-
Submitted 3 September 2014Accepted 14 October 2014Published 18
November 2014
Corresponding authorOffer Erez, [email protected]
Academic editorHendrik Feys
Additional Information andDeclarations can be found onpage
17
DOI 10.7717/peerj.653
Copyright2014 Mastrolia et al.
Distributed underCreative Commons CC-BY 4.0
OPEN ACCESS
Placental vascular pathology andincreased thrombin generation
asmechanisms of disease in obstetricalsyndromesSalvatore Andrea
Mastrolia1,2, Moshe Mazor2, Giuseppe Loverro1,Vered Klaitman2 and
Offer Erez2
1 Department of Obstetrics and Gynecology, Azienda
Ospedaliera-Universitaria Policlinico diBari, School of Medicine,
University of Bari Aldo Moro, Bari, Italy
2 Department of Obstetrics and Gynecology, Soroka University
Medical Center, School ofMedicine, Ben Gurion University of the
Negev, Beer Sheva, Israel
ABSTRACTObstetrical complications including preeclampsia, fetal
growth restriction, pretermlabor, preterm prelabor rupture of
membranes and fetal demise are all the clinicalendpoint of several
underlying mechanisms (i.e., infection, inflammation, throm-bosis,
endocrine disorder, immunologic rejection, genetic, and
environmental),therefore, they may be regarded as syndromes.
Placental vascular pathology andincreased thrombin generation were
reported in all of these obstetrical syndromes.Moreover, elevated
concentrations of thrombin-anti thrombin III complexes andchanges
in the coagulation as well as anticoagulation factors can be
detected in thematernal circulation prior to the clinical
development of the disease in some of thesesyndromes. In this
review, we will assess the changes in the hemostatic system
duringnormal and complicated pregnancy in maternal blood,
maternalfetal interface andamniotic fluid, and describe the
contribution of thrombosis and vascular pathologyto the development
of the great obstetrical syndromes.
Subjects Gynecology and Obstetrics, HematologyKeywords
Coagulation, TAT III complexes, TFPI, Protein Z, Amniotic fluid,
IUGR, PROM,Preeclampsia, Fetal demise, Preterm labor
INTRODUCTIONObstetrical complications including preeclampsia,
fetal growth restriction, preterm labor,
preterm prelabor rupture of membranes and fetal demise are all
the clinical endpoint
of several underlying mechanisms (i.e., infection, inflammation,
thrombosis, endocrine
disorder, immunologic rejection, genetic, and environmental),
therefore, they may be
regarded as syndromes. In this review, we will assess the
changes in the hemostatic system
during normal and complicated pregnancy in maternal blood,
maternalfetal interface and
amniotic fluid, and describe the contribution of thrombosis and
vascular pathology to the
development of the great obstetrical syndromes.
WHAT ARE THE GREAT OBSTETRICAL SYNDROMES?The major obstetrical
complications including preeclampsia, intrauterine growth
restriction (IUGR), preterm labor (PTL), preterm prelabor
rupture of membranes
How to cite this article Mastrolia et al. (2014), Placental
vascular pathology and increased thrombin generation as mechanisms
ofdisease in obstetrical syndromes. PeerJ 2:e653; DOI
10.7717/peerj.653
-
(PROM), fetal demise, and recurrent abortions are all syndromes,
also defined as great
obstetrical syndromes. As reported in The Oxford Medical
Dictionary a syndrome is a
combination of symptoms and/or signs that form a distinct
clinical picture indicative of
a particular disorder. Hence, they represent the clinical
manifestation of many possible
underlying mechanisms of disease (Concise Medical Dictionary,
2010).
Key features of these syndromes are (Romero, 2009): multiple
etiologies; long preclinical
stage; frequent fetal involvement; clinical manifestations which
are often adaptive in
nature; and predisposition to a particular syndrome is
influenced by geneenvironment
interaction and/or complex genegene interactions involving
maternal and/or fetal
genotypes. These mechanisms of disease were identified and
reported in all the obstetrical
complications listed above. This review is focused on the role
of thrombosis and vascular
pathology of the placenta in these syndromes.
WHAT ARE THE CHANGES IN THE COAGULATIONSYSTEM DURING NORMAL
PREGNANCY?In term of the coagulation and hemostatic systems there
are several major compartments:
the maternal circulation, the fetal maternal interface (the
placenta, and the membranes),
the amniotic fluid and the fetus and each has a specific
behavior during gestation.
The changes in the coagulation system during gestation are
considered to be adaptive
mechanisms and are aimed to: (1) the prevention of bleeding at
the time of trophoblast
implantation and the delivery of the fetus; (2) allow the
laminar flow at the intervillous
space; and (3) seal amniotic fluid leak and reduce obstetrical
bleeding (Bellart et al., 1998;
Walker et al., 1997; Srensen, Secher & Jespersen, 1995;
Yuen, Yin & Lao, 1989; de Boer et al.,
1989). Of interest, the fetus is somewhat less involved and its
coagulation system develops
during gestation, and this subject is beyond the scope of this
review.
Indeed, normal pregnancy has been associated with excessive
maternal thrombin
generation (Bellart et al., 1998; Chaiworapongsa et al., 2002)
and a tendency for platelets
to aggregate in response to agonists (Yoneyama et al., 2000;
Sheu et al., 2002). Pregnancy
is accompanied by 2 to 3-fold increase in fibrinogen
concentrations and 20% to 1000%
increase in factors VII, VIII, IX, X, and XII, all of which peak
at term (Bremme, 2003). The
concentration of vWF increase up to 400% by term (Bremme, 2003).
By contrast, those of
pro-thrombin and factor V remain unchanged while the
concentrations of factors XIII and
XI decline modestly (Eichinger et al., 1999). Indeed there is
evidence of chronic low-level
thrombin and fibrin generation throughout normal pregnancy as
indicated by enhanced
concentrations of pro-thrombin fragment 1 and 2,
thrombinantithrombin (TAT) III
complexes, and soluble fibrin polymers (Ku et al., 2003). Free
protein S concentration de-
clines significantly (up to 55%) during pregnancy due to
increased circulating complement
4B-binding protein, its molecular carrier. Protein S nadir at
delivery and this reduction is
exacerbated by cesarean delivery and infection (Bremme, 2003;
Eichinger et al., 1999). As
a consequence, pregnancy is associated with an increase in
resistance to activated protein
C (Eichinger et al., 1999; Ku et al., 2003). The concentration
of PAI-1 increase by 3 to 4-fold
during pregnancy while plasma PAI-2 values, which are negligible
before pregnancy, reach
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 2/26
-
concentrations of 160 mg/L at delivery (Bremme, 2003). Thus,
pregnancy is associated
with increased clotting potential, as well as decreased
anticoagulant properties, and
fibrinolysis (Lockwood, 2006). Therefore, it can be defined as a
prothrombotic state.
One of the most important mediators of the hypercoagulable state
of normal pregnancy
is tissue factor (TF). Indeed, there is a substantial increase
in TF concentrations in the
decidua and myometrium (Erlich et al., 1999; Kuczynski et al.,
2002; Lockwood, Krikun &
Schatz, 2001; Lockwood, Krikun & Schatz, 1999), preventing
placental abruption since this
leads to an increase in the efficiency of clotting function
(Lockwood, 2006). The placenta
is a source of TF, since trophoblast cells constitutively
express it, behaving as activated
endothelium, and leading to a condition of procoagulant state
that, if not controlled by
anticoagulant mechanisms, predisposes to thrombotic
complications (Erlich et al., 1999).
The principal anticoagulant mechanism inhibiting TF activation
pathway is tissue factor
pathway inhibitor (TFPI), which mRNA is highly expressed in the
macrophages in the villi
in term placenta (Edstrom, Calhoun & Christensen, 2000).
Similarly, high TF concentrations have been detected in the
fetal membranes (mainly
the amnion) and amniotic fluid (de Boer et al., 1989; Uszynski
et al., 2001; Lockwood
et al., 1991; Omsj et al., 1985; Creter, 1977). TFPI has been
found in amniotic fluid
as well (Uszynski et al., 2001), but it is not clear if the
presence of TF and its natural
inhibitor is related to coagulation per se or is somehow
connected with embryonic
development (Carmeliet et al., 1996).
In contrast to the changes detected in the amniotic fluid and
the decidua, the median
maternal plasma immunoreactive TF concentration of normal
pregnant women do
not differ significantly from that of non-pregnant patients
(Bellart et al., 1998; Holmes
& Wallace, 2005). However, labor at term increases
significantly the maternal plasma
immunoreactive TF concentration in comparison to the
non-pregnant state (Uszynski et
al., 2001). In addition to the changes in TF, normal pregnancy
is associated with increased
thrombin generation (Bellart et al., 1998; Chaiworapongsa et
al., 2002), as determined by
the elevation of maternal concentrations of fibrinopeptide A,
prothrombin fragments
(PF) 1 and 2, and thrombinantithrombin (TAT) III complexes (de
Boer et al., 1989;
Reber, Amiral & de Moerloose, 1998; Uszynski, 1997;
Reinthaller, Mursch-Edlmayr & Tatra,
1990). The concentration of these complexes further increases
during and after normal
parturition (Uszynski, 1997; Andersson et al., 1996), and
subsequently decreases during the
puerperium (Uszynski, 1997; Andersson et al., 1996).
