of recurrent PE after IVC filter placement is in the 3%-20% range [33, 34] and the rate of
local thrombotic complication (IVC clot, DVT progression, recurrent DVT, or postphlebitic
syndrome) ranges from 5%-57% depending on the series [33-37]. For comparison, the risk of
thromboembolic events in similar patients treated with anticoagulants was 5%-20% [33, 36, 38].
The risk of intracerebral hemorrhage, the main concern of most clinicians in anticoagulating
patients with brain metastases, was 0%-5% [33, 35, 38, 39]. In general, bleeding complications
occurred in the setting of supratherapeutic anticoagulation. In summary, there are not enough
data to make a definitive recommendation for therapy in the setting of a patient with both
thromboembolic disease and brain metastasis. However, anticoagulation is a noninvasive,
inexpensive, reversible intervention that has the advantage of treating the underlying clotting
diathesis present in many of these patients. Although they reduce the PE risk, IVC filters do not
correct the underlying coagulation defects and may themselves undergo thrombosis with its
consequent lower extremity morbidity. This latter complication makes IVC filters an unattractive
but sometimes unavoidable option.
Because they are highly vascular, renal cell and melanoma metastases to the brain are held in
special regard by many clinicians, as these can have spontaneous hemorrhage. However, no
trials have studied their risk of bleeding during anticoagulation. Until further safety information is
available, anticoagulating patients with these metastases to the brain should be avoided.
HEPARIN VERSUS WARFARIN

Does long-term heparin therapy afford any advantage over warfarin in the treatment of
thromboembolic disease in cancer patients? No prospective randomized trial has compared
heparin with warfarin for the treatment of thromboembolic disease. However, in an extensive
retrospective analysis of patients with Trousseau's syndrome, a condition in which recurrent,
migratory thromboembolism is found in patients with adenocarcinoma, it was found that 19% of
patients benefited from warfarin therapy while 65% benefited from heparin therapy [40]. In a
more recent retrospective review, cancer patients treated with warfarin for their first venous
thromboembolism (VTE) had a recurrence rate of 22% within three months in contrast to those
treated with heparin (standard or low molecular weight) who had a recurrence rate of 7% [ 32].
The clinical experience of many practicing oncologists also supports this impression. There are
also anecdotal reports of patients with Trousseau's syndrome responding well to LMWH, which
allows for their convenient outpatient treatment.
On a biochemical level, heparin has several antithrombotic mechanisms that warfarin lacks.
Heparin can release tissue plasminogen activator and tissue factor pathway inhibitor (TFPI) from
endothelial binding sites and increase their circulating levels. TFPI is a tri-domain protein that
binds to the complex formed by tissue factor, factor VIIa, and factor X and suppresses the
generation of Xa by tissue factor [41]. Heparin (both unfractionated and low molecular weight),
but not warfarin, can increase the circulating amount of this protein and also increase its specific
activity. Since tissue factor is an important stimulus to coagulation in cancer patients, activation
of TFPI by heparin may contribute greatly to the overall antithrombotic effect of heparin.
Despite the impressive biochemical and retrospective clinical data already mentioned, there are
no prospective clinical studies that address whether heparin is better than warfarin in the
treatment of the first thromboembolic event in the cancer patient. Given the availability of LMWH
and the added incentive of outpatient treatment for many of these VTE, a study comparing three
to six months of warfarin versus three to six months of LMWH in cancer patients with VTE should
have high priority.
Recurrent VTE in cancer patients on anticoagulant therapy is not uncommon.Prandoni [29]

