Thrombosis Research 134 (2014) 234–239

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Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres

Regular Article

Weight-adjusted LMWH Prophylaxis Provides More Effective Thrombin

Inhibition in Morbidly Obese Pregnant Women
Siti K. Ismail a,⁎, Lucy Norris b, Susan O’Shea c, John R. Higgins a
a
Anu Research Centre, Department of Obstetrics and Gynaecology, University College Cork, Cork University Maternity Hospital, Ireland
b
Coagulation Research Laboratory, Department of Obstetrics and Gynaecology, Trinity Centre for Health Sciences, St. James' Hospital, Dublin, Ireland
c
Comprehensive Coagulation Centre, Department of Haematology, Cork University, Ireland

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Low molecular weight heparin (LMWH) prophylaxis has been recommended for morbidly obese
Received 10 December 2013 pregnant women (N 40 kg/m2). There is very little data on the anticoagulant effects of LMWH in this group. We
Received in revised form 5 April 2014 investigated two different dosing regimens; fixed dose and weight-adjusted dose on the anticoagulant effects
Accepted 7 April 2014 of the LMWH tinzaparin used for thromboprophylaxis in obese pregnant women.
Available online 13 April 2014
Materials and Methods: Twenty morbidly obese pregnant women were started on a fixed dose of tinzaparin
(4,500 iu/day) at 32 weeks gestation and then changed to a weight-adjusted dose (75iu/kg/day) for the
Keywords:
Obesity
remainder of their pregnancy. Four-hour post LMWH, venous bloods were taken after each initial dose and
Thrombin Generation repeated every two weeks until delivery. Twenty normal weight women who did not receive LMWH at the
LMWH same gestation were used as controls.
Pregnancy Results: Prior to LMWH prophylaxis, tissue factor pathway inhibitor (TFPI) levels in the obese group at 32 weeks
Thromboprophylaxis were significantly lower (p b 0.001) and endogenous thrombin potential (ETP) and peak thrombin levels in
obese group were significantly higher, compared with controls (p b 0.0001; p b 0.001).
There was no significant difference between ETP levels before and after fixed LMWH. However, ETP levels were
significantly lower post weight-adjusted dose compared with post fixed dose. There was a significant effect
of LMWH on TFPI levels, (p b 0.0001). ETP correlated positively with total body weight prior to LMWH (r =
0.631) (p b 0.05) and at fixed dose (r = 0.578) (p b 0.05).
Conclusion: Morbidly obese pregnant women have increased thrombin generation and reduced natural anti-
coagulant in third trimester. This prothrombotic state was more effectively attenuated by weight-adjusted
than fixed LMWH doses.
© 2014 Published by Elsevier Ltd.

Introduction In obese pregnant women, recommendations for low molecular

Obesity is a significant risk factor for thrombosis in pregnancy [1].
A triennium report highlighted that more than a third (38%) of
women who died from pulmonary embolism were clinically obese
(BMI N 35 kg/m2) [2]. The obese pregnant woman is particularly at
risk of thrombosis in late pregnancy [2]. According to the RIETE Registry,
most (43%) venous thromboembolism (VTE) in pregnancy occurs in the
third trimester [3]. A recent population-based cohort study reported the
rate of VTE during the third trimester was six times higher than any
time outside pregnancy [4].
⁎ Corresponding author. Tel.: +353 21 4205038; fax: +353 21 4205025.
E-mail address: k.ismail@ucc.ie (S.K. Ismail).
weight heparin (LMWH) are based on expert opinion [5]. There is
very limited data on the anticoagulant effects of LMWH in morbidly
obese pregnant women. In the non-pregnant patient, studies using
anti-Xa have shown that individualised weight-based therapy gener-
ates anti-Xa levels in the required therapeutic range and data suggested
that dosing based on body weight alone, independent of the presence of
obesity, was appropriate and the dose should not be capped because of
body weight [6,7].
We hypothesised that weight-adjusted LMWH dosage would pro-
vide more effective thrombin inhibition in morbidly obese pregnant
women than a fixed dose regimen. The specific aims of this study
were to investigate i) the different thrombin generation profiles in
morbidly obese and normal weight pregnant women and ii) the effects
of two different dosing regimens on thrombin generation; fixed
dose versus weight-adjusted dose of the LMWH tinzaparin used for
thromboprophylaxis in morbidly obese pregnant women.

http://dx.doi.org/10.1016/j.thromres.2014.04.006
0049-3848/© 2014 Published by Elsevier Ltd.