WHAT ARE THE CHANGES IN THE HEMOSTATICSYSTEM ASSOCIATED WITH THE
GREAT OBSTETRICALSYNDROMES?The great obstetrical syndromes are
associated with changes in the hemostatic and vascular
systems in the compartments mentioned above: (1) the maternal
circulation; (2) the
feto-maternal interface of placenta and membranes; (3) and the
amniotic fluid.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 3/26
-
Changes in the hemostatic system of women with
obstetricalsyndromesThe involvement of the hemostatic system in the
pathophysiology of these obstetrical
syndromes is becoming more and more apparent. Indeed, increased
thrombin generation
is reported in the maternal circulation of women with
preeclampsia (Schjetlein et al.,
1999; Chaiworapongsa et al., 2002; Hayashi et al., 1998;
Kobayashi & Terao, 1987; Hayashi
et al., 2002), IUGR (Schjetlein et al., 1999; Chaiworapongsa et
al., 2002; Hayashi et al.,
1998; Hayashi & Ohkura, 2002; Ballard & Marcus, 1972),
fetal demise (Erez et al., 2009),
PTL (Chaiworapongsa et al., 2002; Erez et al., 2009; Elovitz,
Baron & Phillippe, 2001) and
preterm PROM (Chaiworapongsa et al., 2002; Erez et al., 2009;
Rosen et al., 2001).
There are several possible explanations for the increased
thrombin generation in these
patients: (1) increased activation of coagulation cascade in the
maternal circulation due to
pathological processes including bleeding or inflammation; and
(2) depletion of anticoag-
ulation proteins that subsequently leads to increased thrombin
generation (Table 1).
Increased activation of the coagulation cascade and
thrombingeneration in the maternal circulation in patients with
pregnancycomplicationsAll the obstetrical syndromes including
preeclampsia (Schjetlein et al., 1999; Chai-
worapongsa et al., 2002; Hayashi et al., 1998; Kobayashi &
Terao, 1987; Hayashi et al., 2002;
Kobayashi et al., 1999; Kobayashi et al., 2002), IUGR
(Chaiworapongsa et al., 2002; Hayashi
et al., 1998; Hayashi & Ohkura, 2002; Ballard & Marcus,
1972), fetal demise (Erez et al.,
2009), PTL (Chaiworapongsa et al., 2002; Elovitz, Baron &
Phillippe, 2001) and preterm
PROM (Chaiworapongsa et al., 2002; Erez et al., 2009; Rosen et
al., 2001) are associated
with a higher maternal thrombin generation than a normal
pregnancy. These may be of
clinical implication since, in women with preterm labor,
elevated maternal plasma TAT
III complex concentration was associated with a higher chance to
deliver within
-
Tabl
e1
Con
cen
trat
ion
and
acti
vity
inm
ater
nal
plas
ma
ofco
agu
lati
ng
and
anti
coag
ula
tin
gfa
ctor
san
dth
eir
rela
tion
wit
hth
rom
bin
gen
erat
ion
inth
egr
eat
obst
etri
cal
syn
drom
es.
TF
con
cen
trat
ion
and
/or
acti
vity
TFP
Ico
nce
ntr
atio
nan
d/o
rac
tivi
tyTA
TII
Ico
mp
lexe
sco
nce
ntr
atio
nP
rote
inZ
con
cen
trat
ion
Th
rom
bin
gen
erat
ion
Ref
eren
ces
Pre
mat
ure
rupt
ure
ofm
embr
anes
Act
ivit
y
Con
cen
trat
ion
Con
cen
trat
ion
Con
cen
trat
ion
Con
cen
trat
ion
(E
rez
etal
.,20
10;E
rez
etal
.,20
09;K
usan
ovic
etal
.,20
07;G
ris
etal
.,20
02;
Paid
aset
al.,
2005
)
Pre
term
labo
rA
ctiv
ity
Con
cen
trat
ion=
Act
ivit
y=
Con
cen
trat
ion
Con
cen
trat
ion
Con
cen
trat
ion
(E
rez
etal
.,20
10;E
rez
etal
.,20
09;K
usan
ovic
etal
.,20
07;G
ris
etal
.,20
02;
Paid
aset
al.,
2005
)
Feta
ldem
ise
Act
ivit
y=
Con
cen
trat
ion=
Act
ivit
y=
Con
cen
trat
ion
Con
cen
trat
ion
Con
cen
trat
ion
(E
rez
etal
.,20
10;E
rez
etal
.,20
09;K
usan
ovic
etal
.,20
07;G
ris
etal
.,20
02;
Paid
aset
al.,
2005
)
Pre
ecla
mps
iaA
ctiv
ity
Con
cen
trat
ion
Con
cen
trat
ion
Con
cen
trat
ion
Con
cen
trat
ion
(E
rez
etal
.,20
10;E
rez
etal
.,20
09;K
usan
ovic
etal
.,20
07;G
ris
etal
.,20
02;
Paid
aset
al.,
2005
)
Intr
aute
rin
egr
owth
reta
rdat
ion
/sm
all
for
gest
atio
nal
age
Act
ivit
y
Con
cen
trat
ion
Con
cen
trat
ion=
Con
cen
trat
ion
Con
cen
trat
ion
(E
rez
etal
.,20
10;E
rez
etal
.,20
09;K
usan
ovic
etal
.,20
07;G
ris
etal
.,20
02;
Paid
aset
al.,
2005
)
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 5/26
-
Figure 1 Thrombinantithrombin (TAT) III levels in control
patients, patients with preterm laborwho delivered between 21 and 7
days, and patients with preterm labor who delivered within 7
daysfrom admission. Open diamonds, mean levels; black error bars,
SD. P < .05, Student-Newman-Keulsmethod. From Elovitz, Baron
& Phillippe (2001).
membranes and a subsequent preterm delivery (Elovitz, Baron
& Phillippe, 2001; Elovitz
et al., 2000a; Elovitz et al., 2000b); and (3) thrombin has an
inhibitory effect on the
production of TFPI by endothelial cells (Bilsel et al., 2000),
and the increased thrombin
generation observed in patients with PTL may be associated with
a concomitant reduction
in TFPI production by the maternal vascular endothelium (the
depletion of anticoagulant
proteins will be discussed in the following section of this
review).
There is evidence to support that the extrinsic pathway of
coagulation is activated in
many of these pregnancy complications and it is the source of
the increased thrombin
generation (VanWijk et al., 2002). Indeed, increased
immunoreactive TF concentrations
were reported in women with preeclampsia and those with preterm
PROM (Erez et al.,
2010). Moreover, the contribution of preeclampsia to elevated
maternal immunoreactive
TF persisted also among patients with fetal demise, while those
with fetal death who
were normotensive did not have higher median TF concentration
than normal pregnant
women. Indeed, the median TF concentration of patients with
preeclampsia was higher
than in patients with fetal demise without hypertension. These
findings are consistent
with previous studies (Bellart et al., 1998; Erez et al., 2008),
suggesting that elevated
TF immunoreactivity and activity may be associated with the
pathophysiologic process
leading to preeclampsia, rather than being a consequence of the
fetal death.
In some of the obstetrical syndromes there was elevated TF
activity in the maternal
circulation without a concomitant increase in the plasma
concentration of this factor. This
was the case among patients with a small for gestational age
(SGA) neonate and those with
preterm labor (Chaiworapongsa et al., 2002; Erez et al., 2009)
(Table 1). This suggests that
the increased TF activity among patients with PTL as well as
those with an SGA neonate,
contributes to a higher generation of factor Xa that, along with
the physiologic increase in
the maternal plasma concentrations of factor VII and factor X
during gestation (Bremme,
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 6/26
-
2003; Beller & Ebert, 1982; Stirling et al., 1984; Brenner,
2004), may be the underlying
mechanism leading to the increased thrombin generation reported
these syndromes.
The differences between PTL and preterm PROM in term of maternal
plasma TF
concentration and activity may derive from the specific
component of the common
pathway of parturition, which is activated in each obstetrical
syndrome (Romero et al.,
2006). While preterm PROM is associated with the activation of
the decidua and the
membranes, myometrial activation is the major component of
preterm labor with intact
membranes (Romero et al., 2006). This is relevant because the
decidua and the membranes
have a high TF concentration (Lockwood, Krikun & Schatz,
2001; Lockwood, Krikun &
Schatz, 1999; Lockwood et al., 2007).
In summary, the evidence brought herein suggests that increased
thrombin generation
in patients with the great obstetrical syndromes may reflect the
activation of the
coagulation cascade mainly through the extrinsic arm. This
activation can be attributed
to various underlying mechanisms.
Depleted or insufficient anticoagulant proteins concentrationIn
the normal state there is a delicate balance between the proteins
activating/participating
the coagulation cascade and their inhibitors. Increased thrombin
generation may
result, as we presented above, from activation of the
coagulation cascade due to higher
concentrations or activities of the proteins included in the
coagulation cascade. However,
thrombin generation can also result from insufficient
concentration or activity of
anticoagulation proteins.
Tissue factor pathway inhibitor (TFPI), a glycoprotein
comprising of three Kunitz
domains (Broze et al., 1988) that are specific inhibitors of
trypsin-like proteinases
(Laskowski & Kato, 1980), is the main inhibitor of the
extrinsic pathway of coagulation.
TFPI inhibits thrombin generation through the inactivation of
activated factor X and
the factor VIIa/TF complex (Broze et al., 1988; Broze, Girard
& Novotny, 1990). The
mean maternal plasma concentrations of total TFPI increases
during the first half of
pregnancy, remains relatively constant in the second half (Sarig
et al., 2005) and decreases
during labor (Uszynski et al., 2001). There are two types of
TFPI: (1) TFPI-1 is the more
prevalent form in the non-pregnant state in the maternal
circulation and can also be
found in the fetal blood, platelets, endothelial cells and other
organs (Edstrom, Calhoun &
Christensen, 2000; Tay, Cheong & Boo, 2003); and (2) TFPI-2-
the major form of TFPI in
the placenta (Hube et al., 2003; Iino, Foster & Kisiel,
1998; Sprecher et al., 1994; Udagawa et
al., 1998), also known as Placental Protein 5 (PP5) (Kamei et
al., 2001; Kisiel, Sprecher &
Foster, 1994). During pregnancy, the maternal plasma
concentration of TFPI-2 increases
gradually, reaches a plateau at 36 weeks and subsides after
delivery (Butzow et al., 1988;
Chand, Foster & Kisiel, 2005; Seppala, Wahlstrom & Bohn,
1979; Obiewke & Chard, 1981).
