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doi:10.1093/rheumatology/ket167
Advance Access publication 15 May 2013
RHEUMATOLOGY
Original article
Catastrophic antiphospholipid syndrome and
pregnancy: an experience of 13 cases
Guillaume Hanouna1,*, Nathalie Morel1,*, Du Le Thi Huong1, Laurence Josselin2,
Danie`le Vauthier-Brouzes3, David Saadoun1, Adrien Kettaneh2,
Kateri Levesque1, Veronique Le Guern4, Francois Goffinet5, Bruno Carbonne6,
Zahir Amoura1, Jean-Charles Piette1, Jacky Nizard3 and
Nathalie Costedoat-Chalumeau1
Methods. Retrospective series of 13 patients with pregnancy-related CAPS with special focus on the
follow-up.
Results. Eleven patients had known APS and had been treated with low-molecular-weight heparin (n = 10),
aspirin (n = 8), oral anticoagulants (n = 1), HCQ (n = 3) and/or steroids (n = 1) during pregnancy. The most
frequent manifestations of CAPS were cutaneous (n = 11), hepatic (n = 11), renal (n = 10), cardiac (n = 8) and
neurological (n = 5). CAPS usually followed haemolysis, elevated liver enzymes and low platelet count
(HELLP) syndrome (n = 12), which was associated with pre-eclampsia (n = 6) or with eclampsia (n = 3).
No maternal death was observed. The perinatal mortality of 54% was related to prematurity with a
mean gestational age of 26.6 weeks at onset of CAPS or HELLP syndrome. During a mean follow-up
of 4.8 years (range 28 years), seven new pregnancies occurred in five patients and led to one miscarriage, four successful pregnancies and two HELLP syndrome with pre-eclampsia or eclampsia that
occurred at 28 weeks gestation in both cases despite optimal treatment. No relapse of CAPS was
observed. Two mothers suddenly died 2.5 and 6 years after CAPS.
Conclusion. The occurrence of HELLP syndrome in a patient with APS should raise the suspicion of
CAPS in the following days, and anticoagulation should be maintained post-partum or post-abortum.
Subsequent pregnancies are at very high risk.
Key words: antiphospholipid
pregnancy.
syndrome,
catastrophic
antiphospholipid
syndrome,
lupus,
thrombosis,
Introduction
1
Universite Pierre et Marie Curie-Paris 6, Assistance PubliqueHopitaux de Paris, Hopital Pitie-Salpetrie`re, Centre de reference
national pour le Lupus Systemique et le syndrome des
Antiphospholipides, service de medecine interne, Paris, 2Assistance
Publique-Hopitaux de Paris, Hopital Saint Antoine, service de medecine interne, Paris, 3Assistance Publique-Hopitaux de Paris, Service de
Chirurgie Gynecologique et Obstetrique, Centre Hospitalier
Universitaire Pitie-Salpetrie`re, Paris, 4Assistance Publique-Hopitaux
de Paris, Centre de reference maladies auto-immunes et systemiques
rares, Service de medecine interne Pole medecine, Hopital Cochin,
AP-HP, Paris, 5Universite Paris 5, Assistance Publique-Hopitaux
de Paris, Service de gynecologie-obstetrique, Maternite Port-Royal,
Paris and 6Universite Pierre et Marie Curie-Paris 6, Assistance
Publique-Hopitaux de Paris, Service de gynecologie-obstetrique,
Hopital Trousseau, Paris, France.
! The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
CLINICAL
SCIENCE
Abstract
Results
We retrospectively analysed 13 cases of pregnancyrelated CAPS (Table 1).
Patients
Pregnancy description
This study included 13 patients referred to a French national SLE and APS referral centre with a diagnosis of
pregnancy-related CAPS, defined by CAPS occurring
during pregnancy or in the 6 weeks post-partum or postabortum, between 2002 and 2012. Cases 11 and 12 were
followed in Saint Antoine Hospital. Case 11 will be submitted as a case report. Case 12 has been previously reported in French as a case report [5].
