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Rev Clin Esp. 2013;213(2):108---113

Revista Clínica
Española
www.elsevier.es/rce

SPECIAL ARTICLE

Clinical advances of interest in the diagnosis and treatment of

patients with antiphospholipid syndrome夽
J.L. Rodríguez García a , M.A. Khamashta b,∗

a
Servicio de Medicina Interna, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
b
Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, London, England, United Kingdom

Received 26 November 2011; accepted 1 April 2012

Available online 9 January 2013

KEYWORDS Abstract In this paper we review recent studies and consensus documents that we consider
Antiphospholipid relevant to the diagnosis and treatment of patients with antiphospholipid syndrome (APS). The
syndrome; diagnosis of APS is based on the Sydney classification criteria (2006), in which positive laboratory
Review; tests (anticardiolipin antibodies, anti-␤2-glycoprotein I antibodies or lupus anticoagulant) are
Treatment; mandatory. However, it is not uncommon to see patients with clinical features highly suggestive
Seronegative of the syndrome in whom these antibodies are persistently negative. Therefore, we summarize
antiphospholipid the principal clinical and serological findings in a subgroup of patients with seronegative APS in
syndrome the first series published up to date. In addition, a recent study draws attention to the safety
and efficacy of the long-term use of low-molecular-weight heparins in patients with APS not sus-
ceptible to warfarin treatment. There is also a subgroup of women with APS and recurrent fetal
loss with no response to the standard antithrombotic therapy; in this group the materno-fetal
prognosis could be improved by the addition of low-dose prednisolone during the first trimester
of pregnancy. Finally, we list the principal recommendations regarding thromboprophylaxis in
APS drawn from the expert consensus document elaborated at the meeting held in Galvestone
(2010).
© 2013 Elsevier España, S.L. All rights reserved.

PALABRAS CLAVE Avances de interés clínico en el diagnóstico y tratamiento de los pacientes con
Síndrome síndrome antifosfolípido
antifosfolípido;
Revisión; Resumen En este artículo se repasan algunos de los estudios y documentos de consenso
Tratamiento; recientes que hemos creído relevantes en el ámbito del diagnóstico y tratamiento de los
Síndrome pacientes con síndrome antifosfolípido (SAF). El diagnóstico del SAF se basa en los criterios
antifosfolípido de clasificación de Sidney (2006), donde la positividad de las pruebas de laboratorio (antic-
seronegativo uerpos anticardiolipina, anti-␤2 -glicoproteína 1 o anticoagulante lúpico) supone un requisito
necesario. Sin embargo, no es infrecuente encontrar pacientes con clínica muy sugestiva del
síndrome y ausencia de estos anticuerpos. En este sentido, resumimos los principales hallazgos

夽
Please cite this article as: Rodríguez García JL, Khamashta MA. Avances de interés clínico en el diagnóstico y tratamiento de los pacientes
con síndrome antifosfolípido. Rev Clin Esp. 2013;213:108---13.
∗ Corresponding author.

E-mail address: munther.khamashta@kcl.ac.uk (M.A. Khamashta).

2254-8874/$ – see front matter © 2013 Elsevier España, S.L. All rights reserved.
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Diagnosis and treatment of patients with antiphospholipid syndrome 109

clínicos y serológicos de un subgrupo de pacientes con SAF seronegativo en la primera serie

publicada hasta la actualidad.
En relación con el tratamiento antitrombótico, un estudio reciente ha señalado la seguridad y
eficacia del uso de heparinas de bajo peso molecular a largo plazo en pacientes con SAF no sub-
sidiarios de tratamiento con dicumarínicos. Por otro lado, existe un subgrupo de pacientes con
SAF y pérdidas fetales recurrentes, cuyo pronóstico materno-fetal puede verse mejorado con
la administración de bajas dosis de esteroides durante el primer trimestre de gestación. Final-
mente, recogemos las principales recomendaciones sobre tromboprofilaxis en el SAF extraídas
del consenso de expertos de la reunión celebrada en Galvestone (2010).
© 2013 Elsevier España, S.L. Todos los derechos reservados.