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 S.K. Ismail et al. / Thrombosis Research 134 (2014) 234–239 235

Materials and methods
Patients and study design
This is a cohort study in which 1) coagulation parameters of obese
pregnant women were compared to normal weight pregnant women
and 2) the effects of two LMWH prohlylactic doses were compared
within the obese pregnant women. Forty women having given full in-
formed written consent were recruited for this study at Cork University
Maternity Hospital. Twenty morbidly obese pregnant women with BMI
≥40 kg/m2 (Obese Group) and twenty normal weight (defined by BMI
b 25 kg/m2) pregnant women (Normal Weight Group) were recruited
at 30 weeks gestation. Participants were matched for age and parity.
All women had a baseline bio profile done to check for renal and liver
dysfunction prior to inclusion in the study. All women recruited were
Caucasian, non-smokers, had singleton pregnancies, had normal creati-
nine clearance, normal liver function tests, no other contraindications
for LMWH and had no personal or family history of VTE or known
thrombophilia. Ethical approval was obtained from the Cork Teaching
Hospital Ethics Committee. Venous blood was taken from each
woman at 30 weeks gestation.
At 32 weeks gestation, the morbidly obese women were started on a
fixed dose of tinzaparin (4,500 iu/day). These patients were crossed
over after two doses to a weight-adjusted dose (75iu/kg/day) after
48 hour wash-out period and four-hour post dose blood samples were
taken. In the morbidly obese group, LMWH dose was based on their
current pregnancy weight and they continued on this weight-adjusted
dose throughout the remainder of their pregnancy (Fig. 1). The normal
weight pregnant women were not on any LMWH. Anti-Xa monitoring
(Hyphen BioMed, France) performed in the haematology laboratory,
Cork University Hospital was used to check peak levels at 4 hours post
LMWH administration. Target prophylactic anti-Xa range was defined
as 0.1-0.5u/ml for 4,500iu per day. For patients with anti-Xa levels out-
side the target range, dose adjustments were discussed with Consultant

Fig. 1. Flowchart of Venous Blood Sampling Time Points and LMWH administration.

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236 S.K. Ismail et al. / Thrombosis Research 134 (2014) 234–239

Haematologist. Patients continued with the weight-adjusted dose until Table 1

delivery. Patients were advised to withhold LMWH 12 hours prior to Demographic Data. Values presented as mean (±SD). *Body Mass Index (BMI). NS (Non-
significant). **Creatinine clearance was calculated using adjusted body weight (ABW).
planned delivery or if symptoms or signs of labour are present. For the Calculated creatinine clearance and tinzaparin dose only applicable to obese group.
normal weight group, venous bloods were taken at 30 and 32 weeks
of pregnancy. Obese Group Normal BMI p-value
n = 20 Groupn = 20
Sample size calculation was based on anti-Xa data. A previous study
in pregnant women showed that 75 iu/kg will give peak anti-Xa levels Age (years) 32.3 (±4.7) 30.0 (±5.4) NS
Parity 1.2 (±0.4) 1.0(±0.8) NS
of 0.25 +/− 0.10(SD) iu/ml [8]. In order to detect whether the fixed
Weight (kg) 138.9(±18.8) 59.9 (±7.3) p b 0.0001
doses will yield anti-Xa levels lower than 0.1 iu/ml, a sample size of at *BMI (kg/m2) 48.2(±6.7) 22.9(±2.3) p b 0.0001
least fourteen women in each group was required. Therefore, twenty Serum Creatinine (μmol/L) 43.0(±2.3) 42.0(±3.4) NS
patients were recruited in each group. **Calculated Creatinine Clearance 143.2 (±16.7)
(ml/min)
Mean Tinzaparin Dose (iu) 10,420 (±1031)
Blood sampling