The overall balance between the concentration and activity of
the coagulation factors
and the anticoagulation proteins is one of the determining
factors of thrombin generation.
In the normal state, the immunoreactive concentrations of TFPI
in the plasma are 500
to 1,000 times higher than that of TF (Shimura et al., 1997),
suggesting that an excess
of anticoagulant proteins closely control the coagulation
cascade activity. The median
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 7/26
-
Figure 2 (A) Comparison of median maternal plasma TF
concentration between patients with normalpregnancy (n = 79),
pre-eclampsia (n = 133), and women who delivered an SGAneonate (n =
61). (B)Comparison of median maternal plasma TFPI concentration
between patients with normal pregnancy(n= 86), pre-eclampsia (n=
133), and women who delivered an SGA neonate (n= 61). (C)
Comparisonof maternal plasma TFPI/TF ratio between women with
normal pregnancy (n = 79), pre-eclampsia(n= 133), and women who
delivered an SGA neonate (n= 61). From Erez et al. (2008).
maternal plasma TFPI concentration increases during preeclampsia
(Erez et al., 2008;
Abdel Gader et al., 2006), which is associated with an
exaggerated maternal systemic
inflammatory response. However, the increase in the median
maternal TF plasma
concentration is such that the overall balance between TF and
its inhibitor is affected,
leading to increased thrombin generation in this syndrome. In
contrast to preeclampsia,
maternal plasma TFPI concentration decreases in patients with
PTL (Erez et al., 2010)
and preterm PROM (Erez et al., 2008) regardless to the presence
of intra-amniotic
infection/inflammation, as well as in women with fetal demise
(Erez et al., 2009), and
does not change in mothers with SGA fetuses (Erez et al., 2008).
Overall these findings
suggest that the increased thrombin generation observed among
these patients may derive
not only from an increased activation of the hemostatic system,
but also from insufficient
anticoagulation, as reflected by the lower TFPI concentrations
(Fig. 2).
A possible explanation of the lower maternal plasma
concentration observed in some
of the obstetrical syndromes may be that during these syndromes
there is a reduction in
the placental production of TFPI (Hube et al., 2003; Iino,
Foster & Kisiel, 1998; Kamei et al.,
2001; Abdel Gader et al., 2006) (mainly TFPI-2), contributing to
the low maternal plasma
concentrations detected in patients with PTL, in addition to the
thrombin inhibitory
effect to TFPI expression on endothelial cells, as above
mentioned. Indeed, patients with
vascular complications of pregnancy (preeclampsia, eclampsia,
placental abruption, fetal
growth restriction, and fetal demise) have a lower placental
concentration of total TFPI,
and TFPI mRNA expression than in women with normal pregnancies
(Xiong et al., 2010;
Aharon et al., 2005).
Other proteins implicated in the inhibitory control of the
coagulation cascade are
protein S, protein C and protein Z. Protein S is a cofactor to
protein C in the inactivation
of factors Va and VIIIa. This protein exists in two forms: a
free form and a complex
form bound to complement protein C4b-binding protein (C4BP).
Only the free form is
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 8/26
-
active (Castoldi & Hackeng, 2008). Protein S also acts as a
TFPI cofactor, in the presence
of weak procoagulant stimuli, by enhancing the interaction of
TFPI with factor Xa while
using Ca2+ and phospholipids in the process (Hackeng et al.,
2006) without increasinginhibition of factor VIIa-TF by TFPI
(Ndonwi & Broze, 2008). During pregnancy there is
a physiologic change in the relationship between the bound and
the free forms of protein
S in the maternal plasma. The increase in C4BP during gestation
reduces free protein S
concentration in up to 55% of its value out of pregnant state,
reaching its nadir at delivery.
Of interest, cesarean delivery and infection exacerbate the
reduction in free protein S con-
centrations (Bremme, 2003; Faught et al., 1995). Moreover, a
functional protein S deficiency
can explain a poor response to activated protein C (Dahlback,
Carlsson & Svensson, 1993).
The association between the alteration of concentration and
function of protein S
and protein C in the great obstetrical syndromes is not
completely clear. The evidence
regarding the association of protein S and protein C deficiency
and preeclampsia is
controversial (Rodger et al., 2008; Yalinkaya et al., 2006).
While some reported an association between protein S deficiency
and an increased risk
for this syndrome (especially for early onset preeclampsia)
(Rodger et al., 2008) others
could not demonstrate this effect (Yalinkaya et al., 2006).
There is some evidence regarding
the relation of protein S deficiency and increased risk of
stillbirth (Preston et al., 1996)
and mid-trimester IUGR (Kupferminc et al., 2002). An increased
risk of stillbirth has
been reported in patients with protein S deficiency while the
risk was not significantly
increased in cases of protein C deficiency (Preston et al.,
1996), and Kupferminc et al. (2002)
found that protein S, but not protein C deficiency, was
significantly associated with severe
mid-trimester IUGR.
Protein Z, in complex with protein Z-dependent protease
inhibitor (ZPI) (Fig. 3) (Han,
Fiehler & Broze, 1998; Han et al., 1999; Han, Fiehler &
Broze, 2000), acts as a physiologic
inhibitor of activation of prothrombin by factor Xa. Protein Z
is a vitamin K-dependent
plasma glycoprotein (Yin et al., 2000) that is an essential
cofactor for ZPI activity. In
the absence of protein Z, the activity of ZPI is reduced by more
than 1,000-fold (Han,
Fiehler & Broze, 2000). Normal pregnancy is characterized by
an increased plasma
concentration of protein Z (Taylor et al., 1998), probably as a
compensation for the
increase of factor X concentration. Women with preterm labor
without intra-amniotic
infection or inflammation and those with vaginal bleeding who
delivered preterm had
a lower median maternal plasma protein Z concentration than
women with a normal
pregnancy and those with vaginal bleeding who delivered at term
(Kusanovic et al.,
2007). The changes of protein Z concentrations in other
pregnancy complications are
controversial. Some demonstrated that the median plasma
concentration of protein Z
in patients with preeclampsia, IUGR, and late fetal death were
not significantly different
than that of patients with a normal pregnancy (Bretelle et al.,
2005). Others reported
lower median maternal plasma protein Z concentrations in women
with preeclampsia or
pyelonephritis and higher proportion of protein Z deficiency
(defined as protein Z plasma
concentration below the 5th percentile) in patients with
preeclampsia or fetal demise than
in those with a normal pregnancy (Nien et al., 2008). Moreover,
increased maternal plasma
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 9/26
-
Figure 3 Factor X activation and protein Z/protein Z-dependent
protease inhibitor (ZPI) inhibitionof activated factor X. (A) The
formation of the complex of tissue factor (TF) and factor VIIa
(FVIIa) atthe site of injury and activation of extrinsic
coagulation cascade. (B) Activation of circulating factor Xby the
TF/VIIa complex in the presence of exposed phospholipids and Ca2+.
(C) Inhibition of factor Xa(FXa) by the protein Z/ZPI complex by
binding to its active site. Modified from Broze (2001).
anti-protein Z antibodies concentrations were associated with
SGA neonates, fetal demise
and preeclampsia.
The information presented above suggests that it is not only the
concentration of one
coagulation factor or anticoagulation protein, but rather the
overall balance between
the coagulation factors and their inhibitors that increases
thrombin generation in the
great obstetrical syndromes. Indeed, although preterm labor was
not associated with a
significant change in the median maternal plasma TF
concentration, the TFPI/TF ratio of
these patients was lower than that of normal pregnant women,
mainly due to decreased
TFPI concentrations.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 10/26
-
This observation was also reported in patients with preterm PROM
(Erez et al., 2008),
and those with preeclampsia (Erez et al., 2008). The lower
TFPI/TF ratio in patients
with preeclampsia occurs despite the increase in the median
maternal plasma TFPI
concentration observed in these patients. This suggests that the
balance between TF and its
natural inhibitor may better reflect the overall activity of the
TF pathway of coagulation,
than the individual concentrations of TF or TFPI.
Collectively, these observations suggest that our attention
should be focused not only on
the coagulation protein but also on their inhibitors since an
imbalance between them may
contribute to increased thrombin generation leading to the onset
of the great obstetrical
syndromes.
Changes in the feto-maternal interfaceNormal placental
development and the establishment of an adequate feto-maternal
circulation are key points for a successful pregnancy. The
networks of the placental
vascular tree either on the maternal or fetal side are dynamic
structures that can be
substantially altered in cases of abnormal placentation and
trophoblast invasion. The
human trophoblast has properties of endothelial cells and can
regulate the degree of
activation of the coagulation cascade in the intervillous space
(Sood et al., 2006; Sood
et al., 2008). The villous trophoblasts express heparin sulfate,
protein C and protein Z
on their surface that serve as anticoagulant that sustain
laminar blood flow through
the intervillous space. On the other hand, unlike the
endothelium of other organs, the
trophoblast constantly presents the active placental isoform of
TF on its surface (Sood et
al., 2008; Lanir, Aharon & Brenner, 2003; Isermann et al.,
2003; Aharon et al., 2004). This
isoform has a higher affinity for factor VIIa (Butenas &
Orfeo, 2007), which may lead to
increased activation of the coagulation cascade. One of the
leading pathological processes
observed in all these syndromes is thrombosis and vascular
abnormality of the placenta at
the maternalfetal interface. The incidence of these pathological
processes varies among
the different syndromes being more prevalent in preeclampsia,
IUGR, and fetal demise
than in PTL and preterm PROM (Schjetlein et al., 1999;
Chaiworapongsa et al., 2002; Erez et
al., 2009; Elovitz, Baron & Phillippe, 2001).
