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ANTIPHOSPHOLIPID SYNDROME

(APS) AND PREGNANCY


MODERATOR: Dr Manika Agarwal
Associate Prof,
Dept of Obs & Gyn, NEIGRIHMS
Presented by : Sattradhaja Keisham
2008- Batch intern,
Dept. of Obs & Gyn, NEIGRIHMS
OUTLINE
Discovery of APS
A brief review of APS
Introduction
Clinical features
Pathophysiology
Etiology
Epidemiology
Diagnostic criteria
Prognosis
Approach of APS in Pregnancy
History and physical findings
Approach considerations

Management of APS
Obstetrics care
Medical Management
Management in the future
Summary




DISCOVERY OF APS (HUGHES SYNDROME)
Professor Graham Hughes
Consultant Rheumatologist, Head of The London Lupus
Centre

Professor Graham Hughes trained and qualified at The London
Hospital.
In 1969 - 1970 he spent two years Postgraduate Fellowship in
New York at the Rheumatology & Lupus Centre of Dr Charles
Christian.
Professor Hughes became a Consultant Physician
at Hammersmith Hospital where he set up Europes first
dedicated Lupus Clinic in 1973.
In 1983 he described the clotting disorder now known as
Hughes Syndrome. In 1985 he set up the Lupus Unit at St
Thomas Hospital.
In 1993 he received the World Rheumatology (ILAR) Research
Prize for the description of Hughes Syndrome.
He is a member of the American Lupus Hall of Fame, and
Doctor Honoris Causa at the Universities of Marseille and
Barcelona.
Prof. Graham
Hughes
ANTIPHOSPHOLIPID SYNDROME

A BRIEF REVIEW
INTRODUCTION
Antiphospholipid Syndrome (APS) is an autoimmune thrombophilic
condition that is marked by the presence in blood
of antibodies that recognize and attack phospholipid-binding
proteins, rather than phospholipid itself.
APS is associated with pregnancy complications :
- preeclampsia,
- thrombosis,
- autoimmune thrombocytopenia,
- fetal growth restriction, and
- fetal loss.

APS is classified as Primary or Secondary, depending on its association
with other autoimmune disorders.
Primary APS is diagnosed in patients demonstrating the clinical and
laboratory criteria for the disease without other recognized autoimmune
disease.
Secondary APS is diagnosed in patients with other autoimmune
disorders, such as SLE.

INTRODUCTION
Catastrophic Antiphospholipid Syndrome (CAPS)

It represents the severe end of the spectrum with multiple organ thromboses in a
rapid period of time.
It has a mortality rate of approximately 50%.
Multiorgan failure has been seen during pregnancy and also during
postpartum.
The clinical spectrum of this syndrome has widened, with important advances in
the knowledge of its pathogenesis and clinical management made during the
past several years.

INTRODUCTION
Types of patients having antiphospholipid (aPL) antibodies

I. Antiphospholipid syndrome
A. Primary in the absence of SLE
B. Secondary in patients with SLE
II. aPL antibodies stimulated by infection
A. No known association with thrombosis (e.g., syphilis,
Lyme disease, cytomegalovirus, Epstein-Barr virus)
B. Possible association with thrombosis (e.g., varicella,
HIV, hepatitis C)
III. Drug-induced aPL antibodies
(e.g. chlorpromazine and other phenothiazides)
IV. aPL antibodies prevalent in the general population (asymptomatic or
seronegative APS)
Do all people with high aPL antibodies have
APS?
CLINICAL FEATURES OF APS
Nonobstetric features of APS are as follows:
1) Peripheral venous system - deep venous thrombosis [DVT])
2) Central nervous system - cerebrovascular accident [CVA], sinus
thrombosis
3) Hematologic - thrombocytopenia, hemolytic anemia
4) Pulmonary - pulmonary embolism [PE], pulmonary hypertension
5) Dermatologic - livedo reticularis, purpura, infarcts/ulceration
6) Cardiac - Libman-Sacks valvulopathy, MI
7) Ocular - amaurosis, retinal thrombosis
8) Adrenal - infarction/hemorrhage
9) Musculoskeletal - avascular necrosis of bone
CLINICAL FEATURES OF APS
Obstetric features of APS are as follows:

1) Fetal death or stillbirth
2) Recurrent pregnancy loss - 3 or more spontaneous abortions
3) Second or Third trimester fetal death
4) Severe preeclampsia - at less than 34 weeks gestation
5) Unexplained severe fetal growth restriction
6) Chorea gravidarum

PATHOPHYSIOLOGY
Biologic effects mediated by the human aPL antibodies
include the following:

1) Reactivity with endothelial structures that disturbs the balance of
prostaglandin E2/thromboxane production
2) Interaction with platelet PLs, with consequent upregulation of platelet
aggregation
3) Dysregulation of complement activation
4) Interaction of aPL with phosphatidylserine exposed during trophoblast
syncytium formation, which raises the possibility of a more direct effect
of these autoantibodies on placental structures

ETIOLOGY
Like other autoimmune disorders, ASP does not have a known etiology.
There are several hypotheses to explain the probable cause :

Passive transfer of maternal antibodies mediate autoimmune disorders in the
fetus and newborn. The mechanism of excess autoantibody production and
immune complex formation is not well understood.

Familial occurrence of aPL has been reported, and suggested genetic
associations include HLA-DR4, DR7, DRw53 and C4 null allele.

PL molecules are ubiquitous in nature and are present in the inner surface of the
cell and in microorganisms. Therefore, during infectious disease processes,
including viral (eg, HIV, EBV, CMV, adenoviruses), bacterial (eg, bacterial
endocarditis, tuberculosis, Mycoplasma pneumonia), spirochetal (eg, syphilis,
leptospirosis, Lyme disease), and parasitic (eg, malaria infection),the disruption
of cellular membranes may occur during cell damage.
EPIDEMIOLOGY
APS accounts for about 19% to 20% of RPL in the world.
The prevalence of aCL and LAC in normal healthy populations has
been reported to range between
- 1.0% and 5.6% for aCL, and
- 1.0% and 3.6% for LAC.
Age group : 20 yrs to 50 yrs. The prevalence of elevated aPL
antibodies, particularly aCL tend to increase with age .
Sex : Female predominance of about 80% of APS patients (owing to
secondary APS in SLE).
Race : no defined racial predominance for primary APS, although SLE
is more common in African Americans and Hispanic populations.
Geographical distribution : still at infancy stage of data collection.
Hereditary predilection : some reports available, however, it is still
difficult to determine genetic risk factors for aPL and APS because of the
heterogeneity in the antigen specificity, and pathogenesis of the clinical
manifestations of APS.
EPIDEMIOLOGY.
Risk factors for APS:
In SLE patients, 33% are aCL posivitive and LA prevalence is about 15% . A positive LA
appears to be more specific for APS than an elevated aCL. The strength of the
association between aPL and thrombosis varies.
Primarily, aCL are not as strong a risk factor for thrombosis as LA.
Lupus anticoagulant is conistently the most powerful predictor of thrombosis .
About 40% of patients with SLE have aPL, but less than 40% of them will eventually have
thrombotic events .
Titer and isotype are important: IgG aCL is more strongly associated with clinical events
than is IgM aCL, and the risk of thrombosis increases with higher titers (>40 U). IgA aCL
and low titers of IgG and IgM aCL are less frequently associated with complications .
Second-hit hypothesis - a second trigger event - such as cigarette smoking, oral
contraceptives etc.
surgical procedures, prolonged immobilization, or a genetic prothrombotic state -
may increase the likelihood of an aPL positive patient developing a vascular event.
Women with pregnancy events alone have a high likelihood of developing thrombosis
in later years .

DIAGNOSTIC CRITERIA FOR APS
The diagnosis requires that the patient have at least 1 clinical and 1 laboratory criterion.

(updated 2009)
Clinical criteria
1.Vascular thromboses
1 or more documented episodes of arterial, venous, or small vessel thrombosis -
other than superficial venous thrombosis- in any tissue or organ. Thrombosis must
be confirmed by objective validated criteria. For histopathologic
confirmation,thrombosis should be present without significant evidence of
inflammation in the vessel wall.