At each time point, venous blood (4.5mls) was taken from the ante-
cubital fossa with minimum venous stasis using 3.13% sodium citrate as
anticoagulant. Samples were centrifuged at 4˚C for 20 minutes at 2000 g.
The resulting platelet poor plasma was carefully removed, aliquoted
into cryotubes, snap frozen and stored in cardboard cryoboxes at
− 80 ̊C until assay. All samples were processed and stored within
1 hour of phlebotomy.
Laboratory methods
In the obese group, anti-Xa, Tissue Factor Pathway Inhibitor (TFPI),
Thrombin Antithrombin complex (TAT) and endogenous thrombin po-
tential (ETP) were measured using calibrated automated thrombogram
(CAT) in each sample. In the control group, ETP, TFPI and TAT were
measured. All assays were performed in large batches to minimise
intra-assay variation. Anti-Xa activity was measured using chromogenic
substrate assay with tinzaparin used as standard (Hyphen BioMed,
France)[9]. Plasma levels of TAT (Enzygnost® TAT Micro, Siemens,
Marburg, Germany) and TFPI (Quantikine®, R&D Systems, Minneapolis,
USA) were measured with commercially available enzyme linked
immunosorbent assays (ELISA).
Endogenous thrombin potential (Thrombinoscope™, Synapse BV,
Maastricht, Netherlands), was measured as previously described [10].
Briefly, 80 μls of plasma was incubated with 20μls of platelet poor
plasma reagent containing 5pM of Tissue factor. Thrombin generation
was initiated by addition of fluorogenic thrombin substrate (Fluca®
Thrombinoscope™, Maastricht, Netherlands) and quantified by throm-
bin calibration standard. Fluorescence was measured at 20 second
intervals for 60 minutes or until thrombin generation was completed.
Peak thrombin production and area under the thrombin generation
curve (ETP) was determined and reported for each sample.
All patients maintained normal renal and liver function throughout
this study.
There were no patients in the obese group who had anti-Xa levels
significantly outside the target range (0.1-0.5 iu/ml) that the hae-
matologist or obstetrician felt warranted, dose adjustment. None of
the women in either group of this study developed VTE, abnormal
bleeding or poor obstetric outcome. Two patients in the obese group
reported bruising while on weight-adjusted LMWH, which resolved
with rotating injection sites. All patients in this study delivered healthy
live newborns. Twelve (60%) of the patients in the obese group had
caesarean delivery compared with five (25%) in the normal weight group.
Coagulation parameters at 30 weeks gestation in the morbidly obese and
normal weight pregnant women
TFPI and TAT levels were measured in the obese group (prior to
LMWH administration) and were compared with those in a group
of control women of normal weight. TFPI levels in the obese group
were significantly lower than the control group at 30 weeks gesta-
tion (p b 0.0005) (Table 2). TAT levels in the obese group were
higher than control group at 30 weeks but this did not reach statisti-
cal significance (p N 0.05). ETP (Table 2) and Peak thrombin levels in
the obese group were significantly higher compared with control group
at 30 weeks (p b 0.0005; p b 0.01 respectively). Similarly lag time
and time to peak was significantly shorter in the obese group obese
group compared with that in a group of control women of normal weight
(p b 0.0005).
Effects of LMWH on coagulation markers in the morbidly obese pregnant
women in third trimester

Statistical analysis TFPI

Data are expressed as mean ± standard deviation (SD). Distribution
of each parameter was checked for normality using Normal Probability
Plot or formal tests such as the Kolmogorov-Smirnov test and the
Shapiro-Wilks test. Paired and unpaired t tests were used to compare
differences between means. Pearson product–moment correlation coef-
ficient was used to measure the strength of linear dependence between
two variables. In all circumstances, a p value of b0.05 was considered
statistically significant.
Results
Within the obese group, paired t test showed that TFPI levels
were increased significantly post fixed LMWH dose (4500iu tinzaparin)
(p b 0.001) and weight-adjusted dose (p b 0.0001) (Table 3) compared
Table 2
Coagulation Parameters in Morbidly Obese and Normal Weight Pregnant Women at
32 Weeks Gestation. All parameters were measured at 30 weeks in the obese group
(BMI N 40 kg/m2) prior to LMWH administration (n = 20) and compared with those in
a group of normal weight pregnant women (n = 20). ETP = Endogenous thrombin
potential, TAT = Thrombin antithrombin complex, TFPI = Tissue factor pathway
inhibitor. Values expressed as mean (±SD). p values represent independent t test obese
group compared with normal weight group.

