Hypertension in Pregnancy

ISSN: 1064-1955 (Print) 1525-6065 (Online) Journal homepage: https://www.tandfonline.com/loi/ihip20

Longitudinal assessment of D-dimer and

plasminogen activator inhibitor type-1 plasma
levels in pregnant women with risk factors for
preeclampsia

Flávia Campos Lucena, Eura Martins Lage, Patrícia Gonçalves Teixeira,

Alexandre Simões Barbosa, Rejane Diniz, Bashir Lwaleed, André Talvani,
Patrícia Nessralla Alpoim, Luiza Oliveira Perucci & Luci Maria SantAna Dusse

To cite this article: Flávia Campos Lucena, Eura Martins Lage, Patrícia Gonçalves Teixeira,
Alexandre Simões Barbosa, Rejane Diniz, Bashir Lwaleed, André Talvani, Patrícia Nessralla
Alpoim, Luiza Oliveira Perucci & Luci Maria SantAna Dusse (2019): Longitudinal assessment of D-
dimer and plasminogen activator inhibitor type-1 plasma levels in pregnant women with risk factors
for preeclampsia, Hypertension in Pregnancy, DOI: 10.1080/10641955.2019.1577435

To link to this article: https://doi.org/10.1080/10641955.2019.1577435

Published online: 13 Feb 2019.

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HYPERTENSION IN PREGNANCY
https://doi.org/10.1080/10641955.2019.1577435

Longitudinal assessment of D-dimer and plasminogen activator inhibitor type-1

plasma levels in pregnant women with risk factors for preeclampsia
Flávia Campos Lucenaa, Eura Martins Lageb, Patrícia Gonçalves Teixeirab, Alexandre Simões Barbosab, Rejane Dinizc,
Bashir Lwaleedd, André Talvanie, Patrícia Nessralla Alpoima, Luiza Oliveira Peruccif, and Luci Maria SantAna Dussea
a
Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil;
b
Department of Gynecology and Obstetrics, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil; cDepartment of
Epidemiology, Veterinary School, Federal University of Minas Gerais, Belo Horizonte, Brazil; dDepartment of Urology, University of
Soutampton, Southampton, UK; eDepartment of Biological Sciences, Institute of Exact and Biological Sciences, Federal University of Ouro
Preto, Ouro Preto, Brazil; fNucleus of Research in Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil

ABSTRACT ARTICLE HISTORY

Objective: Investigating D-Dimer/D-Di and plasminogen activator inhibitor type-1/PAI-1 levels Received 29 October 2018
throughout gestation in women with preeclampsia/PE risk factors. Accepted 17 January 2019
Methods: D-Di and PAI-1 plasma levels were determined in 28 women at 12–19, 20–29, 30–34 KEYWORDS
and 35–40 weeks of gestation. Preeclampsia; D-dimer;
Results: D-Di was lower at 12–19 weeks and higher at 30–34 weeks in women who developed PE PAI-1; longitudinal study;
versus who did not develop it. D-Di increased throughout gestation in both groups, peaking hypercoagulability
earlier in pregnant women who developed PE versus who did not develop it. PA1-1 increased
across gestation, but it didn’t differ between groups.
Conclusion: D-Di was able to discriminate these groups of women at 12–19 and 30–34 weeks of
gestation.