Placental pathology in the great obstetrical syndromesThere is a
range of placental vascular and thrombotic lesions that are being
observed
in placentas of patients with pregnancy complications.
Thrombotic events of placental
vessels can cause an impairment of placental perfusion, leading
to fetal growth restriction
(FGR), preeclampsia and fetal death as well as in some extents
to PTL and preterm
PROM (Midderdorp, 2007; Martinelli et al., 2001). The frequency
of the specific vascular
placental lesions varies among these obstetrical syndromes
(Kovo, Schreiber & Bar, 2013).
Placental vascular lesions are divided into maternal or fetal
vascular origin (Figs. 4
and 5) (Redline et al., 2005; Bar et al., 2012). Lesions of the
maternal vascular compartment
include placental marginal and retro-placental hemorrhages,
lesions related to maternal
underperfusion (acute atherosis and mural hypertrophy, increased
syncytial knots, villous
agglutination, increased intervillous fibrin deposition, villous
infarcts) (Redline et al.,
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 11/26
-
Figure 4 Histologic features of maternal vessels and
implantation site reaction patterns. (A) Acuteatherosis of maternal
arterioles in the placental membranes: a cluster of decidual
arterioles shows varyingstages of fibrinoid necrosis. The vessel at
the upper right shows full histologic expression with
darkhomogenous fibrinoid replacement of the vessel wall accompanied
by occasional foamy macrophages([original magnification is
indicated for all panels] X 20). (B) Mural hypertrophy of decidual
arteriolesin the placental membranes: a cluster of arterioles shows
medial hypertrophy with the vessel walloccupying greater than one
third of total vessel diameter (X 10). (C) Muscularized basal plate
arterieswith accompanying implantation site abnormalities: maternal
spiral arteries in the basal plate lacknormal trophoblast
remodeling and retain their pre-pregnancy muscular media. Clusters
of immatureintermediate trophoblast and increased placental giant
cells are seen above and below the musculararteries, respectively
(X 10). (D) Acute atherosis of muscularized basal plate arteries
with accompanyingimplantation site abnormalities: three cross
sections of a basal plate artery (continued on next page...)
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 12/26
-
Figure 4 (...continued)
are seen. The two on the left show persistence of the muscular
media while the one on the righthas undergone fibrinoid necrosis of
the media with foamy macrophages (acute atherosis). Clusters
ofimmature intermediate trophoblast are also seen overlying the
arteries (X 4). (E) Immature intermediatetrophoblast: clusters of
abnormally small intermediate trophoblast with focal vacuolation
are surroundedby an excessive amount of basal plate fibrin.
Increased placental site giant cells are also seen at the
lowermargin (X 10). (F) Increased placental site giant cells:
numerous multinucleate placental site giant cells,not usually seen
in the delivered placenta, are scattered in loose decidual tissue
which is devoid of normalintermediate trophoblast and fibrinoid (X
10). From Redline et al. (2004).
2005). Placental fetal vascular obstructive lesions are the
result of stasis, hypercoagulability
and vascular damage within the fetal circulation of the
placenta. Placental fetal vascular
abnormalities include: cord-related abnormalities (as torsion of
cord, over-coiling,
strictures and tight knots (Cromi et al., 2005)) and vascular
lesions consistent with fetal
thrombo-occlusive disease (thrombosis of the chorionic plate and
stem villous vessels,
fibrotic, hypo-vascular and avascular villi (Redline et al.,
2005)). In addition, villitis of
unknown etiology or chronic villitis, defined as
lymphohistiocytic inflammation localized
to the stroma of terminal villi but often extending to the small
vessels of upstream villi is
also associated with obliterative fetal vasculopathy (Redline et
al., 2005) (Figs. 4 and 5).
Preeclampsia. The classic example for an association between
obstetrical syndromes
and vascular placental lesions is preeclampsia. Women who
develop preeclampsia have
an increased rate of abnormalities of the maternal side of the
placental circulation and
maternal underperfusion (Salafia et al., 1998; Roberts &
Post, 2008). The frequency of these
lesions is inversely related to the gestational age in which the
hypertensive disorder was
diagnosed. The earlier the development of
hypertension/preeclampsia the more severe
the vascular lesions are (Mayhew et al., 2003; Ogge et al.,
2011). Moreover, Kovo et al.
(2010) reported that the presence of fetal growth restriction in
women with preeclampsia
also increases the frequency of fetal vascular lesions. Indeed,
patients with early-onset
preeclampsia complicated by FGR had a higher rate of fetal
vascular supply lesions
consistent with fetal thrombo-occlusive disease than women with
early onset disease
without FGR (Kovo et al., 2010).
An assessment of the pathologic changes in placental hemostatic
system has been
performed in patients with preeclampsia. Teng et al. (2010)
studied TF and TFPI placental
levels in pregnant patients with preeclampsia, compared to
normal pregnancies. They
found increased TF placental expression and a reduced expression
of TFPI-1 and TFPI-2,
with a significant correlation between the levels of TF and
TFPI-2 between maternal
plasma and placenta.
Fetal growth restriction. Placentas from pregnancies complicated
by FGR are smaller
and have significantly increased maternal and fetal vascular
lesions compared to placentas
from normal pregnancies with appropriate for gestational age
neonates (AGA) (Rerdline,
2008; Salafia et al., 1995). Maternal vascular lesions were
detected in about 50% of
placentas from pregnancies complicated with FGR at term,
compared to only 20% in
normal pregnancies, while fetal vascular lesions were observed
in 11% of FGR pregnancies
compared to only 4% in placentas from normal pregnancies (Kovo
et al., 2010).
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 13/26
-
Figure 5 Histologic features of villous and intervillous
lesions. (A) Increased syncytial knots: aggre-gates of
syncytiotrophoblast nuclei cluster at one or more poles of distal
villi in the vicinity of largerstem villi (arrowhead) at the
periphery of the lobule ([original magnification is indicated for
all panels]X 10). (B) Villous agglutination: clusters of
degenerating distal villi are adherent to one another andfocally
enmeshed in fibrin (X 4). (C) Distal villous hypoplasia: a long,
thin, non-branching stem villusis surrounded by a markedly reduced
number of small hypoplastic distal villi (X 10). (D)
Increasedintervillous fibrin: stem villi are surrounded by a mantle
of fibrin-type fibrinoid that does not extendto distal villi at the
center of the lobule (X 2). (E) Nodular intervillous (and
intravillous) fibrin: smallaggregates of intervillous fibrin adhere
to, and are focally reepithelialized by, distal villous
trophoblast(X 20). (F) Increased intervillous fibrin with
intermediate trophoblast (X-cells): stem and distal villi
areenmeshed in a matrix of fibrin and fibrinoid containing
prominent intermediate trophoblast (arrowhead)(X 10). From Redline
et al. (2004).
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 14/26
- Placentas from normotensive pregnancies complicated by early
onset FGR (
-
Figure 6 (A) Amniotic fluid tissue factor concentration among
women with normal pregnancies (me-dian 3,710.4 pg/mL, range
2,198.86,268) and patients with a fetal demise (median 8,535.4
pg/mL, range2,208.21,25,990.0). (B) Amniotic fluid tissue factor
activity among women with normal pregnancies(median 28.4 pM, range
10.284.9) and patients with a fetal demise (median 81.6 pM, range
7.21,603.4).From Erez et al. (2009).
of obstetrical complications, Erez et al. (2009) studied the
changes in the intra-amniotic
concentration of TAT III complexes, as well as TF concentration
and activity, in cases of
fetal demise and in normal pregnancies.
Patients with a fetal demise had higher median amniotic fluid TF
concentration and
activity than those with normal pregnancies. Moreover, among
patients with fetal demise
there was a significant correlation (Fig. 6) between the
amniotic fluid TF concentrations
and activity (r = 0.88, P < 0.0001). The median amniotic
fluid TAT III complexesconcentration did not differ significantly
between the groups (normal pregnancy: median:
66.3 mg/L, range 11.42,265.4 vs. fetal demise median: 59.3 mg/L,
range: 13.615,425.3;
P = 0.7). In their study, the median amniotic fluid TF
concentration in normal pregnantwomen was 10 fold higher than in
maternal plasma.
The changes in amniotic fluid thrombin generation were reported
also in women with
preterm parturition. Indeed, intra-amniotic infection and/or
inflammation is associated
with an increased amniotic fluid TAT III complexes (Fig. 7).
This is important since it
represents an increased thrombin generation in the amniotic
cavity during infection
and/or inflammation that may contribute to uterine contractility
and the development
of preterm birth (Stephenson et al., 2005). Of interest,
elevated intra-amniotic TAT
III concentrations were associated with a shorter amniocentesis
to delivery interval
and an earlier gestational age at delivery only in patients with
preterm labor without
intra-amniotic infection or inflammation (Stephenson et al.,
2005). This observation
suggests that in a subset of patients with preterm labor,
activation of the coagulation
system can generate preterm parturition and delivery; while in
those with intra-amniotic
infection and/or inflammation the activation of the coagulation
and thrombin generation
is a byproduct of the inflammatory process leading to preterm
birth.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 16/26
-
Figure 7 Maternal plasma TAT III concentration in women with
preterm labor (PTL) and those with anormal pregnancy. From
Chaiworapongsa et al. (2002).
This represents evidence of the activation and propagation of
coagulation cascade,
being thrombin generation the witness of the former mechanisms
and the inhibitor of the
initiation step (Erez et al., 2009).
CONCLUSIONThe evidence presented herein suggests a role for
increased thrombin generation and
vascular placental lesions in the pathogenesis of the great
obstetrical syndromes. This
process can be the result of the contribution of procoagulant
and vascular abnormalities
as well as inflammatory and infectious mechanisms, representing
the starting point for
pregnancy complications based on vascular disease.
