ANTIPHOSPHOLIPID SYNDROME (APS) and Pregnancy

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ANTIPHOSPHOLIPID SYNDROME (APS) and Pregnancy

• DR. Hanaa Al ani

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Background

• Antiphospholipid syndrome (APS) is a disorder
  that manifests clinically as recurrent venous or
  arterial thrombosis and/or fetal loss.

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Background

• Characteristic laboratory abnormalities in APS
  include persistently elevated levels of
  antibodies directed against membrane anionic
  phospholipids
• anticardiolipin aCL antibody,
• antiphosphatidylserine predominantly beta-2
  glycoprotein I
• or evidence of a circulating anticoagulant.

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Incidence

• It was first described in patients with SLE, but
  it is now recognized both that most patients with
  APS do not fulfill the diagnostic criteria for
  SLE and that those with primary APS do not
  usually progress to SLE.
• The prevalence of aPL in the general obstetric
  population is low (lt2).

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Table 1 - Clinical criteria for the diagnosis of
APS
Thrombosis Venous Arterial Small vessel (e.g. thrombotic microangiopathy in kidney)
Pregnancy morbidity 3 consecutive miscarriages (lt10 weeks' gestation) 1 fetal death (gt10 weeks' gestation with normal fetal morphology) 1 premature birth (lt34 weeks' gestation with normal fetal morphology) due to pre-eclampsia or severe placental insufficiency .
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Table 2 - Other recognized features of APS
Thrombocytopenia Haemolytic anaemia Livedo reticularis Cerebral involvement Epilepsy, cerebral infarction, chorea and migraine, transverse myelopathy/myelitis mitral valve
Heart valve disease Hypertension Pulmonary hypertension Leg ulcers Epilepsy, cerebral infarction, chorea and migraine, transverse myelopathy/myelitis mitral valve

• About 30-40 of women with SLE have aPL.
• About 30 of those with aPL have thrombosis.
• Up to 30 of women with severe early-onset
  pre-eclampsia may have aPL

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Antiphospholipid syndrome. Livedo reticularis
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Antiphospholipid syndrome. Arterial thrombosis
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Clinical features

• Although the clinical features of primary and
  SLE-associated APS are similar, and the antibody
  specificity is the same, the distinction is
  important, and patients with primary APS should
  not be labeled as having lupus.

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Pathogenesis

• The pathogenesis of APS involve a co- factor, ß2
  glycoprotein
• In APS-associated fetal loss, there is typically
  massive infarction and thrombosis of the
  placental and decidual vessels, probably
  secondary to spiral arte vasculopathy. Platelet
  deposition and prostanoid imbalance may be
  implicate in a similar way to pre-eclampsia.

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Pathogenesis

• Many of the adverse outcomes described are the
  end result of defective or abnormal placentation
  and these findings support placental failure,
  being the mechanism by which aPL are associated
  with late loss.

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Pathogenesis

• aPL bind to human trophoblasts in vitro.
  Trophoblast cell membranes behave as targets for
  both ß2GPI-dependent and ß2GPI-independent aPL.
• aPL reduce hCG release and inhibit trophoblast
  invasiveness.

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Diagnosis

• Firm diagnosis of APS requires two or more
  positive readings for LA and/or aCL at least 6
  weeks apart, plus at least one of the clinical
  criteria listed before.

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Diagnosis

• .
• Lupus anticoagulant is a misnomer coined because
  it prolongs coagulation times in vitro. It is
  detected by the prolongation of the activated
  partial thromboplastin time (aPTT) or the dilute
  Russell's viper venom time (dRVVT).

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Diagnosis

• Anticardiolipin antibodies are measured using
  commercially available enzyme-linked
  immunosorbent assay (ELISA) kits. Medium or high
  titres of IgG or IgM are required.

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Effect of pregnancy on APS

• The risk of thrombosis is exacerbated by the
  hypercoagulable pregnant state.
• Pre-existing thrombocytopenia may worsen

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Effect of APS on pregnancy

• The risks of miscarriage, second and third
  trimester fetal death, pre-eclampsia, IUGR and
  placental abruption are increased.
• Establishing causality for first trimester losses
  is difficult, since the risk of miscarriage is
  high (10-15) in the normal population. aPL are
  more common in women suffering three or more
  first-trimester miscarriages, than in those with
  one or two miscarriages.

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Effect of APS on pregnancy

• Fetal death in APS is typically preceded by IUGR
  and oligohydramnios.
• The risk of fetal loss is directly related to
  antibody titre, particularly the IgG aCL,
  although many women with a history of recurrent
  loss have only IgM antibodies.

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Management

• Pre-pregnancy
• Women with a history of thrombosis, recurrent
  miscarriage, intrauterine fetal death, or severe
  early-onset pre-eclampsia or.IUGR should be
  screened for the presence of LA. or aCL.
• A detailed history of the circumstances of the
  fetal loss is essential to exclude other causes
  of late miscarriage, such as cervical
  incompetence or idiopathic premature labour. The
  presence of aPL does not constitute a diagnosis
  of APS unless the clinical features are
  suggestive.

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Management (Cont)

• Antenatal
• Care of pregnant women with APS should be
  multidisciplinary and in centres with expertise
  of caring for these high-risk pregnancies.
• Aspirin inhibits thromboxane and may reduce the
  risk of vascular thrombosis. There are many
  non-randomized studies suggesting that low-dose
  aspirin is effective and it can prevent pregnancy
  loss in experimental APS mice.
• Aspirin is a logical treatment in those with aPLs
  but no clinical features of aps.

