Antiphospholipid Syndrome Dror Mevorach, MD November , 2013

Antiphospholipid Syndrome APLS is a disorder of recurrent arterial or venous thromboses, pregnant losses, and/or thrombocytopenia associated with persistently positive results of anticardiolipin or lupus anticoagulant tests

Antiphospholipid Syndrome History I A hemorrhagic disorder caused by circulating anticoagulant in a patient with SLE. Conley & Hartmann, JCI, 1952 Thrombosis in SLE “despite” circulating anticoagulants. Bowie et al., JCI, 1963 A peripheral vascular syndrome overlapping with SLE. Johansson et al., Dermatologia, 1977 Intra-uterine death and circulating anticoagulant. Nilsson et al., Acta Med Sand, 1975

Antiphospholipid Syndrome History II Lupus anticoagulants binds negatively charged phopholipids. Thiagarajan et al., JCI, 1980 Anticardiolipin antibodies: detection with RIA and association with thrombosis in SLE. Harris et al, Lancet, 1983

Antiphospholipid Syndrome Laboratory False positive for syphilis: Common antigen: cardiolipin-cholesterol-phophatidylcholine Agglutination: RPR (rapid plasma reagin) Flocculation: VDRL (Veneral disease research laboratories) Complement fixation: Wasserman No false positive syphilis: FTA-ABS (fluorescent treponemal antibody absorbed assay)

Anticardiolipin IgG IgM IgA b2GPI Low titer: 10 GPL/MPL/APL Medium titer: 20/30-60 High titer: >60 Correlation with thrombosis: High>Medium>>low IgG>>IgM>IgA

Lupus anticoagulant Date I Failure of correction by normal plasma phos-lipids Date II Activated PTT KCT dilute RVVT Dilute prothrombin time Textarin time

The different anti-phospholipids autoantibodies share antigen epitopes Anticardiolipin False+ VDRL Lupus anticoagulant Anti-b2GPI The different anti-phospholipids autoantibodies share antigen epitopes but are also targeted against different epitopes

Antiphospholipid Syndrome Clinical criteria: One or more clinical episodes of arterial, venous or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by imaging or doppler studies or histopathology, with the exception of superficial venous thrombosis. For histologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall. Arthritis @ Rheum 1999;42 (7):1309-1311

Antiphospholipid Syndrome Clinical criteria: 2. Pregnancy morbidity -One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe preeclampsia or eclampsia, or severe placental insufficiency OR -Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal cause excluded Arthritis @ Rheum 1999;42 (7):1309-1311

Antiphospholipid Syndrome Laboratory criteria (I): 1. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on 2 or more occasions, at least 6 weeks apart, measured by a standardized ELISA for beta-2-GPI-dependent anticardiolipin antibodies.

Antiphospholipid Syndrome Laboratory criteria (II): 2. Lupus anticoagulant present in plasma, on 2 or more occasions at least 6 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Homeostasis in the following steps: Prolonged phospholipid-dependent coagulation demonstrated on a screening test, e.g. activated PTT, KCT, dilute RVVT, dilute prothrombin time, Textarin time.

Antiphospholipid Syndrome Laboratory criteria (III): 3. Failure to correct the prolonged coagulation time on the screening test by mixing with normal platelet-poor plasma. Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipid. Exclusion of other coagulopathies.

Antiphospholipid Syndrome Definite antiphospholipid syndrome is considered to be present if at least 1 of the clinical (thrombosis or pregnant morbidity) and 1 of the laboratory(anticardiolipin or lupus anticoagulant) criteria are met

Antiphospholipid Syndrome: Clinical spectrum Arterial thrombosis: Aorta, eye, hepatic, splenic, brain, etc. Venous thrombosis: DVT, portal Cardiac: Non-infectious endocarditis, CAD Cutaneous: Splinter Hemorrhages, levido reticularis, skin infarcts Neurologic: TIA, CVA, seizures, dementia, TM Obstetrical: Pregnancy loss, IUGR, HELLP syndrome, pre-ecampsia Hematologic: Thrombocytopenia, hemolytic anemia, leukopenia

Antiphospholipid Syndrome: Clinical spectrum Arterial thrombosis: Aorta, eye, hepatic, splenic, brain, etc. Venous thrombosis: DVT, portal Cardiac: Non-infectious endocarditis, CAD Cutaneous: Splinter Hemorrhages, levido reticularis, skin infarcts Neurologic: TIA, CVA, seizures, dementia, TM Obstetrical: Pregnancy loss, IUGR, HELLP syndrome, pre-ecampsia Hematologic: Thrombocytopenia, hemolytic anemia, leukopenia

Antiphospholipid Syndrome: Clinical spectrum Arterial thrombosis: Aorta, eye, hepatic, splenic, brain, etc. Venous thrombosis: DVT, portal Cardiac: Non-infectious endocarditis, CAD Cutaneous: Splinter Hemorrhages, levido reticularis, skin infarcts Neurologic: TIA, CVA, seizures, dementia, TM Obstetrical: Pregnancy loss, IUGR, HELLP syndrome, pre-ecampsia Hematologic: Thrombocytopenia, hemolytic anemia, leukopenia

Antiphospholipid Syndrome: Clinical spectrum Arterial thrombosis: Aorta, eye, hepatic, splenic, brain, etc. Venous thrombosis: DVT, portal Cardiac: Non-infectious endocarditis, CAD Cutaneous: Splinter Hemorrhages, levido reticularis, skin infarcts Neurologic: TIA, CVA, seizures, dementia, TM Obstetrical: Pregnancy loss, IUGR, HELLP syndrome, pre-ecampsia Hematologic: Thrombocytopenia, hemolytic anemia, leukopenia

Antiphospholipid Syndrome: Clinical spectrum Arterial thrombosis: Aorta, eye, hepatic, splenic, brain, etc. Venous thrombosis: DVT, portal Cardiac: Non-infectious endocarditis, CAD Cutaneous: Splinter Hemorrhages, levido reticularis, skin infarcts Neurologic: TIA, CVA, seizures, dementia, TM Obstetrical: Pregnancy loss, IUGR, HELLP syndrome, pre-ecampsia Hematologic: Thrombocytopenia, hemolytic anemia, leukopenia

Antiphospholipid Syndrome Treatment: Anticoagulation Corticosteroids ??? Prevention? Aspirin or low dose LMW heparin for pregnancy loss Full anticoagulation for recurrent thrombotic event Hydroxychloriquine (in SLE) ?