Antiphospholipid Antibody Syndrome

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

Antiphospholipid Antibody A number of Abs directed against either phospholipids or plasma proteins that are bound to phospholipids.

APL Frequency Population Frequency (%) Normal 1-5 DVT 27% PMR Behcet’s PSS 20-25 ITP 30 SS 40 SLE 30-50

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

Lupus Anti-coagulant A/B directed against plasma proteins bound to phospholipids Blocks In Vitro assembly of prothrombinase Prolongs aPTT dRVVT KPC

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% Found in large percentage of primary and secondary APS

False + serologic test for Syphillis Phospholipid dependant tests Syphillis antigen-cardiolipin

Location of Tests in Pathway Levine, NEJM 2002

Pathogenesis of APS Inflammation induce antibodies Antibodies activate endothelial cells and platelets Antibodies alter balance between thrombotic and fibrinolytic pathways 50% APL cause drop in factor XII such that 80% of APS patients are low. Paradoxically low XII results in increaseed thrombosis

Pathogenesis-Other mechanisms Activation of platelets Enhanced monocyte expression of Tissue Factor Inhibition of Prot C ,Prot S and other coagulation factors A/B against other proteins involved in coagulation Heparin Prothrombin Platelet activating factor etc. Complement activation

Disease associations Long list of associated diseases Main Groups SLE Autoimmune Infections and drugs Neoplasms Genetic Other

Clinical Manifestations Thrombotic DVT PE Superficial thrombophlebitis Obstetric morbidity Early fetal loss 35.4% Late fetal loss 16.9% Dermatologic Leg ulcers Livedo reticularis Musculoskeletal Arthralgias Heme Thrombocytopenia Hemolytic anemia Cardiac Heart valve lesions MI Neuro Epilepsy Stroke TIAs Migraine Renal HTN

Libman Sacks

Testing for APS VDRL LA (lupus anticoagulant) aPTT (activated partial thromboplastin time) KCT (kaolin clotting time) dRVVT (dilute Russell viper venom test) ACL (anti-cardiolipin) ELISA Anti-cofactor tests 2-GP-I Prothrombin Annexin V Protein S Protein C

Sensitivity and Specificity for APS Harris. Lupus, 1998.

Criteria for Antiphospholipid Syndrome APS is present if at least 1 clinical and 1 lab criteria are met. Clinical criteria Vascular thrombosis Pregnancy morbidity Unexplained fetal death beyond 10w Premature birth before 34w 3 or more unexplained spontaneous Ab before 10w Lab criteria aCL-IgG or IgM in moderate or high titer 2x over 6 weeks LA on 2 occasions at least 6 weeks apart Definition: a syndrome marked by arterial and/or venous thrombosis, recurrent fetal loss and thrombocytopenia associated with autoantibodies with specificity for anionic phospholipids and their cofactors.