Since the initial description of antiphospholipid syndrome
(APS) more than a quarter century ago, the efforts of basic
and clinical researchers interested in this condition have
focused mainly on two lines of study. The first is related
to improvement of the diagnosis of patients with clinical
suspicion of this syndrome through the establishment of
consensus-based classification criteria (which are currently
those agreed upon in Sydney in 20061 ) and through the study
of new disease markers that could become part of future
classification criteria. The second line of research concerns
the optimization of the management of clinical manifesta-
tions of this condition, mainly those that are characteristics
of the syndrome and accepted as classification criteria, i.e.,
the management of venous and arterial thrombotic events
and obstetric morbidity.
The present special article therefore attempts to compile
novel and relevant issues related to the diagnosis and clinical
management of this syndrome:
(1) seronegative APS;
(2) long-term use of low molecular weight heparins in the
treatment of patients with APS;
(3) results of treatment with prednisolone during the first
trimester in patients with APS and recurrent abortions
refractory to standard antithrombotic treatment; and
(4) a number of the recommendations on thromboprophy-
laxis in APS by the expert consensus at the meeting held
in Galveston (2010).
Seronegative antiphospholipid syndrome
In clinical practice, it is not unusual to find patients with
clinical manifestations suggestive of APS who have persis-
tently negative laboratory tests to detect anticardiolipin
(ACL), lupus anticoagulant (LA) and anti-␤2-glycoprotein
(GP) I. For these cases, the term seronegative APS (SNAPS)
has been coined.2 Although the diagnosis of APS is based
on the detection of these antibodies, other antibodies
have been reported in patients with APS that are directed
against various phospholipids or protein cofactors such as
prothrombin, phosphatidylethanolamine, annexin V and the
vimentin/cardiolipin complex.3 However, the primary dis-
advantage is that this test is not part of the screening tests
due to the lack of standardized laboratory techniques for
measuring these antibodies.
From the description of SNAPS, references to it are based
on the publication of isolated cases. However, the experi-
ence from a series of 67 patients meeting clinical criteria
for APS and with persistent negativity of antiphospholipid
antibodies (APA) was recently published.4 These patients not
only met a major clinical criterion, such as arterial or venous
thrombosis and obstetric morbidity but also met 2 or more
criteria not included in the Sydney classification criteria but
that are accepted as being associated with or forming part of
the syndrome. These criteria include livedo reticularis, Ray-
naud’s phenomenon, neurological manifestations (migraine,
cognitive dysfunction, convulsions, chorea, central nervous
system [CNS] lesions similar to multiple sclerosis, hyperin-
tense lesions in CNS white matter under magnetic resonance
imaging [MRI]), heart valve disease, obstetric morbidity (1---2
miscarriages <10 weeks) and thrombocytopenia. This study
also included 87 patients diagnosed with APS based on the
Sydney criteria (seropositive APS [SPAPS]).
The characteristics of the patients are shown in Table 1.
The prevalence of thrombotic and obstetric manifestations
was similar in both groups (Table 2), including the recur-
rence of vascular events in patients in whom anticoagulation
was suspended or the INR levels (International Normal-
ized Ratio) were not maintained in the therapeutic range.
A lower rate of successful pregnancy was observed (live
births/number of pregnancies) in the SNAPS group (38% vs.
50%; P = 0.03), which may be related to the fact that SNAPS is
a poorly recognized condition, and therefore these patients
did not receive the same treatment during pregnancy as
the patients with SPAPS. There were no differences in the
prothrombotic vascular risk factors, and the patients with
vascular events received anticoagulant therapy and other
concomitant drugs in a similar proportion. A subsequent
analysis of the patients in this study has shown a diagnostic
sensitivity in the SNAPS group of 23.5% when the following
nonstandard laboratory tests were conducted: IgA anti-␤2-
GP I and IgG and IgM phosphatidylserine---prothrombin and
antiphosphatidylethanolamine.5
These results suggest that we should consider the possi-
bility of the presence of APS when there are clinical data
that support this diagnosis, despite the negativity of the
APA included in the classification criteria for the syndrome.
Follow-up of these patients and appropriate antithrombotic
therapy may prevent the recurrence of thrombosis and
improve the maternal---fetal prognosis.
Low molecular weight heparin in the
long-term treatment of antiphospholipid
syndrome
Although vitamin K antagonists are the most frequently rec-
ommended drugs for patients with APS and thrombosis, in
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110 J.L. Rodríguez García, M.A. Khamashta