2. Pregnancy morbidity
(a) 1 or more unexplained deaths of a morphologically normal fetus at or beyond the
10th week of gestation, with normal fetal morphology documented by ultrasound or
by direct examination of the fetus, or
(b) 1 or more premature births of a morphologically normal neonate before the 34th
week of gestation because of: (i) eclampsia or severe pre-eclampsia defined
according to standard definitions, or (ii) recognized features of placental
insufficiency, or
(c) 3 or more unexplained consecutive spontaneous abortions before the 10th week
of gestation, with maternal anatomic or hormonal abnormalities and paternal and
maternal chromosomal causes excluded.
DIAGNOSTIC CRITERIA FOR APS..
Laboratory criteria

Anticardiolipin antibodies - Anticardiolipin IgG or IgM antibodies
present at moderate or high levels (ie, >40 GPL or MPL or >99th
percentile) in the blood on 2 or more occasions at least 12 weeks apart

Lupus anticoagulant - LAC detected in the blood on 2 or more
occasions at least 12 weeks apart

Anti-beta
2
-glycoprotein I antibodies IgG or IgM - In titers above the
99th percentile for normal as defined by the laboratory performing the
test, on 2 or more occasions at least 12 weeks apart

DIAGNOSTIC CRITERIA FOR APS ..
Additional findings in APS:

The following findings may also provide strong clues to the diagnosis of APS,
irrespective of the clinical and laboratory criteria:

1) Unexplained transient ischemic attacks or amaurosis fugax
2) Positive result from the Coombs test
3) Hemolytic anemia
4) Chorea
5) Chorea gravidarum
OTHER HELPFUL INVESTIGATIONS FOR APS

Immunoassays
I. Biologic false-positive serologic test for syphilis
II. Anticardiolipin antibodies (cofactor-dependent assay)
III. Antiphosphatidylserine antibodies
IV. Antiprothrombin antibodies


Coagulation Tests
I. Dilute Russell viper venom time (DRVVT) with confirmatory tests
II. aPTT :




III. Kaolin clotting time
IV. Plasma clotting timeCY
evidence of inhibitor with mixing studies
panel of aPL-sensitive and insensitive aPTT reagents
platelet neutralization procedure
PROGNOSIS
Maternal morbidity
Thrombosis, which may may also be associated with anticoagulation in patients treated
with heparin or lowmolecular-weight heparins in pregnancy. women with APS have an
increased incidence of preeclampsia, which, when it occurs, frequently develops prior to
34 weeks gestation. The incidence of severe preeclampsia requiring premature delivery is
also increased.
APS is also associated with infertility and pregnancy complications, such as spontaneous
abortions, prematurity, and stillbirths.
Landry-Guillain-Barr-Strohl syndrome (LGBSS) although exceedingly rare in
pregnancy, can occur in patients with APS and lupus.
i. Patients usually present with progressive bilateral and symmetrical muscle weakness
accompanied by mild sensory symptoms, including paresthesia, numbness, and
tingling. The disease can progress to involve the respiratory muscles, resulting in
respiratory failure. Two thirds of the patients have a history of viral-like infections 1-3
weeks prior to the onset of symptoms.
ii. CMV infection has been incriminated as a potential etiologic agent in some pregnant
patients presenting with LGBSS.

Maternal mortality
Mortality rates during pregnancy are not well characterized. Multiorgan failure has been
described during pregnancy by Asherson
[2]
and during postpartum by Kochenour.
[3]


PROGNOSIS.
Perinatal morbidity
The aPL antibodies are found in 10-15% of women at high risk for
fetal growth restriction. Neonatal morbidity and mortality may be
influenced by indicated preterm delivery for maternal severe
preeclampsia or fetal growth restriction.
Neonatal lupus dermatitis, a variety of systemic and hematologic
abnormalities, and isolated congenital heart block have been
associated with APS and SLE.
Perinatal mortality
Fetal deaths at or beyond 20 weeks' gestation may be attributable
to APS involvement. The rate of fetal loss may exceed 90% in
untreated patients with APS. Therapy (including aspirin and
heparin) can reduce the rate of fetal loss to 25%, as described by
Cowchock et al.