Dear editor, In this context of hypercoagulability, the D-Dimer

(D-Di) represents the ultimate degradation product of
Preeclampsia (PE) is one of the major contributors to
fibrin by plasmin and is considered a sensitive marker of
maternal and fetal mortality and morbidity worldwide
fibrin formation and degradation (8). Plasminogen activa-
(1). Currently, its diagnosis is based on the appearance
tor inhibitor type 1 (PAI-1) is the main serin protein
of maternal clinical signs and symptoms at gestational age
inhibitor of plasminogen activation into plasmin, the
≥20 weeks. Nevertheless, PE diagnosis is not always clear,
enzyme responsible for the lysis of the fibrin clot (9). The
because many diseases mimic its laboratory and clinical
activation of the blood coagulation cascade is often trig-
findings (2,3). The discovery of specific laboratory mar-
gered by the inflammatory response and physiological/
kers capable of predicting PE would be valuable to
pathological disturbances may induce an increase of D-Di
improve the management of this life-threatening disorder
and PAI-1 inhibitor levels (10). In addition, these mole-
to the pregnant women and their babies.
cules have been pointed as regulators of inflammatory and
It is known that hypercoagulability increases
regulatory cytokines controlling the course of vascular and
throughout pregnancy under physiological conditions
non-vascular disturbances (11,12). Clinically, both D-Di
(4). However, PE has been associated with
and PAI-1 are proposed and investigated as potential mar-
a hypercoagulable state even more evident than in nor-
kers of coagulation activation in distinct clinical settings
mal pregnancy (5). Multiple microthrombi are com-
involving the vascular subjects (13).
monly formed in the placenta of PE women and they
Therefore, the objective of this study was to assess the
exacerbate tissue ischemia resulting from failed spiral
plasma levels of D-Di and PAI-1 during pregnancy in
artery remodeling (6). It has been admitted that the
women with risk factors for PE (who developed or did
ischemic placenta releases circulating factors into the
not develop the disease) in order to clarify whether these
maternal circulation that cause endothelial dysfunction,
clotting markers may be useful for the prediction and
oxidative stress, and an exacerbated inflammatory
monitoring of PE women.
response (7).

CONTACT Patrícia Nessralla Alpoim patnessralla@yahoo.com.br Faculty of Pharmacy (room 4104 – B3), Federal University of Minas Gerais, 6627,
Antônio Carlos Ave, Belo Horizonte MG 31270-901, Brazil
© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 F. C. LUCENA ET AL.
This longitudinal study included 28 Brazilian pregnant
women with at least two risk factors for PE, such as PE in
previous pregnancy, primipaternity, non-white ethnicity,
lower limit of childbearing age and previous hypertension.
From this studied population, only 11 women developed
PE and 17 women remained normotensive until the end of
pregnancy. PE was defined as blood pressure ≥140/
90 mmHg at least in two occasions, four or more hours
apart, after rest, and proteinuria >0.3 g in a 24-h urine
collection or ≥1+ by the semi-quantitative strip method in
a random urine sample at gestational age ≥20 weeks. The
presence of clinical symptoms (for example, headache,
visual disturbances, abdominal pain, nausea, and vomiting)
was also considered for PE diagnosis (2). The exclusion
criteria were obesity, presence of cardiovascular, renal, liver
and autoimmune diseases, disorders of coagulation, dia-
betes, and cancer.
Ethics approval was obtained from Universidade Federal
de Minas Gerais (UFMG) (ETIC 0618.0.203.000-10) and
Hospital das Clínicas da UFMG, and all participants gave
a written informed consent to participate in the study. The
participants were informed that all of their personal data
will be kept confidential. Peripheral blood samples were
collected from the 28 studied pregnant women in EDTA
