.

Antiphospholipid syndrome Dr. Suman Kumari MS OBGY

Graham R.V. Hughes

First discribed by Graham R.V. Hughes in 1983

Introduction

• known as Hughes syndrome.

• Autoimmune disorder associated with acquired

thrombophilia.

• Most common association is SLE.

• Asherson’s syndrome-Catastrophic APS.

• Obstetric complications are “hallmark” of APS.

• Severe FGR,preeclampsia,prematurity imp. Complications.

Introduction conti..

• It is the most common thrombotic defect leading to fetal

wastage.

• Responsible for frequent miscarriages in young female.

• Obstetric care based on medical- obs high risk combined

management.

• Prevalence of antiphospholipid antibodies is 2% in overall

pregnancy.

• 15% of women with recurrent miscarriage.(RCOG)

Introduction conti..

Definition

A patient with definite APS must have

• laboratory criteria.

– persistent high titer antiphospholipid antibodies(APL)

– history of arterial or venous thrombosis or both and

• clinical criteria.

– recurrent pregnancy morbidity.

Talk Plan Sapporo criteria• Diagnostic criteria Sydney criteria primary APS• Classification of APS

• Epidemiology Secondary APS• Pathophysiology• Clinical features• Investigation Preconception

• Management Antenatal• Follow up Postnatal• Recommendation

International consensus conference held in Sapporo(98)

Sapporo criteria

• Helped galvanize research in this disorder .

• High sensitivity and specificity in APS .

• Seen in conjunction with lupus and lupus-like

diseases.

Sapporo criteria conti...

Amendments to the Sapporo criteria –

• more insights into clinical, laboratory, and experimental

criteria.

• No clear cutoffs for “medium to high titers” of IgG and

IgM anticardiolipin(aCL).

• Timing of laboratory testing in relation to the clinical

event was not clarified.

Revised classification criteria for anti-phospholipid syndrome:Sydney criteria

2006Clinical criteria1. Vascular thrombosis• One or more clinical episodes of arterial, venous or small vessel thrombosis

2. Pregnancy morbidity• (a) One or more unexplained deaths of a morphologically normal fetus at or

beyond the 10th week of gestation

• (b) One or more pre-term births of a morphologically normal neonate before the 34th week of gestation because of: (i) eclampsia or

severe pre-eclampsia or (ii) recognized features of placental insufficiency

• (c) Three or more unexplained consecutive spontaneous miscarriages before the 10th week of gestation, (with maternal anatomic or

hormonal abnormalities and chromosomal causes excluded)

Revised classification criteria for anti-phospholipid syndrome:Sydney criteria

2006Laboratory criteria1.Lupus anticoagulant (LA) present in plasma.

2. Anticardiolipin (aCL) antibody of immunoglobulin (Ig)G and/or IgM isotype in serum or plasma, present in medium or high titre (i.e. >40GPL units or MPL units, or > the 99th centile).

3. Anti-β2–glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma (in titre >the 99th centile).

• Antiphospholipid antibody syndrome (APS) is present if at least one of the clinical criteria and one of the laboratory criteria are met

• Presence of aPL on two or more occasion atleast 12 week apart• GPL units, IgG antiphospholipid units; MPL units, IgM antiphospholipid units.

“Non-criteria” APS findings

• Thrombocytopenia and/or hemolytic anemia.

• Transverse myelopathy or myelitis.

• Livido reticularis.

• Cardiac valve disease.

• Nephropathy.

• Non-thrombotic neurologic manifestations, including multiple sclerosis-

like syndrome, chorea, or migraine headaches.

Miyakis, et al., J.Thromb.Haemost., 2006; 4: 295-306

Advancement in criteria 2006

• Better definition of clinical criteria.

• Stratification of patients as per primary or secondary APS.

• Time interval increased to 12 weeks.

• Transient positivity excluded.

• Categorisation of asymptometic aPL and Catastrophic APS

(CAPS).

• APS with or without associated rheumatic disease.

Classification of APS

A. PRIMARY APS (PAPS) B. SECONDARY APS

(Obstetric APS) PRIMARY APS

• Majority of patients with APS are in PAPS group.

• Small proportion of the PAPS may devlops SLE over the period

of 15-20 years.

• some experts recommend evaluation prolonged period of time.

Classification of APS....