APPROACH OF APS IN PREGNANCY
HISTORY AND PHYSICAL FINDINGS (APS)
The diagnosis of APS is based primarily on clinical history and
laboratory data.
Thrombosis and stroke are possible residual neurologic findings in APS.
Tinnitus, ear ache, dizzy spells, headaches, migraines, memory lapses,
etc are usual neglected symptoms which may actually indicate poor
circulation and transient ischaemic attacks.
Aortic Angina
Cutaneous manifestations of APS can include the following:
1. Digital cyanosis
2. Livedo reticularis
3. Digital gangrene
4. Leg ulcers
5. Discoid rash
6. Photosensitivity

Pic 1. Digital cyanosis
Pic 2. Livedo reticularis
Pic 3. Digital gangrene
Pic 4. Discoid rashes
APPROACH CONSIDERATIONS
Pregnant women with APS are considered high-risk obstetric patients, and
medical care is instituted with this in mind.

1. In patients receiving or recently treated with corticosteroid therapy ,
administer supplementation to cover the labor or cesarean delivery.
Therapeutic abortions are generally not indicated in pregnant women
with autoimmune disease.
2. Epidural anesthetic is not recommended if the mother has a marked
drop in the maternal platelet count. The use of forceps or the vacuum
extractor should be individualized.
3. No evidence indicates adverse effects related to breastfeeding,
although breastfeeding is not recommended if high doses of cytotoxic
or immunosuppressive agents are required.

MANAGEMENT OF APS
OBSTETRIC CARE
1. Preconception counselling : Patients should be counseled in all
cases regarding symptoms of thrombosis and thromboembolism and
should be educated regarding, and examined frequently for, the signs
or symptoms of thrombosis or thromboembolism, severe preeclampsia,
or decreased fetal movement.
2. Ultrasonography : is recommended every 3-4 weeks starting at 18-20
weeks gestation, in patients with a poor obstetric history, evidence of
preeclampsia, or evidence of fetal growth restriction.
3. In patients with uncomplicated APS, ultrasonography is recommended
at 30-32 weeks gestation to assess fetal growth. Lagging fetal growth
may reflect uteroplacental insufficiency in patients with APS.
4. hCG values in the first trimester can be followed to evaluate the
viability of the pregnancy. If hCG levels are increasing normally (ie,
doubling every 2 days) in the first month of pregnancy, a successful
outcome is predicted in 80-90% of cases. However, when the
increases are abnormal (ie, slower), a poor outcome is predicted in 70-
80% of cases.
5. Stop cytotoxic Drugs several months prior to becoming pregnant.
MEDICAL CARE OF APS IN OBSTETRIC PATIENT
Seronegative APS i.e. without previous thrombosis and recurrent
early (pre-embryonic or embryonic) miscarriage

Lowdose Aspirin alone or together with either unfractionated heparin
(50007500 IU SC every 12 h)
Or LMWH (usual prophylactic doses: Enoxaparin 40 mg SC every 24 h).
If aspirin was used before pregnancy, it must be switched to low dose
heparine at the time of pregnancy.

Following delivery, postpartum thromboprophylaxis with warfarin or
LMWH is indicated.
MEDICAL CARE
APS without previous thrombosis and fetal death more than 10
weeks gestation or previous early delivery (<34 weeks gestation)
due to severe pre-eclampsia or placental insufficiency

Low-dose aspirin plus unfractionated heparin (750010 000 IU
subcutaneoulsy every 12 h in the first trimester; 10 000 U
subcutaneously every 12 h in the second and third trimesters,
or every 812 h adjusted to maintain the mid-interval aPTT* 15 times
the control mean)
or LMWH (usual prophylactic doses: Enoxaparin 40 mg SC every 24 h).
Following delivery, postpartum thromboprophylaxis with warfarin or
LMWH is indicated.

