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 finding significant proportion of healthy (esp. elderly) population most never thrombosis may be transient

Antiphospholipid Antibodies Clinically significant antiphospholipid antibodies are not antiphospholipid antibodies Antibodies against phospholipid-bound proteins e.g. b2 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 tendency venous or arterial thrombosis recurrent miscarriages with the persistence of one or more antiphospholipid antibodies confirmed 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 aPTT dRVVT(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 antibodies IgG, 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 coagulation Antiphospholipid Ab activation Endothelial cell Monocyte Inducing : Adhesion molecule, Tissue Factor Endothelin TX A2 Antiplatelet Ab Expression : TF TXA2 Platelet activation Aggregation vasoconstriction Thrombosis

Mechanism of fetal loss Antiphospholipid 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 APL a/b in 70-82% of SLE and 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 tips in 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 L.A 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 diseases Main Groups SLE Autoimmune Infections and drugs Neoplasms Genetic Other

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 therapy Pregnancy – controversial Heparin Wafarin Pregnancy – controversial SC 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) Anticoagulation Steroids Plasmapharesis or IVIG Treatment of any precipitant eg. Infection Cytotoxics (if indicated eg.Active SLE )