Table 1 Characteristics of patients with seronegative APS vs. those with seropositive APS.
Seronegative APS (n = 67) Seropositive APS (n = 87) P value
Age 45.7 ± 9.3 46.1 ± 11.1 NS
Age at first obstetric event 25.9 ± 5.7 27.8 ± 6.8 NS
Age at first thrombotic episode 33.8 ± 11.5 36.7 ± 12.7 NS
Gender
Female (%) 66 (98.5) 80 (91.9) NS
Race
Caucasian (%) 64 (95.5) 71 (81) NS
Primary vs. secondary APS 0.002
Primary APS 56 (83.5) 53 (60.9)
APS-SLE (%) 11 (16.4) 34 (39.1)
Clinical manifestations
Venous thrombosis (%) 27 (40,2) 40 (45.9) NS
Arterial thrombosis (%) 23 (34.3) 30 (34.4) NS
Obstetric morbiditya (%) 55/64 (85.9) 54/69 (78.2) NS
SLE: systemic lupus erythematosus; APS: antiphospholipid syndrome.
a According to the Sydney classification criteria.

clinical practice, thrombotic events are observed in the
context of appropriate anticoagulation. The optimal man-
agement of these patients is controversial, and low molec-
ular weight heparins (LMWHs) represent one alternative for
patients with resistance, failure or contraindication for oral
anticoagulants. Among the complications of LMWH are hem-
orrhage, osteoporosis (5%) and thrombocytopenia (0---3%).6
The effects on the long-term safety and efficacy of LMWH
beyond a period of 9 months in non-pregnant patients with
APS is not known. In order to understand the efficacy and
safety of long-term LMWH treatment, a retrospective study
was conducted on 23 patients with APS who met the Sapporo
classification criteria7 and who had received at least one
year of treatment with LMWH at an anticoagulation dosage.8
The demographic and clinical data and the response to
treatment are shown in Tables 3 and 4. The mean length
of treatment with LMWH was 36 months (interval: 14---216).
Sixty-nine percent of the patients received enoxaparin and
the rest received dalteparin or tinzaparin.
A complete or partial response was observed with no
evidence of rethrombosis in 87% of the patients. A com-
plete improvement was observed in 9 (39%) patients, i.e.,
no recurrence of thrombosis, clinical improvement and
improvement of radiological lesions in the 2 patients who
presented neurological manifestations. Partial improvement
was achieved in 48% (11) of the patients in whom there
were no new thrombotic episodes but who had only a slight
improvement in neurological symptoms or a reduction of

Table 2 Clinical manifestations of seronegative vs. seropositive APS patients.