B. SECONDARY APS

1. autoimmune disorder 3. Malignancy SLE 25-50% Ca cervix and ovary Sjogren syndrome-42% Lymphoma Rheumatoid arthritis-33% leukemia

DM Autoimmune thyroid disease. 2 .Drug induced condition 4. infectious disease ocp syphlis, HIV

Epidemiology

• Women : men is 5:1

• Mean age of onset is 31 yrs.

• Risk of thrombosis is 0.5-30 %

• Artheritis,livedo ,migrane more common in female.

• MI,epilepsy arterial thrombosis more common in

male.

Mechanisms by which APS causes pregnancy morbidity

early pregnancy late pregnancy

inhibition to trophoblastic function and differentiation

thrombosis of the Uteroplacentalvasulature

Activation of compliment system at the maternal fetal interface --local inflammatory response.

Pathophysiology

• aPLs –acquired antibodies(IgG,IgM,and/orIgA) -binds to

negatively charged phospholipids.

• Beta2GP-I is major target molecule,present on the surface of

trophoblastic cell membrane.

• Beta 2 GP-1 helps in syncytial trophoblast formation from

cytotrophoblast.

• Inhibit prothrombin to thrombin conversion and activation of

intrensic coagulation pathway and thus inhibits thrombosis.

Pathophysiology

• Anti-β2GP I - most strongly associated with thrombosis (de Laat et al, 2005).

• Anti β2GPI significant association with venous thrombosis.

• strongest association for thrombos is the

combination of LA, anti β2GPI• LA -stronger association with pregnancy loss Opatrny et al, 2006.

Mechanisms for thrombosis in APS

• Increased expression of tissue factor on monocytes and

endothelial cells (Branch & Rodgers, 1993)

• Interference in the protein C anticoagulant pathway

(Malia et al, 1990)

• Inhibition of fibrinolysis (Atsumi et al, 1998b)

• Pregnancy failure may be due to thrombosis in the

placental bed.

Clinical features

• Can affect any organ of the body including the lung,

skin, brain, liver,kidneys, adrenal glands, heart, and

eyes.

• ‘‘classic’’ clinical presentations include peripheral

deep venous thrombosis (DVT), pulmonary embolism

(PE), and/or arterial thrombotic events

Clinical features cont...

• Venous thrombosis in APS is commonly- lower limb deep

vein thrombosis (DVT) and/or pulmonary embolism(PE)

• Any part of the venous system may be involved.

• The most frequent site of arterial thrombosis in APS is in

the cerebral vasculature resulting in transient cerebral

ischaemia/stroke.

Clinical features conti...

• APS -only a minor contribution to the overall burden of

disease fromVTE and stroke.

• Microvascular thrombosis in APS is least common seen

in‘catastrophic antiphospholipid syndrome’

(CAPS)potentially lethal .

• In CAPS -multiorgan failure ,but lungs, brain and kidneys

are spared.

Clinical features conti...

Obstetric features

• Recurrent pregnancy loss

• Unexplained second or third trimester fetal death

• Severe preeclampsia at less than 34 weeks’ gestation

• Unexplained severe fetal growth restriction.

• Chorea gravidarum

• Unexplained primary infertility –only symptom in APS.

Clinical features cont...

Nonobstetric features

• Thrombocytopenia,

• heart valve disease

• chorea,

• stroke

• nephropathy

• SLE or other connective tissue disorder

Clinical features conti...

Nonspecific associations

• Unexplained transient ischemic attack

• Livedo reticularis

• Unexplained prolongation of a clotting assay

• False-positive serologic test result for syphilis

(Miyakis et al, 2006).

Nonspecific associations

Clinical features PAPS APS-SLE notes

thrombocytopenia

20-25% 30-40% Usually mildNo protective effect on thrombotic risk.

Heart valvedefect

12-33% 40% Possibly an additional risk for secondarythromboembolism

Superficial thrombophlebitis

9% Reported in aPL-positive patients but their value stilldebated

nephritis. 35% 39-67% Association with pregnancy complications,

How to diagnose

Who should be tested for aPL???

• recurrent first-trimester miscarriage

• one or more unexplained second-trimester or third-

trimester loss

• Early onset,severe preeclampsia.

• Severe IUGR

Who should be tested for aPL???

• Autoimmune disease or connective tissue disease.

• False positive serological test for syphilis.• Positive autoantibody tests.

RCOG GUIDELINES

Investigation• Antiphospholipid (aPL) antibodies

solid-phase enzyme-linked immunoassays.

• Results -reported in semiquantitative terms such as negative, low positive, medium positive, or high positive.

