ANTIPHOSPHOLIPID ANTIBODY SYNDROME

Presenter : Demitrost Laloo

Introduction

Antiphospholipid antibody syndrome (APS) is an autoimmunity-mediated acquired thrombophilia characterised by : arterial or venous thrombosis and/or pregnancy morbidity in presence of autoantibodies against

phospholipid(PL)- binding plasma proteins

It maybe Primary : occuring alone Secondary : in association with other autoimmune disease

Classification and Nomenclature of Antiphospholipid Antibodies : Antibodies against cardiolipin (aCL)

Antibodies against β2 Glycoproptein I (anti-β2GPI) Lupus anticoagulant(LA): heterogeneous group of

antibodies directed also against PL binding proteins, mainly β2GPI and prothrombin

Antibodies against phospholipids/cholesterol complexes detected as biologic false-positive serologic test for syphilis (BFP-STS) and Venereal Disease Research Laboratory Test (VDRL)

Epidemiology

In normal blood donors Low titer, transient aCL : 10% Moderate-high titer aCL or positive LA : <1%

Prevalence increases with age, more common in females

Epidemiology Antiphospholipid antibodies (aPL) positivity in

10-40% SLE approx. 20% Rheumatoid arthritis 10% of 1st stroke patient, more in young(upto

29%) 20% in women with 3 or more consecutive fetal

losses 14% in recurrent venous thromboembolic

disease

Pathogenesis Trigger unknown

Preceding infection have been proposed

aPL binds to phospholipid-binding plasma protein ß₂ GP I

Pathogenesis aPL most likely related to thrombosis through

multiple mechanisms

Activation of the classical complement pathway

Expression of adhesion molecules and tissue factor

Activation of monocytes and PMN: release of proinflammatory mediators and initiation of prothrombotic stage

Activation of p38 MAPK and NFkB: intracellular signaling cascade

Pathogenesis

PathogenesisOther possible contributory mechanisms inhibition of coagulation cascade

reactions catalyzed by phospholipids induction of tissue factor expression on

monocytes reduction of fibrinolysis interaction with the annexin V

anticoagulant shield in the placenta

Clinical features

Venous thrombosis and related consequences

Deep vein thrombosis

Livedo reticularis

Pulmonary embolism

Superficial thrombophlebitis

Budd-Chiari syndrome

Thrombosis in various other site

Clinical featuresArterial thrombosis and related consequences

Stroke

Cardiac valve thickening/dysfunction and/or Libman-Sacks vegetation's

TIA

Myocardial ischemia and coronary bypass thrombosis

Leg ulcers and/or digital gangrene

Arterial thrombosis in the extremities

Retinal artery thrombosis/amaurosis fugax

Ischemia of visceral organs or avascular necrosis of bone

Multi-infarct dementia

Clinical featuresPregnancy morbidity

Late Fetal losses >10 weeks

Early fetal losses <10 weeks

Early preeclampsia

HELLP syndrome

Premature birth

Clinical featuresOsteoarticular manifestations

Renal manifestations

Arthralgia

Arthritis

Severe hypertension

Renal failure

Hematologic manifestations Neurologic of uncertain etiology

Thrombocytopenia

Autoimmune hemolytic anemia

MigraineEpilepsyChoreaCerebellar ataxiaTransverse myelopathy

Clinical features

CAPS: Catastrophic Antiphospholipid Syndrome

Rare, abrupt, life threatening, mortality as high as 48% despite effective treatment

Multiple thrombosis of medium and small arteries involving multiple organs over a period of days

Causing: Stroke Cardiac, hepatic, adrenal, renal and intestinal

infarction Peripheral gangrene

Diagnostic criteria: Revised Sapporo classification

Diagnostic criteria: Revised Sapporo classification

Diagnostic criteria: Revised Sapporo classification Definite APS : at least 1 clinical and 1

laboratory criteria

Classification avoided if <12 weeks and >5yrs separate +ve aPL test and clinical manifestation

Other findings not included in the criteria but helpful in diagnosis

CAPS criteria

CAPS criteria

Laboratory tests Lupus anticoagulant test

More specific but less sensitive Requires a 4-step process

Anticardiolipin Sensitive but not specific Standardized ELISA test for IgG and IgM Moderate to high titer required for

diagnosis

Laboratory tests Anti ß2GP I

Standardized ELISA for IgG and IgM

Positive aPL test requires a repeat test after 12 or more weeks to rule out transient, clinically unimportant antibody

Laboratory tests False positive syphilis test

does not fulfill laboratory criteria Order aPL test

ANA and Anti-dsDNA Detected in aprrox. 45% primary APS Does not mandate additional diagnosis of SLE

Other tests: Complete hemogram Urine examination

Imaging

CT and MRI of brain for stroke

CT angio or MR angiography if clinical findings suggest medium or large vessel disease

Doppler study for DVT

Echocardiography or cardiac MRI for vegetations or intracardiac thrombi

Pathology

Biopsy of renal, skin or other tissues Thrombotic occlusion of all caliber arteries

and veins Acute and chronic endothelial injury Recanalisation in late lesions

Differential Dx Hereditable deficiency of Protein C, Protein S,

antithrombin III Factor V Leiden and antithrombin mutations Hyperhomocysteinemia Thrombocytopenic purpura Septicemia Disseminated Intravascular Coagulation Hemolytic Uremic Syndrome Polyarteritis nodusa Myxoma Sneddon’s syndrome

Treatment Asymptomatic : no treatment

Venous/arterial thrombosis : warfarin (INR 2.5) indefinitely

Recurrent thrombosis : warfarin (INR 3-4) ± low dose aspirin

Treatment Pregnancy 1st pregnancy : no treatment Single pregnancy loss <10 weeks : no treatment

>1 fetal loss or ≥3 (pre) embryonic loss, no thrombosis : prophylactic heparin + low dose aspirin throughout pregnancy, discontinue 6-12 weeks postpartum

Thrombosis regardless of pregnancy history: therapeutic heparin or low dose aspirin throughout pregnancy, warfarin postpartum

Treatment Valve nodules or deformity

Full anticoagulation if emboli or intracardiac thrombi demonstrated

Valve replacement

Thrombocytopenia >50,000/cumm : no treatment <50,000/cumm : prednisone, IVIG

Treatment CAPS : Anticoagulation + corticosteroids + IVIG

or plasmapheresis

Cyclophosphamide and rituximab in desperate situations

Treatment Aspirin : 81-325mg once daily

LMW heparin : Prophylactic dose : 30-40mg

subcutaneously/day Therapeutic dose : 1 mg/kg, s/c BD or

1.5mg/kg OD

No controlled studies in APS for Clopidogrel Pentoxyfylline Argatobran Hirudin And other new anticoagulants

Outcome Long term functional outcome is poor

At 10yrs : 1/3rd developed permanent organ damage and 1/5th unable to perform everyday activities

Pulmonary hypertension, neurological involvement, myocardial ischemia, gangrene of extremities and catastrophic APS associated with worse prognosis

Outcome 35% of obstretic APS without thrombosis

developed aPL-related clinical events during a 8yr follow up

Long term outcome of children born to APS pregnancies unknown

Many need valve replacement due to severe valvular disease

Rarely may develop renal failure Serious perioperative complications may

occur despite prophylaxis

THANK YOU