Seronegative APS (n = 67) (%) Seropositive APS (n = 87) (%) P value
1. Venous thrombosis 27 (40.2) 40 (45.9) NS
DVT 21 (31.4) 27 (31) NS
Recurring DVT 8 (38.0) 10 (37) NS
PTE 16 (23.8) 25 (28.7) NS
Recurring PTE 5 (31.5) 2 (8) NS
2. Arterial thrombosis 23 (34.3) 30 (34.4) NS
Stroke 10 (14.9) 15 (17.2) NS
Recurring stroke 3 (30) 2 (13.3) NS
TIA 8 (11.9) 9 (10.3) NS
Recurring TIA 1 (12.5) 3 (33.3) NS
Coronary disease 6 (8.9) 4 (4.6) NS
3. Obstetric pathology 60/64 (93.7) 57/69 (82.6) NS
Miscarriage < week 10 43/64 (67.1) 36/69 (52.1) NS
Fetal loss > week 10 40/64 (62.5) 41/69 (59.4) NS
Prematurity < week 34 18/64 (28.1) 15/69 (21.7) NS
Pre/eclampsia 18/64 (28.1) 16/69 (23.1) NS
TIA, transient ischemic attack; APS, antiphospholipid syndrome; PTE, pulmonary thromboembolism; DVT, deep vein thrombosis.
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Diagnosis and treatment of patients with antiphospholipid syndrome 111

Table 3 APS and long-term treatment with LMWH. Clini- Table 4 Significant clinical data on patients with APS
cal and demographic characteristics and previous treatment treated with long-term LMWH.
with warfarin.
Reasons for changing to LMWH
Gender male/female (%) 22/1 (96 vs. 4) Lack of response to warfarin (%) 9 (39)
Race 22/1 (96 vs. 4) Lack of neurological improvement 6 (26)
Caucasian/Afro-Caribbean (%)
(%) Major bleeding (%) 4 (17)
Age (years) 42 (34---48) Other side effects of warfarin (%) 2 (9)
Patient preference (%) 2 (9)
APS
Duration of treatment with LMWH 36 (25---44)
Primary (%) 10 (43)
(months)
Secondary (%) 13 (57)
SLE (%) 11 (47) Type of LMWH
Others (%) 2 (8) Enoxaparin (%) 16 (69)
Other (%) 7 (31)
Cardiovascular risk factors
None (%) 17 (75) Results
HBP (%) 2 (9) Complete clinical improvement 9 (39)
Diabetes (%) 1 (4) and no rethrombosis (%)
Smoking (%) 1 (4) Partial clinical improvement and no 11 (48)
HBP + smoking (%) 1 (4) rethrombosis (%)
Diabetes + smoking (%) 1 (4) No clinical improvement and/or 3 (13)
rethrombosis (%)
Manifestations of APS
Arterial thrombosis (%) 3 (13) Side effects of LMWH
Venous thrombosis (%) 6 (26) None (%) 18 (77)
Arterial and venous 4 (17) Osteoporosis (%) 5 (23)
thrombosis (%) LMWH: low molecular weight heparin; APS: antiphospholipid syn-
Obstetric pathology (%) 1 (4) drome.
Obstetric and vascular 5 (23)
pathology (%)
CNS symptoms with lesions 4 (17) dalteparin. During an average of 309 days of treatment, none
in MRI (%) of the patients included in the study experienced rethrom-
Previous warfarin/duration (months) bosis or major adverse effects.
Yes 18 (77%)/42 (10---84) In short, there are several scenarios in which the
No 5 (23%)/0 (0---0) recurrence of thrombosis may take place despite optimal
anticoagulation therapy, among which include patients with
LMWH, low molecular weight heparin; HBP, high blood pressure;
APS. Until the use of new oral anticoagulant agents becomes
SLE, systemic lupus erythematosus; MRI, magnetic resonance
imaging; APS, antiphospholipid syndrome; CNS, central nervous possible, long-term treatment with LMWH may be an effec-
system. tive and safe alternative for these subjects while we wait
for controlled clinical trials.

