Antiphospholipid symdrome

“APS”

Definition

Disorder of recurrent vascular thrombosis, pregnancy loss and thrombocytopenia associated with persistently raised levels of anti-phospholipid antibodies.

Primary: Occurs alone Secondary: Associated with other autoimmune

or rheumatic diseases

Epidemiology of APLs

Prevalance : Unknown

Women : 60-80 %

Familial disease : Frequent

HLA-DQB

Antiphospholipid Antibodies

Common findingsignificant proportion of healthy (esp. elderly)

populationmost never thrombosismay be transient

Antiphospholipid Antibodies

Clinically significant antiphospholipid antibodies are not antiphospholipid antibodies

Antibodies against phospholipid-bound proteinse.g. 2 glycoprotein 1, prothrombin

Anti-Phospholipid antibodies

Lupus Anti-coagulant Anti-cardiolipin antibody Anti-ß2 glycoprotein I antibody Anti-prothrombin False + serologic test for Syphillis

Antiphospholipid syndrome

Association of a thrombotic tendencyvenous or arterial thrombosisrecurrent miscarriages

with the persistence of one or more antiphospholipid antibodiesconfirmed by two different tests, or IgG or IgM

by ELISA(LA,ACL)repeated after 6 week

Lupus Anti-coagulant

Blocks In Vitro assembly of prothrombinase Prolongs

aPTTdRVVT(Russell viper venum time )KPC(Kaolin clotting )

Anti-cardiolipin antibody

React with phospholipids such as cardiolipin Different immunoglobulin subclasses and

isotypes are associated with anti-cardiolipin antibodiesIgG, IgA, IgM (IgG 1-4)Increased levels of IgG acl incurs a greater risk of

thrombosis 85% concordance LA and ACL

Anti-ß2 glycoprotein I antibody

Inhibitor of coagulation (phospholipid binded) Occurs alone in 11% Also known Apolipoprotein H Phospholipid bound inhibitor of coagulation and

platelet aggregation Inhibits contact activation of clotting Inhibits Prothrombin to Thrombin conversion Found in large percentage of primary and secondary

APS

False + serologic test for Syphillis

Phospholipid dependant tests Syphillis antigen-cardiolipin

Anti-prothrombin

Associated with higher risk of recurrent thrombosis

Risk independent of presence of ACL or LA

Pathogenesis

Mechanism of thrombosis

Antiphospholipid Ab :

Interference in cells of coagulation

Selective inhibition of protein C anticoagulant

pathway

Interference in cells of coagulationAntiphospholipid Ab activation

Endothelial cell

Inducing :

Adhesion molecule,

Tissue Factor

Endothelin

TX A2

Monocyte

Expression :

TF

TXA2

Antiplatelet Ab

Aggregation vasoconstriction

Platelet activation

Thrombosis

Mechanism of fetal lossAntiphospholipid Ab

Direct effect on throphoblast

Endothelial cell lesion of placental vessels

Competes with Annexin

Intraplacental thrombosis

Tissue hypoxia

Fetal loss

Clinical manifestation

Disease associations

Clinical manifestation

Major : Vascular thrombosis Pregnancy morbidity

Minor : Hematologic :Thrombocytopenia,…Dermatologic : ( Livedo reticularis….)Neurologic : ( CVA ….)

Others

Vascular thrombosis

Sporadic In < 50 years Unrelated to antibody level Recurrent Venous : Deep vein thrombosis of the leg Arterial : Stroke Small vessel : Kidneys & Skin

Pregnancy morbidity Unexplained fetal death

Unexplained spontaneous abortion

Premature birth before the 34th weeks of gestation

Others : Fetal distress , preclampsia , post partum thrombotic accident , HELLP syndrome , fetal growth disorder

Hematologic

Thrombocytopenia : Mild to moderate(100,000 – 150,000 )

APL a/b in 70-82% of SLE and thrombocytopenia 30 – 40% with ITP ITP therefore may be associated with thrombosis

