4: Antiphospholipid antibody syndrome

Antiphospholipid Antibody Syndrome

Cristina Drenkard

Emory University School of Medicine, Atlanta, GA, USA

Introduction

Antiphospholipid antibody syndrome (APS) is an autoimmune prothrombotic disorder characterized by the occurrence of venous or arterial thrombosis or pregnancy morbidity and the persistent presence of antiphospholipid antibodies.

APS may present associated with other autoimmune diseases (more frequently SLE) or as a primary condition (PAPS)
Antiphospholipid antibodies (aPL) are a family of antibodies directed against phospholipid–protein complexes, which include lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and anti-beta-2 glycoprotein I (anti-β2GPI) antibodies
aPL have been shown to target a number of phospholipid-binding proteins such as prothrombin, though it is generally accepted that aPL targeting the plasma protein β2-glycoprotein I (β2GPI) are the most relevant

Epidemiology

There are no population-based studies on the prevalence of APL syndrome
The prevalence of aPL antibodies ranges from 1–10% in the general population (usually transient low-titer aCL, with the elderly at the higher end of the range)
The strength of association between aPL and thrombosis varies among studies depending on the aPL test type, transient versus persistent positive aPL, study design, and clinical populations studied
Limited number of uncontrolled and non risk-stratified studies show that individuals with no history of vascular or pregnancy events who are aPL-positive have 0–4% risk of annual thrombosis
Persistent positive titers of aPL and presence of three types of aPL (triple positive) increase the risk of thrombosis
Approximately 5–20% of patients presenting with thrombosis have aPL
aPL antibodies are present in 16% of patients with rheumatoid arthritis, and in 30–40% of patients with SLE
Patients with other autoimmune diseases such as SLE have increased risk of thrombotic or obstetric clinical manifestations associated with aPL

Classification Criteria

According to the Revised Sapporo Classification Criteria for the Antiphospholipid Syndrome, APS is present if at least one of the clinical criteria and one of the laboratory criteria (listed below) are met:

Clinical Criteria

Vascular thrombosis
- One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ
Pregnancy morbidity
- One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, or
- One or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe pre-eclampsia, or recognized features of 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 causes excluded

Laboratory Criteria

Lupus anticoagulant present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis
Anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e. >40 GPL or MPL, or greater than the 99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay (ELISA)
Anti-β2-glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma (in titer greater than the 99th percentile) present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA

Important Considerations Stated by the Revised Sapporo Classification Criteria for the APS

When less than 12 weeks or more than 5 years separate the positive aPL test and the clinical manifestation, classification of APS should be avoided
Patients should not be excluded from APS trials if coexisting inherited or acquired factors for thrombosis are present
Presence and absence of additional risk factors for thrombosis should be recognized to further classify APS patients
Investigators involved in population studies are advised to classify APS patients into four different categories of aPL assay positivity (see Miyakis et al. 2006)

The Clinical Spectrum of APS

The clinical spectrum of patients with positive aPL is widely heterogeneous, including different subgroups:
- Antiphospholipid syndrome with vascular events
- Antiphospholipid syndrome with only pregnancy morbidity
- Antiphospholipid syndrome with both vascular and pregnancy morbidity
- Non-criteria aPL manifestations
  - Skin ulcers
  - Livedo reticularis
  - Thrombocytopenia
  - Hemolytic anemia
  - Antiphospholipid antibody nephropathy
  - Cardiac valve disease
  - Chorea
  - Cognitive dysfunction
  - Diffuse alveolar hemorrhage
- Catastrophic antiphospholipid syndrome
- Asymptomatic aPL positivity

aPL Antibodies Laboratory Testing

Lupus Anticoagulants (LACs)

LACs prolong phospholipid-dependent coagulation tests due to antagonism of reagent phospholipids
No single test will identify all LACs, and it is recommended to perform at least two screening assays
The risk of false-positive results may be increased to an unacceptable level if more than two screening tests are performed
The most commonly used screening assays include the activated partial thromboplastin time (APTT) and dilute Russell viper venom time (DRVVT)
The prothrombin time is not usually prolonged because of the large amount of phospholipid in the thromboplastin reagent
The results of screening tests are considered suggestive of LAC when clotting times are longer than the local cut-off value
A positive screen is followed by a mixing study
- Lupus anticoagulants demonstrate an inhibitor pattern in mixing studies wherein the prolonged coagulation time fails to correct by mixing patient and pooled normal plasma
The presence of LAC is confirmed by demonstrating shortening of the prolonged coagulation time on addition of excess phospholipids

aCL Antibodies and Anti-β2GPI Antibodies

Testing for aCL and anti-β2GPI antibodies (IgG and IgM) by ELISA should be performed concurrently with LAC testing if APS is suspected
Anticardiolipin results are considered positive if present in moderate to high titer, whereas anti-β2GPI results are positive in titer greater than the 99th percentile
Cardiolipin is a negatively charged phospholipid, and aCL antibodies in APS typically require a protein cofactor (such as β2GPI) to create the antigenic target (phospholipid–protein complex)
- Transient aCL antibodies have been identified during infections which characteristically do not have a reactivity against β2GPI
- Therefore, β2GPI-dependent aCL assays are recommended
In general, the aCL assay is more sensitive for APS, whereas the β2GPI assay is more specific

Limitations of aPL Testing

Classification criteria for definite antiphospholipid syndrome require a positive laboratory test between one or more of the three types of assays used to detect aPL (aCL IgG and IgM, anti-β2GPI antibodies IgG and IgM, and/or LAC)
The clinical and diagnostic value of aPL tests is limited by significant interassay and interlaboratory variation in the results of LAC, aCL and anti-β2GPI assays
High variability in the sensitivity and specificity of the tests is observed
Major limitations on clinical aPL testing are related to
- Lack of broad international consensus guidelines on the recommended best practices for testing LAC, aCL, and anti-β2GPI antibodies
- Lack of laboratory standardization in units of measurement
- Inconsistent calibration curves
- Non-standardized cut-off values

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4: Antiphospholipid antibody syndrome

Introduction

Epidemiology