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THROMBOSIS AND HEMOSTASIS
Comparative incidence of a first thrombotic event in purely obstetric
antiphospholipid syndrome with pregnancy loss: the NOH-APS
observational study
Jean-Christophe Gris,1-3 Sylvie Bouvier,1-3 Nicolas Molinari,4 Jean-Philippe Galanaud,2,5 Éva Cochery-Nouvellon,1,2
Érik Mercier,1-3 Pascale Fabbro-Peray,4 Jean-Pierre Balducchi,6 Pierre Marès,7 Isabelle Quéré,2,5 and Michel Dauzat2,5
1Department
of Hematology, University Hospital, Nîmes, France; 2Research Team EA2992, Dysfonction des Interfaces Vasculaires, University of Montpellier 1,
Nîmes, France; 3Laboratory of Hematology, Faculty of Pharmacy and Biological Sciences, Montpellier 1 University, Montpellier, France; and 4Departement of
Biostatistics, Epidemiology and Medical Information, 5Department of Vascular Medicine, 6Department of Internal Medicine, and 7Department of Gynecology and
Obstetrics, University Hospital, Nîmes, France
The incidence of thrombosis in the
purely obstetric form of antiphospholipid syndrome is uncertain. We performed a 10-year observational study of
1592 nonthrombotic women who had experienced 3 consecutive spontaneous
abortions before the 10th week of gestation or 1 fetal death at or beyond the
10th week of gestation. We compared the
frequencies of thrombotic events among
women positive for antiphospholipid Abs
(n ⴝ 517), women carrying the F5 6025 or
F2 rs1799963 polymorphism (n ⴝ 279),
and women with negative thrombophilia
screening results (n ⴝ 796). The annual
rates of deep vein thrombosis (1.46%;
range, 1.15%-1.82%), pulmonary embolism (0.43%; range, 0.26%-0.66%), superficial vein thrombosis (0.44%; range, 0.28%0.68%), and cerebrovascular events
(0.32%; range, 0.18%-0.53%) were significantly higher in aPLAbs women than in
the other groups despite low-dose aspirin
primary prophylaxis. Women carrying 1 of
the 2 polymorphisms did not experience
more thrombotic events than women who
screened negative for thrombophilia. Lupus anticoagulant was a risk factor for
unprovoked proximal and distal deep and
superficial vein thrombosis and women
in the upper quartile of lupus anticoagulant activity had the highest risk. Despite
data suggesting that aPLAbs may induce
pregnancy loss through nonthrombotic
mechanisms, women with purely obstetric antiphospholipid syndrome are at risk
for thrombotic complications. (Blood.
2012;119(11):2624-2632)
Introduction
Antiphospholipid syndrome (APS) is characterized clinically by
the occurrence of vascular events (arterial, venous, or small
vessel thrombosis) and/or pregnancy morbidity (repeated unexplained abortions before the 10th week, unexplained fetal death
at or beyond the 10th week, or premature birth before the 34th
week because of preeclampsia).1-3 The mandatory laboratory
criteria for APS are positive tests for antiphospholipid Abs
(aPLAbs) on 2 or more occasions at least 12 weeks apart.2 The 3
tests exploring aPLAbs are lupus anticoagulant (LA) detected
by coagulation assays, anticardiolipin Ab (aCL), and anti–␤2
glycoprotein I Ab (a␤2GP1) detected by standardized ELISA.2
ELISA-detected positive Abs must be of IgG and or IgM isotype
present in medium or high titer.
When identified in nonthrombotic women, pregnancy morbidity defines purely obstetric APS clinically. The risk of thrombosis in women with purely obstetric APS remains unclear,
although annual prevalence values between 7% and less than 1%
have been described previously.4-6 Discrepancies between the
estimated risk of thrombosis in purely obstetric APS patients has
led to disagreement regarding the benefit of prescribing prophylactic anti-thrombotic treatment for such women.
The Nimes Obstetricians and Hematologists Antiphospholipid Syndrome (NOH-APS) study compared the frequencies of thrombotic
events prospectively among groups of nonthrombotic women who had
experienced a pregnancy loss fulfilling the APS clinical criteria and who
were positive for aPLAbs, bore a constitutional thrombophilia (a F5
6025 or F2 rs1799963 polymorphism), or were negative for
thrombophilia.
Submitted September 22, 2011; accepted December 2, 2011. Prepublished
online as Blood First Edition paper, December 6, 2011; DOI 10.1182/blood-2011-09381913.
and Haemostasis, July 26, 2011 (O-TU-031) and July 27, 2011 (O-We-031) in
Kyoto, Japan.
Methods
Patients
Between January 1, 1995 and January 1, 2005, 6318 patients with
pregnancy loss during spontaneous pregnancies were referred for investigation to the Outpatient Department of Hematology, University Hospital of
Nîmes (Nîmes, France), a tertiary referral center. Exclusion criteria were
any past thrombotic clinical antecedent or any treatment given during
previous pregnancy attempts that may have modified the natural evolution
of their condition, such as antithrombotics, immunosuppressives, or
immunity-modulating drugs (eg, corticosteroids, hydroxychloroquine, or
intravenous gammaglobulins). Women with pregnancy losses that could be
explained by infectious, metabolic (including a fasting blood glucose
The online version of this article contains a data supplement.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
Presented at the XXIII Congress of the International Society on Thrombosis
© 2012 by The American Society of Hematology
There is an Inside Blood commentary on this article in this issue.