showed that recurrent VTE in oncology patients was 1.72 times more likely than for patients
without cancer. There are no clear clinical data to guide the response to this situation. If a cancer
patient has recurrent thromboembolism while on therapeutic doses of warfarin, the oncologist
has three choices: A) continue warfarin at a higher target INR; B) switch to continuous
intravenous unfractionated heparin or intermittent subcutaneous LWMH, or C) put in an IVC filter.
LMWH
A recent addition to the anticoagulant armamentarium in the USA is LMWH. LMWH is prepared by
chemical or enzymatic degradation of unfractionated heparin. Three LMWH preparations are
currently available in the USA: enoxaparin (Lovenox ), dalteparin (Fragmin), and ardeparin
(Normiflo). Compared with traditional unfractionated heparin, LMWH has a narrower range of
molecular weight distribution; unfractionated heparin contains molecules in the 5,000-30,000
dalton range, compared with LMWH molecules that are clustered in the 2,000-8,000 dalton range.
LMWH is readily and consistently absorbed from a subcutaneous administration and has low
serum protein and cellular binding which produces a bioavailability of over 85% compared with
15% for unfractionated heparin. LMWH is primarily excreted by the kidney with an elimination
half-life of 3.5-4.5 h compared with 1.5 h for unfractionated heparin. The high bioavailability and
longer half-life allow for twice-a-day or even daily dosing schedules based on weight to maintain
therapeutic anticoagulation. Standard measurements of anticoagulation such as the partial
thromboplastin time (PTT) are not usually prolonged and need not be regularly followed. If one
does wish to evaluate the extent of anticoagulation with LMWH, an assay measuring the level of
inhibition of factor Xa activation must be obtained. A level between 0.4-0.7 is generally
considered therapeutic, but must be measured against a standard curve constructed using that
specific LMWH.
There are now many reports which have demonstrated that LMWH is at least as safe, effective,
and cost-effective as unfractionated heparin in treating deep venous thrombosis and even
nonmassive PE in the general population [42-46]. In a prospective trial that randomized patients
to unfractionated heparin or enoxaparin, analysis of the subgroup of patients who had cancer
demonstrated that, as in the overall group, enoxaparin given twice a day was as effective as
unfractionated heparin in the prevention of recurrent venous thromboembolism [47]. A
retrospective analysis of the cancer patients participating in a number of trials comparing the
safety and efficacy of unfractionated heparin and LMWH has also demonstrated a trend toward a
mortality benefit independent of bleeding of recurrent thromboembolic disease in those cancer
patients receiving LMWH [48, 49]. While intriguing, this finding must be validated in a prospective
fashion to affect meaningfully the management of thromboembolic disease in cancer patients. In
any case, LMWH offers the oncologist the opportunity to treat the majority of uncomplicated DVT
cases safely, effectively, and cost-effectively at home. In the future, home LMWH treatment may
also extend to the cancer patient with uncomplicated PE as well.
ANTICOAGULANTS AS ANTICANCER THERAPY