Coagulation Obese Group Normal Weight p value

Patient demographics Parameters (n = 20) Group(n = 20)

ETP (nM.min) 2343.40 (±220.58) 1941.51 (±237.86) pb 0.0001

The women in the normal weight group were matched for age, par- Peak (nM) 403.71 (±31.05) 361.30 (±36.30) pb 0.001
ity and gestation with the obese group (Table 1). The average weight in Time to Peak (sec) 5.41 (±0.73) 6.60 (±0.57) pb 0.0001
the obese group was 138.9 (± 18.8) kg, with an average BMI of 48.2 Lagtime (sec) 3.37 (±0.72) 4.31 (±0.43) Pb 0.0001
(±22.9) kg/m2. Calculated creatinine clearance of women in the obese TAT (μg/ml) 4.95 (±0.76) 4.75 (±0.28) p= 0.3
TFPI (ng/ml) 4.76 (±2.94) 9.71 (±1.99) pb 0.0001
group were within normal pregnancy ranges (150-200 ml/min) [11].

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 S.K. Ismail et al. / Thrombosis Research 134 (2014) 234–239 237

Table 3
Coagulation Parameters in Morbidly Obese Pregnant Women on LMWH at 32 Weeks
Gestation In the Obese group levels were measured at 32 weeks prior to LMWH
administration (Pre LMWH Dose) and four hours post LMWH (4500iu tinzaparin)
(Fixed LMWH Dose) (n = 20). After a 48-hour washout period, the Obese group was
changed to a weight-adjusted dose at 32 weeks and levels were determined four hours
post LMWH (75iu/kg tinzaparin) (n = 20). Values represent mean (±SD). * = p b 0.01
compared with pre-dose levels. ** = p b 0.001 compared with pre-dose levels.
† = P b0.001 fixed dose v weight-adjusted dose.

Coagulation Obese Group

Parameters (n = 20)