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BLOOD, 15 MARCH 2012 䡠 VOLUME 119, NUMBER 11
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BLOOD, 15 MARCH 2012 䡠 VOLUME 119, NUMBER 11
THROMBOSIS IN OBSTETRICAL APS
2625
Figure 1. Patient flow diagram for the NOH-APS study
and the 3 groups.
concentration higher than 7mM), anatomic, or hormonal factors were also
excluded. HIV-, hepatitis B–, or hepatitis C–seropositive women were
excluded because of their particular vascular risk. A total of 4801 women
fulfilled 1 of the 2 following inclusion criteria: (1) 3 unexplained consecutive spontaneous abortions before the 10th week of gestation that were not
because of maternal anatomic or hormonal abnormalities or to paternal
and maternal chromosomal causes (recurrent embryo loss subgroup); or
(2) 1 unexplained death of a morphologically normal fetus at or beyond
the 10th week of gestation with the normal fetal morphology documented by ultrasounds or by direct examination of the fetus (fetal loss
subgroup). Patients were also categorized as primary aborters (no
previous successful pregnancy) or secondary aborters (a previous
successful pregnancy).
Women had a standardized thrombophilia screening performed 3-6 months
after the last pregnancy loss, which included a complete whole blood count
and tests for fibrinogen, antithrombin, protein C, protein S, F5 6025 and F2
rs1799963 polymorphisms, JAK2 V617F mutation, LA, aCL, and a␤2GP1.
Women with antithrombin, protein C, or protein S deficiency and women
with an abnormal fibrinogen or the JAK2 V617F mutation were not
included. Women with a completely negative thrombophilia screening and
who agreed to participate in the observational study were temporarily
assigned to the “negative” group and were numbered according to the order
in which they entered the study. Women with an isolated F5 6025 or F2
rs1799963 polymorphism who agreed to participate in the observational
study were assigned to the “constitutional thrombophilia” group. Women
who were initially positive for aPLAb without or with a positive F5 6025 or
F2 rs1799963 polymorphism who agreed to participate in the observational
study were temporarily included in the “aPLAb” group and had a second
testing performed 6 months later. Those women persistently positive for
aPLAbs at the 6-month test were definitively assigned to the aPLAb group.
Finally, all women in the definitive constitutional thrombophilia and aPLAb
groups who consented to participate were included in the study. As each of
these women entered the study, the next woman from the ordered negative
group candidates was definitively assigned to the negative group and
included in the study (Figure 1).
The study was approved by the University Hospital of Nîmes Institutional Review Board and ethics committee and by the local Comité de
Protection des Personnes soumises à la Recherche Biomédicale. This
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2626
BLOOD, 15 MARCH 2012 䡠 VOLUME 119, NUMBER 11
GRIS et al
clinical investigation was performed according to the Declaration of
Helsinki of 1975 as revised in 1996. All the women gave their informed
consent to participate.
Samples
Blood samples were obtained between 8:00 and 10:00 am after overnight
fasting using a clean venipuncture procedure in which the first 2 mL of
blood was systematically rejected. Clean samples were collected in tubes
containing 1/10 volume of CTAD anticoagulant-antiplatelet mixture (0.109M
trisodium citrate, pH 5.4; theophylline; 3.7mM adenosine; 0.198mM
dipyridamole; Diatube-H; Becton Dickinson). After double centrifugation
at 4000g for 20 minutes, aliquots of platelet-poor plasma were immediately
stored at ⫺80°C until tested and were subsequently used nonfiltered.
Two hundred healthy subjects (102 women and 98 men; mean age of
45 years; range, 18-82 years) were recruited in a local public health center
during a systematic medical examination. Aliquots of plasma from each
healthy individual were stored at ⫺80°C and portions were also used to
generate a pool of healthy plasma, which was also stored in aliquots at
⫺80°C. Samples from subjects positive for aPLAbs (n ⫽ 2) were omitted
from the pool of healthy plasma (n ⫽ 198). This pool was systematically
generated from new samples every other year during follow-up, without
significant variations of the computed normal threshold values.
Follow-up
Patients were initially informed about symptoms of superficial vein
thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism
(PE), transient ischemic attack (TIA) or stroke and were told to contact a
study physician immediately if these symptoms occurred. Transient risk
factors for venous thrombosis were detailed (surgery, trauma, significant
immobilization or bed rest ⬎ 3 days, infectious disease, acute inflammatory
reaction, airplane travel lasting more than 4 hours, and pregnancy) and if
any of these occurred, the women were instructed to contact their general
practitioner for evaluation and prophylaxis initiation after a discussion with
a study physician.
Patients were systematically followed and clinically reevaluated each
year in the outpatient department of our institution. Patient loss because of
lack of follow-up was minimized by contacting the general practitioners
and the patients themselves directly. A complete systemic and vascular
clinical examination was performed. Any suspicion of developing systemic
disease led to adapted investigations for diagnosis. Symptoms were
evaluated and the treatments taken during the year were screened. The
information about vascular symptoms and transient risk factors for venous
thromboembolism (VTE) was repeated. No systematic venous ultrasonographic evaluations of the lower limbs were performed. Women from the
aPLAb group had a systematic aPLAb assessment. No systematic aPLAb
assessment was performed at the time any thrombotic events occurred.
Assays
All normal values were assessed from the analysis of the 200 healthy
plasmas. The normal upper threshold values for these samples were
assumed to be in the corresponding computed 99th percentile, the lowest to
be in the corresponding 1st percentile.
