Antiphospholipid Syndrome Flashcards
What type of syndrome is antiphospolipid syndrome ?
- prothrombotic syndrome
- rather than a hemorrhagic one
- most patients do NOT have a history of SLE (but it was first identified in these patients)
- autoantibodies
- often associated with pregnancy morbidity including recurrent first trimester losses and 2nd/3rd trimester deaths
- historically patient’s would have positive syphillis screening test
- this was due to cross-reactivity with cardiolipin
In what situations can low-titer antiphospholipid antibodies be identified ?
- up to 10% of normal individuals (aCL)
- although high titer antibodies have been described
- some have been associated with infectious diseases
- usually transient
- very rarely have clinical manifestations
- uncomplicated pregnancy can have modest autoantibodies to aCL and anti-B2GPI
- Note:
- LACs rarely seen in pregnancy but when present identify a population of patients more likely to have a pregnancy complication
- Note:
What are the lab criteria for diagnosing
antiphospholipid antibody syndrome ?
- Lupus anticoagulant present on 2 or more occasions, 12 weeks apart
- Anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma present in medium to high titer (> 40 GPL or MPL or >99th percentile) on 2 or more occasions at least 12 weeks apart
- Anti-B2 glycoprotein I antibody of IgG and or IgM isotype (titer >99th percentile) present on 2 or more occasions at least 12 weeks apart
see p. 375 for clinical criteria- important
Pathophysiology of antiphospholipid antibody syndrome ?
- complicated, probably mutliple hits rather than just caused by the antibody
- heterogeneous actions too that is why there are multiple manifestations
What is the primary antigen target of pathologic antiphospholipid
antibodies ?
- B2GPI
- formation of antibodies against this protein requires a conformational change to expose a cryptic region in domain I
- antibodies are associated with thrombotic complications
What is the significance of anti-prothrombin antibodies ?
- antibodies that bind to lipid bound prothrombin have been described
- cause an increased risk of thrombosis
- note:
- there are antibodies that bind to prothrombin in the absence of phospholipid, but these have not been shown to contribute to the prothrombotic risk
IMP: a third anti-prothrombin group of antibodies that leads to hypo-prothrombinemia causes hemorrhagic issues
- this is not included in the diagnostic criteria of APS
What is the significance of antiphospholipid antibodies that
do not use a protein cofactor?
- some antibodies bind phospholipids in the absence of a protein cofactor
- these are generally thought to unlikely be involved in APS
- however, some studies show that they are
- their significance is TBD
What has been implicated in the pathophysiology
of APS ?
- disruption of the Annexin A5 anticoagulant shield
- endothelial cell activation
- complement activation
- neutrophil extracellular traps
- platelet activation
- inhibition of natural anticoagulant and fibrinolytic pathways
- protein C pathway
- including binding to protein C (form of acquired protein C resistance)
How are platelets activated by APS autoantibodies ?
- anti-B2GPI antibodies bind to and activate platelets via glycoprotein Ib alpha receptor
- dimerized B2GPI
- has been shown to bind to apoER2 on platelet surfaces
- leads to platlet adhesion to collagen
What tests are used to detect phospholipid dependendent
autoantibodies in APS ?
- immunoassays
- aCL
- anti-B2 GPI
- coagulation assays
- LAC
How is anticardiolipin tested for ?
- immunoassay
- detects antibodies against an immobilized cardiolipin
- also will detect antibodies that bind to phospholipid binding proteins that are introduced into the assay
- report IgG and IgM antibodies
- medium to high titer are significant
How are antibodies against B2GPI tested for ?
- immunoassay
- native B2 GPI is directly bound to an ELISA plate
- IMP
- considered more specific for clinically significant APS as compared to aCL
- some suggest looking for antibodies against domain I but as of now it is just the whole molecule
- positive result is titer >99th percentile
How is the lupus anticoagulant tested for ?
- coagulation assay
- three step strategy
-
screening assay: incorporates a test that is sensitive to the presence of a phospholipid dependent inhibitor
- results in prolongation of the clotting time
- ex: PTT or dilute Russell Viper venom test (dRVVT)
-
mixing studies:
- help rule out a factor deficiency as the cause rather than an inhibitor
-
last
- perform a test with excess phospholipid to over come the phospholipid inhibitor
-
screening assay: incorporates a test that is sensitive to the presence of a phospholipid dependent inhibitor
What is the issue with the mixing study in evaluating the LAC ?
- it can potentially dilute out a weak LAC
- omission of the mixing study can be problematic particularly in patients taking vitamin K antagonists
Why is it recommended to test for all three antibodies
when evaluating for APS ?
- LAC is more predictive and more specific for adverse clinical events and pregnancy morbidity than aCL or B2GPI
- but having all 3 antibodies be positive is a highest predictor of adverse clinical events