• Systemic lupus erythematosus (SLE) -lower serum complement levels,

total hemolytic complement activity (CH50) complement C3 and C4, Ds DNA, ANA ,LE cell test are the basic test for SLE.

Investigation plan

If APS suspected-as per the laboratory

diagnostic criteria following aPL are tested.

• Lupus anti coagulant(LA/LAC)

• Anticardiolipin antibody(aCL).

• Anti beta2 GP-1(β2GP- 1)

Investigation conti...

Lupus anticoagulant(LAC)• Misnomer-associated with hypercoagulable state and

frequently found in patient without SLE.• An immunoglobulin (IgG/IgM/Both) –interfere with one or

more phospholipid-dependent test of in vitro coagulation.• Most common test that identify LAC includes aPTT-activated partial thromboplastin time KCT-the kaolin clot time test dRVVT-dilute Russell viper venom time PCT-plasma clot time.

Screening test for lupus anticoagulants(LAC)test In pregnancy advantage disadvantage sensitivityaPTT increased

factor VIII may mask the result.

Readily available,easily automated.

Vary in sensitivity widely

least

KCT Not affected Very sensitive to LAC if on oral anticoagulant

Not readily automated

most

dRVVT Not affected Easy to perform ,readily available

Affected by ocp and heparin

good

PCT Increased factor VII –blunt LAC effect.

Requires no reagents/equipment.

Must be performed on freshly drawn blood.

good

Confirmation of LAC

Prolonged phospholipid-dependent coagulation mixing with normal plasma

Failure to correct the prolong coagulation time . addition of excess phospholipid

Shortening/correction of prolonged coagulation time

Exclusion of other coagulopathy.

Anti cardiolipin antibody(aCL).

• Cardiolipin(phospholipid) –on membrane.

• ELISA –gold standard.

• IgG,IgM,and IgA-Standard sera available.

• Ability to bind 1 ug of cardiolipin and result in titres.

• Value decline in pregnancy as increase in plasma

volume causes dilution of phohpholipid.

Management

• Pre conception• Antepartum• Postpartum• Follow up

Preconception management

• Pregnant women with APS are considered high-risk

obstetric patients.

• Patients should be counselled regarding symptoms of

thrombosis and thromboembolism.

• Therapeutic abortions -not indicated in pregnant

women with autoimmune disease.

Preconception management cont..

• With no treatment-only 20-30% of patient with aPL antibody

has successful delivery.

• Combination of unfractionated heparin with low dose aspirin

–provide the highest success rate in terms of live birth.

• Low dose heparin with low dose aspirin reduces the

pregnancy loss by 54%

Preconception management cont..

• Low dose aspirin 75 mg should be initiated before

conception and discontinued 4 weeks before EDD.

• M.O.A of aspirin-selective inhibition of thromboxane

production-restoration of balance with

prostaglandin.

Antepartum surveillance

• If h/o first trimester losses-do USG weekly till progress beyond

the point of their prior losses.

• If h/o second /third trimester fetal loss-serial antepartum testing

required.

• close fetal survillance needed in form of 30-32 wk onword

nonstress test-twice weekly.

Biophysical profile weekly.

Daily fetal kick count,

ManagementFeature Pregnant Nonpregnant

APS with prior fetal death or recurrent pregnancy loss

Heparin in prophylactic doses with low-dose aspirin.Calcium and vitamin D supplementation

Optimal management ,no treatment or treatment with low-dose aspirin.

APS with prior thrombosis or stroke

Heparin in therapeutic doses.Calcium and vitamin D supplementation

Warfarin administered daily in doses to maintain international normalized ratio of =3

APS without prior pregnancy loss or thrombosis

No treatment /low-dose aspirin / prophylactic doses of heparin plus low-dose aspirin.

No treatment or daily treatment with low-dose aspirin.

Anticoagulation therapy

• Heparin should be continued until the onset of spontaneous

labor.

• Or night before scheduled induction/operative delivery.

• If the patient is fully anticoagulated and delivery is emergent-

1%protamine sulphate ,iv over 10 min.

Anticoagulation therapy (heparin)

• After confirmation of pregnancy.

5000 units every 12 hr.-

• Platelets and PTT –

base line

every week for 2 weeks

Once ineach trimester throughout pregnancy .

Anticoagulation therapy ( heparin)

• With prior h/o thromboembolism –

therapeutic dose required10000-12000 IU sc/day.

• Does not cross the placenta

• Aim to keep aPTT at the upper end of normal range.