F5 6023 and F2 rs1799963 polymorphisms and the JAK2 V617F
mutation were demonstrated by PCR. Antithrombin was measured by
chromogenic substrate assay (STA-Stachrom ATIII; Stago). Protein C and
protein S activities were measured by chronometric assays (STA-Staclot
Protein C and STA-Staclot protein S; Stago). Free protein S-antigen levels
were measured by ELISA (Asserachrom Free protein S; Stago).
The methods used to test for aPLAbs have been described previously in
detail.7 Briefly, LAs were detected using the following screening assays:
activated partial thromboplastin time (aPTT; PTT LA, Stago), dilute Russell
viper venom time (Bioclot LA; Biopool), and tissue thromboplastin
inhibition test using a 1:500 thromboplastin dilution (Neoplastin CI Plus;
Stago). LAs were first identified in samples that were mixed 1:1 with
healthy pooled plasma and were then confirmed by neutralization procedures according to the recommendations of the Subcommittee on Lupus
Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis.8,9 All coagulation assays were performed on the STA-R automatic
coagulation analyzer (Stago). Plasma aCL IgG and IgM Abs were measured
according to an adaptation of the in-house ELISA method that has been
described previously by Reber et al.10 Plasma a␤2GP1 IgG and IgM Abs
were measured according to an ELISA developed in-house using ␤2glycoprotein I isolated from freshly frozen human citrated plasma as
described by Horbach et al.11
LA activities were quantified using the results of the mixing test and are
expressed as the ratio of the aPTT test result from the patient and healthy
pooled plasma mixed 1:1, divided by the aPTT test result from the healthy
pooled plasma (normal value ⬍ 1.22). All plasmas were secondarily
quantified for the 4 solid-phase aPLAbs based on calibration curves
performed using the Sapporo standards HCAL and EY2C9 kindly provided
by The Binding Site staff (Saint Egrève, France). Normal values are: aCL-G
⬍ 0.85 ␮g/mL, aCL-M ⬍ 1.39 ␮g/mL, a␤2GP1-G ⬍ 0.89 ␮g/mL, and
a␤2GP1-M ⬍ 0.99 ␮g/mL).
Positive results for aPLAbs were categorized as follows according to
the recommendations of the International Society on Thrombosis and
Hemostasis subcommittee: type I, more than 1 laboratory criteria present
(any combination); type IIa, LA present alone; type IIb, aCL-Ab present
alone; and type IIc, a␤2GPI-Ab present alone.2 Triple positivity was defined
by the association of a positive LA test, a positive aCL-Ab test (IgG and/or
IgM), and a positive a␤2GP1-Ab test (IgG and/or IgM).
Primary prophylaxis of thromboses
All of the patients with purely obstetric APS underwent primary prophylaxis treatment for chronic thrombosis consisting of low-dose aspirin
(LDA; 100 mg/d). Compliance was monitored only by self-declaration of
the patient-companion couples. No biologic assay was performed during
follow-up to evaluate LDA compliance and effect. Women in the constitutional thrombophilia and negative groups did not receive prophylaxis for
chronic thrombosis.
Contraception
Initial birth control, if any, was accomplished by mechanical methods,
because most of the included women desired a new pregnancy. In the
aPLAb and constitutional thrombophilia groups, the contraindications for
estro-progestative oral contraceptives (OCs) was systematically discussed,
and women seeking OCs during their follow-up period were given
progestin-only OCs: initially, 17-OH-progesterone or 19-norprogesterone
derivates or a low-dose second-generation progestogen (levonorgestrel)
followed by a low-dose third-generation progestogen (desogestrel). In the
negative group, women seeking an OCs were given levonorgestrel. Current
OC use was defined as OC use during the month before the event.
Antithrombotics during new pregnancies
According to published guidelines, low-molecular-weight heparin (LMWH;
enoxaparin, 4000 IU/d) plus LDA (100 mg/d) were prescribed for all
pregnant aPLAb women from after the positive pregnancy test until
delivery. These treatments continued during the 6-week postpartum period,
with systematic monitoring and investigation for heparin-induced thrombocytopenia according to published recommendations.12-13 Patients from the
constitutional thrombophilia group systematically received the enoxaparin
prophylaxis (4000 IU/d) during the 6-week postpartum period. In patients
with any previous fetal loss, enoxaparin was also prescribed during
pregnancy. Patients from the negative group had no drug-mediated prophylaxis during pregnancy or postpartum. In untreated patients, a transient
enoxaparin-mediated prophylaxis (4000 IU daily) was given systematically
if a transient clinical risk factor existed for venous thrombosis occurring
during pregnancy no matter if it was classic or pregnancy related
(prolonged bed rest for premature delivery symptoms, fetal death or
stillbirth, preeclampsia, abruptio placentae, cesarean section, and primary
postpartum hemorrhage). Elastic compression stockings were prescribed
systematically for all participants.