A final issue is whether anticoagulation provides any benefit in treating the underlying malignant
disease. In vitro studies show that warfarin, heparin, fibrinolytics, and even antiplatelet agents
inhibit tumor growth and metastasis [50]. Thrombin and fibrin have been found to contribute to
the adhesion and implantation of tumor cells, so antifibrin or antithrombin agents might exert
their effects by inhibiting this implantation. Furthermore, heparin has been found to inhibit
vascular endothelial growth factor, tissue factor, and platelet-activating factor, each of which
may contribute to angiogenesis. It has also been hypothesized that fibrin deposits around tumors
may offer protection against immune surveillance, so that anticoagulants might aid in immune
clearance of small deposits of cancer cells. Although there are many hypotheses for in vitro
antitumor activity of anticoagulants, the practical question is whether anticoagulants affect
cancer mortality in a clinical setting.
The use of anticoagulants as an adjunct to cytotoxic chemotherapy has been studied in patients
with small-cell lung cancer (SCLC). In a prospective randomized trial centered in a VA hospital,
patients were given radiation therapy and chemotherapy for SCLC, and randomized to receive
either warfarin or no anticoagulant therapy [51, 52]. The warfarin dose was targeted to give a
prothrombin time twice that of control. Patients with either extensive or limited-stage cancers
were enrolled. There was a statistically significant prolongation of survival demonstrated for
those patients who received warfarin (median survival 49.5 weeks) compared with those who did
not (median survival 23.0 weeks). Response rate was not significantly affected, but survival and
time to relapse were. A follow-up study looking at warfarin as an adjunct in the treatment of
prostate, colorectal, head and neck, and non-SCLC showed no survival benefit in these relatively
chemotherapy-insensitive tumors [52].
In 1989, Cancer and Leukemia Group B (CALGB) described a trial randomizing patients with
extensive stage SCLC to one of three arms [53]. Arm 1 received MACC (methotrexate,
adriamycin, cytoxan, CCNU); arm 2 received MACC plus warfarin (PT 1.5-2 times control); arm 3
received alternating MEPH (mitomycin, etoposide, cisplatin, hexamethylmelamine) and MACC.
There was a statistically insignificant (p = 0.14) overall survival advantage for arm 2 with similar
advantageous trends for the warfarin arm for partial response, complete response, and failure-
free survival (FFS). There was a statistically significant difference (p = 0.027) in overall response
rate of 67% versus 51% favoring the warfarin arm.
In 1997, the CALGB published a study of warfarin added to a combination of ACE (adriamycin,
cytoxan, and etoposide) and PCE (cisplatin, cytoxan, and etoposide) in the treatment of limited-
stage SCLC patients [54]. The warfarin arm showed a survival benefit that did not reach
statistical significance (p = 0.12). The survival curve plateaus were not, however,
superimposable. Responders to chemotherapy who received warfarin had greater than twice the
survival time (33 month versus 13.75 month, p = 0.05).
Another study examined the utility of subcutaneous unfractionated heparin as an adjunct to
chemotherapy in the treatment of extensive and limited-stage SCLC. The heparin was
administered in two or three daily subcutaneous doses starting at 500 U/kg/day, and adjusted to
keep the PTT at two to three times the control value. Heparin was given for five weeks. The
heparin-treated group experienced an increase in complete response (37% versus 23%, p =
0.004) as well as an increased median survival (317 versus 261 d, p = 0.01) [55]. In this study as
in the others, anticoagulant was administered only near the time when chemotherapy was given.
Despite the relatively short period of anticoagulation, benefits of improved survival were realized
months to years later. This is analogous to the situation in venous thromboembolism, where the
benefits of early short-term heparin therapy can be realized as a decreased rethrombosis rate
many months later.
These results, obtained in a prospective, randomized fashion, suggest that there may be some
survival benefit to anticoagulation in the treatment of SCLC. The effect is probably not large,
judging by the difficulty in reaching statistical significance in the CALGB studies, but there does
appear to be a consistent small benefit. The administration of low levels of anticoagulant is, in
general, much less toxic and expensive than the addition of another chemotherapy agent, or the
use of high-dose chemotherapy with stem cell support. While intriguing, however, the data are
not sufficiently convincing to alter current clinical practice. With the introduction of the LWMH,
there is renewed interest in determining whether anticoagulation may improve survival in
oncology patients.
CONCLUSIONS
Thromboembolic disease is a frustrating and common complication of malignancy. The

biochemical basis of the thrombophilia of malignancy is poorly understood and studies to unravel
its cause and relationship to the underlying malignancy are sorely needed. Current treatment for
DVT and PE in cancer patients includes heparin, warfarin, and sometimes IVC filters. The last
option is usually reserved for those patients who are not candidates for anticoagulation. Since
heparin provides some additional antithrombotic effects that warfarin lacks, it will be important to
study whether LMWH may be better than warfarin in the long-term treatment of venous
thromboembolism. Furthermore, there is suggestive evidence that warfarin and heparin may
actually enhance cancer survival rates; prospective studies are currently underway to address
this issue. The introduction of LMWH should greatly improve the convenience of anticoagulation
therapy for oncology patients.
ACKNOWLEDGMENTS
This work was supported by NIH grants CA09172-24 (A.L.), HL54838 (D.K.), and HL61222 (D.K.).
AlphaMed Press
Previous Section
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3. Introduction
4. Thrombophilia of Malignancy
5. Chemotherapy and Thrombosis
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7. Treatment of Thromboembolic Disease in Cancer Patients
8. Heparin versus Warfarin
9. LMWH
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Clinical Articles
Acta Neurochirurgica
September 1990, Volume 102, Issue 3, pp 103-107
First online:
Haemostatic abnormalities in brain tumours