less than 50% in the hyperintense lesions in the CNS white

matter in the MRI. In three patients (13%), neither there
was rethrombosis nor there was neurological improvement,
either clinical or radiological. Osteoporosis confirmed by
densitometry was observed in 23% of the patients, although
all were on maintenance treatment with steroids. There
were no major hemorrhage episodes or thrombocytope-
nia.
Although other treatment options for the patients in
this study have been proposed, such as increasing the INR
to above 3, combining antiplatelet therapy or the use of
other anticoagulants (lepirudin) or hydroxychloroquine, the
results of this study indicate that long-term treatment with
LMWH at anticoagulant dosages is an option for patients
with APS who respond poorly to or who are contraindicated
for oral anticoagulants. In the literature review, there is
only one other study that evaluates the efficacy and safety
of LMWH in patients with APS. Bick and Rice9 published a
series of 24 patients with APS who were resistant or intoler-
ant to warfarin and who were treated for this reason with
Low-dose prednisolone in women with
antiphospholipid syndrome and recurrent
fetal losses
Although fetal losses in women with APS have declined
significantly following the treatment protocol with acetyl-
salicylic acid (AAS) and heparin, there is nonetheless a
subgroup (estimated at 10% of patients) for whom this treat-
ment is ineffective.10
The pathophysiology of obstetric APS is not well-known,
although there is increasing evidence of the role of inflam-
matory mechanisms as the cause for tissue damage in the
human placenta, which can lead to fetal loss. Among these
mechanisms is the activation of the complement cascade.
Prednisolone is capable of changing the activation of the
complement, and this may be the mechanism by which
it could act favorably in patients with refractory obstet-
ric APS. In addition, high concentrations of inflammatory
cells have been observed in the placental bed of women
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112 J.L. Rodríguez García, M.A. Khamashta

Table 5 Recommendations for the prevention and long-term treatment of thrombosis in patients with APA. Galveston Consensus
(2010).a

Degree of
recommendationb
Carriers of APA
Strict control of cardiovascular risk factors in all patients with high-risk APA profiles.c Undetermined
Thrombosis prophylaxis at the standard dose with low molecular weight heparin in at-risk 1C
situations such as surgery, prolonged immobilization and postpartum.
Primary thromboprophylaxis in patients with SLE and APA
Low-dose hydroxychloroquine (1) and AAS (2). 1B (1)
2B (2)
Primary thromboprophylaxis in subjects with APA with no SLE
Long-term prophylaxis with low-dose AAS in patients with high-risk APA profiles especially in 2C
the presence of other thrombosis risk factors.
Secondary thromboprophylaxis
Patients with defined APS and a first venous thrombotic event should receive oral 1B
anticoagulation (INR: 2---3).
Patients with defined APS and arterial thrombosis should be treated with oral Undetermined (lack of
anticoagulation (INR > 3) or combined treatment with antiplatelets (INR: 2---3), although consensus)
other options such as only antiplatelets or anticoagulation for INR 2---3 may be equally valid
options (lack of consensus).
Attention must be paid to the risk of bleeding prior to recommending high-intensity
anticoagulation or combined treatment with antiplatelets.
Patients with APS not associated with SLE who present a first non-cardioembolic arterial Undetermined
cerebral episode, with low-risk APA profiles and the presence of triggering reversible risk
factors may be considered individually as candidates for antiplatelet therapy.
Treatment duration
Patients with defined APS diagnosis should receive indefinite antithrombotic treatment. 1C
In the event of a first venous thrombotic event, low-risk APA profile and known transient Undetermined
triggering factor, the anticoagulation therapy may be limited to 3---6 months.
APA, antiphospholipid antibodies; AAS, acetylsalicylic acid; SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome.
a Source: modified from Ruiz-Irastorza et al.17.
b 1A: strong recommendation, high quality of evidence; 1B: strong recommendation, moderate quality of evidence; 1C: strong rec-

ommendation, low to very low quality of evidence; 2A: weak recommendation, high quality of evidence; 2B: weak recommendation,
moderate quality of evidence; 2C: weak recommendation, low to very low quality of evidence.
c High risk: positive lupus anticoagulant, triple positive (LA + anticardiolipin + anti-␤ -GP I) or anticardiolipin antibodies that are per-
2
sistently positive to medium-high titers. Low risk: isolated and intermittent anticardiolipin antibodies or anti-␤2 -GP I that are positive
to low-medium titers.

