Antiphospholipid Syndrome

Dror Mevorach, MDNovember , 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

LaboratoryFalse positive for syphilis:Common antigen: cardiolipin-cholesterol-

phophatidylcholine • Agglutination: RPR (rapid plasma reagin)• Flocculation: VDRL (Veneral disease research laboratories)• Complement fixation: WassermanNo false positive syphilis:• FTA-ABS (fluorescent treponemal antibody absorbed assay)

Anticardiolipin

• IgG• IgM• IgA• 2GPI

• Low titer: 10 GPL/MPL/APL• Medium titer: 20/30-60• High titer: >60

• Correlation with thrombosis: High>Medium>>low

IgG>>IgM>IgA

Date I

Failure of correction by normal plasma

Correction by phos-lipids

Date II

Failure of correction by normal plasma

Correction by phos-lipids

Activated PTT

KCT

dilute RVVT

Dilute prothrombin time

Textarin time

Lupus anticoagulant

Anticardiolipin

False+ VDRL

Lupus anticoagulant

The different anti-phospholipids autoantibodies share antigen epitopes but are also targeted against different epitopes

Anti-b2GPI

Antiphospholipid Syndrome

Clinical criteria:1. 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

•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 excludedArthritis @ 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

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 lossFull anticoagulation for recurrent thrombotic eventHydroxychloriquine (in SLE) ?