V. P. Singh
, Dinesh Jain
, R. Mohan
, R. Bhatia
, M. Bhargava
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Summary
The coagulation profile of 25 patients with brain tumours was studied preoperatively,
intraoperatively and postoperatively. Ten patients had abnormal coagulation status
preoperatively. Surgical intervention led to either an alteration of preexisting abnormality or
appearance of new coagulation abnormality. Disseminated intravascular coagulation and
fibrinolysis occurred with equal frequency in patients with meningiomas and gliomas. The
alterations as a result of surgery were transient and compensated rapidly.
Keywords
Gliomas meningiomas haemostatic abnormality fibrinolysis disseminated intravascular
coagulation
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References (23)
About this Article
Title
Haemostatic abnormalities in brain tumours
Journal
Acta Neurochirurgica
Volume 102, Issue 3-4 , pp 103-107
Cover Date
1990-09
DOI
10.1007/BF01405422
Print ISSN
0001-6268
Online ISSN
0942-0940
Publisher
Springer-Verlag
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Topics
Interventional Radiology
Neuroradiology
Neurology
Neurosurgery
Surgical Orthopedics
Minimally Invasive Surgery
Keywords
Gliomas
meningiomas
haemostatic abnormality
fibrinolysis
disseminated intravascular coagulation
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Authors
V. P. Singh (1)
Dinesh Jain (2)
R. Mohan (3)
R. Bhatia (1)
M. Bhargava (2)
Author Affiliations
1. Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi,
India
2. Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
3. Department of Surgery, All India Institute of Medical Sciences, New Delhi, India
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Neurosurgery:
May 1983
Brief communications: PDF Only
Chronic Disseminated Intravascular Coagulation and

Metastatic Brain Tumor: A Case Report and Review of the
Literature.
Sawaya, Raymond M.D.; Donlon, Jerome A. M.D., Ph.D.
Abstract
: A patient who had a primary lung carcinoma in remission but had a solitary metastatic lesion to the cerebellum was
referred to the neurosurgery service. He was noted to be thrombocytopenic, and further hemostatic evaluation
revealed chronic disseminated intravascular coagulation. He was treated with heparin and platelet transfusions.
Although the fibrinogen levels improved, the thrombocytopenia persisted. Four weeks after admission, repeat chest
x-ray films and tomograms indicated progressing metastatic nodules. A review of the literature reveals a variety of
hemostatic defects associated with tumor metastatic to the brain. This current case indicates the need for careful
hemostatic evaluation in all patients with brain lesions. (Neurosurgery 12:580-584, 1983)
Copyright (C) by the Congress of Neurological Surgeons
Neurosurgery:
May 1983
Chronic Disseminated Intravascular Coagulation and

Metastatic Brain Tumor: A Case Report and Review of the
Literature.
Sawaya, Raymond M.D.; Donlon, Jerome A. M.D., Ph.D.
Abstract
: A patient who had a primary lung carcinoma in remission but had a solitary metastatic lesion to the cerebellum was
referred to the neurosurgery service. He was noted to be thrombocytopenic, and further hemostatic evaluation
revealed chronic disseminated intravascular coagulation. He was treated with heparin and platelet transfusions.
Although the fibrinogen levels improved, the thrombocytopenia persisted. Four weeks after admission, repeat chest
x-ray films and tomograms indicated progressing metastatic nodules. A review of the literature reveals a variety of
hemostatic defects associated with tumor metastatic to the brain. This current case indicates the need for careful
hemostatic evaluation in all patients with brain lesions. (Neurosurgery 12:580-584, 1983)
Copyright (C) by the Congress of Neurological Surgeons
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Am J Obstet Gynecol. 1996 Sep;175(3 Pt 2):778-83.