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BLOOD, 15 MARCH 2012 䡠 VOLUME 119, NUMBER 11
THROMBOSIS IN OBSTETRICAL APS
2627
Table 1. Clinical characteristics of subjects at baseline and at follow-up
Negative group
n
796
Constitutional thrombophilia group
279
aPLAb group
517
Age, y
30 (5) [17-44]
29 (4) [18-44]
29 (4) [16-41]
Age ⬎ 35 y
43 (5.4%)
12 (4.3%)
15 (2.9%)
Body mass index, kg/m2
25.6 (4.5) [15.3-36.1]
25.9 (4.2) [13.5-34.1]
26.0 (4.6) [15.3-37.0]
⬎ 30
78 (9.8%)
29 (10.4%)
⬍ 18.5
12 (1.5%)
3 (1.1%)
5 (1%)
753 (94.6%)
264 (94.6%)
489 (94.6%)
European
647 (81.3%)
227 (81.4%)
420 (81.2%)
North African
106 (13.3%)
37 (13.2%)
69 (13.4%)
Black African
36 (4.5%)
12 (4.3%)
22 (4.2%)
7 (0.9%)
3 (1.1%)
6 (1.2%)
60 (11.6%)
Ethnicity
White
Asian
P
.21
.086
.16
.58
.66
.87
Pregnancy loss subtype
Embryonic at ⬍ 10 WG
483 (60.7%)
93 (33.3%)
206 (39.8%)
Fetal at ⱖ 10 WG
313 (39.3%)
186 (66.6%)
311 (60.2%)
Primary
549 (68.9%)
185 (66.3%)
342 (66.1%)
Secondary
247 (31.1%)
94 (33.7%)
175 (33.9%)
⬍ .0001
.49
7 (0.9%)
4 (1.4%)
32 (6.2%)
⬍ .0001
Current smokers
83 (10.4%)
30 (10.8%)
50 (9.7%)
.89
Hypertension
19 (2.4%)
8 (2.9%)
17 (3.3%)
.62
Inflammatory disease
Positive history in a first-degree relative
Venous thromboembolism
15 (1.9%)
29 (10.4)
12 (2.3%)
⬍ .0001
Atherothrombosis
96 (12.1%)
46 (16.5%)
53 (10.3%)
.043
Hyperlipidemia
Hypercholesterolemia
42 (5.3%)
13 (4.7%)
31 (6.0%)
.71
Hypertriglyceridemia
34 (4.3%)
11 (3.9%)
27 (5.2%)
.64
187 (23.5%)
58 (20.8%)
117 (22.6%)
.65
Varicose veins
Hormonal contraception, n (%)
Oral, estroprogestative
Oral, progestin only
Lipid-lowering drugs
Follow-up duration, d
38 (4.8%)
2 (0.7%)
5 (0.9%)
⬍ .0001
5 (0.6%)
14 (5.0%)
27 (5.2%)
⬍ .0001
0
3572 (1860) [254-5461]
0
3457 (1781) [274-5452]
0
3392 (1893) [206-5449]
.023
Quantitative data are given as median (interquartile range) 关range兴 and qualitative data as number (percentage) values.
WG indicates weeks of gestation.
Outcome assessment
All suspected thrombotic events were confirmed objectively using clinically adapted objective methods as follows: whole-leg compression ultrasonography for SVT and DVT,14 perfusion lung scan or helical CT scan for
PE, and neuroimaging using CT scans and MRI for TIA and stoke. TIA was
considered for adjudication in cases of ischemic cerebral imaging. VTE was
defined by the occurrence of DVT, PE, or both. Cerebrovascular events
were defined by the occurrence of TIA or stroke.
Major bleeding events were defined according to the Control of
Anticoagulation Subcommittee of the International Society on Thrombosis
and Hemostasis15: fatal bleeding; symptomatic bleeding in a critical area or
organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, or pericardial bleeding; intramuscular bleeding with compartment
syndrome; and/or bleeding that led to a decrease of hemoglobin level of
20 g/L or more or that led to transfusion of 2 or more units of RBCs. All
events were adjudicated by a committee of independent experts blinded to
the thrombophilia screening results.
Statistical analysis
Quantitative data are described by median, interquartile range, and range
values. Qualitative data are described by values and percentages. Comparisons between baseline characteristics and risk factors were performed using
the Student, Mann-Whitney, Kruskall-Wallis, ␹2, and Fisher exact tests as
appropriate.
Definition of groups and analysis of the impact of biologic covariates on
thrombotic incidences were based on values obtained at the initial
inclusion.
All analyses were based on the first thrombotic event that occurred
during follow-up, which was determined by central adjudication. For
women who did not have a thrombotic event, censoring time was defined as
the time from randomization to the earliest of the following: death,
nonavailability for follow-up, or January 1, 2010. For women in the aPLAb
group whose aPLAbs became negative during follow-up, censoring time
was defined as the time from randomization to the last positive assessment.
Time-to-event methods (eg, log-rank tests and Cox regression) were
used to compare thrombotic incidences between groups. The outcomes
analyzed were VTE, PE, DVT (either proximal or distal), SVT, TIA, stroke,
or stroke/TIA. Cox-proportional hazards models were stratified according
to clinical variables that might have a putative effect on the occurrence of
the outcomes (adjusted hazard ratio: age, body mass index, thrombotic
familial antecedents, ethnicity, smoking history, hypertension, hypercholesterolemia, hypertriglyceridemia, current OC use, current progestin-only OC
use, varicose veins, embryonic/fetal pregnancy loss, primary/secondary
pregnancy loss, and any associated systemic disease). Smoking was defined
as smoking at least one cigarette a day. Women were classified as
hypertensive if they were using hypertensive medication or had either a
systolic blood pressure of 140 mmHg or higher or a diastolic blood pressure
of 90 mmHg or higher on 2 readings taken in a supine position 5 minutes
apart on 2 separate occasions. Hypercholesterolemia was defined as a
fasting cholesterol concentration above 5.2mM, and hypertriglyceridemia
as a fasting triglyceride concentration above 1.7mM. The outcome comparisons are presented as annualized rates and adjusted hazard ratios with 95%
nominal confidence intervals.