Anticoagulation therapy

• Side effect of heparin-

Heparin induced thrombocytopenia (HIT)-

o incidence 1% at dose >15000Iu/day(combined with low platelets in

pregnancy.)

o bleeding risks-If platelets counts decreases significantly ,heparin dosage

should be reduced.

o Splenectomy -- early second trimester or at the time of CS may be considered

in patients with thrombocytopenia refractory to glucocorticoid therapy.

Anticoagulation therapy

Heparin induced osteopenia –

o dose >15000 IU/day(combined with normal osteoporosis

associated with pregnancy .

o Heparin-induced osteoporosis occurs in 1-2% of cases

risks of osteopenia-

o Bone density studies should be considered

Anticoagulation therapy

• Warfarin may be substituted for heparin during the

postpartum period to limit further risk of heparin-

induced osteoporosis and bone fracture

UFH vs LMWH

• LMWH-have therapeutic effect with less side effect.

• LMWH-single daily dose.Prophyllactic LMWH- enoxaparin -40mg,s/c once/day dalteparin-5000u s/c once/dayTherapeutic LMWH-enaxaparin-1mg/kg/12 hr dalteparin-200u/kg once daily.Prophyllactic UFH-5000 u sc every 12 hr.Therapeutic UFH-10,000 u s/c every 12 hr.

Calcium and vitamin-D

The heparinised pregnant patient

• increase her calcium to 600 mg BD

• along with vitamin D to optimise the absorption of calcium

and

• reduce the risk of osteopenia.

Delivery plan

• Elective termination of pregnancy at term.• Caesarean delivery associated with higher rate

of peripartum thrombosis.• Vaginal delivery is preferred. Obs gynecol clin N Am 2007

• Epidural anaesthesia is not recommended in marked drop in the maternal platelet count

Postpartum surveillance• Post vaginal delivery-ambulation as soon as possible.• Post cesarean delivery-pneumatic compression

stocking untill ambulation.• Aspirin low dose –reinitiated.

• Heparin should be restarted post partum at lowest

predelivery dosage –continue for 4-6 week.

• In pt. With thromboembolic events-full anticoagulant -

6 wk.

postpartum surveillance

• Supplemental calcium to be continued as long as pt is

on heparin.

• No evidence indicates adverse effects related to

breastfeeding with low dose aspirin and heparin.

• Breastfeeding is not recommended if high doses of

cytotoxic or immunosuppressive agents are

required(secondary APS)

Consultations and Follow-up

• Once the diagnosis-diagnosis for life long. (inspite of resolution).

• Informed about potential maternal and obstetric problems.

• Consultation with specialists in Maternal-Fetal Medicine

and Rheumatology .

• APS and 1 or more prior thrombotic events, lifelong

anticoagulation with warfarin - to avoid recurrent

thrombosis.

Consultations and Follow-upcont..

• Life style modificationmaintain a normal weight.Increased cholesterol –correction.Avoid tobbaco related product.Lifelong aspirin (low dose)/day-should be

continued.

contraception

• Estrogen containing oral contraceptives should be

avoided in repeated positive aPL.

• Progesterone only pills,barrier method,IUD can be

used.

Other drugs in pregnancy

• Previously prednisolone was used-no benifit as per trial.

• IVIG and HCQ –pt. With failed treatment with heparin.

• Warfarin only after organogenesis is complete.(pauzner et al)

new drugs

Rituximab• Helpful intreating low platelets,anemia small

vessel clots

Eculizumab• In refractory APS-under evaluation.Autologous haematopoietic stem cell transplantation (HSCT)

Future

• More specific ,targeted ,immunomodulatory approach in the future.

• Specific compliment inhibitor for pregnancy complication.

• Long term follow up of children born to APS mother.

Recommendations

• Women with recurrent pregnancy loss before 10 weeks

gestation should be screened for aPL.

• For women with APS with recurrent pregnancy loss, antenatal

administration of heparin combined with low dose aspirin is

recommended throughout pregnancy .

• Treatment should begin as soon as pregnancy is confirmed.

Recommendations

• For women with APS and a history of pre-

eclampsia or FGR, low dose aspirin is

recommended.

• Women with aPL should be considered for

post-partum thromboprophylaxis.

Take home message

Be APS minded• It is a correctable cause of RPL,so one has to be APS

minded in patients presenting with pregnancy morbidity.

Identify the at risk women• To identify the at risk women and screen out patient

who warrant thromboprophylaxis and thus we can prevent potentially life threatening complications of thrombosis.

• thanks

Thank you