with APS, which may have been caused by the use of
steroids.11,12
A controlled randomized trial that compared AAS with
prednisolone (40 mg/day) or heparin in prophylaxis doses
showed no differences in the percentage of live births
(LB), although there was an increase in premature births
in the group treated with prednisolone.13 Another study
observed similar results in women treated with AAS versus
AAS with prednisolone (20 mg/day).14 Moreover, other treat-
ments such as the use of immunoglobulins have not improved
these results. Until now, however, the potential benefit of
the combination of corticosteroids and standard treatment
with AAS and heparin was unknown.
Based on these results, a study was conducted that
included 18 women with APS between 1999 and 2008 who
had at least one miscarriage while on treatment with AAS
and LMWH and who were administered, in addition to the
standard anticoagulation therapy, prednisolone at a dosage
of 10 mg/day from the confirmation of a positive pregnancy
test to the 14th week.10 The mean age of the patients
was 36 years (range: 33---40), and prior to treatment, 93
miscarriages (mean: 4; range: 3---6.8) and 4 live births
(4%) were recorded. Twenty-three pregnancies were sup-
plemented with prednisolone, of which 14 (61%) resulted
in LBs, 8 of which were uncomplicated pregnancies. There
were no congenital abnormalities or late fetal deaths, and
there was no maternal morbidity as a result of the use of
prednisolone. There was no relationship between the full-
term pregnancy and variables such as the number of previous
fetal losses (before and after week 10), the number of pre-
vious LBs, the patients’ age and the serological profile (APA,
ANA).
In conclusion, this study suggests that women with refrac-
tory APS due to fetal losses may see improvements in the
maternal---fetal prognosis when low doses of steroids are
added in the first trimester of pregnancy.
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Diagnosis and treatment of patients with antiphospholipid syndrome
Recommendations for antithrombotic
treatment in antiphospholipid syndrome:
Galveston consensus (2010)
The management of thrombosis in patients with APS remains
a controversial subject. The fact that this syndrome repre-
sents an acquired thrombophilia that affects 20% of young
patients with venous thromboembolism or ictus is relevant,
and observational studies indicate that there is a high rate
of recurrence in patients with APS in whom antithrombotic
treatment is suspended.15,16 However, it is well known that
long-term anticoagulation represents a real risk of poten-
tially severe bleeding. In addition, it also raises the dilemma
of the need for primary thromboprophylaxis in subjects who
carry APA. To respond to these issues, a consensus document
was developed on primary and secondary prophylaxis in APA
carriers at the 13th International Congress on Antiphospho-
lipid Antibodies, which took place in Galveston on April
2010.17
The classification of different levels of risk using clin-
ical and immunological parameters (first thrombosis vs.
recurring event, arterial vs. venous thrombosis, presence
of systemic lupus erythematosus [SLE] vs. APS not associ-
ated with SLE, degree of risk of the APA profile [Table 5])
may serve as a guideline for selecting a more appropri-
ate treatment for each patient, in particular the intensity
and duration of anticoagulation therapy. Among the various
types of APA, LA is the marker that best predicts thrombotic
risk, and the greatest risk for arterial or venous thrombosis
is in patients with triple positivity (ACL, LA and anti-␤2-GP
I). In addition, the presence of APA is a major determi-
nant of the development of thrombosis in patients with
SLE.
The summary of the recommendations for antithrom-
botic treatment in patients with APS is shown in Table 5. As
the document itself ultimately states, the majority of the
recommendations are based on weak and incomplete data
(levels of evidence B or C). It would therefore be prudent
that any modification to the proposals for thromboprophy-
laxis listed in the document be supported by new studies
with conclusions based on greater scientific evidence.
Conflicts of interest
The authors have no conflicts of interest to declare.
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