Definition:

Antiphospholipid syndrome (APS) is an autoimmune

disorder characterised by arterial and venous

thrombosis, adverse pregnancy outcomes (for mother

and fetus), and raised levels of antiphospholipid

(aPL) antibodies.

Synonyms:

• Anti-phospholipid syndrome. The immune system produces

abnormal blood proteins called antiphospholipid antibodies.

• lupus anti-coagulant syndrome: synonym can be

confusing bec. patients with APS may not necessarily have 

SLE, LA is associated with thrombotic rather than

hemorrhagic complications.

• Anti-cardiolipin antibody syndrome

• Sticky blood syndrome. people with this condition are

more likely to form clots in blood vessels

• Hughes syndrome: named after Dr. Graham Hughes

along with his team in London who described the disease

between 1983 & 1985.

History of APS: Anti-phospholipid antibodies were first noted in a

group of people who had positive tests for syphilis

without signs of infection (false-positive tests).

It was then noticed that some of these individuals

developed systemic lupus erythematosus (SLE) and

other rheumatic conditions.

Later studies found a protein called the lupus

anticoagulant in a number of individuals with SLE,

provided further understanding of APS, including the

testing for anticardiolipin antibodies.

1- 5% of healthy individuals have aPL antibodies.

Incidence of APS: about 5 cases per 100,000 persons

per year.

50 % of APS cases : not associated with another

rheumatic disease ( PAPS).

APL antibodies : found in about 30-40% of patients

with SLE, but only about 10% have APS.

Epidemiology :

APS is the cause of : - 14% of all strokes.

- 11% of MI.

- 10% of DVT.

- 6% of pregnancy morbidity.

- 9% of pregnancy losses.

Catastrophic APS has mortality rate about 50% due to

multi-organ infarctions over a period of days.

Sex : A female predominance specially for secondary

APS.

Age : APS is common in young to middle-aged adults.

•.Diagnostic criteria ( Sapporo criteria):

At least:

One of the clinical criteria

One of the laboratory criteria .

I- Clinical criteria Vascular thrombosis: one or more episodes of arterial,

venous or small vessel thrombosis.

Pregnancy morbidity: Three or more unexplained spontaneous abortion before 10

weeks of gestation where anatomical, hormonal and chromosomal causes have been excluded.

At least one unexplained death of a morphologically normal fetus at or after the 10th week of gestation.

At least one pre-term birth of a morphologically normal neonate (before 34 weeks of gestation) due to eclampsia, severe pre-eclampsia or placental insufficiency.

II - Laboratory criteria

Lupus anticoagulant (LA) is positive.

Anticardiolipin (aCL) antibody is present in serum, in

medium or high titre (ie ≥40 GPL units or MPL units or

≥99th percentile).

Anti-B2-glycoprotein-1 antibody in serum (in titre ≥99th

percentile).

All should be present on two or more occasions, at

least 12 weeks apart.

• Diagnostic clues (but not as classification criteria):

Cardiac valve disease

Livedeo reticularis

Thrombocytopenia

Renal thrombotic microangiopathy

Neurological manifestations sp. chorea

Pathophysiology:

The homeostatic regulation of blood coagulation is altered.

Phospholipids are an integral part of platelet And endothelial

cell surface membranes , it is expected that these antibodies

have a effect on them.

PathophysiologyPathophysiology

APLAntibodies

plateletsCoagulation

cascade Endothelial cells

increase TF, adhesion molecules

and proinflammatory

cytokines

Placental tissue

decreaseTrophoblastic cell

growth, increase apoptosis

Inhibit Protein C, Protein S

, thrombomodulin, antithrombin III

fibrinolysis

Activate platelet

aggregation

In pregnancyIn pregnancy

Classification

• Primary APS : when occurs in patients without

evidence of any associated disease.

• Secondry APS: occurs in association with SLE or

another rheumatic & autoimmune disorders.

• Catastrophic form :

A rapidely progressive lethal form of PAPS with

widespread vascular occlusion ( in medium or small

sized arteries) in multiple organs ( > 3 organs) in few

days.

Mortality rate 50%

Seronegative APS: Clinical picture is highly suggestive for APS, while the laboratory

tests fail to detect LAC or aCL.

These cases could be APS with other aPL which are not included in

the criteria : e.g anti-cardiolipin IgA or other aPL( e.g: false positive

test for syphilis, AMA).

It is also possible that during the acute event of thrombosis, aPL

cannot be detected bec. they are consumed in the blood clot.

Repeated measurement of these autoantibodies several weeks later

Associated disorders ( secondary APS )

•  SLE.

