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The contact between placenta and
maternal circulation is crucial for
the success of pregnancy. Pro-
thrombotic changes and
thrombosis may interfere with
these processes leading to
adverse pregnancy outcomes at
any gestational age
The antiphospholipid syndrome.
hyperhomocysteinemia (C677T) mutation ).
FV Leiden mutation (A506G) mutation ).
mutation in prothrombin (G 20210 A) .
The prothrombin II (PTII) mutation.
protein S deficiency.
Protein C deficiency.
lupus anticoagulant antibodies
Placental pathologists use the term placental
vasculopathy to describe pathological placental
changes were found to be associated with
some clinical conditions such as preeclampsia,
IUGR, placental abruption and some cases of
fetal loss and preterm labor .
In the antiphospholipid
antibody syndrome the body
(part of a cell's membrane)
as foreign and produces
antibodies against them.
APA syndrome is an acquired
autoimmune thrombophilia in which
vascular thrombosis and/or recurrent
pregnancy losses occur in patients
having laboratory evidence for
antibodies against phospholipids or
phospholipid-binding protein cofactors
in their blood.
Antiphospholipid antibodies are a family of
approximately 20 antibodies directed
against negatively charged phospholipid
only the lupus anticoagulant and
anticardiolipin antibodies (IgG and IgM
subclass, but not IgA) have been shown to
be of clinical significance.
primary APS (PAPS) (53%)
secondary APS (47%) .
(37%) Secondary APS (SAPS) associated
with SLE or SLE-like syndrome.
Females are more frequently affected
than males. It mainly affects the second
and third decades of life.
"Euro-Phospholipid Project Group". in a cohort of 1000 patients. Arthritis
The mechanism of aPL-associated
pregnancy loss is related to the
adverse effect of these
antibodies on embryonic
implantation, trophoblast function
and differentiation. and placental
PRINCIPAL PATHOGENIC MECHANISMS MEDIATED BY APL
protein C/S pathway
a) soluble coagulation
induction of a pro-adhesive, pro-
inflammatory and pro-coagulant
induction of a procoagulant
phenotype in monocytes
b) coagulation cells:
reduction of proliferation and
a) trophoblast cells:
An International Consensus Conference held in
Sapporo in 1998 stated that recurrent arterial and/or
venous thrombosis and/or miscarriages in the
persistent presence of a positive anti-phospholipid test
are formal classification criteria for APS
thrombosis, one or more confirmed episodes of
venous, arterial, or small vessels disease .
pregnancy criteria :
one or more unexplained fetal deaths after ten weeks
one or more preeclampsia or placental
insufficiencies occurring before 34 weeks .
three or more unexplained consecutive spontaneous
abortions less than 10 weeks.
OBSTETRICAL AND FETAL MANIFESTATIONS IN THE COHORT OF 1,000
ENROLLED BY THE EUROPEAN APL FORUM
0.3Post-partum cardio-pulmonary syndrome
36Early fetal losses
17Late fetal losses
The laboratory criteria are medium or high
titer, not low titer, IgG or IgM anticardiolipin
antibody, and/or a lupus anticoagulant on
two or more occasions at least six weeks
When the aPTT is prolonged and not
"correctable" by mixture with normal plasma,
the presence of an "anticoagulant" or
"inhibitor" should be suspected
three important inherited thrombophilias :
mutation in factor V causing Resistance to activated
protein C (responsible of 20–30% of venous
mutation in prothrombin (guanine 20210 adenine )
mutation in methylenetetrahydrofolate reductase
(MTHFR) (cytosine 677 thymine (C677T) ) The
mutation is responsible for reduced MTHFR activity
and is the most frequent cause of mild
hyperhomocysteinemia and can be found in 5–15% of
A high rate of protein S deficiency,
APCR, hyperhomocysteinemia and
aCL IgG or IgM was found in women
with severe preeclampsia .
Dekker et al Am J Obstet Gynecol 1995
higher prevalence of FV Leiden mutation
in women with severe preeclampsia
compared to controls.
Nagy et al Clin genet 1998
120 women with severe preeclampsia,
(72% nulliparous) and 101 healthy
matched for age and parity. 18.3% of
preeclamptic women were carriers of the
FV Leiden mutation compared to 3% in
Rigo et al Hypertens Pregnancy 2000
110 healthy women who had during pregnancy
severe preeclampsia, IUGR , severe abruptio
placentae and stillbirth were enrolled in the study.
The control group comprised 110 healthy
matched women with normal pregnancies. All 220
patients were tested for all known thrombophilias
at least 2 months after delivery.
The total prevalence of all thrombophilias
detected in the 110 women with complications
was 65% compared to 18% in controls.
Kupferminc et al N Eng J Med 1999
in USA tested the genetic thrombophilic
mutations in 110 women with severe
preeclampsia and 97 controls. Most
women were nulliparous and 60% of them
were African Americans. No difference
was found in the prevalence of
thrombophilias between the women with
severe preeclampsia and control women
groups, or in fetal genetic thrombophilias.
Livingstone et al Am J Obstet Gynecol 2001
tested 113 nulliparous women with
preeclampsia: 100 with severe disease, 13
with mild disease and 103 controls for the
C677T polymorphism of the MTHFR gene.