Putative predictors of the various outcomes among the clinical predictors (age, body mass index, thrombotic familial antecedents, ethnicity,
smoking history, varicose veins, embryonic/fetal pregnancy loss, primary/
secondary pregnancy loss, and initial inflammatory disease) and the
biologic predictors at randomization (positive LA, positive aCL-G, positive
aCL-M, positive a␤2GP1-G, positive a␤2GP1-M, triple positivity and the
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BLOOD, 15 MARCH 2012 䡠 VOLUME 119, NUMBER 11
GRIS et al
Table 2. Prevalence of thrombophilias at baseline
Negative group
Constitutional thrombophilia group
aPLAb group
Positive for LA
0
0
319 (61.7%)
LA: activity
0.99 (0.09) [0.82-1.20]
1.02 (0.09) [0.79-1.21]
1.42 (0.78) [0.79-2.68]
LA
Anti-cardiolipin IgG
Positive for aCL-G
0
0
244 (47.2%)
aCL-G titer, ␮g/ml
0.39 (0.21) [0.05-0.84]
0.41 (0.22)[0.07-0.84]
0.70 (1.37) [0.05-7.1]
Anti-cardiolipin IgM
Positive for aCL-M
0
0
372 (71.9%)
aCL-M titer, ␮g/ml
0.54 (0.32) [0.08-1.35]
0.51 (0.29) [0.05-1.34]
1.60 (1.55) [0.05-18.1]
Anti–␤2-glycoprotein I IgG
Positive for a␤2GP1-G
0
0
114 (22.1%)
a␤2GP1-G titer, ␮g/ml
0.23 (0.14) [0.05-0.86]
0.26 (0.18) [0.02-0.84]
0.57 (0.55) [0.03-6.9]
Anti–␤2-glycoprotein I IgM
Positive for a␤2GP1-M
0
0
210 (40.6%)
a␤2GP1-M titer, ␮g/ml
0.41 (0.24) [0.04-0.98]
0.47 (0.34) [0.02-0.98]
0.72 (0.85) [0.05-19.4]
Categories of positive aPLAb
I
383 (74.1%)
IIa
31 (6%)
IIb
103 (19.9%)
IIc
0
LA ⫹ aCL ⫹ a␤2GP1
149 (28.8%)
Constitutional thrombophilias
F5 6025 or F2 rs1799963
0
279 (100%)
17 (3.3%)
Quantitative data are given as median (interquartile range) 关range兴 values and qualitative data as number (percentage) values.
F5 6025 or F2 rs1799963 polymorphisms) were evaluated in women from
the aPLAb group, first by univariate analysis and then by multivariate
analysis. For multivariate models, a stepwise variable selection was
performed, starting with all of the variables from the univariate models
having P ⬍ .25 as potential predictors, with adjustment being finally
performed for all variables with P ⬍ .25 in the univariate models. If triple
positivity was an eligible potential predictor, multivariate analysis only
considered clinical predictors and Leiden polymorphisms. The final model
included only main effects with P ⬍ .10. For cases in which a significant
biologic predictor emerged from the multivariate models, a new analysis
was performed categorizing the biologic covariate into 4 quartiles according to the activity levels. P values were considered statistically significant at
a level of .05 or less. Statistical analyses were performed using SASWindows Version 9.1 software.
Results
Baseline patient characteristics
The NOH-APS study included 1592 women (Table 1). Recurrent
unexplained embryonic loss was the most frequent inclusion
criterion in the negative group and fetal loss was the most frequent
inclusion criterion in the other groups. A VTE history or an
atherothrombotic history was more frequent in the first-degree
relatives of women included in the constitutional thrombophilia
group than in those of the other groups. Underlying chronic
inflammatory disease was more frequent in the aPLAb group than
in the other groups and consisted mainly of mild rheumatoid
arthritis, Sjogren syndrome, discoid lupus erythematosus, or systemic sclerosis. Few women were initially taking OCs. Secondgeneration estro-progestative compound use was more frequent
and progestin-only compound use was less frequent in the negative
group than in the 2 other groups.
In the aPLAb group, aCL-M Abs or LA were the 2 features
present most frequently (Table 2). Three-quarters of the women
were positive for more than one marker, 19.9% of the women were
positive only for aCL Abs (8.5% had only aCL-M Abs). None had
only a␤2GP1 Abs. Nearly one-third of the patients exhibited triple
positivity defined without any isotype restriction,16 which was due
in part to the high frequency of aCL-M–positive patients. Systematic aPLAbs assessment during follow-up revealed that 26 initially
positive women became negative for all aPLAbs: 6 of 31, 6 of 59,
and 14 of 44 among the patients with an initially isolated positive
LA, aCL-G, and aCL-M, respectively.
Follow-up vascular data
The median follow-up duration was close to 9.5 years and was
slightly shorter for the aPLAb group (Table 1). Thirty-seven
patients (2.3%) were lost to follow-up. No patient died during
follow-up.
Nineteen patients (1.2%) were diagnosed with cancer (in the
negative group, n ⫽ 9; in the constitutional thrombophilia group,
n ⫽ 2; in the aPLAb group, n ⫽ 8) and 11 (2.1%) aPLAb patients
developed systemic lupus erythematosus. None of them developed
any symptomatic thrombosis.
The number of DVT (total, proximal, and distal subtypes), PE,
and SVT events was higher in aPLAb patients than in the other
groups (Table 3). There were no cases of isolated PE, the 31 adjudicated
events being associated with DVT. Women from the aPLAb group
experienced more strokes and more TIA or stroke than did the women in
the negative or constitutional thrombophilia groups. Among the 12 cases
of stroke, all were ischemic and 8 had at least 1 probable cause: large
artery atherosclerosis (n ⫽ 3); lacune (calling for small artery disease;
n ⫽ 2); or cardioembolism (n ⫽ 3).
