Antiphospholipid Syndrome (APS): Comprehensive Clinical Overview
Definition and Pathophysiology
Antiphospholipid Syndrome is a thrombo-inflammatory autoimmune disease driven by antiphospholipid antibodies that induce thrombosis, pregnancy morbidity, and other autoimmune manifestations through recognition of phospholipid surfaces and phospholipid-binding proteins. 1 The syndrome can occur as a primary condition or secondary to other autoimmune diseases, most commonly systemic lupus erythematosus (SLE), with approximately 30% of SLE patients having antiphospholipid antibodies. 2
The pathogenesis involves complex interactions between antiphospholipid antibodies, phospholipid-binding proteins (particularly beta-2 glycoprotein I), complement system activation, and endothelial cell dysfunction. 3, 4
Diagnostic Criteria and Laboratory Testing
Core Laboratory Tests Required
Three key antiphospholipid antibodies must be tested: lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG/IgM, and anti-beta2 glycoprotein I antibodies (aβ2GPI) IgG/IgM. 2
Lupus Anticoagulant Testing
- LA testing requires a 3-step methodology: screening, mixing, and confirmation, with parallel testing using BOTH activated partial thromboplastin time (APTT) AND dilute Russell's viper venom time (dRVVT). 1, 5
- Omitting either APTT or dRVVT increases the risk of underdiagnosis in up to 55% of triple aPL-positive samples. 2, 5
- Results should be reported as positive or negative with warnings about potential interferences. 5
Anticardiolipin and Anti-Beta2 Glycoprotein I Antibodies
- Both aCL and aβ2GPI should be measured by solid phase assays (ELISA or validated non-ELISA systems) for IgG and IgM isotypes. 1, 5
- Results must be reported with their level, with positivity defined as values above the 99th percentile of normal controls. 1, 5
- The 2023 ACR/EULAR classification criteria define moderate and high titer thresholds at 40 Units and 80 Units, respectively, abandoning the 99th percentile cutoff calculation. 1
Confirmation Requirements
Two consecutive positive tests at least 12 weeks apart are mandatory to confirm persistent positivity and rule out transient antibody presence. 1, 2, 5 This requirement distinguishes clinically significant persistent antibodies from transient positivity that may occur with infections or other conditions. 5
Testing During Anticoagulation
- LA testing during anticoagulation may be unreliable but is sometimes necessary. 2, 5
- For patients on direct oral anticoagulants (DOACs), pretest DOAC removal procedures can be used. 2, 5
- For patients on vitamin K antagonists (VKAs), Taipan snake venom time/ecarin time (TSVT/ET) can be used, though it doesn't have 100% sensitivity. 2, 5
- Ideally, LA should be assessed 1-2 weeks after discontinuation of VKA (with or without bridging to low molecular weight heparin). 5
Risk Stratification
High-Risk Profile
Triple positivity (LA, aCL, and aβ2GPI all positive) carries the highest thrombotic risk and represents the most clinically significant antibody profile. 2, 5, 6
Additional high-risk features include:
- Double positivity with concordant isotype (both aCL and aβ2GPI of the same isotype, particularly IgG). 5, 6
- Medium/high titer antibodies (>40 Units or >99th percentile). 2, 5
- IgG isotype antibodies, which are clinically more relevant than IgM. 2, 5, 6
Moderate-Risk Profile
Lower-Risk Profile
- Isolated IgM aβ2GPI at low-medium titers. 6
- Single positive aCL or aβ2GPI at low titers. 5
- Persistent single-positive LA has lower thrombotic risk than triple aPL positivity. 5
Special Considerations for Obstetric APS
In women with suspected obstetric APS, both IgM and IgG should be tested, as isolated IgM aβ2GPI is more frequent and represents an independent risk factor in obstetric APS. 6 Late pregnancy loss is more strongly associated with antiphosphatidylserine/prothrombin (aPS/PT) antibodies than early pregnancy loss. 2
Emerging Risk Markers
- Antiphosphatidylserine/prothrombin (aPS/PT) antibodies may be considered in patients negative for LA, aCL, and aβ2GPI where there is strong clinical suspicion of APS. 2, 5
- These antibodies show particular relevance in obstetric APS and may provide additional risk stratification. 2
Clinical Manifestations
Thrombotic Manifestations
APS can cause thrombosis in any vascular bed:
- Venous thrombosis (most common): deep vein thrombosis, pulmonary embolism. 4, 7
- Arterial thrombosis: stroke, myocardial infarction, peripheral arterial occlusion. 4, 7
- Microvascular thrombosis: can affect multiple organ systems. 3, 8
Antiphospholipid antibodies are positive in approximately 13% of patients with stroke, 11% with myocardial infarction, 9.5% of patients with deep vein thrombosis. 7
Obstetric Manifestations
Pregnancy morbidity criteria include:
- Three or more consecutive losses prior to 10 weeks' gestation. 1
- One or more fetal losses at or after 10 weeks' gestation. 1