As presented, these changes affect the mother, the placenta, the
membranes and the
amniotic fluid. Moreover, preliminary evidence suggests that
some of the changes in the
hemostatic system in the mother and in the amniotic fluid
predate the clinical presentation
of the disease. This means that better understanding of the
vascular and coagulation
changes associated with the great obstetrical syndromes may
assist us in earlier detection
and the development or introduction of therapeutic modalities
for these syndromes.
ADDITIONAL INFORMATION AND DECLARATIONS
FundingThe authors declare there was no funding for this
work.
Competing InterestsOffer Erez is an Academic Editor for
PeerJ.
Author Contributions Salvatore Andrea Mastrolia, Moshe Mazor,
Giuseppe Loverro, Vered Klaitman and Offer
Erez wrote the paper, prepared figures and/or tables, reviewed
drafts of the paper.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 17/26
-
REFERENCESAbdel Gader AM, Al-Mishari AA, Awadalla SA, Buyuomi
NM, Khashoggi T, Al-Hakeem M.
2006. Total and free tissue factor pathway inhibitor in
pregnancy hypertension. InternationalJournal of Gynaecology and
Obstetrics 95:248253 DOI 10.1016/j.ijgo.2006.07.014.
Aharon A, Brenner B, Katz T, Miyagi Y, Lanir N. 2004. Tissue
factor and tissue factor pathwayinhibitor levels in trophoblast
cells: implications for placental hemostasis. Thrombosis
andHaemostasis 92:776786.
Aharon A, Lanir N, Drugan A, Brenner B. 2005. Placental TFPI is
decreased in gestationalvascular complications and can be restored
by maternal enoxaparin treatment. Journal ofThrombosis and
Haemostasis 3:23552357 DOI 10.1111/j.1538-7836.2005.01564.x.
Andersson T, Lorentzen B, Hogdahl H, Clausen T, Mowinckel MC,
Abildgaard U. 1996.Thrombin-inhibitor complexes in the blood during
and after delivery. Thrombosis Research82:109117 DOI
10.1016/0049-3848(96)00057-6.
Arias F, Rodriquez L, Rayne SC, Kraus FT. 1993. Maternal
placental vasculopathy andinfection: two distinct subgroups among
patients with preterm labor and pretermruptured membranes. American
Journal of Obstetrics and Gynecology 168:585591DOI
10.1016/0002-9378(93)90499-9.
Ballard HS, Marcus AJ. 1972. Primary and secondary platelet
aggregation in uraemia.Scandinavian Journal of Haematology 9:198203
DOI 10.1111/j.1600-0609.1972.tb00931.x.
Bar J, Schreiber L, Ben-Haroush A, Ahmed H, Golan A, Kovo M.
2012. The placental vascularcomponent in early and late
intrauterine fetal death. Thrombosis Research 130:901905DOI
10.1016/j.thromres.2012.09.013.
Bellart J, Gilabert R, Miralles RM, Monasterio J, Cabero L.
1998. Endothelial cell markers andfibrinopeptide A to D-dimer ratio
as a measure of coagulation and fibrinolysis balance innormal
pregnancy. Gynecologic and Obstetric Investigation 46:1721 DOI
10.1159/000009989.
Beller FK, Ebert C. 1982. The coagulation and fibrinolytic
enzyme system in pregnancy and in thepuerperium. European Journal
of Obstetrics & Gynecology and Reproductive Biology
13:177197DOI 10.1016/0028-2243(82)90028-4.
Bilsel AS1, Onaran N, Moini H, Emerk K. 2000. Long-term effect
of 17beta-estradiol andthrombin on tissue factor pathway inhibitor
release from HUVEC. Thrombosis Research99:173178 DOI
10.1016/S0049-3848(00)00228-0.
Bremme KA. 2003. Haemostatic changes in pregnancy. Best Practice
& Research ClinicalHaematology 16:153168 DOI
10.1016/S1521-6926(03)00021-5.
Brenner B. 2004. Haemostatic changes in pregnancy. Thrombosis
Research 114:409414DOI 10.1016/j.thromres.2004.08.004.
Bretelle F, Arnoux D, Shojai R, DErcole C, Sampol J, Dignat F,
Camoin-Jau L. 2005. ProteinZ in patients with pregnancy
complications. American Journal of Obstetrics and
Gynecology193:16981702 DOI 10.1016/j.ajog.2005.04.006.
Broze JG. 2001. Protein-Z and thrombosis. Lancet 357:900901DOI
10.1016/S0140-6736(00)04229-X.
Broze GJ, Girard TJ, Novotny WF. 1990. Regulation of coagulation
by a multivalent Kunitz-typeinhibitor. Biochemistry 29:75397546 DOI
10.1021/bi00485a001.
Broze Jr GJ, Warren LA, Novotny WF, Higuchi DA, Girard JJ,
Miletich JP. 1988. Thelipoprotein-associated coagulation inhibitor
that inhibits the factor VII-tissue factor complexalso inhibits
factor Xa: insight into its possible mechanism of action. Blood
71:335343.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 18/26
-
Butenas S, Orfeo T, Brummel-Ziedins KE, Mann KG. 2007. Tissue
factor in thrombosis andhemorrhage. Surgery 142:S2S14 DOI
10.1016/j.surg.2007.06.032.
Butzow R, Virtanen I, Seppala M, Narvanen O, Stenman UH,
Ristimaki A, Bohn H. 1988.Monoclonal antibodies reacting with
placental protein 5: use in radioimmunoassay, Westernblot analysis,
and immunohistochemistry. Journal of Laboratory and Clinical
Medicine111:249256.
Carmeliet P, Mackman N, Moons L, Luther T, Gressens P, Van
Vlaenderen I, Demunck H,Kasper M, Breier G, Evrard P, Muller M,
Risau W, Edgington T, Collen D. 1996. Role of tissuefactor in
embryonic blood vessel development. Nature 383:7375 DOI
10.1038/383073a0.
Castoldi E, Hackeng TM. 2008. Regulation of coagulation by
protein S. Current Opinions inHematology 15:529536 DOI
10.1097/MOH.0b013e328309ec97.
Chaiworapongsa T, Espinoza J, Yoshimatsu J, Kim YM, Bujold E,
Edwin S, Yoon BH,Romero R. 2002. Activation of coagulation system
in preterm labor and preterm prematurerupture of membranes. Journal
of MaternalFetal and Neonatal Medicine 11(6):368373DOI
10.1080/jmf.11.6.368.373.
Chaiworapongsa T, Yoshimatsu J, Espinoza J, Kim YM, Berman S,
Edwin S, Yoon BH,Romero R. 2002. Evidence of in vivo generation of
thrombin in patients withsmall-for-gestational-age fetuses and
pre-eclampsia. Journal of MaternalFetal and NeonatalMedicine
11:362367 DOI 10.1080/jmf.11.6.362.367.
Chand HS, Foster DC, Kisiel W. 2005. Structure, function and
biology of tissue factor pathwayinhibitor-2. Thrombosis and
Haemostasis 94:11221130.
Concise Medical Dictionary. 2010. Oxford: Oxford University
Press.
Creter D. 1977. Amnioplastin: new reagent for coagulation tests.
Lancet 2:251DOI 10.1016/S0140-6736(77)92871-9.
Cromi A, Ghezzi F, Durig P, Di Naro E, Raio L. 2005. Sonographic
umbilical cord morphometryand coiling patterns in twin-twin
transfusion syndrome. Prenatal Diagnosis 25:851855DOI
10.1002/pd.1273.
Dahlback B, Carlsson M, Svensson PJ. 1993. Familial
thrombophilia due to a previouslyunrecognized mechanism
characterized by poor anticoagulant response to activated protein
C:prediction of a cofactor to activated protein C. Proceedings of
the National Academy of Sciencesof the United States of America
90:10041008 DOI 10.1073/pnas.90.3.1004.
de Boer K, ten Cate JW, Sturk A, Borm JJ, Treffers PE. 1989.
Enhanced thrombin generation innormal and hypertensive pregnancy.
American Journal of Obstetrics and Gynecology 160:95100DOI
10.1016/0002-9378(89)90096-3.
Edstrom CS, Calhoun DA, Christensen RD. 2000. Expression of
tissue factor pathwayinhibitor in human fetal and placental
tissues. Early Human Development 59:7784DOI
10.1016/S0378-3782(00)00084-0.
Eichinger S, Weltermann A, Philipp K, Hafner E, Kaider A, Kittl
EM, Brenner B, Mannhalter C,Lechner K, Kyrle PA. 1999. Prospective
evaluation of hemostatic system activation andthrombin potential in
healthy pregnant women with and without factor V Leiden.
Thrombosisand Haemostasis 82:12321236.
Elovitz MA, Ascher-Landsberg J, Saunders T, Phillippe M. 2000a.
The mechanisms underlyingthe stimulatory effects of thrombin on
myometrial smooth muscle. American Journal ofObstetrics and
Gynecology 183:674681 DOI 10.1067/mob.2000.106751.
Elovitz MA, Baron J, Phillippe M. 2001. The role of thrombin in
preterm parturition. AmericanJournal of Obstetrics and Gynecology
185:10591063 DOI 10.1067/mob.2001.117638.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 19/26
-
Elovitz MA, Saunders T, Ascher-Landsberg J, Phillippe M. 2000b.
Effects of thrombin onmyometrial contractions in vitro and in vivo.
American Journal of Obstetrics and Gynecology183:799804 DOI
10.1067/mob.2000.108897.