Comparisons between vascular outcomes are shown in Table 3.
The upper limits of the annualized rates of venous events for
women in the negative group were low: 0.22% for PE, 0.61% for
DVT, 0.36% for proximal DVT, and 0.35% for distal DVT.
Upper limits of the annualized rates of arterial events were
0.14% for TIA and 0.12% for stoke in the negative patients. The
incidences of venous and arterial thrombotic events for the
patients in the constitutional thrombophilia group were not
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BLOOD, 15 MARCH 2012 䡠 VOLUME 119, NUMBER 11
THROMBOSIS IN OBSTETRICAL APS
2629
Table 3. Comparison of rates of vascular events between women positive for aPLAb or Leiden mutation (constitutional thrombophilia) and
those negative for thrombophilias (negative)
Outcomes
Group
n (%)
P
Annualized rates, % (range)
aHR*
⬍ .0001
PE
Negative
9 (1.13)
0.12 (0.05-0.22)
Reference
Constitutional thrombophilia
3 (1.08)
0.11 (0.02-0.33)
0.98 (0.26-3.61)
20 (3.87)
0.43 (0.26-0.66)
1.93 (1.30-2.87)
aPLAb
⬍ .0001
DVT
P†
.0005
.97
.001
⬍ .0001
Negative
33 (4.15)
0.43 (0.30-0.61)
Reference
Constitutional thrombophilia
15 (5.38)
0.57 (0.32-0.93)
1.33 (0.73-2.46)
.35
aPLAb
68 (13.15)
1.46 (1.15-1.82)
1.85 (1.50-2.28)
⬍ .0001
Negative
17 (2.14)
0.22 (0.13-0.36)
Reference
⬍ .0001
Proximal DVT
Constitutional thrombophilia
⬍ .0001
7 (2.51)
0.27 (0.11-0.54)
1.21 (0.50-2.92)
.67
aPLAb
38 (7.35)
0.82 (0.58-1.11)
1.93 1.45-2.58)
⬍ .0001
Negative
16 (2.01)
0.21 (0.12-0.35)
Reference
8 (2.87)
0.31 (0.13-0.60)
1.47 (0.63-3.44)
.38
30 (5.80)
0.65 (0.44-0.91)
1.76 (1.30-2.38)
.0003
11 (1.38)
0.14 (0.07-0.26)
Reference
9 (3.23)
0.34 (0.16-0.65)
2.36 (0.97-5.71)
.06
21 (4.06)
0.44 (0.28-0.68)
1.78 (1.23-2.56)
.002
Distal DVT
.0009
Constitutional thrombophilia
aPLAb
Superficial vein thrombosis
.0004
.0085
Negative
Constitutional thrombophilia
aPLAb
TIA
.021
.19
.165
Negative
4 (0.50)
0.05 (0.01-0.14)
Reference
Constitutional thrombophilia
4 (1.43)
0.15 (0.04-0.39)
2.95 0.74-11.8)
.13
aPLAb
7 (1.35)
0.15 (0.06-0.31)
1.68 (0.91-3.12)
.096
Stroke
.039
.059
Negative
3 (0.38)
0.04 (0.01-0.12)
Reference
Constitutional thrombophilia
1 (0.36)
0.04 (0.01-0.21)
0.97 (0.10-9.26)
.97
aPLAb
8 (1.55)
0.17 (0.07-0.34)
2.10 (1.08-4.08)
.028
7 (0.88)
0.09(0.04-0.19)
Reference
5 (1.79)
0.19(0.06-0.44)
2.09 (0.66-6.58)
.21
15 (2.90)
0.32(0.18-0.53)
1.87 (1.20-2.93)
.006
TIA or stroke
.021
Negative
Constitutional thrombophilia
aPLAb
.014
*aHR indicated adjusted hazard ratio (adjustment for age, body mass index, thrombotic familial antecedents, ethnicity, smoking history, hypertension, hypercholesterolemia, hypertriglyceridemia, current oral estro-progestative OC use, current oral progestin-only OC use, varicose veins, embryonic/fetal pregnancy loss, primary/secondary
pregnancy loss, and any associated systemic disease).
†By log-rank test.
significantly different from those in the negative group despite a
strong trend for higher rates of SVT and TIA. The rates of DVT
(total, proximal, or distal), PE, SVT, and stroke were significantly higher in the aPLAb patients than in the negative group,
and the mean risk rates for these events were nearly universally
twice as high. The upper limits of the annualized rates for the
aPLAb women were 0.66% for PE, 1.82% for DVT (1.11% for
proximal DVT and 0.91% for distal DVT), 0.68% for SVT, and
0.34% for stroke. Venous thromboembolism–free survival rates
are shown in Figure 2.
Predictors in the aPLAb group
The predictors of the various thrombotic events were evaluated in
aPLAb patients (supplemental Table 1, available on the Blood Web
site; see the Supplemental Materials link at the top of the online
article). Proximal and distal DVTs were categorized into either
provoked events (n ⫽ 9 and n ⫽ 16, respectively) or unprovoked
events (n ⫽ 29 and n ⫽ 14, respectively). LA was a predictor of
VTE and DVT events combined, unprovoked proximal DVT,
unprovoked distal DVT, and SVT. After categorization into quartiles (Q1: 0.79-1.05; Q2: 1.051-1.42; Q3: 1.421-1.83; and
Q4: ⬎ 1.83), the higher LA activity quartiles were correlated with
higher risks of thrombotic events. Patients positive for aCL-M were
significantly protected against PE, provoked proximal DVT, and
provoked distal DVT. An F5 6025 polymorphism enhanced the risk
of TIA. None of the putative predictors we studied appeared to be
significant risk factors for stroke.