Screening and diagnosis of coagulation disorders.
Lusher JM1.
Author information
Abstract
After clinical assessment, pertinent history, and family history, the
clinician often has a good idea concerning the cause of a patient's
bleeding. The most appropriate laboratory tests can then be
ordered. Routine screening tests include a complete blood cell
count, platelet count, and evaluation of a peripheral blood sample, a
prothrombin time, and an activated partial thromboplastin time.
Thrombocytopenia may result from idiopathic thrombocytopenic
purpura, disseminated intravascular coagulation, or, less commonly,
acute leukemia, aplastic anemia, thrombotic thrombocytopenic
purpura, or a particular drug that a patient is taking. Again, the
patient's history, physical findings, and evaluation of a well-prepared
peripheral blood smear will be helpful in determining the cause of
the patient's thrombocytopenia. An isolated prolongation of the
activated partial thromboplastin time may result from low levels of
factors VIII, IX, or XI. A slightly prolonged activated partial
thromboplastin time and a moderate decrease in factor VIII may
reflect von Willebrand disease or the "carrier" state for hemophilia A.
In women a greatly prolonged activated partial thromboplastin time
and very low levels of factor VIII (< 3%) most often result from an
acquired factor VIII inhibitor (autoantibody against factor VIII) or
from severe (type III) von Willebrand disease. If von Willebrand
disease is suspected (because of menorrhagia with or without other
mucous membrane bleeding, a positive family history, and a
prolonged activated partial thromboplastin time), more specific
laboratory tests for this disease should be done. These include
assays of factor VIII, von Willebrand factor antigen, von Willebrand
factor activity (measured by the ristocetin cofactor assay), and
template bleeding time. In von Willebrand disease the defect is in
von Willebrand factor. The affected individual may have subnormal
levels of structurally and functionally normal von Willebrand factor
(this is called "classic" or type I von Willebrand disease) or may
produce von Willebrand factor that is structurally and functionally
abnormal (von Willebrand disease type 2). Individuals who inherit a
gene for von Willebrand disease from both parents have severe
(type 3) von Willebrand disease and will have extremely low levels
(< 3%) of von Willebrand factor and factor VIII and will have a very
prolonged bleeding time. In most populations type I disease is the
most common form, whereas type 3 is the least commonly
encountered form. It should be noted that levels of von Willebrand
factor can be influenced by the patient's blood type (persons who
have blood type AB have 60% to 70% higher levels than do persons
who have blood type O) and can be elevated during pregnancy,
stress, and hyperthyroidism. The two major functions of von
Willebrand factor are to serve as a "bridge" between platelets and
injury sites in blood vessel walls and to protect circulating factor VIII
from rapid proteolytic degradation. Thus, if a patient has either too
little or functionally abnormal von Willebrand factor, the bleeding
time will be prolonged and factor VIII will be decreased (because it
is not being protected by von Willebrand factor). It should be
determined which type of von Willebrand disease a particular
patient has because treatment depends on type. Multimeric analysis
of von Willebrand factor can be done with use of sodium dodecyl
sulfate gels, radiolabeled antibody to von Willebrand's factor, and
autoradiography. This will allow visualization of the multimeric
structure of von Willebrand factor. In type I disease all bands are
present, whereas in the type 2 variants 2A and 2B no high-
molecular-weight multimers are seen. Desmopressin acetate (which
is available in parenteral form for intravenous use and in a highly
concentrated intranasal spray formulation) is the treatment of choice
for classic type I disease. The drug effects a rapid release of von
Willebrand factor from endothelial cell stor
PMID:
8828561
[PubMed - indexed for MEDLINE]
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Perioper Med (Lond)

Perioper Med (Lond). 2015; 4: 9.

Effects of different colloid infusions on

ADP adenosine diphosphate

aPTT activated thromboplastin time

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MCF maximal clot formation

ROTEM rotational thromboelastometry

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