Pre-dose Fixed dose Weight-adjusted

dose

ETP (nM.min) 2341.79 2215.04 1370.82**

(±228.82) (±224.95) (±306.82)
Peak (nM) 404.08 298.99** 128.17**†
(±32.18) (±45.68) (±48.88)
Time to Peak (sec) 5.41 (±0.73) 8.27 (±0.79)** 12.89(±2.45)**†
Lagtime (sec) 3.33 (±0.73) 5.13 (±0.33)** 6.27 (±0.81)**†
TAT (μg/ml) 4.92 (±0.95) 4.45 (±0.95)* 3.54 (±0.77)**†
TFPI (ng/ml) 4.76 (±2.94) 8.32 (±3.61)** 17.47(±7.24)**†
Fig. 2. Anti-Xa in Morbidly Obese Pregnant Women on LMWH at 32 Weeks Gestation.
In the Obese group anti-Xa was measured prior to LMWH administration (Pre LMWH
Dose) and four hours post LMWH (4500iu tinzaparin) (Fixed LMWH Dose) at 32 weeks
with pre-dose levels. Venous blood taken post standard LMWH dose (n = 20). After a 48-hour washout period, the Obese group was changed to a weight-
adjusted dose and anti-Xa was determined four hours post LMWH (75iu/kg tinzaparin)
(4500iu tinzaparin) yielded a significantly lower TFPI level compared
(n = 20). The boundary of each box closest to zero indicates 25th percentile, the boundary
with post weight-adjusted dose (75iu/kg tinzaparin)(p b 0.0001). furthest from zero indicated 75th percentile. The line within each box represents the
median. Error bars represent the 90th and 10th percentiles. *** represents significant
results (p b 0.0001) as calculated by paired t-test.
Thrombin generation
Similar ETP levels were found pre-LMWH and post fixed LMWH
Correlation between ETP and total body weight in morbidly obese pregnant
(Table 3) within the obese group in our study. However, following
women on LMWH
weight-adjusted LMWH, ETP levels were significantly lower compared
with pre-dose and post fixed LMWH levels (p b 0.0001). Before LMWH
There was a significant moderate positive correlation between ETP
prophylaxis, peak thrombin levels were significantly higher compared
levels prior to LMWH administration and total body weight in the
with post fixed LMWH in the obese group (p b 0.0001) and post
morbidly obese pregnant women (r = 0.631) (p b 0.05). ETP levels
weight-adjusted LMWH (p b 0.0001) (Table 3). Peak thrombin levels
had a significant positive correlation with total body weight at fixed
were higher following fixed LMWH compared with weight-adjusted
LMWH dose (r = 0.578) (p b 0.05). There was no significant correlation
LMWH (p b 0.0001). Similarly, lag times and time to peak were longer
between ETP levels and total body weight at weight-adjusted LMWH
after both LMWH regimens compared with pre dose (P b 0.0001).
dose.
Shorter lag times and time to peak were recorded after fixed LMWH com-
pared with after weight-adjusted LMWH (P b 0.0001).
Discussion
TAT
The first aim of our study was to demonstrate the different thrombin
Higher TAT levels were found following fixed dose LMWH compared
generation profiles between normal weight and morbidly obese preg-
with Pre dose (p b 0.01) and weight-adjusted LMWH (p b 0.001). TAT
nant women in the third trimester. Increased ETP and peak thrombin
levels were also significantly reduced in the weight-adjusted compared
have been correlated with risk of recurrent VTE [12–14]. We found
with the fixed dose LMWH (p b 0.05.)
that ‘potential thrombin formation’, as measured by ETP and peak
thrombin is higher in a morbidly obese pregnant group. Our values of
Effects of LMWH on anti Xa levels in the morbidly obese pregnant women in ETP and peak thrombin in normal weight pregnant women in this
third trimester study are comparable to values reported elsewhere in late pregnancy
(30-34weeks gestation) [15]. Lagtime reflects the initiation phase of
Lower anti-Xa levels were obtained while on fixed doses of thrombin generation [16]. We found shorter lagtime and time to peak
tinzaparin compared with levels found in women following a weight- thrombin formation in our obese group which is consistent with the hy-
adjusted dose (p b 0.0001) (Fig. 2). Pre-LMWH administration, peak percoagulability associated with obesity. In non-pregnant morbidly
anti-Xa levels were generally lower than limit of detection of the assay obese patients, lagtime is found to be shorter when compared to pa-
(0.05 iu/ml). Levels of anti-Xa following either weight-adjusted or tients with normal weight [17]. TAT is a marker of thrombin formed
fixed dose LMWH prophylaxis were within the target range (0.1- in vivo. We did not find a significant difference in TAT levels between
0.5 IU/ml. the obese and normal weight group in this study. To our knowledge,
this is the first study to demonstrate a reduction of TFPI in the morbidly
Correlation between ETP and anti-Xa levels in morbidly obese pregnant obese pregnant women. A potential mechanism for this decrease in TFPI
women on LMWH may be related to higher circulating oestrogen levels in obesity [18,19].
Our results show that morbidly obese pregnant women demonstrate an
ETP levels had a significant negative correlation with anti-Xa levels enhanced activation of the coagulation pathway resulting in increased
at weight-adjusted dose (r = − 0.570) (p b 0.05) but not at fixed thrombin potential and reduction in the concentration of the TFPI.
dose LMWH (r = −0.309) (p = 0.282). When TFPI and anti-Xa levels There were no significant changes in coagulation parameters such as
were analysed, a significant positive correlation was found in both TFPI, Peak and ETP in normal weight pregnant women between 30–36
fixed (r = 0.735) (p b 0.01) and weight-adjusted LMWH doses (r = weeks gestation (data not shown). These findings are supported by
0.750) (p b 0.01). other authors [20,21].