Methods
SLE was defined according to the ACR classification criteria [6]. APS was defined according to the Sydney criteria
[1]. Lupus anticoagulant was diagnosed with both aPTTbased assays and DRVVT. Regarding anti-B2GP1 antibodies, both IgG and IgM isotypes were measured. CAPS
was defined according to the 2005 criteria: (i) involvement
of three or more organs, tissues or systems; (ii) development of manifestations in less than 1 week; (iii) histological
confirmation of small vessel occlusion; (iv) presence of
aPLs (LA and/or aCLs) detected on two or more occasions at least 6 weeks apart [7]. Haemolysis, elevated
liver enzymes and low platelet count (HELLP) syndrome
was defined by biological criteria: aspartate amino transferase >2-fold the normal, platelet count <100 000/mm3
and lactate dehydrogenase >600 U/l [8].
For each patient we retrospectively collected clinical,
biological, ultrasonographic and therapeutic data during
pregnancy and data regarding neonates. Four patients
had routine antenatal care in our centre before diagnosis
of CAPS and nine were referred to us after CAPS. In these
cases we provided medical guidelines for the following
pregnancies. Follow-up focused on new manifestations
of APS and new obstetric events.
Statistical analyses
A 2 test was performed for qualitative variables. The level of
significance was set at 0.05. Statistical analyses were performed with SAS version 9.2 (SAS Institute, Cary, NC, USA).
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CAPS description
CAPS occurred during pregnancy in 1 patient and postpartum or post-abortum in 12 patients (with an onset
concomitant with labour in 3 patients). In 9 of these 12
patients there was an initial improvement of the maternal
condition between the HELLP syndrome and CAPS, with
a mean delay of 9.1 days (range 228 days).
The most frequent manifestations of CAPS were cutaneous (n = 11), hepatic (n = 11), renal (n = 10), cardiac
(n = 8) and neurological (n = 5). Cutaneous manifestations
included skin necrosis (n = 5, with ear involvement in 4),
purpura (n = 3), splinter haemorrhage (n = 3) and hand
and/or foot erythema (n = 2). Renal involvement required
dialysis in five cases. Cardiac involvement led to severe
cardiac insufficiency in four patients: one required extracorporeal membrane oxygenation (ECMO) and another
had a cardiac arrest and was successfully resuscitated.
Neurological manifestations included convulsions (n = 3),
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aCL, B2GP1
Nonea
PAPS
Nonea
PAPS
SLE, APS
PAPS
Case 3
(2006)
Case 4
(2008)
Case 5
(2009)
Case 6
(2006)
Case 7
(2004)
Case 8
(2002)
29
32
37
26
PAPS
Case 2
(2010)
SLE, APS
Case 1
(2008)
Patients
Known
CTD
None
None
Treatment during
pregnancy
+4 weeks
+0
+5 days
+3 days
25 WG
+8 days
+15 days
CAPS
onset (WG or
post-partum)
HELLP (36.5)
No
HELLP, preeclampsia
(30.5)
HELLP/preeclampsia (WG)
CAPS
treatment
Neonates
(weight in
grams)
Cardiac, neurological,
pulmonary, renal
(biopsy +), hepatic,
pancreatic, splenic,
ocular, thrombopenia
Adrenal, cutaneous,
Heparin,
hepatic, thrombocytosteroids
penia, HA
6.2
6.2
Deathb (NA)
Deathb (NA)
2.6
Healthy child
(2730)
Deathb (NA)
3.9
5.8
2.3
3.9
Follow-up
(years)
Deathb (690)
Cardiac, neurological,
Heparin, sterrenal (biopsy +), cutaoids (IVMP),
neous, ocular, HA
IVIG, plasma
exchange,
CYC, dialysis
CAPS features
Laboratory
findingsa obstetric
or thrombosis
(V or A)
Age, yearsa
(continued)
Renal insufficiency,
stroke at 4 years
(insufficient anticoagulation), sudden
death at 6 years
Adrenal insufficiency
1 child at 37 WG (on
steroids, HCQ,
LMWH, aspirin)
1 child at 34 WG with
SLE flare (on steroids, HCQ,
azathioprine,
LMWH, aspirin)
1 child at 38 WG (on
steroids, HCQ,
azathioprine,
LMWH, aspirin)
1 HELLP + eclampsia +