MEDICAL CARE
APS with thrombosis

Low-dose aspirin plus unfractionated heparin (subcutaneously every 8
12 h adjusted to maintain the midinterval aPTT*
or heparin concentration (anti-Xa activity)* in the therapeutic range)
or LMWH (usual therapeutic dose-eg, enoxaparin 1 mg/kg
subcutaneously,
or dalteparin 100 U/kg subcutaneously every 12 h,
or enoxaparin 15 mg/kg/day subcutanously,
or dalteparin 200 U/kg/day subcutaneously)

MEDICAL CARE
APS with prior fetal death or recurrent pregnancy loss

If Pregnant
a. Heparin in prophylactic doses (15000-20000 U of unfractioned heparin
or equivalent per day) administerd SC in divided doses with low dose
aspirin daily.
b. Calcium and vitamin D supplementation

If non-pregnant
a. Optimal management is uncertain; options include no treatment or daily
treatment with low-dose aspirin
MEDICAL CARE
APS with prior thrombosis or stroke

If Pregnant : Heparin to achieve full anticoagulation(does
not cross placenta)

Non pregnant : Warfarinadministered daily in doses to
maintain INR of = 3
MEDICAL CARE
Pregnant LGBSS : High dose iv IG at 400-1500 mg/kg/day
for several days

Non pregnant LGBSS : iv IG at 400-1500 mg/kg/day for
several days
PERSONAL CARE OF APS PATIENT
Consultations : Rheumatologist Hematologist Neurologist, cardiologist,
pulmonologist, hepatologist, ophthalmologist (depending on clinical
presentation) Obstetrician with experience in high-risk pregnancies

Diet : If warfarin therapy is instituted, instruct the patient to avoid
excessive consumption of foods that contain vitamin K.

Activity : No specific limitations on activity are necessary. Individualize
the activity according to the clinical setting. Instruct the patient to avoid
sports with excessive contact if taking warfarin. Limit activity in patients
with acute DVT. Instruct the patient to avoid prolonged immobilization.

MANAGEMENT OF APS IN THE FUTURE
Potential future therapies for antiphospholipid syndrome :

Combination antiaggregant therapy (low-dose aspirin plus
clopidogrel or dipyridamole)
Oral antifactor Xa drugs (rivaroxaban, apixaban)
Direct thrombin inhibitors (dabigatran)
B-cell depletion (rituximab)
Statins (fluvastatin, rosuvastatin)
Hydroxychloroquine
SUMMARY OF APS MANAGEMENT
1. In women with well-recognized obstetric APS, anticoagulant
prophylaxis is recommended during pregnancy and the postpartum
period.
2. Pregnant women with APS are considered at risk for thrombosis and
pregnancy loss.
3. Data suggest low-dose aspirin and heparin (either unfractionated
heparin or LMWH) to be the treatments of choice for prevention of
pregnancy loss in pregnant women with APS and previous pregnancy
losses.
4. Pregnant women with APS and a history of thrombosis but no
pregnancy loss require only treatment with heparin.
5. Treatment is optional for patients with no history of pregnancy loss or
thrombosis

REFERENCES
1. Hughes GR: Thrombosis, abortion, cerebral disease
and the lupus anticoagulant. BMJ 1983, 287:1088-
1089.
2. Hughes GRV. The antiphospholipid syndrome: ten
years on. Lancet 1993; 342: 341-44.
3. Roubey RAS, Hoffman M. From antiphospholipid
syndrome to antibody-mediated thrombosis. Lancet
1997; 350:1491-3.
4. Khamashta MA, Cervera R, Asherson RA, Font J, Gil
A, Coltart DJ, Vzquez JJ, Par C, Ingelmo M, Oliver
J, et al. Association of antibodies against phospholipids
with heart valve disease in systemic lupus
erythematosus. Lancet 1990; 335:1541-1544.
5. Mialdea M, Sangle SR and D'Cruz DP. Antiphospholipid
(Hughes) syndrome: beyond pregnancy
morbidity and thrombosis. Journal of Autoimmune Diseases
2009;19:6:3.
6. Asherson RA, Khamashta MA, Ordi-Ros J, Derksen
RH, Machin SJ, Barquinero J, et al. The "primary" antiphospholipid
syndrome: major clinical and serological
features. Medicine (Baltimore). Nov 1989;
68(6):366-74.
7. Kochenour NK, Branch DW, Rote NS, et al. A new
postpartum syndrome associated with antiphospholipid
antibodies. Obstet Gynecol. Mar 1987; 69(3
Pt 2):460-8.
Etc etc etc.

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