The mean incidence of triple positivity, which is a high-risk
aPLAb profile in asymptomatic carriers,16 was 1.18% for VTE,
0.36% for PE, and 0.20% for stroke plus TIA. The computed risks
were globally concordant with those of being LA positive only for
most of the vascular events (supplemental Table 1). Although triple
positivity was a predictor of PE, LA was not.
Follow-up safety data
Primary vascular prophylaxis with LDA in aPLAb patients did not
induce any major bleeding events. Minor hemorrhages were
limited to local minor bruising (mainly as a result of trauma),
venipuncture-related bruising, and minor gum bleeding because of
tooth brushing. Heavy menses, defined as a Janssen score17 higher
than 185, was infrequent (n ⫽ 12; 2.31%). Thirty-nine patients
(7.54%) had significant signs of gastrointestinal intolerance and
stopped LDA prophylaxis. No other prophylactic treatment was
prescribed and the patients developed no vascular symptoms.
Discussion
Our observational results in patients with pregnancy loss show that
the risks of venous thromboembolism and of cerebrovascular
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2630
GRIS et al
BLOOD, 15 MARCH 2012 䡠 VOLUME 119, NUMBER 11
Figure 2. VTE-free survival. Shown are the VTE-free survival rates in initially nonthrombotic women with pregnancy loss (3 unexplained consecutive spontaneous abortions
before the 10th week or 1 unexplained fetal death at or beyond the 10th week) with positive aPLAbs, with a positive F5 6025 or F2 rs1799963 polymorphism (constitutional
thrombophilia), or with a negative thrombophilia screening (negative).
manifestations are higher in women with purely obstetric APS than
in women without APS. These risks are not higher in women
carrying the F5 6025 or F2 rs1799963 polymorphism, 2 prevalent
low-risk constitutive thrombophilias. These elevated risk levels
were apparent despite the use of LDA primary vascular prophylaxis
in APS women.
Purely obstetric APS patients who experienced a new pregnancy during follow-up were treated using the combination of
LDA and LMWH for obstetrical purposes according to expert
recommendations,18 even if the option of monotherapy with LDA
has not been definitively ruled out by others.3 The addition of
LMWH may have contributed to the limitation of vascular events
during pregnancy. Patients also received a chronic LDA-mediated
primary prophylaxis against thrombosis, which reflects to a great
extent clinical practice, but which is not evidence-based medicine,
pointing to crucial lacks in that clinical setting.
Before the present study, few data were available on the risk of
VTE in women with purely obstetric APS. Management currently
depends on expert opinion and on the perception of the physician.19
Limited retrospective studies have detected either a higher20 or a
slightly elevated6 frequency of thrombotic events after pregnancy
loss in APS. The adjusted rate of VTE events was almost twice as
high in women with APS compared with patients without APS.
Furthermore, this rate was close to the one observed in asymptomatic aPL-positive subjects receiving LDA primary prophylaxis
(2.7%).21 Our data from patients receiving primary prophylaxis
with LDA suggest that APS is an important predictor of subsequent
VTE. Further evaluations are needed to determine an evidencebased mode of prevention.
We found the overall cerebrovascular risk to be nearly doubled
in APS women compared with those without APS, but observed
few events. A population-based study found relative odds of stroke
that were similar to those found in our study, despite the absence of
prophylactic antiplatelet treatments.22 The RATIO study found
strikingly higher risks in aPL-positive women, particularly for LA
and ischemic stroke (odds ratio ⫽ 43).23 In comparison, we observed very few stroke cases, but aPL-positive patients had a
primary prophylaxis that might have modified the spontaneous
arterial risks.
Among all aPLAbs, LA was the unique risk factor independent
of other aPLAbs for various clinical subtypes of the venous
thrombotic disease, including proximal unprovoked DVT, distal
unprovoked DVT, and SVT. We also found a dose-effect relationship between LA intensity and clinical outcome. LA is considered
to be the most powerful predictor of thrombosis.3,24,25 Strong risk
factors for thrombosis are generally associated with spontaneous,
rather than provoked, thrombotic events,26 which fits with the
Rosendaal thrombosis potential model.27,28 Being aCL-M positive
lowered the risk of provoked proximal and distal DVTs. ACL-M–
positive status was associated with late pregnancy losses between
13 and 24 weeks in a meta-analysis study,29 but there are no strong
data linking aCL-M to vascular morbidity. The discrepancy between aCL-M–positive status and the risk for the 2 APS main
clinical areas may explain this protective effect of aCL-M: the
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BLOOD, 15 MARCH 2012 䡠 VOLUME 119, NUMBER 11
THROMBOSIS IN OBSTETRICAL APS
absence of a switch from IgM synthesis to IgG synthesis might
prevent more pathogenic Abs from being produced.
Triple aPLAb positivity in subjects positive for LA, aCL, and
a␤2GP1 Abs has been described as a high-risk aPLAb profile in
asymptomatic carriers.16 The mean incidence of venous and
arterial (mainly arterial) events for these patients may be as high as
5.3% per year, and male sex is a strong indicator. Our female
recruitment and LDA prophylaxis may explain the differences in
these results. In some univariate analyses, triple positivity, like
LA, was found to be a risk factor. However, high LA activities
were associated with higher risks after multivariate analysis.
Finally, a significant amount of triple positivities were associated with positive aCL-M, in which thrombotic impact is
questionable.