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Management (Cont)

• Antenatal
• . Most centres now advocate treatment with
  low-doses aspirin for all women with APS, prior
  to conception, in the belief that the placental
  damage occurs early in gestation, and that
  aspirin may prevent failure of placentation.

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Antenatal (Cont)

• Women with APS and previous thromboembolism are
  at extremely high risk of further
  thromboembolism in pregnancy and the puerperium
  and should receive antenatal thromboprophylaxis
  with a high prophylactic dose of low
  molecular-weight heparin (LMWH) (e.g.
  Enoxaparin 40 mg b.d.) . Many of these women
  are on life-long anticoagulation therapy with
  warfarin. The change from warfarin to heparin
  should be achieved prior to 6 weeks' gestation to
  avoid warfarin embryopathy.
• A few women with cerebral arterial thrombosis due
  to APS on long-term warfarin may experience
  transient ischemic symptoms when LMWH is
  substituted for warfarin. If these do not improve
  on higher (full anticoagulant) doses of LMWH, the
  reintroduction of warfarin is justified to
  prevent maternal stroke.

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Antenatal (Cont)

• Opinion is divided about the best therapy for
  those with recurrent pregnancy loss, but without
  a history of thromboembolism.
• Treatment with high-dose steroids (in the absence
  of active lupus) to suppress LA and aCL, in
  combination with aspirin, is no longer
  recommended because of the maternal side effects
  from such prolonged high doses of steroids. This
  strategy has been abandoned in favour of
  anticoagulant treatment with aspirin and/or s.c.
  LMWH. Such regimens give equivalent fetal outcome
  with fewer maternal side effects than
  combinations of aspirin and steroids.

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Table 3 - Therapeutic management of APS
pregnancies
Clinical History Anticoagulant therapy
No thrombosis, no miscarriage, no adverse pregnancy outcome Aspirin 75 mg o.d. from pre-conception
Previous thrombosis On maintenance warfarin transfer to aspirin and LMWH (enoxaparin 40 mg b.d.) as soon as pregnancy confirmed Not on warfarin aspirin 75 mg o.d. from preconception and commence LMWH (enoxaparin 40 mg o.d.) once pregnancy confirmed. Increase LMWH to bd at 16-20 weeks No prior
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Table 4 - Therapeutic management of APS
pregnancies
Clinical History Anticoagulant therapy
Recurrent miscarriage lt10 weeks No prior anticoagulant therapy Aspirin 75 mg o.d. from pre-conception Prior miscarriage with aspirin alone Aspirin 75 mg o.d. from pre-conception and LMWH (enoxaparin 40 mg o.d.) once pregnancy confirmed. Consider discontinuation of LWWH at 20 weeks' gestation if uterine artery waveform is normal
Late fetal loss, neonatal death or adverse outcome due to pre-eclampsia, IUGR or abruption Aspirin 75 mg o.d. from pre-conception and LMWH (enoxaparin 40 mg o.d.) once pregnancy confirmed
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Antenatal (Cont)

• Any additional benefit of heparin must be
  balanced against the risk of heparin-induced
  osteoporosis (0.04 with LMWHs), and the cost and
  inconvenience of daily injections.
• In women with recurrent miscarriage, but without
  a history of thrombosis, there is evidence to
  support the use of no therapy, aspirin alone, and
  aspirin and LMWH. A pragmatic approach is to
  offer aspirin alone, particularly if the history
  is of less than three miscarriages and then if
  miscarriage occurs despite aspirin therapy to
  offer LMWH in addition.

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Antenatal (Cont)

• Antithrombotic strategies vary in different
  centres around the world.
• LMWH is given in prophylactic doses (enoxaparin
  Clexane 40 mg o.d. dal-teparin Fragmin
  5000 units o.d.) when given for fetal
  indications, but in women with previous
  thrombosis higher doses (e.g. enoxaparin
  Clexane 40 mg b.d. dalteparin Fragmin 5000
  units b.d.), are indicated.

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Antenatal (Cont)

• Immunosuppression with azathioprine, i.v.
  immunoglobulin (IVIg) and plasmapheresis have all
  been tried. The numbers treated do not allow firm
  conclusions regarding efficacy, although there is
  some evidence available for IVIg. IVIg is
  extremely expensive, precluding its use outside a
  research setting in most centres.

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Antenatal (Cont)

• Close fetal monitoring is essential. Uterine
  artery Doppler waveform analysis at 20-24 weeks'
  gestation helps predict the higher-risk
  pregnancies. Monthly growth scans are performed
  from 28 weeks if the uterine artery Doppler wave
  form at 24 weeks shows pre-diastolic 'notching'.
• High-risk women require closer surveillance with
  regular blood pressure checks and urinalysis to
  detect early-onset pre-eclampsia.
• Such intensive monitoring allows for timely
  delivery, which may improve fetal outcome.

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Postpartum

• Women on long-term warfarin treatment may
  recommence this postpartum (starting days 2-3)
  and LMWH is discontinued when the international
  normalised ratio (INR) is gt2.0.
• Women with previous thrombosis should receive
  postpartum heparin or warfarin for 6 weeks.
• Women without previous thrombosis should receive
  postpartum heparin for at least 5 days to 6
  weeks, depending on the presence of other risk
  factors.

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The End
Thank you