What is the diagnostic approach, differential diagnosis, management, complications, and prognosis of Antiphospholipid Syndrome (APS)?

Antiphospholipid Syndrome: Diagnostic Approach, Differential Diagnosis, Management, Complications, and Prognosis

Antiphospholipid syndrome (APS) is a thrombo-inflammatory autoimmune disease that requires testing for three key antiphospholipid antibodies with two consecutive positive tests at least 12 weeks apart for diagnosis, and management primarily involves anticoagulation therapy tailored to the specific clinical presentation. 1, 2

Diagnostic Approach

Core Laboratory Testing

• Testing for three key antiphospholipid antibodies is essential: lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG/IgM, and anti-beta2 glycoprotein I antibodies (aβ2GPI) IgG/IgM 2, 3
• Two consecutive positive tests at least 12 weeks apart are required to confirm persistent positivity and rule out transient antibody presence 2, 4
• LA testing requires a 3-step methodology (screening, mixing, confirmation) with parallel testing using both activated partial thromboplastin time (APTT) and dilute Russell's viper venom time (dRVVT) 3
• Omitting either APTT or dRVVT increases risk of underdiagnosis in up to 55% of triple aPL-positive samples 3
• aCL and aβ2GPI should be measured by solid phase assays with results reported with their level; positivity defined as values above the 99th percentile of normal controls 2, 4

Risk Stratification

• Triple positivity (LA, aCL, and aβ2GPI) carries the highest thrombotic risk 2, 4
• IgG isotype antibodies are clinically more relevant than IgM isotypes 2, 4
• Medium/high titer antibodies (>40 Units) are of utmost importance for diagnosis 2, 1
• 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, 4

Special Testing Considerations

• LA testing during anticoagulation may be unreliable; for patients on direct oral anticoagulants (DOACs), pretest DOAC removal procedures can be used 3
• For patients on vitamin K antagonists (VKAs), Taipan snake venom time/ecarin time can be used 3
• Ideally, LA should be assessed 1-2 weeks after discontinuation of VKA (with or without bridging to LMWH) 3

Differential Diagnosis

• Systemic lupus erythematosus (SLE) - often coexists with APS; approximately 30% of SLE patients have antiphospholipid antibodies 2, 5
• Thrombotic thrombocytopenic purpura (TTP) - distinguished by severely reduced ADAMTS13 activity (≤10%) 2
• Other causes of thrombophilia (Factor V Leiden, Protein C/S deficiency, etc.) 6
• Heparin-induced thrombocytopenia (HIT) 6
• Drug-induced lupus anticoagulant (antibiotics, anticonvulsants) 7

Management

Thrombotic APS

• Long-term anticoagulation with vitamin K antagonists (VKAs) is the standard of care for thrombotic APS 2, 7
• Target INR of 2.0-3.0 for venous thrombosis and 3.0-4.0 for arterial thrombosis or recurrent thrombosis despite therapeutic INR 8
• There is currently insufficient evidence to recommend the routine use of direct oral anticoagulants (DOACs) in thrombotic APS 7, 8

Obstetric APS

• Combination of low-dose aspirin and prophylactic low molecular weight heparin (LMWH) is recommended for pregnant women with APS and history of pregnancy complications 2, 6
• Late pregnancy loss is more strongly associated with aPS/PT antibodies than early pregnancy loss 2

Catastrophic APS (CAPS)

• Catastrophic APS requires early implementation of triple therapy: anticoagulation, high-dose glucocorticoids, and plasma exchange 2
• Emerging evidence suggests potential efficacy of eculizumab (complement inhibitor) in catastrophic APS 2
• Rituximab may be beneficial in refractory cases 2, 8

Primary Prophylaxis

• For asymptomatic aPL carriers, risk factor modification and low-dose aspirin should be considered, especially in high-risk patients (triple positivity) 8

Complications

• Recurrent thrombosis (venous and/or arterial) 9
• Pregnancy morbidity (recurrent early miscarriages, fetal death, premature birth) 6, 9
• Thrombocytopenia 7
• Neurological manifestations (stroke, seizures, cognitive dysfunction) 9
• Cardiac valve disease (Libman-Sacks endocarditis) 6
• Catastrophic APS with multi-organ failure (mortality rate 30-50%) 5
• Chronic kidney disease due to thrombotic microangiopathy 7

Monitoring and Prognosis

• Regular monitoring of LA, aCL, and aβ2GPI is recommended annually to evaluate fluctuation of titers and changes in antibody profile 2, 4
• Prognosis depends on antibody profile, with triple positivity carrying the highest risk for recurrent thrombosis 2, 4
• Patients with SLE and APS have worse outcomes compared to those with primary APS 2
• Catastrophic APS has a mortality rate of 30-50% despite aggressive treatment 5
• Long-term anticoagulation significantly reduces recurrent thrombotic events but increases bleeding risk 7, 8

Common Pitfalls and Caveats

• Inappropriate use of classification criteria may lead to misdiagnosis or underdiagnosis of APS 3
• Classification criteria (designed for research) are stricter than diagnostic criteria (used in clinical practice) 3
• Single positive IgM antibody is considered less clinically relevant than IgG 3, 4
• Laboratory results must be interpreted in clinical context with knowledge of anticoagulation status 3, 4
• Close interaction between the laboratory and clinician is essential for proper interpretation 3