Our study has several limitations. This is not a multicentric
study. Our results apply only to patients referred by primary care
physicians to the hematologists, gynecologists, and obstetricians of
a tertiary referral center. A significant number of patients may have
been available for investigation through a purely private medical
sector. Because LA has been strongly associated with recurrent
miscarriage before the 24th week of gestation in women without
autoimmune disease,29 this might have also induced a recruitment
bias if LA-positive patients were favored among our purely
obstetric APS women. The absence of an association between early
miscarriages and a␤2GP1 Abs29 may explain the low frequency of
patients positive for a␤2GP1 Abs in our population of women and
the absence of association between a␤2GP1 Abs and subsequent
thrombotic events. Most of the lost embryos were not submitted to
karyotype analysis; a significant number of recurrent early losses
may have been because of embryonic chromosomal abnormalities.
Nevertheless, embryonic karyotyping is not mandatory for APS
clinical criteria.2 We also did not check any biologic parameter of
poor responsiveness to LDA in APS women, and therapeutic
compliance was assessed only through self-reporting. We did not
look for asymptomatic venous thrombosis systematically and did
not evaluate patients for the presence of atherosclerotic lesions
using, for example, ultrasonographic methods.
Another limitation of our study is that only aPLAbs patterns at
randomization were used for analysis. We observed some variations in the aPLAbs patterns during follow-up, but women whose
aPLAbs all became negative were censored at the time of last
positive assessment; therefore, a bias in the global evaluation of the
thrombotic risks in case of aPLAb positivity is unlikely. We did not
determine aPLAbs during follow-up in women with initially
negative aPLAbs, and it may be that some of them subsequently
revealed aPLAbs, which may limit our results. The variations of the
aPLAb patterns may have some impact on the evaluation of the
thrombotic risk predictors in aPLAb-positive women. However,
there is currently no available integrated system allowing evaluating the risks according to the continuous variations of the 5 APS
markers during follow-up. We have initiated new algorithm and
statistical developments, hoping for adapted solutions, but these
will have to be validated.
Our study also has several strengths. The annualized rates of
VTE events in our negative/nonthrombophilic group were similar
2631
to those reported previously.6 The rate of stroke in this group also
overlaps the overall incidence rate described for subjects under the
age of 45.30,31 A cohort study showed that women who experience
recurrent spontaneous pregnancy loss or stillbirth are not at higher
risk of stroke later in life.32 We were able to rely heavily on the
Nı̂mes Obstetricans and Haematologist (NOHA) administrative
region hospital medical network.33 This network was able to recruit
a substantial number of patients, particularly purely obstetric APS
women. Follow-up lengths tended to be long for these patients and
losses to follow-up were very limited because of the efficiency of
the NOHA human network. We therefore believe that the number
of symptomatic vascular events that occurred in patients and that
were not registered into the database were minimal or absent.
The results of studies in mouse models suggest that obstetrical APS may be a nonthrombogenic syndrome,34-37 but mechanisms of pregnancy loss involving thrombosis have been
described recently36-38 and this agrees with our observational
results, at least in a subset of patients. LDA-mediated primary
prophylaxis was well tolerated in our purely obstetric APS
patients, which might have limited the numbers of subsequent
thrombotic events. Multicentric prospective, randomized, controlled studies are warranted to determine the efficacy of this
prophylaxis in this patient population.
Acknowledgments
The authors thank all of the study participants—the patients who
finally agreed to join us in this long-distance running adventure;
H. Bres and F. Sauvan for technical assistance; the NOHA network
of gynecologists, obstetricians, and general practitioners who
actively contributed to the study; the adjudication committee
(S. Ripart and E. Arnaud); G. Lissalde-Lavigne, M. L. Tailland,
D. Dupaigne, M. Hoffet, J. P. Bertinchant, G. Cayla, A. PerezMartin, M. Dandurand, P. Labauge, S. Bouly, G. Castelnovo,
C. Bengler, B. Branger, P. Reboul, E. Picard, P. Branchereau, and
A. Sotto for efficient help in the management of the patients; and
the research staff of the Direction de la Recherche Clinique et de
l’Innovation of the University Hospital of Nîmes: S. Clément,
C. Meyzonnier, N. Best, S. Granier, B. Lafont, H. Obert, H. Léal,
O. Albert, C. Suehs, P. Rataboul, and M. P. Francheschi.
Authorship
Contribution: J.-C.G, J.-P.B., P.M., J.-P.G., I.Q., and M.D. designed
the research and wrote the manuscript; N.M. and P.-F.P. performed
the statistical analysis and wrote the manuscript; J.-C.G., J.-P.G.,
J.-P.B., P.M., and I.Q. performed the research; and S.B., E.C.-N.,
and E.M. contributed analytical tools and wrote the manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Jean-Christophe Gris, MD, PhD, Laboratory
of Hematology, University Hospital Caremeau, Place du Pr Robert
Debré, 30029 Nîmes cedex 9, France; e-mail: [email protected].
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2012 119: 2624-2632
doi:10.1182/blood-2011-09-381913 originally published
online December 6, 2011
Comparative incidence of a first thrombotic event in purely obstetric
antiphospholipid syndrome with pregnancy loss: the NOH-APS
observational study
Jean-Christophe Gris, Sylvie Bouvier, Nicolas Molinari, Jean-Philippe Galanaud, Éva
Cochery-Nouvellon, Érik Mercier, Pascale Fabbro-Peray, Jean-Pierre Balducchi, Pierre Marès,
Isabelle Quéré and Michel Dauzat
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