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The second aim of our study was to investigate the anticoagulant
effects of two different dosing regimens; fixed dose versus weight-
adjusted dose of LMWH tinzaparin used for thromboprophylaxis in
morbidly obese pregnant women. There was significant increase in
TFPI and decrease in TAT levels following LMWH prophylaxis at both
fixed dose and weight-adjusted dose. However, the weight-adjusted
dose provided greater inhibition of thrombin production and a more
significant increase in TFPI levels. Our findings are comparable to
data from non-pregnant obese subjects where increased levels of
TFPI (3-fold above basal) post tinzaparin at 75iu/kg were demon-
strated in obese subjects [20]. This higher TFPI release with increased
LMWH exposure may suggest that TFPI release post LMWH may be
invoked in a dose dependant fashion. In the morbidly obese pregnant
women, ETP levels were significantly lower after receiving weight-
adjusted LMWH but not with fixed dose LMWH when compared to
pre-dose levels. These results indicate that both the in vivo thrombin
production and the potential to clot (as measured by ETP) are more
effectively reduced by weight-adjusted prophylaxis. It is noteworthy
that previous in-vitro pharmacokinetic studies showed that tinzaparin
inhibited ETP and peak thrombin by a targeted 50% at anti-Xa
concentration of over 0.1iu/ml [21] which is similar to that observed
in our study.
In our study, we obtained anti-Xa levels after the second dose of
LMWH, which due to the administration schedule, coincided with
patient’s antenatal clinic. We accept that it is not known when a
steady-state level is reached in the morbidly obese pregnant women.
Within the obese group, 4-hour post (weight-adjusted LMWH) samples
taken at 32, 34 and 36 weeks showed no significant effect of gestation
on anti-Xa levels (data not shown). We focused on the most widely ac-
cepted pharmacokinetic measurement which is the 4-hour post dose
anti Xa levels. This would give us the best opportunity to compare
results with other studies. A pharmacokinetic study of enoxaparin in
obese volunteers did show that time to maximum anti-Xa activity was
one hour longer compared to non-obese [23]. However, there is specific
evidence that tinzaparin administered at 75iu/kg (or 175iu/kg) to
healthy, obese volunteers, demonstrated area under the activity-time
curve and maximum anti-Xa activity similar to that of non-obese volun-
teers [6]. Based on our experience, acquiring samples for 24-hour profile
data is not feasible for this special group of women. Our knowledge on
24-hour anti-Xa profile post LMWH administration in pregnancy main-
tains that anti-Xa levels peak at 4-hour post dose and declines to trough
levels after 18 hours of administration [24,25]. The anti-Xa levels
observed in this study were within the recommended prophylactic
range and are unlikely to predispose to haemorrhagic complications
[8,24,26]. We also reported no evidence of abnormal bleeding. Our
study showed that prior to LMWH administration, ETP correlates with
total body weight but not with weight-adjusted LMWH prophylaxis.
Available data evaluating LMWH in the non-pregnant obese population
does not support capping of doses [6,7,22,27]. Our results are in agree-
ment with this since we showed that levels of anti-Xa following
weight-adjusted LMWH did not exceed the upper limit of the target
range.
Although this study is too small to fully establish the clinical efficacy
and safety of routine antenatal thromboprophylaxis for morbidly obese
pregnant women, it provides a number of important observations. First,
in morbidly obese pregnant women, coagulation activation and throm-
bin generation is substantially increased compared to normal weight
pregnant women. Second, ETP is sensitive to the anticoagulant effects
of LMWH at different dosages and is a potential tool for monitoring
LMWH in the morbidly obese as has previously been suggested [28,
29]. Third, taken in aggregate, our data suggests that weight-adjusted
LMWH dose is superior to fixed dose in reversing the increased throm-
botic tendency in morbidly obese pregnant women. Larger studies are
needed to overcome the limitations of our study and to investigate
the efficacy and safety of weight-adjusted LMWH prophylaxis in obese
pregnant women.
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Conflict of interest statement
JRH has received honoraria for guest lectures from Leo Pharma. JRH,
SO’S and LN have received unrestricted research grants from Leo
Pharma.
Acknowledgement
The authors would like to thank Dr Ali Kashan for his expertise in
statistical analysis and Ms Noelle Gill for her invaluable assistance in
patient recruitment.
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