- Delivery at <34 weeks due to preeclampsia, intrauterine growth restriction, or fetal distress. 1
Antiphospholipid antibodies are positive in approximately 6% of patients with pregnancy morbidity. 7
Non-Thrombotic Manifestations
- Thrombocytopenia: present in a proportion of patients and can complicate management, though it does not appear to reduce thrombotic risk. 9
- Neurological symptoms: beyond stroke, including cognitive dysfunction and seizures. 3
- Cardiac manifestations: valvular disease, myocardial dysfunction. 3
- Renal involvement: thrombotic microangiopathy. 3
Catastrophic Antiphospholipid Syndrome (CAPS)
Catastrophic APS is a rare, severe variant marked by rapid-onset, widespread thrombosis leading to multi-organ failure, often triggered by infections, surgical procedures, or cessation of anticoagulation therapy. 3
Management of CAPS
CAPS requires early implementation of triple therapy: anticoagulation, high-dose glucocorticoids, and plasma exchange. 2, 3
Additional therapeutic options:
- Intravenous immunoglobulin as part of the multidisciplinary approach. 3
- Eculizumab (complement inhibitor) shows emerging evidence of potential efficacy in catastrophic APS. 2
- Rituximab may be beneficial in refractory cases. 2
Treatment Strategies
Thrombotic APS
Vitamin K antagonists (warfarin) remain the mainstay of treatment for patients with antiphospholipid antibodies and venous thromboembolism. 4, 9 Clinical trials have demonstrated that patients with antiphospholipid antibodies and venous thromboembolism should be treated with vitamin K antagonists. 9
For ischemic stroke, treatment may include aspirin or warfarin. 9
Obstetric APS
Women with recurrent pregnancy loss should receive prophylactic-dose heparin and aspirin. 9 This combination has been demonstrated in clinical trials to improve pregnancy outcomes in women with APS-related pregnancy morbidity. 9
Special Populations
For patients with APS-associated thrombocytopenia:
- The presence of thrombocytopenia does not appear to reduce thrombotic risk in patients with APS, who can develop thromboembolic complications necessitating antithrombotic treatment. 9
- Treatment of the thrombocytopenia may be necessary to facilitate administration of antithrombotic agents. 9
- The risks and benefits of antithrombotic therapy must be balanced against the severity of the thrombocytopenia and its potential bleeding risks. 9
Contraception in APS Patients
For women with positive antiphospholipid antibodies:
- Combined estrogen and progesterone contraceptives are contraindicated due to increased thrombotic risk. 1
- Safe options include: copper IUD, progestin IUD, progestin implant, and progestin-only pills. 1
- Depot medroxyprogesterone acetate (DMPA) is contraindicated in patients with positive aPL due to thrombotic risk. 1
Monitoring and Follow-up
Regular monitoring of LA, aCL, and aβ2GPI is recommended annually to evaluate fluctuation of titers and changes in antibody profile over time. 2, 6 This ongoing assessment helps identify changes in risk profile and potential therapeutic consequences. 1, 2
Laboratory results must be interpreted in clinical context with knowledge of anticoagulation status, and close interaction between the laboratory and clinician is essential for proper interpretation. 5, 6
Prognosis
Prognosis depends on antibody profile, with triple positivity carrying the highest risk for recurrent thrombosis. 2 Patients with SLE and APS have worse outcomes compared to those with primary APS. 2
The incidence of APS is around 5 new cases per 100,000 persons per year, with prevalence around 40-50 cases per 100,000 persons. 7
Critical Diagnostic Pitfalls to Avoid
Classification vs. Diagnostic Criteria
Classification criteria (designed for research) are stricter than diagnostic criteria (used in clinical practice), and inappropriate use of classification criteria may lead to misdiagnosis or underdiagnosis of APS. 1, 5 Classification criteria are meant for participant inclusion in studies to study homogeneous populations, while diagnostic criteria in daily practice are broader to optimize patient management. 1
Laboratory Interpretation Errors
- Low positive results around the cutoff value should be interpreted with caution due to potential 10% imprecision of solid phase methods. 5
- Single positive IgM antibody is considered less clinically relevant than IgG. 5, 6
- LA testing can be affected by anticoagulant therapy, acute phase proteins, and other interferences. 5
- Patients with lower-titer aCL and/or anti-β2GPI (or non-criteria aPL) who do not meet laboratory classification criteria may still have some degree of risk that is difficult to quantify. 1
Testing Sequence Errors
The distinction between testing for classification versus routine clinical care is critical. 1 In general, testing for aPL should be performed in patients with SLE or SLE-like disease and in patients with suggestive histories or physical findings. 1