Erez O, Espinoza J, Chaiworapongsa T, Gotsch F, Kusanovic JP,
Than NG, Mazaki-Tovi S,Vaisbuch E, Papp Z, Yoon BH, Han YM,
Hoppensteadt D, Fareed J, Hassan SS, Romero R.2008. A link between
a hemostatic disorder and preterm PROM: a role for tissue factor
andtissue factor pathway inhibitor. Journal of MaternalFetal and
Neonatal Medicine 21:732744DOI 10.1080/14767050802361807.
Erez O, Gotsch F, Mazaki-Tovi S, Vaisbuch E, Kusanovic JP, Kim
CJ, Chaiworapongsa T,Hoppensteadt D, Fareed J, Than NG, Nhan-Chang
CL, Yeo L, Pacora P, Mazor M, Hassan SS,Mittal P, Romero R. 2009.
Evidence of maternal platelet activation, excessive
thrombingeneration, and high amniotic fluid tissue factor
immunoreactivity and functional activityin patients with fetal
death. Journal of MaternalFetal and Neonatal Medicine 22:672687DOI
10.1080/14767050902853117.
Erez O, Romero R, Hoppensteadt D, Than NG, Fareed J, Mazaki-Tovi
S, Espinoza J,Chaiworapongsa T, Kim SS, Yoon BH, Hassan SS, Gotsch
F, Friel L, Vaisbuch E,Kusanovic JP. 2008. Tissue factor and its
natural inhibitor in pre-eclampsia and SGA. Journalof MaternalFetal
and Neonatal Medicine 21:855869 DOI 10.1080/14767050802361872.
Erez O, Romer R, Vaisbuch E, Chaiworapongsa T, Kusanovic JP,
Mazaki-Tovi S, Gotsch F,Gomez R, Maymon E, Pacora P, Edwin SS, Kim
CJ, Than NG, Mittal P, Yeo L, Dong Z,Yoon BH, Hassan SS, Mazor M.
2009. Changes in amniotic fluid concentration
ofthrombinantithrombin III complexes in patients with preterm
labor: evidence of anincreased thrombin generation. Journal of
MaternalFetal and Neonatal Medicine 22:971982DOI
10.3109/14767050902994762.
Erez O, Romero R, Vaisbuch E, Kusanovic JP, Mazaki-Tovi S,
Chaiworapongsa T, Gotsch F,Fareed J, Hoppensteadt D, Than NG, Yoon
BH, Edwin S, Dong Z, Espinoza J, Mazor M,Hassan SS. 2010. High
tissue factor activity and low tissue factor pathway
inhibitorconcentrations in patients with preterm labor. Journal of
MaternalFetal and Neonatal Medicine23:2333 DOI
10.3109/14767050902994770.
Erlich J, Parry GC, Fearns C, Muller M, Carmeliet P, Luther T,
Mackman N. 1999. Tissue factoris required for uterine hemostasis
and maintenance of the placental labyrinth during
gestation.Proceedings of the National Academy of Sciences of the
United States of America 96:81388143DOI
10.1073/pnas.96.14.8138.
Faught W, Garner P, Jones G, Ivey B. 1995. Changes in protein C
and protein S levelsin normal pregnancy. American Journal of
Obstetrics and Gynecology 172:147150DOI
10.1016/0002-9378(95)90104-3.
Gervasi MT, Chaiworapongsa T, Naccasha N, Pacora P, Berman S,
Maymon E, Kim JC,Kim YM, Yoshimatsu J, Espinoza J, Romero R. 2002.
Maternal intravascular inflammationin preterm premature rupture of
membranes. Journal of MaternalFetal and Neonatal Medicine11:171175
DOI 10.1080/jmf.11.3.171.175.
Gomez R, Romero R, Nien JK, Medina L, Carstens M, Kim YM,
Chaiworapongsa T, Espinoza J,Gonzalez R. 2005. Idiopathic vaginal
bleeding during pregnancy as the only clinicalmanifestation of
intrauterine infection. Journal of MaternalFetal and Neonatal
Medicine18:3137 DOI 10.1080/14767050500217863.
Gris JC, Quere I, Dechaud H, Mercier E, Pincon C, Hoffet M,
Vasse M, Mares P. 2002. Highfrequency of protein Z deficiency in
patients with unexplained early fetal loss. Blood99:26062608 DOI
10.1182/blood.V99.7.2606.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 20/26
-
Hackeng TM, Sere KM, Tans G, Rosing J. 2006. Protein S
stimulates inhibition of the tissue factorpathway by tissue factor
pathway inhibitor. Proceedings of the National Academy of Sciences
ofthe United States of America 103:31063111 DOI
10.1073/pnas.0504240103.
Han X, Fiehler R, Broze GJ. 1998. Isolation of a protein
Z-dependent plasma protease inhibitor.Proceedings of the National
Academy of Sciences of the United States of America 95:92509255DOI
10.1073/pnas.95.16.9250.
Han X, Fiehler R, Broze GJ. 2000. Characterization of the
protein Z-dependent protease inhibitor.Blood 96:30493055.
Han X, Huang ZF, Fiehler R, Broze Jr GJ. 1999. The protein
Z-dependent protease inhibitor is aserpin. Biochemistry
38:1107311078 DOI 10.1021/bi990641a.
Hayashi M1, Inoue T, Hoshimoto K, Negishi H, Ohkura T, Inaba N.
2002. Characterization offive marker levels of the hemostatic
system and endothelial status in normotensive pregnancyand
pre-eclampsia. European Journal of Haematology 69:297302DOI
10.1034/j.1600-0609.2002.02691.x.
Hayashi M, Numaguchi M, Ohkubo N, Yaoi Y. 1998. Blood macrophage
colony-stimulatingfactor and thrombinantithrombin III complex
concentrations in pregnancy and preeclampsia.American Journal of
the Medical Sciences 315:251257DOI
10.1097/00000441-199804000-00007.
Hayashi M, Ohkura T. 2002. Elevated levels of serum macrophage
colony-stimulating factor innormotensive pregnancies complicated by
intrauterine fetal growth restriction. ExperimentalHematology
30:388393 DOI 10.1016/S0301-472X(02)00790-7.
Holmes VA, Wallace JM. 2005. Haemostasis in normal pregnancy: a
balancing act? BiochemicalSociety Transactions 33:428432 DOI
10.1042/BST0330428.
Hube F, Reverdiau P, Iochmann S, Trassard S, Thibault G, Gruel
Y. 2003. Demonstration of atissue factor pathway inhibitor 2
messenger RNA synthesis by pure villous cytotrophoblastcells
isolated from term human placentas. Biology of Reproduction
68:18881894DOI 10.1095/biolreprod.102.011858.
Iino M, Foster DC, Kisiel W. 1998. Quantification and
characterization of human endothelialcell-derived tissue factor
pathway inhibitor-2. Arteriosclerosis, Thrombosis, and Vascular
Biology18:4046 DOI 10.1161/01.ATV.18.1.40.
Isermann B, Sood R, Pawlinski R, Zogg M, Kalloway S, Degen JL,
Mackman N, Weiler H. 2003.The thrombomodulin-protein C system is
essential for the maintenance of pregnancy. NatureMedicine 9:331337
DOI 10.1038/nm825.
Kamei S, Kazama Y, Kuijper JL, Foster DC, Kisiel W. 2001.
Genomic structure and promoteractivity of the human tissue factor
pathway inhibitor-2 gene. Biochimica et BiophysicaACTA/General
Subjects 1517:430435 DOI 10.1016/S0167-4781(00)00298-0.
Kim YM, Chaiworapongsa T, Gomez R, Bujold E, Yoon BH, Rotmensch
S, Thaler HT,Romero R. 2002. Failure of physiologic transformation
of the spiral arteries in the placental bedin preterm premature
rupture of membranes. American Journal of Obstetrics and
Gynecology187:11371142 DOI 10.1067/mob.2002.127720.
Kisiel W, Sprecher CA, Foster DC. 1994. Evidence that a second
human tissue factor pathwayinhibitor (TFPI-2) and human placental
protein 5 are equivalent. Blood 84:43844385.
Kobayashi T, Sumimoto K, Tokunaga N, Sugimura M, Nishiguchi T,
Kanayama N, Terao T.2002. Coagulation index to distinguish severe
preeclampsia from normal pregnancy. Seminarsin Thrombosis and
Hemostasis 28:495500 DOI 10.1055/s-2002-36689.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 21/26
-
Kobayashi T, Terao T. 1987. Preeclampsia as chronic disseminated
intravascular coagulation.Study of two parameters:
thrombinantithrombin III complex and D-dimers. Gynecologic
andObstetric Investigation 24:170178 DOI 10.1159/000298799.
Kobayashi T, Tokunaga N, Sugimura M, Suzuki K, Kanayama N,
Nishiguchi T, Terao T. 1999.Coagulation/fibrinolysis disorder in
patients with severe preeclampsia. Seminars in Thrombosisand
Hemostasis 25:451454 DOI 10.1055/s-2007-994949.
Kovo M, Schreiber L, Bar J. 2013. Placental vascular pathology
as a mechanism ofdisease in pregnancy complications. Thrombosis
Research 131(Suppl 1):S18S21DOI 10.1016/S0049-3848(13)70013-6.
Kovo M, Schreiber L, Ben-Haroush A, Gold E, Golan A, Bar J.
2012. The placental component inearly-onset and late-onset
preeclampsia in relation to fetal growth restriction. Prenatal
Diagnosis32:632637 DOI 10.1002/pd.3872.
Kovo M, Schreiber L, Ben-Haroush A, Wand S, Golan A, Bar J.
2010. Placental vascularlesion differences in pregnancy-induced
hypertension and normotensive fetalgrowth restriction. American
Journal of Obstetrics and Gynecology 202:561.e1561.e5DOI
10.1016/j.ajog.2010.01.012.
Ku DH, Arkel YS, Paidas MP, Lockwood CJ. 2003. Circulating
levels of inflammatory cytokines(IL-1 beta and TNF-alpha),
resistance to activated protein C, thrombin and fibrin generation
inuncomplicated pregnancies. Thrombosis and Haemostasis
90:10741079.
