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

Antiphospholipid Syndrome (APS): Comprehensive Management and Diagnostic Approach

Antiphospholipid syndrome (APS) is a thrombo-inflammatory autoimmune disorder characterized by persistent antiphospholipid antibodies (aPL) that cause thrombosis, pregnancy morbidity, and other inflammatory manifestations, requiring accurate diagnosis and lifelong anticoagulation for optimal outcomes.

Diagnostic Approach

Laboratory Testing

• The cornerstone of APS diagnosis requires testing for three key antiphospholipid antibodies: lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG/IgM, and anti-beta2 glycoprotein I antibodies (aβ2GPI) IgG/IgM 1, 2
• Two consecutive positive tests at least 12 weeks apart are required to confirm persistent positivity and rule out transient antibody presence 2, 3
• 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) 2
• Omitting either APTT or dRVVT increases risk of underdiagnosis in up to 55% of triple aPL-positive samples 2
• 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, 3

Risk Stratification

• Triple positivity (LA, aCL, and aβ2GPI) carries the highest thrombotic risk 2, 3
• IgG isotype antibodies are clinically more relevant than IgM isotypes 2, 3
• Medium/high titer antibodies (>40 Units) are of utmost importance for diagnosis 1, 2
• Antiphosphatidylserine/prothrombin (aPS/PT) antibodies may be considered in patients negative for LA, aCL, and aβ2GPI where there is strong clinical suspicion of APS 1, 3

Clinical Presentation

Thrombotic Manifestations

• Venous thromboembolism (VTE) and stroke are the most common and potentially life-threatening presentations 4
• Arterial thrombosis commonly affects cerebral, coronary, and peripheral arteries 5
• Microvascular thrombosis can lead to multi-organ dysfunction 5, 6

Obstetric Manifestations

• Recurrent early pregnancy losses (before 10 weeks) 7
• Fetal death after 10 weeks of gestation 7
• Premature birth before 34 weeks due to preeclampsia, eclampsia, or placental insufficiency 7
• Late pregnancy loss is more strongly associated with aPS/PT antibodies than early pregnancy loss 1

Non-thrombotic Manifestations

• Thrombocytopenia 5
• Neurological manifestations (migraine, seizures, cognitive dysfunction) 5
• Livedo reticularis and other cutaneous manifestations 5, 7
• Cardiac valve disease 7

Differential Diagnosis

• Systemic lupus erythematosus (SLE) - often coexists with APS; approximately 30% of SLE patients have antiphospholipid antibodies 1, 8
• Thrombotic thrombocytopenic purpura (TTP) - distinguished by severely reduced ADAMTS13 activity (≤10%) 1
• Complement-mediated thrombotic microangiopathy (TMA) 1
• Shiga-toxin-hemolytic uremic syndrome 1
• Drug-induced or infection-related thrombosis 1
• Malignancy-associated thrombosis 1
• Other inherited or acquired thrombophilias 7

Management

Thrombotic APS

• Vitamin K antagonists (VKAs) remain the cornerstone of therapy for thrombotic APS, with lifelong anticoagulation recommended as long as antibodies persist 4, 6
• For venous thrombosis, target INR should be 2.0-3.0 6
• For arterial thrombosis, VKA with or without low-dose aspirin is the treatment of choice, with some cases requiring target INR above 3.0 6
• Direct oral anticoagulants (DOACs) are not recommended for triple-positive patients or those with arterial thrombosis but may be considered in selected patients with venous thrombosis and negative LA 4, 6
• Low molecular weight heparin may be used in special situations such as pregnancy or when VKAs are contraindicated 9, 6

Obstetric APS

• Low-dose aspirin combined with prophylactic low molecular weight heparin is recommended during pregnancy 7
• Treatment should begin as soon as pregnancy is confirmed and continue throughout pregnancy and postpartum period 7
• Close monitoring of fetal growth and maternal blood pressure is essential 7

Catastrophic APS (CAPS)

• CAPS is a rare, severe variant characterized by rapid-onset, widespread thrombosis leading to multi-organ failure 5
• Early implementation of triple therapy is crucial: anticoagulation, high-dose glucocorticoids, and plasma exchange 1, 6
• Intravenous immunoglobulins may be added to the regimen 5, 6
• Emerging evidence suggests potential efficacy of eculizumab (complement inhibitor) in catastrophic APS 1
• Rituximab may be beneficial in refractory cases 1

Primary Prevention

• Low-dose aspirin is recommended for primary thromboprophylaxis in asymptomatic aPL carriers, especially when additional cardiovascular risk factors are present 4, 6
• Hydroxychloroquine and statins may be useful adjunctive therapies, particularly in complex settings 4
• Aggressive management of traditional cardiovascular risk factors is essential 4, 6

Monitoring and Follow-up

• Regular monitoring of LA, aCL, and aβ2GPI is recommended annually to evaluate fluctuation of titers and changes in antibody profile 3
• Accurate assessment of anticoagulation intensity is essential to optimize dosing and minimize risks 9
• Special consideration for monitoring is needed in patients with APS-related renal impairment, thrombocytopenia, or during pregnancy 9
• LA testing during anticoagulation may be unreliable; for patients on DOACs, pretest DOAC removal procedures can be used, while for patients on VKAs, Taipan snake venom time/ecarin time can be used 2
• Ideally, LA should be assessed 1-2 weeks after discontinuation of VKA (with or without bridging to LMWH) 2

Prognosis

• Prognosis depends on antibody profile, with triple positivity carrying the highest risk for recurrent thrombosis 2, 3
• Early diagnosis and appropriate anticoagulation significantly improve outcomes 7
• CAPS has a high mortality rate (approximately 30-50%) despite aggressive treatment 5, 6
• Patients with SLE and APS have worse outcomes compared to those with primary APS 8, 7
• Recurrent thrombosis occurs in approximately 20-30% of patients despite adequate anticoagulation 7

Common Pitfalls and Caveats

• Inappropriate use of classification criteria may lead to misdiagnosis or underdiagnosis of APS 2
• Laboratory results must be interpreted in clinical context with knowledge of anticoagulation status 2, 3
• Single positive IgM antibody is considered less clinically relevant than IgG positivity 2, 3
• Low positive results around the cutoff value should be interpreted with caution due to potential 10% imprecision of solid phase methods 2
• Close interaction between the laboratory and clinician is essential for proper interpretation of test results 2