abruptio placenta at
28 WG: 600 g live
child (on steroids,
LMWH, aspirin)
1 miscarriage at 7 WG
(on steroids, LMWH,
aspirin), 1
HELLP + preeclampsia at 28
WG: 500 g alive girl
(on steroids, LMWH,
aspirin, HCQ)
New events
during FU
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PAPS
PAPS
PAPS
PAPS (9),
aCL (13), LA (12),
APS+SLE (2),
B2GP1 (10),
Nonea (2)
Venous (8),
Arterial (5),
Obstetric (4)
Case 11
(2010)
Case 12
(2007)
Case 13
(2007)
Total
(number)
31 (23-37)
23
27
32
36
32
+0
+0
+3 days
+2 days
CAPS
onset (WG or
post-partum)
HELLP (15)
HELLP (30)
HELLP/preeclampsia (WG)
Oral
anticoagulantsc
Treatment during
pregnancy
Heparin,
steroids
Fetal death at
13 WG (NA)
Fetal death at
17 WG (NA)
Healthy child
(2285)
4.5
5.2
Follow-up
(years)
Cardiac, cutaneous,
Heparin, sterhepatic, placenta (hisoids (IVMP),
tology +),
IVIG
thrombocytopenia
Cardiac, renal,
Cutaneous, thrombocytopenia, HA
Neonates
(weight in
grams)
Cutaneous, hepatic,
Heparin, sterrenal, adrenal, thromoids, plasma
bocytopenia, gallbladexchange,
der (histology +)
dialysis
Cardiac, neurological,
renal, hepatic, pancreatic, cutaneous,
thrombocytopenia,
HA
CAPS features
CAPS
treatment
1 miscarriage, 1
HELLP + preeclampsia (28 WG),
1
HELLP + eclampsia
(28 WG), 4 deliveries
of healthy children,
2 maternal deaths
Sudden death at
2.5 years
Renal insufficiency
with proteinuria,
high blood pressure
1 child at 36 WG (on
steroids, HCQ,
LMWH, aspirin and
eculizumab)
Autoimmune hepatitis
and primary biliary
cirrhosis
Adrenal insufficiency
New events
during FU
High dose of LMWH means dose adjusted to have anti-Xa activity at least greater than 0.5 (usually two s.c. injections of enoxaparin adjusted to the patients weight). PAPS: primary
APS; CTD: connective tissue disease; VT: venous thrombosis; AT: arterial thrombosis; HA: haemolytic anaemia. aSLE and APS were diagnosed at the time of CAPS. bElective
termination of pregnancy for maternal reasons. cThe pregnancy was unknown until delivery and the patient was treated with her usual treatment (fluindione with mean INR around 2.9).
LA, aCL,
B2GP1, VT
LA, aCL, AT
LA, aCL,
B2GP1, VT
PAPS
Case 10
(2007)
LA, aCL, VT
PAPS
Case 9
(2005)
Patients
Laboratory
findingsa obstetric
or thrombosis
(V or A)
Age, yearsa
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Known
CTD
TABLE 1 Continued
Discussion
Follow-up
The median follow-up after CAPS was 4.8 years (range
28 years). Seven new pregnancies occurred in five patients. One patient (case 1) had a miscarriage at 7 WG and
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Pregnancy and the post-partum period are well-known predisposing factors for venous thrombosis due to procoagulation physiological changes. We report our experience of
13 cases of CAPS occurring during this period.
Patients had different clinical features of APS before
CAPS (arterial, venous and obstetric). We found a high
rate (69%) of triple positivity for aPLs (LA, aCL and antib2-glycoprotein I antibodies) and a higher proportion of LA
than expected in APS: 92.3% vs 53.6% in a cohort of
1000 APS patients [10] (P < 0.001). This is not surprising,
for different reasons. First, the triple positivity for aPLs
corresponds to a high-risk anti-phospholipid profile [11];
in the multicentre prospective observational PROMISSE
study, the presence of an LA was the most significant
risk factor for adverse obstetric outcome, with a risk of
39% compared with 3% in its absence (P < 0.0001) [12].
Second, the presence of an LA is >80% in patients with
CAPS [13]. Similar to Gomez-Puerta et al. [4], who reported three new cases and reviewed a total of 15
cases of pregnancy-related CAPS, previous obstetric
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References
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