Kuczynski J, Uszynski W, Zekanowska E, Soszka T, Uszynski M.
2002. Tissue factor(TF) and tissue factor pathway inhibitor (TFPI)
in the placenta and myometrium.European Journal of Obstetrics &
Gynecology and Reproductive Biology 105:1519DOI
10.1016/S0301-2115(02)00113-6.
Kupferminc MJ, Many A, Bar-Am A, Lessing JB, Ascher-Landsberg J.
2002. Mid-trimester severeintrauterine growth restriction is
associated with a high prevalence of thrombophilia.
BJOG109:13731376 DOI 10.1046/j.1471-0528.2002.02194.x.
Kusanovic JP, Espinoza J, Romero R, Hoppensteadt D, Nien JK, Kim
CJ, Erez O, Soto E,Fareed J, Edwin S, Chaiwerapongsa T, Than NG,
Yoon BH, Gomez R, Papp Z, Hassan SS.2007. Plasma protein Z
concentrations in pregnant women with idiopathic
intrauterinebleeding and in women with spontaneous preterm labor.
Journal of MaternalFetal andNeonatal Medicine 20:453463 DOI
10.1080/14767050701398272.
Lanir N, Aharon A, Brenner B. 2003. Procoagulant and
anticoagulant mechanisms in humanplacenta. Seminars in Thrombosis
and Hemostasis 29:175184 DOI 10.1055/s-2003-38833.
Laskowski M, Kato I. 1980. Protein inhibitors of proteinases.
Annual Review of Biochemistry49:593626 DOI
10.1146/annurev.bi.49.070180.003113.
Lockwood CJ. 2006. Pregnancy-associated changes in the
hemostatic system. Clinical Obstetricsand Gynecology 49:836843 DOI
10.1097/01.grf.0000211952.82206.16.
Lockwood CJ, Bach R, Guha A, Zhou XD, Miller WA, Nemerson Y.
1991. Amniotic fluid containstissue factor, a potent initiator of
coagulation. American Journal of Obstetrics and
Gynecology165:13351341 DOI 10.1016/S0002-9378(12)90756-5.
Lockwood CJ, Krikun G, Rahman M, Caze R, Buchwalder L, Schatz F.
2007. The role ofdecidualization in regulating endometrial
hemostasis during the menstrual cycle,gestation, and in
pathological states. Seminars in Thrombosis and Hemostasis
33:111117DOI 10.1055/s-2006-958469.
Lockwood CJ, Krikun G, Schatz F. 1999. The decidua regulates
hemostasis in humanendometrium. Seminars in Reproductive
Endocrinology 17:4551 DOI 10.1055/s-2007-1016211.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 22/26
-
Lockwood CJ, Krikun G, Schatz F. 2001. Decidual cell-expressed
tissue factor maintainshemostasis in human endometrium. Annals of
the New York Academy of Sciences 943:7788DOI
10.1111/j.1749-6632.2001.tb03793.x.
Lockwood CJ, Toti P, Arcuri F, Paidas M, Buchwalder L, Krikun G,
Schatz F. 2005. Mechanismsof abruption-induced premature rupture of
the fetal membranes: thrombin-enhancedinterleukin-8 expression in
term decidua. American Journal of Pathology 167:14431449DOI
10.1016/S0002-9440(10)61230-8.
Mackenzie AP, Schatz F, Krikun G, Funai EF, Kadner S, Lockwood
CJ. 2004. Mechanisms ofabruption-induced premature rupture of the
fetal membranes: thrombin enhanced decidualmatrix
metalloproteinase-3 (stromelysin-1) expression. American Journal of
Obstetrics andGynecology 191:19962001 DOI
10.1016/j.ajog.2004.08.003.
Martinelli I, Legnani C, Bucciarelli P, Grandone E, De Stefano
V, Mannucci PM. 2001. Risk ofpregnancy-related venous thrombosis in
carriers of severe inherited thrombophilia. Thrombosisand
Haemostasis 86:800803.
Mayhew TM, Ohadike C, Baker PN, Crocker IP, Mitchell C, Ong SS.
2003. Stereologicalinvestigation of placental morphology in
pregnancies complicated by pre-eclampsia with andwithout
intrauterine growth restriction. Placenta 24:219226 DOI
10.1053/plac.2002.0900.
Midderdorp S. 2007. Thrombophilia and pregnancy complications:
cause or association? Journalof Thrombosis and Haemostasis 5(Suppl
1):276282 DOI 10.1111/j.1538-7836.2007.02501.x.
Nath CA, Ananth CV, Smulian JC, Shen-Schwarz S, Kaminsky L.
2007. New Jersey-placentalabruption study investigators. Histologic
evidence of inflammation and risk ofplacental abruption. American
Journal of Obstetrics and Gynecology 197:319.e1319.e6DOI
10.1016/j.ajog.2007.06.012.
Ndonwi M, Broze G. 2008. Protein S enhances the tissue factor
pathway inhibitor inhibitionof factor Xa but not its inhibition of
factor VIIa-tissue factor. Journal of Thrombosis andHaemostasis
6:10441046 DOI 10.1111/j.1538-7836.2008.02980.x.
Nien JK, Romero R, Hoppensteadt D, Erez O, Espinoza J, Soto E,
Kusanovic JP, Gotsch F,Kim CJ, Mittal P, Fareed J, Santolaya J,
Chaiworapongsa T, Edwin S, Pineles B, Hassan S.2008. Pyelonephritis
during pregnancy: a cause for an acquired deficiency of protein Z.
Journalof MaternalFetal and Neonatal Medicine 21:629637 DOI
10.1080/14767050802214659.
Obiewke BC, Chard T. 1981. Placental protein 5: circulating
levels in twin pregnancyand some observations on the analysis of
biochemical data from multiple pregnancy.European Journal of
Obstetrics & Gynecology and Reproductive Biology 12:135141DOI
10.1016/0028-2243(81)90068-X.
Ogge G, Chaiworapongsa T, Romero R, Hussein Y, Kusanovic JP, Yeo
L, Kim CJ, Hassan SS.2011. Placental lesions associated with
maternal underperfusion are more frequent inearly-onset than in
late-onset preeclampsia. Journal of Perinatal Medicine 39:641652DOI
10.1515/jpm.2011.098.
Omsj IH, Oian P, Maltau JM, Osterud B. 1985. Thromboplastin
activity in amniotic fluid.Gynecologic and Obstetric Investigation
19:15 DOI 10.1159/000299000.
sterud B, Bjrklid E. 2006. Sources of tissue factor. Seminars in
Thrombosis and Hemostasis32:1123 DOI 10.1055/s-2006-933336.
Paidas MJ, Ku DH, Lee MJ, Manish S, Thurston A, Lockwood CJ,
Arkel YS. 2005. Protein Z, pro-tein S levels are lower in patients
with thrombophilia and subsequent pregnancy complications.Journal
of Thrombosis and Haemostasis 3:497501 DOI
10.1111/j.1538-7836.2005.01158.x.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 23/26
-
Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard
J, Fontcuberta J, Makris M,Mariani G, Noteboom W, Pabinger I,
Legnani C, Scharrer I, Schulman S, Van der Meer FJ.1996. Increased
fetal loss in women with heritable thrombophilia. Lancet
348:913916DOI 10.1016/S0140-6736(96)04125-6.
Reber G, Amiral J, de Moerloose P. 1998. Modified antithrombin
III levels during normalpregnancy and relationship with prothrombin
fragment F1 + 2 and thrombinantithrombincomplexes. Thrombosis
Research 91:4547 DOI 10.1016/S0049-3848(98)00043-7.
Redline RW, Heller D, Keating S, Kingdom J. 2005. Placental
diagnostic criteriaand clinical correlationa workshop report.
Placenta 26(Suppl A):S114S117DOI
10.1016/j.placenta.2005.02.009.
Redline RW, Boyd T, Campbell V, Hyde S, Kaplan C, Khong TY,
Prashner HR, Waters BL,Society for Pediatric Pathology, Perinatal
Section, Maternal Vascular Perfusion NosologyCommittee. 2004.
Maternal vascular underperfusion: nosology and reproducibility of
placentalreaction patterns. Pediatric and Developmental Pathology
7(3):237249.
Reinthaller A, Mursch-Edlmayr G, Tatra G. 1990.
Thrombinantithrombin III complex levels innormal pregnancy with
hypertensive disorders and after delivery. British Journal of
Obstetricsand Gynaecology 97:506510 DOI
10.1111/j.1471-0528.1990.tb02520.x.
Rerdline RW. 2008. Placental pathology: a systematic approach
with clinical correlations. Placenta29(Suppl A):S86S91 DOI
10.1016/j.placenta.2007.09.003.
Roberts DJ, Post MD. 2008. The placenta in pre-eclampsia and
intrauterine growth restriction.Journal of Clinical Pathology
61:12541260 DOI 10.1136/jcp.2008.055236.
Rodger MA, Paidas M, McLintock C, Middeldorp S, Kahn S,
Martinelli I, Hague W, RoseneMontella K, Greer I. 2008. Inherited
thrombophilia and pregnancy complications revisited.Obstetrics and
Gynecology 112:320324 DOI 10.1097/AOG.0b013e31817e8acc.
Romero R. 2009. Prenatal medicine: the child is the father of
the man. 1996. Journal ofMaternalFetal and Neonatal Medicine
22:636639 DOI 10.1080/14767050902784171.
Romero R, Espinoza J, Kusanovic JP, Gotsch F, Hassan S, Erez O,
Chaiworapongsa T,Mazor M. 2006. The preterm parturition syndrome.
BJOG 113(Suppl 3):1742DOI 10.1111/j.1471-0528.2006.01120.x.