anticoagulant-coated tubes in four stages of pregnancy
(12–19, 20–29, 30–34 and 35–40 weeks). In total, 22 sam-
ples were collected from pregnant women who developed
PE [12–19 (N = 5), 20–29 (N = 11), 30–34 (N = 5) and
35–40 weeks (N = 1)]; and 58 samples were collected from
pregnant women who did not develop PE [12–19 (N = 14),
20–29 (N = 16), 30–34 (N = 17) and 35–40 weeks (N = 11)].
The plasma was separated by centrifugation spin at 3,000 g,
at room temperature, for 15 min and stored at −80°C until
the assays. D-Di and PAI-1 plasma levels were measured by
enzyme-linked immunosorbent assays (Sekisui
Diagnostics, LLC, Lexington, USA), according to the man-
ufacturer’s instructions.
Statistical analysis was performed using the Statistical
Package for Social Sciences (SPSS) 19.0 software (SPSS
IBM Corporation, Armonk, NY, USA). The normality of
continuous variables was assessed by Shapiro-Wilk’s
Table 1. Clinical characteristics of the studied pregnant women.
Pregnant women who did
Parameters not develop PE (N = 17)
Age (years)a 26.1 (8.1)
BMI at study admission (kg/m2)b 23.9 ± 2.4
SBP at study admission (mmHg)b 110 ± 10.8
DBP at study admission (mmHg)b 68.8 ± 9.0
2nd SBP measurement (mmHg)b 114.9 ± 8.6
2nd DBP measurement (mmHg)b 71.1 ± 7.7
SBP before delivery (mmHg)b 115.7 ± 9.4
DBP before delivery (mmHg)b 75.4 ± 8.0
Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; PE, preeclampsia.
a
Mann–Whitney U-test. Non-parametric data are presented as median (interquartile range).
b
Student’s t-test. Parametric data are presented as mean ± standard deviation (SD). *P < 0.05 = statistically significant.
W-test. Regarding the clinical characteristics of the stu-
died participants, the comparison of continuous variables
with normal distribution was performed by Student’s
t-test, and the comparison of continuous variables not
normally distributed was made by Mann–Whitney
U-test. Parametric data are presented as mean ± standard
deviation (SD) and non-parametric data as median (inter-
quartile range). D-Di (ng/mL) and PAI-1 (ng/mL) data
were normalized using Log10 transformation and then
a bivariate GLM analysis was performed to evaluate the
influence of the gestational outcome and the gestational
period (fixed factors) in D-Di and PAI-1 plasma levels
(dependent variables). A value of P < 0.05 was considered
statistically significant.
Table 1 summarizes the clinical characteristic of the
28 women enrolled in this study. As expected, systolic
and diastolic blood pressures before delivery were sig-
nificantly higher in women who developed PE. The
other clinical characteristics were similar between the
two groups.
There was a significant difference in D-Di plasma levels
according to the group (P = 0.003) and gestational period
(P < 0.001) evaluated. In addition, there was a significant
interaction between these parameters (P < 0.001). As
shown in Figure 1, D-Di levels at 12–19 weeks, were
lower in women who developed PE comparing to those
who did not develop the disease. Women who developed
PE had higher D-Di levels at 30–34 weeks comparing to
pregnant women who remained normotensive across
gestation and these levels continued to rise until the end
of the gestation. In pregnant women who did not develop
PE, a peak of D-Di was seen only at 35–40 weeks of
gestation. Concerning PAI-1, an increase was observed in
their levels throughout gestation, peaking at 35–40 weeks
in both groups. PAI-1 levels were influenced by the gesta-
tional age (P < 0.001), but not by the pregnancy outcome
(normotensive or preeclamptic) (Figure 2).
Our group performed a systematic review and meta-
analysis that reported an increase of D-Di levels in PE
women during the third trimester of gestation in studies
that measured this molecule by ELISA (14). In the current
Pregnant women who
developed PE (N = 11) P
27.1 (5.2) 0.239
30.9 ± 9.3 0.094
116.2 ± 9.6 0.270
75.8 ± 8.0 0.138
122.2 ± 17.6 0.254
79.0 ± 11.7 0.072
152.0 ± 15.5 0.001*
104.2 ± 10.8 0.001*
 HYPERTENSION IN PREGNANCY 3