Hemolytic anemia : Positive combs test

Dermatologic Raynoud phenomen Livedo reticularis Superficial

thrombophelebitis Leg ulcer Cutaneous necrosis Splinter hemorrhage Acrocyanosis

Livedo reticularis

Livedo reticularis with necrotic finger tipsin Antiphospholipid syndrome

Neurologic Migraine headache Stroke & TIA Chorea Memory loss Dementia Multiple sclerosis-like syndrome Transverse myelitis Seizure Non focal neurologic symptoms Guillene-barre

Others Libman-sacks endocarditis

Valvular insufficiency

Pulmonary hypertension

Renal failure

Laboratory tests

Laboratory tests

Anti cardiolipin ( ACL ) & Lupus anti coagulant ( LA ) test : for people suspected of having APS

Anti B2GP1 : for people with signs of APS but normal ACL & LA tests

Platelet , ANA , ESR , Urinalysis : for patient with SLE

Drug induced APLa

Drug induced APS

Phenytoin , Hydralazine , Chlorpromazine , Procainamide

IgM isotype of antiphospholipid Ab

Antiphospholipid no related to B2GP1

Thrombosis and Thrombocytopenia

DIAGNOSIS

Diagnosis

Definite APS is considered to be persist if

at least one of the clinical and one of the

laboratory criteria are presented

Vascular thrombosis :

One or more clinical episode of arterial , venous or small-vessel thrombosis in any tissue or organ and Thrombosis confirmed by imaging or Doppler

studies or histopathology , with the exception of superficial venous thrombosis

Histopathologic confirmation with thrombosis in the absence of inflammation in the vessel wall

Pregnancy morbidity

Unexplained fetal death : After the 10th weeks of gestation (one or more)

Unexplained spontaneous abortion : before the 10th weeks of gestation (3 or more)

Premature birth before the 34th weeks of gestation (one or more)

Laboratory criteria ACL Ab

IgG and/or IgM isotype in blood Medium or high titer on two or more occasions at

least six weeks apart Measured by standard ELISA for B2GP1

dependent L.A Ab

Present in plasma on two or more occasions at least six weeks apart,

Diseases association

Disease associations

Long list of associated diseasesSLE

Main GroupsAutoimmuneInfections and drugsNeoplasmsGeneticOther

Non-Autoimmune causes for positive Antiphosphospholipid Ab tests

Assay Antibody type Causes

ELISA B2GP1 independent Syphlis,lyme Leptospirosis, HIV

B2GP1 dependent Advanced age Drug Lymphoproliferative Hyperimmunoglobulin M

LA Either HIV , Drugs

Catastrophic APS

Catastrophic vascular occulsion syndrome

Multiple vascular of medium and small arteries that occurring over a period of day

Risk factors : Infection, Drugs, Small surgery, Anticoagulant withdrawal, Post partum period

Often history of SLE or PAPS Stroke , Cardiac , Hepatic , Adrenal , Renal and

Intestinal infarction , Peripheral gangrene , Thrombocytopenia , Hemolytic anemia , Hypertension

Biopsy : Non-inflammatory vascular occlusion 50% mortality

Treatment

Treatment-General

Thrombotic therapyHeparinWafarin

Pregnancy – controversialSC heparin and/or Aspirin

Immunosuppresion – rarely used Treat associated condition eg.SLE Risk factor modification eg.smoking , OCP

APS treatment Asymptomatic Positive antiphospholipid

Ab : no treatment

Venous thrombosis :

Peripheral venous thrombosis : INR = 2 Proximal thrombosis , Budd-chiari

syndrome , Cavernous or sagittal sinus thrombosis , Pulmonary emboli : INR =3

Arterial Thrombosis : INR = 3

APS treatment First pregnancy, Single pregnancy loss

< 10th week : Low dose Aspirin

Recurrent fetal loss , loss after 10th week : Heparin 5000 U bid throughout pregnancy Discontinue 6-12 weeks postpartum

Recurrent fetal loss , loss after 10th week +Thrombosis : Heparin 5000 U bid throughout pregnancy and Warfarin postpartum

Treatment-Other

Plasmapharesis IVIG Experimental – fibrinolytics, prostacyclin anti-

cytokines

Treatment - CAPS

Uncontrolled data to suggest intensive treatment betters outcome(70% recovery)AnticoagulationSteroidsPlasmapharesis or IVIGTreatment of any precipitant eg. InfectionCytotoxics (if indicated eg.Active SLE )