Romero R, Goncalves LF, Kusanovic JP, Devesa R, Espinoza J.
2006. Mechanisms of pretermlabor and preterm premature rupture of
the membranes. In: Kurjak A, Chervenak F, eds.Textbook of perinatal
medicine. 2nd Edition. Milton Park: Informa Healthcare,
13791393.
Rosen T, Kuczynski E, ONeill LM, Funai EF, Lockwood CJ. 2001.
Plasma levels ofthrombinantithrombin complexes predict preterm
premature rupture of the fetal membranes.Journal of MaternalFetal
and Neonatal Medicine 10:297300 DOI 10.1080/jmf.10.5.297.300.
Rosen T, Schatz F, Kuczynski E, Lam H, Koo AB, Lockwood CJ.
2002. Thrombin-enhancedmatrix metalloproteinase-1 expression: a
mechanism linking placental abruption withpremature rupture of the
membranes. Journal of MaternalFetal and Neonatal Medicine11:1117
DOI 10.1080/jmf.11.1.11.17.
Salafia CM, Minior VK, Pezzullo JC, Popek EJ, Rosenkrantz TS,
Vintzileos AM. 1995.Intrauterine growth restriction in infants of
less than thirty-two weeks gestation: associatedplacental
pathologic features. American Journal of Obstetrics and Gynecology
173:10491057DOI 10.1016/0002-9378(95)91325-4.
Salafia CM, Pezzullo JC, Ghidini A, Lope`z-Zeno JA, Whittington
SS. 1998. Clinical correlationsof patterns of placental pathology
in preterm pre-eclampsia. Placenta 19:6772DOI
10.1016/S0143-4004(98)90100-X.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 24/26
-
Salafia CM, Vogel CA, Vintzileos AM, Bantham KF, Pezzullo J,
Silberman L. 1991. Placentalpathologic findings in preterm birth.
American Journal of Obstetrics and Gynecology165:934938 DOI
10.1016/0002-9378(91)90443-U.
Sarig G, Blumenfeld Z, Leiba R, Lanir N, Brenner B. 2005.
Modulation of systemic hemostaticparameters by enoxaparin during
gestation in women with thrombophilia and pregnancy loss.Thrombosis
and Haemostasis 94:980985.
Schjetlein R, Abdelnoor M, Haugen G, Husby H, Sandset PM, Wislff
F. 1999. Hemostaticvariables as independent predictors for fetal
growth retardation in preeclampsia. ACTAObstetricia et Gynecologica
Scandinavica 78:191197 DOI 10.1080/j.1600-0412.1999.780304.x.
Seppala M, Wahlstrom T, Bohn H. 1979. Circulating levels and
tissue localization of placentalprotein five (PP5) in pregnancy and
trophoblastic disease: absence of PP5 expression in themalignant
trophoblast. International Journal of Cancer 24:610 DOI
10.1002/ijc.2910240103.
Sheu JR, Hsiao G, Luk HN, Chen YW, Chen TL, Lee LW, Lin CH, Chou
DS. 2002. Mechanismsinvolved in the antiplatelet activity of
midazolam in human platelets. Anesthesiology 96:651658DOI
10.1097/00000542-200203000-00022.
Shimura M, Wada H, Wakita Y, Nakase T, Hiyoyama K, Nagaya S,
Mori Y, Shiku H.1997. Plasma tissue factor and tissue factor
pathway inhibitor levels in patients withdisseminated intravascular
coagulation. American Journal of Hematology 55:169174DOI
10.1002/(SICI)1096-8652(199707)55:43.0.CO;2-Q.
Sood R, Kalloway S, Mast AE, Hillard CJ, Weiler H. 2006.
Fetomaternal cross talk in theplacental vascular bed: control of
coagulation by trophoblast cells. Blood 107:31733180DOI
10.1182/blood-2005-10-4111.
Sood R, Sholl L, Isermann B, Zogg M, Coughlin SR, Weiler H.
2008. Maternal Par4 and plateletscontribute to defective placenta
formation in mouse embryos lacking thrombomodulin. Blood112:585591
DOI 10.1182/blood-2007-09-111302.
Srensen JD, Secher NJ, Jespersen J. 1995. Perturbed
(procoagulant) endothelium and deviationswithin the fibrinolytic
system during the third trimester of normal pregnancy. A
possiblelink to placental function. ACTA Obstetricia et
Gynecologica Scandinavica 74:257261DOI
10.3109/00016349509024445.
Sprecher CA, Kisiel W, Mathewes S, Foster DC. 1994. Molecular
cloning, expression, and partialcharacterization of a second human
tissue-factor-pathway inhibitor. Proceedings of the NationalAcademy
of Sciences of the United States of America 91:33533357 DOI
10.1073/pnas.91.8.3353.
Stephenson CD, Lockwood CJ, Ma Y, Guller S. 2005.
Thrombin-dependent regulation of matrixmetalloproteinase (MMP)-9
levels in human fetal membranes. Journal of MaternalFetal
andNeonatal Medicine 18:1722 DOI 10.1080/14767050500123632.
Stirling Y, Woolf L, North WR, Seghatchian MJ, Meade TW. 1984.
Haemostasis in normalpregnancy. Thrombosis and Haemostasis
52:176182.
Tay SP, Cheong SK, Boo NY. 2003. Circulating tissue factor,
tissue factor pathway inhibitor andD-dimer in umbilical cord blood
of normal term neonates and adult plasma. Blood Coagulation&
Fibrinolysis 14:125129 DOI 10.1097/00001721-200302000-00002.
Taylor FB, Chang AC, Peer G, Li A, Ezban M, Hedner U. 1998.
Active site inhibited factor VIIa(DEGR VIIa) attenuates the
coagulant and interleukin-6 and -8, but not tumor necrosis
factor,responses of the baboon to LD100 Escherichia coli. Blood
91:16091615.
Teng Y, Jiang R, Lin Q, Ding C, Ye Z. 2010. The relationship
between plasma and placental tissuefactor, and tissue factor
pathway inhibitors in severe pre-eclampsia patients.
ThrombosisResearch 126:e41e45 DOI
10.1016/j.thromres.2010.02.012.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 25/26
-
Udagawa K, Miyagi Y, Hirahara F, Miyagi E, Nagashima Y,
Minaguchi H, Misugi K,Yasumitsu H, Miyazaki K. 1998. Specific
expression of PP5/TFPI2 mRNA bysyncytiotrophoblasts in human
placenta as revealed by in situ hybridization. Placenta19:217223
DOI 10.1016/S0143-4004(98)90011-X.
Uszynski M. 1997. Generation of thrombin in blood plasma of
non-pregnant and pregnantwomen studied through concentration of
thrombinantithrombin III complexes.European Journal of Obstetrics
& Gynecology and Reproductive Biology 75:127131DOI
10.1016/S0301-2115(97)00101-2.
Uszynski M, Zekanowska E, Uszynski W, Kuczynski J. 2001. Tissue
factor (TF) and tissue factorpathway inhibitor (TFPI) in amniotic
fluid and blood plasma: implications for the mechanismof amniotic
fluid embolism. European Journal of Obstetrics & Gynecology and
ReproductiveBiology 95:163166 DOI
10.1016/S0301-2115(00)00448-6.
VanWijk MJ, Boer K, Berckmans RJ, Meijers JC, Van der Post JA,
Sturk A, VanBavel E,Nieuwland R. 2002. Enhanced coagulation
activation in preeclampsia: the role of APCresistance,
microparticles and other plasma constituents. Thrombosis and
Haemostasis88:415420.
Walker MC, Garner PR, Keely EJ, Rock GA, Reis MD. 1997. Changes
in activated proteinC resistance during normal pregnancy. American
Journal of Obstetrics and Gynecology177:162169 DOI
10.1016/S0002-9378(97)70456-3.
Xiong Y, Zhou Q, Jiang F, Zhou S, Lou Y, Guo Q, Liang W, Kong D,
Ma D, Li X. 2010. Changesof plasma and placental tissue factor
pathway inhibitor-2 in women with preeclampsia andnormal pregnancy.
Thrombosis Research 125:e317e322 DOI
10.1016/j.thromres.2010.02.017.
Yalinkaya A, Erdemoglu M, Akdeniz N, Kale A, Kale E. 2006. The
relationship betweenthrombophilic mutations and preeclampsia: a
prospective case-control study. Annals of SaudiMedicine
26:105109.
Yin ZF, Huang ZF, Cui J, Fiehler R, Lasky N, Ginsburg D, Broze
Jr GJ. 2000. Prothromboticphenotype of protein Z deficiency.
Proceedings of the National Academy of Sciences of the UnitedStates
of America 97:67346738 DOI 10.1073/pnas.120081897.
Yoneyama Y, Suzuki S, Sawa R, Otsubo Y, Power GG, Araki T. 2000.
Plasma adenosine levelsincrease in women with normal pregnancies.
American Journal of Obstetrics and Gynecology182:12001203 DOI
10.1067/mob.2000.104832.
Yuen PM, Yin JA, Lao TT. 1989. Fibrinopeptide A levels in
maternal and newbornplasma. European Journal of Obstetrics &
Gynecology and Reproductive Biology 30:239244DOI
10.1016/0028-2243(89)90007-5.
Mastrolia et al. (2014), PeerJ, DOI 10.7717/peerj.653 26/26
Placental vascular pathology and increased thrombin generation
as mechanisms of disease in obstetrical syndromesIntroductionWhat
are the Great Obstetrical Syndromes?What are the Changes in the
Coagulation System During Normal Pregnancy?What are the Changes in
the Hemostatic System Associated with the Great Obstetrical
Syndromes?Changes in the hemostatic system of women with
obstetrical syndromesChanges in the feto-maternal
interfaceHemostatic changes in the amniotic fluid of women with
obstetrical syndromes
ConclusionReferences