No difference in homozygosity for MTHFR
was found between the 2 groups
(preeclampsia 3% vs controls 6%)
Laivuori et al in Finland Obstet Gynecol 2000,
factor V Leiden
adenine 506 guanine (A506G) mutation in factor V
(factor V Leiden) (a substitution of glutamine for
arginine at amino acid 506 of factor V) Factor V
Leiden (FVL) is a mutation in the factor V
molecule, rendering it resistant to cleavage
by activated protein C. Factor V remains a
procoagulant and thus predisposes the
carrier to clot formation.
It has been linked with an increased risk for
venous thromboembolism due to Resistance to
activated protein C and is responsible of 20–
30% of venous thromboembolism events
The Factor V Leiden (FVL) mutation, present in 3-
8% of the general population, leads to less than
normal anticoagulant response to activated
protein C resulting in an increased risk for
Individuals with one copy of the FVL gene
mutation (heterozygotes) have a seven fold
increased risk for thrombosis compared to the
general population whereas homozygotes have
an eighty fold increase.
factor V Leiden
prothrombin (G20210A) mutation
A change of G to A at position 20210
in prothrombin (prothrombin 20210A)
elevates baseline prothrombin levels
and thrombin formation.
MTHFR (C677T) mutation
cytosine 677 thymine (C677T) mutation (a C to T
change at position 677 of MTHFR) is responsible
for reduced MTHFR activity results in decreased
synthesis of 5-methyltetrahydrofolate, the primary
methyl donor in the conversion of homocysteine to
methionine and the resulting increase in plasma
( Hyperhomocysteinemia ) is a risk factor for
Dietary restriction of folate and vitamin B12 remains
the most common cause.
A homozygous methylenetetrahydrofolate
reductase (MTHFR) mutation, present in
1-4% of the general population, is
associated with a three fold increased risk
for DVT or PE, as well as preeclampsia
and placental abruption.
MTHFR (C677T) mutation
Protein S deficiency
Protein S deficiency (PSD), present in up
to 2% of the general population, is found
in approximately 15% of individuals with a
DVT or PE and 6% of women with
obstetrical complications including a
relatively high risk for stillbirth.
Protein C deficiency
Protein C deficiency (PCD), present in
about 1.5% of the general population, is
associated with a lower risk for obstetrical
complications than PSD and is found in 3-
5% of individuals with a DVT or PE.
Furthermore, PCD combined with a FVL
mutation is a relatively common cause of
DVTs and show a higher risk for
thrombosis compared to FVL alone.
Antithrombin III deficiency
Antithrombin III deficiency (ATIII), present
in less than 0.5 % of the general
population, as with PSD and PCD, may
rarely result from mutational events
Because of its relative rarity, actual risks
for thrombotic events are difficult to
estimate, but without question this entity
contributes to thrombotic risks during
The gold standard therapy to prevent miscarriages
and obstetrical complications is represented by the
association of low-dose aspirin and heparin
(unfractionated or low molecular weight heparin).
Intravenous immunoglobulin has been used in
pregnant women with APS, but a recent controlled
study found no benefit in comparison to the
aspirin-heparin treatment .
The Pregnancy Loss Study Group. Am J Obstet Gynecol 2000; 182: 122-7
Recently, the Cochrane Collaboration reported a 15%
reduction in the risk of preeclampsia (32 trials with
29,331 women) and a 14% reduction in fetal and/or
neonatal death (30 trials with 30,093 women). This
reduction in death was the greatest amongst high-risk
women (4134 women).
The combination of aspirin and heparin or low
molecular weight (LMW) heparin is effective in
recurrent fetal loss in APS syndrome and could be
considered for women with inherited thrombophilias
and history of severe preeclampsia, IUGR, abruptio
placentae or fetal loss, although no controlled studies
on the subject are currently available
Antiplatelet drugs for prevention of pre-eclampsia and its
consequences: Systematic review.
Recurrent pre-eclampsia and/ or
embryonic loss without history of
1) Standard heparin: 5,000 - 7,500 U every 12
hours in the first trimester; 5,000 - 10,000 U every
12 hours in the second and third trimesters.
2) Low molecular weight heparin:
1) Enoxaparin 40 mg/day or dalteparin 5,000 U/day
or 2) Enoxaparin 30 mg every 12 hours or
dalteparin 5,000 U every 12 hours.
Fetal death or severe early pre-
eclampsia or severe placental
insufficiency, without history of
1) Standard heparin: 7,500 - 10,000 U every 12
hours in the first trimester; 10,000 U every 12
hours in the second and third trimesters.
2) Low molecular weight heparin:
1) Enoxaparin 40 mg/day daily or dalteparin 5,000
2) Enoxaparin 30 mg every 12 hours or dalteparin
5,000 U every 12 hours
Anticoagulation treatment in
women with previous thrombotic
1) Standard heparin: 7,500 U every 8-12 hours
adjusted to maintain the mid-interval heparin levels in
the therapeutic range.
2) Low molecular weight heparin:
1) Weight-adjusted (e.g., enoxaparin 1 mg/kg every 12
hours or dalteparin 200 U/kg every 12 hours), or
2) Intermediate dosage (e.g., enoxaparin 40 mg/day or
dalteparin 5,000 U/day until 16 weeks' gestation and
every 12 hours from 16 weeks' gestation onwards)
Treatment should be prolonged for life if aPL
positivity persists .
Whether or not APS patients can be safely
treated with intermediate-intensity warfarin
treatment (INR range from 2.0 to 2.9) or with a
high-intensity treatment (INR =3.0), is still a
matter for debate due to the report of severe
hemorrhagic complications associated with
high-intensity anticoagulation therapy .