Figure 1. Log10 of D-Di plasma levels in the four evaluated gestational periods for women who did not develop PE (circles) and
developed PE (squares).

Figure 2. Log10 of PAI-1 plasma levels in the four evaluated gestational periods for women who did not develop PE (circles) and
developed PE (squares).

study, we also found an increase of D-Di levels at the third
trimester of gestation (at 30–34 weeks) in women who
developed PE comparing to those that did not develop the
disease. However, two previous longitudinal studies
found no difference in D-Di levels between these groups
in late pregnancy (15,16). Although, the clinical symp-
toms of PE appear late in gestation (at ≥20 weeks), this
disease results from dysfunctions related to inflammation,
endothelial dysfunction, and coagulation that begin in the
first trimester (7). Unexpectedly, D-Di levels were lower
in the beginning of gestation (at 12–19 weeks) in women
who developed PE in the current study. The only two
longitudinal studies found in the literature that evaluated
D-Di plasma levels in early pregnancy found similar D-Di
4 F. C. LUCENA ET AL.
levels in pregnant women who developed or not PE
(15,16). It is important to note that Hale et al. (15) used
immunoturbidimetry to measure D-Di levels, and differ-
ent methodologies may interfere with the outcomes of the
studies. Besides, D-Di levels might be influenced by the
genetic background of the studied populations (Brazilian
vs. North American and Australian), knowing that ethni-
city may affect coagulation factors in women (17).
Our data show that D-Di plasma levels increased
during gestation in women who did not develop PE,
peaking at 35–40 weeks. Indeed, several studies that
evaluated circulating D-Di levels during normotensive
pregnancy showed a progressive increase (18–21). This
is in agreement with the physiological importance of
the gradual activation of the coagulation system during
gestation in order to prevent excessive postpartum
bleeding (22). However, the D-Di cutoff during preg-
nancy under physiological conditions is not well estab-
lished in detriment of the distinct assay sensitivities due
the differences in the monoclonal antibodies and the
calibration standards used for the tests.
Among women who developed PE, D-Di levels were
higher at 30–34 weeks of gestation when compared to
the earlier gestational periods. Hale et al. also found
that D-Di plasma levels were higher in late pregnancy
than in early pregnancy in women who developed
complicated hypertension during pregnancy (15). Of
note, D-Di levels peaked earlier in women who devel-
oped PE (30–34 weeks) when compared to those who
did not develop PE (35–40 weeks) in our study, corro-
borating with the hypercoagulable state in the disease
in relation to normotensive pregnancy (5).
On the other hand, PAI-1 could not differentiate preg-
nant women who developed or not PE, which is in accor-
dance with other works in the literature (15,23,24).
Although the statistical analysis did not reveal significant
differences between the two groups of pregnant women in
our study, there was a trend of PAI-1 increase in PE
women who developed PE in the last gestational period
evaluated (35–40 weeks). Other studies have reported an
increase of PAI-1 levels in pregnant women who devel-
oped PE, but at different time points (25–28). PAI-1 up-
regulation might be associated with the inhibition of the
fibrinolytic system in PE (29). As PAI-1 is synthesized by
endothelial cells (9), the hypothesis that the increase of
PAI-1 in PE women reflects the endothelial dysfunction
associated with this disease may be not be discarded (30).
Similarly to D-Di, evidences indicate that PAI-1
levels increase gradually in normotensive pregnant
women (27,31–34), as also reinforced in our study. In
agreement with our data, two previous studies in the
literature have found that PAI-1 plasma levels also
increase throughout gestation among women who
develop PE (31,35). The down-regulation of the fibri-
nolytic system throughout gestation, which is impor-
tant to prevent excessive bleeding during delivery,
tended to be more pronounced in PE women according
to ours findings. Therefore, the assessment of hemo-
static parameters is a promising path to find out bio-
markers clinically relevant to PE prediction.
We conclude that D-Di and PAI-1 plasma levels
increase in both preeclamptic and normotensive
pregnant women in a week-dependent time, where
D-Di was able to differentiate these pregnancy con-
ditions at 12–19 and 30–34 weeks of gestation.
Although a variety of clinical, biophysical, and
laboratory tests have been proposed for the early
detection of PE, most of them have poor sensitivity
and predictive values. Moreover, PE clinical signs
and symptoms overlap with those from other dis-
eases, what makes PE correct diagnosis a challenge.
Despite the intensive research over the last decades,
to date, there is no specific test available for the
prediction of PE with a favorable cost-effectiveness
ratio (3). The use of laboratory tests that are already
available in the clinical practice, like D-Di, is also
desirable.
Of note, to the best of our knowledge, this was the first
study that measured D-Di and PAI-1 circulating levels
throughout gestation in Brazilian women who developed
or did not developed PE. In this study, we included
a limited number of participants. Certainly, it would be
necessary a larger number of pregnant women and blood
samples (at each gestational period) to safely determine
D-Di and PAI-1 cutoff values for PE diagnosis, and to
better evaluate if these molecules could act as biomarkers
for the prediction of PE in the first or second trimesters of
pregnancy. It is opportune to highlight the complexity of
conducting longitudinal studies, especially because parti-
cipants tend to drop out over time. However, we believe
that this study will encourage new projects, carefully
designed, and surrounded by measures to minimize the
loss of participants over the time.
Acknowledgments
The authors thank the researchers from the Fetal Medicine
Center at Clinical Hospital/Federal University of Minas
Gerais, who were essential to this study. LMSD and AT are
grateful for CNPq fellowship.
Disclosure statement
No potential conflict of interest was reported by the authors.

Funding
This work was supported by FAPEMIG under Grant #00764-
16 and CNPq/Brazil under Grant #404353/2016-9.
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