• Rheumatoid arthritis.

• Systemic sclerosis.

• Behçet's disease.

• Temporal arteritis.

• Sjögren's syndrome.

• Psoriatic arthropathy.

Other clinical associations :

Infections : HIV, hepatitis C, syphilis, malaria.

Malignant lymphoma.

Drug exposure: phenothiazines, phenytoin, hydralazine.

Autoimmune thrombocytopenia.

Autoimmune haemolytic anaemia.

Sickle cell anaemia.

Clinical presentation:

Skin disorders: - Livedo reticularis (most common). - Splinter haemorrhages . - Leg ulcers.  -Superficial thrombophlebitis . - Vasculitis.

Neurological defects: - Migraine headaches. - Seizures. - Dementia.Cardiac abnormalities: - MI. - Cardiac valve vegetations.

• Blood abnormalities: - Thrombocytopenia.

- Haemolytic anaemia.

• Renal abnormalities: - hypertension.

-proteinuria due to thrombotic microangiopathy.

• Catastrophic antiphospholipid syndrome : The condition

is serious and often lethal.

Levideo reticularis

Levideo reticularis

Splinter haemorrhages

Vasculitis

Differential Diagnosis :

Disseminated Intravascular Coagulopathy(DIC).

Infective Endocarditis.

Thrombotic Thrombocytopenic Purpura(TTP).

SO, Younger patients with a history of DVT,

pulmonary embolism, MI , or CVA need to be

investigated for antiphospholipid syndrome, particularly if

no other risk factors for thrombosis are present.

MANAGEMENT OF APS

Treatment regimens for APS must be according to the patient's

clinical condition and history of thrombotic events.

Asymptomatic individuals (with positive blood tests) :

no specific treatment.

Prophylactic therapy: Elimination of risk factors (e.g : oral

contraceptives, smoking, hypertension, or hyperlipidemia.

General roules:

Prophylaxis is needed during surgery or hospitalization, as

well as any associated autoimmune disease.

Low-dose aspirin is used widely in prophylaxis; however,

the effectiveness of low-dose aspirin as primary prevention

for APS remains unproven .

In patients with SLE, consider hydroxychloroquine, which

may have intrinsic antithrombotic properties.

• Full anticoagulation with IV or SC heparin followed by

warfarin therapy.

• Our target for INR is 2 - 3 for venous thrombosis and 3 for

arterial thrombosis.

• Patients with recurrent thrombotic events, may require an

INR of 3 - 4.

• Severe or refractory cases : a combination of warfarin and

aspirin may be used.

• Treatment for significant recurrent thrombotic events in

patients with APS is generally lifelong.

Thrombosis

Rituximab can be considered for recurrent thrombosis

despite adequate anticoagulation. A prospective study

showed rituximab to be effective for non-criteria aPL

manifestations (ie, thrombocytopenia and skin ulcers).

APS & pregnancy

Asymptomatic (positive aPL) No TTT or LDA

Single pregnancy loss < 10 weeks No TTT or LDA

Recurrent pregnancy losses < 10

weeks or foetal loss > 10 weeks +

no history of thrombosis

LDA + prophylactic dose of

heparin ( continued till 6 – 12

weeks postpartum ) & then

switched to LDA.

Recurrent pregnancy loss < 10

weeks or foetal loss > 10 weeks +

history of thrombosis

LDA + therapeutic doses of

heparin) then switched to warfarin

postpartum

• Treatment of catastrophic APS:

Hospitalization

Anticoagulation

Plasmapharesis

IVIG

Corticosteroids

Cyclophosphamide (especially in SLE-associated CAPS).

DosesDoses

• Warfarin: 5 – 15 mg / day for 2-5 days

• LMWH : Low dose : 20-40mg/day SC.

High dose 1 mg/kg bid SC.

• Unfractionated heparin: 5000-10,000u /12h SC.

• Hydroxychloroquine : 200 – 400 mg/d

• IV IG : 400 mg/kg/d IV. for 5 days

• Steroids : Prednisolone 1 mg/kg

•Aspirin : 81 mg/day

• Rituximab 1000mg IV (2 doses separated by 2 weeks).

• Surgical care: Recurrent DVT may need an inferior vena

cava filter.

• Diet : If warfarin therapy is instituted, instruct the patient to

avoid excessive consumption of foods that contain vitamin K.

• Activities: No specific limitations (according to the clinical

condition). Avoid sports with excessive contact if taking warfarin. Limit activity in patients with DVT. Instruct the patient to avoid prolonged immobilization.